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"abstract": "OBJECTIVE\nShort-term treatment with granulocyte colony-stimulating factor (G-CSF) has been established as the standard regimen for mobilizing allogeneic peripheral blood progenitor cells (PBPC) from healthy donors. The pegylated form of filgrastim (pegfilgrastim) has a longer elimination half-life because of decreased serum clearance and might be a convenient alternative for stem cell mobilization.\n\n\nMETHODS\nTwenty-five family (n=15) or unrelated (n=10) healthy donors received a single-dose of 12 mg pegfilgrastim for mobilization of allogeneic PBPC. Donors with inadequate mobilization (blood CD34+ cells <or=5/microL on day 3 or <or=20/mL on day 4) were given additional daily doses of 10 mg/kg conventional filgrastim. Leukapheresis was planned to start on day 5.\n\n\nRESULTS\nAll harvests were completed successfully. In 20 out of 25 donors (80 %) only a single apheresis was necessary. Additional non-pegylated filgrastim had to be given to only one 74-year old family donor. The maximum concentration of circulating CD34+ cells occurred on day 5 (median 67/microL, range 10-385/mL). The median yield of CD34+ cells was 9.3 (range 3.2-39.1)x10(6)/kg of the recipient's body weight. The median number of T cells in the apheresis products was 3.9 (range 2.7-10.8)x10(8)/kg. Bone pain, headaches and transient elevations of alkaline phosphatase and lactate dehydrogenase were the main adverse events.\n\n\nCONCLUSIONS\nThe study shows that collection of allogeneic PBPC after administration of a single dose of pegfilgrastim is feasible. The toxicity profile, graft composition and impact on the recipients' outcome need further investigation.",
"affiliations": "University Hospital Dresden, 1st Medical Department, Dresden, Germany. kroschinsky@mk1.med.tu-dresden.de",
"authors": "Kroschinsky|Frank|F|;Hölig|Kristina|K|;Poppe-Thiede|Kirsten|K|;Zimmer|Kristin|K|;Ordemann|Rainer|R|;Blechschmidt|Matthias|M|;Oelschlaegel|Uta|U|;Bornhauser|Martin|M|;Rall|Gabi|G|;Rutt|Claudia|C|;Ehninger|Gerhard|G|",
"chemical_list": "D018952:Antigens, CD34; D011994:Recombinant Proteins; D016753:Interleukin-10; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D000069585:Filgrastim",
"country": "Italy",
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"issue": "90(12)",
"journal": "Haematologica",
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"medline_ta": "Haematologica",
"mesh_terms": "D000328:Adult; D000368:Aged; D018952:Antigens, CD34; D004341:Drug Evaluation; D005260:Female; D000069585:Filgrastim; D005434:Flow Cytometry; D006086:Graft vs Host Disease; D016179:Granulocyte Colony-Stimulating Factor; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D016753:Interleukin-10; D007937:Leukapheresis; D007958:Leukocyte Count; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D009000:Monocytes; D010146:Pain; D010147:Pain Measurement; D036102:Peripheral Blood Stem Cell Transplantation; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012189:Retrospective Studies; D013163:Splenomegaly; D050378:T-Lymphocytes, Regulatory; D014184:Transplantation, Homologous",
"nlm_unique_id": "0417435",
"other_id": null,
"pages": "1665-71",
"pmc": null,
"pmid": "16330441",
"pubdate": "2005-12",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Single-dose pegfilgrastim for the mobilization of allogeneic CD34+ peripheral blood progenitor cells in healthy family and unrelated donors.",
"title_normalized": "single dose pegfilgrastim for the mobilization of allogeneic cd34 peripheral blood progenitor cells in healthy family and unrelated donors"
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"abstract": "Prolonged use of topical corticosteroids, particularly in infants, albeit rare, may lead to Cushing syndrome. Central nervous system abnormalities including brain atrophy and delayed myelination on cranial magnetic resonance imaging has been reported in patients with corticosteroid treatment. We herein report a 5-month-old female infant referred to Department of Pediatric Endocrinology, Edirne, Turkey with brain atrophy and myelination delay that might be due to iatrogenic Cushing syndrome caused by topical corticosteroid use.",
"affiliations": "Department of Pediatric Radiology, Trakya University, Faculty of Medicine, Edirne, Turkey.;Department of Pediatric Radiology, Trakya University, Faculty of Medicine, Edirne, Turkey.;Department of Pediatric Endocrinology, Faculty of Medicine, Trakya University, Edirne, Turkey.;Department of Pediatric Radiology, Trakya University, Faculty of Medicine, Edirne, Turkey.;Department of Pediatric Radiology, Trakya University, Faculty of Medicine, Edirne, Turkey.",
"authors": "Dogan|Sumeyra|S|;S Dogan|Mehmet|M|;Tutunculer|Filiz|F|;Yapiciugurlar|Ozge|O|;Genchellac|Hakan|H|",
"chemical_list": null,
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"fulltext": "\n==== Front\nIran J Child NeurolIran J Child NeurolIJCNIranian Journal of Child Neurology1735-46682008-0700Shahid Beheshti University of Medical Sciences Tehran, Iran ijcn-12-101Case ReportBrain Atrophy and Hypomyelination Associated with Iatrogenic Cushing Syndrome in an Infant DOGAN Sumeyra MD1S DOGAN Mehmet MD1TUTUNCULER Filiz MD2YAPICIUGURLAR Ozge MD1GENCHELLAC Hakan MD1\n1 Department of Pediatric Radiology, Trakya University, Faculty of Medicine, Edirne, Turkey.\n2 Department of Pediatric Endocrinology, Faculty of Medicine, Trakya University, Edirne, Turkey.Corresponding Author: Dogan MS. MD, Radiology Clinic, Edirne Sultan 1. Murat State Hospital, Edirne, Turkey. Fax: (+90) 284 2123241 , Email: msaitdogan@hotmail.comWinter 2018 12 1 101 104 13 5 2016 28 12 2016 23 7 2017 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Prolonged use of topical corticosteroids, particularly in infants, albeit rare, may lead to Cushing syndrome. Central nervous system abnormalities including brain atrophy and delayed myelination on cranial magnetic resonance imaging has been reported in patients with corticosteroid treatment. We herein report a 5-month-old female infant referred to Department of Pediatric Endocrinology, Edirne, Turkey with brain atrophy and myelination delay that might be due to iatrogenic Cushing syndrome caused by topical corticosteroid use.\n\nKey Words\nDiaper dermatitisIatrogenic Cushing’s syndromeBrain atrophyMyelinationMagnetic resonance imaging\n==== Body\nIntroduction\nCushing syndrome (CS) is a rarely seen entity in childhood. Iatrogenic or exogenous CS due to chronic administration of glucocorticoids is the most common form of CS in children. Peroral or parenteral forms of glucocorticoids are more likely to cause CS than topical glucocorticoids (1). However, infants are more vulnerable to the side effects of topical glucocorticoids compared to older individuals because they have higher ratio of body surface area to body weight, and thinner skin barrier (2, 3). Therefore, long term use of potent topical corticosteroids may lead to iatrogenic CS in infants (2-7). \n\nBrain atrophy has been reported in both pediatric and adult patients being treated with steroids with the indication of respiratory, rheumatological, and autoimmune diseases (8). Few cases have been reported regarding CS caused by topical steroid misuse (2-7). However, to our knowledge, associated imaging findings of brain atrophy and myelination delay have not been reported in children. \n\nWe herein report a 5-month-old infant with brain atrophy and myelination delay associated with iatrogenic CS caused by topical corticosteroid use.\n\nCase Report\nA 5-month-old girl was referred to Department of Pediatric Endocrinology, Edirne, Turkey with the complaint of excessive weight gain (1300 g in one month). She was born at term as the first child of the family. Her birth and family history were otherwise unremarkable. Her birth weight, height, and head circumference were within normal limits. On physical examination her weight was 6.9 kg (50-75th percentile), length was 56.8 cm (3rd-10th percentile), and head circumference was 38.5 cm (3rd percentile). While body temperature was within normal limits, blood pressure was above the 95th percentile for this age group (135/102 mmHg). Tachycardia and tachypnea were also present. She had cushingoid face, buffalo hump, truncal obesity, paperthin skin, and telengiectasies involving her face and body (Fig. 1).\n\nDetailed history obtained from her mother revealed unprescribed usage of a topical steroid (clobetasol-17-propionate) for diaper dermatitis for last two months in every diaper change with the recommendation of her grandmother. There was no history of any oral or parenteral medication. Laboratory data revealed trombocytosis (618000/mm3) and elevated levels of aspartate aminotransferase (104 UI/L). Basal serum cortisol and adrenocorticotropic hormone (ACTH) levels were low (0.8 µg/dL and 8.6 pg/mL, respectively) consistent with iatrogenic Cushing sydrome. To exclude tertiary adrenal insufficiency, low dose ACTH stimulation was performed. As 1 µg ACTH stimulation test was normal with maximum cortisol of 19.4 µg/dL, tertiary adrenal insufficiency was excluded and hydrocortisone replacement therapy was not started. Other blood test results and urinalysis were within normal limits. Abdominal ultrasonography was normal except for grade 1 hepatosteatosis. On the seventh day of hospitalization she was presented with fever, fontanelle bulging, lethargy, feeding problems, and vomitting. \n\nOn cranial magnetic resonance imaging (MRI) obtained to rule out the increased intracranial pressure, prominent intra- and extraaxial subarachnoid spaces and decreased cerebral volume consistent with brain atrophy were detected. Furthermore, delayed myelination was also encountered (Fig. 2). Leukocytosis was detected (11800/mm3) on complete blood count. Although the lumbar puncture revealed a normal level of white blood cell count, lower cerebrospinal-to-serum glucose ratio was also noted. Thus, acute bacterial meningitis could not be excluded and intravenous ceftriaxone (100 mg/kg/day) was started. Her symptoms resolved gradually. Antibiotherapy was continued for ten days although cerebrospinal fluid culture was negative. Subsequently, she was discharged with the advice of 1 month follow-up. In the follow up controls, the Cushingoid appearance recovered completely at 9-month-old. When she reached one-year-old, she could stand on her own and started to walk, she could use spoon, she was able to hold a pen and scribble, understand and say some words. Therefore she was considered at the same level as her peers in terms of neuromotor development. The follow-up controls of the patient in healthy child polyclinic are ongoing. \n\nInformed consent was taken from her parents and the study was approved by Ethics Committee of the hospital.\n\nFig.1 Typical cushingoid face of the patient\n\nFig.2.a-c. On coronal (a) and axial (b) T2W images, prominent intra- and extraaxial subarachnoid spaces and decreased cerebral volume consistent with brain atrophy are seen. Hyperintensity on T1W images resembling myelination is seen at posterior limbs of internal capsules and optic radiations (arrows). There are no evidence of T1 hyperintensities at the splenium of corpus callosum which is expected to be myelinated by the age of 4 months (dashed arrows) (c). Note the thickened subcutaneous fat in all series\n\nDiscussion\nIn current case, misuse of a potent topical corticosteroid for diaper dermatitis may be responsible for CS, brain atrophy, and delayed myelination. Iatrogenic CS caused by topical corticosteroid use is a rare entity that has been reported mostly in infants with diaper dermatitis (2, 7). The long term administration of topical corticosteroids with high potency to the skin covered with diaper or clothes are the risk factors that may cause systemic side effects like CS and adrenal suppression (7). Our patient had many of these risk factors. \n\nOne of the most potent topical steriod, clobetasol-17-propionate was applied after every diaper change for two months. In a study recruiting 18 children who had CS due to using nappy rash ointments, clobetasol was the most frequently used agent with the percentage of 73%. In this study, the duration of application of steroid including ointments was variable, with the period of at least 3 weeks in one patient to more than 1 year in 3 patients. Another result of this study was the high rate (72% of the cases) of self medication (7). Self medication is a common public health problem in developing countries that may lead to severe health problems as discussed in this case. If necessary, these products should be used under the supervision of physicians and parents should be informed about the use and potential side effects of the drug. Furthermore, purchasing of these products from the drugstores without prescription should be prohibited.\n\nThere are also other systemic side effects of corticosterids apart from CS including hypertension, dyslipidaemia, adrenal insufficiency, failure to thrive, skin atrophy, striae, cataract, glaucoma, and predisposition to infections (3-6). At presentation, our patient had hypertension and findings indicating failure to thrive. Adrenal insufficiency was excluded in the light of normal low dose ACTH stimulation test. Furthermore, long-term application of the topical corticosteroid might have lead to tendency to infection that was considered as meningitis in our case. Our search for literature revealed a case of urinary infection and two cases of disseminated cytomegalovirus infection due to misuse of topical corticosteroid in children (4-6).\n\nMRI abnormalities including brain atrophy and delayed myelination have been reported in both pediatric and adult patients being treated with corticosteroids (8). The evidence of dose-dependent brain atrophy and myelination delay was also shown in animal studies that investigated the side effects of antenatal administration of corticosteroids (9). The pathogenetic mechanisms of brain atrophy and myelination delay caused by chronic corticosteroid treatment is not well-known (8, 9). Glucocorticoids are thought to play inhibitory role in the neuronal maturation and myelination process by restraining the differentiation of oligodendrocyte precursors (9). Reduced glucose uptake in the brain, increased effects of excitatory amino acid neurotransmitters, decline in neurotrophic factors, and decrease in neurogenesis are deemed as mechanisms that account for brain atrophy (8). MRI is not only a very useful tool to show the details of brain anatomy without exposure to radiation, but also the best diagnostic modality to evaluate myelination of the developing brain (10). T1 is the most valuable sequence for demonstrating myelination in the first year of life, whereas T2-weighted (T2W) images provide additional information in later stages of myelin maturation. Myelinated white matter is seen hyperintense on T1-weighted (T1W) images consistent with increasing amount of cholesterol and galactocerebroside within myelin membranes, and hypointense on T2W images owing to reduced free water content between hydrophobic myelin sheats in maturing white matter (10). In our patient, normal myelination was only seen at bilateral perirolandic centrum semiovale, posterior limbs of internal capsules, optic radiations, brainstem, and deep cerebellar white matter on T1W images. Although the splenium of corpus callosum is expected to be myelinated and seen hyperintense on T1W images by the age of 4 months (10), there was no evidence of T1 hyperintensity at these areas in this 5-month-old infant. Therefore delayed myelination was considered in addition to brain atrophy.\n\n\nIn conclusion, this is the unique case of iatrogenic CS with the findings of brain atrophy and delayed myelination demonstrated on MRI. The physicians should be well aware of potential systemic and neurodevelopmental side effects of topical steroids.\n\nAuthors’ Contribution:\nSumeyra Dogan: Drafting, designing of the work, analysis, collecting radiological data and final approval of the work.\n\nMehmet S Dogan: Drafting, designing of the work, analysis, and final approval of the work.\n\nFiliz Tutunculer: Clinical evaluation of the patient, Designing of the work, interpretation and final approval of the work.\n\nOzge Yapici Ugurlar: Designing of the work, collecting radiological data, analysis, and final approval of the work.\n\nHakan Genchellac: Designing of the work, interpretation and final approval of the work.\n\nAll authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\n\nAcknowledgment\nwe would like to thanks patient family for their cooperation.\n\nConflict of Interest:\n No conflict of interest exists for our writing.\n==== Refs\nReferences\n1 Stratakis CA Cushing syndrome in pediatrics Endocrinol Metab Clin North Am 2012 41 4 793 803 23099271 \n2 Tempark T Phatarakijnirund V Chatproedprai S Watcharasindhu S Supornsilchai V Wananukul S Exogenous Cushing's syndrome due to topical corticosteroid application: case report and review literature Endocrine 2010 38 3 328 334 20972726 \n3 Katar S Akdeniz S Ozbek MN Yaramıs A Infantile Iatrogenic Cushing's Syndrome Indian J Dermatol 2008 53 4 190 191 19882032 \n4 Ozdemir A Bas VN Iatrogenic Cushing's syndrome due to overuse of topical steroid in the diaper area J Trop Pediatr 2014 10 60 5 404 406 25016382 \n5 Guven A Karadeniz S Aydin O Akbalık M Aydın M Fatal disseminated cytomegalovirus infection in an infant with Cushing's syndrome caused by topical steroid Horm Res 2005 64 1 35 38 16088205 \n6 Semiz S Balci YI Ergin Ş Candemir M Polat A Two cases of Cushing's syndrome due to overuse of topical steroid in the diaper area Pediatr Dermatol 2008 25 5 544 547 18950396 \n7 Sattar H Manzoor J Mirza L Abdul Malik S Butt TA Iatrogenic Cushing's syndrome in children presenting at Children's Hospital Lahore using nappy rash ointments J Pak Med Assoc 2015 65 5 463 466 26028377 \n8 Patil CG Lad SP Katznelson L Laws ER Jr Brain atrophy and cognitive deficits in Cushing's disease Neurosurg Focus 2007 23 3 E11 \n9 Salpietro V Polizzi A Di Rosa G Romeo AC Dipasquale V Morabito P Adrenal disorders and the paediatric brain: pathophysiological considerations and clinical implications Int J Endocrinol 2014 282489 1 16 \n10 Welker KM Patton A Assessment of normal myelination with magnetic resonance imaging Semin Neurol 2012 32 1 15 28 22422203\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1735-4668",
"issue": "12(1)",
"journal": "Iranian journal of child neurology",
"keywords": "Brain atrophy; Diaper dermatitis; Iatrogenic Cushing’s syndrome; Magnetic resonance imaging; Myelination",
"medline_ta": "Iran J Child Neurol",
"mesh_terms": null,
"nlm_unique_id": "101463836",
"other_id": null,
"pages": "101-104",
"pmc": null,
"pmid": "29379569",
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"publication_types": "D002363:Case Reports",
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"title": "Brain Atrophy and Hypomyelination Associated with Iatrogenic Cushing Syndrome in an Infant.",
"title_normalized": "brain atrophy and hypomyelination associated with iatrogenic cushing syndrome in an infant"
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"abstract": "Ceftobiprole is a relatively new cephalosporin with broad-spectrum activity and good tolerability. Despite its promising characteristics, to our knowledge, only two case reports, previously published also by some of us, is available concerning its administration for the treatment of infective endocarditis. Hereby we report our experience in this field.\n\n\n\nAll the patients with infective endocarditis treated with ceftobiprole were enrolled.\n\n\n\n12 cases of endocarditis were treated with ceftobiprole, 11/12 in combination with daptomycin and 1/12 as monotherapy. Gram-positive bacteria were isolated in 12/12 patients; 3 cases were polymicrobial. Cure rate was 83% (10/12 patients). In 9/12 (75%) cases, patients were switched to ceftobiprole following failure of previous antimicrobial regimen. In 3/3 patients in which ceftobiprole was administered because of persistently positive blood culture, bacteraemia clearance was rapidly achieved.\n\n\n\nCeftobiprole, especially in combination, could be a promising alternative treatment for infective endocarditis.",
"affiliations": "First Division of Infectious Diseases, Cotugno Hospital, AORN dei Colli, via Bianchi snc, Naples, Italy. Electronic address: c.tascini@gmail.com.;First Division of Infectious Diseases, Cotugno Hospital, AORN dei Colli, via Bianchi snc, Naples, Italy. Electronic address: rosa.zampino@tin.it.;Department of Infectious Disease, San Raffaele Hospital, via Stamira d'Ancona, Milan, Italy. Electronic address: ripa.marco@hsr.it.;UOSD Advanced Techniques in Cardiosurgery, Monaldi Hospital, AORN dei Colli, via Bianchi, snc, Naples, Italy. Electronic address: antonio.carozza@email.it.;Section of Infectious Diseases, Department of Medicine, University of Perugia, Piazzale Gambuli, 1, Perugia, Italy; UOC Infectious Diseases, San Donato Hospital, Azienda USL Toscana Sud Est, via Nenni, 22, Arezzo, Italy. Electronic address: pallottoc@gmail.com.;Microbiology and Virology Unit, Cotugno Hospital, AORN dei Colli, via Bianchi snc, Naples, Italy. Electronic address: marianobernardo@fastwebnet.it.;Section of Infectious Diseases, Department of Medicine, University of Perugia, Piazzale Gambuli, 1, Perugia, Italy. Electronic address: daniela.francisci@unipg.it.;Department of Infectious Disease, San Raffaele Hospital, via Stamira d'Ancona, Milan, Italy. Electronic address: oltolini.chiara@hsr.it.;First Division of Infectious Diseases, Cotugno Hospital, AORN dei Colli, via Bianchi snc, Naples, Italy. Electronic address: giulia.palmiero@ospedalideicolli.it.;Department of Infectious Disease, San Raffaele Hospital, via Stamira d'Ancona, Milan, Italy. Electronic address: scarpellini.paolo@hsr.it.",
"authors": "Tascini|Carlo|C|;Attanasio|Vittorio|V|;Ripa|Marco|M|;Carozza|Antonio|A|;Pallotto|Carlo|C|;Bernardo|Mariano|M|;Francisci|Daniela|D|;Oltolini|Chiara|C|;Palmiero|Giulia|G|;Scarpellini|Paolo|P|",
"chemical_list": "D002511:Cephalosporins; C443755:ceftobiprole; D017576:Daptomycin",
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"issue": "20()",
"journal": "Journal of global antimicrobial resistance",
"keywords": "Ceftobiprole; Infective endocarditis; MRSA",
"medline_ta": "J Glob Antimicrob Resist",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002511:Cephalosporins; D017576:Daptomycin; D004359:Drug Therapy, Combination; D004696:Endocarditis; D005260:Female; D006094:Gram-Positive Bacteria; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome",
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"title": "Ceftobiprole for the treatment of infective endocarditis: A case series.",
"title_normalized": "ceftobiprole for the treatment of infective endocarditis a case series"
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"abstract": "Myelofibrosis (MF) is often associated with chronic myeloid leukemia, myelodysplastic syndrome and primary myeloproliferative neoplasms (MPN), but few number cases of malignant lymphoma with myelofibrosis was reported, and a few cases about follicular lymphoma with MF were found. Here we described a case of follicular lymphoma (FL) complicated by myelofibrosis.\nA 43-year-old man was diagnosed with follicular lymphoma (FL) complicated by MF, besides, the lymphoma staging of this patient was AnnArbor IV B. The cytokines of plated-derived growth factor (PDGF), basic fibroblast growth factor (b-FGF), vascular endothelial growth factor (VEGF), tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), interleukin-2 (IL-2), and transforming growth factor-β (TGF-β) were positive, while JAK2V617F, MPL, and CALR mutations were negative. After first course of chemotherapy, the peripheral blood and MF improved. The systemic superficial lymph nodes and spleen were significantly narrowed after the third cycle of chemotherapy.\nThe production of various cytokines, such as b-FGF, TNF-α, TGF-β, PDGF, IL-1β, IL-2, IL-6, IL-10, may contribute to the development of MF.",
"affiliations": "Department of Haematology, Hebei General Hospital, Shijiazhuang, Hebei, People's Republic of China.;Department of Hematology, Hebei Province Hospital of Chinese Medicine, Shijiazhuang, Hebei, People's Republic of China.;Department of Haematology, Hebei General Hospital, Shijiazhuang, Hebei, People's Republic of China.;Department of Pathology, Hebei General Hospital, Shijiazhuang, Hebei, People's Republic of China.;Department of Nuclear Medicine, Hebei General Hospital, Shijiazhuang, Hebei, People's Republic of China.;Department of Haematology, Hebei General Hospital, Shijiazhuang, Hebei, People's Republic of China.",
"authors": "Kong|Ling-Zhijie|LZ|0000-0002-5397-7937;Li|Jing|J|;Wang|Rui-Cang|RC|;Kang|Lin|L|;Wei|Qiang|Q|;Li|Yan|Y|",
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"fulltext": "\n==== Front\nOnco Targets Ther\nOnco Targets Ther\nott\nott\nOncoTargets and therapy\n1178-6930\nDove\n\n313428\n10.2147/OTT.S313428\nCase Report\nSimultaneous Follicular Lymphoma and Myelofibrosis: Report of a Case with Review of the Literature\nKong et al\nKong et al\nhttp://orcid.org/0000-0002-5397-7937\nKong Ling-zhijie 1 2\nLi Jing 3\nWang Rui-Cang 1\nKang Lin 4\nWei Qiang 5\nLi Yan 1\n1 Department of Haematology, Hebei General Hospital, Shijiazhuang, Hebei, People’s Republic of China\n2 Hebei North University, Zhangjiakou, Hebei, People’s Republic of China\n3 Department of Hematology, Hebei Province Hospital of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China\n4 Department of Pathology, Hebei General Hospital, Shijiazhuang, Hebei, People’s Republic of China\n5 Department of Nuclear Medicine, Hebei General Hospital, Shijiazhuang, Hebei, People’s Republic of China\nCorrespondence: Yan Li Department of Haematology, Hebei General Hospital, No. 348, Heping West Road, Shijiazhuang, Hebei, 050051, People’s Republic of ChinaTel +86 18931866300 Email liyan98_win@163.com\n24 8 2021\n2021\n14 45514559\n30 4 2021\n26 7 2021\n© 2021 Kong et al.\n2021\nKong et al.\nhttps://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).\nBackground\n\nMyelofibrosis (MF) is often associated with chronic myeloid leukemia, myelodysplastic syndrome and primary myeloproliferative neoplasms (MPN), but few number cases of malignant lymphoma with myelofibrosis was reported, and a few cases about follicular lymphoma with MF were found. Here we described a case of follicular lymphoma (FL) complicated by myelofibrosis.\n\nCase Presentation\n\nA 43-year-old man was diagnosed with follicular lymphoma (FL) complicated by MF, besides, the lymphoma staging of this patient was AnnArbor IV B. The cytokines of plated-derived growth factor (PDGF), basic fibroblast growth factor (b-FGF), vascular endothelial growth factor (VEGF), tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), interleukin-2 (IL-2), and transforming growth factor-β (TGF-β) were positive, while JAK2V617F, MPL, and CALR mutations were negative. After first course of chemotherapy, the peripheral blood and MF improved. The systemic superficial lymph nodes and spleen were significantly narrowed after the third cycle of chemotherapy.\n\nConclusion\n\nThe production of various cytokines, such as b-FGF, TNF-α, TGF-β, PDGF, IL-1β, IL-2, IL-6, IL-10, may contribute to the development of MF.\n\nKeywords\n\nfollicular lymphoma\nmyelofibrosis\nimmunohistochemistry\ncytokines\n==== Body\nIntroduction\n\nWe described a case report of simultaneous follicular lymphoma with myelofibrosis, which leads to a serious of problem in diagnosis, etiology and treatment, and promotes us to critically review the literature. Follicular lymphoma (FL) is the second most common lymphoma in western countries, accounting for about 35% of all of non-Hodgkin’s lymphoma (NHL).1,2 In China, follicular lymphoma accounts for a slightly lower proportion of non-Hodgkin’s lymphoma, but it is still a common type.3 Follicular lymphoma is an indolent B-cell lymphoma typically presenting with diffuse lymphadenopathy, bone marrow involvement, and splenomegaly. Extranodal involvement is less common.2 The majority of FL patients have the characteristic of t(14;18) (q32;q21) translocation, which results in the overexpression of the BCL-2 protein.4 In most cases, immunohistochemical staining is positive for CD19, CD20, CD10, monoclonal immunoglobulin and bcl-2 protein.2 Myelofibrosis (MF) is characterized by the increase in BM stromal fibers composed of reticulin and collagen.5 A wide variety of hematological malignancies result in myelofibrosis, including chronic myeloid leukemia, acute megaloblastic leukemia, hairy cell leukemia and myelodysplastic syndrome. But MF complicated with malignant lymphoma is rare,6 and we found a few case reports of FL with myelofibrosis.7,8\n\nCase Presentation\n\nA 43-year-old-man presented us with enlarged lymph nodes from May 2020, and he was treated at the local hospital. Then he developed sore limbs and pancytopenia, therefore, he was referred to our department in late August. A detailed medical history was collected: body temperature 36.6°C, pulse 88/minute, respiration 22/minute, blood pressure 128/69 mmHg, clear consciousness, pallor of the complexion and palpebral conjunctiva, and splenomegaly. A few enlarged lymph nodes were palpable in bilateral cervical, axillary and inguinal regions, the largest of which measuring about 4 cm in size is located in the right inguinal region. The main symptom of this patient is significant splenomegaly and pancytopenia.\n\nThe laboratory findings at the time of admission are shown in Table 1. His serum levels of LDH, β2 microglobulin and IL-6 were elevated. In addition, his serum level of vascular endothelial growth factor (VEGF) was normal (Figure 1). The detection of EB virus was negative. Flow cytometry (FC) was performed on the peripheral blood specimen because of dry tap aspiration. Monoclonal B lymphocytes accounted for 1.47% of karyocyte in peripheral blood samples. The aberrant lymphocytes population expressed CD19, CD20, CD10, FMC7, CD81, cKappa, and partially expressed CD79b, CD200, CD22, CD1d, sIgM but did not express CD11c, CD103, CD5, CD23, CD43, CD38, CD25, sIgD, cLambda, and CD138. The immunophenotyping by FC was consistent with the phenotype of CD5-, CD10+ monoclonal B lymphocytes (Figure 2). The biopsy of right cervical lymph node combining with the immunohistochemistry supported the diagnosis of follicular lymphoma (3A). Immunostaining revealed that the tumor cells were positive for CD20, CD79α, Bcl-2, Bcl-6, CD10, PAX-5, CD5 (Interfollicular region), CD3 (Interfollicular region), CD43 (Interfollicular region), CD21 (FDC net), CD23 (FDC net), MUM-1, VEGF, b-FGF, TNF-α, TGF-β, PDGF, IL-1β, IL-2, IL-6, IL-10 and negative for SOX-11, CD38, CD138, Kappa, Lambda, CyclinD1. Ki-67 stain showed nuclear positivity in 60% nodal tumour cells and 30% extranodal tumour cells (Figure 3)Table 1 The Laboratory Findings\n\nCRP\tCRP\t35.19mg/L↑\t\nCBC\tWBC\t1.36×109/L↓\t\nNE\t0.88×109/L↓\t\nLY\t0.32×109/L↓\t\nEO\t0.01×109/L↓\t\nRBC\t1.93×1012/L↓\t\nHb\t57.00g/L↓\t\nPLT\t59.00×109/L↓\t\nESR\tESR\t97mm/h↑\t\nCoagulation\tFbg\t4.35g/L↑\t\nDD\t1.93mg/L FEU↑\t\nCoombs test\tDirect Coombs test\tNegative\t\nIndirect Coombs test\tNegative\t\nβ2 microglobulin\tβ2-MG\t4.58ug/mL↑\t\nANA\tANA\tWeak positive 1:100\t\nRCT\tRCT%\t3.16%↑\t\nBiochemistry\tT.P\t63.4g/L↓\t\nGLOP\t19.8g/L↓\t\nALP\t125.8U/L↑\t\nLDH\t488.1U/L↑\t\nHBD\t360.4U/L↑\t\nMb\t77ng/mL↑\t\nFBG\t7.16mmol/L↑\t\nP\t1.74mmol/L↑\t\nMg\t0.73mmol/L↓\t\nUric acid\t506.5umol/L↑\t\nTG\t1.85mmol/L↑\t\nHDL\t0.70mmol/L↓\t\nApo A1\t0.93g/L↓\t\nSerum iron metabolism\tFer\t581.4ng/mL↑\t\nUIBC\t55.00umol/L↑\t\nInterleukin-6\tIL-6\t17.10pg/mL↑\t\nNotes: ↑Denotes above the upper limit of the reference range, ↓denotes below the lower limit of the reference range.\n\nAbbreviations: CBC, complete blood count; CRP, C-reactive protein; WBC, white blood cell; NE, neutrophil; LY, lymphocyte; Eo, eosinocyte; RBC, red blood cell; Hb, hemoglobin; PLT, plate; ESR, erythrocyte sedimentation rate; Fbg, fibrinogen; DD, Ddimer; RCT, reticulocyte; T.P, total protein; GLOB, globulin; ALP, alkaline phosphatase; LDH, lactate dehydrogenase; HBD, hydroxybutyrate dehydrogenase; Mb, myoglobin; GLU, FBG, fasting blood glucose; TG, triglyceride; HDL, high density lipoprotein; Apo A1, Apolipoprotein A1; Fer, ferritin; UIBC, unsaturated iron binding capacity; IL-6, interleukin-6.\n\nFigure 1 The changes of β2-MG, IL-6, VEGF, LDH. The series of β2-MG, IL-6 are drawn on the primary axis, and the series of VEGF, LDH are drawn on the secondary axis.\n\nFigure 2 Flow cytometry of peripheral blood. (A–F) Before chemotherapy, the aberrant lymphocytes population expressed CD19, CD20, CD10, cKappa; (H–M) after three courses of chemotherapy, these became negative.\n\nFigure 3 The immunostaining of right cervical lymph node for cytokines. (A) (b-FGF;×200), positive; (B) (IL-1β;×200), positive; (C) (IL-2;×200), positive; (D) (IL-6;×200), positive; (E) (IL-10,×200), positive; (F) (MUM-1×200), positive; (G) (PDGF×200), positive; (H) (TGF-β×200), positive; (I) (TNF-α×200), positive; (J) (VEGF×200), positive; (K) HE, ×40.\n\nBone marrow aspiration yielded a dry tap, and the bone marrow biopsy showed active myeloproliferative activity. Granulocytes were rare, mainly in the mature stage; erythroid cells were rare, mainly middle and late erythrocytes; the number of megakaryocytes was normal, mainly polymorphonuclear cell; the proliferation of lymphocytes was active, and the proliferation of collagen fibers can be seen in mesenchymal tissue of bone marrow. The immunostaining showed that the aberrant lymphocytes population was positive for CD34, CD117, CD61, CD3, CD20, CD138, E-CAD, MPO, CD45RA, VEGF, b-FGF, TNF-α, TGF-β, PDGF, IL-1β, IL-2, IL-6, IL-10. The reticular fiber staining was grade 3 (Figure 4). Bone marrow examination of our hospital showed atypical lymphocytes, accounting for about 80% of lymphocytes. And the peripheral blood smear showed tear‑drop cells. The PET images were consistent with the performances of AnnArbor IV: General hypermetabolic enlarged lymph nodes were be seen in both sides of diaphragm, especially in the abdomen; the metabolism of bone marrow and left kidney was elevated. In addition, the PET scan showed splenomegaly obviously without hypermetabolism, which were induced by MF probably (Figure 5). The patient underwent peripheral blood examinations for JAK2, MPL, and CALR mutations, and all of these are negative. Fluorescence in situ hybridization (FISH) analysis performed on paraffin embedded tissue sections from the right cervical lymph node were positive for the BCL2 (18q21) split signal and IGH/BCL2 fusion signal, and negative for MYC rearrangement and BCL6 (3q27) split signals (Figure 6).Figure 4 The immunostaining of bone marrow before treatment. (A) (b-FGF;×200), positive; (B) (CD20;×100), positive; (C) (CD61×100), positive; (D) (IL-10;×200), positive; (E) HE 100×; (F) (IL-1β;×200), positive; (G) (PDGF×200), positive; (H) (TGF-β×200), positive; (I) (VEGF×200), positive; (J) reticular fiber staining revealed diffuse fibrosis (MF-3) 100×; (K) (IL-2;×200), positive; (L) (IL-6;×200), positive; (M) (TNF-α×200), positive.\n\nFigure 5 PET/CT finding. (A–C) Before chemotherapy. (The largest lymph nodes was in the lower abdominal mesenteric region 68mm x 42mm, SUVmax =8.2). (D–F) After three courses of chemotherapy (The spleen reduced obviously, whose metabolism was normal (SUVmax=2.6)). (A) Widespread lymph node enlargement and hypermetabolism, splenomegaly, kidney hypermetabolism (blue arrows) and diffuse bone marrow hypermetabolism. Its inferior border approached the upper margin of pelvis (SUVmax= 2.9); (B) spinal hypermetabolism (blue arrow); (SUVmax =9.0); (C) iliac hypermetabolism (blue arrows); (D) no abnormal lymph nodes were found. The volume of spleen was smaller than before, and the metabolism of bone marrow, kidney metabolism were normal (red arrows); (E) normal spine metabolism, (SUVmax =3.3) (red arrow); (F) normal ilium metabolism (red arrows).\n\nFigure 6 Fluorescence interphase in situ hybridization on lymph node biopsy. (A) IGH-BCL2 dual-colour dual-fusion probe displays two fused green and red signals, one isolated green and one isolated red signal in most of tumour nuclei with t(14;18) (q21;q32)/IGH-BCL2. Arrow indicates positive nuclei. (B) BCL2 dual-colour break-apart (BAP) probe shows one co-localised green and red signal, one isolated green and one isolated red signal in most of tumour nuclei; (C) BCL6 dual-colour break-apart (BAP) probe shows two co-localised green and red signal; (D) MYC dual-colour break-apart (BAP) probe shows one co-localised green and red signal.\n\nBased on those, the patient was diagnosed with FL (3A, AnnArbor IVB) complicated by MF. In the first course of chemotherapy, the patient received the R-COP therapy (rituximab 700mg, ivgtt: day 0; cyclophosphamide 600mg, ivgtt: day 1; vindesine 3mg, ivgtt: day 1; prednisone 100mg, p.o: day 1–5). After the improvement of hemogram, he was given the R-CHOP therapy (rituximab 700mg, ivgtt: day 0; cyclophosphamide 800mg, ivgtt: day 1; doxorubicin 60mg, ivgtt: day 1; vindesine 4mg, ivgtt: day 1; prednisone 100mg, p.o: day 1–5). During the second course, the patient developed serious adverse gastrointestinal reactions, so prednisone was replaced by methylprednisolone. The pancytopenia was responding well to treatment (Table 2). The immunostaining of bone marrow showed the tumor cells were negative for CD19, CD117, b-FGF, TNF-α, TGF-β, PDGF, IL-1β, IL-2, IL-6, IL-10, except for VEGF after two courses (Figures 7 and 8). After the first course, the MF in the bone marrow improved. The reticular fiber staining was grade 1 (Figure 7). And the serum LDH, β2-MG and IL-6 levels were declined, but these parameters were still higher than that in normal cases. After two courses of chemotherapy, the serum levels of LDH, β2-MG and IL-6 continued to fall to normal levels. However, the serum VEGF level elevated a lot. After the third course, VEGF level was declined, but IL-6 and LDH elevated again (Figure 1). Meanwhile, the serum levels of IL-1β, IL-8, IL-10, TNF-α were normal. The PET images showed improvement of the lymphadenopathy (Figure 5).Table 2 The Analysis of Peripheral Blood\n\n\tBefore Treatment\tAfter First Course\tAfter Second Course\tAfter Third Course\t\nRBC\t1.93×1012/L\t3.29×1012/L\t4.01×1012/L\t4.04×1012/L\t\nHb\t57.00g/L\t97.00g/L\t125.00g/L\t122.00 g/L\t\nWBC\t1.36×109/L\t3.33×109/L\t4.12×109/L\t5.04×109/L\t\nPLT\t59.00×109/L\t135×109/L\t214×109/L\t175×109/L\t\nNote: The pancytopenia is responding well to treatment.\n\nFigure 7 The immunostaining of bone marrow after one course of chemotherapy. (A) (b-FGF;×200), positive; (B) (CD19;×200), negative; (C) (CD117×200), negative; (D) (IL-1β;×200), positive; (E) (IL-2;×200), positive; (F) (IL-6;×200), positive; (G) (IL-10;×200), positive; (H) (PDGF×200), positive; (I) (TGF-β×200), positive; (J) (TNF-α×200), positive; (K) (VEGF×100), positive; (L) reticular fiber staining ×200, MF-1.\n\nFigure 8 The immunostaining of bone marrow after two courses of chemotherapy. (A) (b-FGF;×200), negative; (B) (CD19;×200), negative; (C) (CD117;×200), negative; (D) (IL-1β;×200), negative; (E) (IL-2;×100), negative; (F) (IL-6;×200), negative; (G) (IL-10;×200), negative; (H) (PDGF×200), negative; (I) (TGF-β×200), negative; (J) (TNF-α×200), negative; (K) (VEGF×100), positive; (L) reticular fiber staining 100×, MF 0–1.\n\nDiscussion\n\nMF can occur not only after lymphoma, but also at the same time or earlier than lymphoma.9 However, when MF occurs at the same time with lymphoma, we cannot make a final diagnosis of primary myelofibrosis (PMF) or secondary myelofibrosis (SMF) easily. Analyses of JAK2, MPL, and CAL mutations are highly specific for the diagnosis of PMF. Ninety percent of PMF patients can be detected a mutation among three genes. However, the triple-negative result of gene mutations in our case cannot make us reach a final definite decision since 10% patients with PMF have none of mutation in these three genes. Thus, we could not distinguish triple-negative PMF from SMF.10,11 However, in this case, the diagnosis of primary myelofibrosis lacks necessary criteria: presence of megakaryocytic proliferation and atypia; presence of another clonal marker in the absence of JAK2, CALR, or MPL mutation.12 Meanwhile, the MF improved after the chemotherapy for FL. Therefore, the patient was diagnosed with SMF. The pathological mechanisms of MF in patients with malignant lymphoma remains unclear, intensive studies are required in this condition. The main causes of MF are cytokines and growth factors, especially those related to fibrogenic properties, such as TGF-β, IL-1, PDGF and so on.13 And some studies have revealed that cytokines including TGF-β, b-FGF and PDGF may play an important role for the MF associated with malignant lymphoma.14\n\nAs we know, a total of 49 cases of lymphoma with myelofibrosis have been reported except the present case, including 5 cases of Hodgkin lymphoma, 25 cases of Non Hodgkin’s T-cell lymphoma and 19 cases of Non Hodgkin’s B-cell lymphoma. There have been a few cases of FL complicated with MF among these cases.7,8 The development of the MF are associated with the production of various cytokines, such as TGF-β, IL-1, PDGF, b-FGF, VEGF.13,15 However, the accurate cause of MF with concurrent lymphoma is not clear yet. It was reported that MF may be attributable to the lymphoma cells producing PDGF in a case of angioimmunoblastic T-cell lymphoma (AITL) with complicating MF. Meanwhile, the b-FGF produced by the bone marrow megakaryocytes was considered as an irrelevant factor of the development of concurrent MF.15 On the contrary, another report showed that b-FGF played an important role in the case of MF complicated with peripheral T cell lymphoma (PTCL).16 In addition, there were a few other case reports consenting to the contribution of cytokines. In a report of peripheral T cell lymphoma-not otherwise specified (PTCL-NOS) with myelofibrosis, the cytokines of PDGF, TNF-α, and TGF-β made a contribution to simultaneous MF, but VEGF was not associated with the presence of the MF.14 Besides that, several cases implicated that TGF-β were associated with simultaneous MF.17–20\n\nAs previously described, the expression of these cytokines was immunohistochemically performed to explore the mechanism of simultaneous MF with malignant lymphoma. In present case, the immunostaining of bone marrow showed the negativity for b-FGF, TNF-α, TGF-β, PDGF, IL-1β, IL-2, IL-6, IL-10 with the improvement of MF, which suggested these cytokines may contribute to the development of MF. This case of bone marrow biopsy revealed diffuse fibrosis (MF-3) diagnosed with FL (3A, AnnArbor IVB). The patient presented enlargement of lymph nodes, for example in the bilateral cervical neck, bilateral axillae, mediastinum, retroperitoneum before treatment, accompanied with spleen enlargement. The metabolism of bone was elevated meanwhile. However, the lymph node, spleen and bone were normal after three courses of chemotherapy. We hypothesize that late disease easily complicates with myelofibrosis. This may be related to tumor cell invasion into the bone marrow or cytokine released during lymphoma cell growth. Lymphoma cells may promote fibroblast proliferation and bone marrow collagen by secreting TGF‐β and b-FGF, leading to the development of MF.\n\nIn conclusion, our experience is limited to one patient, further research is needed to explore the potential pathogenesis of the FL with MF.\n\nAcknowledgments\n\nThis study was financially supported by the Department of science and technology of Hebei Province Plan Project (Priority research and development Project 18277720D).\n\nEthical Approval\n\nThe publication of this case report gained ethical approval from the Ethics Committee of Hebei General Hospital.\n\nConsent for Publication\n\nWritten informed consent was obtained from the patient for publication of this paper and any accompanying images.\n\nInformed Consent\n\nWritten informed consent for this case report has been obtained from the patient.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n\n1. Swerdlow StevenH, CampoE, Pileri StefanoA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127 (20 ):2375–2390. doi:10.1182/blood-2016-01-643569 26980727\n2. FreedmanA, JacobsenE. Follicular lymphoma: 2020 update on diagnosis and management. Am J Hematol. 2020;95 (3 ):316–327. doi:10.1002/ajh.25696 31814159\n3. LiuYL, WangWJ, WangXN. [Pathological characteristics of bone marrow in non-Hodgkin’s lymphoma patients with secondary myelofibrosis and their relationship with prognosis]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2015;23 (3 ):674–678. Chinese. 26117015\n4. Green MichaelR. Chromatin modifying gene mutations in follicular lymphoma. Blood. 2018;131 (6 ):595–604. doi:10.1182/blood-2017-08-737361 29158360\n5. BaeE, ParkC-J, ChoY-U, et al. Differential diagnosis of myelofibrosis based on WHO 2008 criteria: acute panmyelosis with myelofibrosis, acute megakaryoblastic leukemia with myelofibrosis, primary myelofibrosis and myelodysplastic syndrome with myelofibrosis. Int J Lab Hematol. 2013;35 (6 ):629–636. doi:10.1111/ijlh.12101 23693053\n6. FuR, YuH, WuY-H, LiuH, ShaoZ-H. Hodgkin’s lymphoma associated with myelofibrosis: a case report. Oncol Lett. 2015;10 (3 ):1551–1554. doi:10.3892/ol.2015.3438 26622707\n7. KurodaH, AbeT, JomenW, et al. [Follicular lymphoma complicated with myelofibrosis and macroglobulinemia at initial presentation]. Rinsho Ketsueki. 2013;54 (11 ):2068–2073. Japanese.24305541\n8. TabataR, TabataC, NagaiT, YasumizuR. Follicular lymphoma with prominent fibrosis complicated by peripheral eosinophilia. Ann Hematol. 2012;91 (6 ):965–967. doi:10.1007/s00277-011-1342-9 21938445\n9. WangW, DongL, YinQ, SongY, WeiX, LiY. [Clinical analysis of 5 cases of lymphoma with myelofibrosis and literature review]. Zhonghua Xue Ye Xue Za Zhi. 2016;37 (02 ):157–159. Chinese. 27014989\n10. KumagaiT, SatohY, KoshiishiM, et al. 18F-FDG-PET/CT is effective in distinguishing myelofibrosis due to bone marrow infiltration of diffuse large B-cell lymphoma from triple-negative primary myelofibrosis. Jpn J Clin Hematol. 2017;58 (3 ):228–232.\n11. TsutsuiM, YasudaH, OtaY, KomatsuN. Splenic marginal zone lymphoma with prominent myelofibrosis mimicking triple-negative primary myelofibrosis. Case Rep Oncol. 2019;12 (3 ):834–837. doi:10.1159/000504129 31762757\n12. ArberDA, OraziA, HasserjianR, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127 (20 ):2391–2405. doi:10.1182/blood-2016-03-643544 27069254\n13. RameshwarP, OhHS, YookC, GasconP, ChangVT. Substance p-fibronectin-cytokine interactions in myeloproliferative disorders with bone marrow fibrosis. Acta Haematol. 2003;109 (1 ):1–10. doi:10.1159/000067268 12486316\n14. SekiguchiY, ShiraneS, ShimadaA, et al. Peripheral T cell lymphoma, not otherwise specified with myelofibrosis: report of a case with review of the literature. Int J Clin Exp Pathol. 2015;8 (4 ):4186–4203.26097612\n15. SekiguchiY, MatsuzawaN, ShimadaA, et al. Angioimmunoblastic T-cell lymphoma with intramedullary production of platelet-derived growth factor and possibly complicating myelofibrosis: report of a case with review of the literature. Int J Hematol. 2013;98 (2 ):250–257. doi:10.1007/s12185-013-1386-9 23846384\n16. KikukawaM, UmaharaT, KikawadaM, et al. Peripheral T-cell lymphoma presenting as myelofibrosis with the expression of basic fibroblast growth factor. Geriatr Gerontol Int. 2009;9 (4 ):395–398. doi:10.1111/j.1447-0594.2009.00556.x 20002760\n17. UeharaE, TasakaT, MatsuhashiY, et al. Peripheral T-cell lymphoma presenting with rapidly progressing myelofibrosis. Leuk Lymphoma. 2003;44 (2 ):361–363. doi:10.1080/1042819021000029966 12688359\n18. OkabeS, MiyazawaK, IguchiT, et al. Peripheral T-cell lymphoma together with myelofibrosis with elevated plasma transforming growth factor-β1. Leuk Lymphoma. 2005;46 (4 ):599–602. doi:10.1080/10428190400029809 16019489\n19. MatsuiK, AdachiM, TominagaT, ShinoharaK, KameiT. Angioimmunoblastic T cell lymphoma associated with reversible myelofibrosis. Intern Med. 2008;47 (21 ):1921–1924. doi:10.2169/internalmedicine.47.1236 18981638\n20. MatsunagaT, TakemotoN, MiyajimaN, et al. Splenic marginal zone lymphoma presenting as myelofibrosis associated with bone marrow involvement of lymphoma cells which secrete a large amount of TGF-beta. Ann Hematol. 2004;83 (5 ):322–325. doi:10.1007/s00277-003-0806-y 15060752\n\n",
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"keywords": "cytokines; follicular lymphoma; immunohistochemistry; myelofibrosis",
"medline_ta": "Onco Targets Ther",
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"title": "Simultaneous Follicular Lymphoma and Myelofibrosis: Report of a Case with Review of the Literature.",
"title_normalized": "simultaneous follicular lymphoma and myelofibrosis report of a case with review of the literature"
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"abstract": "Sinonasal undifferentiated carcinoma (SNUC) is an uncommon aggressive tumor. Locally advanced disease is usually diagnosed at presentation. Multidisciplinary approach is essential and aims to ensure optimal trimodal strategy. Induction chemotherapy is preferred in order to select patients who will benefit from chemoradiotherapy or surgery. Immunotherapy is not indicated in patients with recurrent SNUC. We describe an impressive response in a young man previously treated with radiotherapy and chemotherapy and demolitive surgery who had metastatic bone and lung disease. We also report data on PD-L1, next-generation sequencing, and neutrophil/platelets ratio.",
"affiliations": "Medical Oncology Santa Croce and Carle General Hospital Cuneo, Cuneo, Italy.;Consultant, Candiolo Cancer Institute, FPO-IRCCS Turin, Cuneo, Italy.;Medical Oncology Santa Croce and Carle General Hospital Cuneo, Cuneo, Italy.;Medical Oncology Santa Croce and Carle General Hospital Cuneo, Cuneo, Italy.;Medical Oncology Unit, Department of Medical Oncology, ASST Spedali Civili di Brescia, Brescia, Italy.",
"authors": "Denaro|Nerina|N|https://orcid.org/0000-0002-8605-4290;Merlano|Marco|M|;Numico|Gianmauro|G|;Garrone|Ornella|O|https://orcid.org/0000-0001-7359-5410;Bossi|Paolo|P|",
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"issue": "107(6)",
"journal": "Tumori",
"keywords": "Sinonasal undifferentiated cancer; immunotherapy; multidisciplinary approach",
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"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Complete response to immunotherapy in sinonasal undifferentiated carcinoma.",
"title_normalized": "complete response to immunotherapy in sinonasal undifferentiated carcinoma"
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"abstract": "In this article, we describe the case of a 61-year-old woman who presented with altered mental status and was found to have Klebsiella pneumoniae meningitis, bacteremia, and hepatic abscess. Despite intravenous antibiotic therapy and percutaneous drainage of the hepatic abscess, the patient developed worsening meningitis with ventriculitis, which led to her death. This invasive Klebsiella syndrome is characterized by metastatic infections with a hypervirulent strain and a poor clinical prognosis. Important elements of this patient's case-including the widespread and highly aggressive course-and of those reported in the literature are reviewed. Although the invasive Klebsiella syndrome is an increasingly recognized clinical entity, most often in the Eastern hemisphere, it remains rare in the United States with approximately 20 cases reported in the literature, and given its high morbidity, it is vitally important for clinicians to recognize.",
"affiliations": "Medical University of South Carolina, Charleston, SC, USA.;Carolinas Medical Center, Charlotte, NC, USA.;Medical University of South Carolina, Charleston, SC, USA.",
"authors": "Maheswaranathan|Mithu|M|;Ngo|Tue|T|;Rockey|Don C|DC|",
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"doi": "10.1177/2324709618806552",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case RepJ Investig Med High Impact Case RepHICsphicJournal of Investigative Medicine High Impact Case Reports2324-7096SAGE Publications Sage CA: Los Angeles, CA 10.1177/232470961880655210.1177_2324709618806552Case ReportIdentification and Management of the Hypervirulent Invasive Klebsiella pneumoniae Syndrome: A Unique and Distinct Clinical Entity Maheswaranathan Mithu MD1Ngo Tue MD2Rockey Don C. MD11 Medical University of South Carolina, Charleston, SC, USA2 Carolinas Medical Center, Charlotte, NC, USADon C. Rockey, MD, Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, CSB, Room 803, Charleston, SC 29425, USA. Email: rockey@musc.edu16 10 2018 Jan-Dec 2018 6 232470961880655231 5 2018 17 8 2018 30 8 2018 © 2018 American Federation for Medical Research2018American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution 4.0 License (http://www.creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).In this article, we describe the case of a 61-year-old woman who presented with altered mental status and was found to have Klebsiella pneumoniae meningitis, bacteremia, and hepatic abscess. Despite intravenous antibiotic therapy and percutaneous drainage of the hepatic abscess, the patient developed worsening meningitis with ventriculitis, which led to her death. This invasive Klebsiella syndrome is characterized by metastatic infections with a hypervirulent strain and a poor clinical prognosis. Important elements of this patient’s case—including the widespread and highly aggressive course—and of those reported in the literature are reviewed. Although the invasive Klebsiella syndrome is an increasingly recognized clinical entity, most often in the Eastern hemisphere, it remains rare in the United States with approximately 20 cases reported in the literature, and given its high morbidity, it is vitally important for clinicians to recognize.\n\nsepsisabscessmeningitisventriculitisdiabetes mellituscover-dateJanuary-December 2018\n==== Body\nIntroduction\nKlebsiella pneumoniae causes nosocomial and community-acquired infections, including pneumonia, bacteremia, urinary tract infection, surgical wound infections, liver abscess, cholangitis, and peritonitis. K pneumoniae has also been increasingly recognized as a cause of community-acquired pyogenic liver abscess, in the absence of underlying hepatobiliary disease, especially in patients from Eastern countries (Singapore, Hong Kong, Korea, and Vietnam) and in those with underlying risk factors such as diabetes mellitus.1 Metastatic infection has also been associated with K pneumoniae liver abscess.\n\nPyogenic liver abscesses are typically treated with management of the underlying condition (ie, biliary obstruction), drainage, and antibiotics and typically have an excellent prognosis.2 However, the biology, and especially the natural history of K pneumoniae liver abscess and associated invasive syndrome is substantial, with mortality rates ranging from 3% to 42%.3 Here, we report on a patient with invasive K pneumoniae syndrome with pyogenic liver abscess associated with meningitis and ventriculitis that was fatal.\n\nCase Presentation\nA 61-year-old Chinese female with no known past medical history presented to the hospital with altered mental status for 1 week with associated fever, neck pain, nausea, and vomiting. It was not possible to obtain history from her due to her altered mental status; her family denied complaints of abdominal pain, headache, visual changes, focal weakness, chest pain, or dyspnea. She had been waking up in the middle of the night to cook meals and clean her house, and was intermittently somnolent. The patient did not smoke, drink alcohol, or use illicit drugs. She was born in China and immigrated to the United States, where she resided for the past 30 years with no foreign travel during that time. She had not seen a physician in her adult life and took no medications. Given her altered mental status and concern about the stability of her airway, she was intubated in the emergency department.\n\nOn admission to the intensive care unit, the patient’s vital signs were as follows: temperature 36.5°C, heart rate 90 beats/min, respiratory rate 22 breaths/min, blood pressure 108/61 mm Hg, and oxygen saturation of 100% on an FiO2 (fraction of inspired oxygen) of 40%. Physical examination demonstrated a positive Brudzinski sign and neck stiffness, even while sedated. Pupils were equal round and reactive to light, and she responded to painful stimuli. Her lungs were clear to auscultation bilaterally, and cardiac examination was unremarkable without a murmur. Her abdominal examination was normal with no hepatomegaly or ascites.\n\nAdmission laboratory data demonstrated white blood cell count of 19 900/mm3 (81% neutrophils), hemoglobin 11.8 g/dL, platelet count 170 000/µL, creatinine 0.5 mg/dL, bilirubin 0.6 mg/dL, aspartate transaminase 49 IU/L, alanine transaminase 81 IU/L, alkaline phosphatase 142 IU/L, and albumin 1.9 g/dL. Electrolytes were within normal limits. C-reactive protein was 4.19 mg/dL, and erythrocyte sedimentation rate was >100 mm/h. She had mild hyperglycemia on admission, with glucose 132 mg/dL and hemoglobin A1c of 6.4%.\n\nMagnetic resonance imaging of the brain demonstrated diffuse leptomeningeal enhancement most conspicuous along the bilateral temporal lobes and insula, subarachnoid space of the basal cisterns, and the ventricular system, and proteinaceous material and pus were visualized within the subarachnoid space and bilateral lateral ventricles (Figure 1). Neurosurgery placed an external ventricular device to help drain cerebrospinal fluid (CSF). Lumbar puncture yielded clear CSF with an opening pressure of 22 cm H2O, a white blood cell count of 5051/mm3 (neutrophils 87%), protein 803 mg/dL, and a glucose 4 mg/dL. CSF culture was positive for K pneumoniae.\n\nFigure 1. Brain magnetic resonance imaging demonstrating meningitis and ventriculitis. The arrow on the left points to diffuse leptomeningeal enhancement most conspicuous along the bilateral temporal lobes/insula, subarachnoid space of the basal cisterns and ventricular system. The arrow on the right points to additional proteinaceous material/pus within the subarachnoid space and dependently in the bilateral lateral ventricles.\n\nMagnetic resonance imaging of the abdomen demonstrated a complex multiloculated cystic space occupying lesion 6.3 × 4.6 cm with a small amount of surrounding edema and no intrahepatic or extrahepatic biliary dilatation (Figure 2). Percutaneous aspiration yielded 25 cc of thick, purulent fluid, which was positive for K pneumoniae; a catheter was placed into the hepatic abscess. Blood cultures were positive for K pneumoniae.\n\nFigure 2. Liver magnetic resonance imaging demonstrating a pyogenic liver abscess. The arrow points to a thick-walled cystic lesion 6.3 × 4.6 cm with small amount of surrounding edema (the image on the left is a T1 image and right is a T2 image). There is no intrahepatic or extrahepatic biliary dilatation, lymphadenopathy, or free fluid. Aspiration of the complex multiloculated lesion returned purulent material consistent with pyogenic hepatic abscess.\n\nShe was initially treated with meropenem and intrathecal gentamicin. She subsequently developed seizures. With concern of lowered seizure threshold from meropenem, this was changed to cefepime. Ciprofloxacin was added as she developed worsened mental status, and repeat central nervous system (CNS) imaging revealed increasing leptomeningeal enhancement and fluid within the occipital horns, consistent with worsening meningitis and ventriculitis. Her external ventricular devices repeatedly clogged and a total of 6 external ventricular drains were placed. Thirty days after admission, she developed diabetes insipidus, uncal herniation, and progressed to brain death.\n\nDiscussion\nKlebsiella pneumoniae is recognized as a common pathogen in both nosocomial and community-acquired infections. It is a classic cause of pneumonia, especially in alcoholic and diabetic patients. It is also well known to cause bacteremia and pyogenic liver abscess. To date, some 800 cases of K pneumoniae liver abscess have been reported from Eastern countries and Southeast Asia, but a substantially lower number have been reported in Europe, North America, and South America.1 Several case series in the United States have evaluated pyogenic liver abscess, with those involving K pneumoniae being reported to occur in 7% to 35%.4,5 A very small proportion (approximately 20 cases overall) of those reported in the United States appear to have been caused by the hypervirulent strain.6\nK pneumoniae infection has also become a major cause of community-acquired meningitis in Asia, and remarkably has been linked to pyogenic liver abscess.3 Particularly noteworthy are the points that invasive K pneumoniae syndrome is associated with primary hepatic abscess and systemic infection is associated with a high morbidity and mortality.\n\nThis hypervirulent strain of K pneumoniae was first reported in Taiwan starting in the mid-1980s, where patients without hepatobiliary disease presented with community-acquired hepatic abscess with a propensity for disseminated spread.1,3,6 This particular strain appears to be different from classic K pneumoniae strains, because it has a propensity for metastatic spread to unusual sites and because it often occurs in previously healthy hosts3; the metastatic spread and aggressive nature of the disease has led to the term “Invasive Klebsiella Syndrome.” It has been proposed that the syndrome is “definitive” in the presence of a K pneumoniae liver abscess with extrahepatic infection, including in the CNS, endophthalmitis, or necrotizing fasciitis.1 Our patient met the clinical criteria for the definitive invasive syndrome as evidenced by liver abscess and concomitant meningitis and ventriculitis.\n\nPatients with primary K pneumoniae liver abscess have been reported to develop metastatic infection at a rate of 8% to 24%,1,2 with the most common metastatic foci being meningitis or endophthalmitis1 in the invasive syndrome. In addition to meningitis, other CNS infections including brain abscess and subdural empyema have been described in the metastatic syndrome.3 Other sites of systemic infection include the lungs (septic pulmonary emboli or empyema), musculoskeletal system (osteomyelitis, muscle abscess, or necrotizing fasciitis),1 or the spleen (splenic abscess) or the peritoneum.3,7 High mortality has been noted in patients with meningitis, septic pulmonary emboli, or empyema.1,2\n\nThe most common clinical manifestations in patients with liver abscesses are fever, chills, abdominal pain, nausea, and vomiting.2 Interestingly, abdominal pain and gastrointestinal symptoms are not always present in patients with the invasive form of the disease.1 Importantly, several risk factors have been put forward for the invasive syndrome, including Asian descent and diabetes mellitus.1 The invasive syndrome has been reported to be prominently associated with diabetes mellitus.5 Additionally, typical laboratory findings include leukocytosis, thrombocytopenia, hyperglycemia, abnormal liver function tests, and elevated C-reactive protein. Our patient was of Asian descent and had impaired glucose tolerance without meeting diagnostic criteria for diabetes mellitus.\n\nPatients with the invasive syndrome have been found to have a hypermucoviscous K pneumoniae strain and also serotypes K1 or K2.1 This hypermucoviscous variant phenotype is identified by a positive “string test” in the laboratory. The positive “string test” is defined as an inoculation loop generating a viscous string greater than 5 mm in length when manipulating bacterial colonies on an agar plate.1,3 Our patient’s colonies were reported to exhibit a positive string test. It has been hypothesized that the hypermucoviscosity phenotype of the hypervirulent K pneumoniae strain may make catheter drainage difficult.3 In our patient, we hypothesize that the high viscosity of this organism likely explains the difficulty draining the hepatic abscess and the recurrent clogging of the external ventricular drains with need for repeated drain replacement.\n\nThe most effective antibiotic for treatment of K pneumoniae abscess includes the cephalosporins.1 Extended spectrum β-lactamase producing K pneumoniae are rare but can be treated with carbapenem therapy.1,2 The most appropriate duration of therapy ranges from a minimum of 2 to 4 weeks for solitary liver abscess to over 6 weeks for complicated (multiple) abscesses. In patients with diabetes mellitus, strict glycemic control appears to be important as this can prevent development of extrahepatic complications.1 Treatment of metastatic infection is typically guided by the site of foci involved.\n\nMorbidity and mortality from the invasive K pneumoniae syndrome are substantial, with mortality rates ranging from 3% to 42%.3\nK pneumoniae meningitis has a particularly high mortality, with rates from 38% to 91%.8 Thrombocytopenia has been associated with a 3-fold increased mortality rate over patients with normal platelet counts (37% vs 11%).5\n\nThe reason for the aggressive pathogenesis of the invasive K pneumoniae syndrome is unclear. Given the predilection for those of Asian descent, possibilities include genetically predisposed susceptibility or perhaps pathogen exposure based on geography. Studies have demonstrated that a substantial proportion of individuals of Asian descent are colonized with hypervirulent K pneumoniae strains, with the dominant site of colonization being the gastrointestinal tract.3 For example, studies of fecal carriers of K pneumoniae in healthy Chinese people have found a prevalence of K pneumoniae of 75% in healthy adults with high prevalence of the K1 or K2 serotype isolates (23%), which is considerably higher than prevalence in European fecal samples (10% to 19%).1 Thus, it is possible that colonization with the virulent K1 or K2 serotype may predispose to translocation of K pneumoniae in the setting of dysregulated gut barrier function from the gastrointestinal tract to the hepatic circulation.1,2,9\n\nIt is important for clinicians to be aware of the invasive Klebsiella syndrome, particularly with its increasing spread outside of Asia. Additionally, microbiologists should be aware that K pneumoniae with hypermucoviscous phenotype suggests an invasive K pneumoniae strain,1 which should prompt notification of clinicians to ensure appropriate screening for extrahepatic manifestations. Additionally, in any patient with K pneumoniae meningitis, endophthalmitis, or other extrahepatic infection (particularly in those of Asian descent or with uncontrolled diabetes mellitus), patients should be investigated for possible liver abscess. By recognizing the features of the invasive Klebsiella syndrome, rapid diagnosis and treatment may improve outcomes.\n\nConclusion\nThe invasive K pneumoniae syndrome is associated with significant morbidity and mortality. Atypical Klebsiella infections associated with this invasive syndrome include meningitis, endophthalmitis, and necrotizing fasciitis. Additionally, in patients with atypical Klebsiella infection, a high index of suspicion for the presence of pyogenic liver abscess is important. Although the disseminated K pneumoniae has been previously reported in the literature, our case demonstrates the importance of recognizing disseminated K pneumoniae infection as part of an invasive syndrome with unique extrahepatic manifestations. Finally, this disease causes significant morbidity and mortality and appears to be underappreciated by clinicians in Western nations. Indeed, early recognition of the disorder is vitally important.\n\nWe would like to thank our colleagues in the Department of Internal Medicine and the Division of Infectious Diseases for their insightful comments and discussions. We also wish to specifically thank Dr Arindam Chatterjee for help in creating high-resolution radiographic images from the institution’s electronic medical record.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Our institution does not require institution review board approval for anonymous case reports.\n\nInformed Consent: Verbal informed consent was obtained from the patient’s family.\n==== Refs\nReferences\n1 \nSiu LK Yeh KM Lin JC Fung CP Chang FY. \nKlebsiella pneumoniae liver abscess: a new invasive syndrome . Lancet Infect Dis . 2012 ;12 :881 -887 .23099082 \n2 \nSharara AI Rockey DC. \nPyogenic liver abscess . Curr Treat Options Gastroenterol . 2002 ;5 :437 -442 .12408780 \n3 \nShon AS Bajwa RP Russo TA. \nHypervirulent (hypermucoviscous) Klebsiella pneumoniae: a new and dangerous breed . Virulence . 2013 ;4 :107 -118 .23302790 \n4 \nPastagia M Arumugam V. \nKlebsiella pneumoniae liver abscesses in a public hospital in Queens, New York . Travel Med Infect Dis . 2008 ;6 :228 -233 .18571114 \n5 \nBraiteh F Golden MP. \nCryptogenic invasive Klebsiella pneumoniae liver abscess syndrome . Int J Infect Dis . 2007 ;11 :16 -22 .16473034 \n6 \nNadasy KA Domiati-Saad R Tribble MA. \nInvasive Klebsiella pneumoniae syndrome in North America . Clin Infect Dis . 2007 ;45 :e25 -e28 .17599300 \n7 \nLee HC Chuang YC Yu WL et al \nClinical implications of hypermucoviscosity phenotype in Klebsiella pneumoniae isolates: association with invasive syndrome in patients with community-acquired bacteraemia . J Intern Med . 2006 ;259 :606 -614 .16704562 \n8 \nTang LM Chen ST Hsu WC Chen CM. \nKlebsiella meningitis in Taiwan: an overview . Epidemiol Infect . 1997 ;119 :135 -142 .9363011 \n9 \nLin JC Chang FY Fung CP et al \nHigh prevalence of phagocytic-resistant capsular serotypes of Klebsiella pneumoniae in liver abscess . Microbes Infect . 2004 ;6 :1191 -1198 .15488738\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2324-7096",
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"journal": "Journal of investigative medicine high impact case reports",
"keywords": "abscess; diabetes mellitus; meningitis; sepsis; ventriculitis",
"medline_ta": "J Investig Med High Impact Case Rep",
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"pubdate": "2018",
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"title": "Identification and Management of the Hypervirulent Invasive Klebsiella pneumoniae Syndrome: A Unique and Distinct Clinical Entity.",
"title_normalized": "identification and management of the hypervirulent invasive klebsiella pneumoniae syndrome a unique and distinct clinical entity"
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"abstract": "This case report presents a 44-year-old man with a history of schizophrenia who developed neutropenia on risperidone therapy. The patient's laboratory reports showed a gradual decline of leukocytes and neutrophils after resolution and rechallenging. This was reversed with the discontinuation of risperidone and by switching to olanzapine. In this case report, we also discuss the updated evidence base for management of risperidone-induced neutropenia.",
"affiliations": "College of Medicine, University of Illinois, Chicago, IL, USA.;Mount Sinai Beth Israel Medical Center, New York, NY, USA.;Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.;Harlem Hospital Center, New York, NY, USA.;Department of Psychiatry & Behavioral Sciences, The University of Texas McGovern Medical School, Houston, TX, USA.",
"authors": "Kattalai Kailasam|Vasanth|V|;Chima|Victoria|V|;Nnamdi|Uchechukwu|U|;Sharma|Kavita|K|;Shah|Kairav|K|",
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"fulltext": "\n==== Front\nNeuropsychiatr Dis TreatNeuropsychiatr Dis TreatNeuropsychiatric Disease and TreatmentNeuropsychiatric Disease and Treatment1176-63281178-2021Dove Medical Press 10.2147/NDT.S141472ndt-13-1975Case ReportRisperidone-induced reversible neutropenia Kattalai Kailasam Vasanth 1Chima Victoria 2*Nnamdi Uchechukwu 3*Sharma Kavita 4*Shah Kairav 5\n1 College of Medicine, University of Illinois, Chicago, IL, USA\n2 Mount Sinai Beth Israel Medical Center, New York, NY, USA\n3 Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA\n4 Harlem Hospital Center, New York, NY, USA\n5 Department of Psychiatry & Behavioral Sciences, The University of Texas McGovern Medical School, Houston, TX, USACorrespondence: Kairav Shah, Department of Psychiatry & Behavioral Sciences, The University of Texas McGovern Medical School 1941 East Road, Houston, TX 77054, USA, Email kairav2305@gmail.com* These authors contributed equally to this work\n\n2017 25 7 2017 13 1975 1977 © 2017 Kattalai Kailasam et al. This work is published and licensed by Dove Medical Press Limited2017The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.This case report presents a 44-year-old man with a history of schizophrenia who developed neutropenia on risperidone therapy. The patient’s laboratory reports showed a gradual decline of leukocytes and neutrophils after resolution and rechallenging. This was reversed with the discontinuation of risperidone and by switching to olanzapine. In this case report, we also discuss the updated evidence base for management of risperidone-induced neutropenia.\n\nKeywords\nrisperidoneantipsychoticsneutropeniablood dyscrasias\n==== Body\nIntroduction\nHematologic abnormalities are frequent and may be life-threatening complications of antipsychotics.1 Neutropenia, defined as a consistently low absolute neutrophil count (ANC; <1,500/uL), can be due to reduced production or increased peripheral destruction.2 There is a class warning stating that antipsychotics may cause blood dyscrasias, which include leukopenia, neutropenia, and agranulocytosis. Neutropenia is a rare side effect of risperidone. Clozapine requires regular monitoring of white blood cells (WBCs)/ANC with computed based registry. Risperidone, olanzapine, and other antipsychotics do not have the same monitoring regulatory process as clozapine. We report a case of leukopenia and neutropenia occurring during treatment with risperidone, reversible with discontinuation of the medication, reoccurrence during rechallenge, and resolution after switching to olanzapine.\n\nCase\nA 44-year-old Hispanic man was admitted to our Comprehensive Psychiatric Emergency Program (CPEP) with complaints of auditory hallucinations and suicidal ideation. The patient had a history of schizophrenia, multiple suicide attempts and self-injurious behavior, alcohol use disorder, and cocaine use disorder. His medical history was significant for Hepatitis B and bronchial asthma. He reported taking risperidone for schizophrenia for 10 days, but compliance was questionable. He reported auditory hallucinations, depressed mood, hopelessness, helplessness, and both poor sleep and appetite. No abnormalities were detected in baseline laboratory values. WBC count was 5,600/μL, ANC 3,600/μL, lymphocytes 1,200/μL, monocytes 700/μL, eosinophils 0.0/μL, and basophils 0.0/μL. Urine toxicology was positive for cocaine. Patient was started on risperidone 1 mg po twice daily for psychosis and escitalopram 20 mg daily for depression. On the second day, routine laboratory tests showed a decrease in both his WBCs and ANC. WBCs decreased to 3,800/μL and neutrophils to 0.0/μL; lymphocytes were 700/μL, monocytes 90/μL, eosinophils 10/μL, and basophils 0.0/μL. The following day, the values of WBC continued to drop up to 1,100/μL, and neutrophils to 0.0/μL, lymphocytes were 220/μL, monocytes 400/μL, eosinophils 0.0/μL, and basophils 0.0/μL. The patient spiked a fever on his third day in CPEP. The patient was transferred to the Internal Medicine ward for further management. Imaging studies and culture reports were not suggestive of any infective foci. Meanwhile, the patient was receiving risperidone 1 mg po twice daily on the Internal Medicine ward. Both Infectious Disease and Hematology/Oncology consultation teams gave an impression of medication-induced neutropenic fever and suggested discontinuation of risperidone. After discontinuation of risperidone, neutrophil count improved. On the 7th day after discontinuing risperidone, the count reached the baseline value. WBCs increased to 5,200/μL and neutrophils to 1,800/μL (35.2%). The patient was unwilling to be switched to another antipsychotic medication and left the hospital against medical advice. He presented to CPEP again after one month, with suicidal ideation and noncompliance with medication. He was rechallenged with risperidone because of patient preference. His WBC count dropped from a baseline value of 4,500 μL to 2,100 μL and neutrophils – 2,300 μL to 1,200 μL within 7 days. He was then switched from risperidone to olanzapine 10 mg po daily. It was tolerated well, and his WBC and neutrophil count gradually increased; WBC – 2,400 μL and neutrophils – 300 μL after 7 days. The patient was not experiencing any psychotic symptoms at this time. His depressive symptoms improved, and so he was discharged home. The patient scored 7 on the Naranjo Adverse Drug Reaction Probability Scale,3 ie, a probable causation by risperidone.\n\nThe patient gave written informed consent for all administered drugs and for the publication of his case.\n\nDiscussion\nA literature search was done on PubMed database for available evidence on management of risperidone-induced leukopenia and neutropenia. Review was limited to articles focusing on leukopenia, neutropenia, agranulocytosis, bicytopenia, and underlying pathophysiological mechanisms. The authors manually searched the reference lists of identified papers and other publications by their authors to ensure all articles meeting the criteria were identified. Case reports, case series, and review articles were assessed.\n\nThere is anecdotal evidence of leukopenia or neutropenia from risperidone, but there is no evidence-based recommendation for alternate antipsychotic medications.4–15 In one case, olanzapine appeared to be hematologically safe in patients who developed blood dyscrasias on clozapine and risperidone. The authors reported a case of a patient with treatment-resistant schizophrenia, who had previously developed leucopenia and neutropenia first on clozapine and subsequently on risperidone. However, when switched to olanzapine, leukocyte and neutrophil began to return to baseline counts. He was thus maintained on it for more than 2 years.9\n\nIn our case, the patient had been taking risperidone on and off for more than 2 years. His hematological parameters were at baseline during admission in our facility. Restarting risperidone at the lowest recommended dose caused a decline in WBCs and ANC levels. Rechallenging after discontinuation, because of patient preference in the hospital setting, decreased WBCs and ANC. There was subsequent resolution with discontinuation of risperidone and initiation of olanzapine. The patient had no history of HIV/AIDS or any other immunocompromised state, and this was confirmed by Infectious Disease and Hematology teams. He was supported with intravenous antibiotics and recombinant human granulocyte-colony stimulating factor during the inpatient stay for neutropenic fever. Our case adds to the available evidence that leukopenia/neutropenia induced by risperidone and olanzapine could be due to different pathophysiological mechanisms.\n\nCurrently, there is not enough evidence to identify a tangible mechanism of action of risperidone’s effect on different blood cells. Existing studies have proposed different mechanisms in different antipsychotics. For example, a recent study by Chen et al16 showed that risperidone, but not haloperidol, has been shown to affect the immune functions of mature Dendritic Cells. Risperidone-treated mature dendritic cell has been shown to produce TNF-α, which has the potential to cause death of neutrophils. No studies are available at this time comparing risperidone with olanzapine dendritic cell. Nooijen et al17 attributed toxicity of clozapine to the direct toxic effect of the drug on bone marrow or increased peripheral destruction. Husain et al18 proposed oxidative stress-induced apoptotic changes in granulocytes as a possible mechanism of drug toxicity in patients with clozapine, while Konakanchi et al19 postulated that olanzapine being structurally similar to clozapine gives rise to an intermediate toxic metabolite, nitrenium ion, which irreversibly binds to the calls, causing neutropenia.\n\nToxic metabolites were proposed for risperidone-induced blood dyscrasias, similar to olanzapine and clozapine, but the mechanism appears to be different from olanzapine and is as yet unclear. Effects of lactational exposure of olanzapine and risperidone on the hematology of mice neonates have shown distinct abnormalities in both medications. Bone marrow differential leukocyte count also revealed a dose-dependent decrease of the neutrophil percentage on olanzapine exposure, but not in the risperidone-exposed group.20\n\nConclusion\nBased on the above evidence, olanzapine seems to be safe in risperidone-induced reversible leukopenia/neutropenia. As highlighted in our case, risperidone-induced neutropenia could occur during restarting the medication even at a lower dose. For these reasons, we suggest careful monitoring of WBC count in patients on risperidone. We recommend continued research in this domain for evidence-based management of antipsychotic-induced blood dyscrasias.\n\nDisclosure\n\nThe authors report no conflicts of interests in this work.\n==== Refs\nReferences\n1 Manfredi G Solfanelli A Dimitri G Risperidone-induced leukopenia: a case report and brief review of literature Gen Hosp Psychiatry 2013 35 1 102.e3 102.e6 \n2 Oyesanmi O Kunkel EJ Monti DA Field HL Hematologic side effects of psychotropics Psychosomatics 1999 40 5 414 421 10479946 \n3 Naranjo CA Busto U Sellers EM A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 2 239 245 7249508 \n4 Shah K Rizvi M Bicytopenia: adverse effect of risperidone Current Psychiatry 2014 13 4 E1 \n5 Meylan C Bondolfi G Aubert AC Baumann P Reversible neutropenia during a cold: possible involvement of risperidone? A case report Eur Neuropsychopharmacol 1995 5 1 1 2 \n6 Bondolfi G Morena P Dascal DR Bertschy G Risperidone and reversible neutropenia: a negative rechallenge Eur Neuropsychopharmacol 1996 6 3 257 8880087 \n7 Godleski LS Sernyak MJ Agranulocytosis after addition of risperidone to clozapine treatment Am J Psychiatry 1996 153 5 735 736 \n8 Dernovsek Z Tavcar R Risperidone-induced leucopenia and neutropenia Br J Psychiatry 1997 171 393 394 \n9 Dernovsek MZ Tavcar R Olanzapine appears haematologically safe in patients who developed blood dyscrasia on clozapine and risperidone Int Clin Psychopharmacol 2000 15 4 237 238 10954065 \n10 Finkel B Lerner AG Oyffe I Sigal M Risperidone-associated agranulocytosis Am J Psychiatry 1998 155 6 855 856 \n11 Etain B Roubaud L Le Heuzey MF Mouren Simeoni MC Un cas de leucopénie sous traitement par rispéridone chez un adolescent [A case of leukopenia in treatment with risperidone in an adolescent] Encéphale 2000 26 5 81 84 French \n12 Biswas A Mittal P Chaturvedi S Prasad A Risperidone induced cytopenias J Assoc Physicians India 2000 48 11 1122 1123 11310398 \n13 Sluys M Güzelcan Y Casteelen G de Haan L Risperidone-induced leucopenia and neutropenia: a case report Eur Psychiatry 2004 19 2 117 15051112 \n14 López Altimiras FX Muñoz Rodríguez FJ Escoté Llobet S Leucopenia asociada al uso de risperidona: presentación de un caso y revisión de la literatura [Leukopenia associated with the use of risperidone: a case report and review of the literature] Rev Clin Esp 2006 206 3 162 163 Spanish 16597389 \n15 Uzun S Kozumplik O Jakovljević M Folnegović-Smalc V Leukopenia during therapy with risperidone long-acting injectable: two case reports J Clin Psychopharmacol 2008 28 6 713 714 19011449 \n16 Chen ML Tsai TC Wang LK Risperidone modulates the cytokine and chemokine release of dendritic cells and induces TNF-α-directed cell apoptosis in neutrophils Int Immunopharmacol 2012 12 1 197 204 22154580 \n17 Nooijen PM Carvalho F Flanagan RJ Haematological toxicity of clozapine and some other drugs used in psychiatry Hum Psychopharmacol 2011 26 2 112 119 21416507 \n18 Husain Z Almeciga I Delgado JC Increased FasL expression correlates with apoptotic changes in granulocytes cultured with oxidized clozapine Toxicol Appl Pharmacol 2006 214 3 326 334 16510162 \n19 Konakanchi R Grace JJ Szarowicz R Olanzapine prolongation of granulocytopenia after clozapine discontinuation J Clin Psychopharmacol 2000 20 6 703 704 11106146 \n20 Mishra AC Mohanty B Effects of lactational exposure of olanzapine and risperidone on hematology and lymphoid organs histopathology: a comparative study in mice neonates Eur J Pharmacol 2010 634 1–3 170 177 20176014\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1176-6328",
"issue": "13()",
"journal": "Neuropsychiatric disease and treatment",
"keywords": "antipsychotics; blood dyscrasias; neutropenia; risperidone",
"medline_ta": "Neuropsychiatr Dis Treat",
"mesh_terms": null,
"nlm_unique_id": "101240304",
"other_id": null,
"pages": "1975-1977",
"pmc": null,
"pmid": "28794632",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "22520716;11192809;15051112;11106146;16510162;9373440;9619165;8615431;21416507;19011449;11310398;7249508;7542050;10479946;10954065;8880087;22154580;20176014;16597389",
"title": "Risperidone-induced reversible neutropenia.",
"title_normalized": "risperidone induced reversible neutropenia"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/17/0092713",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": "1",
... |
{
"abstract": "The combinations of melphalan, bortezomib, and prednisolone (VMP) and of lenalidomide and dexamethasone (Rd) are standard treatment strategies for transplant-ineligible newly diagnosed multiple myeloma (NDMM). To make the most of these two strategies, we investigated the efficacy and feasibility of first-line treatment with 4 cycles of VMP followed by continuous Rd therapy in a multi-institutional phase 2 study in Japanese patients with transplant-ineligible NDMM. Thirty-six patients of median age 74 years old with NDMM initially received 35-day cycles of VMP: oral melphalan (6 mg/m2) and prednisolone (60 mg/m2) on days 1 to 4 and bortezomib (1.3 mg/m2) on days 1, 8, 15, and 22. After 4 cycles of VMP, treatment was switched to 28-day cycles of Rd, which was continued until disease progression or emergence of an unacceptable adverse event (AE) in 33 patients, while one patient who achieved CR after VMP continued VMP at the physician's discretion. The overall response rates after VMP and after Rd were 66.7% and 86.1%, including CR rates of 5.6% and 36.1%, respectively. In a median follow-up period of 34.3 months, the progression-free survival and overall survival rates at 3 years were 43.2% and 81.3%, respectively. Grade 3-4 hematological AEs included neutropenia (39% with VMP and 24% with Rd) and thrombocytopenia (11% with VMP and 3% with Rd). There was no death due to an AE. In conclusion, sequential therapy with VMP followed by Rd is effective and mostly feasible for transplant-ineligible NDMM. The study is registered as UMIN000034815.",
"affiliations": "Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Hematology, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan.;Department of Hematology, Omihachiman Community Medical Center, Omihachiman, Japan.;Department of Hematology, Omihachiman Community Medical Center, Omihachiman, Japan.;Department of Hematology, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan.;Department of Hematology, Aiseikai Yamashina Hospital, Kyoto, Japan.;Department of Hematology, Aiseikai Yamashina Hospital, Kyoto, Japan.;Department of Hematology, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan.;Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Hematology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan.;Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Hematology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan.;Department of Hematology, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan.;Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan. junkuro@koto.kpu-m.ac.jp.",
"authors": "Isa|Reiko|R|;Uoshima|Nobuhiko|N|;Takahashi|Ryoichi|R|;Nakano-Akamatsu|Sonoko|S|;Kawata|Eri|E|;Kaneko|Hiroto|H|;Shimura|Kazuho|K|;Kamitsuji|Yuri|Y|;Takimoto-Shimomura|Tomoko|T|;Mizutani|Shinsuke|S|;Chinen|Yoshiaki|Y|;Ohshiro|Muneo|M|;Fujino|Takahiro|T|;Kawaji|Yuka|Y|;Uchiyama|Hitoji|H|;Sasaki|Nana|N|;Tsukamoto|Taku|T|;Shimura|Yuji|Y|;Kobayashi|Tsutomu|T|;Taniwaki|Masafumi|M|;Kuroda|Junya|J|http://orcid.org/0000-0001-6130-1550;|||",
"chemical_list": "D000069286:Bortezomib; D003907:Dexamethasone; D011239:Prednisolone; D000077269:Lenalidomide; D008558:Melphalan",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-019-03859-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "99(1)",
"journal": "Annals of hematology",
"keywords": "Bortezomib; Lenalidomide; Multiple myeloma; Transplant-ineligible",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069286:Bortezomib; D003907:Dexamethasone; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008558:Melphalan; D009101:Multiple Myeloma; D011239:Prednisolone; D015996:Survival Rate",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "137-145",
"pmc": null,
"pmid": "31768675",
"pubdate": "2020-01",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Sequential therapy of four cycles of bortezomib, melphalan, and prednisolone followed by continuous lenalidomide and dexamethasone for transplant-ineligible newly diagnosed multiple myeloma.",
"title_normalized": "sequential therapy of four cycles of bortezomib melphalan and prednisolone followed by continuous lenalidomide and dexamethasone for transplant ineligible newly diagnosed multiple myeloma"
} | [
{
"companynumb": "JP-TAKEDA-2020TUS004673",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe aim of this study was to clarify the effectiveness and safety of sofosbuvir/ribavirin therapy for elderly patients with genotype 2-infected chronic hepatitis C (CHC) in Japan.\n\n\nMETHODS\nA multicenter, retrospective study evaluated the effectiveness and safety of sofosbuvir/ribavirin based on real-world clinical data.\n\n\nRESULTS\nThe subjects consisted of 270 patients, 47.0% of whom were aged ≥65 years. The sustained virological response rates in patients aged <65 and ≥65 years were 98.6% and 95.3%, respectively. Hemoglobin levels decreased during treatment due to ribavirin-related hemolysis, and were significantly lower in patients aged ≥65 years than those aged <65 years at all time-points. A reduction in ribavirin dose was necessary in 31.0% (26/84) of patients with hemoglobin levels <13.0g/dL and in 70.7% (39/127) of those aged >65 years. Although the most frequent adverse event was anemia, no patients discontinued the use of either ribavirin or sofosbuvir. The incidence of ribavirin-related anemia in patients aged ≥65 years was 34.6% and significantly higher compared with that in patients aged <65 years (2.8%).\n\n\nCONCLUSIONS\nTreatment with sofosbuvir/ribavirin for genotype 2-infected CHC was effective and safe even for elderly patients, although the incidence of adverse events including ribavirin-related anemia was relatively high.",
"affiliations": "Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Chiba, Japan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan. Electronic address: momogachi@yahoo.co.jp.;Core Research Facilities for Basic Science, Research Center for Medical Sciences, Jikei University School of Medicine, Tokyo, Japan.;Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Chiba, Japan.;Division of Gastroenterology and Hepatology, Otakanomori Hospital, Kashiwa, Chiba, Japan.;Department of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Matsudo, Chiba, Japan.;Department of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Matsudo, Chiba, Japan.;Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Chiba, Japan.;Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Chiba, Japan.;Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Chiba, Japan.;Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.;Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.",
"authors": "Atsukawa|Masanori|M|;Tsubota|Akihito|A|;Kondo|Chisa|C|;Shimada|Noritomo|N|;Abe|Hiroshi|H|;Kato|Keizo|K|;Okubo|Tomomi|T|;Arai|Taeang|T|;Itokawa|Norio|N|;Iio|Etsuko|E|;Tanaka|Yasuhito|Y|;Iwakiri|Katsuhiko|K|",
"chemical_list": "D000998:Antiviral Agents; D012367:RNA, Viral; D012254:Ribavirin; D000069474:Sofosbuvir",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.dld.2017.04.012",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1590-8658",
"issue": "49(9)",
"journal": "Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver",
"keywords": "Chronic hepatitis; Elderly; Ribavirin; Sofosbuvir",
"medline_ta": "Dig Liver Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D007564:Japan; D008103:Liver Cirrhosis; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral; D012189:Retrospective Studies; D012254:Ribavirin; D000069474:Sofosbuvir; D000072230:Sustained Virologic Response",
"nlm_unique_id": "100958385",
"other_id": null,
"pages": "1029-1035",
"pmc": null,
"pmid": "28499694",
"pubdate": "2017-09",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Effectiveness and safety of community-based treatment with sofosbuvir plus ribavirin for elderly patients with genotype 2 chronic hepatitis C.",
"title_normalized": "effectiveness and safety of community based treatment with sofosbuvir plus ribavirin for elderly patients with genotype 2 chronic hepatitis c"
} | [
{
"companynumb": "JP-GILEAD-2017-0291358",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": null,
... |
{
"abstract": "Human herpesvirus-8 (HHV8) is a recognised precursor for a number of neoplastic and non-neoplastic processes. Immunosuppressed recipients of both solid organ and haematopoietic stem cell transplants are at risk of life-threatening lytic reactivations of HHV8-infected B-lymphocytes, primary infections after receiving grafts from HHV8-seropositive donors and more rarely by the direct transplantation of malignant Kaposi sarcoma cells seeded within graft tissue. We describe the case of an HHV8-seronegative patient with confirmed, post-orthotopic liver transplant transmission of HHV8 from a seropositive donor with quantitative evidence of viraemia and subsequent development of disseminated visceral and cutaneous Kaposi sarcoma with a rapidly fatal outcome.",
"affiliations": "Regional Liver Unit, Belfast Health and Social Care Trust, Belfast, UK mcopeland03@qub.ac.uk.;Institute of Pathology, Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast, UK.;Regional Liver Unit, Belfast Health and Social Care Trust, Belfast, UK.;Regional Liver Unit, Belfast Health and Social Care Trust, Belfast, UK.",
"authors": "Copeland|Matthew Moore McCrea|MMM|;Trainor|James|J|;Cash|W Johnny|WJ|;Braniff|Conor|C|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-236061",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(6)",
"journal": "BMJ case reports",
"keywords": "gastroenterology; infectious diseases; liver disease; malignant disease and immunosuppression; transplantation",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D006566:Herpesviridae Infections; D019288:Herpesvirus 8, Human; D006801:Humans; D016031:Liver Transplantation; D012514:Sarcoma, Kaposi; D014019:Tissue Donors; D014766:Viremia",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34158319",
"pubdate": "2021-06-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal donor-derived Kaposi sarcoma following liver transplantation.",
"title_normalized": "fatal donor derived kaposi sarcoma following liver transplantation"
} | [
{
"companynumb": "GB-BAUSCH-BL-2021-042246",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe study aims to assess the clinical evidence, outcome and cost of off-label use of medicines in the hospital setting.\n\n\nMETHODS\nA multicentric prospective cohort study of patients treated with off-label medicines was carried out in five tertiary hospitals from May 2011 to May 2012. Information on clinical characteristics of patients, drugs, outcomes and costs was collected. Patients were followed up to 6 months, and information was assessed by reviewing clinical records and interviewing physicians.\n\n\nRESULTS\nA total of 226 patients were included. The median (interquartile range (IQR)) age of patients was 46 (33-62) years; 59 % were women. Patients had received a median of three previous treatments, and a lack of response (or suboptimal) was the main reason for off-label use (72.1 %). A total of 232 off-label medicines were administered for 102 different indications. The most frequent medicines were rituximab (49; 21.1 %), botulinum toxin (25; 10.7 %) and omalizumab (14; 6.0 %). In 117 (51.8 %) cases, the level of clinical evidence for their use was low. A partial clinical response was observed in 82 patients (36.3 %), complete response in 71 (31.4 %) and stabilization in 11 (4.9 %). A total of 58 (26.5 %) patients had adverse effects, which in 11 (4.9 %) were severe. The median (IQR) cost per patient was <euro>2,943.07 (541.9-5,872.54).\n\n\nCONCLUSIONS\nThere was a high variability of off-label medicines and indications. Although the clinical evidence of off-label medicines was often low, clinical response was observed in many patients with previous multiple treatment failure, but at the expense of some adverse effects and a high cost. Registers of patients would be helpful for clinical decisions, although clinical trials are needed.",
"affiliations": "Clinical Pharmacology Service, Fundació Institut Català de Farmacologia. Hospital Universitari Vall d'Hebron, Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron, 119-129, Barcelona, Spain, idanes.ficf@gmail.com.",
"authors": "Danés|I|I|;Agustí|A|A|;Vallano|A|A|;Alerany|C|C|;Martínez|J|J|;Bosch|J A|JA|;Ferrer|A|A|;Gratacós|L|L|;Pérez|A|A|;Olmo|M|M|;Marron|S M Cano|SM|;Valderrama|A|A|;Bonafont|X|X|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00228-014-1746-2",
"fulltext": "\n==== Front\nEur J Clin Pharmacol\nEur. J. Clin. Pharmacol\nEuropean Journal of Clinical Pharmacology\n0031-6970\n1432-1041\nSpringer Berlin Heidelberg Berlin/Heidelberg\n\n1746\n10.1007/s00228-014-1746-2\nPharmacoepidemiology and Prescription\nOutcomes of off-label drug uses in hospitals: a multicentric prospective study\nDanés I. 34.93.428.30.29 idanes.ficf@gmail.com\n\nAgustí A.\nVallano A.\nAlerany C.\nMartínez J.\nBosch J. A.\nFerrer A.\nGratacós L.\nPérez A.\nOlmo M.\nMarron S. M. Cano\nValderrama A.\nBonafont X.\nClinical Pharmacology Service, Fundació Institut Català de Farmacologia. Hospital Universitari Vall d’Hebron, Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Passeig Vall d’Hebron, 119-129 Barcelona, Spain\nClinical Pharmacology Service, Hospital Universitari de Bellvitge, IDIBELL, Department of Pathology and Experimental Therapeutics, Universitat de Barcelona, Hospitalet de Llobregat, Barcelona, Spain\nPharmacy Service, Hospital Universitari Vall d’Hebron, Barcelona, Spain\nMedical Direction, Department of Internal Medicine, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain\nPharmacy Service, Hospital Universitari de Bellvitge, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain\nPharmacy Service, Hospital Universitari Josep Trueta, Girona, Spain\nPharmacy Service, Hospital Universitari Arnau de Vilanova, Lleida, Spain\nClinical Pharmacology Service, Hospital Universitari Germans Trias i Pujol, Badalona, Spain\nPharmacy Service, Hospital Universitari Germans Trias i Pujol, Badalona, Spain\n9 9 2014\n9 9 2014\n2014\n70 11 13851393\n11 6 2014\n26 8 2014\n© The Author(s) 2014\nOpen Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.\nPurpose\n\nThe study aims to assess the clinical evidence, outcome and cost of off-label use of medicines in the hospital setting.\n\nMethods\n\nA multicentric prospective cohort study of patients treated with off-label medicines was carried out in five tertiary hospitals from May 2011 to May 2012. Information on clinical characteristics of patients, drugs, outcomes and costs was collected. Patients were followed up to 6 months, and information was assessed by reviewing clinical records and interviewing physicians.\n\nResults\n\nA total of 226 patients were included. The median (interquartile range (IQR)) age of patients was 46 (33–62) years; 59 % were women. Patients had received a median of three previous treatments, and a lack of response (or suboptimal) was the main reason for off-label use (72.1 %). A total of 232 off-label medicines were administered for 102 different indications. The most frequent medicines were rituximab (49; 21.1 %), botulinum toxin (25; 10.7 %) and omalizumab (14; 6.0 %). In 117 (51.8 %) cases, the level of clinical evidence for their use was low. A partial clinical response was observed in 82 patients (36.3 %), complete response in 71 (31.4 %) and stabilization in 11 (4.9 %). A total of 58 (26.5 %) patients had adverse effects, which in 11 (4.9 %) were severe. The median (IQR) cost per patient was €2,943.07 (541.9–5,872.54).\n\nConclusions\n\nThere was a high variability of off-label medicines and indications. Although the clinical evidence of off-label medicines was often low, clinical response was observed in many patients with previous multiple treatment failure, but at the expense of some adverse effects and a high cost. Registers of patients would be helpful for clinical decisions, although clinical trials are needed.\n\nElectronic supplementary material\n\nThe online version of this article (doi:10.1007/s00228-014-1746-2) contains supplementary material, which is available to authorized users.\n\nKeywords\n\nOff-label use\nDrug therapy\nEfficiency\nRituximab\nOmalizumab\nBotulinum toxin\nPharmacy and therapeutics committees\nissue-copyright-statement© Springer-Verlag Berlin Heidelberg 2014\n==== Body\nIntroduction\n\nOff-label medicine use includes the prescription of a medicine for an indication, a route of administration or a patient group that is not approved in the summary product characteristics [1]. The off-label use of medicines is a common and widespread clinical practice worldwide [2, 3]. However, the use of medicines outside the approved clinical indications may lead to several problems. Evidence on the use of these medicines in unapproved indications is often scarce, and doctors have little information on how to use them. In addition, off-label use of medicines can cause adverse effects and the risk may outweigh the potential benefits. Furthermore, ethical and legal issues related to the commercial promotion of off-label use of these medications have also been raised [4–6].\n\nSince 2009, a new Spanish legislation regulates and classifies the availability of drug use in special situations: the use of medicines in unapproved conditions, the compassionate use of investigational medicines and the use of medicines not marketed in the country [7]. Currently, only a doctor’s report to justify the use of the off-label medicines and the patient’s informed consent are required. Nevertheless, the widespread use of these drugs may often increase spending on drugs, especially in the hospital setting. In order to avoid unwarranted risks and cost of drugs with limited data on their efficacy, the Catalan Health Service has put internal procedures in place [8]. This regulation states that the drug and therapeutics committees of each hospital needs to perform an evaluation of all cases of drug use in special situations, and the medical director of each hospital must give individual authorisation for each patient.\n\nSeveral studies have evaluated the use of off-label medicines, but they have often focused on specific groups of drugs or medicines, such as anticancer drugs [9–11] or rituximab [12, 13], or on specific populations, such as children [14–17]. However, very few studies have evaluated the clinical outcomes of off-label medicines in terms of effectiveness and safety as well as the associated costs [12, 18, 19]. The aim of our study was to assess the clinical and economic outcomes and the clinical evidence for off-label use of medicines in the hospital setting.\n\nMethods\n\nA prospective longitudinal study of patients treated with off-label drugs was carried out in five public hospitals belonging to the Catalan Institute of Health for a period of 1 year (from 19th May 2011 to 19th May 2012). Requests for drugs use in special situations, taking into account the current Spanish legislation, received in the pharmacy services of the hospitals during the study period were identified. All requests for off-label uses were included, and those for compassionate use of investigational drugs and for unauthorized drugs in Spain (if requested for conditions approved in other countries) were excluded. In addition, those for off-label drug use that were not authorized by hospital medical directors, those for which patient informed consent was not obtained or those in whom medicines were not finally administered, were also excluded. A prospective review of the application forms of off-label drug use and the patients’ electronic medical records was conducted to obtain information on patients’ demographic characteristics, morbidity (clinical, biological and other complementary explorations), previous and concurrent drug uses for the target disease, the requested drug and dosages, the clinical indications and the reasons for the requested off-label drug use, and the clinical outcomes (effectiveness and adverse drug effects). Patients were followed for a period of 6 months after starting off-label drug treatment (or until the end of treatment in cases of an acute disease), and the clinical outcomes were assessed by reviewing electronic clinical records and interviewing physicians responsible for the patient’s care.\n\nDrugs were classified according to the ATC classification, and The International Classification of Diseases, ninth edition (ICD-9), was used to classify medical indication for off-label drug use. Off-label drug use condition was rated as an unapproved indication, unapproved condition (population, route or other) or both. The reasons for requesting the off-label drug use were categorized as the following: lack of clinical response to previous treatments (or suboptimal), intolerance or contraindications to the alternatives or other reasons such as unavailability of approved drugs for that indication/condition or preferred in that patient to the alternatives due to clinical or logistical reasons.\n\nA review of published evidence for every drug use in each clinical indication was performed searching for information on the PubMed database. In addition, a search looking at ongoing clinical trials for every drug use in each clinical indication was conducted in clinicaltrials.gov register [20]. The Oxford Centre for Evidence Based Medicine criteria was used to classify the available evidence found for each requested drug in each indication [21]. The level of evidence was pooled into two categories: the high level category that included the 1a to 2c categories (mainly randomized clinical trials or cohort studies) and the low level that included the 3 to 5 categories (mainly case-control studies, series of cases, cases and expert opinions).\n\nThe clinical responses to off-label use of drugs were classified as complete response (CR), partial response (PR), stabilization (S) and no response (NR) taking into account different parameters of efficacy for each disease. For example, the criteria used in the more common diseases are specified. For botulinum toxin in anal fissure, the healing of the lesion was considered CR and its persistence without symptoms was considered PR. In patients with esophageal achalasia, clinical criteria were also used: CR if the patients were able to eat without dysphagia and PR if they felt some improvement. CR to omalizumab in chronic urticaria was considered if corticosteroids could be withdrawn and the patient was asymptomatic or had minimal symptoms; other minor improvements were classified as PR. To assess the response to rituximab in patients with organ transplant rejection, anatomopathological criteria were used, and in pemphigus and myasthenia, clinical criteria were used (resolution was considered CR, and improvement PR). In patients with systemic lupus erythematosus, the symptoms and scores of disease activity were taken into account [CR, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) of ≤4 or clinical remission; PR, improvement of ≥50 % in SLEDAI]. For human-unspecific immunoglobulins in immune encephalitis, clinical criteria (resolution or improvement) were considered.\n\nAdverse drug events were assessed by clinical pharmacologists and/or pharmacists trained in using the methods and the algorithm of the Spanish Pharmacovigilance System.\n\nThe actual sale price of medicines paid by participant hospitals was taken into account in the analysis of the cost of treatments. The total cost per patient was calculated according to the duration of treatment up to a maximum of 6 months.\n\nThe study was conducted in accordance with the international ethics recommendations and according to the Spanish post-authorization studies legislation. The study protocol was approved by the ethics committees of clinical investigation in each participating hospital.\n\nStatistical analysis of categorical and continuous variables was made by means of the distribution of frequencies, proportions, means, standard deviation (SD) and median and interquartile range (IQR). Statistical differences were evaluated using the chi-square test and Student’s t test. Significance was set at a level of 0.05 and was two-tailed. The statistical analysis was performed using IBM SPSS Statistics version 20 statistical package (IBM corp., NY, USA).\n\nResults\n\nA total of 398 requests for treating the corresponding patients were received, and 226 were included in the study (each participating hospital contributed with 85 (37.6 %), 56 (24.8 %), 42 (18.6 %), 28 (12.4 %) and 15 (6.6 %) cases, respectively). The reasons for the exclusions are shown in Fig. 1. The characteristics of patients treated are shown in Table 1. The median age (IQR) of treated patients was 46 (33–62) years and 59 % were women. The patients involved had received on average three previous treatments for the target diseases, and in 163 cases (72.1 %), lack of response to previous treatments (or suboptimal) was the main reason for requesting the off-label drug use. In 90.3 % of cases, the requested off-label drugs were for an unapproved indication. Clinical services that most frequently requested off-label drug use were gastroenterology, internal medicine and neurology.Fig. 1 Flowchart of the included patients in the study\n\nTable 1 Clinical characteristics of patients and requests\n\nCharacteristics\tPatients (N = 226)\t\nAge (median, IQR) years\t46 (33–62)\t\n < 18 years (%)\t28 (12.4)\t\n 18–64 years (%)\t147 (65.0)\t\n ≥65 years (%)\t51 (22.6)\t\nGender (%)\t\n Female\t133 (59)\t\n Male\t93 (41)\t\nMorbidity (%)\t\n Arterial hypertension (%)\t58 (25.7)\t\n Hyperlipidemia (%)\t32 (14.2)\t\n Diabetes (%)\t25 (11.1)\t\n Chronic renal failure (%)\t14 (6.2)\t\n Coronary heart disease\t13 (5.7)\t\n Heart failure (%)\t3 (1.3)\t\nPrevious treatments for the target diseases (median, IQR)\t3 (2–5)\t\nClinical services (%)\t\n Gastroenterology\t33 (14.6)\t\n Internal medicine\t30 (13.3)\t\n Neurology\t28 (12.4)\t\n Paediatrics\t24 (10.6)\t\n Oncology\t14 (6.2)\t\n Allergy\t14 (6.2)\t\n Nephrology\t13 (5.8)\t\n Haematology\t13 (5.8)\t\n Dermatology\t12 (5.3)\t\n Othersa\t45 (19.9)\t\nOff-label drug use condition (%)\t\n Unapproved indication\t204 (90.3)\t\n Unapproved condition\t10 (4.4)\t\n Unapproved indication and condition\t12 (5.3)\t\nReasons for off-label drug use (%). Lack of clinical response (or suboptimal) to the previous treatments\t163 (72.1)\t\n No other drugs approved for that indication/condition\t28 (12.4)\t\n Intolerance to the previous treatments\t26 (11.5)\t\n Preferred to the alternative drugs for that patient (clinical/logistical reasons)\t20 (8.8)\t\n Contraindications to the alternatives\t10 (4.4)\t\na Pneumology (9), rheumatology (9), otorhinolaryngology (6), ophthalmology (4), intensive care medicine (4), thoracic surgery (4), gastrointestinal surgery (3), vascular surgery (2) and other services with only one case (4)\n\nA total of 232 off-label medicines were requested and administered to the 226 patients for 102 different diseases. Two hundred and twenty (97.3 %) patients were treated with one off-label medicine and six (2.7 %) with a combination of two medicines. The most frequent pharmacological subgroups were the monoclonal antibodies (in 56 patients; 24.1 %) and other muscle relaxants (25; 10.8 %). The most frequent medicines were rituximab (49; 21.1 %), botulinum toxin (25; 10.7 %) and omalizumab (14; 6.0 %). Rituximab was used in 22 different indications, botulinum toxin in 5 and omalizumab in 5 (more information on therapeutic subgroups and medicines is available in the annex 1 of the supplementary material). Diseases of the nervous system (31 patients; 13.7 %), neoplasms (30; 13.3 %), diseases of the digestive system (29; 12.8 %) and diseases of the skin and subcutaneous tissue (27; 12 %) were the most frequent conditions. Table 2 shows the most frequent clinical indications in which each off-label medicine was used. Botulinum toxin was used to treat 13 (5.6 %) patients with anal fissure and 8 (3.6 %) with achalasia. Rituximab was used to treat seven (3 %) patients with an acute humoral rejection of a solid organ transplant and six (2.6 %) with pemphigus vulgaris. Omalizumab was used to treat seven patients (3 %) with chronic urticaria.Table 2 Level of evidence-based of most frequently used medicines in each indication\n\nMedicine\tIndication\tNumber (%)\tLevel of evidence\tOngoing clinical trial\t\nRituximab\tComplications of organ or tissue transplant, failure or rejection\t7 (3.0)\t4\tPhase III\t\nPemphigus\t6 (2.6)\t4\tPhase III\t\nMyasthenia gravis\t4 (1.7)\t4\tPhase II\t\nSystemic lupus erythematosus (SLE)\t4 (1.7)\t2b\t–\t\nCryoglobulinemic purpura\t3 (1.3)\t2b\tPhase II\t\nLupus nephritis\t3 (1.3)\t2b\t–\t\nWegener granulomatosis\t3 (1.3)\t1b\tPhase III\t\nEncephalitis, myelitis and encephalomyelitis\t2 (0.8)\t4\t–\t\nGlomerulonephritis, membranous\t2 (0.8)\t4\tPhase III\t\nIdiopathic thrombocytopenic purpura\t2 (0.8)\t1b\tPhase III\t\nRelapsing polychondritis\t2 (0.8)\t4\t–\t\nGlomerulonephritis, minimal change disease\t1 (0.4)\t2b\tPhase III\t\nGraft-versus-host disease\t1 (0.4)\t2a\tPhase II\t\nLymphoproliferative disorder\t1 (0.4)\t2b\t–\t\nNeuromyelitis optica\t1 (0.4)\t4\tPhase I\t\nPolymyositis\t1 (0.4)\t4\t–\t\nPolyradiculoneuropathy, chronic inflammatory demyelinating\t1 (0.4)\t4\t–\t\nSarcoidosis\t1 (0.4)\t4\tPhase II\t\nSjögren syndrome\t1 (0.4)\t2b\tPhase II\t\nSystemic scleroderma\t1 (0.4)\t2b\tPhase II\t\nThrombocytopenia in SLE\t1 (0.4)\t4\t–\t\nWaldenström macroglobulinaemia\t1 (0.4)\t2b\tPhase II\t\nSubtotal\t49 (21.1)\t\t\t\nBotulinum toxin\tAnal fissure\t13 (5.6)\t1a\tPhase IV\t\nEsophageal achalasia\t8 (3.4)\t1a\t–\t\nGeneralized hyperhidrosis\t2 (0.8)\t1a\tPhase IV\t\nEyelid retraction\t1 (0.4)\t2b\tPhase IV\t\nMyofascial pain\t1 (0.4)\t2b\tPhase IV\t\nSubtotal\t25 (10.8)\t\t\t\nOmalizumab\tChronic urticaria\t7 (3.0)\t2b\tPhase III\t\nFood-induced anaphylaxis\t3 (1.3)\t4\tPhase II\t\nCold-induced urticaria\t2 (0.8)\t4\t–\t\nExtrinsic allergic asthma\t1 (0.4)\t4\tPhase IV\t\nNasal polyps\t1 (0.4)\t4\tPhase IV\t\nSubtotal\t14 (6.0)\t\t\t\nInformation about the other used medicines is available in annex 2 of the supplementary material\n\nIn 117 cases (51.8 %), the level of clinical evidence for using the medicines in the requested conditions was low, and in 109 (48.2 %) was high. The level of evidence was 4 in 107 (47.4 %) cases, 2b in 48 (21.2 %), 1a in 29 (12.8 %), 1b in 23 (10.2 %), 5 in 10 (4.4 %), 1c and 2a each with 4 (1.8 %) and 2c in 1 (0.4 %). There were ongoing clinical trials assessing the efficacy of off-label medicines in 122 cases (54 %), 84 of whom on phases III or IV. Table 2 shows the level of clinical evidence and information about ongoing clinical trials for each pair of clinical conditions and off-label medicines.\n\nIn 164 (72.6 %) patients, a clinical response was observed (82 [36.3 %] with a partial clinical response, 71 [31.4 %] with a complete clinical response and 11 [4.9 %] with a stabilization); in 59 patients (26.1 %), a lack of response was documented and in 3 (1.3 %), it was unknown. Patients were concomitantly treated with a median of 2 drugs (IQR 2–4), mainly prednisone (77 cases), metilprednisolone (19), immunoglobulins (13), mycophenolate mofetil (12), tacrolimus (11) and azatioprine (11). Table 3 shows the clinical response to off-label medicines in the different conditions. No statistically significant differences were observed between patients treated with a medicine with a high level of evidence and those treated with medicines with a low level of evidence (76.9 vs. 70.4 %, respectively, p = 0,278).Table 3 Outcomes for the most frequently used medicines in each indication\n\n\tComplete response (N)\tPartial response (N)\tStabilization (N)\tNo response (N)\tTotal (N)\t\nRituximab\t\n Complications of organ or tissue transplant, failure or rejection\t3\t2\t–\t2\t7\t\n Pemphigus\t1\t4\t–\t1\t6\t\n Myasthenia gravis\t2\t–\t1\t1\t4\t\n Systemic lupus erythematosus (SLE)\t0\t2\t–\t2\t4\t\n Cryoglobulinemic purpura\t2\t1\t–\t–\t3\t\n Lupus nephritis\t1\t1\t–\t1\t3\t\n Wegener granulomatosis\t–\t3\t–\t–\t3\t\n Encephalitis, myelitis and encephalomyelitis\t–\t1\t–\t1\t2\t\n Glomerulonephritis, membranous\t–\t1\t–\t1\t2\t\n Idiopathic thrombocytopenic purpura\t–\t–\t–\t2\t2\t\n Relapsing polychondritis\t–\t–\t–\t2\t2\t\n Glomerulonephritis, minimal change disease\t1\t–\t–\t–\t1\t\n Graft-versus-host disease\t–\t1\t–\t–\t1\t\n Lymphoproliferative disorder\t1\t–\t–\t–\t1\t\n Neuromyelitis optica\t–\t1\t–\t–\t1\t\n Polymyositis\t1\t–\t–\t–\t1\t\n Polyradiculoneuropathy, chronic inflammatory demyelinating\t–\t1\t–\t–\t1\t\n Sarcoidosis\t–\t–\t–\t1\t1\t\n Sjögren syndrome\t–\t1\t–\t–\t1\t\n Systemic sclerodermia\t–\t–\t1\t–\t1\t\n Thrombocytopenia in SLE\t1\t–\t–\t–\t1\t\n Waldenström macroglobulinaemia\t–\t1\t–\t–\t1\t\nSubtotal (%)\t13 (26.5)\t20 (40.8)\t2 (4.1)\t14 (28.6)\t49 (100)\t\nBotulinum toxin\t\n Anal fissure\t6\t4\t–\t3\t13\t\n Esophageal achalasia\t6\t1\t–\t–\t7a\t\n Generalized hyperhidrosis\t–\t1\t–\t1\t2\t\n Eyelid retraction\t1\t–\t–\t–\t1\t\n Myofascial pain\t–\t1\t–\t–\t1\t\nSubtotal (%)\t13 (54.2)\t7 (29.1)\t–\t4 (16.7)\t24 (100)a\t\nOmalizumab\t\n Chronic urticaria\t5\t1\t–\t1\t7\t\n Food-induced anaphylaxia\t2\t–\t–\t1\t3\t\n Cold-induced urticaria\t–\t2\t–\t–\t2\t\n Extrinsic allergic asthma\t–\t1\t–\t–\t1\t\n Nasal polyps\t1\t–\t–\t–\t1\t\nSubtotal (%)\t8 (57.1)\t4 (28.6)\t–\t2 (14.3)\t14 (100)\t\nInformation about the other used medicines is available in annex 3 of the supplementary material\n\naOne unknown response\n\nA total of 58 (25.7 %) patients experienced 105 adverse effects. The most frequent adverse effects were infections (11 patients; 5.3 %), fatigue (11; 4.9 %), diarrhoea (9; 4 %), rash and other skin disorders (9; 4 %), leukopenia, neutropenia and/or lymphopenia (8; 3.5 %) and nausea and vomiting (5; 2.2 %) and thrombocytopenia (5; 2.2 %). Rituximab, erlotinib and bendamustine were the drugs involved in more adverse effects. In 11 patients (4.9 %), the adverse effects were severe and in 10 patients, this resulted in treatment being withdrawn. In one patient, the adverse effect (varicella pneumonia with rituximab added to other immunosuppressants in a patient with myasthenia gravis) was fatal.\n\nThe total cost of off-label medicine treatments was €997,494.71. The median (IQR) cost per patient was €2,943.07 (541.9–5,872.54). The total cost of off-label medicine treatments in clinical conditions with some response was €705,157.35 and for those with no response was €281,626.71. The median cost per patient (IQR) without response was higher (€4,262.8 [594.55–6,770.40]) than that of patients with response (€2,669.01 [449.7–5,463.93]). The total cost of off-label medicines with a high level of evidence was €485,235.89 and for those with a low level was €512,258.82. The median cost per patient (IQR) treated with a medicine with a low level of clinical evidence was higher (€3,085.38 [1,083.76–5,046.81]) than that of patients treated with a medicine with a high level (€2,693.50 [165.48–6,552.0]).\n\nDiscussion\n\nOur study shows that a high percentage of patients treated with off-label medicines had some response, either complete or partial, despite the fact that most of them had failed to respond to several previous treatments. However, one out of four treated patients had adverse events, and the median cost of off-label treatments was relatively high. Although several articles have reported the use of off-label medicines, few of them have assessed outcomes in clinical practice, and most have focused on one specific medicine [12, 18]. We believe this is the first study where the outcomes of patients treated with different off-label medicines have been reported.\n\nIt is also interesting to note the wide variety of off-label medicines and indications observed in the study. This high variety has been described previously [22]. New technological medicines such as biological products were frequently used by patients who had severe or life-threatening diseases that had not responded to previous treatments. This is not surprising, given that the study was performed in tertiary hospitals that have highly specialized services. Biologic medicines are being employed more often in clinical practice as off-label treatments in patients with autoimmune diseases and severe clinical symptoms [23]. Rituximab was the most frequently used off-label medicine as has been reported in other studies [12, 13, 18, 22]. In addition, rituximab was used in a lot of different diseases because it is an anti-CD20 monoclonal antibody against B lymphocytes that can be potentially useful in a heterogeneous group of autoimmune and inflammatory diseases. The most frequent indications were transplant-related and dermatological uses, autoimmune tissue and renal diseases. Globally, the responses observed with rituximab were high, but the partial responses predominated. However, variations in the response were observed. In transplant-related issues (mainly humoral acute rejection), more patients with a complete response were identified. In contrast, more patients with non-response were seen in idiopathic thrombocytopenic purpura. Other studies have shown similar outcomes with off-label use of rituximab [12, 18].\n\nOther frequently used medicines were botulinum toxin and omalizumab, but in a smaller range of indications. Botulinum toxin was mainly used in anal fissure and esophageal achalasia. The most prevalent response was a complete response in both diseases. In a systematic review and meta-analysis, botulinum toxin has been similar to glyceryltrinitrate [24] and inferior to the lateral internal sphincterotomy in the management of anal fissure [25]. Omalizumab was often used in chronic spontaneous urticaria, and the responses have been good in most cases. Efficacy of omalizumab in symptomatic patients despite H1-antihistamine therapy has been shown in a clinical trial [26]. Recently, the Committee for Medicinal Products for Human Use (CHMP) from the European Medicines Agency has adopted a positive opinion recommending its use as an add-on therapy to the treatment of chronic urticaria [27].\n\nIn our study, the evidence to use these medicines was often low as well as the frequency of ongoing clinical trials assessing their efficacy. In general, the evidence supporting the use of off-label medicines has also been reported as low, although the classifications used to rate the evidence have been quite variable [2, 9, 12, 13, 28]. Moreover, the level of evidence could be influenced by the health area, period of study, kind of medicines and evaluated indications. Thus, on the one hand, Radley et al. described that most off-label medicines used in outpatient care had little or no scientific support [2]. On the other hand, Mellor et al. reported that most off-label anticancer medicines are supported by guidelines or published peer-review research [9]. Future studies should analyse the variability in the level of evidence of off-label medicines according to the different factors mentioned above.\n\nThe most frequent reason for off-label use of medicines was for unapproved indications in adults and only a few cases were in children. Our study did not have children as a target population, as opposed to other studies [14–17]. In addition, the use of off-label medicines was identified through the requests for medicines received in pharmacy services. In general, most of these requested medicines are sophisticated and expensive, and these types of medicines are less frequently used in children especially as off-label use.\n\nRisk from medicines is often based on studies performed in approved conditions but limited data are available on safety in unapproved indications. Moreover, patients’ characteristics in unapproved conditions can substantially differ from those of approved indications due to the basal disease state and the immunological situation. Therefore, in case of off-label medicines use, the benefit-risk relation is even more important given the limited available evidence on the efficacy and also safety. Thus, data from the Spanish registry BIOBADASER 2.0 showed a higher frequency of adverse reactions when TNF antagonists were used in unapproved rheumatic conditions than when they were used in approved rheumatic indications [29]. In children, off-label medicines were also more likely to be implicated in an adverse drug reaction than authorized medicines [30]. In our study, around one out of four patients had an adverse reaction related to off-label medicines use and some reactions were severe or life-threatening. Infections followed by gastrointestinal, cutaneous and haematological reactions were the ones most frequently observed. These types of reactions are to be expected bearing in mind how the most frequently administered medicines work.\n\nAnother important issue in off-label drug uses is the benefit-cost relation. In our study, the median cost per patient was high because most administered medicines are expensive. However, other studies have shown that the cost of treatment with medicines is higher when they are used for non-approved conditions than for approved indications [31]. Interestingly, in our study, the median cost per patient without response was higher than that of a patient with response, although the difference was not statistically significant. Further studies should analyse the cost of off-label use of medicines compared to the outcomes.\n\nIn our study, different medicines were administered for off-label use for a diverse range of clinical conditions and often with a low level of available evidence. Randomized clinical trials should be performed in these conditions but problems in financing and recruiting patients who have rare diseases may make it difficult to conduct them. Alternatively, national or international registers of patients treated with off-label medicines may be useful as a source of information on their effectiveness and safety. In any case, use of these medicines requires a careful assessment of each case and a sensible expectation in relation to clinical outcomes. Le Jeunne et al. proposed a control system for all off-label prescriptions with a dedicated committee which would determine the frame of off-label prescriptions, in order to improve the use of these medicines [32].\n\nOur study has several limitations. Firstly, we did an observational study without a control group of patients and, hence, some biased results could be present in the assessment of clinical outcomes. Secondly, we included a heterogeneous range of diseases and medicines, with few cases in each group followed for a short period of time, and this hinders the analysis and interpretation of results. Thirdly, our study was based on the requests for off-label uses, and this can limit the validity of the study results. Fourthly, the study was performed in five tertiary hospitals in our area, and this limits the extrapolation of results to other hospitals with different characteristics or geographic areas. Nevertheless, the main strength of our study is the assessment of clinical outcomes in different off-label medicines use. Moreover, we have done a multicentric study in large tertiary university hospitals that cover most medical and surgical specialities to a high level of complexity.\n\nIn conclusion, in our study, a high variability of off-label medicines and indications was found. Although the clinical evidence of off-label medicines was often low, a high percentage of some clinical responses in patients with previous multiple treatment failures was observed. However, this was at the expenses of adverse effects (some of them severe) and a high cost. Even though more evidence from clinical trials would be desirable, they can be difficult to carry out and finance especially where rare diseases are concerned. Meanwhile, data from observational studies and registers of patients treated with off-label medicines should be kept to obtain information and to assist in prescribing decisions in clinical practice.\n\nElectronic supplementary material\n\nESM 1 (DOC 618 kb)\n\nWe would to thank the Spanish Ministry of Health, Social Affairs and Equality for their financial support given though a grant from the scholarship EC-206 in the public call for the promotion of independent clinical research (SAS/2370/2010 order of September 27).\n\nAuthor contributions\n\nAgustí A and Bosch JA, as directors and project leaders, had devised and wrote the proposal for obtaining the grant. Agustí A, Vallano A, Danés I and Bosch JA wrote the manuscript and had the final responsibility for the decision to submit the manuscript for publication. Danés I, Agustí A, Vallano, Alerany, Martínez J, Bosch JA, Ferrer A, Gratacós L, Pérez A, Olmo M, Cano Marron SM, Valderrama A and Bonafont X, contributed to the study design, coordinated the data collection in each hospital, interpreted the data, reviewed the manuscript, provided comments and approved the final text of the manuscript. Vidal X conducted statistical analysis. Ballarín E and Pérez E controlled and monitorized quality data. Barroso X designed the database. Valdivia C, Duero M, Rebolledo M, Simon C, Marquez P, Jodar R, Pedrós C, Aguilar R, Martínez M, Schoenenberger JA and Costa J collected the data.\n\nConflict of interest\n\nThe authors declare no competing interests.\n\nOn behalf of ICISE investigators\n\nIndependent clinical investigation in special situations (ICISE) investigators\n\nHospital Universitari Vall d’Hebron: Danés I, Agustí A, Alerany C, Martínez J, Valdivia C, Duero M, Ballarín E, Pérez E, Vidal X, Bosch JA, Barroso X.\n\nHospital Universitari de Bellvitge: Vallano A, Ferrer A, Rebolledo M, Simon C, Marquez P, Jodar R, Pedrós C.\n\nHospital Universitari Josep Trueta: Pérez A, Gratacós L, Aguilar R.\n\nHospital Universitari Arnau de Vilanova: Martínez M, Olmo M, Cano Marron SM, Schoenenberger JA.\n\nHospital Universitari Germans Trias i Pujol: Valderrama A, Bonafont X, Costa J.\n==== Refs\nReferences\n\n1. Day R Off-label prescribing Aust Prescr 2013 36 182 3\n2. Radley DC Finkelstein SN Stafford R Off-label prescribing among office-based physicians Arch Intern Med 2006 166 1021 6 10.1001/archinte.166.9.1021 16682577\n3. Eguale T Buckeridge DL Winslade NE Benedetti A Hanley JA Tamblyn R Drug, patient, and physician characteristics associated with off-label prescribing in primary care Arch Intern Med 2012 172 781 8 10.1001/archinternmed.2012.340 22507695\n4. Roehr B (2012) Free speech rights outweight restrictions on promoting drugs off-label, court rules. BMJ 345:e8324.\n5. Hampton T Experts weight in on promotion, prescription off-label drugs JAMA 2007 297 683 4 10.1001/jama.297.7.683 17312280\n6. Kesselheim AS Mello MM Avorn J FDA regulation of off-label drug promotion under attack JAMA 2013 309 445 6 10.1001/jama.2012.207972 23385267\n7. Royal Decree 1015/2009 of 19 June, on the availability of drugs in special situations is regulated. Official State Bulletin. No. 174 Monday, 20 July 2009. Sec.I. Page 60904 [Document in Spanish] Available at:http://www.boe.es/boe/dias/2009/07/20/pdfs/BOE-A-2009-12002.pdf\n8. CatSalut (2010) Instruction 05/2010. Use of drugs approved under conditions other than those laid down in the technical details. [Document in Catalan] Available at: http://www20.gencat.cat/docs/salut/Minisite/catsalut/Proveidors_professionals/normatives_instruccions/Documents/Arxius/instruccio_05_2010.pdf\n9. Mellor JD Van Koeverden P Yip SW Thakerar A Kirsa SW Michael M Access to anticancer drugs: many evidence-based treatments are off-label and unfunded by the Pharmaceutical Benefits Scheme Intern Med J 2012 42 1224 9 10.1111/j.1445-5994.2012.02751.x 22372936\n10. Roila F, Ballatori E, Labianca R, De Braud F, Borgonovo K, Martelli O, Gallo C, Tinazzi A, Perrone F; Italian Medical Oncology Association (AIOM) Off-label prescription of antineoplastic drugs: an Italian prospective, observational, multicenter survey Tumori 2009 95 647 51 20210223\n11. Joerger M Schaer-Thuer C Koeberle D Matter-Walstra K Gibbons-Marsico J Diem S Thuerlimann B Cerny T Off-label use of anticancer drugs in eastern Switzerland: a population-based prospective cohort study Eur J Clin Pharmacol 2014 70 719 25 10.1007/s00228-014-1662-5 24609468\n12. Danés I Agustí A Vallano A Martínez J Alerany C Ferrer A López A Cortés-Hernández J Bosch JA Available evidence and outcome of off-label use of rituximab in clinical practice Eur J Clin Pharmacol 2013 69 1689 99 10.1007/s00228-013-1518-4 23700188\n13. O’Connor K Liddle C Prospective data collection of off-label use of rituximab in Australian public hospitals Intern Med J 2013 43 863 70 10.1111/imj.12206 23735074\n14. Jong GW van der Linden PD Bakker EM van der Lely N Eland IA Stricker BH van den Anker JN Unlicensed and off-label drug use in a paediatric ward of a general hospital in the Netherlands Eur J Clin Pharmacol 2002 58 293 297 10.1007/s00228-002-0479-9 12136376\n15. Schirm E Tobi H Risk factors for unlicensed and off-label drug use in children outside the hospital Pediatrics 2003 111 291 295 10.1542/peds.111.2.291 12563053\n16. Lindell-Osuagwu L Korhonen MJ Saano S Helin-Tanninen M Naaranlahti T Kokki H Off-label and unlicensed drug prescribing in three paediatric wards in Finland and review of the international literature J Clin Pharm Ther 2009 34 277 87 10.1111/j.1365-2710.2008.01005.x 19650250\n17. Langerová P Vrtal J Urbánek K Incidence of unlicensed and off-label prescription in children Ital J Pediatr 2014 40 12 10.1186/1824-7288-40-12 24495454\n18. Chay J Donovan P Cummins S Kubler P Pillans P Experience with low dose rituximab in off-label indications at two tertiary hospitals Int Med J 2013 43 871 82 10.1111/imj.12207\n19. Kesselheim AS Myers JA Solomon DH Winkelmayer WC Levin R Avorn J The prevalence and cost of unapproved uses of top-selling orphan drugs PLoS ONE 2012 7 e31894 10.1371/journal.pone.0031894 22363762\n20. U.S.National Institutes of Health (2012) Clinicaltrials.gov. Available at: http://clinicaltrials.gov/ct2/home. Accessed 20 Dec 2012\n21. Oxford Centre for Evidence-based Medicine (2009) Levels of evidence. Available at: http://www.cebm.net/?o=1025. Accessed 20 Dec 2012\n22. Danés I, Alerany C, Ferrer A, Vallano A (2013) [Off-label drug use in hospitals.] Med Clin (Barc) Oct 29. pii: S0025-7753(13)00605-2. doi:10.1016/j.medcli.2013.09.003\n23. Gatto M Kiss E Naparstek Y Doria A In-/off-label use of biologic therapy in systemic lupus erythematosus BMC Med 2014 12 30 10.1186/1741-7015-12-30 24528782\n24. Sajid MS Vijaynagar B Desai M Cheek E Baig MK Botulinum toxin vs glyceryltrinitrate for the medical management of chronic anal fissure: a meta-analysis Colorectal Dis 2008 10 541 6 10.1111/j.1463-1318.2007.01387.x 17868403\n25. Shao WJ Li GC Zhang ZK Systematic review and meta-analysis of randomized controlled trials comparing botulinum toxin injection with lateral internal sphincterotomy for chronic anal fissure Int J Colorectal Dis 2009 24 995 1000 10.1007/s00384-009-0683-5 19266207\n26. Maurer M Rosén K Hsieh HJ Saini S Grattan C Gimenéz-Arnau A Agarwal S Doyle R Canvin J Kaplan A Casale T Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria N Engl J Med 2013 368 924 35 10.1056/NEJMoa1215372 23432142\n27. European Medicines Agency. Summary of opinion (post authorisation). Xolair EMA/CHMP/20684/2014. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion/human/000606/WC500160092.pdf. Accessed 29 May 2014\n28. Shimazawa R Ikeda M Japanese regulatory system for approval of off-label drug use: evaluation of safety and effectiveness in literature-based applications Clin Ther 2012 34 2104 2116 10.1016/j.clinthera.2012.09.004 23036337\n29. Carmona L, Descalzo MA, Ruiz-Montesinos D, Manero-Ruiz FJ, Perez-Pampin E, Gomez-Reino JJ; BIOBADASER 2.0 Study Group (2011) Safety and retention rate of off-label uses of TNF antagonists in rheumatic conditions: data from the Spanish registry BIOBADASER 2.0. Rheumatology (Oxford) 50:85–92\n30. Bellis JR Kirkham JJ Thiesen S Conroy EJ Bracken LE Mannix HL Bird KA Duncan JC Peak M Turner MA Smyth RL Nunn AJ Pirmohamed M Adverse drug reactions and off-label and unlicensed medicines in children: a nested case-control study of inpatients in a pediatric hospital BMC Med 2013 11 238 10.1186/1741-7015-11-238 24229060\n31. Ruiz-Antorán B Agustí Escasany A Vallano Ferraz A Danés Carreras I Riba N Mateu Escudero S Costa J Sánchez Santiago MB Laredo L Durán Quintana JA Castillo JR Abad-Santos F Payares Herrera C Díaz S de Rada B Gómez Ontañón E Use of non-specific intravenous human immunoglobulins in Spanish hospitals; need for a hospital protocol Eur J Clin Pharmacol 2010 66 633 41 10.1007/s00228-010-0800-y 20204337\n32. Le Jeunne C Billon N Dandon A Berdaï D Adgibi Y Bergmann JF Bordet R Carpentier A Cohn E Courcier S Girault D Goni S Jolliet P Liard F Prot-Labarthe S Simon T Vernotte C Westerloppe J Off-label prescriptions: how to identify them, frame them, announce them and monitor them in practice? Therapie 2013 68 225 239 10.2515/therapie/2013039 23981260\n\n",
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"issn_linking": "0031-6970",
"issue": "70(11)",
"journal": "European journal of clinical pharmacology",
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"medline_ta": "Eur J Clin Pharmacol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D003327:Coronary Disease; D003920:Diabetes Mellitus; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006333:Heart Failure; D006801:Humans; D006949:Hyperlipidemias; D006973:Hypertension; D007676:Kidney Failure, Chronic; D008297:Male; D008875:Middle Aged; D056687:Off-Label Use; D011446:Prospective Studies; D013030:Spain; D062606:Tertiary Care Centers; D055815:Young Adult",
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"pubdate": "2014-11",
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"title": "Outcomes of off-label drug uses in hospitals: a multicentric prospective study.",
"title_normalized": "outcomes of off label drug uses in hospitals a multicentric prospective study"
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"abstract": "Traumatic brain injury (TBI) is a major cause of death and disability, but there are currently no therapies with proven efficacy for optimizing regeneration of repair during rehabilitation. Using standard stimulation tests, as many as 40-50% of survivors of severe TBI have deficiency of one or more pituitary hormones. Of these, the somatotropic axis is the most commonly affected, with Growth Hormone (GH) deficiency affecting ~20% of persons with severe TBI. Treatment with recombinant human Growth Hormone (rhGH) is generally effective in reversing the effects of acquired GH deficiency, but there is no evidence documenting functional or neurocognitive improvement after GH replacement in TBI patients. As a consequence, screening for GH deficiency and GH replacement when deficiency is found is not routinely performed as part of the rehabilitation of TBI survivors. Given that most of the recovery after TBI occurs within the first 6-12 months after injury and IGF-1 and GH are part of a coordinated restorative neurotrophic system, we hypothesized that patients will optimally benefit from GH therapy during the window of maximal neuroregenerative activity. We performed a Phase IIa, randomized, double-blind, placebo-controlled feasibility trial of recombinant human Growth Hormone (rhGH), starting at discharge from an inpatient rehabilitation unit, with follow up at 6 and 12 months. Our primary hypothesis was that treatment with rhGH in the subacute period would result in improved functional outcomes 6 months after injury. Our secondary hypothesis proposed that treatment with rhGH would increase IGF-1 levels and be well tolerated. Sixty-three subjects were randomized, and 40 completed the trial. At baseline, there was no correlation between IGF-1 levels and peak GH levels after L-arginine stimulation. IGF-1 levels increased after rhGH treatment, but it took longer than 1 month for levels to be higher than for placebo-treated patients. rhGH therapy was well-tolerated. The rhGH group was no different from placebo in the Disability Rating Scale, Glasgow Outcome Scale-Extended, or neuropsychological function. However, a trend toward greater improvement from baseline in Functional Independence Measure (FIM) was noted in the rhGH treated group. Future studies should include longer treatment periods, faster titration of rhGH, and larger sample sizes.",
"affiliations": "Department of Physical Medicine and Rehabilitation, Baylor Institute for Rehabilitation, Dallas, TX, United States.;Department of Physical Medicine and Rehabilitation, Baylor Institute for Rehabilitation, Dallas, TX, United States.;Department of Physical Medicine and Rehabilitation, Baylor Institute for Rehabilitation, Dallas, TX, United States.;Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, United States.;Department of Physical Medicine and Rehabilitation, Baylor Institute for Rehabilitation, Dallas, TX, United States.;Center for Neuro Skills, Bakersfield, CA, United States.;Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States.;Department of Neurology, University of Pennsylvania, Philadelphia, PA, United States.",
"authors": "Dubiel|Rosemary|R|;Callender|Librada|L|;Dunklin|Cynthia|C|;Harper|Caryn|C|;Bennett|Monica|M|;Kreber|Lisa|L|;Auchus|Richard|R|;Diaz-Arrastia|Ramon|R|",
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"doi": "10.3389/fendo.2018.00520",
"fulltext": "\n==== Front\nFront Endocrinol (Lausanne)Front Endocrinol (Lausanne)Front. Endocrinol.Frontiers in Endocrinology1664-2392Frontiers Media S.A. 10.3389/fendo.2018.00520EndocrinologyClinical TrialPhase 2 Randomized, Placebo-Controlled Clinical Trial of Recombinant Human Growth Hormone (rhGH) During Rehabilitation From Traumatic Brain Injury Dubiel Rosemary 1Callender Librada 1Dunklin Cynthia 1Harper Caryn 2Bennett Monica 1Kreber Lisa 3Auchus Richard 4Diaz-Arrastia Ramon 5*1Department of Physical Medicine and Rehabilitation, Baylor Institute for Rehabilitation, Dallas, TX, United States2Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, United States3Center for Neuro Skills, Bakersfield, CA, United States4Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States5Department of Neurology, University of Pennsylvania, Philadelphia, PA, United StatesEdited by: Hubert Vaudry, Université de Rouen, France\n\nReviewed by: Virginie Tolle, Institut National de la Santé et de la Recherche Médicale (INSERM), France; Lin Kooi Ong, University of Newcastle, Australia\n\n*Correspondence: Ramon Diaz-Arrastia ramon.diaz-arrastia@uphs.upenn.eduThis article was submitted to Neuroendocrine Science, a section of the journal Frontiers in Endocrinology\n\n10 9 2018 2018 9 52006 12 2017 20 8 2018 Copyright © 2018 Dubiel, Callender, Dunklin, Harper, Bennett, Kreber, Auchus and Diaz-Arrastia.2018Dubiel, Callender, Dunklin, Harper, Bennett, Kreber, Auchus and Diaz-ArrastiaThis 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.Traumatic brain injury (TBI) is a major cause of death and disability, but there are currently no therapies with proven efficacy for optimizing regeneration of repair during rehabilitation. Using standard stimulation tests, as many as 40–50% of survivors of severe TBI have deficiency of one or more pituitary hormones. Of these, the somatotropic axis is the most commonly affected, with Growth Hormone (GH) deficiency affecting ~20% of persons with severe TBI. Treatment with recombinant human Growth Hormone (rhGH) is generally effective in reversing the effects of acquired GH deficiency, but there is no evidence documenting functional or neurocognitive improvement after GH replacement in TBI patients. As a consequence, screening for GH deficiency and GH replacement when deficiency is found is not routinely performed as part of the rehabilitation of TBI survivors. Given that most of the recovery after TBI occurs within the first 6–12 months after injury and IGF-1 and GH are part of a coordinated restorative neurotrophic system, we hypothesized that patients will optimally benefit from GH therapy during the window of maximal neuroregenerative activity. We performed a Phase IIa, randomized, double-blind, placebo-controlled feasibility trial of recombinant human Growth Hormone (rhGH), starting at discharge from an inpatient rehabilitation unit, with follow up at 6 and 12 months. Our primary hypothesis was that treatment with rhGH in the subacute period would result in improved functional outcomes 6 months after injury. Our secondary hypothesis proposed that treatment with rhGH would increase IGF-1 levels and be well tolerated. Sixty-three subjects were randomized, and 40 completed the trial. At baseline, there was no correlation between IGF-1 levels and peak GH levels after L-arginine stimulation. IGF-1 levels increased after rhGH treatment, but it took longer than 1 month for levels to be higher than for placebo-treated patients. rhGH therapy was well-tolerated. The rhGH group was no different from placebo in the Disability Rating Scale, Glasgow Outcome Scale-Extended, or neuropsychological function. However, a trend toward greater improvement from baseline in Functional Independence Measure (FIM) was noted in the rhGH treated group. Future studies should include longer treatment periods, faster titration of rhGH, and larger sample sizes.\n\ninsulin-like growth factor Iglasgow outcome scaledisability rating scalefunctional independence measureshort form 36National Institute of Disability, Independent Living, and Rehabilitation Research10.13039/100009157H133A020526\n==== Body\nIntroduction\nTraumatic brain injury (TBI) is a major cause of death and disability, with an estimated cost of 45 billion dollars a year in the United States alone. Every year, ~2.5 million people in the United States sustain a TBI, of which 53,000 people die, and another 284,000 are hospitalized and survive the injury (1). Currently, more than 5.3 million Americans (or 3% of the population) live with disabilities resulting from TBI and virtually no injury is without consequence (1). The magnitude of this problem has led to numerous clinical trials aimed at improving survival and/or functional outcome, yet no effective therapies have been identified. In particular, no therapies aimed at optimizing regeneration and repair during the rehabilitation period have been demonstrated to be effective.\n\nTBI has long been recognized as a chronic cause of neuroendocrine dysfunction. While overt deficiency of the somatotropic, gonadotropic, thyroid, or adrenal axis have been recognized for many decades, subtler deficiencies have come to light only more recently. Using standard stimulation tests, as many as 40–50% of survivors of severe TBI have deficiency of one or more pituitary hormones (2). Of these, the somatotropic axis is the most vulnerable, with estimates of Growth Hormone (GH) deficiency affecting ~20% of persons with severe TBI (3). In contrast, thyroid hormone and adrenocorticotrophic hormone deficiency are relatively uncommon, with rates averaging 4–6%, while the gonadotrophic axis shows intermediate rates of dysfunction, between 8 and 12% (4–6). The clinical consequences of GH deficiency include decrease in muscle strength, decrease in lean body mass, and increase in abdominal fat, and reduced basal metabolic rate. However, the most common symptoms are neuropsychiatric, particularly fatigue, asthenia, depression, sleep disturbances, and memory problems (2). In a recently published study, GH deficiency, or insufficiency was associated with neurobehavioral deficits, decreased concentration, depression, and reduced quality of life (7) which underscores why GH deficiency after TBI is underdiagnosed as the symptoms and signs are non-specific and are often mistaken for or masked by the underlying traumatic injury.\n\nTreatment with recombinant human Growth Hormone (rhGH) is generally effective in reversing the effects of acquired GH deficiency (8). In randomized controlled trials of adult patients with acquired GH deficiency (resulting primarily from pituitary tumors), rhGH therapy resulted in improved cognitive function, well-being, and quality of life (8, 9), in addition to improvements in metabolic factors such as bone mineral density and lean body mass. While studies have demonstrated the presence of GH deficiency in patients surviving TBI, there has been a paucity of evidence documenting functional or neurocognitive improvement after GH replacement therapy in TBI patients (10–13). A consequence of such lack of evidence is that screening for GH deficiency (and GH replacement when deficiency is found) is not routinely performed as part of the rehabilitation of TBI survivors.\n\nGiven that most of the recovery after TBI occurs within the first 6–12 months after injury and IGF-1 and GH are part of a coordinated restorative neurotrophic system, it is likely that they exert their effects in synergy with a host of other trophic and restorative factors that are maximally functioning within the first few months after injury. While treatment >1 year after injury in patients who remain GH deficient holds promise, we hypothesized that many patients will optimally benefit from GH therapy (and resulting elevations in IGF-1 levels) during the window of maximal neuroregenerative activity.\n\nTreating only patients who have GH deficiency defined using stimulation tests (either glucagon or GHRH + L-arginine, which were developed for non-trauma populations), as was done in a past clinical trial, may be too conservative (14), as it may deny therapy to many patients with hypothalamic dysfunction and serum IGF-1 concentrations suboptimal to maximize recovery. It remains unclear what the optimal IGF-1 level is in patients recovering from TBI, and patients with serum IGF-1 levels in the lower end of the normal distribution may benefit from augmenting IGF-1 production with GH treatment, to maintain concentrations of this neurotrophic factor near the upper third of the normal range during the time window of maximal repair and regeneration.\n\nThis study is a Phase IIa, randomized, double-blind, placebo-controlled feasibility trial of rhGH, starting at discharge from an inpatient rehabilitation unit or while in a transitional rehabilitation setting, with follow up at 6 and 12 months. Our primary hypothesis was that treatment with recombinant human Growth Hormone (rhGH) in the subacute period after TBI would result in improved functional outcomes 6 months after injury as compared to placebo. Our secondary hypothesis proposed that treatment with rhGH would result in increased IGF-1 levels, that rhGH therapy would be well tolerated, and would not result in an increased rate of diabetes mellitus, arthralgias, or peripheral edema.\n\nMethods\nParticipants who suffered acute TBI were recruited into the study from an acute inpatient rehabilitation or patients receiving care at a transitional post-acute rehabilitation setting. Our goal was to enroll participants who suffered a sufficiently severe injury to require inpatient rehabilitation or transitional rehab care and were at a timeframe with the most potential for neuroregeneration. Table 1 details eligibility criteria used for screening. This study was approved by the Institutional Review Boards at Baylor University Medical Center and the University of Texas Southwestern Medical Center, both in Dallas, Texas. Written consent was obtained from all participants or their legally authorized representatives, when the participant did not have capacity to provide informed consent. In these latter cases assent was obtained from the participant. The trial was registered with ClinicalTrials.gov (NCT 00766038) prior to the first enrollment.\n\nTable 1 Inclusion and exclusion criteria.\n\nInclusion criteria\tExclusion criteria\t\n1. Non-penetrating TBI\t1. History of pre-existing neurologic disease\n (such as brain tumors, meningitis, cerebral palsy, encephalitis, brain abscesses, vascular malformations, cerebrovascular disease, Alzheimer's disease, multiple sclerosis, or HIV-encephalitis)\t\n2. Age 16–65 years\t2. History of premorbid disabling condition that interfere with outcome assessments\t\n3. Randomization within 2–24 weeks of injury.\t3. Contraindication to rhGH therapy\n (hypersensitivity to rhGH or any of the components of the supplied product, including metacresol, glycerin, or benzyl alcohol)\t\n4. Rancho Los Amigos Rating IV or better at the time of randomization. Should not be at Rancho IV level for more than 18 weeks before randomization\t4. Penetrating traumatic brain injury\t\n5. Availability of caregiver to oversee administration of medications\t5. Discharged from rehabilitation on insulin therapy and/or hypoglycemic agents\t\n6. Reasonable expectation for completion of outcome measures\t6. Obesity (BMI > 35)\t\n7. Residence inside the United States\t7. Active infection\t\n\t8. Hypothyroidism or Adrenal Insufficiency\t\n\t9. Previous diagnosis of renal or hepatic failure\t\n\t10. Active malignant disease\t\n\t11. Acute critical illness, heart failure, or acute respiratory failure\t\n\t12. Membership in a vulnerable population (prisoner)\t\n\t13. Pregnancy. Women of childbearing age will be given a pregnancy test during screening to exclude pregnancy\t\n\t14. Lactating females\t\nSubjects\nFigure 1 shows a CONSORT diagram which shows the flow of patient activity from screening through completion of the project. Informed consent was obtained from all participants before any study activities were conducted.\n\nFigure 1 CONSORT diagram showing the flow of participants from screening through study completion.\n\nA total of 63 subjects out of 126 subjects who consented were eligible for randomization into the study with 31 randomized to treatment with rhGH and 32 randomized to placebo. IGF-1 levels were measured on all patients with some patients undergoing dynamic GH testing. Initial inclusion criteria required low initial IGF-1 (<1 standard deviation below mean) and/or a low Peak GH upon stimulation (</= 1.4 ng/mL). Age and gender-specific reference ranges (mean and SDs) were taken from published tables (15). Due to a national unavailability of intravenous L-arginine which developed during the study, dynamic stimulation testing was not available for all participants. Eligible patients were randomized in a double-blind fashion to (Group 1) rhGH subcutaneously or (Group 2) placebo. The vehicle for placebo treatment was normal saline, packaged in multi-dose injectors identical to the rhGH given to the treatment group. The GH treatment arm received a starting dose of 400 μg/day, with increases (or decreases) in dose by 100–200 μg/day based on IGF-1 labs results obtained at 1 and 3 months, until target IGF-1 (in the upper quintile of the range for age and body weight) was reached up to maximum dose of 1,000 μg/day. Doses for participants receiving placebo were also adjusted monthly to maintain the blinding. Treatment continued for a period of 6 months.\n\nTreatment was overseen by a board certified endocrinologist (RA) according to practice guidelines released by the Endocrine Society “Clinical Guidelines for Evaluation and Treatment of Adult Growth Hormone Deficiency” (16, 17). In this study, to accommodate both GH-deficient and GH-sufficient strata, the treatment goal was serum IGF-1 as close as possible to the upper limit for the age-adjusted reference range without exceeding the normal range. The dose of GH (or placebo) was adjusted by the study physician depending on the occurrence and severity of adverse effects.\n\nSafety assessments\nSafety was assessed by clinical evaluations at 1, 3, and 6 and 12 months after initiating therapy. At these evaluations participants and their caregivers were asked about possible adverse effects of GH treatment, including fluid retention, paresthesias, joint stiffness, peripheral edema, arthralgias, and myalgias. Additionally, blood was obtained for assessment of glucose, free T4, lipid profile, and insulin level.\n\nStudy visits and procedures at each visit are depicted in Table 2.\n\nTable 2 Procedures at each visit.\n\nProcedure\tBaseline\t1 month\t3 months\t6 months\t12 months\t\nInformed consent\tX\t\t\t\t\t\nEducation on injections\tX\tX\tX\t\t\t\nGlascow Outcome Scale Extended (GOS-E)\t\t\tX\tX\tX\t\nDisability Rating Scale (DRS)\tX\t\tX\tX\tX\t\nFunctional Independence Measure (FIM)\tX\t\tX\tX\tX\t\nNeuropsych. battery\t\t\t\tX\tX\t\nL-Arginine stimulation test\tX\t\t\t\tX\t\nGlucose, free T4, lipid profile, and insulin\tX\tX\tX\tX\tX\t\nSerum Insulin-like Growth Factor-1 (IGF-1) levels\tX\tX\tX\tX\tX\t\nMedication compliance\t\tX\tX\tX\t\t\nFunctional outcomes and neuropsychological testing\nAn abridged neuropsychological battery was conducted at baseline, with additional tests at 6 and 12 months (Table 2). These measures are designed to capture a broad perspective of functional and cognitive parameters that are important following TBI, and utilizes scales that have a long history in TBI research. Further, there is convincing evidence that they can be reliably administered 6–12 month after injury. Functional Independence Measure (FIM) was tracked at baseline, 3, 6, and 12 months as a measure of the severity of functional impairment, during the course of study enrollment. FIM consists of 18 items, with each item rated on a 7-point scale, ranging from 1 (total assistance) to 7 (complete independence). Global function was measured by the Disability Rating Scale (DRS) and Glasgow Outcome Scale—Extended (GOSE). Cognitive executive function was measured with the Galveston Orientation and Amnesia Test (GOAT), Digit Span and Processing Speed Index from the WAIS-III, the DKEFS Stroop test, Trail Making Test—Part A and B, California Verbal Learning Test-2 (CVLT-2), and Controlled Word Association (COWA). Emotional behavior function was measured with the Brief Symptom Inventory (BSI), Fatigue Severity Scale (FSS), and the Rivermead Post Concussion Symptom Questionnaire. Finally, quality of life was assessed using the Satisfaction with Life Scale (SWLS) and the Short-Form 36 (SF-36).\n\nBiochemical tests\nIGF-1 levels were measured by Quest Laboratories using a liquid chromatrography/mass spectrometry assay. This laboratory also carried out the safety lab assessments (glucose, insulin, lipid profile). See legend at bottom of Table 7 for normative lab values.\n\nStatistical analysis\nIn this Phase II study, for the primary hypothesis, the design of our study was that of a non-futility study, powered to not reject a potentially useful therapy, rather than prove efficacy. All participants in the GH treatment arm did not achieve goal serum IGF-1 values in the first month, data was analyzed in an intention-to-treat manner.\n\nFinal analysis included 40 subjects who completed 6 month follow up measures. Baseline characteristics for the treatment and placebo groups were compared using t-tests or Mann–Whitney-U-test for numerical variables and chi-square or Fisher's exact tests for categorical variables. To compare IGF-1 levels between groups at each visit, Mann–Whitney U-tests were used. Other functional and neuropsychological outcomes listed in Table 2 were compared at both the 6-month visit and the 12 month visit. T-tests, Mann–Whitney U-tests or chi-square tests were performed, as appropriate, to determine if there were significant differences in each outcome. Comparison of adverse events between treatment groups were performed using Fisher's exact tests due to low counts. To determine if participants who withdrew or were lost to follow-up were different than those who completed the 6 month visit, baseline characteristics were compared using the same tests mentioned above. All analyses were performed using SAS 9.4 with a 5% significance level of 5%.\n\nResults\nSixty-three subjects were randomized into the study, 31 in the rhGH intervention group and 32 in the placebo group. Of those randomized, 40 subjects (20 in each group) completed treatment through the 6 month follow up visit. Table 3 shows the baseline characteristics of those participants who completed 6 months of treatment, stratified by treatment and placebo groups. On average, subjects were 31.1 ± 14.3 years old, male (85%), and White (92.5%). There were no significant differences between the intervention and placebo group except in cause of injury and FIM admission scores.\n\nTable 3 Baseline characteristics by treatment group and overall.\n\n\tAll with 6 month f/u\n\n(n = 40)\trhGH\n\n(n = 20)\tPlacebo\n\n(n = 20)\tp-value\t\nAge (years), mean (STD)\t31.1 (14.3)\t32.2 (15.2)\t30.1 (13.7)\t0.656\t\nGender, Male, n (%)\t34 (85)\t17 (85)\t17 (85)\t1.00\t\nEthnicity, Hispanic, n (%)\t6 (15)\t3 (15)\t3 (15)\t1.00\t\nRace, White, n (%)\t37 (92.5)\t18 (90)\t19 (95)\t0.548\t\nInjury Mechanism\t\t\t\t0.037\t\nMotor vehicle, n (%)\t18 (45)\t5 (25)\t13 (65)\t\t\nOther vehicular, n (%)\t15 (37.5)\t9 (45)\t6 (30)\t\t\nFall, n (%)\t3 (7.5)\t3 (15)\t0 (0)\t\t\nOther, n (%)\t4 (10)\t3 (15)\t1 (5)\t\t\nDays from injury to randomization, mean (STD)\t64.1 (35.9)\t65.7 (30.4)\t62.5 (41.4)\t0.782\t\nSeverity as measured by Glascow Coma Score (GCS) and Post-traumatic Amnesia (PTA)*\t\t\t\t0.186\t\nMild, n (%)\t4 (10)\t3 (15)\t1 (5)\t\t\nModerate, n (%)\t3 (7.5)\t0 (0)\t3 (15)\t\t\nSevere, n (%)\t32 (80)\t17 (85)\t15 (75)\t\t\nUnknown/Missing, n (%)\t1 (2.5)\t0 (0)\t1 (5)\t\t\nDisability Rating Scale (DRS), mean (STD)\t8 (4.1)\t7.6 (3)\t8.4 (5.1)\t0.546\t\nFUNCTIONAL INDEPENDENCE MEASURE (FIM) ADMIT\t\nMotor, mean (STD)\t38.3 (18.4)\t31.7 (17.4)\t44.3 (17.6)\t0.033\t\nCognitive, mean (STD)\t9.3 (6.0)\t7.3 (4.8)\t11.1 (6.6)\t0.053\t\nTotal, mean (STD)\t47.7 (22.2)\t39.1 (20.3)\t55.4 (21.5)\t0.022\t\nFIM DISCHARGE\t\nMotor, mean (STD)\t79.0 (22.0)\t80.0 (23.0)\t78.0 (21.5)\t0.784\t\nCognitive, mean (STD)\t23.9 (8.1)\t23.2 (7.1)\t24.6 (9.1)\t0.590\t\nTotal, mean (STD)\t102.9 (28.4)\t103.2 (28.0)\t102.6 (29.5)\t0.952\t\nFIM CHANGE\t\nMotor, mean (STD)\t39.0 (17.1)\t44.5 (17.9)\t33.7 (14.9)\t0.043\t\nCognitive, mean (STD)\t14.5 (7.3)\t15.5 (6.7)\t13.5 (7.9)\t0.408\t\nTotal, mean (STD)\t53.5 (22.2)\t60.4 (21.0)\t47.2 (21.8)\t0.066\t\nIGF-1 below age and gender specific mean, n (%)\t21 (54)\t12 (60)\t9 (47.7)\t0.525\t\nIGF-1<1 STD below mean, n (%)\t6 (15.4)\t3 (15.8)\t3 (15)\t0.946\t\nPeak L-Arginine (n = 24), median [IQR]\t1.3 [0.5, 5.8]\t2.2 [0.6, 5.9]\t1.2 [0.5, 5.7]\t0.395\t\nCVLT Score, mean (STD)\t29.4 (17.0)\t25.4 (18.7)\t33.4 (14.9)\t0.093\t\nCVLT t-score, mean (STD)\t30.5 (17.8)\t27.2 (18.6)\t34 (16.9)\t0.159\t\nTrails A Score, mean (STD)\t54.7 (23.7)\t57.8 (25.9)\t51.9 (22.1)\t0.462\t\nTrails A t-score, mean (STD)\t26.5 (14.6)\t26 (16.3)\t27.1 (13.4)\t0.908\t\nTrails B Score, mean (STD)\t156.4 (97.9)\t142 (106.8)\t167.8 (92.7)\t0.603\t\nTrails B t-score, mean (STD)\t29.7 (18.3)\t28.7 (19.4)\t30.5 (18.1)\t0.908\t\n* Severity defined according to Mayo classification system: Malec et al. (18). Bold values highlight those that meet the pre-specified nominal threshold for statistical significance (p < 0.05).\n\nOnly 24 participants were underwent dynamic GH testing (Table 3), due to the unforeseen unavailability of L-arginine mid-way through the study. Figure 2 shows a scatterplot that depicts there was no correlation between IGF-1 levels and peak GH levels after L-arginine stimulation.\n\nFigure 2 IGF-1 levels vs. peak L-arginine level. The Pearson correlation between IGF-1 and peak L-arginine is 0.03, p > 0.2.\n\nTable 4 shows a crude analysis of IGF-1 levels between the treatment and placebo groups. There was a significant difference between the two groups at 3 and 6 months (p < 0.05), but not after 1 month of treatment. The lack of difference between the 2 groups at 1 month was expected, as the initial dose of rhGH chosen was relative low and time was required to adjust the dose of rhGH properly to therapeutic levels based on measured drug levels. As expected, there were no longer differences in IGF-1 levels at 12 months since treatment with either drug or placebo ended 6 months.\n\nTable 4 IGF-1, crude analysis.\n\nVisit\trhGH, median [IQR]\tPlacebo, median [IQR]\tp-value\t\nBaseline\t218.5 ng/mL [147.0, 263.5]\t194.0 ng/mL [151.0, 279.0]\t0.911\t\n1 Month\t272.5 ng/mL [212.5, 354.0]\t246.0 ng/mL [197.0, 312.0]\t0.337\t\n3 Month\t282.0 ng/mL [183.0, 377.0]\t213.0 ng/mL [158.0, 259.0]\t0.035\t\n6 Month\t245.5 ng/mL [203.5, 321.5]\t173.0 ng/mL [145.0, 237.0]\t0.005\t\n12 Month\t185.5 ng/mL [143.0, 252.0]\t172.5 ng/mL [148.0, 222.0]\t0.836\t\n2-sided p-value from PROC NPAR1WAY Wilcoxon Rank Sum Test; Baseline through 6 Month contain only participants with 6 month follow-up (n = 40; 20 each group); 12 month contains only participants with 12 month follow-up (n = 16 for rhGH, n = 18 for placebo).\n\nTables 5, 6 show the primary outcomes, including neuropsychological testing and functional outcomes, stratified by the treatment and placebo groups. There were no significant differences seen between the two groups for any of the neuropsychological measures or DRS. While neuropsychological testing was conducted at 3 months, the results are not shown in table form as they are consistent with the results at 6 and 12 months, showing no statistically significant differences. However, there was variation in FIM scores, with the rhGH treatment group showing significantly greater change for FIM motor, FIM cognitive, and FIM total from baseline to 6 month follow up (p = 0.02 for all strata). At 12 month follow up FIM motor change and FIM total change were significantly greater in the rhGH treatment group compared to the placebo group (p = 0.02 and p = 0.01, respectively). There was no correction for multiple comparisons.\n\nTable 5 Selected outcomes at 6 months.\n\n\tOverall,\n\nn = 40 median [IQR]\trhGH\n\nn = 20 median [IQR]\tPlacebo\n\nn = 20 median [IQR]\tp-value\t\nDisability Rating Scale (DRS)\t1.5 [0.0, 4.0]\t2.0 [0.0, 4.5]\t1.0 [0.0, 3.5]\t0.59\t\nGalveston Orientation Assessment Test (GOAT)\t99.5 [90.0, 100]\t98.5 [92.5, 100]\t99.5 [89.0, 100]\t1.0\t\nDigit span age standardized score\t9.0 [6.0, 13.0]\t9.0 [6.5, 12.0]\t9.0 [6.0, 13.0]\t0.84\t\nProcessing speed index age standardized score\t84.0 [73.0, 99.0]\t82.5 [73.0, 96.0]\t88.0 [79.0, 99.0]\t0.80\t\nDigit symbol age standardized score\t7.0 [5.0, 9.0]\t6.0 [4.0, 9.0]\t7.0 [6.0, 9.0]\t0.31\t\nSymbol search age standardized score\t8.0 [6.0, 11.0]\t7.0 [5.0, 11.0]\t8.0 [7.0, 11.0]\t0.44\t\nCalifornia Verbal Learning Test (CVLT) T score\t41.5 [32.0, 55.0]\t38.0 [32.0, 59.0]\t42.0 [32.0, 55.0]\t0.81\t\nTrails A T score\t42.0 [34.0, 51.0]\t39.5 [19.5, 53.5]\t43.0 [40.0, 50.0]\t0.34\t\nTrails B T score\t47.0 [33.0, 56.0]\t47.0 [29.5, 53.5]\t47.0 [35.0, 56.0]\t0.46\t\nControlled Oral Word Association Test (COWA) T score\t34.0 [26.0, 44.0]\t31.0 [24.5, 45.5]\t36.0 [33.0. 42.0]\t0.26\t\nBrief Symptom Inventory (BSI)—Average T score\t51.2 [43.9, 59.2]\t51.6 [46.9, 59.6]\t48.8 [43.9, 58.6]\t0.89\t\nFunctional Independence Measure (FIM) Motor\t110.0 (17.9)\t112.2 (12.9)\t107.8 (22.0)\t0.82\t\nFIM cognitive\t31.5 (5.3)\t31.9 (3.7)\t31.2 (6.7)\t0.89\t\nFIM total\t141.5 (21.9)\t144.1 (14.3)\t139.0 (27.6)\t0.99\t\nFIM motor change from baseline\t71.3 (22.3)\t80.1 (18.9)\t63.5 (22.6)\t0.02\t\nFIM cognitive change from baseline\t22.3 (7.1)\t24.7 (6.0)\t20.1 (7.4)\t0.02\t\nFIM total change from baseline\t93.6 (26.6)\t104.8 (20.8)\t83.6 (27.7)\t0.02\t\nPatient Health Questionnaire (PHQ-9)\t9.8 (19.6)\t6.5 (7.5)\t13.2 (26.7)\t0.85\t\nFatigue severity scale\t26.5 (14.9)\t23.6 (13.0)\t29.5 (16.6)\t0.27\t\nRivermead post-concussion symptoms questionnaire\t14.4 (13.9)\t15.2 (15.0)\t13.6 (13.0)\t0.78\t\nSatisfaction with life scale\t21.2 (9.5)\t22.2 (10.2)\t20.3 (9.0)\t0.56\t\nShort Form health survey (SF 36)—physical health\t266.6 (57.8)\t274.6 (50.1)\t258.3.7 (65.4)\t0.74\t\nShort Form health survey (SF 36)—mental health\t246.2 (55.4)\t260.3 (55.4)\t231.3 (52.8)\t0.10\t\n6 month Glascow Outcome Score-Extended (GOSE) score\t\t\t\t0.72\t\n3—Severe disability\t6\t3\t3\t\t\n4\t6\t5\t1\t\t\n5—Moderate disability\t4\t2\t2\t\t\n6\t5\t1\t4\t\t\n7—Good recovery\t11\t4\t7\t\t\n8\t8\t5\t3\t\t\n2-sided p-value (α = 0.05) from PROC NPAR1WAY Wilcoxon Rank sum test. Bold values highlight those that meet the pre-specified nominal threshold for statistical significance (p < 0.05).\n\nTable 6 Selected outcomes at 12 months.\n\n\tOverall, n = 34 median [IQR]/mean (sd)\trhGH n = 16 median [IQR]/mean (sd)\tPlacebo n = 18 median [IQR]/mean (sd)\tp-value\t\nDisability Rating Scale (DRS)\t0.0 [0.0, 4.0]\t0.5 [0.0, 3.0]\t0.0 [0.0, 4.0]\t0.73\t\nGalveston Orientation Assessment Test (GOAT)\t100 [87.0, 100]\t99.5 [91.0, 100]\t100 [87.0, 100]\t0.93\t\nDigit span age standardized score\t11.0 [8.0, 13.0]\t10.5 [8.0, 14.5]\t11.0 [9.0, 13]\t0.93\t\nProcessing speed index age standardized score\t88.0 [79.0, 99.0]\t86.0 [76.0, 111]\t89.5 [81.0, 99.0]\t0.90\t\nDigit symbol age standardized score\t8.0 [6.0, 9.0]\t8.0 [6.0, 12.0]\t8.0 [6.0, 9.0]\t0.68\t\nSymbol search age standardized score\t9.0 [6.0, 11.0]\t9.0 [6.0, 12.0]\t9.0 [7.0, 11.0]\t0.97\t\nCalifornia Verbal Learning Test (CVLT) T score\t43.5 [32.0, 59.0]\t41.0 [28.5, 62.0]\t47.0 [41.0, 59.0]\t0.37\t\nTrails A T score\t49.0 [44.0, 55.0]\t47.0 [26.0, 56.0]\t51.0 [44.0, 55.0]\t0.56\t\nTrails B T score\t52.0 [46.0, 62.0]\t50.0 [35.0, 62.0]\t54.0 [48.0, 62.0]\t0.38\t\nControlled Oral Word Association Test (COWA) T score\t38.0 [30.0, 47.0]\t33.0 [22.0, 47.0]\t38.0 [34.0. 49.0]\t0.30\t\nBrief Symptom Inventory (BSI)—Average T score\t50.3 [45.5, 60.9]\t56.6 [44.8, 63.0]\t49.6 [47.9, 56.6]\t0.82\t\nFunctional Independence Measure (FIM) Motor\t113.5 (14.9)\t115.9 (8.0)\t111.4 (19.1)\t0.56\t\nFIM cognitive\t31.7 (4.3)\t32.2 (3.3)\t31.3 (5.2)\t0.87\t\nFIM total\t142.5 (17.5)\t148.1 (9.5)\t142.7 (22.4)\t0.85\t\nFIM motor change from baseline admit\t74.8 (21.5)\t83.7 (18.6)\t66.8 (21.2)\t0.02\t\nFIM cognitive change from baseline admit\t22.7 (6.1)\t24.9 (5.6)\t20.8 (6.0)\t0.05\t\nFIM total change from baseline admit\t97.5 (25.1)\t108.6 (20.9)\t87.6 (24.9)\t0.01\t\nPatient Health Questionnaire (PHQ-9)\t4.7 (6.0)\t6.2 (7.4)\t3.4 (4.2)\t0.54\t\nFatigue severity scale\t25.4 (14.0)\t24.3 (13.8)\t26.5 (14.6)\t0.54\t\nRivermead post-concussion symptoms questionnaire\t11.1 (10.6)\t11.1 (9.9)\t11.1 (11.5)\t0.86\t\nSatisfaction with life scale\t22.7 (8.1)\t23.4 (8.5)\t22.1 (8.0)\t0.58\t\nShort Form health survey (SF 36)—Physical health\t277.7 (31.9)\t287.8 (33.8)\t268.1 (27.6)\t0.08\t\nShort Form health survey (SF 36)—Mental health\t245.7 (48.0)\t244.9 (59.2)\t246.4 (36.3)\t0.54\t\n12 month Glascow Outcome Score-Extended (GOSE) score\t\t\t\t0.59\t\n3—Severe disability\t4\t1\t3\t\t\n4\t4\t3\t1\t\t\n5—Moderate disability\t1\t0\t1\t\t\n6\t8\t4\t4\t\t\n7—Good recovery\t5\t1\t4\t\t\n8\t12\t7\t5\t\t\n2-sided p-value (α = 0.05) from PROC NPAR1WAY Wilcoxon Rank sum test. Bold values highlight those that meet the pre-specified nominal threshold for statistical significance (p < 0.05).\n\nThere was no difference among safety labs between rhGH and placebo groups as outlined in Table 7. Finally, adverse events between the rhGH and placebo groups for all 63 participants are described in Table 8. Two participants in the rhGH group and 3 participants in the placebo group discontinued the study drug and participation in the project due to adverse events. There was no statistically significant difference in the reporting of undesirable side effects in the treatment group compared to the placebo group.\n\nTable 7 Comparison of safety lab values.\n\n\trhGH,\n\nmean (sd)\tPlacebo,\n\nmean (sd)\tp-value\t\nHDL CHOLESTEROL\t\nBaseline\t39.9 (11.7)\t37.7 (10.2)\t0.84\t\n1 Month\t49.3 (13)\t43.3 (10.5)\t0.13\t\n3 Month\t48.3 (13.3)\t42.2 (9.5)\t0.20\t\n6 Month\t47.3 (10.6)\t44.4 (8.6)\t0.45\t\n12 Month\t48.9 (14.8)\t41.3 (13.9)\t0.23\t\nLDL CHOLESTEROL\t\nBaseline\t108.1 (33.3)\t109.7 (29.6)\t0.54\t\n1 Month\t109.9 (26.8)\t112.7 (33.7)\t0.66\t\n3 Month\t110.2 (35.1)\t100.6 (31)\t0.35\t\n6 Month\t108.9 (34.9)\t102.4 (40.2)\t0.46\t\n12 Month\t108.9 (32.2)\t109.9 (35)\t0.93\t\nTOTAL CHOLESTEROL\t\nBaseline\t172.9 (41)\t176.6 (40.2)\t0.76\t\n1 Month\t183.8 (32.8)\t184.5 (39.1)\t0.88\t\n3 Month\t188.2 (43.9)\t177.9 (36.9)\t0.35\t\n6 Month\t182.5 (40.6)\t187.4 (42.5)\t0.97\t\n12 Month\t186.6 (42.5)\t184.2 (32.5)\t0.74\t\nTRIGLYCERIDES\t\nBaseline\t127.5 (64.1)\t147.3 (67.3)\t0.23\t\n1 Month\t123 (48.4)\t141.9 (56)\t0.23\t\n3 Month\t150.7 (100.9)\t175.6 (91.9)\t0.29\t\n6 Month\t130.8 (72.2)\t192.5 (139.8)\t0.17\t\n12 Month\t143.8 (82.5)\t164.9 (80.2)\t0.38\t\nGLUCOSE\t\nBaseline\t84.4 (9.2)\t86 (8.3)\t0.42\t\n1 Month\t69.7 (25.3)\t80 (16.2)\t0.27\t\n3 Month\t83.6 (22.1)\t90.2 (20.5)\t0.41\t\n6 Month\t88.7 (15.8)\t84.5 (10.3)\t0.25\t\n12 Month\t88.3 (10.8)\t89.1 (12.1)\t0.90\t\nt4, FREE\t\nBaseline\t1.6 (2.1)\t1.1 (0.3)\t0.89\t\n1 Month\t1.4 (1.6)\t1.1 (0.3)\t0.99\t\n3 Month\t1.7 (2.2)\t1.1 (0.2)\t0.33\t\n6 Month\t1.9 (2.3)\t1.2 (0.2)\t0.90\t\n12 Month\t1.2 (0.2)\t1.2 (0.2)\t0.86\t\nINSULIN\t\nBaseline\t3.2 (3.1)\t7.1 (9.5)\t0.21\t\n1 Month\t5.9 (9.9)\t5.4 (5.9)\t0.34\t\n3 Month\t11.9 (20)\t11.1 (14.7)\t0.44\t\n6 Month\t9.8 (15.1)\t8.4 (8.9)\t0.38\t\n12 Month\t7.3 (12.9)\t16.9 (16.9)\t0.04\t\nAll laboratory diagnostics were performed via Quest Diagnostics. Normal lab value references: Cholesterol, total 125–200 mg/dL; HDL Cholesterol > or + 40 mg/dL; Triglycerides <150 mg/dL; LDL Cholesterol <130 mg/dL; Glucose 65–99 mg/dL; T4, free 0.8–1.8 ng/dL; Insulin <17 uIU/mL; Growth hormone: Using the GH stimulation test, the following results would rule out GH deficiency: Adults (> or + 20 years) – Arginine/GHRH > or = 5.1 ng/mL, Children (<20 years) – Arginine/GHRH > or = 10 ng/mL; IGF 1 50–303 ng/mL.\n\nrhGH n = 20 at baseline, 3 and 6 months, n = 16 at 12 months; placebo n = 20 at baseline, 3 and 6 months, n = 18 at 12 months.\n\nTable 8 Comparison of adverse events.\n\n\tAll (n = 63)\trhGH\n\n(n = 31)\tPlacebo\n\n(n = 32)\tp-value\t\nNone reported\t36 (57.1)\t19 (61.3)\t17 (53.1)\t\t\nArthralgia\t8 (12.7)\t2 (6.5)\t6 (18.8)\t0.256\t\nMyalgia\t7 (11.1)\t1 (3.2)\t6 (18.8)\t0.104\t\nHeadache\t4 (6.3)\t1 (3.2)\t3 (9.4)\t0.613\t\nElective surgery\t10 (15.9)\t6 (19.4)\t4 (12.5)\t0.509\t\nUrinary issue\t3 (4.8)\t0 (0)\t3 (9.4)\t0.238\t\nBack pain\t1 (1.6)\t1 (3.2)\t0 (0)\t0.492\t\nBroken ribs and scapula\t1 (1.6)\t0 (0)\t1 (3.1)\t1.0\t\nBruising at injection site\t1 (1.6)\t1 (3.2)\t0 (0)\t0.492\t\nDrowsiness\t2 (3.2)\t1 (3.2)\t1 (3.1)\t1.0\t\nDizziness\t1 (1.6)\t1 (3.2)\t0 (0)\t0.492\t\nDry mouth\t4 (6.3)\t1 (3.2)\t3 (9.4)\t0.613\t\nEye puffiness\t1 (1.6)\t0 (0)\t1 (3.1)\t1.0\t\nHair growth\t1 (1.6)\t1 (3.2)\t0 (0)\t0.492\t\nHair loss\t1 (1.6)\t0 (0)\t1 (3.1)\t1.0\t\nWeight gain\t1 (1.6)\t0 (0)\t1 (3.1)\t1.0\t\nIrritability\t1 (1.6)\t0 (0)\t1 (3.1)\t1.0\t\nNumbness in extremities\t1 (1.6)\t0 (0)\t1 (3.1)\t1.0\t\nPeripheral edema\t1 (1.6)\t0 (0)\t1 (3.1)\t1.0\t\nSeizure\t2 (3.2)\t2 (6.5)\t0 (0)\t0.613\t\nGreatest Action Taken\t\t\t\t0.317\t\nNot Applicable (N/A)\t36 (57.1)\t19 (61.3)\t17 (53.1)\t\t\nNone required\t15 (23.8)\t9 (29)\t6 (18.8)\t\t\nTreatment given\t7 (11.1)\t1 (3.2)\t6 (18.8)\t\t\nStudy drug temporarily stopped\t2 (3.2)\t0 (0)\t2 (6.3)\t\t\nStudy drug discontinued\t3 (4.8)\t2 (6.5)\t1 (3.1)\t\t\nDiscussion\nThere is extensive data from experimental models that GH and IGF-1 are part of the neuro-restorative response after TBI and other acquired brain injuries, such as ischemic stroke, hypoxia-ischemia, and excitotoxins. Treatment with rhGH (19–24) or IGF-1 (19, 25–27) results in improved neurological and cognitive outcome in multiple experimental models. This is particularly the case when therapy is administered early after injury (21, 23). In humans, higher levels of IGF-1 are associated with greater white matter recovery after TBI (16), and improved functional outcome after ischemic stroke (28, 29). These well-established observations formed the scientific rationale for this study.\n\nWhile GH deficiency is a well-recognized consequence of TBI, there is little Class I evidence that rhGH replacement produces clinical benefits. A consequence of such lack of evidence is that screening for GH deficiency (and GH replacement when deficiency is found) is not routinely performed as part of the rehabilitation of TBI survivors. Several small clinical trials provide useful information on the issue of whether replacement therapy with rhGH is clinically beneficial in chronic post-TBI patients (>1 year after injury). High et al. (11) randomized 23 subjects to either GH replacement or placebo. Despite the small sample size, this study clearly showed that GH replacement therapy is effective in increasing serum IGF-1 levels in GH deficient and insufficient subjects, defined as a GH peak under 3 or 8 ng/ml (respectively) upon glucagon stimulation. There was also an indication that GH replacement was associated with improvement in several neuropsychological measures. Moreau et al. (12) conducted an open-label study on 23 TBI patients with GH deficiency (average 7.8 years after injury), compared to 27 controls (not treated with rhGH because they had normal or near-normal somatotropic function (n = 24) or who had contra-indications or refused treatment with rhGH. There were benefits in cognitive function, particularly in attention, memory, and visuospatial abilities. Reimunde et al. (13) treated 11 patients (average 3.7 years after injury) with GH deficiency with rhGH, and compared them with 8 controls without GH deficiency, and found evidence of greater improvement in several cognitive tests in the rhGH treated group. Devesa et al. (10) reported treated 13 TBI patients (2.5 months to 11 years after injury) with rhGH; 5 patients had GH deficiency and 8 did not. In this open label study inconsistent cognitive improvements were noted.\n\nFor the primary hypothesis, the treatment group had significantly greater FIM motor change and FIM total change from baseline that the placebo group at 6 and 12 months. This must be interpreted with caution given that the treatment group had a significant lower FIM motor and total FIM score at baseline as compared to the placebo group. However, the treatment group did achieve a statistically significant improvement in the FIM cognitive change at 6 months despite the two groups having similar FIM cog scores at baseline. However, there was no significance seen in the FIM cognitive change at 12 months that was seen at 6 months testing. The most likely reason for FIM change significance is the imbalance of the functional measures at entry to the study and the possible statistical artifact with regression of the treatment group toward the mean. Additionally, there was no statistically significant difference in the FIM motor, FIM cognitive or FIM total scores between the two groups at either time period.\n\nOur key secondary analyses did show increased IGF-1 levels in those treated with rhGH, however the first measure where IGF-1 levels statistically differed from the placebo group was not seen until month 3. The fact that this effect took at least 3 months to manifest was likely due to the design of the study in which subjects were started at lower rhGH doses which were likely to be well-tolerated. It is possible that more aggressive initial dosing, faster titration of dosing, or longer period of treatment may be necessary to see an observable impact on functional outcomes.\n\nPatients treated with rhGH did achieve higher IGF-1 levels that those receiving placebo, with significant increases seen at 3 and 6 months with IGF-1 levels returning to pre-treatment levels by 12 months. At the 12-month timeframe, both groups had similar IGF-1 levels, indicating that IGF-1 does not stay elevated after cessation of treatment. Clinically this could hold promise since IGF-1 is a putative neuroregenerative factor after TBI. Recent preclinical and clinical data suggests that maintenance of high IGF-1 levels would be beneficial after TBI. IGF-1 is a neurotrophic factor (30), both in experimental models (27) as well as in human diseases such as Alzheimer's disease and vascular dementia (31). It appears that IGF-1 is part of a neurotrophic response to multiple types of injury to the CNS, including TBI (32). In rodents, hypoxic-ischemic injury is ameliorated by recombinant IGF-1 administration (25), regardless of whether the drug is administered 2 h after or 1 h before injury. In the cortical stab injury model, blockade of IGF-1 by an anti-IGF-1 antibody reduces neovascularization at the wound site (30). In the same model, administration of IGF-1 4 and 12 h post-injury resulted in improved motor activity and decrease in apoptotic cells in the peritraumatic area (26). In the fluid percussion model in rats, administration of IGF-1 starting 15 min postinjury and continuing for 14 days resulted improved neuromotor function and enhanced learning ability, which was evident 14 days after injury but not at 2 or 7 days (27).\n\nThere have been studies that found greater incidence of depression and decreased quality of life in GH-deficient subjects (7). While no significance was reached in clinical outcomes at 6 and 12 months, there was a trend in the rhGH treated group to have higher SF 36 Physical health verse the placebo group at 6 months and another trend was seen in the rhGH treated group to having higher scores on the SF 36 mental health at 12 months. Additionally, it is important to note that the majority of those in the study (both drug and placebo groups) achieved relatively good functional outcomes, with high moderate disability to good recovery noted on the Glasgow Outcome Scale-Extended (GOSE) by 12 months. It is possible that rhGH would have a more favorable effect in more severely injured subjects, destined for less favorable recovery.\n\nWe were able to show that treatment with rhGH was overall well-tolerated in subjects with no significant side effects compared to placebo in developing rates of undesirable side effects that can occur with rhGH replacement. In fact, comparison of adverse event data revealed that there were only 2 events in the treatment group requiring temporary cessation or discontinuation of the study drug compared to 3 such events in the placebo group.\n\nThere are limitations that need mentioning. Due to low power based on smaller than projected enrollment and a moderate number of dropouts, we were not able to show that IGF-1 is a prognostic biomarker (meaning that those that have a higher baseline IGF-1 have improved outcomes). Additionally, analysis of the data in only male subjects in order to address sex differences in regards to treatment effect was not able to be performed due to lack of sufficient power. Another limitation of our study was the lack of all patients having dynamic testing of GH. While there are studies that report IGF-1 levels to be highly predictive of GH deficiency (5, 33), GH levels are most routinely assessed following stimulation with arginine, glucagon, or an insulin tolerance test. Due to national shortage of L-arginine during the study, not all patients were assessed with dynamic testing methods.\n\nConclusions\nThis phase IIa, randomized, double-blind, placebo-controlled trial showed that it is feasible to achieve IGF-1 levels in the upper quartile in patients following severe TBI in the subacute period, and that treatment with rhGH is well-tolerated. While the rhGH treatment group did achieve statistically greater FIM total and FIM motor change than the placebo group, it is impossible to ascribe such change to rhGH treatment, since the relatively low sample size made it impossible to adjust for multiple comparisons and possible confounders. Future studies should look at longer treatment periods, consider faster titration of rhGH during the treatment period as well as seek further evidence in supporting rhGH treatment effect on clinical outcomes.\n\nAuthor contributions\nRD, LC,CD, CH, LK, MB, and RD-A contributed to the design of the study, participated in patient enrollment and followup, and was involved in data analysis and preparation or manuscript for publication. RA participated in study design and adjusted medication doses in a blinded fashion.\n\nConflict of interest statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nFunding. National Institute of Disability, Independent Living, and Rehabilitation Research (Award H133A020526). Pfizer contributed rhGH and placebo preparations (Award GA62816O).\n==== Refs\nReferences\n1. Centers for Disease Control and Prevention \nReport to Congress on Traumatic Brain Injury in the United States: Epidemiology and Rehabilitation . Atlanta (2015 ).\n2. Schneider M Schneider HJ Stalla GK . Anterior pituitary hormone abnormalities following traumatic brain injury . J Neurotrauma (2005 ) 22 :937 –46 . 10.1089/neu.2005.22.937 16156709 \n3. Agha A Walker D Perry L Drake WM Chew SL Jenkins PJ . Unmasking of central hypothyroidism following growth hormone replacement in adult hypopituitary patients . Clin Endocrinol. (2007 ) 66 :72 –7 . 10.1111/j.1365-2265.2006.02688.x 17201804 \n4. Agha A Rogers B Sherlock M O'Kelly P Tormey W Phillips J . Anterior pituitary dysfunction in survivors of traumatic brain injury . J Clin Endocrinol Metab. (2004 ) 89 :4929 –36 . 10.1210/jc.2004-0511 15472187 \n5. Aimaretti G Ambrosio MR Di Somma C Fusco A Cannavo S Gasperi M . Traumatic brain injury and subarachnoid haemorrhage are conditions at high risk for hypopituitarism: screening study at 3 months after the brain injury . Clin Endocrinol. (2004 ) 61 :320 –6 . 10.1111/j.1365-2265.2004.02094.x 15355447 \n6. Bondanelli M De Marinis L Ambrosio MR Monesi M Valle D Zatelli MC . Occurrence of pituitary dysfunction following traumatic brain injury . J Neurotrauma (2004 ) 21 :685 –96 . 10.1089/0897715041269713 15253797 \n7. Kelly DF McArthur DL Levin HS Swimmer S Dusik JR Cohan P . Neurobehavioral and quality of life changes associated with Growth Hormone insufficiency after complicated mild, moderate, and severe traumatic brain injury . J Neurotrauma (2006 ) 23 :928 –42 . 10.1089/neu.2006.23.928 16774477 \n8. Carroll PV Christ ER Bengtsson BA Carlsson L Christiansen JS Clemmons D . Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review. Growth Hormone Research Society Scientific Committee . J Clin Endocrinol Metab . (1998 ) 83 :382 –95 . 9467546 \n9. Burman P Broman JE Hetta J Wiklund I Erfurth EM Hagg E . Quality of life in adults with growth hormone (GH) deficiency: response to treatment with recombinant human GH in a placebo-controlled 21-month trial . J Clin Endocrinol Metab . (1995 ) 80 :3585 –90 . 8530603 \n10. Devesa J Reimunde P Devesa P Barbera M Arce V . Growth hormone (GH) and brain trauma . Horm Behav. (2013 ) 63 :331 –44 . 10.1016/j.yhbeh.2012.02.022 22405763 \n11. High WM JrBriones-Galang M Clark JA Gilkison C Mossberg KA Zgaljardic DJ . Effect of growth hormone replacement therapy on cognition after traumatic brain injury . J Neurotrauma (2010 ) 27 :1565 –75 . 10.1089/neu.2009.125 20578825 \n12. Moreau OK Cortet-Rudelli C Yollin E Merlen E Daveluy W Rousseaux M . Growth hormone replacement therapy in patients with traumatic brain injury . J Neurotrauma (2013 ) 30 :998 –1006 . 10.1089/neu.2012.2705 23323993 \n13. Reimunde P Quintana A Castanon B Casteleiro N Vilarnovo Z Otero A . Effects of growth hormone (GH) replacement and cognitive rehabilitation in patients with cognitive disorders after traumatic brain injury . Brain Inj. (2011 ) 25 :65 –73 . 10.3109/02699052.2010.536196 21117918 \n14. Leal-Cerro A Flores JM Rincon M Murillo F Pujol M Garcia-Pesquera F . Prevalence of hypopituitarism and growth hormone deficiency in adults long-term after severe traumatic brain injury . Clin Endocrinol. (2005 ) 62 :525 –32 . 10.1111/j.1365-2265.2005.02250.x 15853820 \n15. Brabant G von zur MA Wuster C Ranke MB Kratzsch J Kiess W . Serum insulin-like growth factor I reference values for an automated chemiluminescence immunoassay system: results from a multicenter study . Horm Res. (2003 ) 60 :53 –60 . 10.1159/000071871 12876414 \n16. Feeney C Sharp DJ Hellyer PJ Jolly AE Cole JH Scott G . Serum insulin-like growth factor-I levels are associated with improved white matter recovery after traumatic brain injury . Ann Neurol. (2017 ) 82 :30 –43 . 10.1002/ana.24971 28574152 \n17. Molitch ME Clemmons DR Malozowski S Merriam GR Shalet SM Vance ML . Evaluation and treatment of adult growth hormone deficiency: an endocrine society clinical practice guideline . J Clin Endocrinol Metab. (2006 ) 91 :1621 –34 . 10.1210/jc.2011-0179 16636129 \n18. Malec JF Brown AW Leibson CL Flaada JT Mandrekar JN Diehl NN . The Mayo classification system for traumatic brain injury severity . J Neurotrauma (2007 ) 24 :1417 –24 . 10.1089/neu.2006.0245 17892404 \n19. Bianchi VE Locatelli V Rizzi L . Neurotrophic and neuroregenerative effects of GH/IGF1 . Int J Mol Sci. (2017 ) 18 :E2441 . 10.3390/ijms18112441 29149058 \n20. Devesa P Reimunde P Gallego R Devesa J Arce VM . Growth hormone (GH) treatment may cooperate with locally-produced GH in increasing the proliferative response of hippocampal progenitors to kainate-induced injury . Brain Inj. (2011 ) 25 :503 –10 . 10.3109/02699052.2011.559611 21456999 \n21. Heredia M Fuente A Criado J Yajeya J Devesa J Riolobos AS . Early growth hormone (GH) treatment promotes relevant motor functional improvement after severe frontal cortex lesion in adult rats . Behav Brain Res. (2013 ) 247 :48 –58 . 10.1016/j.bbr.2013.03.012 23518437 \n22. Ong LK Chow WZ TeBay C Kluge M Pietrogrande G Zalewska K . Growth hormone improves cognitive function after experimental stroke . Stroke (2018 ) 49 :1257 –66 . 10.1161/STROKEAHA.117.020557 29636425 \n23. Scheepens A Sirimanne ES Breier BH Clark RG Gluckman PD Williams CE . Growth hormone as a neuronal rescue factor during recovery from CNS injury . Neuroscience (2001 ) 104 :677 –87 . 11440801 \n24. Zhang H Han M Zhang X Sun X Ling F . The effect and mechanism of growth hormone replacement on cognitive function in rats with traumatic brain injury . PLoS ONE (2014 ) 9 :e108518 . 10.1371/journal.pone.0108518 25268832 \n25. Guan J Williams C Gunning M Mallard C Gluckman P . The effects of IGF-1 treatment after hypoxic-ischemic brain injury in adult rats . J Cereb Blood Flow Metab. (1993 ) 13 :609 –16 . 8314914 \n26. Kazanis I Bozas E Philippidis H Stylianopoulou F . Neuroprotective effects of insulin-like growth factor-I (IGF-I) following penetrating brain injury in rats . Brain Res . (2003 ) 991 :34 –45 . 14575874 \n27. Saatman KE Contreras PC Smith DH Raghupathi R McDermott KL Fernandez SC \nInsulin-like Growth Factor-1 (IGF-1) improves both neurologic motor and cognitive outcome following experimental brain injury . Exp Neurol. (1997 ) 147 :418 –27 .9344566 \n28. Aberg D Jood K Blomstrand C Jern C Nilsson M Isgaard J . Serum IGF-I levels correlate to improvement of functional outcome after ischemic stroke . J Clin Endocrinol Metab. (2011 ) 96 :E1055 –64 . 10.1210/jc.2010-2802 21508132 \n29. Bondanelli M Ambrosio MR Onofri A Bergonzoni A Lavezzi S Zatelli MC . Predictive value of circulating insulin-like growth factor I levels in ischemic stroke outcome . J Clin Endocrinol Metab. (2006 ) 91 :3928 –34 . 10.1210/jc.2006-1040 16882751 \n30. Lopez-Lopez C LeRoith D Torres-Aleman I . Insulin-like growth factor I is required for vessel remodeling in the adult brain . Proc Natl Acad Sci USA. (2004 ) 101 :9833 –8 . 10.1073/pnas.0400337101 15210967 \n31. Watanabe T Miyazaki A Katagiri T Yamamoto H Idei T Iguchi T \nRelationship between serum insulin-like growth factor-I levels and Alzheimer's disease and vascular dementia . J Am Geriatr Soc. (2005 ) 53 :1748 –53 . 10.1111/j.1532-5415.2005.53524.x 16181175 \n32. Walter HJ Berry M Hill DJ Logan A \nSpatial and temporal changes in the insulin-like growth factor (IGF) axis indicate autocrine/paracrine actions of IGF-1 within wounds of the rat brain . Endocrinology (1997 ) 138 :3024 –34 .9202248 \n33. de Boer H Blok GJ van der Veen EA . Clinical aspects of growth hormone deficiency in adults . Endocr Rev. (1995 ) 16 :63 –86 . 10.1210/edrv-16-1-63 7758433\n\n",
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"journal": "Frontiers in endocrinology",
"keywords": "disability rating scale; functional independence measure; glasgow outcome scale; insulin-like growth factor I; short form 36",
"medline_ta": "Front Endocrinol (Lausanne)",
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"references": "29636425;16181175;16774477;23518437;15355447;7758433;9202248;12876414;17201804;8530603;23323993;20578825;8314914;9467546;11440801;16882751;15253797;15472187;21508132;15210967;25268832;14575874;21456999;29149058;16156709;16636129;22405763;9344566;28574152;15853820;21117918;17892404",
"title": "Phase 2 Randomized, Placebo-Controlled Clinical Trial of Recombinant Human Growth Hormone (rhGH) During Rehabilitation From Traumatic Brain Injury.",
"title_normalized": "phase 2 randomized placebo controlled clinical trial of recombinant human growth hormone rhgh during rehabilitation from traumatic brain injury"
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"abstract": "Objectives. The primary objective of this study is to evaluate the use of cinacalcet in the management of hyperparathyroidism in kidney transplant recipients. The secondary objective is to identify baseline factors that predict cinacalcet use after transplantation. Methods. In this single-center retrospective study, we conducted a chart review of all patients having been transplanted from 2003 to 2012 and having received cinacalcet up to kidney transplantation and/or thereafter. Results. Twenty-seven patients were included with a mean follow-up of 2.9 ± 2.4 years. Twenty-one were already taking cinacalcet at the time of transplantation. Cinacalcet was stopped within the first month in 12 of these patients of which 7 had to restart therapy. The main reason for restarting cinacalcet was hypercalcemia. Length of treatment was 23 ± 26 months. There were only 3 cases of mild hypocalcemia. There was no statistically significant association between baseline factors and cinacalcet status a year later. Conclusions. Discontinuing cinacalcet within the first month of kidney transplantation often leads to hypercalcemia. Cinacalcet appears to be an effective treatment of hypercalcemic hyperparathyroidism in kidney transplant recipients. Further studies are needed to evaluate safety and long-term benefits.",
"affiliations": "Division of Nephrology, Maisonneuve-Rosemont Hospital and the Department of Medicine, University of Montreal, Montreal, QC, Canada.;Division of Nephrology, Maisonneuve-Rosemont Hospital and the Department of Medicine, University of Montreal, Montreal, QC, Canada.;Division of Nephrology, Maisonneuve-Rosemont Hospital and the Department of Medicine, University of Montreal, Montreal, QC, Canada.;Division of Nephrology, Maisonneuve-Rosemont Hospital and the Department of Medicine, University of Montreal, Montreal, QC, Canada.;Division of Nephrology, Maisonneuve-Rosemont Hospital and the Department of Medicine, University of Montreal, Montreal, QC, Canada.;Division of Nephrology, Maisonneuve-Rosemont Hospital and the Department of Medicine, University of Montreal, Montreal, QC, Canada.;Division of Nephrology, Maisonneuve-Rosemont Hospital and the Department of Medicine, University of Montreal, Montreal, QC, Canada.;Division of Nephrology, Maisonneuve-Rosemont Hospital and the Department of Medicine, University of Montreal, Montreal, QC, Canada.;Division of Nephrology, Maisonneuve-Rosemont Hospital and the Department of Medicine, University of Montreal, Montreal, QC, Canada.;Division of Nephrology, Maisonneuve-Rosemont Hospital and the Department of Medicine, University of Montreal, Montreal, QC, Canada.;Division of Nephrology, Maisonneuve-Rosemont Hospital and the Department of Medicine, University of Montreal, Montreal, QC, Canada.;Division of Nephrology, Maisonneuve-Rosemont Hospital and the Department of Medicine, University of Montreal, Montreal, QC, Canada.",
"authors": "Mawad|Habib|H|;Bouchard|Hugues|H|;Tran|Duy|D|;Ouimet|Denis|D|;Lafrance|Jean-Philippe|JP|0000-0001-7876-0446;Bell|Robert Zoël|RZ|;Bezzaoucha|Sarah|S|;Boucher|Anne|A|;Collette|Suzon|S|;Pichette|Vincent|V|;Senécal|Lynne|L|;Vallée|Michel|M|0000-0002-4856-5057",
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"doi": "10.1155/2017/8720283",
"fulltext": "\n==== Front\nJ TransplantJ TransplantJTRANSJournal of Transplantation2090-00072090-0015Hindawi 10.1155/2017/8720283Clinical StudyRetrospective Study Looking at Cinacalcet in the Management of Hyperparathyroidism after Kidney Transplantation Mawad Habib Bouchard Hugues Tran Duy Ouimet Denis http://orcid.org/0000-0001-7876-0446Lafrance Jean-Philippe Bell Robert Zoël Bezzaoucha Sarah Boucher Anne Collette Suzon Pichette Vincent Senécal Lynne http://orcid.org/0000-0002-4856-5057Vallée Michel \n*\nDivision of Nephrology, Maisonneuve-Rosemont Hospital and the Department of Medicine, University of Montreal, Montreal, QC, Canada*Michel Vallée: mvallee.hmr@ssss.gouv.qc.caAcademic Editor: Simon C. Robson\n\n2017 13 3 2017 2017 872028310 11 2016 26 2 2017 Copyright © 2017 Habib Mawad et al.2017This 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.\nObjectives. The primary objective of this study is to evaluate the use of cinacalcet in the management of hyperparathyroidism in kidney transplant recipients. The secondary objective is to identify baseline factors that predict cinacalcet use after transplantation. Methods. In this single-center retrospective study, we conducted a chart review of all patients having been transplanted from 2003 to 2012 and having received cinacalcet up to kidney transplantation and/or thereafter. Results. Twenty-seven patients were included with a mean follow-up of 2.9 ± 2.4 years. Twenty-one were already taking cinacalcet at the time of transplantation. Cinacalcet was stopped within the first month in 12 of these patients of which 7 had to restart therapy. The main reason for restarting cinacalcet was hypercalcemia. Length of treatment was 23 ± 26 months. There were only 3 cases of mild hypocalcemia. There was no statistically significant association between baseline factors and cinacalcet status a year later. Conclusions. Discontinuing cinacalcet within the first month of kidney transplantation often leads to hypercalcemia. Cinacalcet appears to be an effective treatment of hypercalcemic hyperparathyroidism in kidney transplant recipients. Further studies are needed to evaluate safety and long-term benefits.\n==== Body\n1. Introduction\nSuccessful kidney transplantation corrects many abnormalities of bone and mineral metabolism associated with end stage renal disease (ESRD). Nevertheless, hyperparathyroidism does not completely resolve in a significant number of patients even after several years of restored renal function [1]. The severity of preexisting hyperparathyroidism seems to be one of the most important predictors of persistence after transplantation [2]. Other factors include time spent on dialysis and longstanding hyperparathyroidism. The ongoing functional demand for parathyroid hormone (PTH) in ESRD causes morphological transformation of parathyroid tissue [3]. Following kidney transplantation, PTH levels usually decrease considerably within the first 3 to 6 months [4]. However, complete normalization does not often ensue because of the slow involution rate of hyperplastic tissue [5].\n\nResidual hyperparathyroidism in kidney transplant recipients is commonly associated with hypercalcemia which generally manifests 3 to 6 months after transplantation [6]. Persistent hyperparathyroidism has been identified as an independent risk factor for fractures in kidney transplant recipients [7]. Furthermore, It has been associated with decreased allograft survival and increased mortality [8]. Optimal management of hypercalcemic hyperparathyroidism in kidney transplant recipients is not known. Many transplant nephrologists favor parathyroidectomy as primary approach. Observational studies have suggested that cinacalcet might also be an effective option [9]. In a recent randomized controlled trial, cinacalcet was found to be superior to placebo in correcting hypercalcemia and PTH levels [10]. There were no new safety signals although follow-up was rather short. These findings are very encouraging but further studies are needed particularly in regard to long-term clinical outcomes [11]. Moreover, there is an unresolved issue as to whether cinacalcet should be discontinued or pursued at the time of kidney transplantation.\n\nThe primary objective of this study is to evaluate the patterns of use of cinacalcet in the management of hyperparathyroidism in a transplant setting. We will report our local experience and compare the different management options that were attempted. The secondary objective is to identify baseline factors that predict cinacalcet use 1 year after transplantation. This would help clinicians determine which patients are more likely to profit from early parathyroidectomy versus medical management until spontaneous resolution.\n\n2. Materials and Methods\nThis retrospective study was carried out in a large academic hospital in Montreal, Quebec, Canada. The study protocol was approved by our institution's research ethics committee. All patients receiving cinacalcet up to kidney transplantation and/or thereafter were included. Patients were identified using electronic health records. Data were collected from the time of transplantation up to January 1, 2013, by reviewing medical charts and laboratory results. Laboratory results were available the day of transplantation, every 3 months in the first 2 years, and every 6 months thereafter. Presumptive cause of ESRD was extracted from patients' pretransplant assessment notes. It was not always specified whether the diagnosis was biopsy proven or not.\n\nCollected data were analyzed using commercially available statistical software. Continuous variables were expressed as mean ± standard deviation. Fisher's exact test was used to compare categorical variables and the Mann-Whitney-Wilcoxon test was used for continuous variables. Baseline variables with p values < 0.2 were considered in univariate and multivariate logistic regression models.\n\n3. Results\nA total of 449 patients underwent kidney transplantation from March 2003 to October 2012. Baseline PTH was available in 390 patients and was 48.6 ± 45.7 pmol/L. Twenty-seven patients were included in the study consisting mainly of middle-aged Caucasian men (Table 1). Graft function was satisfactory throughout follow-up with a mean estimated glomerular filtration rate 1 year after transplantation of 49 ± 16 mL/min per 1.73 m2. Six patients initiated cinacalcet only after transplantation. The remaining 21 were already taking cinacalcet prior to transplantation. Cinacalcet was stopped within the first month in 12 of these patients of which 7 had to restart therapy (Figure 1). The main reason for restarting cinacalcet was hypercalcemia. Calcium levels increased after kidney transplantation especially in the first 6 months (Figure 2). On the other hand, PTH decreased considerably in the first 3 months but remained well above normal for the remainder of the follow-up (Figure 3). Baseline PTH in the study participants was 99.6 ± 79.3 pmol/L. Serum phosphate levels decreased rapidly after transplantation and remained within the normal range (Figure 4).\n\nCinacalcet use among all participants averaged 23.5 ± 25.6 months. There were only 3 cases of mild hypocalcemia (lowest value of 1.98 mmol/L). There were no reports of adverse events and all attempts to stop cinacalcet or reduce dose aimed to lighten the patient's “pill burden.” Average length of follow-up was 2.9 ± 2.4 years. At the end of the study, only 8 patients had stopped cinacalcet. Attempts to reduce dose or to stop cinacalcet altogether were carried out in over 80% of patients (Figure 2). One patient underwent parathyroidectomy while 5 others were awaiting operating-room availability or surgery consultation.\n\nAmong the 21 patients already taking cinacalcet, follow-up of at least 12 months was available in 17 (Table 2). Using logistic regression models, there was no statistically significant association between baseline factors and cinacalcet status at one year (Table 3).\n\nTypical maintenance immunosuppression included prednisone, mycophenolate, and a calcineurin inhibitor (Table 4). Most patients were receiving calcium and a vitamin D analogue during the first month after transplantation. In the following months and years, these rates dropped considerably.\n\n4. Discussion\nThese results bring to light existing challenges in the management of hyperparathyroidism in kidney transplant recipients. In the majority of patients, efforts were made to either stop cinacalcet or reduce the dose. These attempts were predominantly unsuccessful owing to recurrent hypercalcemia. Consistent with previous studies, laboratory results revealed a transient increase in calcemia within the first 3 months after transplantation. This is likely due to restored calcitriol production and PTH-induced calcium release from bone [6, 12]. Hypercalcemia is presumably the reason why the majority of these patients did not have vitamin D or calcium supplements as would be expected with prolonged corticosteroid therapy. Cinacalcet use among all participants averaged 23.5 ± 25.6 months. There were no significant adverse effects reported suggesting good tolerability. These results support cinacalcet use in a transplant setting as a bridge to parathyroidectomy or as an alternative in the case of hypercalcemia. However, it is important to reiterate that cinacalcet is not yet approved for use in renal transplant recipients. Moreover it is not clear whether either of these treatments is appropriate even if safety and biochemical efficacy are assumed [11]. Bone disease following kidney transplantation is a complex problem with multiple etiologies related to dialysis, corticosteroid therapy, calcineurin inhibitors, and persistent hyperparathyroidism [13]. Studies of bone histomorphology in renal transplant patients have shown surprisingly high prevalence of adynamic bone disease (low-bone turnover) despite hypercalcemia and hyperparathyroidism [14]. Therefore, there is a concern that cinacalcet may exacerbate low-bone turnover [15]. There is in fact a lack of published data showing improved clinical outcomes such as reduced fractures or increased bone mineral density. This raises the question of cost-effectiveness in comparison with parathyroidectomy [16] especially given prolonged survival of renal transplant recipients.\n\nFor our secondary objective, we could not identify any baseline factors predictive of cinacalcet status one year after kidney transplantation. This is certainly due to insufficient statistical power because of limited sample size.\n\n5. Limitation of the Study\nInherent to the study's retrospective design, selection and information biases could not be excluded. Additionally, this was a single-center study and there was no control group for comparison. Sample size was rather small but similar to other published observational studies. However, the length of follow-up and the duration of cinacalcet use after kidney transplantation were longer than previous studies.\n\n6. Conclusion\nSpontaneous resolution of hyperparathyroidism after transplantation is uncommon despite lengthy follow-up and satisfactory graft function. Discontinuing cinacalcet within the first month of kidney transplantation often leads to hypercalcemia. Cinacalcet appears to be an effective treatment of persistent hyperparathyroidism and may serve as a bridge to parathyroidectomy or as an alternative. Further studies are needed to evaluate safety and long-term benefits. No baseline factors could be identified as predictors of cinacalcet use 1 year after transplantation.\n\nAcknowledgments\nThe authors thank Naoual Elftouh from Maisonneuve-Rosemont Hospital for her help in the statistical analysis of the data.\n\nDisclosure\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest regarding the publication of this paper.\n\nFigure 1 Patterns of cinacalcet use. All reported follow-up times start at kidney transplantation.\n\nFigure 2 Evolution of corrected calcium after kidney transplantation. ∗p value < 0.05 compared to t = 0.\n\nFigure 3 Evolution of parathyroid hormone after kidney transplantation. ∗p value < 0.05 compared to t = 0.\n\nFigure 4 Evolution of serum phosphate after kidney transplantation. ∗p value < 0.05 compared to t = 0.\n\nTable 1 Patient characteristics.\n\nCharacteristics\t\nn = 27\t\nAge (years)\t52 ± 12\t\nMale\t17 (63%)\t\nBody mass index (kg/m2)\t26.9 ± 5.2\t\nEthnicity\t \t\n Caucasian\t16 (59%)\t\n Black\t8 (30%)\t\nPresumptive cause of ESRD\t \t\n Hypertensive nephrosclerosis\t6 (22%)\t\n Chronic glomerulonephritis\t6 (22%)\t\n Diabetic nephropathy\t5 (19%)\t\n Other\t10 (37%)\t\nComorbidities\t \t\n Hypertension\t26 (97%)\t\n Dyslipidemia\t20 (74%)\t\n Diabetes\t7 (26%)\t\n Coronary artery disease\t9 (33%)\t\n Smoking\t5 (19%)\t\nDialysis modality\t \t\n In-center hemodialysis\t17 (63%)\t\n Home hemodialysis\t4 (15%)\t\n Peritoneal dialysis\t5 (19%)\t\n Predialysis\t1 (4%)\t\nTime spent on dialysis (years)\t5.8 ± 4.3\t\nPrior kidney transplantation\t3 (11%)\t\nPrior subtotal parathyroidectomy\t2 (7%)\t\nFollow-up after transplant (years)\t2.9 ± 2.4\t\nCinacalcet use after transplant (months)\t23.5 ± 25.6\t\nContinuous variables are expressed as mean ± standard deviation; categorical variables are expressed as count (%).\n\nTable 2 Baseline characteristics according to cinacalcet status 1 year after kidney transplantation.\n\nCharacteristics\tNo cinacalcet\nn = 6\tCinacalcet \nn = 11\t\np value\t\nAge (years)\t51 ± 11\t55 ± 10\tns\t\nMale\t4 (67%)\t9 (82%)\tns\t\nBody mass index (kg/m2)\t23.4 ± 4.9\t27.1 ± 4.0\t0.105\t\nEthnicity\t \t \t \t\n Caucasian\t3 (50%)\t6 (55%)\tns\t\n Black\t2 (33%)\t4 (36%)\tns\t\nPresumptive cause of ESRD\t \t \t \t\n Diabetic nephropathy\t1 (17%)\t3 (27%)\tns\t\n Hypertensive nephrosclerosis\t2 (33%)\t3 (27%)\tns\t\n Polycystic renal disease\t1 (17%)\t3 (27%)\tns\t\n Other\t2 (33%)\t2 (18%)\tns\t\nComorbidities\t \t \t \t\n Hypertension\t6 (100%)\t11 (100%)\tns\t\n Dyslipidemia\t4 (67%)\t9 (82%)\tns\t\n Diabetes\t1 (17%)\t4 (36%)\tns\t\n Coronary artery disease\t2 (33%)\t4 (36%)\tns\t\n Heart failure\t0 (0%)\t6 (55%)\t0.043\t\n Smoking\t1 (17%)\t1 (9%)\tns\t\nDialysis modality\t \t \t \t\n In-center hemodialysis\t4 (67%)\t6 (55%)\tns\t\n Home hemodialysis\t1 (17%)\t3 (27%)\tns\t\n Peritoneal dialysis\t1 (17%)\t2 (18%)\tns\t\nTime spent on dialysis (years)\t8.7 ± 5.0\t6.9 ± 3.8\tns\t\nBaseline biochemistry\t \t \t \t\n PTH (pmol/L)\t142.5 ± 140.2\t66.7 ± 35.0\t0.102\t\n Corrected calcium (mmol/L)\t2.3 ± 0.1\t2.3 ± 0.1\tns\t\n Phosphate (mmol/L)\t1.6 ± 0.6\t1.2 ± 0.3\t0.196\t\nPTH: parathyroid hormone; ns: not significant; p values < 0.05 are considered statistically significant; p values < 0.2 are indicated because variables were included in logistic regression model; continuous variables are expressed as mean ± standard deviation; categorical variables are expresses as count (%).\n\nTable 3 Logistic regression models for cinacalcet status 1 year after kidney transplantation.\n\nVariables\tUnit change\t Univariate model\t Multivariate model\t\nOR\t95% CI\tOR\t95% CI\t\nBMI (kg/m2)\t5\t2.79\t0.79; 9.82\t1.97\t0.52; 7.52\t\nPhosphate (mmol/L)\t0.1\t0.80\t0.60; 1.08\t0.92\t0.74; 1.13\t\nPTH (pmol/L)\t10\t0.89\t0.76; 1.05\t1.04\t0.69; 1.56\t\nHeart failure\t1 versus 0\t15.37\t0.55; 427.5\t9.52\t0.39; 231.3\t\nBMI: body mass index; PTH: parathyroid hormone; only variables with p values < 0.2 were included in logistic regression models; the odds ratio (OR) of having cinacalcet 1 year after kidney transplantation is reported for a determined unit change of each variable using univariate and multivariate models. Each odds ratio is reported with a 95% confidence interval (95% CI).\n\nTable 4 Medication after kidney transplantation.\n\nTime after transplantation\t0\t1 month\t12 months\t24 months\t36 months\t\nAvailable data\t27\t27\t19\t15\t11\t\nCalcium carbonate\t19 (70%)\t13 (48%)\t4 (21%)\t2 (13%)\t0 (0%)\t\nVitamin D analogues\t21 (78%)\t18 (67%)\t7 (37%)\t6 (40%)\t4 (36%)\t\n Cholecalciferol\t1 (4%)\t0 (0%)\t1 (5%)\t0 (0%)\t1 (9%)\t\n Alfacalcidol\t13 (48%)\t11 (41%)\t3 (16%)\t4 (27%)\t2 (18%)\t\n Calcitriol\t8 (30%)\t7 (26%)\t3 (16%)\t2 (13%)\t2 (18%)\t\nBisphosphonate\t \t16 (59%)\t12 (63%)\t10 (67%)\t8 (73%)\t\nImmunosuppression\t \t \t \t \t \t\n Prednisone\t \t27 (100%)\t19 (100%)\t15 (100%)\t11 (100%)\t\n CNI\t \t25 (93%)\t17 (89%)\t12 (80%)\t8 (73%)\t\n Mycophenolate\t \t27 (100%)\t16 (84%)\t13 (87%)\t9 (82%)\t\n Azathioprine\t \t0 (0%)\t1 (5%)\t2 (13%)\t2 (18%)\t\n mTOR inhibitor\t \t2 (7%)\t2 (11%)\t3 (20%)\t3 (27%)\t\nCNI: calcineurin inhibitors; mTOR: mammalian target of rapamycin; results are expressed as count (% of the available data at that point in time).\n==== Refs\n1 Torres A. Lorenzo V. Salido E. Calcium metabolism and skeletal problems after transplantation Journal of the American Society of Nephrology 2002 13 2 551 558 11805187 \n2 Messa P. Sindici C. Cannella G. Persistent secondary hyperparathyroidism after renal transplantation Kidney International 1998 54 5 1704 1713 10.1046/j.1523-1755.1998.00142.x 2-s2.0-0031759893 9844148 \n3 Drüeke T. B. Cell biology of parathyroid gland hyperplasia in chronic renal failure Journal of the American Society of Nephrology 2000 11 6 1141 1152 2-s2.0-0343238871 10820180 \n4 Bonarek H. Merville P. Bonarek M. Reduced parathyroid functional mass after successful kidney transplantation Kidney International 1999 56 2 642 649 10.1046/j.1523-1755.1999.00589.x 2-s2.0-0032782758 10432404 \n5 Parfitt A. M. The hyperparathyroidism of chronic renal failure: a disorder of growth Kidney International 1997 52 1 3 9 10.1038/ki.1997.297 2-s2.0-0030861757 9211340 \n6 Evenepoel P. Claes K. Kuypers D. Maes B. Bammens B. Vanrenterghem Y. Natural history of parathyroid function and calcium metabolism after kidney transplantation: a single-centre study Nephrology Dialysis Transplantation 2004 19 5 1281 1287 10.1093/ndt/gfh128 2-s2.0-2442449233 \n7 Perrin P. Caillard S. Javier R. M. Persistent hyperparathyroidism is a major risk factor for fractures in the five years after kidney transplantation American Journal of Transplantation 2013 13 10 2653 2663 10.1111/ajt.12425 2-s2.0-84884903740 24034142 \n8 Pihlstrøm H. Dahle D. O. Mjøen G. Increased risk of all-cause mortality and renal graft loss in stable renal transplant recipients with hyperparathyroidism Transplantation 2015 99 2 351 359 10.1097/TP.0000000000000583 2-s2.0-84923015231 25594550 \n9 Cohen J. B. Gordon C. E. Balk E. M. Francis J. M. Cinacalcet for the treatment of hyperparathyroidism in kidney transplant recipients: a systematic review and meta-analysis Transplantation 2012 94 10 1041 1048 10.1097/tp.0b013e31826c3968 2-s2.0-84870246784 23069843 \n10 Evenepoel P. Cooper K. Holdaas H. A randomized study evaluating cinacalcet to treat hypercalcemia in renal transplant recipients with persistent hyperparathyroidism American Journal of Transplantation 2014 14 11 2545 2555 10.1111/ajt.12911 2-s2.0-84911985198 25225081 \n11 Coyne D. W. Santos R. D. Evaluating the safety and rationale for cinacalcet posttransplant hyperparathyroidism and hypercalcemia American Journal of Transplantation 2014 14 11 2446 2447 10.1111/ajt.12913 2-s2.0-84911987315 25223316 \n12 Rodriguez M. Martin-Malo A. Martinez M. E. Torres A. Felsenfeld A. J. Llach F. Calcemic response to parathyroid hormone in renal failure: role of phosphorus and its effect on calcitriol Kidney International 1991 40 6 1055 1062 10.1038/ki.1991.314 2-s2.0-0026054778 1762306 \n13 Leca N. Laftavi M. Gundroo A. Early and severe hyperparathyroidism associated with hypercalcemia after renal transplant treated with cinacalcet American Journal of Transplantation 2006 6 10 2391 2395 10.1111/j.1600-6143.2006.01475.x 2-s2.0-33748478391 16869807 \n14 Borchhardt K. Sulzbacher I. Benesch T. Födinger M. Sunder-Plassmann G. Haas M. Low-turnover bone disease in hypercalcemic hyperparathyroidism after kidney transplantation American Journal of Transplantation 2007 7 11 2515 2521 10.1111/j.1600-6143.2007.01950.x 2-s2.0-35248873344 17725680 \n15 Borchhardt K. A. Diarra D. Sulzbacher I. Benesch T. Haas M. Sunder-Plassmann G. Cinacalcet decreases bone formation rate in hypercalcemic hyperparathyroidism after kidney transplantation American Journal of Nephrology 2010 31 6 482 489 10.1159/000304180 2-s2.0-77951534081 20431285 \n16 Narayan R. Perkins R. M. Berbano E. P. Parathyroidectomy versus cinacalcet hydrochloride-based medical therapy in the management of hyperparathyroidism in ESRD: a cost utility analysis American Journal of Kidney Diseases 2007 49 6 801 813 10.1053/j.ajkd.2007.03.009 2-s2.0-34248998172 17533023\n\n",
"fulltext_license": "CC BY",
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"title": "Retrospective Study Looking at Cinacalcet in the Management of Hyperparathyroidism after Kidney Transplantation.",
"title_normalized": "retrospective study looking at cinacalcet in the management of hyperparathyroidism after kidney transplantation"
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"abstract": "We report the case of a 56 year-old Gabonese man under treatment by candesartan-hydrochlorothiazide for essential hypertension. After 2 months of treatment, he presented with pneumonia and severe respiratory failure. The chest radiography showed centrilobular nodules resembling tumor metastases, but no evidence of a primary tumor. Laboratory and imaging found no evidence of infectious or autoimmune disease. The computed tomography findings led to a diagnosis of diffuse alveolitis. The candesartan treatment was stopped and oral corticosteroid therapy (50 mg/day) initiated. The rapid favorable outcome supports the diagnosis of a drug-induced infiltrative lung disease.",
"affiliations": "Service de Médecine A, Centre Hospitalier de Libreville, Libreville, Gabon. ibabajose@yahoo.fr",
"authors": "Iba Ba|J|J|;Mounguengui|D|D|;Ella Ondo|T|T|",
"chemical_list": "D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; D006852:Hydrochlorothiazide; C081643:candesartan",
"country": "France",
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"issue": "22(2)",
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"medline_ta": "Med Sante Trop",
"mesh_terms": "D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D006801:Humans; D006852:Hydrochlorothiazide; D008171:Lung Diseases; D008297:Male; D008875:Middle Aged; D011650:Pulmonary Alveoli; D011859:Radiography; D013777:Tetrazoles",
"nlm_unique_id": "101581406",
"other_id": null,
"pages": "137-9",
"pmc": null,
"pmid": "22890134",
"pubdate": "2012",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Centrilobular nodules with ground-glass opacities in the lungs.",
"title_normalized": "centrilobular nodules with ground glass opacities in the lungs"
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"companynumb": "PHHY2013GA047163",
"fulfillexpeditecriteria": "1",
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"abstract": "Several immune-related adverse events (irAEs) are reported to be associated with therapeutic efficacy of immune checkpoint inhibitors, yet whether pituitary dysfunction, a life-threatening irAE, affects overall survival (OS) in patients with malignancies is unclear. This prospective study examined the association of pituitary dysfunction (pituitary-irAE) with OS of patients with non-small cell lung carcinoma (NSCLC) or malignant melanoma (MM).\n\n\n\nA total of 174 patients (NSCLC, 108; MM, 66) treated with ipilimumab, nivolumab, pembrolizumab, or atezolizumab at Nagoya University Hospital were evaluated for OS and the development of pituitary-irAE. Kaplan-Meier curves of OS as a function of the development of pituitary-irAE were produced with the log-rank test as a primary endpoint.\n\n\n\nPituitary-irAE was observed in 16 patients (4 (3.7%) with NSCLC, 12 (18.2%) with MM) having two different disease types: hypophysitis with deficiency of multiple anterior pituitary hormones accompanied by pituitary enlargement, and isolated adrenocorticotropic hormone (ACTH) deficiency without pituitary enlargement. Among these patients, 6 developed pituitary-irAE while being treated with ipilimumab (6/25 patients (24.0%) treated with ipilimumab) and 10 developed pituitary-irAE during treatment with nivolumab or pembrolizumab (10/167 (6.0%)). All 16 patients had ACTH deficiency and were treated with physiological doses of hydrocortisone. The development of pituitary-irAE was associated with better OS in patients with NSCLC (not reached vs 441 (95% CI not calculated) days, p<0.05) and MM (885 (95% CI 434 to 1336) vs 298 (95% CI 84 to 512) days, p<0.05).\n\n\n\nIn our study cohort, the incidence of pituitary-irAE was higher than previously reported and the development of pituitary-irAE predicted better prognosis for both NSCLC and MM when patients were treated with physiological doses of hydrocortisone.\n\n\n\nUMIN000019024.",
"affiliations": "Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan siwama@med.nagoya-u.ac.jp arima105@med.nagoya-u.ac.jp.;Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan.;Department of Otorhinolaryngology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Otorhinolaryngology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan.;Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan siwama@med.nagoya-u.ac.jp arima105@med.nagoya-u.ac.jp.",
"authors": "Kobayashi|Tomoko|T|;Iwama|Shintaro|S|0000-0002-3281-0337;Yasuda|Yoshinori|Y|;Okada|Norio|N|;Okuji|Takayuki|T|;Ito|Masaaki|M|;Onoue|Takeshi|T|;Goto|Motomitsu|M|;Sugiyama|Mariko|M|;Tsunekawa|Taku|T|;Takagi|Hiroshi|H|;Hagiwara|Daisuke|D|;Ito|Yoshihiro|Y|;Suga|Hidetaka|H|;Banno|Ryoichi|R|;Yokota|Kenji|K|;Hase|Tetsunari|T|;Morise|Masahiro|M|;Hashimoto|Naozumi|N|;Ando|Masahiko|M|;Fujimoto|Yasushi|Y|;Hibi|Hideharu|H|;Sone|Michihiko|M|;Ando|Yuichi|Y|;Akiyama|Masashi|M|;Hasegawa|Yoshinori|Y|;Arima|Hiroshi|H|",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1136/jitc-2020-000779",
"fulltext": "\n==== Front\nJ Immunother Cancer\nJ Immunother Cancer\njitc\njitc\nJournal for Immunotherapy of Cancer\n2051-1426 BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\njitc-2020-000779\n10.1136/jitc-2020-000779\nClinical/Translational Cancer Immunotherapy\n1506\n2435\nOriginal researchPituitary dysfunction induced by immune checkpoint inhibitors is associated with better overall survival in both malignant melanoma and non-small cell lung carcinoma: a prospective study\nKobayashi Tomoko 1 http://orcid.org/0000-0002-3281-0337Iwama Shintaro 1 Yasuda Yoshinori 1 Okada Norio 1 Okuji Takayuki 1 Ito Masaaki 1 Onoue Takeshi 1 Goto Motomitsu 1 Sugiyama Mariko 1 Tsunekawa Taku 1 Takagi Hiroshi 1 Hagiwara Daisuke 1 Ito Yoshihiro 12 Suga Hidetaka 1 Banno Ryoichi 13 Yokota Kenji 4 Hase Tetsunari 5 Morise Masahiro 5 Hashimoto Naozumi 5 Ando Masahiko 6 Fujimoto Yasushi 7 Hibi Hideharu 8 Sone Michihiko 7 Ando Yuichi 9 Akiyama Masashi 4 Hasegawa Yoshinori 5 Arima Hiroshi 1 \n1 \nDepartment of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan\n\n\n2 \nDepartment of CKD Initiatives Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan\n\n\n3 \nResearch Center of Health, Physical Fitness and Sports, Nagoya University, Nagoya, Japan\n\n\n4 \nDepartment of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan\n\n\n5 \nDepartment of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan\n\n\n6 \nCenter for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan\n\n\n7 \nDepartment of Otorhinolaryngology, Nagoya University Graduate School of Medicine, Nagoya, Japan\n\n\n8 \nDepartment of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan\n\n\n9 \nDepartment of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan\n\nCorrespondence to Dr Shintaro Iwama; siwama@med.nagoya-u.ac.jp; Dr Hiroshi Arima; arima105@med.nagoya-u.ac.jp\n2020 \n30 6 2020 \n8 2 e00077926 5 2020 © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2020http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.Background\nSeveral immune-related adverse events (irAEs) are reported to be associated with therapeutic efficacy of immune checkpoint inhibitors, yet whether pituitary dysfunction, a life-threatening irAE, affects overall survival (OS) in patients with malignancies is unclear. This prospective study examined the association of pituitary dysfunction (pituitary-irAE) with OS of patients with non-small cell lung carcinoma (NSCLC) or malignant melanoma (MM).\n\nMethods\nA total of 174 patients (NSCLC, 108; MM, 66) treated with ipilimumab, nivolumab, pembrolizumab, or atezolizumab at Nagoya University Hospital were evaluated for OS and the development of pituitary-irAE. Kaplan-Meier curves of OS as a function of the development of pituitary-irAE were produced with the log-rank test as a primary endpoint.\n\nResults\nPituitary-irAE was observed in 16 patients (4 (3.7%) with NSCLC, 12 (18.2%) with MM) having two different disease types: hypophysitis with deficiency of multiple anterior pituitary hormones accompanied by pituitary enlargement, and isolated adrenocorticotropic hormone (ACTH) deficiency without pituitary enlargement. Among these patients, 6 developed pituitary-irAE while being treated with ipilimumab (6/25 patients (24.0%) treated with ipilimumab) and 10 developed pituitary-irAE during treatment with nivolumab or pembrolizumab (10/167 (6.0%)). All 16 patients had ACTH deficiency and were treated with physiological doses of hydrocortisone. The development of pituitary-irAE was associated with better OS in patients with NSCLC (not reached vs 441 (95% CI not calculated) days, p<0.05) and MM (885 (95% CI 434 to 1336) vs 298 (95% CI 84 to 512) days, p<0.05).\n\nConclusions\nIn our study cohort, the incidence of pituitary-irAE was higher than previously reported and the development of pituitary-irAE predicted better prognosis for both NSCLC and MM when patients were treated with physiological doses of hydrocortisone.\n\nClinical trials registration\nUMIN000019024.\n\nimmunotherapymelanomalung neoplasmsspecial-featureunlocked\n==== Body\nBackground\nImmune checkpoint inhibitors (ICIs) including antibodies against anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) and anti-programmed cell death-1 (PD-1) have recently emerged as promising treatments for advanced malignancies.1 However, ICIs can cause adverse events, termed immune-related adverse events (irAEs), including pneumonitis, skin toxicities, colitis, and endocrine dysfunction.2 3\n\n\nICIs were reported to have better antitumor efficacy in patients who developed some irAEs.4–9 In terms of the relationship of irAE to overall survival (OS), several studies reported that skin-irAE is associated with better OS in both patients with malignant melanoma (MM) and non-small cell lung carcinoma (NSCLC),4 8 10 11 whereas another study found that OS of patients with NSCLC was similar between those who developed skin-irAE and those who did not.7 The different outcomes of these previous clinical trials and retrospective studies could be due to the different study designs including evaluation methods and definition of irAEs.\n\nEndocrine-irAEs comprise pituitary dysfunction, adrenal insufficiency, thyroid dysfunction, hypoparathyroidism, and type 1 diabetes mellitus (T1DM).12 13 Among them, thyroid-irAE induced by an anti-PD-1 antibody (aPD-1 Ab) was reported to be associated with better OS in patients with NSCLC in a phase I clinical trial14 and retrospective studies.5 15 16 In contrast, thyroid-irAE induced by aPD-1 Ab was not associated with better OS of patients with MM,16 suggesting that the association of thyroid-irAE with improved outcomes varied among patients with NSCLC or MM. On the other hand, pituitary-irAE is almost always accompanied by adrenocorticotropic hormone (ACTH) deficiency,17 a life-threatening disorder, and a retrospective study reported that pituitary dysfunction induced by ipilimumab was associated with better OS in patients with MM.18 However, symptoms of ACTH deficiency, such as fatigue, appetite loss, and weight loss, frequently occur in patients with malignancies even if they do not develop pituitary-irAE. As such, pituitary-irAE could be overlooked when pituitary hormones are not measured regularly, and its incidence may not have been accurately reflected in previous studies.\n\nTo clarify the association of pituitary-irAE with OS in patients with NSCLC or MM, we performed a prospective study in which endocrine-irAEs induced by ICIs were set as a primary endpoint.\n\nMethods\nPatients\nTo clarify the clinical features of endocrine-irAEs, we conducted a prospective study to analyze irAEs in patients treated with ICIs since November 2, 2015 (UMIN000019024). All patients with NSCLC or MM who started ICI treatment between November 2, 2015 and August 30, 2019 at Nagoya University Hospital were included in this study (figure 1). Patients who had more than two malignancies were excluded. Written informed consent was obtained from all patients. Ipilimumab was administered at 3 mg/kg every 3 weeks for 4 cycles. Nivolumab was administered at 3 mg/kg or 240 mg every 2 weeks, with the exception of some patients with MM, who were treated with 2 mg/kg every 3 weeks. Pembrolizumab was administered at 2 mg/kg or 200 mg every 3 weeks. Atezolizumab was administered at 1200 mg every 3 weeks. All ICI treatment was continued until disease progressed, death, or unacceptable severe adverse events occurred, or if patients withdrew consent for treatment.\n\n\nFigure 1\n Enrollment of study subjects. ICI, immune checkpoint inhibitor; MM, malignant melanoma; NSCLC, non-small cell lung carcinoma; OS, overall survival.\n\nAssessments\nTo examine endocrine-irAEs, ACTH, cortisol, free T3 (FT3), free T4 (FT4), thyroid-stimulating hormone (TSH), and blood glucose levels were assessed at baseline and every 6 weeks after the first administration of ICI for 24 weeks as previously described.19 After the initial 24 weeks, pituitary hormones were measured if clinically needed until the visits stopped. Each endocrine-irAE was defined according to the Japan Endocrine Society clinical guidelines for endocrine-irAEs.12 The cut-off for the diagnosis of ACTH deficiency was decreased peak serum cortisol value (<18 µg/dL) and impaired responses of ACTH (<2-fold of baseline) in corticotropin-releasing hormone loading tests (intravenous injection with 100 µg human corticorelin),20 which were performed in the morning. The frequency of hyponatremia, defined as a serum sodium concentration <135 mEq/L, at the onset of pituitary-irAE was compared with that for patients who did not develop pituitary-irAE. In the latter group, the frequency was evaluated around the median time of onset of pituitary-irAE induced by each ICI (ipilimumab, 71 days; nivolumab, 171 days; pembrolizumab, 127 days). OS was determined for participants in this study until death from any cause. Patients with MM were excluded from the OS analysis if they were treated with ICIs as an adjuvant therapy (figure 1). Non-endocrine-irAEs, as reported in the guideline,13 were diagnosed by attending physicians and subjected to analysis if the grade was higher than 1. All irAEs were monitored and graded using CTCAE 5.0 criteria. Fifty-eight patients treated with nivolumab and 78 patients treated with pembrolizumab were included in our previous study that analyzed the incidence of thyroid dysfunction.19 21\n\n\nStatistical analysis\nContinuous variables of patient characteristics (eg, age, days to diagnosis) are expressed as means±SD or median and IQR. Differences among continuous variables were tested for significance with the two-sample t-test. Values of nominal variables were compared using Fisher’s exact test. OS was analyzed using the Kaplan-Meier method, expressed as median and 95% CI and compared using a log-rank test. All statistical tests were two sided, and significance was defined as a p value of <0.05. All statistical analyses were performed with IBM SPSS Statistics V.25.\n\nResults\nPatient characteristics\nA total of 174 patients with either NSCLC or MM who started ipilimumab, nivolumab, pembrolizumab, or atezolizumab therapy were enrolled in this study (figure 1). Clinical variables for patients with NSCLC and MM are presented in table 1. IrAEs occurred in 34/108 patients (31.5%) with NSCLC and 38/66 patients (57.6%) with MM (table 1). Endocrine-irAEs including pituitary-irAE, thyroid-irAE, and T1DM occurred in 13/108 (12.0%) patients with NSCLC and 20/66 (30.3%) patients with MM. The number of each type of irAE observed, including pituitary-irAE, thyroid-irAE, T1DM, interstitial pneumonitis (lung-irAE), skin toxicities (skin-irAE), and gastrointestinal toxicities (GI-irAE), is shown in table 1. No cases were treated with a reduced dose of ICI due to the development of irAEs.\n\nTable 1 Clinical characteristics and number of each irAE type among patients with NSCLC and MM\n\n\tNSCLC\tMM\t\nCharacteristic\tn=108\tn=66\t\nAge, years\t67±10\t69±12\t\nSex\t\t\t\n Female\t29 (26.9%)\t27 (40.9%)\t\n Male\t79 (73.1%)\t39 (59.1%)\t\nDrugs\t\t\t\n Ipi\t0\t24 (36.4%)\t\n Niv\t57 (52.8%)\t34 (51.5%)\t\n Pem\t51 (47.2%)\t30 (45.5%)\t\n Ipi+Niv\t0\t1 (1.5%)\t\n Ate\t9 (8.3%)\t0\t\nHistory of prior ICI use\t0\t12 (18.2%)\t\nTreatment lines\t\t\t\n Adjuvant\t0\t14 (21.2%)\t\n First line\t32 (29.6%)\t33 (50.0%)\t\n ≥Second line\t76 (70.4%)\t19 (28.8%)\t\nFollow-up, days\t396±304\t343±319\t\nTotal no. of patients who developed irAEs\t34 (31.5%)\t38 (57.6%)\t\n Pituitary-irAE\t4 (3.7%)\t12 (18.2%)\t\n Thyroid-irAE\t8 (7.4%)\t11 (16.7%)\t\n T1DM\t2 (1.9%)\t1 (1.5%)\t\n Lung-irAE\t13 (12.0%)\t6 (9.1%)\t\n Skin-irAE\t5 (4.6%)\t4 (6.1%)\t\n GI-irAE\t4 (3.7%)\t12 (18.2%)\t\n Other\t3 (2.8%)\t4 (6.1%)\t\nData are mean±SD or n (%).\n\nAte, atezolizumab; GI-irAE, gastrointestinal irAE; ICI, immune checkpoint inhibitor; Ipi, ipilimumab; irAE, immune-related adverse event; MM, malignant melanoma; Niv, nivolumab; NSCLC, non-small cell lung carcinoma; Pem, pembrolizumab; T1DM, type 1 diabetes mellitus.\n\nPituitary dysfunction induced by ICIs\nPituitary-irAE occurred in 6/25 patients (24.0%) during treatment with ipilimumab, 10/167 patients (6.0%) during treatment with nivolumab or pembrolizumab. Pituitary-irAE did not occur during treatment with atezolizumab (0/9). Pituitary-irAE induced by aPD-1 Ab, nivolumab, or pembrolizumab was observed in 6/59 patients with MM and 4/108 patients with NSCLC. There was no difference in the frequency of pituitary-irAE induced by aPD-1 Ab between patients with MM and those with NSCLC (10.2% (6/59) in patients with MM vs 3.7% (4/108) in patients with NSCLC, p=0.168). Among the 16 patients who developed pituitary-irAE, three demonstrated clinical characteristics of hypophysitis such as pituitary enlargement and deficiencies in multiple anterior pituitary hormones including ACTH (online supplementary table S1). These three patients presented with headache as an initial symptom that could be caused by enlargement of the pituitary glands at irAE onset. A representative MRI showing an enlargement of the pituitary gland at hypophysitis onset is shown in figure 2A. This enlargement was completely resolved at 6 months after onset (figure 2B) and did not change during a 1-year follow-up (data not shown). The other 13 patients developed isolated ACTH deficiency (IAD), but none exhibited enlarged pituitary glands at IAD onset (online supplementary table S1 and figure 2C). Re-evaluation of pituitary gland size 6 months and/or 1 year after IAD onset for 11 of these patients showed no change in size for seven patients (representative MRI image, figure 2D) and a slightly decreased size for the other four patients. In terms of clinical characteristics of patients who developed hypophysitis and IAD, the usage rate of aCTLA-4 Ab and incidence of pituitary enlargement were significantly higher for patients who developed hypophysitis than those who had IAD (table 2). The time to diagnosis of pituitary-irAE after the first ICI administration was significantly shorter in patients with hypophysitis compared with those with IAD (table 2). There were no significant differences in the other clinical variables we examined (eg, malignancy type, age, sex, and history of prior immunotherapy) (table 2). ACTH deficiency was observed in all cases with pituitary-irAE (online supplementary table S2), and these patients were treated with physiological doses of hydrocortisone (10–20 mg/day). ICI was re-administered with the same dose initially used after general conditions were stabilized by hormone replacement therapy. During the observation period of this study, no patients discontinued hormone replacement therapies (hydrocortisone and/or levothyroxine). The frequency of hyponatremia was significantly higher in patients who developed pituitary-irAE than those who did not (6/16 (37.5%) vs 10/120 (8.3%), p<0.01).\n\n10.1136/jitc-2020-000779.supp1Supplementary data \n\n\n\n \nFigure 2\n MRI of the pituitary gland in a patient with pituitary immune-related adverse event (pituitary-irAE). Representative MRI for a patient (Ipi001) who developed hypophysitis shows that the pituitary gland was enlarged at pituitary-irAE onset (A) but had returned to normal size 6 months after the onset (B). Representative MRI for a patient (Niv096) who developed isolated adrenocorticotropic hormone deficiency show a normal-sized pituitary gland at pituitary-irAE onset (C) and absence of changes at 6 months after onset (D).\n\nTable 2 Clinical characteristics of patients who developed pituitary-irAE\n\n\tHypophysitis\nn=3\tIAD\nn=13\tP value\t\nMalignancy\t\t\t0.529\t\n NSCLC\t0\t4 (30.8%)\t\n MM\t3 (100%)\t9 (69.2%)\t\nAge, years\t59±11\t67±10\t0.251\t\nSex\t\t\t0.509\t\n Female\t0\t5 (38.5%)\t\n Male\t3 (100%)\t8 (61.5%)\t\nHistory of prior immunotherapy\t2 (66.7%)\t3 (23.1%)\t0.214\t\nLatest ICI\t\t\t0.036\t\n aCTLA-4 Ab\t3 (100%)\t3 (23.1%)\t\n aPD-1 Ab\t0\t10 (76.9%)\t\nDays to diagnosis from the first administration of the latest drug\t56±27\t162±108\t0.008\t\nNo. of cases with enlarged pituitary by MRI\t3 (100%)\t0\t0.002\t\nData are n (%) or mean±SD.\n\naCTLA-4 Ab, anti-cytotoxic T-lymphocyte antigen 4 antibodies; aPD-1 Ab, anti-programmed cell death-1 antibodies; IAD, isolated adrenocorticotropic hormone deficiency; ICI, immune checkpoint inhibitor; irAE, immune-related adverse event; MM, malignant melanoma; NSCLC, non-small cell lung carcinoma.\n\nThyroid dysfunction induced by ICIs\nThyroid-irAE occurred in 1/25 patients (4.0%) during treatment with ipilimumab and in 18/167 patients (10.8%) during treatment with nivolumab or pembrolizumab. The incidence of thyroid-irAE tended to be higher in patients treated with aPD-1 Ab than those who received aCTLA-4 Ab, although the difference was not significant (18/167 (10.8%) vs 1/25 (4.0%), p=0.477). The number of patients who developed destructive thyroiditis, hypothyroidism, and hyperthyroidism was 13, 5, and 1, respectively. All five patients who developed hypothyroidism and 12/13 who developed destructive thyroiditis required hormone therapy with levothyroxine.\n\nPatients who developed any irAE had longer OS than those without irAEs\nOS was significantly longer for both patients with NSCLC and MM who developed any irAE than those without irAEs (NSCLC: not reached vs 378 (95% CI 220 to 536) days, p<0.01, figure 3A, online supplementary table S3; MM: 534 (95% CI 245 to 823) vs 189 (95% CI 52 to 326) days, p<0.05, figure 3B, online supplementary table S3). To examine the contribution of endocrine-irAEs to increased OS, 13 patients with NSCLC and 14 patients with MM who developed endocrine-irAEs were included in OS analysis. OS was significantly longer for patients with NSCLC who developed endocrine-irAEs than those who did not (not reached vs 401 days (95% CI 240 to 562), p<0.01, figure 3C, online supplementary table S3). In patients with MM, there were no significant differences in OS between patients who developed endocrine-irAEs and those who did not (649 days (95% CI 367 to 931) vs 342 days (95% CI 131 to 553), p=0.107, figure 3D, online supplementary table S3).\n\n\nFigure 3\n Overall survival (OS) after initiation of immune checkpoint inhibitor treatment in patients with and without immune-related adverse events (irAEs). OS of patients with non-small cell lung carcinoma (NSCLC) (A, C, E, G) or malignant melanoma (MM) (B, D, F, H). Solid and dashed lines indicate OS of patients who did and did not develop each irAE, respectively. The OS was significantly prolonged for patients who developed any irAEs than those who did not for both patients with NSCLC and MM (A, B). The OS was significantly prolonged for patients who developed endocrine-irAEs than those who did not for patients with NSCLC (C) but not patients with MM (D). Among patients with NSCLC and those with MM, the OS was significantly prolonged for patients who developed pituitary-irAE than those who did not (E, F). The OS was significantly prolonged for patients who developed thyroid-irAE than those who did not for patients with NSCLC (G) but not patients with MM (H).\n\nPituitary-irAE was associated with prolonged OS in patients with NSCLC or MM\nFour patients with NSCLC and nine patients with MM with pituitary-irAE were included in the analysis of OS. OS was significantly longer for both patients with NSCLC and MM who developed pituitary-irAE than those who did not (NSCLC: not reached vs 441 days (95% CI not calculated), p<0.05, figure 3E, online supplementary table S3; MM: 885 days (95% CI 434 to 1336) vs 298 says (95% CI 84 to 512), p<0.05, figure 3F, online supplementary table S3). There were no significant differences between patients with NSCLC (online supplementary table S4) or MM (online supplementary table S5) who developed pituitary-irAE and those who did not in terms of sex, drugs used, prior history of other ICIs, and treatment lines, although the mean ages were significantly younger and the ipilimumab usage rate was significantly higher for patients with MM who developed pituitary-irAE compared with those who did not (online supplementary table S5). The analysis of OS included patients treated with ICI monotherapy as well as sequential use of several ICIs because the number of patients who were treated with only one ICI during the study period was too small (online supplementary table S6). There were no significant differences in the usage rate of multiple ICIs between patients who developed pituitary-irAE for patients with either NSCLC (0/4 with pituitary-irAE vs 8/104 without pituitary-irAE. p=1.000) or MM (5/9 with pituitary-irAE vs 20/43 without pituitary-irAE. p=0.722). There were no differences in the number of cycles of ICI between patients who developed pituitary-irAE and those who did not, except for patients with MM treated with nivolumab (online supplementary tables S7 and S8). In this group, the number of cycles was significantly higher in the pituitary-irAE group (online supplementary table S8). The time of follow-up was significantly longer for the patients with NSCLC and MM who developed pituitary-irAE than those who did not (online supplementary tables S7 and S8).\n\nThyroid-irAE was associated with prolonged OS in patients with NSCLC, but not MM\nOS was significantly longer for patients with NSCLC who developed thyroid-irAE than those who did not (not reached vs 441 days (95% CI 317 to 565), p<0.05, figure 3G, online supplementary table S3). In contrast, patients with MM who developed thyroid-irAE and those who did not had similar OS (427 days (95% CI 0 to 871) vs 393 days (95% CI 219 to 567), p=0.875, figure 3H, online supplementary table S3). There were no significant differences between patients with NSCLC (online supplementary table S9) or MM (online supplementary table S10) who developed thyroid-irAE and those who did not for other clinical factors including sex, drugs used, prior history of other ICIs, and treatment lines. Moreover, there were no significant differences in the usage rate of multiple ICIs between patients who developed thyroid-irAE and those who did not among patients with NSCLC (0/8 with thyroid-irAE vs 8/100 without thyroid-irAE; p=1.000) or MM (2/7 with thyroid-irAE vs 24/45 without thyroid-irAE; p=0.419).\n\nOS was not associated with other types of irAE in patients with NSCLC or MM\nAlthough patients who had any irAE showed longer OS than those without irAEs, the development of non-endocrine-irAEs was not associated with longer OS in patients with either NSCLC or MM (NSCLC: 585 days (95% CI 321 to 849) vs 441 days (95% CI 297 to 585), p=0.247, online supplementary figure 1A, table S3; MM: 534 days (95% CI 268 to 800) vs 241 days (95% CI 0 to 523), p=0.268, online supplementary figure 1B, table S3). As for each non-endocrine-irAE, there were no differences in OS between patients who developed lung-irAE, skin-irAE, or GI-irAE and those who did not for patients with NSCLC (lung-irAE, 488 days (95% CI 167 to 809) vs 474 days (95% CI 334 to 614), p=0.710; skin-irAE, 669 days (95% CI 438 to 900) vs 441 days (95% CI 310 to 572), p=0.550; GI-irAE, not reached vs 481 days (95% CI 351 to 597), p=0.731) or MM (lung-irAE, 1259 days (95% CI 0 to 2655) vs 393 days (95% CI 237 to 549), p=0.202; skin-irAE, 649 days (95% CI not calculated) vs 379 (95% CI 252 to 506), p=0.560; GI-irAE, 491 days (95% CI 152 to 830) vs 393 days (95% CI 174 to 612), p=0.581) (online supplementary figure 1C‒H, table S3). For skin-irAEs, exanthema and erythema, but not vitiligo, were observed in this study.\n\n10.1136/jitc-2020-000779.supp2Supplementary data \n\n\n\n Discussion\nThis prospective study, in which all patients with pituitary-irAE were treated with physiological doses of hydrocortisone, revealed that pituitary-irAE was associated with prolonged OS in patients with MM or NSCLC. Furthermore, our study confirmed the findings of previous retrospective studies and a phase I trial that thyroid-irAE was associated with prolonged OS in patients with NSCLC but not those with MM. Thus, the outcome of pituitary-irAEs and thyroid-irAEs in terms of OS differed between NSCLC and MM.\n\nThe results of this prospective study clearly demonstrated that the incidence of pituitary-irAE was higher (24.0% and 6.0% for patients treated with aCTLA-4 Ab and aPD-1 Ab, respectively) than previously reported.17 22–24 In a retrospective analysis of a medical record database, Faje et al reported that the incidence of pituitary dysfunction induced by aCTLA-4 Ab and aPD-1 Ab was 13.6% or 0.5%, respectively.25 Pituitary-irAE could have been overlooked in that study because most symptoms associated with pituitary-irAE such as fatigue, appetite loss, and weight loss also occur in patients with malignancies. One strength of the present prospective study is that pituitary-irAE was far more likely to be detected because of the scheduled endocrine evaluation during the fixed period regardless of whether ICIs were continued. In addition, this study has less selection bias than clinical trials because all patients treated with ICIs in our hospital were prospectively included. Thus, the incidence of pituitary-irAE observed in this study is more likely to reflect that which occurs in a real-world clinical practice.\n\nConcerning the association of pituitary-irAE with OS, only one retrospective study that analyzed a clinical record database reported an association of pituitary dysfunction induced by a CTLA-4 Ab (ipilimumab) with prolonged OS in patients with MM18 and no prior studies have shown an association of pituitary-irAE with OS in patients with NSCLC. It is also unclear whether pituitary dysfunction induced by aPD-1 Ab is associated with OS. This study analyzed the association of OS with pituitary dysfunction induced by aCTLA-4 Ab or aPD-1 Ab, and clarified that pituitary-irAE is associated with prolonged OS in patients with MM and also those with NSCLC. Thus, pituitary-irAE could be a potential biomarker to predict better outcome of ICI treatments for these types of malignancies, although it sometimes develops several months after the initial administration of ICIs.\n\nGiven the contribution of pituitary-irAE to better OS, it is important to understand its clinical characteristics, how to manage them appropriately, and why pituitary-irAE is associated with prolonged survival. This study clearly demonstrated that ICI can induce two types of pituitary dysfunction: hypophysitis, associated with deficiencies in multiple pituitary hormones accompanied by pituitary enlargement, and IAD without pituitary enlargement. Our data also showed that (1) ACTH deficiency was observed in all cases, (2) IAD can be induced by either aCTLA-4 Ab or aPD-1 Ab, and (3) hypophysitis was induced only by aCTLA-4 Ab.\n\nThe mechanisms underlying the association of pituitary-irAE with better outcome of ICI treatments are still unknown. The development of vitiligo was associated with better tumor response in patients with MM,10 suggesting that melanoma cells and normal melanocytes may have shared antigens. It would be interesting to explore whether there are shared antigens between pituitary cells and MM or NSCLC cells to determine if they are involved in development of pituitary-irAE. Previous studies proposed that complement activation following aCTLA-4 Ab binding to CTLA-4 expressed on pituitary cells is involved in pathogenesis of hypophysitis induced by aCTLA-4 Ab in mice26 and humans.17 Given that aCTLA-4 Ab is an IgG1 and aPD-1 Ab is an IgG4 that cannot activate complement, the mechanism underlying pituitary-irAEs likely differs among ICIs.\n\nDetermining effective treatment strategies for pituitary dysfunction induced by ICIs is critical. Although the effect of high-dose glucocorticoids to treat pituitary-irAE has not been fully examined, retrospective studies reported that such doses did not affect recovery of pituitary function27 and instead shortened OS.18 In this study, all patients who developed pituitary-irAE were treated with physiological doses of hydrocortisone. In addition, all patients who developed pituitary-irAE were re-administered ICIs after their general conditions were stabilized by hormone treatment. Although pituitary-irAE can be life threatening,28 29 this study demonstrated the association of pituitary-irAE with better OS when patients are treated with physiological doses of hydrocortisone.\n\nAlthough hyponatremia can accompany adrenal insufficiency, some patients with cancer also often develop hyponatremia30 due to inappropriate anti-diuretic hormone secretion,31 gastrointestinal or renal losses and/or diminished sodium intake, use of diuretics, hypervolemic state, renal failure, or intake of hypotonic fluids.32 33 In this study, we first demonstrated that the frequency of hyponatremia was significantly higher in the patients who developed pituitary-irAE compared with those who did not. These data suggest that ACTH and cortisol levels in the blood should be measured to detect development of pituitary-irAE when hyponatremia is observed in patients treated with ICIs.\n\nPrevious studies reported an association between better OS with irAEs other than endocrine-irAEs, including skin-irAE or lung-irAE.4 7 8 10 11 We clearly demonstrated the association of pituitary-irAE with better ICI treatment outcomes, yet no irAE type other than endocrine-irAEs was associated with better OS. Endocrine-irAEs were definitely determined as primary outcomes according to Japan Endocrine Society clinical guidelines,12 whereas other irAEs were diagnosed by attending physicians in practice, which may have affected the results of this study.\n\nThis study has some limitations. First, analysis of OS for each ICI regimen did not yield statistically significant results likely due to small sample sizes. We therefore included both patients treated with ICI monotherapy as well as those treated with several ICIs sequentially in the analyses. Second, to calculate the incidence of pituitary dysfunction, we defined the drug that was in use at onset of pituitary dysfunction to be the causative drug, and we cannot exclude the possibility that a previously used ICI may have affected the development of irAEs. Third, there may be a bias in that pituitary-irAE can be observed in patients who survived for a longer time. Actually, some patients showed late onset of pituitary-irAE in this study. Additional studies that include landmark analyses for larger study populations are needed to address these limitations.\n\nConclusions\nOur prospective study clarified the exact incidence of pituitary-irAE in a real-world clinical practice and the association of pituitary-irAE accompanied by ACTH deficiency with a better outcome of ICI treatments in both NSCLC and MM when patients were treated with physiological doses of hydrocortisone. Our findings indicate that we should measure pituitary hormones when pituitary-irAE is suspected based on hyponatremia, so that ACTH deficiency in patients treated with ICI will not be overlooked.\n\nContributors: SI designed the study. TK and SI performed the clinical study. TK, SI, and HA analyzed the data. All authors treated the patients who were enrolled, collected and discussed the data. TK, SI, and HA wrote the manuscript. All authors were involved in revising the manuscript.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: SI receives personal fees from Ono Pharmaceutical Company, Bristol-Myers Squibb, MSD K.K., and Chugai Pharmaceutical Co., Ltd. TO receives personal fees from MSD K.K. HT receives grants from MSD K.K. YI receives grants from Sanwa Kagaku Kenkyusho, Kowa Pharmaceutical, MSD K.K., Dainippon Sumitomo, Kyowa Kirin Co., Ltd., Chugai Pharmaceutical Co., Ltd., Boehringer Ingelheim, Nihon Medi-Physics Co., Ltd., and personal fees from Astellas Pharma, Daiichi Sankyo, and Ono Pharmaceutical Company. KY receives personal fees from Ono Pharmaceutical Company, MSD K.K., and Bristol-Myers Squibb. TH received personal fees from Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Company, and Bristol-Myers Squibb while the study was being conducted. TH also received grants from Boehringer Ingelheim, Taiho Pharmaceutical Co., Ltd., and personal fees from Boehringer Ingelheim outside the submitted work. MMS receives personal fees from Ono Pharmaceutical Company, Bristol-Myers Squibb, MSD K.K., and Chugai Pharmaceutical Co., Ltd. MA receives grants from Kyowa Kirin Co., Ltd. YA receives grants and personal fees from Ono Pharmaceutical Company, Chugai Pharmaceutical Co., Ltd., and Taiho Pharmaceutical Co. Ltd. as well as personal fees from Bristol-Myers Squibb. MA receives grants and personal fees from Ono Pharmaceutical Company, MSD K.K., and personal fees from Bristol-Myers Squibb. YH receives grants and personal fees from Ono Pharmaceutical Company, Chugai Pharmaceutical Co., Ltd., Eli Lilly, Boehringer Ingelheim, Bristol-Myers Squibb, MSD K.K., and Pfizer; grants from Novartis and Taiho Pharmaceutical Co., Ltd., and personal fees from Astra Zeneca. HA receives grants from Ono Pharmaceutical Company, MSD K.K., Chugai Pharmaceutical Co. Ltd., and personal fees from Ono Pharmaceutical Company, Bristol-Myers Squibb, and MSD K.K.\n\nPatient consent for publication: Not required.\n\nEthics approval: This study was approved by the Ethical Committee of Nagoya University Hospital, No. 2015-0273. Written informed consent was obtained from all patients.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nData availability statement: Data are available on reasonable request.\n==== Refs\nReferences\n1 \nPostow MA , Callahan MK , Wolchok JD \nImmune checkpoint blockade in cancer therapy\n. JCO \n2015 ;33 :1974 –82\n. 10.1200/JCO.2014.59.4358 \n\n2 \nScott LJ \nNivolumab: a review in advanced melanoma\n. Drugs \n2015 ;75 :1413 –24\n. 10.1007/s40265-015-0442-6 \n26220912 \n3 \nGraziani G , Tentori L , Navarra P \nIpilimumab: a novel immunostimulatory monoclonal antibody for the treatment of cancer\n. Pharmacol Res \n2012 ;65 :9 –22\n. 10.1016/j.phrs.2011.09.002 \n21930211 \n4 \nFreeman-Keller M , Kim Y , Cronin H , et al \nNivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes\n. Clin Cancer Res \n2016 ;22 :886 –94\n. 10.1158/1078-0432.CCR-15-1136 \n26446948 \n5 \nGrangeon M , Tomasini P , Chaleat S , et al \nAssociation between immune-related adverse events and efficacy of immune checkpoint inhibitors in non-small-cell lung cancer\n. Clin Lung Cancer \n2019 ;20 :201 –7\n. 10.1016/j.cllc.2018.10.002 \n30442524 \n6 \nIndini A , Di Guardo L , Cimminiello C , et al \nImmune-related adverse events correlate with improved survival in patients undergoing anti-PD1 immunotherapy for metastatic melanoma\n. J Cancer Res Clin Oncol \n2019 ;145 :511 –21\n. 10.1007/s00432-018-2819-x \n30539281 \n7 \nRicciuti B , Genova C , De Giglio A , et al \nImpact of immune-related adverse events on survival in patients with advanced non-small cell lung cancer treated with nivolumab: long-term outcomes from a multi-institutional analysis\n. J Cancer Res Clin Oncol \n2019 ;145 :479 –85\n. 10.1007/s00432-018-2805-3 \n30506406 \n8 \nHaratani K , Hayashi H , Chiba Y , et al \nAssociation of immune-related adverse events with nivolumab efficacy in non-small-cell lung cancer\n. JAMA Oncol \n2018 ;4 :374 –8\n. 10.1001/jamaoncol.2017.2925 \n28975219 \n9 \nOkada N , Kawazoe H , Takechi K , et al \nAssociation between immune-related adverse events and clinical efficacy in patients with melanoma treated with nivolumab: a multicenter retrospective study\n. Clin Ther \n2019 ;41 :59 –67\n. 10.1016/j.clinthera.2018.11.004 \n30528047 \n10 \nTeulings H-E , Limpens J , Jansen SN , et al \nVitiligo-like depigmentation in patients with stage III–IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis\n. J Clin Oncol \n2015 ;33 :773 –81\n. 10.1200/JCO.2014.57.4756 \n25605840 \n11 \nFujisawa Y , Yoshino K , Otsuka A , et al \nRetrospective study of advanced melanoma patients treated with ipilimumab after nivolumab: analysis of 60 Japanese patients\n. J Dermatol Sci \n2018 ;89 :60 –6\n. 10.1016/j.jdermsci.2017.10.009 \n29079332 \n12 \nArima H , Iwama S , Inaba H , et al \nManagement of immune-related adverse events in endocrine organs induced by immune checkpoint inhibitors: clinical guidelines of the Japan Endocrine Society\n. Endocr J \n2019 ;66 :581 –6\n. 10.1507/endocrj.EJ19-0163 \n31243183 \n13 \nBrahmer JR , Lacchetti C , Schneider BJ , et al \nManagement of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline\n. J Clin Oncol \n2018 ;36 :1714 –68\n. 10.1200/JCO.2017.77.6385 \n29442540 \n14 \nOsorio JC , Ni A , Chaft JE , et al \nAntibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer\n. Ann Oncol \n2017 ;28 :583 –9\n. 10.1093/annonc/mdw640 \n27998967 \n15 \nKim HI , Kim M , Lee S-H , et al \nDevelopment of thyroid dysfunction is associated with clinical response to PD-1 blockade treatment in patients with advanced non-small cell lung cancer\n. Oncoimmunology \n2017 ;7 :e1375642. 10.1080/2162402X.2017.1375642 \n29296533 \n16 \nYamauchi I , Yasoda A , Matsumoto S , et al \nIncidence, features, and prognosis of immune-related adverse events involving the thyroid gland induced by nivolumab\n. PLoS One \n2019 ;14 :e0216954. 10.1371/journal.pone.0216954 \n31086392 \n17 \nCaturegli P , Di Dalmazi G , Lombardi M , et al \nHypophysitis secondary to cytotoxic T-lymphocyte-associated protein 4 blockade: insights into pathogenesis from an autopsy series\n. Am J Pathol \n2016 ;186 :3225 –35\n. 10.1016/j.ajpath.2016.08.020 \n27750046 \n18 \nFaje AT , Lawrence D , Flaherty K , et al \nHigh-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma\n. Cancer \n2018 ;124 :3706 –14\n. 10.1002/cncr.31629 \n29975414 \n19 \nKobayashi T , Iwama S , Yasuda Y , et al \nPatients with antithyroid antibodies are prone to develop destructive thyroiditis by nivolumab: a prospective study\n. J Endocr Soc \n2018 ;2 :241 –51\n. 10.1210/js.2017-00432 \n29600292 \n20 \nYanase T , Tajima T , Katabami T , et al \nDiagnosis and treatment of adrenal insufficiency including adrenal crisis: a Japan Endocrine Society clinical practice guideline [Opinion]\n. Endocr J \n2016 ;63 :765 –84\n. 10.1507/endocrj.EJ16-0242 \n27350721 \n21 \nOkada N , Iwama S , Okuji T , et al \nAnti-thyroid antibodies and thyroid echo pattern at baseline as risk factors for thyroid dysfunction induced by anti-programmed cell death-1 antibodies: a prospective study\n. Br J Cancer . In Press \n2020 ;122 :771 –7\n. 10.1038/s41416-020-0736-7 \n32009131 \n22 \nFaje A \nImmunotherapy and hypophysitis: clinical presentation, treatment, and biologic insights\n. Pituitary \n2016 ;19 :82 –92\n. 10.1007/s11102-015-0671-4 \n26186958 \n23 \nCorsello SM , Barnabei A , Marchetti P , et al \nEndocrine side effects induced by immune checkpoint inhibitors\n. J Clin Endocrinol Metab \n2013 ;98 :1361 –75\n. 10.1210/jc.2012-4075 \n23471977 \n24 \nGonzález-Rodríguez E , Rodríguez-Abreu D , Spanish Group for Cancer Immuno-Biotherapy (GETICA) \nImmune checkpoint inhibitors: review and management of endocrine adverse events\n. Oncologist \n2016 ;21 :804 –16\n. 10.1634/theoncologist.2015-0509 \n27306911 \n25 \nFaje A , Reynolds K , Zubiri L , et al \nHypophysitis secondary to nivolumab and pembrolizumab is a clinical entity distinct from ipilimumab-associated hypophysitis\n. Eur J Endocrinol \n2019 ;181 :211 –9\n. 10.1530/EJE-19-0238 \n31176301 \n26 \nIwama S , De Remigis A , Callahan MK , et al \nPituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody\n. Sci Transl Med \n2014 ;6 :230ra245. 10.1126/scitranslmed.3008002 \n\n27 \nMin L , Hodi FS , Giobbie-Hurder A , et al \nSystemic high-dose corticosteroid treatment does not improve the outcome of ipilimumab-related hypophysitis: a retrospective cohort study\n. Clin Cancer Res \n2015 ;21 :749 –55\n. 10.1158/1078-0432.CCR-14-2353 \n25538262 \n28 \nArlt W , Allolio B \nAdrenal insufficiency\n. Lancet \n2003 ;361 :1881 –93\n. 10.1016/S0140-6736(03)13492-7 \n12788587 \n29 \nBergthorsdottir R , Leonsson-Zachrisson M , Odén A , et al \nPremature mortality in patients with Addison's disease: a population-based study\n. J Clin Endocrinol Metab \n2006 ;91 :4849 –53\n. 10.1210/jc.2006-0076 \n16968806 \n30 \nBerardi R , Antonuzzo A , Blasi L , et al \nPractical issues for the management of hyponatremia in oncology\n. Endocrine \n2018 ;61 :158 –64\n. 10.1007/s12020-018-1547-y \n29417373 \n31 \nRaftopoulos H \nDiagnosis and management of hyponatremia in cancer patients\n. Support Care Cancer \n2007 ;15 :1341 –7\n. 10.1007/s00520-007-0309-9 \n17701059 \n32 \nBerghmans T , Paesmans M , Body JJ \nA prospective study on hyponatraemia in medical cancer patients: epidemiology, aetiology and differential diagnosis\n. Support Care Cancer \n2000 ;8 :192 –7\n. 10.1007/s005200050284 \n10789959 \n33 \nOnitilo AA , Kio E , Doi SAR \nTumor-related hyponatremia\n. Clin Med Res \n2007 ;5 :228 –37\n. 10.3121/cmr.2007.762 \n18086907\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2051-1426",
"issue": "8(2)",
"journal": "Journal for immunotherapy of cancer",
"keywords": "immunotherapy; lung neoplasms; melanoma",
"medline_ta": "J Immunother Cancer",
"mesh_terms": "D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung; D005260:Female; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007167:Immunotherapy; D008175:Lung Neoplasms; D008297:Male; D008545:Melanoma; D010900:Pituitary Diseases; D011446:Prospective Studies; D016019:Survival Analysis",
"nlm_unique_id": "101620585",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32606047",
"pubdate": "2020-07",
"publication_types": "D016428:Journal Article",
"references": "12788587;27750046;25538262;32009131;29975414;30506406;27998967;26446948;31176301;30528047;26220912;27350721;31086392;16968806;28975219;29079332;29600292;29417373;23471977;25605845;27306911;29442540;18086907;31243183;17701059;21930211;26186958;30539281;29296533;10789959;30442524;24695685;25605840",
"title": "Pituitary dysfunction induced by immune checkpoint inhibitors is associated with better overall survival in both malignant melanoma and non-small cell lung carcinoma: a prospective study.",
"title_normalized": "pituitary dysfunction induced by immune checkpoint inhibitors is associated with better overall survival in both malignant melanoma and non small cell lung carcinoma a prospective study"
} | [
{
"companynumb": "JP-BRISTOL-MYERS SQUIBB COMPANY-BMS-2016-074593",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METOCLOPRAMIDE"
},
"dru... |
{
"abstract": "OBJECTIVE\nPiperacillin/tazobactam (TZP ) is commonly used against multi-resistant nosocomial Pseudomonas infections. While TZP-induced thrombocytopenia is a well-known and easily diagnosed complication, we herein present an unusual case of spontaneous TZP-induced bleeding caused by platelet dysfunction.\n\n\nMETHODS\nA 73-year-old-man experienced severe pulmonary hemorrhage and bloody diarrhea during the treatment with TZP for Pseudomonas aeruginosa ventilator-associated pneumonia. While both platelet count and coagulation tests were normal, platelet functional test revealed severely impaired ADP-dependent platelet aggregation.\n\n\nCONCLUSIONS\nPlatelet dysfunction is a little-known mechanism of TZP-induced bleeding. This is the second reported case of TZP-related bleeding that has been attributed to platelet dysfunction, and the first case report that has not been associated with surgery. While thrombocytopenia is easily recognized, this form of TZP-induced bleeding can be detected only by platelet functional tests.",
"affiliations": null,
"authors": "Skoric|Bosko|B|;Agic|Antonio|A|;Pasalic|Marijan|M|;Samardzic|Jure|J|;Milicic|Davor|D|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000077725:Piperacillin, Tazobactam Drug Combination; D010878:Piperacillin",
"country": "Germany",
"delete": false,
"doi": "10.5414/CP203721",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0946-1965",
"issue": "58(8)",
"journal": "International journal of clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Int J Clin Pharmacol Ther",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D001791:Blood Platelet Disorders; D003428:Cross Infection; D006801:Humans; D010878:Piperacillin; D000077725:Piperacillin, Tazobactam Drug Combination; D053717:Pneumonia, Ventilator-Associated",
"nlm_unique_id": "9423309",
"other_id": null,
"pages": "454-456",
"pmc": null,
"pmid": "32324131",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe bleeding caused by piperacillin/tazobactam-induced platelet dysfunction
.",
"title_normalized": "severe bleeding caused by piperacillin tazobactam induced platelet dysfunction"
} | [
{
"companynumb": "HR-SA-2020SA117989",
"fulfillexpeditecriteria": "1",
"occurcountry": "HR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM"
},
"drugaddi... |
{
"abstract": "This study investigated to which degree levetiracetam (LEV) and perampanel (PER), antiseizure medications (ASM) that are both known to cause aggression and irritability, share the same or different, behavioral side-effect profiles. In this self-report study, 68 participants with epilepsy treated with LEV (n = 35) or PER (n = 33) as part of their medication were asked to rate their behavioral experience with the respective drug as positive, neutral, or negative. Results of a German adaptation of the Adverse Events Profile (AEP) and of the \"FPZ\", a German personality questionnaire, were analyzed as a function of drug and rating. Thirty-eight percent of the LEV group and 36% of the PER group experienced negative change after the evaluated drug was introduced. By subdividing participants in the LEV sample into those who attributed the negative effects to LEV and those with neutral or positive experience with LEV, a negative evaluation of LEV was associated with significantly worse scores in cognition, mood, and physical domains (80% versus 20-40%). Subdividing participants in the PER sample into those who attributed negative the side effects to PER, and those with a neutral or positive experience with PER, significance could be shown for mood domains only (100% versus 50%), and within this domain only for increased aggression and irritability. Comparing features of the behavioral negative side effects of LEV and PER revealed that LEV appears to have a negative impact on a much broader range of behaviors than PER, which specifically seems to induce aggression and irritability and no other psychiatric side effects. Further research should aim at different expression and different mechanisms of aggression and irritability underlying the superficially similar effects of the two drugs.",
"affiliations": "Department of Epileptology, University Hospital Bonn, Venusberg Campus 1, 53127 Bonn, Germany. Electronic address: randi.von.wrede@ukbonn.de.;Department of Epileptology, University Hospital Bonn, Venusberg Campus 1, 53127 Bonn, Germany.;Department of Epileptology, University Hospital Bonn, Venusberg Campus 1, 53127 Bonn, Germany.;Department of Epileptology, University Hospital Bonn, Venusberg Campus 1, 53127 Bonn, Germany.",
"authors": "von Wrede|Randi|R|;Meschede|Carolin|C|;Brand|Fiona|F|;Helmstaedter|Christoph|C|",
"chemical_list": "D000927:Anticonvulsants; D009570:Nitriles; D011728:Pyridones; D000077287:Levetiracetam; C551441:perampanel; D010889:Piracetam",
"country": "United States",
"delete": false,
"doi": "10.1016/j.yebeh.2021.107806",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-5050",
"issue": "117()",
"journal": "Epilepsy & behavior : E&B",
"keywords": "Aggression; Irritability; Levetiracetam; Perampanel; Side effects",
"medline_ta": "Epilepsy Behav",
"mesh_terms": "D000374:Aggression; D000927:Anticonvulsants; D006801:Humans; D000077287:Levetiracetam; D009570:Nitriles; D010889:Piracetam; D011728:Pyridones; D057566:Self Report",
"nlm_unique_id": "100892858",
"other_id": null,
"pages": "107806",
"pmc": null,
"pmid": "33621813",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Levetiracetam, perampanel, and the issue of aggression: A self-report study.",
"title_normalized": "levetiracetam perampanel and the issue of aggression a self report study"
} | [
{
"companynumb": "DE-UCBSA-2021012676",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PERAMPANEL"
},
"drugadditional": "3",
"dr... |
{
"abstract": "Hyperammonemia following hematopoietic cell transplantation (HCT) has been characterized as idiopathic and is associated with a very high mortality. A causal relationship between Ureaplasma infection and hyperammonemia in immunocompromised lung transplant recipients has recently been described. We document the first case of hyperammonemia following HCT associated with Ureaplasma parvum. The initiation of appropriate antibiotics resulted in rapid resolution of hyperammonemic encephalopathy and eradication of the implicating organism.",
"affiliations": "Department of Pediatrics, University of Arizona, Tucson, AZ, USA.;Department of Pediatrics, University of Arizona, Tucson, AZ, USA.;Department of Pediatrics, University of Arizona, Tucson, AZ, USA.;Department of Pediatrics, University of Arizona, Tucson, AZ, USA.",
"authors": "Graetz|Riley|R|;Meyer|Robyn|R|;Shehab|Kareem|K|;Katsanis|Emmanuel|E|http://orcid.org/0000-0003-1466-6965",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12839",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "20(2)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "\nUreaplasma parvum\n; hematopoietic cell transplantation; hyperammonemia",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000900:Anti-Bacterial Agents; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D022124:Hyperammonemia; D016867:Immunocompromised Host; D008297:Male; D014509:Ureaplasma; D016869:Ureaplasma Infections; D055815:Young Adult",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e12839",
"pmc": null,
"pmid": "29359847",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful resolution of hyperammonemia following hematopoietic cell transplantation with directed treatment of Ureaplasma parvum infection.",
"title_normalized": "successful resolution of hyperammonemia following hematopoietic cell transplantation with directed treatment of ureaplasma parvum infection"
} | [
{
"companynumb": "US-PFIZER INC-2018175512",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BUSULFAN"
},
"drugadditional": null,
... |
{
"abstract": "We herein report four patients with desquamative esophagitis that developed one to nine days after peripheral blood stem cell transplantation (PBSCT). Three patients underwent allogeneic PBSCT for leukemia, and the other underwent autologous PBSCT for pineoblastoma. Esophagogastroduodenoscopy revealed mucosal sloughing and fresh blood in the esophagus. Fasting and intravenous proton pump inhibitor therapy in addition to blood transfusion improved the esophageal lesions within five to seven days in three patients. These cases indicate that desquamative esophagitis can occur in patients who receive hematopoietic stem cell transplantation. Although blood transfusions may be required, it can be resolved within seven days.",
"affiliations": "Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Japan.;Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.;Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.;Department of Pathology, Okayama University Hospital, Japan.;Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Japan.;Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Japan.;Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Japan.;Department of Practical Gastrointestinal Endoscopy, Okayama University Hospital, Japan.;Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Japan.",
"authors": "Iwamuro|Masaya|M|;Ennishi|Daisuke|D|;Matsuoka|Ken-Ichi|KI|;Tanaka|Takehiro|T|;Okanoue|Shotaro|S|;Obayashi|Yuka|Y|;Sakae|Hiroyuki|H|;Kawahara|Yoshiro|Y|;Okada|Hiroyuki|H|",
"chemical_list": "D054328:Proton Pump Inhibitors",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.4977-20",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918 1349-7235 The Japanese Society of Internal Medicine \n\n32759586\n10.2169/internalmedicine.4977-20\nCase Report\nFour Cases of Desquamative Esophagitis Occurring after Hematopoietic Stem Cell Transplantation\nIwamuro Masaya 1 Ennishi Daisuke 2 Matsuoka Ken-ichi 2 Tanaka Takehiro 3 Okanoue Shotaro 1 Obayashi Yuka 1 Sakae Hiroyuki 1 Kawahara Yoshiro 4 Okada Hiroyuki 1 \n1 Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Japan\n\n2 Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan\n\n3 Department of Pathology, Okayama University Hospital, Japan\n\n4 Department of Practical Gastrointestinal Endoscopy, Okayama University Hospital, Japan\nCorrespondence to Dr. Masaya Iwamuro, iwamuromasaya@yahoo.co.jp\n\n\n4 8 2020 \n1 12 2020 \n59 23 3015 3022\n30 3 2020 22 6 2020 Copyright © 2020 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).We herein report four patients with desquamative esophagitis that developed one to nine days after peripheral blood stem cell transplantation (PBSCT). Three patients underwent allogeneic PBSCT for leukemia, and the other underwent autologous PBSCT for pineoblastoma. Esophagogastroduodenoscopy revealed mucosal sloughing and fresh blood in the esophagus. Fasting and intravenous proton pump inhibitor therapy in addition to blood transfusion improved the esophageal lesions within five to seven days in three patients. These cases indicate that desquamative esophagitis can occur in patients who receive hematopoietic stem cell transplantation. Although blood transfusions may be required, it can be resolved within seven days. \n\ndesquamative esophagitissloughing esophagitisesophagitis dissecans superficialisperipheral blood stem cell transplantation\n==== Body\nIntroduction\nDesquamative esophagitis, also known as sloughing esophagitis or esophagitis dissecans superficialis, is a benign condition characterized by sheets of sloughed squamous tissue in the esophagus (1-3). While a rare disorder, cases of desquamative esophagitis have been reported to be associated with skin diseases (e.g., pemphigus vulgaris and lichen planus), medication intake (e.g., bisphosphonates, non-steroidal anti-inflammatory drugs, and direct oral anticoagulants), esophageal injury (e.g., hot beverages, endoscopic dilatation, and sclerotherapy), and underlying esophageal disorders (e.g., eosinophilic esophagitis) (4-10). In contrast, few cases of desquamative esophagitis occurring after stem cell transplantation have been reported (11-13).\n\nWe herein report four cases of desquamative esophagitis that developed after peripheral blood stem cell transplantation (PBSCT). Of note, although the esophageal mucosa sloughing remained unchanged in one patient despite treatment, esophagogastroduodenoscopy performed five to seven days later revealed the improvement of desquamative esophagitis in the other three patients.\n\nCase Reports\nThe patient characteristics of the four cases of desquamative esophagitis after PBSCT are shown in Table 1. The medications used by the patients during the period from myeloablative conditioning therapy to the diagnosis of desquamative esophagitis are listed in Table 2.\n\nTable 1. Characteristics of Patients who Developed Desquamative Esophagitis after Hematopoietic Stem Cell Transplantation.\n\nCase\tAge (years)\tSex\tUnderlying disease\tSCT\tDays from SCT to the diagnosis of DE\tOutcome of DE\t\n1\t18\tF\tPineoblastoma\tAutologous PBSCT\t1\tDE was healed on day 7 after the diagnosis\t\n2\t29\tM\tB-cell acute lymphoblastic leukemia\tAllogeneic PBSCT from an HLA-haploidentical related donor\t6\tDE was healed on day 7 after the diagnosis\t\n3\t21\tM\tT-cell acute lymphoblastic leukemia\tAllogeneic PBSCT from an HLA-haploidentical related donor\t9\tDE was healed on day 5 after the diagnosis\t\n4\t16\tM\tAcute myeloid leukemia\tAllogeneic PBSCT from an HLA-1-locus mismatched related donor\t5\tDE persisted on day 7 after the diagnosis\t\nSCT: stem cell transplantation, DE: desquamative esophagitis, PBSCT: peripheral blood stem cell transplantation\n\nTable 2. The Medications Used by the Patients During the Period from Myeloablative Conditioning Therapy to the Diagnosis of Desquamative Esophagitis.\n\n\tAntacid\tAntibiotic\tAntiemetic\tImmunosuppressive agent\tChemotherapeutic agent\tOthers\t\n1\tEsomeprazole, lansoprazole\tAcyclovir, cefepime, doripenem, fluconazole, levofloxacin, micafungin\tAprepitant, fosaprepitant, granisetron, metoclopramide, prochlorperazine, ramosetron\tHydrocortisone\tCyclophosphamide, melphalan, nogitecan\tAcetaminophen, diphenhydramine, famotidine, furosemide, glycyrrhizin, haptoglobin, hydroxyzine, morphine, sodium bicarbonate, ursodeoxycholic acid, zonisamide\t\n2\tLansoprazole, omeprazole, rabeprazole, sodium alginate\tAcyclovir, fluconazole, letermovir, meropenem, micafungin, sulfamethoxazole/trimethoprim, valacyclovir, vancomycin, voriconazole\tAprepitant, granisetron, metoclopramide, olanzapine\tCyclophosphamide, hydrocortisone, mycophenolate mofetil, tacrolimus\tFludarabine, mesna\tAcetaminophen, calcium gluconate, clostridium butyricum, dalteparin sodium, d-chlorpheniramine, furosemide, lenograstim, magnesium sulfate, potassium chloride, potassium hydrogen phosphate, sodium bicarbonate, ursodeoxycholic acid\t\n3\tOmeprazole, vonoprazan\tAcyclovir, cefepime, letermovir, levofloxacin, meropenem, micafungin, pentamidine, sulfamethoxazole/trimethoprim, valacyclovir, voriconazole\tAprepitant, granisetron, prochlorperazine\tCyclophosphamide, dexamethasone, hydrocortisone, mycophenolate mofetil, tacrolimus\tFludarabine, melphalan, mesna\tAcetaminophen, alfacalcidol, carbazochrome, clostridium butyricum, dalteparin sodium, d-chlorpheniramine, filgrastim, furosemide, lenograstim, levothyroxine, magnesium oxide, magnesium sulfate, midodrine, morphine, oxycodone, potassium chloride, potassium hydrogen phosphate, ramelteon, sodium bicarbonate, thiamazole, ursodeoxycholic acid, zolpidem\t\n4\tLansoprazole, omeprazole, vonoprazan\tAcyclovir, caspofungin, itraconazole, letermovir, levofloxacin, meropenem, pentamidine, sulfamethoxazole/trimethoprim, tazobactam/piperacillin, teicoplanin, valacyclovir, vancomycin\tAprepitant, domperidone, granisetron, metoclopramide, prochlorperazine\tdexamethasone, hydrocortisone, methotrexate, tacrolimus\tGemtuzumab ozogamicin, cyclophosphamide, mesna\tAcetaminophen, brotizolam, carbazochrome, clostridium butyricum, dalteparin sodium, d-chlorpheniramine, fentanyl, furosemide, haptoglobin, herbal medicine Choreito, hydroxyzine, lenograstim, loperamide, magnesium sulfate, mosapride, nicardipine, potassium chloride, sodium bicarbonate, tranexamic acid, ursodeoxycholic acid\t\nCase 1\nAn 18-year-old Japanese woman underwent autologous PBSCT for refractory pineoblastoma. She received seven cycles of chemotherapy with ifosfamide, cisplatin, and etoposide before PBSCT. After conditioning with a myeloablative regimen consisting of topotecan, melphalan, and cyclophosphamide, seven days before PBSCT, the patient developed febrile neutropenia and was treated with cefepime followed by doripenem. The administration of acyclovir was also started seven days before PBSCT. On the day of PBSCT, she manifested oral mucositis and diarrhea, and morphine was administered. Since she vomited blood a day after undergoing PBSCT, we performed esophagogastroduodenoscopy, which revealed extensive sloughing of the esophageal mucosa and fresh blood (Fig. 1A-C). We therefore diagnosed her with desquamative esophagitis.\n\nFigure 1. Endoscopic images of case 1. An 18-year-old woman developed desquamative esophagitis one day after PBSCT (A-C). She was treated with fasting, intravenous administration of lansoprazole, and red blood cell transfusion. Esophagogastroduodenoscopy performed seven days later showed improvement of the esophageal lesion (D, E). PBSCT: peripheral blood stem cell transplantation\n\nA histopathological examination of the esophageal mucosal biopsy samples revealed necrotic tissues and degenerative squamous cells (Fig. 2). Immunostaining for herpes simplex virus was negative. Concomitantly, her white blood cells were 40/μL, hemoglobin was 6.5 g/dL, and platelets were 57,000/μL. She was treated with fasting and intravenous lansoprazole along with red blood cell transfusions. Esophagogastroduodenoscopy performed seven days later showed a healed esophageal mucosa (Fig. 1D, E).\n\nFigure 2. Pathological examination findings of case 1. The biopsy specimen from the sloughed esophageal mucosa revealed necrotic tissue and degenerative squamous cells.\n\nCase 2\nA 29-year-old Japanese man underwent haploidentical PBSCT for B-cell acute lymphoblastic leukemia. Although the leukemia was initially treated with intensive induction polychemotherapy, remission was not achieved. Thus, the patient received two cycles of inotuzumab ozogamicin and subsequently underwent PBSCT. Myeloablative conditioning was performed with 12 Gy of total body irradiation and fludarabine. The administration of dalteparin sodium was started the day before PBSCT to prevent sinusoidal obstruction syndrome. Valacyclovir and letermovir administration was also initiated the day before and after PBSCT, respectively. After PBSCT, the patient received a two-day infusion of cyclophosphamide, followed by the administration of mycophenolate mofetil and tacrolimus. Six days after PBSCT, he developed melena and hematochezia. His white blood cell count was 20/μL, hemoglobin level was 5.6 g/dL, and platelet count was 14,000/μL. Esophagogastroduodenoscopy showed a huge bloodlike lump in the middle to lower esophagus. In the middle part of the esophagus, the bloody mass occupied approximately half of the esophageal lumen and was also partly observed in the longitudinal border (Fig. 3A, arrows). In the esophagogastric junction, squamous mucosa was seen in the lower end of the lesion (Fig. 3B, arrows). We therefore suspected that a hematoma had formed after desquamation of the esophageal mucosa.\n\nFigure 3. Endoscopic images of case 2. A 29-year-old man who underwent haploidentical PBSCT developed desquamative esophagitis on day 6 (A, B). A bloody mass was observed at the longitudinal border in the middle part of the esophagus (A, arrows), and squamous mucosa was found in the lower end of the lesion (B, arrows). Treatment with fasting, administration of omeprazole and sodium alginate, and red blood cell and platelet transfusion was initiated. However, the sloughed esophageal mucosa remained unchanged four days later (C, D). Improvement of the esophageal lesions was confirmed by esophagogastroduodenoscopy performed seven days after the diagnosis (E, F). Half of the mucosa of the middle esophagus was reddish, which we considered to be vestiges of the desquamated area (E, arrows). Damaged esophageal mucosa was also partly observed in the reddish area (F, arrow). PBSCT: peripheral blood stem cell transplantation\n\nThe patient was treated with fasting and intravenous omeprazole therapy, and per-oral sodium alginate. The administration of dalteparin sodium was stopped. Red blood cells and platelets were also transfused. Esophagogastroduodenoscopy performed four days after treatment showed persistence of mucosal sloughing, hematoma, and bleeding (Fig. 3C, D). Although the esophageal lesions mostly healed seven days after the diagnosis of desquamative esophagitis, half of the mucosa of the middle esophagus was reddish, which we considered to be vestiges of the desquamated area (Fig. 3E, arrows). Damaged esophageal mucosa was partly observed in the reddish area (Fig. 3F, arrow).\n\nCase 3\nA Japanese boy was diagnosed with T-cell acute lymphoblastic leukemia at 5 years of age and underwent haploidentical PBSCT at 7 years of age. However, the leukemia recurred, and he received multiple chemotherapies. Thus, a second haploidentical PBSCT procedure was planned at 21 years of age. Myeloablative conditioning was performed with total body irradiation, fludarabine, and melphalan. Intravenous injection of dalteparin sodium was started six days before PBSCT to prevent sinusoidal obstruction syndrome. Valacyclovir and letermovir administrations were also initiated seven days before and on the day of PBSCT, respectively. After PBSCT, mycophenolate mofetil and tacrolimus were administered on day 5. On day 9, he developed hematemesis. Esophagogastroduodenoscopy results revealed fresh blood and peeled esophageal mucosa (Fig. 4A, B). Desquamative esophagitis was treated with fasting, intravenous omeprazole therapy, and discontinuation of dalteparin sodium. Since his white blood cell count was 30/μL, hemoglobin was 8.9 g/dL, and platelet count was 24,000/μL, platelet transfusion was performed. Esophagogastroduodenoscopy performed five days later showed epithelialized esophageal mucosa (Fig. 4C, D).\n\nFigure 4. Endoscopic images of case 3. On day 9 after haploidentical PBSCT, a 21-year-old man developed desquamative esophagitis (A, B). Esophagogastroduodenoscopy performed five days later showed epithelialized esophageal mucosa (C, D). PBSCT: peripheral blood stem cell transplantation\n\nCase 4\nA 15-year-old Japanese boy was diagnosed with acute myelomonocytic leukemia and received chemotherapy with daunorubicin and cytarabine, followed by consolidation and post-remission therapies. However, the leukemia recurred at 16 years of age. Salvage chemotherapy with fludarabine, cytarabine, and mitoxantrone failed, after which gemtuzumab ozogamicin was administered. Subsequently, he underwent allogeneic PBSCT from his human leukocyte antigen (HLA)-1-locus mismatched mother. Myeloablative conditioning was performed with total body irradiation and cyclophosphamide. Dalteparin sodium injection was administered once five days before PBSCT. Tacrolimus was administered a day before PBSCT, and methotrexate was administered on day 3 after PBSCT. Valacyclovir and letermovir administrations were also initiated seven days before and on the day of PBSCT, respectively. On day 5, the patient developed hematemesis, and esophagogastroduodenoscopy showed a bloody mass in the esophagus (Fig. 5A, B). Because the endoscopic images (Fig. 3C, D) and the patient's clinical course resembled that of case 2, we diagnosed the patient with desquamative esophagitis.\n\nFigure 5. Endoscopic images of case 4. A 16-year-old boy who underwent HLA-1-locus mismatched PBSCT developed desquamative esophagitis on day 5 (A, B). Esophagogastroduodenoscopy performed seven days after the diagnosis revealed that the sloughed esophageal mucosa was unchanged (C, D). The lower end of the lesion was partly membranous (D, arrows), which we considered to be peeled-off esophageal mucosa. PBSCT: peripheral blood stem cell transplantation, HLA-1: human leucocyte antigen-1\n\nHis white blood cell count was 10/μL, hemoglobin was 9.1 g/dL, and platelet count was 14,000/μL. Subsequently, red blood cells and platelets were transfused. Although the esophagitis was treated with fasting and intravenous omeprazole, esophagogastroduodenoscopy performed seven days after the diagnosis revealed that the clump of blood-like substance was unchanged (Fig. 5C). The lower end of the lesion was partly membranous (Fig. 5D, arrows), which we considered to be peeled-off esophageal mucosa. Because his systemic status had deteriorated, no additional endoscopy examinations were performed.\n\nDiscussion\nWe herein present the reports of four cases of desquamative esophagitis that occurred one to nine days after PBSCT. McDonald et al. reported that, among 63 patients with chronic graft-versus-host disease who were examined after allogeneic bone marrow transplantation, 8 had esophageal involvement (13). Although an endoscopic examination was not performed in one patient, all other patients developed desquamative esophagitis. The mean duration until the esophageal symptom onset was 220 days after transplantation (range, 69-632 days). Other previous reports of desquamative esophagitis after hematopoietic stem cell transplantation have described it as a manifestation of chronic graft-versus-host disease (11,12). However, in our four patients, desquamative esophagitis was diagnosed within nine days after PBSCT, indicating that esophageal mucosal sloughing can occur in the acute phase in patients who undergo hematopoietic stem cell transplant.\n\nThe typical endoscopic appearance of desquamative esophagitis includes sheets of partially sloughed, crumpled, or detached mucosa and linear strips of desquamated mucosal layers (1-4). In the present study, all of the patients showed blood adhesion in the esophagus and sloughed mucosa. Thrombocytopenia after hematopoietic stem cell transplantation and dalteparin sodium therapy, which was continuously administered in cases 2 and 3, may have caused the bleeding from the desquamated esophageal wall, which resulted in hematemesis, melena, and/or hematochezia. In addition, a hematoma (Fig. 3A, B) and a clump of blood were observed in case 2 (Fig. 3C) and case 4 (Fig. 5A, C). We speculated that, as described above, hematoma formation had occurred beneath the desquamated esophageal mucosa. The clump of blood might have been composed of rolled up sloughed mucosa and blood. However, because we did not perform a pathological analysis of the hematoma or the clump of blood, the mechanisms underlying the occurrence of these lesions have not been elucidated.\n\nSeveral hypotheses may be able to explain the pathogenesis of desquamative esophagitis in the present four patients: graft-versus-host disease, infection, radiation, intensive treatment sequences, and medication-induced mucosal damage. In general, the esophagus is infrequently affected by acute graft-versus-host disease. Furthermore, no patient manifested symptoms of acute graft-versus-host disease, such as skin rashes, diarrhea, or high levels of liver enzymes. However, an aggressive alloimmune reaction may have been involved in the development of desquamative esophagitis in cases 2-4, as these patients underwent HLA-mismatched PBSCT.\n\nViruses, such as cytomegalovirus and herpes simplex virus, can affect the esophagus, particularly in immunocompromised critically ill patients. Patients in the acute phase after PBSCT are susceptible to viral infection even under prophylactic antibiotic treatment. Thus, although antiviral drugs had been administered to all our patients prior to PBSCT, viral infection may have induced esophageal damage. Radiation therapy also causes inflammation, edema, erythema, and erosion of the mucosal surface of the esophagus. Therefore, it may lead to desquamative esophagitis. Nevertheless, radiation-induced mucosal damage is unlikely to be the common etiology for desquamative esophagitis in our patients because case 1 did not undergo total body irradiation. Among those who underwent allogeneic transplant, all three were young and had recurrent/refractory leukemia; therefore, intensive pretransplant treatments and HLA-mismatched PBSCTs with myeloablative conditioning were performed. Such intensive treatment sequences might have affected the esophageal tissue.\n\nOther drugs administered before symptom onset could also be possible causes of medication-related toxicity and/or esophageal infection, which resulted in esophageal mucosal sloughing. Mycophenolate mofetil has been reported to induce gastrointestinal tract abnormalities, such as circumferential inflammation, ulcers, and esophageal stricture (14-16). However, only two patients received mycophenolate mofetil, whereas the other two did not take the drug. As shown in Table 2, the common drugs administered to all four patients were mesna, acyclovir, aprepitant, granisetron, cyclophosphamide, hydrocortisone, furosemide, sodium bicarbonate, and ursodeoxycholic acid. Some of these drugs are known to cause adverse gastrointestinal manifestations (17-19). Thus, one of these drugs or their combination might have caused the desquamative esophagitis in our patients. Further investigations will be required to determine the etiology of desquamative esophagitis that develops in the acute phase after PBSCT.\n\nIt is noteworthy that three of the four patients recovered from desquamative esophagitis within seven days of the diagnosis. Although the infusion of red blood cells and/or platelets was required for the treatment of anemia and thrombocytopenia, patients were treated with fasting and the intravenous administration of proton pump inhibitors. These results indicate that desquamative esophagitis occurring in the acute phase of PBSCT is only transient damage to the superficial esophageal mucosa and should be treated conservatively.\n\nIn conclusion, our patients developed desquamative esophagitis one to nine days after PBSCT. Fasting and intravenous administration of proton pump inhibitors in combination with blood transfusion helped ameliorate the sloughed esophageal mucosa in three of the four patients. Although the exact pathogenesis is uncertain, we believe that understanding the unique manifestation and outcome of this esophageal lesion will help hematologists and gastroenterologists manage adverse events in patients undergoing hematopoietic stem cell transplantation.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Akhondi H \nSloughing esophagitis: a not so common entity\n. Int J Biomed Sci \n10 : 282 -286\n, 2014 .25598761 \n2. Purdy JK , Appelman HD , McKenna BJ \nSloughing esophagitis is associated with chronic debilitation and medications that injure the esophageal mucosa\n. Mod Pathol \n25 : 767 -775\n, 2012 .22282305 \n3. Carmack SW , Vemulapalli R , Spechler SJ , Genta RM \nEsophagitis dissecans superficialis (“sloughing esophagitis”): a clinicopathologic study of 12 cases\n. Am J Surg Pathol \n33 : 1789 -1794\n, 2009 .19809273 \n4. Shah R , Thoguluva V , Bansal N , Manocha D \nEsophageal dissecans: a rare life-threatening presentation of recurrent pemphigus vulgaris\n. Am J Emerg Med \n33 : e1 -e2\n, 2015 .\n5. Ma H , Chen M , Liu J , Li Y , Li J \nSerious stomatitis and esophagitis: a peculiar mucous reaction induced by pegylated liposomal doxorubicin\n. An Bras Dermatol \n90 : 209 -211\n, 2015 .26312719 \n6. Shah SA , Cho M , Chaptini L , Parikh N \nSloughing esophagitis: an atypical cause of food impaction\n. ACG Case Rep J \n3 : e85 , 2016 .27807547 \n7. Dumas-Campagna M , Bouchard S , Soucy G , Bouin M \nIgG4-related esophageal disease presenting as esophagitis dissecans superficialis with chronic strictures\n. J Clin Med Res \n6 : 295 -298\n, 2014 .24883156 \n8. Hart PA , Romano RC , Moreira RK , Ravi K , Sweetser S \nEsophagitis dissecans superficialis: clinical, endoscopic, and histologic features\n. Dig Dis Sci \n60 : 2049 -2057\n, 2015 .25701324 \n9. Hokama A , Yamamoto Y , Taira K , et al \nEsophagitis dissecans superficialis and autoimmune bullous dermatoses: a review\n. World J Gastrointest Endosc \n2 : 252 -256\n, 2010 .21160615 \n10. Nidimusili AJ , Dhadam GC , Shaheen K \nSloughing esophageal mucosa\n. QJM \n107 : 77 -78\n, 2014 .23359722 \n11. Trabulo D , Ferreira S , Lage P , Rego RL , Teixeira G , Pereira AD \nEsophageal stenosis with sloughing esophagitis: a curious manifestation of graft-vs-host disease\n. World J Gastroenterol \n21 : 9217 -9222\n, 2015 .26290649 \n12. Nakshabendi IM , Maldonado ME , Coppola D , Mamel JJ \nEsophageal cast: a manifestation of graft-versus-host disease\n. Dig Dis \n18 : 103 -105\n, 2000 .11060473 \n13. McDonald GB , Sullivan KM , Schuffler MD , Shulman HM , Thomas ED \nEsophageal abnormalities in chronic graft-versus-host disease in humans\n. Gastroenterology \n80 : 914 -921\n, 1981 .7009315 \n14. Matin T , Zhao Y , Goyal J , Weber F \nMycophenolate induced GI mucosal injury - case report and review of the literature\n. MOJ Clin Med Case Rep \n8 : 96 -98\n, 2018 .\n15. Liu K , Kia L \nMycophenolate mofetil-induced esophagitis\n. Clin Gastroenterol Hepatol \n17 : e139 , 2019 .29857144 \n16. Delacruz V , Weppler D , Island E , et al \nMycophenolate mofetil-related gastrointestinal mucosal injury in multivisceral transplantation\n. Transplant Proc \n42 : 82 -84\n, 2010 .20172286 \n17. Blijlevens NM \nCytotoxic treatment-induced gastrointestinal symptoms\n. Curr Opin Support Palliat Care \n1 : 16 -22\n, 2007 .18660719 \n18. Liu T , Wu Y , Wang L , et al \nA more robust gut microbiota in calorie-restricted mice is associated with attenuated intestinal injury caused by the chemotherapy drug cyclophosphamide\n. mBio \n10 : e02903 -e02918\n, 2019 .30862756 \n19. Xie JH , Fan ST , Nie SP , et al \nLactobacillus plantarum NCU116 attenuates cyclophosphamide-induced intestinal mucosal injury, metabolism and intestinal microbiota disorders in mice\n. Food Funct \n7 : 1584 -1592\n, 2016 .26906433\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "59(23)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "desquamative esophagitis; esophagitis dissecans superficialis; peripheral blood stem cell transplantation; sloughing esophagitis",
"medline_ta": "Intern Med",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D001803:Blood Transfusion; D004941:Esophagitis; D005215:Fasting; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007564:Japan; D008297:Male; D054328:Proton Pump Inhibitors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "3015-3022",
"pmc": null,
"pmid": "32759586",
"pubdate": "2020-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26906433;22282305;27807547;7009315;26290649;20172286;19809273;25598761;24883156;25983121;23359722;18660719;25701324;21160615;29857144;30862756;26312719;11060473",
"title": "Four Cases of Desquamative Esophagitis Occurring after Hematopoietic Stem Cell Transplantation.",
"title_normalized": "four cases of desquamative esophagitis occurring after hematopoietic stem cell transplantation"
} | [
{
"companynumb": "JP-TEVA-2021-JP-1914838",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MEROPENEM"
},
"drugadditional": "3",
... |
{
"abstract": "Pyogenic granuloma (PG) is a benign, neoplastic, soft tissue growth of granulation and fibrous tissue that may rarely occur in the mouth of patients after hematopoietic cell transplant (HCT). This case series describes 5 pediatric/adolescent patients who developed oral PG after HCT for acute lymphoblastic leukemia, Fanconi anemia, nodular sclerosis Hodgkin's lymphoma, or junctional epidermolysis bullosa. The underlying mechanism for the appearance of oral PG after HCT is unknown, but it is suggested that calcineurin inhibitors used for graft versus host disease (GVHD) may play a role, as all patients were on cyclosporine A or tacrolimus at the time of development of oral PG. Three of the patients were being treated for chronic GVHD, and 1 other treated for acute GVHD. Overall, this report illustrates that PG should be considered in the differential diagnoses when encountering oral lesions in pediatric/adolescent patients after undergoing HCT, especially in the context of chronic GVHD and calcineurin inhibitors use.",
"affiliations": "Department of Pediatrics, Division of Pediatric Blood and Marrow Transplant, University of Minnesota, Minneapolis, MN.",
"authors": "Cheney-Peters|Dianna|D|;Lund|Troy C|TC|",
"chemical_list": "D065095:Calcineurin Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000000593",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "38(7)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D065095:Calcineurin Inhibitors; D002648:Child; D006086:Graft vs Host Disease; D017789:Granuloma, Pyogenic; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D009059:Mouth Diseases; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "570-3",
"pmc": null,
"pmid": "27271813",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Oral Pyogenic Granuloma After Bone Marrow Transplant in the Pediatric/Adolescent Population: Report of 5 Cases.",
"title_normalized": "oral pyogenic granuloma after bone marrow transplant in the pediatric adolescent population report of 5 cases"
} | [
{
"companynumb": "US-APOTEX-2016AP015101",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GANCICLOVIR"
},
"drugadditional": "3",
... |
{
"abstract": "Standard chemoradiotherapy (CRT) for local advanced rectal cancer (LARC) rarely induce rectal perforation. Here we report a rare case of rectal perforation in a patient with LARC in the midst of preoperative CRT. A 56-year-old male was conveyed to our hospital exhibiting general malaise. Colonoscopy and imaging tests resulted in a clinical diagnosis of LARC with direct invasion to adjacent organs and regional lymphadenopathy. Preoperative 5-fluorouracil-based CRT was started. At 25 d after the start of CRT, the patient developed a typical fever. Computed tomography revealed rectal perforation, and he underwent emergency sigmoid colostomy. At 12 d after the surgery, the remaining CRT was completed according to the original plan. The histopathological findings after radical operation revealed a wide field of tumor necrosis and fibrosis without lymph node metastasis. We share this case as important evidence for the treatment of LARC perforation in the midst of preoperative CRT.",
"affiliations": "Nobuhisa Takase, Kimihiro Yamashita, Yasuo Sumi, Hiroshi Hasegawa, Masashi Yamamoto, Shingo Kanaji, Yoshiko Matsuda, Takeru Matsuda, Taro Oshikiri, Tetsu Nakamura, Satoshi Suzuki, Yoshihiro Kakeji, Division of Gastrointestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.;Nobuhisa Takase, Kimihiro Yamashita, Yasuo Sumi, Hiroshi Hasegawa, Masashi Yamamoto, Shingo Kanaji, Yoshiko Matsuda, Takeru Matsuda, Taro Oshikiri, Tetsu Nakamura, Satoshi Suzuki, Yoshihiro Kakeji, Division of Gastrointestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.;Nobuhisa Takase, Kimihiro Yamashita, Yasuo Sumi, Hiroshi Hasegawa, Masashi Yamamoto, Shingo Kanaji, Yoshiko Matsuda, Takeru Matsuda, Taro Oshikiri, Tetsu Nakamura, Satoshi Suzuki, Yoshihiro Kakeji, Division of Gastrointestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.;Nobuhisa Takase, Kimihiro Yamashita, Yasuo Sumi, Hiroshi Hasegawa, Masashi Yamamoto, Shingo Kanaji, Yoshiko Matsuda, Takeru Matsuda, Taro Oshikiri, Tetsu Nakamura, Satoshi Suzuki, Yoshihiro Kakeji, Division of Gastrointestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.;Nobuhisa Takase, Kimihiro Yamashita, Yasuo Sumi, Hiroshi Hasegawa, Masashi Yamamoto, Shingo Kanaji, Yoshiko Matsuda, Takeru Matsuda, Taro Oshikiri, Tetsu Nakamura, Satoshi Suzuki, Yoshihiro Kakeji, Division of Gastrointestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.;Nobuhisa Takase, Kimihiro Yamashita, Yasuo Sumi, Hiroshi Hasegawa, Masashi Yamamoto, Shingo Kanaji, Yoshiko Matsuda, Takeru Matsuda, Taro Oshikiri, Tetsu Nakamura, Satoshi Suzuki, Yoshihiro Kakeji, Division of Gastrointestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.;Nobuhisa Takase, Kimihiro Yamashita, Yasuo Sumi, Hiroshi Hasegawa, Masashi Yamamoto, Shingo Kanaji, Yoshiko Matsuda, Takeru Matsuda, Taro Oshikiri, Tetsu Nakamura, Satoshi Suzuki, Yoshihiro Kakeji, Division of Gastrointestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.;Nobuhisa Takase, Kimihiro Yamashita, Yasuo Sumi, Hiroshi Hasegawa, Masashi Yamamoto, Shingo Kanaji, Yoshiko Matsuda, Takeru Matsuda, Taro Oshikiri, Tetsu Nakamura, Satoshi Suzuki, Yoshihiro Kakeji, Division of Gastrointestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.;Nobuhisa Takase, Kimihiro Yamashita, Yasuo Sumi, Hiroshi Hasegawa, Masashi Yamamoto, Shingo Kanaji, Yoshiko Matsuda, Takeru Matsuda, Taro Oshikiri, Tetsu Nakamura, Satoshi Suzuki, Yoshihiro Kakeji, Division of Gastrointestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.;Nobuhisa Takase, Kimihiro Yamashita, Yasuo Sumi, Hiroshi Hasegawa, Masashi Yamamoto, Shingo Kanaji, Yoshiko Matsuda, Takeru Matsuda, Taro Oshikiri, Tetsu Nakamura, Satoshi Suzuki, Yoshihiro Kakeji, Division of Gastrointestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.;Nobuhisa Takase, Kimihiro Yamashita, Yasuo Sumi, Hiroshi Hasegawa, Masashi Yamamoto, Shingo Kanaji, Yoshiko Matsuda, Takeru Matsuda, Taro Oshikiri, Tetsu Nakamura, Satoshi Suzuki, Yoshihiro Kakeji, Division of Gastrointestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.;Nobuhisa Takase, Kimihiro Yamashita, Yasuo Sumi, Hiroshi Hasegawa, Masashi Yamamoto, Shingo Kanaji, Yoshiko Matsuda, Takeru Matsuda, Taro Oshikiri, Tetsu Nakamura, Satoshi Suzuki, Yoshihiro Kakeji, Division of Gastrointestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.;Nobuhisa Takase, Kimihiro Yamashita, Yasuo Sumi, Hiroshi Hasegawa, Masashi Yamamoto, Shingo Kanaji, Yoshiko Matsuda, Takeru Matsuda, Taro Oshikiri, Tetsu Nakamura, Satoshi Suzuki, Yoshihiro Kakeji, Division of Gastrointestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.;Nobuhisa Takase, Kimihiro Yamashita, Yasuo Sumi, Hiroshi Hasegawa, Masashi Yamamoto, Shingo Kanaji, Yoshiko Matsuda, Takeru Matsuda, Taro Oshikiri, Tetsu Nakamura, Satoshi Suzuki, Yoshihiro Kakeji, Division of Gastrointestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.;Nobuhisa Takase, Kimihiro Yamashita, Yasuo Sumi, Hiroshi Hasegawa, Masashi Yamamoto, Shingo Kanaji, Yoshiko Matsuda, Takeru Matsuda, Taro Oshikiri, Tetsu Nakamura, Satoshi Suzuki, Yoshihiro Kakeji, Division of Gastrointestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.",
"authors": "Takase|Nobuhisa|N|;Yamashita|Kimihiro|K|;Sumi|Yasuo|Y|;Hasegawa|Hiroshi|H|;Yamamoto|Masashi|M|;Kanaji|Shingo|S|;Matsuda|Yoshiko|Y|;Matsuda|Takeru|T|;Oshikiri|Taro|T|;Nakamura|Tetsu|T|;Suzuki|Satoshi|S|;Koma|Yu-Ichiro|YI|;Komatsu|Masato|M|;Sasaki|Ryohei|R|;Kakeji|Yoshihiro|Y|",
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"country": "United States",
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"doi": "10.12998/wjcc.v5.i1.18",
"fulltext": "\n==== Front\nWorld J Clin CasesWJCCWorld Journal of Clinical Cases2307-8960Baishideng Publishing Group Inc jWJCC.v5.i1.pg1810.12998/wjcc.v5.i1.18Case ReportLocal advanced rectal cancer perforation in the midst of preoperative chemoradiotherapy: A case report and literature review Takase Nobuhisa Yamashita Kimihiro Sumi Yasuo Hasegawa Hiroshi Yamamoto Masashi Kanaji Shingo Matsuda Yoshiko Matsuda Takeru Oshikiri Taro Nakamura Tetsu Suzuki Satoshi Koma Yu-Ichiro Komatsu Masato Sasaki Ryohei Kakeji Yoshihiro Nobuhisa Takase, Kimihiro Yamashita, Yasuo Sumi, Hiroshi Hasegawa, Masashi Yamamoto, Shingo Kanaji, Yoshiko Matsuda, Takeru Matsuda, Taro Oshikiri, Tetsu Nakamura, Satoshi Suzuki, Yoshihiro Kakeji, Division of Gastrointestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, JapanYu-Ichiro Koma, Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe 657-8501, JapanMasato Komatsu, Division of Diagnostic Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe 657-8501, JapanMasato Komatsu, Department of Surgery, Hyogo Cancer Center, Akashi 673-8558, JapanRyohei Sasaki, Department of Radiation Oncology, Kobe University Graduate School of Medicine, Kobe 657-8501, JapanAuthor contributions: Yamashita K and Sumi Y operated on the patient and designed the report; Hasegawa H, Yamamoto M, Kanaji S, Matsuda Y, Matsuda T, Oshikiri T, Nakamura T and Suzuki S drafted the paper; Koma YI, Komatsu M, Sasaki R and Kakeji Y critically revised the paper with an important conceptual and editorial input.\n\nCorrespondence to: Kimihiro Yamashita, MD, PhD, Division of Gastrointestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. kiyama@med.kobe-u.ac.jp\n\nTelephone: +81-78-3825925 Fax: +81-78-3825939\n\n16 1 2017 16 1 2017 5 1 18 23 24 8 2016 11 11 2016 1 12 2016 ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.2017This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.Standard chemoradiotherapy (CRT) for local advanced rectal cancer (LARC) rarely induce rectal perforation. Here we report a rare case of rectal perforation in a patient with LARC in the midst of preoperative CRT. A 56-year-old male was conveyed to our hospital exhibiting general malaise. Colonoscopy and imaging tests resulted in a clinical diagnosis of LARC with direct invasion to adjacent organs and regional lymphadenopathy. Preoperative 5-fluorouracil-based CRT was started. At 25 d after the start of CRT, the patient developed a typical fever. Computed tomography revealed rectal perforation, and he underwent emergency sigmoid colostomy. At 12 d after the surgery, the remaining CRT was completed according to the original plan. The histopathological findings after radical operation revealed a wide field of tumor necrosis and fibrosis without lymph node metastasis. We share this case as important evidence for the treatment of LARC perforation in the midst of preoperative CRT.\n\nLocal advanced rectal cancerPreoperative chemoradiotherapyRectal perforation5-fluorouracilTumor necrosis\n==== Body\nCore tip: Standard chemoradiotherapy (CRT) for local advanced rectal cancer (LARC) rarely induces rectal perforation. This case report presents a case of rectal perforation in a patient with LARC in the midst of 5-fluorouracil-based preoperative CRT. We decided to complete CRT according to the original plan after supporting emergency recovery. The histopathological findings after radical operation revealed a wide field of tumor necrosis and fibrosis without lymph node metastasis, suggesting the efficacy of the CRT. We believe that establishing a standard treatment for CRT-related LARC perforation may improve the prognosis of such cases.\n\nINTRODUCTION\nCurrently, the best proven approach to local advanced rectal cancer (LARC) is a combination of surgery and preoperative chemoradiotherapy (CRT)[1,2]. Compared to preoperative radiotherapy (RT) alone, the incidence of local recurrence at 5 years was significantly lower in the preoperative CRT group[3]. We previously reported that the pathological response to preoperative 5-fluorouracil (FU)-based CRT may be a useful predictor of LARC survival[4]. However, preoperative CRT is associated with various adverse effects that can be life-threatening. Among the life-threatening side effects, CRT-related perforation of colorectal cancer is not well understood. We herein report a case of perforated LARC associated with preoperative CRT.\n\nCASE REPORT\nA 56-year-old Japanese male was transported to our facility with chief complaints of fever and general malaise. Though he had had anemia 3 years prior, he did not seek medical attention. He had used alcohol for at least 34 years. His serum level of carcino embryonic antigen was increased to 21.0 ng/mL (normal < 2.5). The colonoscopy examination revealed a low anterior circumferential rectal lesion (Figure 1A).\n\nFigure 1 Evaluation of clinical findings. Colonoscopy showed a circumferential mass at the lower rectum (A); Sagittal magnetic resonance imaging (MRI) of the pelvis showed rectal mass with involvement prostate and seminal vesicles (red arrows) (B), and perirectal fat (C); The enlarged lymph node in the left obturator detected by coronal MRI (red arrow) showed obvious metabolically active foci 18-fluorodeoxyglucose-positron emission tomography/computed tomography evaluation (D).\n\nAn endoscopic biopsy histologically confirmed the clinical diagnosis of adenocarcinoma. Magnetic resonance imaging (MRI) findings revealed LARC with involvement of perirectal fat, the prostate and the seminal vesicles (Figure 1B). Some of the lymph nodes in the tumor area were enlarged (Figure 1C) and 18-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) showed metabolically active foci in the left obturator lymph node (Figure 1D). No evidence of distant spread was seen.\n\nThe patient was scheduled for preoperative 5-FU-based CRT. Administration of a fixed dose of tegafur/uracil (UFT) (300 mg/body per day) and leucovorin (LV) (75 mg/body per day) was planned for days 1-28. Concurrent RT administration to the whole pelvis (Figure 2A) was planned in fractions of 1.8 Gy/d, 5 d a week for 5 wk (45 Gy in 25 fractions). However, the patient developed a typical fever at 25 d after starting CRT (36 Gy in 20 fractions received). The CT findings revealed rectal perforation with air-fluid around the left side of the seminal vesicle adjacent to the rectum (Figure 2B), and the colonoscopic examination also showed the perforation of the tumor wall (Figure 2C). The patient underwent construction of a sigmoid colostomy as an emergency surgery.\n\nFigure 2 Rectal tumor perforation suggestive of chemoradiationdamage. Radiotherapy was delivered to the whole pelvis through three (one posterior-anterior and two lateral) or four (one anterior-posterior, one posterior-anterior and two lateral) fields using a 10-MV linear accelerator in the prone position (A); Coronal computed tomography findings showed a small bubble of extra-luminal gas (red arrow) (B); Preoperative colonoscopicfindings for radical surgery showed excavation with mucosa necrosis (red arrow) suggestive of chemoradiationdamage in the rectal tumor (C).\n\nAt 12 d after the surgery with no inflammatory findings, the remaining CRT was commenced, and was completed safely according to plan. The patient underwent abdominoperineal resection of the rectum including the prostate and seminal vesicle with a laparoscopic technique as minimally invasive surgery. The histopathological findings revealed that a wide area of tumor tissue had been replaced by necrotic tissue and fibrous tissue, suggesting that chemoradiation had been effective (Figure 3). The Union for International Cancer Control (UICC) TNM staging[5] of the tumor was pT3, N0 (0/34), M0. No evident disease recurrence has been observed in the patients for 8 mo.\n\nFigure 3 Histological findings of the resected specimen showed a wide field of tumor necrosis with fibril formation (H-E stain).\n\nDISCUSSION\nRT is one of the useful modalities for various cancers including rectal cancer. Currently, more than 50% of cancer patients receive RT with or without chemotherapy[6]. RT gives rise to various cellular responses including both DNA and membrane damage[7]. The DNA damage leads to cell cycle arrest, apoptosis, stress and the activation of DNA repair processes through coordinating intracellular signal pathways involving poly ADP ribose polymerase, ERK1/2, p53 and ataxia telangiectasia mutated[7,8]. Concerning pelvic RT with concurrent 5-FU-based chemotherapy, 5-FU can increase radiation sensitivity[3,9]. However, RT causes various side effects that damage healthy cells and tissues near the treatment area.\n\nRadiation-related tissue injuries are well known to occur in the gastrointestinal tract. Acute radiation-related small bowel toxicity often occurs during RT for LARC. The overall incidence of acute Grade 3-4 diarrhea was 16%-39% in prospective studies of preoperative RT[10]. Concerning the rectum, radiation proctitis is generally classified as acute or chronic phase by the timeframe of the symptoms, and chronic proctitis may include acute proctitis defined as an inflammatory process. However, the detailed pathogenesis of RT-induced proctitis is not yet clear. Acute proctitis including symptoms of diarrhea, nausea, cramps, tenesmus, urgency, mucus discharge and minor bleeding occurs within 6 wk after the start of RT[11]. Severe bleeding, strictures, perforation, fistula and bowel obstruction occur in the chronic phase, which may not become apparent for months to years[12]. Concerning pelvic RT with concurrent 5-FU-based chemotherapy, severe acute small-bowel toxicity was found to be associated with radiation in a dose-dependent manner[13,14].\n\nColorectal perforation is a life-threatening complication. The causes of rectal perforation include fecal impaction, enema, and cancer and its therapy, including RT, chemotherapy and molecular-targeted therapy. Among them, rectal perforation from pelvic RT is an extremely rare adverse event. The mechanisms of radiation-related perforation, especially the difference in responses between normal rectal tissue and LARC tissue, remain elusive. RT-induced normal tissue perforation is generally caused by accumulation of radiation-induced irreversible ischemic mechanisms with submucosal fibrosis and obliteration of small blood vessels[15]. In addition to the ischemic change, cancer tissue with high radiation sensitivity results in massive necrotic death, which in turn triggers an inflammatory reaction analogous to a wound-healing response[15-17].\n\nThere is general agreement that radiation-induced gastrointestinal injuries are associated with the dose of radiation. Late normal tissue reactions are more dependent on the dose per fraction than acute reactions[18]. Still, Do et al[12] reported that a total dose of 45 to 50 Gy delivered to the pelvis for adjuvant or neoadjuvant treatment for rectal malignancies generally causes very few acute and late morbidities.\n\nHowever, total treatments of > 70 Gy cause significant and long-standing injury to the surrounding area[12,19]. In the present case, the main cause of the standard 5-FU-based CRT-related rectal perforation was thought to be not direct radiation morbidity but a secondary effect of the tumor necrosis. In addition to excessive treatment effects of CRT, the potential risks for CRT-related LARC perforation may include the presence of diverticula, collagenosis and tumor ulceration. Khan et al[20] also argue that the biological behavior of the tumor may have a large influence on whether an event occurs because all transrectal tumors have the potential for perforation. Pathological and immunohistochemical analyses of various factors in colorectal tumor perforation compared with non-perforated tumor showed significant associations of tumor location and cell differentiation[21].\n\nWe searched all common literature search engines (PubMed, Medline, Google Scholar). To our knowledge, only 6 cases of perforated LARC associated with 5-FU-based preoperative CRT have been reported[20,22,23] (Table 1). Among them, the cases of perforation in the midst of preoperative CRT were only 2 in number. Furthermore, completion of preoperative CRT according to the original plan after supporting emergency recovery for CRT-related rectal perforation has never before been described.\n\nTable 1 Characteristics of perforated local advanced rectal cancer associated with 5-fluorouracil-based preoperative chemoradiotherapy\n\nCase\tRef.\tSex\tTime to perforation\tSurgical intervention (additional surgery)\tTNM\tOutcome\t\n\t\tAge\tTotal dose of RT (Gy/fr)\t\tClassification1\t\t\n1\tLee et al[22]\tF\t5 D after planned CRT\tLAR\tcT4, NX, MX\tAlive\t\n\t\t67\t50 Gy/28 fr\t\tpT4, N2, M0\t\t\n2\tLee et al[22]\tF\tImmediately after planned CRT\tIleostomy\tcT4, NX, MX\tAlive\t\n\t\t78\t54 Gy/unknown\t\t\t\t\n3\tLee et al[22]\tM\t2 W in the middle of planned CRT\tColostomy\tcT3, NX, MX\tPerioperative death\t\n\t\t72\t21.6 Gy/unknown\t\t\t\n4\tLee et al[22]\tM\t4 W in the middle of planned CRT\tColectomy with ileostomy\tcT3, NX, MX\tPerioperative death\t\n\t\t76\t36 Gy/unknown\t\t\t\n5\tKhan et al[20]\tM\t1 W after planned CRT\tLAR\tcT3, N1, M0\tAlive\t\n\t\t47\t50.45 Gy/28 fr\t\tpT3, N2, M0\t\t\n6\tElGendy et al[23]\tF\t2 W after planned CRT\tLAR\tcT3, N1, M0\tAlive\t\n\t\t55\t45 Gy/unknown\t\tpT3, N2, M0\t\t\n7\tOur case\tM\t25 D in the middle of planned CRT\tColectomy (APR after remaining planned CRT)\tcT4, N2, M0\tAlive\t\n\t\t56\t36 Gy/20 fr\t\tpT3, N0, M0\t\t\n1 According to the TNM classification by Union for International Cancer Control (UICC)[5]. The following cases searched common literature search engines (PubMed, Medline, Google Scholar) through August 2016, using search terms related to rectal cancer, perforation and chemoradiotherapy. LAR: Low anterior resection; APR: Abdominoperineal resection; CRT: Chemoradiotherapy; RT: Radiotherapy; F: Female; M: Male.\n\nIn recent years, various molecularly targeted agents have been used clinically for colorectal cancer. However, the spread of molecularly targeted therapies including combination RT has resulted in more cases of agent-induced gastrointestinal perforation[24,25]. Gastrointestinal perforation has occurred in both non-tumor tissue and tumor tissue including rectal cancer[26]. To avoid severe complications related to CRT, such as LARC perforation, regimens of chemotherapy as well as methods of radiation therapy should be carefully considered.\n\nIn conclusion, we documented an extremely rare case of LARC that developed preoperative rectal perforation in the midst of 5-FU-based preoperative CRT. We share this case as important evidence for the treatment for LARC perforation in the midst of preoperative CRT. Our case findings imply that completing preoperative CRT after supporting emergency recovery may enhance the anti-tumor effect, resulting in a better prognosis for such cases.\n\nCOMMENTS\nCase characteristics\nA 56-year-old male with locally advanced rectal cancer (LARC) developed preoperative rectal perforation in the midst of 5-fluorouracil (FU)-based preoperative chemoradiotherapy (CRT).\n\nClinical diagnosis\nColonoscopy and imaging tests resulted in a clinical diagnosis of LARC with direct invasion to adjacent organs and regional lymphadenopathy.\n\nDifferential diagnosis\nInflammatory associated rectal perforation.\n\nLaboratory diagnosis\nPreoperative serum level of carcino embryonic antigen was increased to 21.0 ng/mL (normal < 2.5).\n\nImaging diagnosis\nThe computed tomography findings revealed rectal perforation with air-fluid around the left side of the seminal vesicle adjacent to the rectum.\n\nPathological diagnosis\nA wide area of tumor tissue was replaced by necrotic tissue and fibrous tissue, suggesting that chemoradiation had been effective.\n\nTreatment\nThe patient completed preoperative CRT after supporting emergency recovery.\n\nRelated reports\nTo our knowledge, only 6 cases of perforated LARC associated with 5-FU-based preoperative CRT have been reported.\n\nExperiences and lessons\nThe authors share this case as important evidence for the treatment of LARC perforation in the midst of preoperative CRT.\n\nPeer-review\nThis case report demonstrated that completing preoperative CRT after supporting emergency recovery may enhance the anti-tumor effect, resulting in a better prognosis.\n\nManuscript source: Unsolicited manuscript\n\nSpecialty type: Medicine, research and experimental\n\nCountry of origin: Japan\n\nPeer-review report classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): 0\n\nGrade C (Good): C\n\nGrade D (Fair): D\n\nGrade E (Poor): 0\n\nInstitutional review board statement: This case report was exempt from the Institutional review board standards at Kobe University Graduate School of Medicine and Hospital, Kobe, Japan.\n\nInformed consent statement: The patient participant to the study provided informed written consent.\n\nConflict-of-interest statement: The authors declare no conflict of interest associated with this manuscript.\n\nPeer-review started: August 25, 2016\n\nFirst decision: October 28, 2016\n\nArticle in press: December 2, 2016\n\nP- Reviewer: Rasmussen SL, Trevisani L S- Editor: Qi Y L- Editor: A E- Editor: Li D\n==== Refs\n1 Sauer R Liersch T Merkel S Fietkau R Hohenberger W Hess C Becker H Raab HR Villanueva MT Witzigmann H Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years J Clin Oncol 2012 30 1926 1933 22529255 \n2 Roh MS Colangelo LH O’Connell MJ Yothers G Deutsch M Allegra CJ Kahlenberg MS Baez-Diaz L Ursiny CS Petrelli NJ Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03 J Clin Oncol 2009 27 5124 5130 19770376 \n3 De Caluwé L Van Nieuwenhove Y Ceelen WP Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer Cochrane Database Syst Rev 2013 2 CD006041 23450565 \n4 Tomono A Yamashita K Kanemitsu K Sumi Y Yamamoto M Kanaji S Imanishi T Nakamura T Suzuki S Tanaka K Prognostic significance of pathological response to preoperative chemoradiotherapy in patients with locally advanced rectal cancer Int J Clin Oncol 2016 21 344 349 26338272 \n5 Sobin LH Gospodarowicz MK Wittekind C TNM classification of malignant tumours, 7th edn. Wiley-Blackwell, Oxford 2009 \n6 Bentzen SM Preventing or reducing late side effects of radiation therapy: radiobiology meets molecular pathology Nat Rev Cancer 2006 6 702 713 16929324 \n7 Watters D Molecular mechanisms of ionizing radiation-induced apoptosis Immunol Cell Biol 1999 77 263 271 10361259 \n8 Xiao M Whitnall MH Pharmacological countermeasures for the acute radiation syndrome Curr Mol Pharmacol 2009 2 122 133 20021452 \n9 Kvols LK Radiation sensitizers: a selective review of molecules targeting DNA and non-DNA targets J Nucl Med 2005 46 Suppl 1 187S 190S 15653668 \n10 Grann A Minsky BD Cohen AM Saltz L Guillem JG Paty PB Kelsen DP Kemeny N Ilson D Bass-Loeb J Preliminary results of preoperative 5-fluorouracil, low-dose leucovorin, and concurrent radiation therapy for clinically resectable T3 rectal cancer Dis Colon Rectum 1997 40 515 522 9152176 \n11 Williams G Yan BM Endoscopic ultrasonographic features of subacute radiation proctitis J Ultrasound Med 2010 29 1495 1498 20876905 \n12 Do NL Nagle D Poylin VY Radiation proctitis: current strategies in management Gastroenterol Res Pract 2011 \n13 Baglan KL Frazier RC Yan D Huang RR Martinez AA Robertson JM The dose-volume relationship of acute small bowel toxicity from concurrent 5-FU-based chemotherapy and radiation therapy for rectal cancer Int J Radiat Oncol Biol Phys 2002 52 176 183 11777636 \n14 Minsky BD Conti JA Huang Y Knopf K Relationship of acute gastrointestinal toxicity and the volume of irradiated small bowel in patients receiving combined modality therapy for rectal cancer J Clin Oncol 1995 13 1409 1416 7751886 \n15 Clarke RE Tenorio LM Hussey JR Toklu AS Cone DL Hinojosa JG Desai SP Dominguez Parra L Rodrigues SD Long RJ Hyperbaric oxygen treatment of chronic refractory radiation proctitis: a randomized and controlled double-blind crossover trial with long-term follow-up Int J Radiat Oncol Biol Phys 2008 72 134 143 18342453 \n16 Grivennikov SI Greten FR Karin M Immunity, inflammation, and cancer Cell 2010 140 883 899 20303878 \n17 Wei-Xing Z Craig BT Necrotic death as a cell fate Genes Dev 2006 20 1 15 16391229 \n18 Di Staso M Bonfili P Gravina GL Di Genesio Pagliuca M Franzese P Buonopane S Osti MF Valeriani M Festuccia C Enrici RM Late morbidity and oncological outcome after radical hypofractionated radiotherapy in men with prostate cancer BJU Int 2010 106 1458 1462 20518760 \n19 Coia LR Myerson RJ Tepper JE Late effects of radiation therapy on the gastrointestinal tract Int J Radiat Oncol Biol Phys 1995 31 1213 1236 7713784 \n20 Khan A Suhaibani YA Sharief AA Rectal cancer perforation: a rare complication of neoadjuvant radiotherapy for rectal cancer Int J Oncol 2009 7 1 5 \n21 Medina-Arana V Martínez-Riera A Delgado-Plasencia L Rodríguez-González D Bravo-Gutiérrez A Álvarez-Argüelles H Alarcó-Hernández A Salido-Ruiz E Fernández-Peralta AM González-Aguilera JJ Clinicopathological analysis of factors related to colorectal tumor perforation: influence of angiogenesis Medicine (Baltimore) 2015 94 e703 25881846 \n22 Lee J Chen F Steel M Keck J Mackay J Perforated rectal cancer associated with neoadjuvant radiotherapy: report of four cases Dis Colon Rectum 2006 49 1629 1632 17039387 \n23 ElGendy K Rectal perforation after neoadjuvant chemoradiotherapy for low-lying rectal cancer BMJ Case Rep 2015 \n24 Takada S Hoshino Y Ito H Masugi Y Terauchi T Endo K Kimata M Furukawa J Shinozaki H Kobayashi K Extensive bowel necrosis related to bevacizumab in metastatic rectal cancer patient: a case report and review of literature Jpn J Clin Oncol 2015 45 286 290 25489005 \n25 Samantha LK Allison FL Patrick GJ Pedro ADB Michael BA Bowel perforation associated with robust response to BRAF/MEK inhibitor therapy for BRAF-mutant melanoma: a case report Melanoma Management 2015 2 115 120 \n26 Borzomati D Nappo G Valeri S Vincenzi B Ripetti V Coppola R Infusion of bevacizumab increases the risk of intestinal perforation: results on a series of 143 patients consecutively treated Updates Surg 2013 65 121 124 23532741\n\n",
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"issn_linking": "2307-8960",
"issue": "5(1)",
"journal": "World journal of clinical cases",
"keywords": "5-fluorouracil; Local advanced rectal cancer; Preoperative chemoradiotherapy; Rectal perforation; Tumor necrosis",
"medline_ta": "World J Clin Cases",
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"nlm_unique_id": "101618806",
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"pages": "18-23",
"pmc": null,
"pmid": "28138443",
"pubdate": "2017-01-16",
"publication_types": "D002363:Case Reports",
"references": "10361259;11777636;15653668;16391229;16929324;17039387;18342453;19770376;20021452;20303878;20518760;20876905;22144997;22529255;23450565;23532741;25489005;25564637;25881846;26338272;30190840;7713784;7751886;9152176",
"title": "Local advanced rectal cancer perforation in the midst of preoperative chemoradiotherapy: A case report and literature review.",
"title_normalized": "local advanced rectal cancer perforation in the midst of preoperative chemoradiotherapy a case report and literature review"
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"abstract": "Osimertinib is a third-generation tyrosine kinase inhibitor that became the preferred first-line treatment option for metastatic non-small cell lung cancer with sensitizing epidermal growth factor receptor mutations. Drug-induced pneumonitis is known to occur with osimertinib. In case of severe pneumonitis, discontinuation of treatment and therapy with corticosteroids is recommended, and a treatment switch is usually performed. We herein report the treatment course in three patients who were rechallenged with osimertinib under steroid protection following an osimertinib-induced pneumonitis. All our patients were initially re-exposed to a lower dose of osimertinib. Two patients were successfully rechallenged under prednisolone protection. The third patient, who was initially retreated with osimertinib without steroid protection, suffered from a recurrent pneumonitis, and was later rechallenged successfully under steroid protection. Our case series indicates that rechallenge with osimertinib following recovery from osimertinib-induced pneumonitis allows a successful rechallenge in individual cases when alternative treatment options are lacking. Concomitant steroids appear to protect against flares of pneumonitis during rechallenge.",
"affiliations": "Department of Medicine V, University Hospital, LMU Munich, Member of the German Center for Lung Research, Klinikum Großhadern, Marchioninistr, 15, Munich, Bavaria 81377, Germany.;Department of Medicine V, University Hospital, LMU Munich, Member of the German Center for Lung Research, Munich, Bavaria, Germany.;Department of Medicine V, University Hospital, LMU Munich, Member of the German Center for Lung Research, Munich, Bavaria, Germany.;Department of Medicine V, University Hospital, LMU Munich, Member of the German Center for Lung Research, Munich, Bavaria, Germany.;Department of Medicine V, University Hospital, LMU Munich, Member of the German Center for Lung Research, Munich, Bavaria, Germany.;Department of Medicine V, University Hospital, LMU Munich, Member of the German Center for Lung Research, Munich, Bavaria, Germany.;Department of Medicine V, University Hospital, LMU Munich, Member of the German Center for Lung Research, Munich, Bavaria, Germany.",
"authors": "Bickert|Christiane|C|https://orcid.org/0000-0003-4121-6687;Kahnert|Kathrin|K|;Kauffmann-Guerrero|Diego|D|;Götschke|Jeremias|J|https://orcid.org/0000-0002-3426-2194;Syunyaeva|Zulfiya|Z|;Behr|Jürgen|J|;Tufman|Amanda|A|",
"chemical_list": null,
"country": "England",
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"doi": "10.1177/17588359211018028",
"fulltext": "\n==== Front\nTher Adv Med Oncol\nTher Adv Med Oncol\nTAM\nsptam\nTherapeutic Advances in Medical Oncology\n1758-8340\n1758-8359\nSAGE Publications Sage UK: London, England\n\n10.1177/17588359211018028\n10.1177_17588359211018028\nCase Series\nOsimertinib rechallenge under steroid protection following osimertinib-induced pneumonitis: three case studies\nhttps://orcid.org/0000-0003-4121-6687\nBickert Christiane *Department of Medicine V, University Hospital, LMU Munich, Member of the German Center for Lung Research, Klinikum Großhadern, Marchioninistr, 15, Munich, Bavaria 81377, Germany\n\nKahnert Kathrin *Department of Medicine V, University Hospital, LMU Munich, Member of the German Center for Lung Research, Munich, Bavaria, Germany\n\nKauffmann-Guerrero Diego Department of Medicine V, University Hospital, LMU Munich, Member of the German Center for Lung Research, Munich, Bavaria, Germany\n\nhttps://orcid.org/0000-0002-3426-2194\nGötschke Jeremias Department of Medicine V, University Hospital, LMU Munich, Member of the German Center for Lung Research, Munich, Bavaria, Germany\n\nSyunyaeva Zulfiya Department of Medicine V, University Hospital, LMU Munich, Member of the German Center for Lung Research, Munich, Bavaria, Germany\n\nBehr Jürgen Department of Medicine V, University Hospital, LMU Munich, Member of the German Center for Lung Research, Munich, Bavaria, Germany\n\nTufman Amanda Department of Medicine V, University Hospital, LMU Munich, Member of the German Center for Lung Research, Munich, Bavaria, Germany\n\nchristiane.bickert@med.uni-muenchen.de\n* These authors contributed equally to this work.\n\n10 6 2021\n2021\n13 1758835921101802825 1 2021\n23 4 2021\n© The Author(s), 2021\n2021\nSAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nOsimertinib is a third-generation tyrosine kinase inhibitor that became the preferred first-line treatment option for metastatic non-small cell lung cancer with sensitizing epidermal growth factor receptor mutations. Drug-induced pneumonitis is known to occur with osimertinib. In case of severe pneumonitis, discontinuation of treatment and therapy with corticosteroids is recommended, and a treatment switch is usually performed. We herein report the treatment course in three patients who were rechallenged with osimertinib under steroid protection following an osimertinib-induced pneumonitis. All our patients were initially re-exposed to a lower dose of osimertinib. Two patients were successfully rechallenged under prednisolone protection. The third patient, who was initially retreated with osimertinib without steroid protection, suffered from a recurrent pneumonitis, and was later rechallenged successfully under steroid protection. Our case series indicates that rechallenge with osimertinib following recovery from osimertinib-induced pneumonitis allows a successful rechallenge in individual cases when alternative treatment options are lacking. Concomitant steroids appear to protect against flares of pneumonitis during rechallenge.\n\nepithelial growth factor receptor\ninterstitial lung disease\nimmunotherapy\nnon-small cell lung cancer\ntyrosine kinase inhibitor\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nTargeted therapies have significantly improved the prognosis of patients with non-small cell lung cancer (NSCLC) harboring activating epidermal growth factor receptor (EGFR) mutations. Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) that has become a very effective first-line treatment option for metastatic NSCLC with sensitizing EGFR mutations. 1 It demonstrated efficacy against brain lesions, 2 and improved overall survival compared with patients receiving either gefitinib or erlotinib. 3 Osimertinib is generally well tolerated, but common side effects include diarrhea, rash, dry skin, and decreased appetite. A rare, but possibly life-threatening adverse event is pneumonitis, occurring in 1.8–4% of patients.4,5 In case of severe pneumonitis, discontinuation of treatment and therapy with corticosteroids is usually recommended. A treatment switch to other EGFR TKIs or chemotherapy is, especially for patients with brain metastases, problematic due to less efficacy in the central nervous system (CNS) compared with osimertinib.5–7 Due to its excellent CNS efficacy and effectiveness in T790M-resistance mutation, 5 re-exposure to osimertinib would be the preferred treatment option for selected patients, even after severe pneumonitis.\n\nHere, we report the treatment course in three EGFR-positive NSCLC patients who were rechallenged with osimertinib under steroid protection following an osimertinib-induced pneumonitis.\n\nCase reports\n\nCase 1\n\nPatient 1 (58 years, female, ex-smoker, 10 pack-years) was initially diagnosed with an adenocarcinoma of the left lower-lung lobe (activating EGFR mutation, deletion exon 19) in June 2017. The stage at first diagnosis was cT2aN2M1c (metastatic pattern: diffuse bone metastasis, lymph node metastasis) and treatment with afatinib was initiated. Following a 2-year period of progression-free survival, a follow-up staging showed new brain metastases. Liquid biopsy confirmed the presence of the initial EGFR mutation without T790M-resistance mutation. Off-label treatment with osimertinib (80 mg daily) was started due to higher CNS activity. Within 8 weeks, the patient developed dyspnea, and the general condition deteriorated. Lung-function testing showed mild hypoxemia (partial pressure of oxygen [pO2] 71 mmHg) and a significant decrease of diffusion capacity (TLCO) from 76% predicted to 55% predicted. Chest computed tomography (CT) imaging showed bipulmonal ground-glass opacities (Figure 1). There was no evidence of bacterial or viral infection in the bronchoalveolar lavage (BAL), but differential cell count showed a relevant lymphocytosis (75%) in the BAL fluid. Based on these findings, osimertinib-induced pneumonitis was diagnosed and intravenous treatment with prednisolone (1 mg/kg) was started and gradually reduced to 5 mg within 4 weeks. After 4 weeks, the patient showed a clinical and respiratory improvement, and rechallenge with osimertinib 40 mg daily under oral steroid protection (20 mg prednisolone daily) was started. Within a period of 4 months, prednisolone was gradually reduced (10 mg daily). Suspecting progression of cerebral metastases, we increased the osimertinib dosing (alternating 40/80 mg) under prednisolone protection with 10 mg daily. Diffusing capacity improved to 82% of predicted 4 months after the beginning of the re-exposition. The dose of osimertinib was increased to 80 mg daily with good tolerability. At the time of this case report, the latest positron emission tomography (PET) CT scan showed no evidence for recurrent pneumonitis and showed stable disease (Figure 1).\n\nFigure 1. Radiologic and medication details of patient 1.\n\n(a) Radiologic details; (b) details of medication history.\n\nCase 2\n\nPatient 2 (65 years, female, never-smoker) was diagnosed with an adenocarcinoma (activating EGFR mutations: ELREA [deletion exon 19], T790M [exon 20] and L858R [exon 21] mutation) of the left upper-lung lobe. The TNM classification of malignant tumors (TNM) at initial diagnosis was cT3cN2pM1c (metastatic pattern: three CNS lesions; one cerebellar and two occipital cerebral metastases). Stereotactic radiation therapy of the cerebral metastases was performed, and systemic therapy with osimertinib 80 mg daily was initiated. After 7 weeks, the patient presented in the emergency room with increasing respiratory deterioration. Lung function testing showed severe hypoxemia in room air (pO2 47 mmHg) and a significant decrease of the diffusion capacity (TLCO) (34% predicted compared with baseline of 104% predicted). The CT scan of the thorax showed basal bipulmonal ground-glass opacities (Figure 2). BAL showed no evidence of acute infection, and a relevant lymphocytosis (58%) was seen in the BAL differential cell count. Based on these results, pneumonitis was diagnosed. Osimertinib was paused and prednisolone pulse therapy was initiated. The patient experienced quick recovery. At 4 weeks later, progression of the cerebral metastases was observed. Due to the rapid cerebral progress and the patient’s reluctance to undergo whole-brain irradiation, re-exposition with osimertinib (40 mg daily) under steroid protection (0.5 mg/kg prednisolone daily) was started. The patient was monitored closely, and lung-function measurements, including diffusing capacity, were performed weekly. After 2 weeks, follow-up staging showed regression of the primary tumor site, as well as brain metastases. With stable lung function and good tolerability of osimertinib, the dose was increased (alternating 80 mg and 40 mg) under protection with 30 mg prednisolone daily. The prednisolone dose was reduced to 5 mg daily over the course of the treatment, and the follow-up PET scan showed stable disease 3 months after re-exposition (Figure 2). After 5 months of the osimertinib/prednisolone combination, PET CT scan showed recurrent tumor at the primary tumor site, lymph nodes, and brain metastasis. Re-biopsy revealed a new concomitant MET exon 14 skipping mutation and the disappearance of the T790M-resistance mutation. Radiation of the primary tumor was performed, and treatment was completely switched to a combined treatment with afatinib and crizotinib. 8\n\nFigure 2. Radiologic and medication details of patient 2.\n\n(a) Radiologic details; (b) details of medication history.\n\nCase 3\n\nPatient 3 (64 years, male, never-smoker) was diagnosed with a poorly differentiated adenocarcinoma (activating EGFR mutation, L858R mutation in exon 21) of the right upper-lung lobe. The initial TNM staging was cT3N3M1a. The treatment was initiated with afatinib and later changed to osimertinib due to T790M mutation. After 9 months, the patient suffered from late-onset eosinophilic pneumonitis (grade 3) as described by our research group. 9 Tumor-specific therapy was stopped for 3 months. Follow-up PET CT scan showed progression of lymphatic metastases, and chemotherapy with pemetrexed was started. Due to a renewed tumor progression, the therapy was switched to carboplatin/nab-paclitaxel. Despite intensified chemotherapy, new brain metastases developed. In consent with the patient, an osimertinib rechallenge (40 mg daily, without steroid protection) was performed. Within 2 weeks, the diffusion capacity decreased from 90% to 57% predicted and the patient suffered from dyspnea. Again, thoracic CT scan showed bipulmonal ground-glass opacities (Figure 3). The differential cell count showed a lymphocytosis (54%) and 1% eosinophils in the BAL fluid. Recurrent pneumonitis was suspected, and prednisolone pulse therapy led to rapid clinical improvement. Tumor-specific treatment was switched to dacomitinib. Within 12 weeks, the tumor showed further progression with multiple new lung metastases, as well as progression of brain metastases. Despite the high risk of re-occurrence of potential life-threatening pneumonitis, due to missing alternative treatment options the patient agreed to renewed treatment with osimertinib. Osimertinib was started (40 mg daily) with accompanying prednisolone therapy (1 mg/kg body weight), which was gradually decreased to 40 mg prednisolone daily within 3 weeks. With good clinical tolerability and stable lung function, osimertinib dosage was increased to alternating 40/80 mg daily and prednisolone was gradually reduced to 5 mg daily. At 6 months after the second osimertinib rechallenge, the patient is in excellent clinical and respiratory condition and follow-up PET CT scans, as well as brain magnetic resonance imaging, showed stable tumor status.\n\nFigure 3. Radiologic and medication details of patient 3.\n\n(a) Radiologic details; (b) details of medication history.\n\nDiscussion\n\nThis case series shows that re-exposure to osimertinib is possible despite previous drug-induced pneumonitis. All three patients received concomitant prednisolone, which may have prevented pneumonitis flares. Osimertinib is an efficient third-generation TKI and is a preferred first-line therapy for EGFR-mutated NSCLC. 10 Previous investigations showed an advantage of osimertinib compared with the combination of platinum and pemetrexed therapy 5 and to standard EGFR–TKIs. 4 Particularly, the effect of osimertinib on CNS is superior to other TKIs. 11 CNS penetration of osimertinib is 16% 12 and therefore higher than CNS penetration rate of erlotinib (2.5–13%),13–15 gefitinib (1.1–3.58%),14,16–18 and afatinib (under 1%). 19 The pivotal study of dacomitinib excluded patients with CNS metastases, and the CNS penetration rate has not been evaluated yet. 20 In addition, osimertinib is so far the only medication that adequately treats the resistance mutation T790M. This is the reason why in daily clinical practice there is often a need to re-administer osimertinib despite previous serious side effects.\n\nA rare, but life-threatening adverse event of osimertinib is pneumonitis, with mortality rates of 10–25%.4,5,21 In case of pneumonitis, discontinuation of osimertinib treatment and therapy with corticosteroids is recommended. Further treatment options are chemotherapeutic treatment approaches, or alternative TKIs. However, erlotinib, gefitinib, afatinib and dacomitinib may only have little success in treating brain lesions due to limited CNS penetration.13–19\n\nConsidering the risks and benefits of alternative treatment options, osimertinib retreatment should be discussed. Rechallenge after osimertinib-induced pneumonitis was reported in eight patients during the past 3 years.22–28 The mechanism of osimertinib-induced pneumonitis is not fully understood, but in association with other drug-induced interstitial lung diseases, the pathogenesis is multifactorial, including a significant part of immunoreaction such as release of cytocines. 29 This indicates that steroids could potentially protect from recurrent pneumonitis in case of rechallenge. To confirm the diagnosis of pneumonitis we recommend, whenever possible, a bronchoscopy with BAL to exclude infectious causes and to prove lymphocytosis in the BAL.\n\nWe believe that osimertinib rechallenge can be a safe therapeutic option for patients under close clinical monitoring. All our patients were initially re-exposed to the lower dose of 40 mg daily. Two patients were successfully rechallenged under prednisolone protection (0.5 mg/kg body weight). The third patient was initially re-exposed to osimertinib without steroid protection, suffered from a recurrent pneumonitis and was later rechallenged successfully under steroid protection. This underlines that patients benefit from steroid protection, and that it should be considered when rechallenging a patient with osimertinib.\n\nOur case series is in line with previous results, indicating that osimertinib rechallenge under steroid protection is an appropriate treatment option for patients. We showed that steroid protection allows a successful rechallenge in individual cases when alternative treatment options are lacking. Nonetheless, future research is needed to evaluate the lowest effective prednisolone dosage, the respective reduction scheme, and the starting dose, as well as the gradual enhancement of osimertinib to offer an effective and safe osimertinib rechallenge in EGFR-mutated patients.\n\nConclusion\n\nThis small case series describes osimertinib rechallenge as an appropriate treatment option for patients with advanced EGFR-mutated NSCLC despite previous osimertinib-induced pneumonitis. Furthermore, our report highlights the relevance of concomitant treatment with steroids. The optimal steroid dosage should be evaluated in further studies.\n\nConflict of interest statement: Dr Bickert, Dr Kahnert, Dr Götschke, Dr Syunyaeva and Dr Behr: none.\n\nDr Kauffmann-Guerrero reports personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Pfizer, grants and personal fees from Takeda, outside the submitted work.\n\nDr Tufman reports personal fees from Lilly, grants and personal fees from AstraZeneca, personal fees from Takeda, personal fees from Roche, personal fees from Celgene, personal fees from MSD, personal fees from BMS, personal fees from Pfizer, outside the submitted work.\n\nFunding: The authors received no financial support for the research, authorship, and/or publication of this article.\n\nEthics and patients: Written informed consent was given by the patients for the publication of the cases and figures. A copy of the signed consent form is available on request. Approval was obtained from the Institutional Ethics Committee (project number 21-0057 KB).\n\nORCID iDs: Christiane Bickert https://orcid.org/0000-0003-4121-6687\n\nJeremias Götschke https://orcid.org/0000-0002-3426-2194\n==== Refs\nReferences\n\n1 Planchard D Popat S Kerr K , et al . Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018; 29 : iv192–iv237.\n2 Ballard P Yates JWT Yang Z , et al . Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin Cancer Res 2016; 22 : 5130–5140.27435396\n3 Ramalingam SS Vansteenkiste J Planchard D , et al . Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med 2020; 382 : 41–50.31751012\n4 Soria J-C Ohe Y Vansteenkiste J , et al . Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Engl J Med 2018; 378 : 113–125.29151359\n5 Mok TS Wu Y-L Ahn M-J , et al . Osimertinib or platinum–pemetrexed in EGFR T790M–positive lung cancer. N Engl J Med 2017; 376 : 629–640.27959700\n6 Reungwetwattana T Nakagawa K Cho BC , et al . CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non–small-cell lung cancer. JCO 2018; 36 : 3290–3297.\n7 Barlesi F Gervais R Lena H , et al . Pemetrexed and cisplatin as first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) with asymptomatic inoperable brain metastases: a multicenter phase II trial (GFPC 07-01). Ann Oncol 2011; 22 : 2466–2470.21321089\n8 Kauffmann-Guerrero D Kahnert K Kumbrink J , et al . Successful treatment of a patient with NSCLC harboring an EGFR mutation and a concomitant met exon 14 skipping mutation combining afatinib and crizotinib. Clin Lung Cancer 2019; 20 : 59–62.30341016\n9 Syunyaeva Z Berghof K Kauffmann-Guerrero D , et al . Late-onset severe pneumonitis under osimertinib. AME Case Rep 2019; 3 : 39.31728437\n10 National Comprehensive Cancer Network clinical practice guidelines in oncology (NCCN guidelines). Non-Small Cell Lung Cancer. Version 8. 2020.\n11 Heon S Yeap BY Lindeman NI , et al . The impact of initial gefitinib or erlotinib versus chemotherapy on central nervous system progression in advanced non-small cell lung cancer with EGFR mutations. Clin Cancer Res 2012; 18 : 4406–4414.22733536\n12 Yang JCH Kim S-W Kim D-W , et al . Osimertinib in patients with epidermal growth factor receptor mutation–positive non–small-cell lung cancer and leptomeningeal metastases: the BLOOM study. JCO 2020; 38 : 538–547.\n13 Togashi Y Masago K Hamatani Y , et al . Successful erlotinib rechallenge for leptomeningeal metastases of lung adenocarcinoma after erlotinib-induced interstitial lung disease: a case report and review of the literature. Lung Cancer 2012; 77 : 464–468.22579408\n14 Togashi Y Masago K Masuda S , et al . Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer. Cancer Chemother Pharmacol 2012; 70 : 399–405.22806307\n15 Deng Y Feng W Wu J , et al . The concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung cancer. Mol Clin Oncol 2014; 2 : 116–120.24649318\n16 Zhao J Chen M Zhong W , et al . Cerebrospinal fluid concentrations of gefitinib in patients with lung adenocarcinoma. Clin Lung Cancer 2013; 14 : 188–193.22846582\n17 Chen Y Wang M Zhong W , et al . Pharmacokinetic and pharmacodynamic study of gefitinib in a mouse model of non-small-cell lung carcinoma with brain metastasis. Lung Cancer 2013; 82 : 313–318.24011632\n18 Franceschi E Cavallo G Lonardi S , et al . Gefitinib in patients with progressive high-grade gliomas: a multicentre phase II study by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO). Br J Cancer 2007; 96 : 1047–1051.17353924\n19 Hoffknecht P Tufman A Wehler T , et al . Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)–pretreated non–small-cell lung cancer patients with brain metastases or leptomeningeal disease. J Thorac Oncol 2015; 10 : 156–163.25247337\n20 Wu Y-L Cheng Y Zhou X , et al . Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol 2017; 18 : 1454–1466.28958502\n21 Ahn M Tsai C Shepherd FA , et al . Osimertinib in patients with T790M mutation-positive, advanced non–small cell lung cancer: long-term follow-up from a pooled analysis of 2 phase 2 studies. Cancer 2019; 125 : 892–901.30512189\n22 Miyauchi E Ichinose M Inoue A. Successful osimertinib rechallenge in a patient with T790M-mutant non–small cell lung cancer after osimertinib-induced interstitial lung disease. J Thorac Oncol 2017; 12 : e59–e61.28434520\n23 Mamesaya N Kenmotsu H Katsumata M , et al . Osimertinib-induced interstitial lung disease after treatment with anti-PD1 antibody. Invest New Drugs 2017; 35 : 105–107.27599705\n24 Kiriu T Tamura D Tachihara M , et al . Successful osimertinib rechallenge with steroid therapy after osimertinib-induced interstitial lung disease. Intern Med 2018; 57 : 91–95.29033419\n25 Nagasaka M Gadgeel SM. Retreatment with osimertinib following pneumonitis. Clin Lung Cancer 2018; 19 : e53–e55.28736180\n26 Satoh S Shiroyama T Tamiya M , et al . Successful osimertinib rechallenge after osimertinib-induced pneumonitis in a patient with lung adenocarcinoma. Respir Med Case Rep 2018; 23 : 68–70.29487786\n27 Lu H Dowell J. Osimertinib in pulmonary manifestations: two case reports and review of the literature. In Vivo 2020; 34 : 315–319.31882494\n28 Ahn JH. Successful osimertinib retreatment after extremely early onset severe pneumonitis in first-line treatment of lung adenocarcinoma. Thorac Cancer 2020; 11 : 2713–2716.32666714\n29 Camus P Fanton A Bonniaud P , et al . Interstitial lung disease induced by drugs and radiation. Respiration 2004; 71 : 301–326.15316202\n\n",
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"title": "Osimertinib rechallenge under steroid protection following osimertinib-induced pneumonitis: three case studies.",
"title_normalized": "osimertinib rechallenge under steroid protection following osimertinib induced pneumonitis three case studies"
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"abstract": "Ochroconis gallopavum is a potentially fatal dematiaceous fungus causing opportunistic infections in immunocompromised hosts. We report the first case of disseminated O. gallopavum infection in a 13-year-old renal transplant recipient, which involved the brain, lung and spleen. He was treated with amphotericin B, itraconazole and voriconazole, a new antifungal agent first used to treat such an infection. Besides antifungal treatment, all immunosuppressive agents were stopped and automated peritoneal dialysis was resumed. The initial infection was under control with both clinical and radiological improvements after treatment. However, the patient later acquired Acremonium spp. peritonitis; he failed to respond to high-dose amphotericin B, and finally succumbed. A total of 13 reported O. gallopavum human infections, including the one described here, are reviewed. The most common site of involvement is the brain and the crude mortality rate is up to 46%. As the disease is potentially lethal in immunocompromised hosts, empirical antifungal coverage should be considered in post-renal transplant recipients with suspected brain abscess. Early biopsy of lesion for histopathological and microbiological diagnosis would be essential in managing such cases.",
"affiliations": "Centre of Infection, Department of Microbiology, Queen Mary Hospital, University of Hong Kong, Hong Kong, SAR, China.",
"authors": "Wang|T K F|TK|;Chiu|W|W|;Chim|S|S|;Chan|T M|TM|;Wong|S S Y|SS|;Ho|P L|PL|",
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"mesh_terms": "D000293:Adolescent; D000935:Antifungal Agents; D001921:Brain; D017809:Fatal Outcome; D006801:Humans; D016867:Immunocompromised Host; D016030:Kidney Transplantation; D008168:Lung; D008297:Male; D003904:Mitosporic Fungi; D009181:Mycoses; D009894:Opportunistic Infections; D010530:Peritoneal Dialysis; D013154:Spleen",
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"title": "Disseminated ochroconis gallopavum infection in a renal transplant recipient: the first reported case and a review of the literature.",
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... |
{
"abstract": "Adult T-cell leukemia/lymphoma (ATLL) is an aggressive disease caused by the human T-cell leukemia virus type 1. Real-world data of ATLL in Latin America are lacking.\n\n\n\nWe analyzed patients with ATLL (acute, lymphomatous, chronic, and smoldering) encountered in 11 Latin American countries between 1995 and 2019. Treatment response was assessed according to the 2009 consensus report. Survival curves were estimated using the Kaplan-Meier method and log-rank test.\n\n\n\nWe identified 253 patients; 226 (lymphomatous: n = 122, acute: n = 73, chronic: n = 26, and smoldering: n = 5) had sufficient data for analysis (median age 57 years). Most patients with ATLL were from Peru (63%), Chile (17%), Argentina (8%), and Colombia (7%). Hypercalcemia was positively associated with acute type (57% v lymphomatous 27%, P = .014). The median survival times (months) were 4.3, 7.9, 21.1, and not reached for acute, lymphomatous, chronic, and smoldering forms, with 4-year survival rates of 8%, 22%, 40%, and 80%, respectively. First-line zidovudine (AZT)-interferon alfa (IFN) resulted in an overall response rate of 63% (complete response [CR] 24%) for acute. First-line chemotherapy yielded an overall response rate of 41% (CR 29%) for lymphomatous. CR rate was 42% for etoposide, cyclophosphamide, vincristine, doxorubicin, and prednisone versus 12% for cyclophosphamide, vincristine, doxorubicin, and prednisone-like regimen (P < .001). Progression-free survival at 1 year for acute type patients treated with AZT-IFN was 67%, whereas 2-year progression-free survival in lymphomatous type patients who achieved CR after chemotherapy was 77%.\n\n\n\nThis study confirms Latin American ATLL presents at a younger age and has a high incidence of lymphomatous type, low incidence of indolent subtypes, and worse survival rates as compared with Japanese patients. In aggressive ATLL, chemotherapy remains the preferred choice for lymphomatous favoring etoposide-based regimen (etoposide, cyclophosphamide, vincristine, doxorubicin, and prednisone), whereas AZT-IFN remains a good first-line option for acute subtype.",
"affiliations": "Division of Cancer Medicine, Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.;Departamento de Oncologia Medica, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru.;Departamento de Oncología y Radioterapia, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru.;Hematology Section, Hospital Del Salvador, Santiago, Chile.;Hospital Universitario del Valle, Cali, Colombia.;Hematología, Hospital Italiano de La Plata, La Plata, Argentina.;Hematología, Hospital Italiano de La Plata, La Plata, Argentina.;Sección Hematología, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.;Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS) UBA-CONICET, Buenos Aires, Argentina.;Hospital Guillermo Almenara, Lima, Peru.;Departamento de Oncologia Medica, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru.;Universidad Nacional Federico Villareal, Lima, Peru.;Department of Pediatrics, Weill Cornell Medicine, New York, NY.;Facultad de Salud, Universidad del Valle, Cali, Colombia.;Sección Hematología, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.;Servicio de Hematologia, Hospital Municipal Emilio Ferreyra, Necochea, Buenos Aires, Argentina.;Hospital Privado Universitario de Córdoba, Cordoba, Argentina.;Hematology Section, Hospital de Puerto Montt, Puerto Montt, Chile.;Hematology Section, Hospital Sótero de Rio, Santiago de Chile, Chile.;Hematology Section, Hospital Del Salvador, Santiago, Chile.;Departamento de Oncología y Radioterapia, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru.;Cátedra de Hematología, Hospital de Clínicas, Facultad de Medicina, Montevideo, Uruguay.;Hospital Solca Quito, Hospital de los Valles, Universidad San Francisco de Quito, Quito, Ecuador.;Servicio de Hematologia, Instituto Oncológico Nacional Dr. Juan Tanca Marengo, Guayaquil, Ecuador.;Hospital de Especialidades Materno Infantil-Caja Nacional de Salud, La Paz, Bolivia.;Research Division, Instituto Nacional de Cancerología, Mexico City, Mexico.;Department of Hematology, Instituto de Prevision Social, Asuncion, Paraguay.;Liga Nacional Contra el Cancer, Instituto de Cancerología-INCAN, Ciudad de Guatemala, Guatemala.;Universidad Central de Venezuela, Caracas, Venezuela.;Bing Center for Waldenström Macroglobulinemia, Dana Farber Cancer Institute, Boston, MA.;Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL.;Universidad Del Valle de Mexico, Campus Hermosillo, Hospital Fernando Ocaranza del ISSSTE, Sonora, Mexico.;Departamento de Oncología y Radioterapia, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru.",
"authors": "Malpica|Luis|L|0000-0002-7082-1846;Enriquez|Daniel J|DJ|0000-0002-0855-8936;Castro|Denisse A|DA|0000-0001-5330-9309;Peña|Camila|C|0000-0002-8076-2077;Idrobo|Henry|H|0000-0002-7686-5874;Fiad|Lorena|L|;Prates|Maria|M|;Otero|Victoria|V|;Biglione|Mirna|M|;Altamirano|Milagros|M|;Sandival-Ampuero|Gustavo|G|0000-0002-4759-2328;Aviles-Perez|Ursula|U|0000-0001-8394-8152;Meza|Kelly|K|0000-0002-1777-2360;Aguirre-Martinez|Laura|L|0000-0002-7423-0824;Cristaldo|Nancy|N|;Maradei|Juan L|JL|;Guanchiale|Luciana|L|;Soto|Pablo|P|0000-0002-4312-4519;Viñuela|Jose L|JL|;Cabrera|Maria E|ME|0000-0001-9059-3871;Paredes|Sally Rose|SR|;Riva|Eloisa|E|;Di Stefano|Marcos|M|0000-0002-6749-6261;Noboa|Andrea|A|;Choque|Juan A|JA|0000-0002-1994-4234;Candelaria|Myrna|M|0000-0002-5478-714X;Von Glasenapp|Alana|A|0000-0002-1805-5830;Valvert|Fabiola|F|0000-0003-0687-2419;Torres-Viera|Maria A|MA|0000-0001-6188-8494;Castillo|Jorge J|JJ|0000-0001-9490-7532;Ramos|Juan Carlos|JC|0000-0002-6282-4406;Villela|Luis|L|;Beltran|Brady E|BE|0000-0003-4469-3817",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1200/GO.21.00084",
"fulltext": "\n==== Front\nJCO Glob Oncol\nJCO Glob Oncol\ngo\ngo\nGO\nJCO Global Oncology\n2687-8941\nWolters Kluwer Health\n\n34270330\nGO.21.00084\n10.1200/GO.21.00084\nORIGINAL REPORTS\nHematologic Malignancies\nReal-World Data on Adult T-Cell Leukemia/Lymphoma in Latin America: A Study From the Grupo de Estudio Latinoamericano de Linfoproliferativos\nhttps://orcid.org/0000-0002-7082-1846\nMalpica Luis MD 1\nhttps://orcid.org/0000-0002-0855-8936\nEnriquez Daniel J. MD 2\nhttps://orcid.org/0000-0001-5330-9309\nCastro Denisse A. MD 3 4\nhttps://orcid.org/0000-0002-8076-2077\nPeña Camila MD 5\nhttps://orcid.org/0000-0002-7686-5874\nIdrobo Henry MD 6\nFiad Lorena MD 7\nPrates Maria MD 7\nOtero Victoria MD 8\nBiglione Mirna MD 9\nAltamirano Milagros MD 10\nhttps://orcid.org/0000-0002-4759-2328\nSandival-Ampuero Gustavo MD 2\nhttps://orcid.org/0000-0001-8394-8152\nAviles-Perez Ursula MD 11\nhttps://orcid.org/0000-0002-1777-2360\nMeza Kelly MD 12\nhttps://orcid.org/0000-0002-7423-0824\nAguirre-Martinez Laura MD 13\nCristaldo Nancy MD 8\nMaradei Juan L. MD 14\nGuanchiale Luciana MD 15\nhttps://orcid.org/0000-0002-4312-4519\nSoto Pablo MD 16\nViñuela Jose L. MD 17\nhttps://orcid.org/0000-0001-9059-3871\nCabrera Maria E. MD 5\nParedes Sally Rose MD 3 4\nRiva Eloisa MD 18\nhttps://orcid.org/0000-0002-6749-6261\nDi Stefano Marcos MD 19\nNoboa Andrea MD 20\nhttps://orcid.org/0000-0002-1994-4234\nChoque Juan A. MD 21\nhttps://orcid.org/0000-0002-5478-714X\nCandelaria Myrna MD 22\nhttps://orcid.org/0000-0002-1805-5830\nVon Glasenapp Alana MD 23\nhttps://orcid.org/0000-0003-0687-2419\nValvert Fabiola MD 24\nhttps://orcid.org/0000-0001-6188-8494\nTorres-Viera Maria A. MD 25\nhttps://orcid.org/0000-0001-9490-7532\nCastillo Jorge J. MD 26\nhttps://orcid.org/0000-0002-6282-4406\nRamos Juan Carlos MD 27\nVillela Luis MD 28\nhttps://orcid.org/0000-0003-4469-3817\nBeltran Brady E. MD 3 4\n1 Division of Cancer Medicine, Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX\n2 Departamento de Oncologia Medica, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru\n3 Departamento de Oncología y Radioterapia, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru\n4 Centro de Investigación de Medicina de Precisión, Universidad de San Martin de Porres, Lima, Peru\n5 Hematology Section, Hospital Del Salvador, Santiago, Chile\n6 Hospital Universitario del Valle, Cali, Colombia\n7 Hematología, Hospital Italiano de La Plata, La Plata, Argentina\n8 Sección Hematología, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina\n9 Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS) UBA—CONICET, Buenos Aires, Argentina\n10 Hospital Guillermo Almenara, Lima, Peru\n11 Universidad Nacional Federico Villareal, Lima, Peru\n12 Department of Pediatrics, Weill Cornell Medicine, New York, NY\n13 Facultad de Salud, Universidad del Valle, Cali, Colombia\n14 Servicio de Hematologia, Hospital Municipal Emilio Ferreyra, Necochea, Buenos Aires, Argentina\n15 Hospital Privado Universitario de Córdoba, Cordoba, Argentina\n16 Hematology Section, Hospital de Puerto Montt, Puerto Montt, Chile\n17 Hematology Section, Hospital Sótero de Rio, Santiago de Chile, Chile\n18 Cátedra de Hematología, Hospital de Clínicas, Facultad de Medicina, Montevideo, Uruguay\n19 Hospital Solca Quito, Hospital de los Valles, Universidad San Francisco de Quito, Quito, Ecuador\n20 Servicio de Hematologia, Instituto Oncológico Nacional Dr. Juan Tanca Marengo, Guayaquil, Ecuador\n21 Hospital de Especialidades Materno Infantil—Caja Nacional de Salud, La Paz, Bolivia\n22 Research Division, Instituto Nacional de Cancerología, Mexico City, Mexico\n23 Department of Hematology, Instituto de Prevision Social, Asuncion, Paraguay\n24 Liga Nacional Contra el Cancer, Instituto de Cancerología-INCAN, Ciudad de Guatemala, Guatemala\n25 Universidad Central de Venezuela, Caracas, Venezuela\n26 Bing Center for Waldenström Macroglobulinemia, Dana Farber Cancer Institute, Boston, MA\n27 Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL\n28 Universidad Del Valle de Mexico, Campus Hermosillo, Hospital Fernando Ocaranza del ISSSTE, Sonora, Mexico\nLuis Malpica, MD, Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blv, Unit 429, Houston, TX 77030; e-mail: LEMalpica@mdanderson.org.\n2021\n16 7 2021\n7 GO.21.000844 3 2021\n15 4 2021\n18 6 2021\n© 2021 by American Society of Clinical Oncology\n2021\nAmerican Society of Clinical Oncology\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/\n\nPURPOSE\n\nAdult T-cell leukemia/lymphoma (ATLL) is an aggressive disease caused by the human T-cell leukemia virus type 1. Real-world data of ATLL in Latin America are lacking.\n\nPATIENTS AND METHODS\n\nWe analyzed patients with ATLL (acute, lymphomatous, chronic, and smoldering) encountered in 11 Latin American countries between 1995 and 2019. Treatment response was assessed according to the 2009 consensus report. Survival curves were estimated using the Kaplan-Meier method and log-rank test.\n\nRESULTS\n\nWe identified 253 patients; 226 (lymphomatous: n = 122, acute: n = 73, chronic: n = 26, and smoldering: n = 5) had sufficient data for analysis (median age 57 years). Most patients with ATLL were from Peru (63%), Chile (17%), Argentina (8%), and Colombia (7%). Hypercalcemia was positively associated with acute type (57% v lymphomatous 27%, P = .014). The median survival times (months) were 4.3, 7.9, 21.1, and not reached for acute, lymphomatous, chronic, and smoldering forms, with 4-year survival rates of 8%, 22%, 40%, and 80%, respectively. First-line zidovudine (AZT)-interferon alfa (IFN) resulted in an overall response rate of 63% (complete response [CR] 24%) for acute. First-line chemotherapy yielded an overall response rate of 41% (CR 29%) for lymphomatous. CR rate was 42% for etoposide, cyclophosphamide, vincristine, doxorubicin, and prednisone versus 12% for cyclophosphamide, vincristine, doxorubicin, and prednisone–like regimen (P < .001). Progression-free survival at 1 year for acute type patients treated with AZT-IFN was 67%, whereas 2-year progression-free survival in lymphomatous type patients who achieved CR after chemotherapy was 77%.\n\nCONCLUSION\n\nThis study confirms Latin American ATLL presents at a younger age and has a high incidence of lymphomatous type, low incidence of indolent subtypes, and worse survival rates as compared with Japanese patients. In aggressive ATLL, chemotherapy remains the preferred choice for lymphomatous favoring etoposide-based regimen (etoposide, cyclophosphamide, vincristine, doxorubicin, and prednisone), whereas AZT-IFN remains a good first-line option for acute subtype.\n==== Body\npmcINTRODUCTION\n\nAdult T-cell leukemia/lymphoma (ATLL) is a mature, peripheral T-cell neoplasm caused by the human T-cell leukemia virus type 1 (HTLV-1).1,2 HTLV-1 infects up to 10 million people worldwide and it is predominantly transmitted via breastfeeding, blood transfusion, sharing of needles, and sexual intercourse.3 The virus is endemic in southwestern Japan, the Caribbean Basin, South America, Western and Central Africa, and central Australia.3,4 In Latin America, the highest prevalence is found in the Dominican Republic, Brazil, and Peru.4,5\n\nCONTEXT\n\nKey Objective\n\nDoes adult T-cell leukemia/lymphoma (ATLL) present differently in Latin America than other parts of the world?\n\nKnowledge Generated\n\nLatin American ATLL overwhelmingly presents at a younger age and with aggressive disease, characterized by higher incidence of lymphomatous type, low incidence of indolent types, and low survival outcomes compared with Japanese patients.\n\nRelevance\n\nIn aggressive ATLL, etoposide-based regimen (etoposide, cyclophosphamide, vincristine, doxorubicin, and prednisone) is a reasonable first-line choice over cyclophosphamide, vincristine, doxorubicin, and prednisone–like chemotherapy, whereas combination of zidovudine with interferon alfa-2b is a good option for nonbulky acute ATLL subtype.\n\nATLL is a generally incurable disease where CD4+ T cells carry clonally integrated copies of the HTLV-1 genome.6 The cumulative lifetime risk of developing ATLL is estimated as 4%-7% among HTLV-1 carriers, with most cases presenting during the sixth decade of life in Japan and during the fifth decade in the Hispanic and Afro-Caribbean population.5,7-9 Clinically, the disease is classified by the Shimoyama10 criteria into four subtypes: acute, lymphomatous, chronic, and smoldering. The acute and lymphomatous are the most common and are often grouped as aggressive ATLL. The chronic and smoldering have a less aggressive course and are grouped as indolent ATLL.5,7,10,11\n\nATLL carries a dismal prognosis despite modern intensive therapies, with shorter survival rates compared with other peripheral T-cell lymphomas.12 The treatment of ATLL remains challenging with no clearly established standard of care at the present time. To date, clinicoepidemiologic studies evaluating the incidence and management of ATLL in endemic and nonendemic areas for HTLV-1 infection in Latin America are lacking. Cognizant of this, the Grupo de Estudio Latinoamericano de Linfoproliferativos developed a clinical data registry of patients diagnosed with ATLL in Latin America. Herein, we describe the group's analysis and provide an in-depth insight into the epidemiology, clinical features, treatment, and disease outcome of patients with ATLL encountered collectively over the past 25 years in participating sites.\n\nPATIENTS AND METHODS\n\nPatients\n\nWe conducted a retrospective analysis of patients diagnosed with ATLL between January 1995 and December 2019. Twenty-four centers from 11 Latin American countries participated in the ATLL database query (Appendix Table A1). Patient demographics and clinical data were obtained from available medical records. Each Institutional Review Board approved this study.\n\nDiagnosis, Disease Classification, and Risk Stratification\n\nThe diagnosis of ATLL was based on serologic evidence of HTLV-1 by enzyme-linked immunosorbent assay. Confirmation by reflex Western blot was performed in most cases, but not in some because of unavailability or high cost. In all cases, identification of clonal CD4+ CD7– CD25+/– T cells in peripheral blood and/or tissues was determined by histology, immunophenotyping, and gene rearrangement studies. Patient cases were classified according to the Shimoyama10 criteria. Two indexes were used for risk stratification in aggressive ATLL: the International Prognostic Index (IPI) and the Prognostic Index for Peripheral T-Cell Lymphoma (PIT).13,14\n\nTherapy Approaches\n\nThe therapy approaches investigated were classified into first-line therapy with (1) zidovudine (AZT)-interferon alfa (IFN) alone, (2) multiagent chemotherapy alone, (3) combined chemotherapy with AZT-IFN, and (4) single-agent chemotherapy and/or regional therapy (ie, topical therapy and phototherapy). The centers that used parenteral AZT-IFN had a comparable therapy protocol on the basis of previously published data.15 In general, the chemotherapy regimens used at any time included cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP)–like regimens; etoposide-based regimens (eg, etoposide, cyclophosphamide, vincristine, doxorubicin, and prednisone [CHOEP] and EPOCH), platinum-based regimens, other non–platinum-based regimens, single-agent chemotherapy, and allogeneic transplant (allogeneic hematopoietic stem-cell transplant [allo-HSCT]). Regimens were selected by the treating physician on the basis of ATLL subtype and according to local institutional practices (Table 1).\n\nTABLE 1 Demographics and Clinical Features of Patients With Adult T-Cell Leukemia/Lymphoma\n\nResponse Criteria\n\nTherapy responses were assessed according to the 2009 consensus report for ATLL.16 The Cheson criteria was used to assess response through computerized tomography imaging.17 Complete response (CR) required a decrease in the absolute lymphocyte count to < 4 × 109/L with < 5% of flower cells remaining along normalization of all nodal and extranodal lesions (including bone marrow); partial response (PR) was defined as ≥ 50% disease reduction; and progressive disease (PD) as ≥ 50% increase in the count of flower cells and absolute lymphocyte count > 4 × 109/L at any time, and/or ≥ 50% increase in size of any nodal and/or extranodal lesions. Stable disease (SD) was defined as a failure to attain CR or PR in the absence of PD. Responses (CR, PR, and SD) should persist for at least 4 weeks to be classified as such.\n\nStatistical Analysis\n\nDemographics, clinical features, and therapies received were summarized using descriptive statistics. The primary study outcomes were treatment response, progression-free survival (PFS), and overall survival (OS). Event-free patients were censored at the date of last clinical follow-up. Alive patients were censored at last follow-up in clinic or by telephone. Survival estimates were calculated by the Kaplan-Meier method and compared using the log-rank test. The Clopper-Pearson method was used to estimate the two-sided 95% CI in response rates. Statistical analysis was performed using IBM SPSS Statistics version 23.\n\nRESULTS\n\nEpidemiologic and Clinical Features\n\nA total of 253 patients with ATLL were identified between January 1995 and December 2019. Demographic and clinical features of patients with ATLL are shown in Figure 1 and Table 1.\n\nFIG 1 Geographical distribution map of patients with ATLL encountered in Latin America in Grupo de Estudio Latinoamericano de Linfoproliferativos cohort (N = 253). ATLL, adult T-cell leukemia/lymphoma.\n\nThe majority (n = 211; 83%) had aggressive ATLL (lymphomatous: n = 127, 50%; acute: n = 83, 33%), and 31 (12%) had indolent ATLL (chronic: n = 26, 10%; smoldering: n = 5, 2%). Twelve cases (5%) were unclassifiable because of lack of laboratory or imaging information. The median age at diagnosis was 57 years, with a female predominance in acute (n = 47; 58%) and smoldering (n = 5; 100%) subtypes. Most patients with ATLL were from Peru (n = 159; 63%), Chile (n = 44; 17%), Argentina (n = 20; 8%), and Colombia (n = 17; 7%) (Fig 1). During the ATLL data query, participating centers from Guatemala, Uruguay, and Venezuela did not report ATLL cases during the past 10-15 years.\n\nHypercalcemia was associated with acute ATLL (40% v lymphomatous 27%, P = .014). The PIT score yielded a higher risk classification than the IPI score (high-risk PIT [n = 139, 55%] v high-risk IPI [n = 73, 29%], respectively; P < .001). Coinfections were seen in 7% (n = 17) of cases with strongyloidiasis (n = 5) and Pneumocystis jirovecii pneumonia (n = 5) as the most commonly observed.\n\nDisease Outcome\n\nTwo hundred twenty-six patients (lymphomatous: n = 122, acute: n = 73, and chronic and smoldering: n = 31) had sufficient data for analysis. With a median follow-up of 12 months (range 1 month to 15 years), the median OS times were 4.3 months, 7.9 months, 21.1 months, and not reached for acute, lymphomatous, chronic, and smoldering ATLL (P < .001), with 4-year survival rates of 8%, 22%, 40%, and 80%, respectively (Fig 2).\n\nFIG 2 OS of patients with ATLL according to clinical subtype: (A) all ATLL and (B) aggressive ATLL. ATLL, adult T-cell leukemia/lymphoma; OS, overall survival.\n\nTherapy Approaches and Responses\n\nThe therapy approaches used during the first two lines of therapy are summarized in Table 2. The median number of treatment regimens administered in all patients was 1 (range 1-3). Sixteen (6%) patients did not receive first-line treatment and had best supportive care because of very poor performance status led by a rapid disease progression. No biologic agents were used in our cohort mainly because of lack of access to these agents. Data on patients managed for CNS involvement are presented in Appendix Table A2.\n\nTABLE 2 Approaches Used During the First Two Therapy Evaluations in All Patients\n\nAZT-IFN–Based Regimen\n\nTable 3 summarizes the response rates in patients with ATLL according to treatment regimen. Of the evaluable patients, 44 received either AZT-IFN alone (n = 20) or in combination with multiagent chemotherapy (n = 24). First-line AZT-IFN alone (n = 17) resulted in an overall response rate (ORR) of 71% and CR of 42% (acute: n = 8, ORR 63%, CR 24%; lymphomatous: n = 8, ORR 75%, CR 50%; and smoldering: n = 1, CR 100%). First-line combination of AZT-IFN with multiagent chemotherapy (either concurrent or sequentially) resulted in an ORR of 67% and a CR of 17% (acute: n = 11, ORR 54%, CR 27%; lymphomatous: n = 11, ORR 73%, CR 9%; chronic: n = 1, PR 100%; and smoldering: n = 1, PR 100%). Second-line AZT-IFN alone (n = 3) yielded an ORR of 67% and a CR of 33% (one acute PR, one chronic CR, and one lymphomatous SD).\n\nTABLE 3 Response Rates in Patients With Adult T-Cell Leukemia/Lymphoma According to Treatment Regimen\n\nChemotherapy-Based Regimen\n\nA total of 187 patients received multiagent chemotherapy either as first line (n = 154) or as second line (n = 33). First-line chemotherapy resulted in an ORR of 32% and a CR of 21% (acute: n = 38, ORR 21%, CR 8%; lymphomatous: ORR 41%, CR 29%; chronic: n = 21, ORR 10%, CR 10%; and one with unknown ATLL subtype had CR). Second-line chemotherapy resulted in an ORR of 9% and a CR of 6% (acute: n = 6, ORR 17%, CR 17%; lymphomatous: n = 20, ORR 5%, PR 5%; chronic: n = 6, ORR 0%; and one with unknown ATLL subtype had CR). The most commonly used first-line regimens were CHOP or CHOP-like regimen (n = 117, 59%) and CHOEP regimens (n = 40, 20%) with an ORR of 29% (CR 12%) and 60% (CR 42%), respectively (P < .001) (Table 3). LSG-15–like regimen was used in four patients with an ORR of 0% (SD, n = 2, 50%) and hyperCVAD in four patients with one patient achieving CR (SD, n = 2, 50%).\n\nComparing Therapy Regimens\n\nThere were no differences in PFS in patients with acute or lymphomatous ATLL receiving either first-line AZT-IFN alone, chemotherapy alone, or combination therapy (Appendix Fig A1). However, in patients with aggressive ATLL who achieved CR, first-line AZT-IFN (alone or in combination with chemotherapy) yielded a better PFS compared with chemotherapy alone in acute ATLL (AZT-IFN–based: n = 5, median 30.4 months, 1-year PFS 67% v chemotherapy-based: n = 3, median 2.8 months, 1-year PFS 0%). Chemotherapy resulted in improved PFS in patients with lymphomatous ATLL compared with AZT-IFN–based approach (AZT-IFN–based: n = 4, median 17.7 months, 2-year PFS 37% v chemotherapy-based: n = 26, median 67.1 months, 2-year PFS 77%) (Appendix Fig A1). However, these differences were not statistically significant.\n\nTable 4 summarizes the therapy approaches and outcomes of patients with ATLL who achieved first complete remission.\n\nTABLE 4 Clinical Characteristics, Therapy Approach, and Outcome of Patients With Adult T-Cell Leukemia/Lymphoma Who Achieved First Complete Remission\n\nDISCUSSION\n\nTo our knowledge, this study is the first international, multi-institutional study evaluating the epidemiology, diagnosis, therapy approaches, and outcomes of patients with HTLV-1–related ATLL encountered in different Latin American countries over the past 25 years. In this study, Latin American patients with ATLL were predominantly women and were diagnosed at a younger age (median 57 years, range 18-95), which is in line with previous Latin American and US reports describing that Hispanic and Afro-Caribbean patients are diagnosed approximately a decade younger than Japanese patients.5,7,18-22\n\nHTLV-1 is commonly found in indigenous peoples of the Pacific Islands (Australia and Melanesia) and the Americas.23-27 In Latin America, there are more than 400 indigenous groups, ranging from 45 to 50 million individuals.28-30 The 2020 International Work Group for Indigenous Affairs reported Bolivia as the country housing the largest indigenous population in Latin America (48% of the population), followed by Guatemala (43.8%), Mexico (21.5%), Chile (12.8%), and Peru (12.5%).28 In countries such as Venezuela, Paraguay, Brazil, El Salvador, and Uruguay, indigenous people comprise < 3% of the population.28-30 Besides Brazil, HTLV-1 infection is predominantly presented in indigenous people living in the Andes of Peru (Quechua and Aymara), Chile (Mapuche and Rapa Nui), and Colombia (Paez); in the Peruvian Amazon (Shipibo-Konibo); and in the Chaco region (Qulla and Puná of northwestern Argentina).3,26,27 The prevalence of HTLV-1 infection in countries of Central America and Mexico is poorly known; however, it is estimated to be low on the basis of few studies performed in blood donors.25-27,31\n\nIn our study, ATLL cases were primarily encountered in Peru, encompassing 63% of the studied patients. Chile, Argentina, and Colombia also reported numerous cases, most of them in indigenous people living in areas close to the mountains and where the virus has been reported as endemic. Participating centers from Bolivia, Ecuador, Mexico, and Paraguay reported very few cases, whereas centers from Venezuela, Uruguay, and Guatemala did not report any cases during the past 2 decades. Possible explanations to our findings are as follows: (1) some participating centers in this study are located far from known HTLV-1 endemic areas, which might have yielded to underreporting the number of ATLL cases; however, all participating centers are referral cancer centers in their countries, with ATLL as a common motive for referral; and (2) limited resources and lack of standardized protocols for HTLV testing in Latin America (countries particularly known for having large indigenous population such as Bolivia, Ecuador, and Mexico had screening rates of HTLV-1/2 in blood donors of 0%, 8%, and 0%, respectively, during 2016-2017).31 Although our findings seem to correlate with what is known regarding the geographical distribution of HTLV-1 infection in Latin America, there is an unmet need to better understanding the current incidence and prevalence of HTLV-1 infection in this region of the world. Brazil, a known highly endemic country for HTLV-1 infection, was not included in this study because of its recent incorporation to the Grupo de Estudio Latinoamericano de Linfoproliferativos; nonetheless, data of ATLL in Brazil are well-established, whereas these same data are lacking in other Latin American countries.32-35\n\nIn our cohort, lymphomatous (50%) ATLL was most commonly encountered compared with acute (33%) ATLL. This finding correlates with what has been previously described in other Latin American and US studies5,20,36 but is dissimilar to Japanese and some other US cohorts where acute ATLL was the most common subtype.7,21,22 We acknowledge that our patients were classified using archived records, therefore representing a potential risk for biases. However, there was a distinction between the acute and lymphomatous groups in our cohort, including higher rates of hypercalcemia and poorer outcomes in patients with acute ATLL. The 1-year OS rates of 24% for acute ATLL compared with 44% for lymphomatous ATLL (P < .001) are consistent with the natural history of ATLL (Fig 2B). A relative poorer survival has been reported in Hispanic and Afro-Caribbean patients as opposed to Japanese patients.5,7,20-22,36 Although limited health care access in Latin American countries could ultimately influence patient outcome, our clinical findings suggest that Latin American patients with ATLL present with more aggressive clinical course than Japanese patients. Furthermore, a recent study reported that North American ATLL (mostly composed of patients of Caribbean descent) has a distinct genomic landscape with a high frequency of prognostic epigenetic mutations affecting p53 function and is consequently associated to chemorefractoriness.37 This could potentially explain the differences in aggressiveness seen in American and Caribbean ATLL populations compared with Japanese population, despite sharing the same HTLV-1 serotype.\n\nIn this study, patients with acute ATLL who received first-line AZT-IFN either alone (n = 16) or in combination with chemotherapy (n = 22) had a tendency toward higher ORR (AZT-IFN alone: ORR 63% [CR 24%]; AZT-IFN combination: ORR 54% [CR 27%]) as compared with those treated with first-line multiagent chemotherapy (n = 132; ORR 21% [CR 8%]). This finding is in line with previous meta-analysis where patients with aggressive ATLL had an ORR of 66% and a CR of 35%.38 Importantly, patients with acute ATLL who achieved CR after AZT-IFN had a longer PFS as compared with those who achieved CR after chemotherapy alone (30.4 months v 2.8 months, respectively) as only three of 38 acute type patients achieved CR after chemotherapy (Appendix Fig A1C). Previous studies have reported this positive outcome, suggesting that AZT-IFN is a good first-line option to attempt for patients with leukemic ATLL.5,38 Although not formally studied in this cohort, a common disease feature we saw in responders to AZT-IFN was lymph node size of ≤ 3 cm in patients with acute ATLL and mass ≤ 3.5 cm, suggesting that this therapy may only be effective in ATLL presenting with nonbulky disease. Despite the long-term responses seen with AZT-IFN, most patients will eventually experience disease progression, which confirms this therapy is suppressive but not curative, reason why patients in clinical remission should be evaluated for stem-cell transplantation or remain on maintenance therapy indefinitely, if deemed unfit for transplantation.5,15,38\n\nIn lymphomatous ATLL, although response rates were low in patients treated with first-line multiagent chemotherapy (ORR 41% and CR 29%), superior outcomes were observed in those who achieved a CR compared with first-line AZT-IFN (67.1 months v 17.7 months, respectively). However, this was not statistically significant because of the low number of patients treated (Appendix Fig A1D). This finding provides further evidence that chemotherapy should remain the standard first-line treatment of this subtype, as was observed in previous studies.5,16,38 In this study, CHOEP regimen (n = 40) yielded higher response rates compared with CHOP or CHOP-like regimen (n = 117) (ORR 60%, CR 42% v ORR 29%, CR 12%, respectively; P < .001). Only four patients received the modified intensive regimen vincristine, cyclophosphamide, doxorubicin, and prednisone-doxorubicin and prednisone-vincristine, etoposide, carboplatin, and prednisone (known as LSG-15 regimen, vincristine, cyclophosphamide, doxorubicin, and prednisone-doxorubicin, ranimustine and prednisone-vincristine, etoposide, carboplatin, and prednisone), of whom two had SD and the other two PD. A previous study found no difference in outcomes between the above regimens, but this could have been related to the small sample size in the study.5 Therefore, it would be reasonable to use CHOEP, or a similar regimen, in patients with aggressive ATLL who are good candidates for high-dose chemotherapy and allo-HSCT. In our study, only two patients with lymphomatous ATLL underwent allo-HSCT, one as second line after achieving CR with dexamethasone, cytarabine, and cisplatin (PFS 12 months, died from relapsed disease) and the other after achieving CR with first-line AZT-IFN (remains disease-free, PFS 17 months).\n\nFinally, this study not only provides a comprehensive assessment of this rare and generally incurable disease but also offers a better understanding on the limitations the different participating institutions face during the initial and subsequent evaluation of patients with ATLL in Latin America. We identified disparities among countries in the following: (1) sophisticated imaging such as positron emission tomography and magnetic resonance imaging almost universally lacked in public or governmental institutions; (2) biologic agents (eg, interferon alfa-2b, mogamulizumab, and alemtuzumab) were not readily available for the management of ATLL in most Latin American countries, and if available, the cost was borne by the patient, which makes its use almost impossible; and (3) there was limited access to clinical trials for ATLL in Latin American countries (only two countries had mogamulizumab as a therapy option under a clinical trial in the past 25 years).\n\nIn conclusion, ATLL continues to carry a dismal outcome with conventional therapies, urging the development of novel approaches. Our study found that in Latin America, patients present at a younger age, with female predominance, high incidence of lymphomatous type, low incidence of indolent types, and worse survival rates as compared with previously reported Japanese patients. AZT-IFN produced durable responses in patients with acute ATLL who achieved CR as compared with chemotherapy alone. On the other hand, chemotherapy responses, especially after CHOEP, were more durable in lymphomatous type patients who achieved CR than the acute type. Our findings suggest that in the management of aggressive ATLL, chemotherapy remains the preferred first-line choice for lymphomatous type favoring the etoposide-based regimen CHOEP, whereas AZT-IFN is a good option to attempt for acute type up front, with consideration of allo-HSCT in those patients who achieve a good response to therapy. Further characterization of Latin American ATLL through genomic analysis is planned.\n\nPRIOR PRESENTATION\n\nAUTHOR CONTRIBUTIONS\n\nConception and design: Luis Malpica, Daniel J. Enriquez, Camila Peña, Laura Aguirre-Martinez, Jorge J. Castillo, Brady E. Beltran\n\nAdministrative support: Milagros Altamirano\n\nProvision of study materials or patients: Denisse A. Castro, Camila Peña, Lorena Fiad, Victoria Otero, Mirna Biglione, Gustavo Sandival-Ampuero, Ursula Aviles-Perez, Laura Aguirre-Martinez, Luciana Guanchiale, Pablo Soto, Jose L. Viñuela, Maria E. Cabrera, Eloisa Riva, Andrea Noboa, Myrna Candelaria, Fabiola Valvert, Maria A. Torres-Viera\n\nCollection and assembly of data: Luis Malpica, Daniel J. Enriquez, Denisse A. Castro, Camila Peña, Henry Idrobo, Lorena Fiad, Maria Prates, Victoria Otero, Mirna Biglione, Milagros Altamirano, Gustavo Sandival-Ampuero, Ursula Aviles-Perez, Kelly Meza, Laura Aguirre-Martinez, Nancy Cristaldo, Juan L. Maradei, Luciana Guanchiale, Pablo Soto, Jose L. Viñuela, Maria E. Cabrera, Sally Rose Paredes, Marcos Di Stefano, Andrea Noboa, Juan A. Choque, Myrna Candelaria, Fabiola Valvert, Maria A. Torres-Viera\n\nData analysis and interpretation: Luis Malpica, Daniel J. Enriquez, Denisse A. Castro, Henry Idrobo, Jose L. Viñuela, Eloisa Riva, Alana Von Glasenapp, Jorge J. Castillo, Juan Carlos Ramos, Luis Villela, Brady E. Beltran\n\nManuscript writing: All authors\n\nFinal approval of manuscript: All authors\n\nAccountable for all aspects of the work: All authors\n\nAUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST\n\nThe following represents disclosure information provided by the authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/go/authors/author-center.\n\nOpen Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).\n\nAppendix\n\nFIG A1 PFS of patients with aggressive ATLL after first-line therapy according to clinical subtype and treatment approach: (A) acute ATLL, (B) lymphomatous ATLL, (C) acute ATLL after CR, and (D) lymphomatous ATLL after CR. AI, AZT (zidovudine) with Interferon alpha 2b; ATLL, adult T-cell leukemia/lymphoma; CR, complete response; PFS, progression-free survival.\n\nTABLE A1 Latin American Hospitals With Expertise in Cancer Services Participating in Adult T-Cell Leukemia/Lymphoma Database Query\n\nTABLE A2 Clinical Features and Outcome of Patients Diagnosed With ATLL and CNS Involvement (n = 11)\n\nPresented in part at the ASH Annual Meeting, virtual, December 2020.\n\n* L.M., D.J.E., D.A.C., C.P., and H.I. contributed equally to this work as first authors.\n\nDenisse A. Castro\n\nConsulting or Advisory Role: Johnson & Johnson del Perú S.A.\n\nCamila Peña\n\nHonoraria: Janssen, Bristol Myers Squibb/Medarex\n\nConsulting or Advisory Role: Janssen\n\nTravel, Accommodations, Expenses: Tecnofarma\n\nVictoria Otero\n\nEmployment: AstraZeneca\n\nEloisa Riva\n\nHonoraria: Sanofi\n\nTravel, Accommodations, Expenses: Roemmers\n\nMaria A. Torres-Viera\n\nSpeakers' Bureau: Takeda\n\nJorge J. Castillo\n\nConsulting or Advisory Role: Janssen, Roche/Genentech, Beigene, AbbVie/Pharmacyclics\n\nResearch Funding: Pharmacyclics, AbbVie, Janssen, BeiGene, TG Therapeutics\n\nJuan Carlos Ramos\n\nResearch Funding: miRagen\n\nLuis Villela\n\nConsulting or Advisory Role: Jazz Pharmaceuticals, Roche-Syntex, AstraZeneca LATAM\n\nSpeakers' Bureau: Amgen Mexico, AbbVie\n\nNo other potential conflicts of interest were reported.\n\nDenisse A. Castro\n\nConsulting or Advisory Role: Johnson & Johnson del Perú S.A.\n\nCamila Peña\n\nHonoraria: Janssen, Bristol Myers Squibb/Medarex\n\nConsulting or Advisory Role: Janssen\n\nTravel, Accommodations, Expenses: Tecnofarma\n\nVictoria Otero\n\nEmployment: AstraZeneca\n\nEloisa Riva\n\nHonoraria: Sanofi\n\nTravel, Accommodations, Expenses: Roemmers\n\nMaria A. Torres-Viera\n\nSpeakers' Bureau: Takeda\n\nJorge J. Castillo\n\nConsulting or Advisory Role: Janssen, Roche/Genentech, Beigene, AbbVie/Pharmacyclics\n\nResearch Funding: Pharmacyclics, AbbVie, Janssen, BeiGene, TG Therapeutics\n\nJuan Carlos Ramos\n\nResearch Funding: miRagen\n\nLuis Villela\n\nConsulting or Advisory Role: Jazz Pharmaceuticals, Roche-Syntex, AstraZeneca LATAM\n\nSpeakers' Bureau: Amgen Mexico, AbbVie\n\nNo other potential conflicts of interest were reported.\n==== Refs\nREFERENCES\n\n1. Yoshida M Miyoshi I Hinuma Y : Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its implication in the disease. Proc Natl Acad Sci USA 79 :2031-2035, 1982 6979048\n2. Poiesz BJ Ruscetti FW Reitz MS , et al : Isolation of a new type C retrovirus (HTLV) in primary uncultured cells of a patient with Sézary T-cell leukaemia. Nature 294 :268-271, 1981 6272125\n3. Verdonck K González E Van Dooren S Vandamme A-M Vanham G Gotuzzo E : Human T-lymphotropic virus 1: Recent knowledge about an ancient infection. Lancet Infect Dis 7 :266-281, 2007 17376384\n4. Gessain A Cassar O : Epidemiological aspects and world distribution of HTLV-1 infection. Front Microbiol 3 :388, 2012 23162541\n5. Malpica L Pimentel A Reis IM , et al : Epidemiology, clinical features, and outcome of HTLV-1-related ATLL in an area of prevalence in the United States. Blood Adv 2 :607-620, 2018 29545256\n6. Azran I Schavinsky-Khrapunsky Y Aboud M : Role of Tax protein in human T-cell leukemia virus type-I leukemogenicity. Retrovirology 1 (1 ):20, 2004 15310405\n7. Katsuya H Ishitsuka K Utsunomiya A , et al : Treatment and survival among 1594 patients with ATL. Blood 126 :2570-2577, 2015 26361794\n8. Satake M Yamada Y Atogami S , et al : The incidence of adult T-cell leukemia/lymphoma among human T-lymphotropic virus type 1 carriers in Japan. Leuk Lymphoma 56 :1806-1812, 2015 25219595\n9. Malpica Castillo LE Peña C Rojas C , et al : Identifying a simple clinical prognostic model for aggressive adult T-cell leukemia/lymphoma in Latin American population and its validation: A large International Study of the Latin America Working Group for Lymphomas (GELL). Blood 134 , 2019 (suppl 1 ; abstr 4045)\n10. Shimoyama M : Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. Br J Haematol 79 :428-437, 1991 1751370\n11. Castillo LM Dittus C : Adult T-cell leukemia/lymphoma, in Novel Therapeutics for Rare Lymphomas. Springer Nature Switzerland AG, Springer International Publishing, 2019, pp 137-164\n12. Vose J Armitage J Weisenburger D : International T-cell lymphoma project. International peripheral T-cell and natural killer/T-cell lymphoma study: Pathology findings and clinical outcomes. J Clin Oncol 26 :4124-4130, 2008 18626005\n13. Gallamini A Stelitano C Calvi R , et al : Peripheral T-cell lymphoma unspecified (PTCL-U): A new prognostic model from a retrospective multicentric clinical study. Blood 103 :2474-2479, 2004 14645001\n14. International Non-Hodgkin's Lymphoma Prognostic Factors Project: A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med 329 :987-994, 1993 8141877\n15. Ramos JC Ruiz P Ratner L , et al : IRF-4 and c-Rel expression in antiviral-resistant adult T-cell leukemia/lymphoma. Blood 109 :3060-3068, 2007 17138822\n16. Tsukasaki K Hermine O Bazarbachi A , et al : Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia-lymphoma: A proposal from an international consensus meeting. J Clin Oncol 27 :453-459, 2009 19064971\n17. O'Connor OA Pro B Illidge T , et al : Phase 3 trial of brentuximab vedotin and CHP versus CHOP in the frontline treatment of patients (pts) with CD30+ mature T-cell lymphomas (MTCL). J Clin Oncol 32 , 2014. (abstr TPS8612)\n18. Oliveira PD de Carvalho RF Bittencourt AL : Adult T-cell leukemia/lymphoma in South and Central America and the Caribbean: Systematic search and review. Int J STD AIDS 28 :217-228, 2017 28178905\n19. Enriquez DJ Haro JC Rioja P , et al : New prognostic classification for adult T cell lymphoma/leukemia based on hypercalcemia and neutrophil-to-lymphocyte ratio. Blood 130 , 2017 (suppl 1 ; abstr 4164)\n20. Beltran BE Cotacallapa E Castillo JJ : Adult T-cell leukemia/lymphoma in Peru: A report of 120 cases. Blood 120 , 2012 (abstr 5110)\n21. Zell M Assal A Derman O , et al : Adult T-cell leukemia/lymphoma in the Caribbean cohort is a distinct clinical entity with dismal response to conventional chemotherapy. Oncotarget 7 :51981-51990, 2016 27341021\n22. Phillips AA Shapira I Willim RD , et al : A critical analysis of prognostic factors in North American patients with human T-cell lymphotropic virus type-1-associated adult T-cell leukemia/lymphoma. Cancer 116 :3438-3446, 2010 20564100\n23. Balduin B Priore C Acosta C , et al : Infección por virus linfotrópico de células T humanas (HTLV) en Uruguay: identificación de problemas. Anales de la Facultad de Medicina Universidad de la República Uruguay 4 :41-51, 2017. http://www.anfamed.edu.uy/index.php/rev/article/view/286\n24. Mosquera-Herrera CE Aspiazu-Miranda EP de Waard JH , et al : A high prevalence of human T-lymphotropic virus (HTLV 1/2) infection among Afro-descendants, Esmeraldas province, Ecuador—Need for the implementation of surveys and control programs. Infect Drug Resist 12 :1969-1974, 2019 31360069\n25. Palma P Barrientos JM Posadas MA , et al : Prevalencia del virus linfotrópico de células T humanas (HTLV) I/II en donantes de sangre. Cienc Tecnol Salud 4 :15-50, 2017\n26. Eusebio-Ponce E Candel FJ Anguita E : Human T-cell lymphotropic virus type 1 and associated diseases in Latin America. Trop Med Int Heal 24 :934-953, 2019\n27. Paiva A Casseb J : Origin and prevalence of human T-lymphotropic virus type 1 (HTLV-1) and type 2 (HTLV-2) among indigenous populations in the Americas. Rev Inst Med Trop Sao Paulo 57 :1-13, 2015\n28. Nathaniel Berger D Bulanin N García-Alix L , et al : 2 IWGIA-the indigenous world-2020. www.NickPurserDesign.com\n29. Congressional Research Service: Indigenous Peoples in Latin America: Statistical Information. Bethesda, MD, 2020. https://fas.org/sgp/crs/row/R46225.pdf\n30. Cruz-Saco MA : Indigenous Communities and Social Inclusion in Latin America—United Nations. Connecticut, 2018. https://www.un.org/development/desa/family/wp-content/uploads/sites/23/2018/05/2-1.pdf\n31. Organización Panamericana de la Salud: Suministro de sangre para transfusiones en los países de América Latina y el Caribe 2016-2017. 2020. https://iris.paho.org/handle/10665.2/52150\n32. Ishak R De Oliveira Guimarães Ishak M Vallinoto ACR : The challenge of describing the epidemiology of HTLV in the Amazon region of Brazil. Retrovirology 17 :4, 2020 32059740\n33. Rosadas C Puccioni‐Sohler M Oliveira ACP , et al : Adult T‐cell leukaemia/lymphoma in Brazil: A rare disease or rarely diagnosed? Br J Haematol 188 :e46-e49, 2020 31743423\n34. Pereira FM de Almeida MdCC Santos FLN , et al : Evidence of new endemic clusters of human T-cell leukemia virus (HTLV) infection in Bahia, Brazil. Front Microbiol 10 :1002, 2019 31156570\n35. Pombo De Oliveira MS Loureiro P Bittencourt A , et al : Geographic diversity of adult T-cell leukemia/lymphoma in Brazil. Int J Cancer 83 :291-298, 1999 10495418\n36. Beltran B Quiñones P Morales D , et al : Different prognostic factors for survival in acute and lymphomatous adult T-cell leukemia/lymphoma. Leuk Res 35 :334-339, 2011 20828817\n37. Shah UA Chung EY Giricz O , et al : North American ATLL has a distinct mutational and transcriptional profile and responds to epigenetic therapies. Blood 132 :1507-1518, 2018 30104217\n38. Bazarbachi A Plumelle Y Carlos Ramos J , et al : Meta-analysis on the use of zidovudine and interferon-alfa in adult T-cell leukemia/lymphoma showing improved survival in the leukemic subtypes. J Clin Oncol 28 :4177-4183, 2010 20585095\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2687-8941",
"issue": "7()",
"journal": "JCO global oncology",
"keywords": null,
"medline_ta": "JCO Glob Oncol",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001118:Argentina; D002677:Chile; D003105:Colombia; D006801:Humans; D007843:Latin America; D015459:Leukemia-Lymphoma, Adult T-Cell; D008223:Lymphoma; D008875:Middle Aged; D010568:Peru",
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"pages": "1151-1166",
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"pmid": "34270330",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article",
"references": "20828817;30104217;32059740;31360069;18626005;20564100;26361794;19064971;14645001;31183938;10495418;31743423;8141877;6979048;28178905;1751370;29545256;20585095;23162541;15310405;31156570;17376384;25219595;27341021;17138822;25651320;6272125",
"title": "Real-World Data on Adult T-Cell Leukemia/Lymphoma in Latin America: A Study From the Grupo de Estudio Latinoamericano de Linfoproliferativos.",
"title_normalized": "real world data on adult t cell leukemia lymphoma in latin america a study from the grupo de estudio latinoamericano de linfoproliferativos"
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"abstract": "Stroke is a common cause of mortality and serious long-term disability worldwide. In the acute setting, current American Heart Association/American Stroke Association guidelines do not recommend routine anticoagulation for the management of acute ischemic strokes. However, short-term use of unfractionated heparin (UFH) in select subpopulations has demonstrated improved outcomes. While tools such as CHADSVASC and HASBLED scores are useful in stratifying risk of long-term anticoagulation in patients with nonvalvular atrial fibrillation and additional risk factors, the carefully selected patient populations for the design of these studies do not account for risk of hemorrhage from other preexisting conditions. Here, we present a patient with a posterior circulation intraluminal thrombus treated with UFH, who manifested with a near-fatal intra-abdominal hemorrhage from a previously undetected renal angiomyolipoma (AML).",
"affiliations": "Institute for Stroke and Cerebrovascular Disease, The University of Texas Health Science Center, Houston, Texas, USA.;Institute for Stroke and Cerebrovascular Disease, The University of Texas Health Science Center, Houston, Texas, USA.;Institute for Stroke and Cerebrovascular Disease, The University of Texas Health Science Center, Houston, Texas, USA.;Department of Radiology, The University of Texas Health Science Center, Houston, Texas, USA.;Department of Radiology, The University of Texas Health Science Center, Houston, Texas, USA.;Institute for Stroke and Cerebrovascular Disease, The University of Texas Health Science Center, Houston, Texas, USA.",
"authors": "Hsieh|Billie|B|;Tariq|Muhammad B|MB|;Ibrahim|Lamya|L|;Khanpara|Shekhar D|SD|;Kramer|Larry A|LA|;Savitz|Sean I|SI|",
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"doi": "10.1159/000514090",
"fulltext": "\n==== Front\nCase Rep Neurol\nCase Rep Neurol\nCRN\nCase Reports in Neurology\n1662-680X\nS. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com\n\n10.1159/000514090\ncrn-0013-0388\nSingle Case − General Neurology\nHeparin for Vertebral Intraluminal Thrombus Causing Retroperitoneal Hemorrhage from Occult Renal Angiomyolipoma\nHsieh Billie a*\nTariq Muhammad B. a\nIbrahim Lamya a\nKhanpara Shekhar D. b\nKramer Larry A. b\nSavitz Sean I. a\naInstitute for Stroke and Cerebrovascular Disease, The University of Texas Health Science Center, Houston, Texas, USA\nbDepartment of Radiology, The University of Texas Health Science Center, Houston, Texas, USA\n*Billie Hsieh, billieqhsieh@gmail.com\nMay-Aug 2021\n14 6 2021\n14 6 2021\n13 2 388393\n2 12 2020\n25 12 2020\n2021\nCopyright © 2021 by S. Karger AG, Basel\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.\nStroke is a common cause of mortality and serious long-term disability worldwide. In the acute setting, current American Heart Association/American Stroke Association guidelines do not recommend routine anticoagulation for the management of acute ischemic strokes. However, short-term use of unfractionated heparin (UFH) in select subpopulations has demonstrated improved outcomes. While tools such as CHADSVASC and HASBLED scores are useful in stratifying risk of long-term anticoagulation in patients with nonvalvular atrial fibrillation and additional risk factors, the carefully selected patient populations for the design of these studies do not account for risk of hemorrhage from other preexisting conditions. Here, we present a patient with a posterior circulation intraluminal thrombus treated with UFH, who manifested with a near-fatal intra-abdominal hemorrhage from a previously undetected renal angiomyolipoma (AML).\n\nKeywords\n\nStroke\nIschemic\nHeparin\nAtrial fibrillation arrhythmia\nHemorrhage\nTumor subject terms\nIschemic stroke\nImaging\nBlood pressure\nAtrial fibrillation\nArrhythmias\n==== Body\nIntroduction/Background\n\nApproximately 795,000 people suffer from a stroke every year in the USA; 87% of which are ischemic, while the remaining majority are due to intracranial or subarachnoid hemorrhages [1]. Proposed benefits for the use of heparin in acute ischemic strokes include early clot lysis, stopping propagation of the clot, reduction in blood viscosity and recurrent thromboembolism, as well as possible anti-inflammatory properties [2, 3, 4]. The timing of anticoagulation initiation in the early phase is debatable [5]. Heparin use can be complicated by hemorrhage in 2–3% of patients or even higher percentages depending on the clinical case [6]. Bleeding can potentially occur from any site, but gastrointestinal bleeds are most common, and intracranial hemorrhages are the most dreaded. A case-by-case review of individual patients prior to starting anticoagulation can mitigate this risk [7, 8].\n\nCase Presentation\n\nThe patient is a 70-year-old man with a medical history of hypertension, gout, and rectal cancer with liver metastases who presented with 4 days of nausea, vomiting, and gait instability. On physical examination, he was found to have right ptosis, left arm tremor, and right arm dysmetria. CT head showed cerebellar infarction with surrounding cerebral edema in the territory of the right posterior inferior cerebellar artery (PICA). CT angiography of the head and neck showed right vertebral thrombus with distal reconstitution from retrograde flow along with moderate-to-severe stenosis in his bilateral posterior cerebral arteries. He was not a candidate for thrombolysis with tissue plasminogen activator or endovascular intervention being outside of the thrombectomy treatment window.\n\nStroke workup was completed, with a normal transthoracic echocardiogram, elevated hemoglobin A1c, and elevated LDL. He received an aspirin 325 mg load and then was started on aspirin 81 mg and a statin for secondary stroke prophylaxis. His blood pressure was slowly decreased from permissive hypertension with his home antihypertensives. MRI brain confirmed a subacute stroke of the right PICA territory with secondary right tonsillar herniation and no hemorrhagic transformation (Fig. 1). Mass effect was also seen with compression of the fourth ventricle without hydrocephalus. He further underwent MR angiography of his head and neck, which was significant for occlusion of his right vertebral artery from V1 to the distal V2 segment, with distal reconstitution. That is, trickle flow at the V3 segment level and normal caliber at V4 reflecting clot burden and likely retrograde flow from the basilar artery.\n\nIntravenous heparin infusion without bolus was started for the right vertebral thrombus with therapeutic partial thromboplastin time reached on the second day of admission. The patient began complaining of abdominal pain on the third day, with recurrence of nausea and vomiting. He became hypotensive and had tachycardia. Hemoglobin dropped from 9.4 to 5.9 mmol/L. Abdominal X-ray showed possible ileus, with bowel diameter >10 cm. CT abdomen showed left retroperitoneal hematoma from a ruptured 1.2 cm renal angiomyolipoma (mildly complex and posterior). Aspirin and heparin were stopped. He was given 3 units of packed red blood cells (PRBCs) and emergently taken for mesenteric/visceral angiography with embolization by interventional radiology (IR) (Fig. 2).\n\nPost-procedurally, he was initially hemodynamically stable but had new-onset atrial fibrillation with rapid ventricular response to the 160s on telemetry and his systolic blood pressure dropped to 70 mm Hg. Repeat angiography of the embolized site was reviewed with IR. There was no active extravasation. He was given 1 L of fluids, 2 units of PRBCs along with amiodarone bolus and then started on an amiodarone infusion which was stopped the next day. Repeat electrocardiograms showed sinus rhythms. His hemoglobin was repeated every 8–12 h, then daily. Due to a high CHADSVASC score of 5, it was felt strongly that he needed to be on antithrombotic therapy. Repeat CT abdomens showed a stable hematoma; thus, he was restarted on aspirin 81 mg, 4 days after his embolization.\n\nThe case was further discussed with IR, oncology, hematology, surgery, gastrointestinal, and urology. The decision was that the benefits of anticoagulation outweighed the risks of rebleeding after embolization. His hemoglobin remained stable. On day 7 after embolization, he was started on an aspirin to warfarin bridge. Device implantation or atrial ablation for atrial fibrillation management was not selected due to patient preference. At this point, he was discharged from the hospital with home health and close multispecialty follow-up. At 6 months follow-up, he was on anticoagulation and functioning close to his baseline at home.\n\nDiscussion\n\nWe present a case of a stroke patient who needed anticoagulation for a vertebral artery thrombus which had resulted in cerebellar infarction. Given the vertebral thrombus, the patient was at risk of further propagation into a brainstem stroke. Brainstem strokes are by themselves associated with a high mortality of 17% [9] and cerebellar strokes with a mortality of 23%. Given the potentially devastating complications, he was started on unfractionated heparin to aid in clot dissolution, which was partially achieved on repeat imaging. However, the patient bled due to an unknown AML. The dilemma in this case is the unexpected pathology.\n\nExtracranial bleeding on heparin is uncommon (3%), and only a small proportion of bleeding on anticoagulation is associated with an occult lesion [10, 11, 12]. Thus, routine abdominal imaging prior to starting anticoagulation is not commonly practiced. AML is a rare tumor, with a prevalence of 0.2–0.6% in the general adult population [13]. Hence, data on the number of bleeds from these occult tumors after starting anticoagulation is limited. Furthermore, there is no evidence on withholding anticoagulation even if an incidental AML is identified.\n\nAfter the AML bled and was embolized, this patient went into atrial fibrillation, another condition associated with recurrent strokes. Paroxysmal atrial fibrillation could have gone previously undetected, with provoking factors being significant hypotension and related stressors, and the arrhythmia in turn causing a second episode of shock. Atrial fibrillation typically requires long-term anticoagulation [14]. With a high CHADSVASC score of 5, the risk of stroke, transient ischemic attack, or systemic embolism is as high as 10% per year [15]. Anticoagulation can decrease this risk by two-thirds and should be considered in all patients with high CHADSVASC scores [16]. However, the patient's HASBLED score was 3, which shows a 5.8% risk for major bleeding [17]. Additionally, while there is no data for risk of AML bleeding on anticoagulation, or on whether anticoagulation would increase the inherent risk of bleeding, long-term follow-up of patients after embolization of their AMLs shows a rebleeding risk of 11–15% [18].\n\nIn this situation with high risk of future strokes and devastating nature of posterior circulation ischemic strokes sans treatment, while concurrently weighing a high risk of major hemorrhage with treatment, it is important to involve the patient in the decision-making process. The other critical aspect is early involvement of multiple subspecialties for their anecdotal input in such cases where no large studies exist.\n\nStatement of Ethics\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nConflict of Interest Statement\n\nThe authors have no conflicts of interest to disclose.\n\nFunding Sources\n\nNo sources of funding to disclose.\n\nAuthor Contributions\n\nBillie Hsieh MD wrote/edited the manuscript and created the figure, Muhammad B. Tariq MD co-wrote and edited the manuscript, Lamya Ibrahim MD co-wrote and edited the manuscript, Shekhar D. Khanpara MD helped create the figure, Larry A. Kramer MD helped create the figure and legend, and Sean I. Savitz MD edited the manuscript.\n\nFig. 1 a Restricted diffusion in the right posteromedial inferior cerebellum (arrow) compatible with a right PICA subacute infarction. No hematoma is identified. b Early phase of a reconstructed dynamic contrast MRA brain and neck. The left vertebral artery is well visualized throughout its course. There is some reflux of contrast in the right vertebral artery from the left vertebral artery (arrow). c Noncontrast MRA set to display flow in the rostral direction. Near the craniovertebral junction, only flow in the left vertebral artery is seen (arrow). d CT abdomen axial showing a defect in the lower pole of the left kidney containing fat density measuring <4 cm in diameter (AML) with contiguous large retroperitoneal hemorrhage (arrows). PICA, posterior inferior cerebellar artery.\n\nFig. 2 e Pre-embolization arterial phase angiogram showing a hypervascular blush (arrow) in the right inferior renal pole with active contrast extravasation extending inferior to the kidney in multiple streams (asterisks). f Post-embolization arterial phase angiogram showing normal vascularization of the upper pole of the left kidney and hypovascularity of the lower pole (arrow) without active contrast extravasation.\n==== Refs\nReferences\n\n1 Virani Salim S Alonso A Benjamin Emelia J Bittencourt Marcio S Callaway Clifton W Carson April P Heart disease and stroke statistics–2020 update: a report from the american heart association Circulation 2020 141 (9) e139 e596 31992061\n2 Ruff IM Jindal JA Use of heparin in acute ischemic stroke: is there still a role? Curr Atheroscler Rep 2015 17 (9) 51 26194057\n3 Mokin M Kass-Hout T Kass-Hout O Radovic V Siddiqui AH Levy EI Intravenous heparin for the treatment of intraluminal thrombus in patients with acute ischemic stroke: a case series J Neurointerv Surg 2013 5 (2) 144 50 22345142\n4 Rocha EA Ji R Ay H Li Z Arsava EM Silva GS Reduced ischemic lesion growth with heparin in acute ischemic stroke J Stroke Cerebrovasc Dis 2019 28 (6) 1500 8 30935810\n5 Shahpouri MM Mousavi S Khorvash F Mousavi SM Hoseini T Anticoagulant therapy for ischemic stroke: a review of literature J Res Med Sci 2012 17 (4) 396 401 23267405\n6 Onishi A St Ange K Dordick JS Linhardt RJ Heparin and anticoagulation Front Biosci 2016 21 1372 92\n7 Lip GY Nieuwlaat R Pisters R Lane DA Crijns HJ Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation Chest 2010 137 (2) 263 72 19762550\n8 Pisters R Lane DA Nieuwlaat R de Vos CB Crijns HJ Lip GY A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro heart survey Chest 2010 138 (5) 1093 100 20299623\n9 Macdonell RA Kalnins RM Donnan GA Cerebellar infarction: natural history, prognosis, and pathology Stroke 1987 18 (5) 849 55 3629642\n10 Zidane M Schram MT Planken EW Molendijk WH Rosendaal FR van der Meer FJ Frequency of major hemorrhage in patients treated with unfractionated intravenous heparin for deep venous thrombosis or pulmonary embolism: a study in routine clinical practice Arch Intern Med 2000 160 (15) 2369 73 10927736\n11 The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group Lancet 1997 349 (9065) 1569 81 9174558\n12 Flack KF Desai J Kolb JM Chatterjee P Wallentin LC Ezekowitz M Major gastrointestinal bleeding often is caused by occult malignancy in patients receiving warfarin or dabigatran to prevent stroke and systemic embolism from atrial fibrillation Clin Gastroenterol Hepatol 2017 15 (5) 682 90 27765728\n13 Vos N Oyen R Renal angiomyolipoma: the good, the bad, and the ugly J Belg Soc Radiol 2018 102 (1) 41 30039053\n14 Wolf PA Dawber TR Thomas HE Jr Kannel WB Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: the Framingham study Neurology 1978 28 (10) 973 7 570666\n15 Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials Arch Intern Med 1994 154 (13) 1449 57 8018000\n16 Friberg L Rosenqvist M Lip GY Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182,678 patients with atrial fibrillation: the Swedish atrial fibrillation cohort study Eur Heart J 2012 33 (12) 1500 10 22246443\n17 Lip GY Frison L Halperin JL Lane DA Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile inr, elderly, drugs/alcohol concomitantly) score J Am Coll Cardiol 2011 57 (2) 173 80 21111555\n18 Andersen PE Thorlund MG Wennevik GE Pedersen RL Lund L Interventional treatment of renal angiomyolipoma: immediate results and clinical and radiological follow-up of 4.5 years Acta Radiol Open 2015 4 (7) 2058460115592442 26346549\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-680X",
"issue": "13(2)",
"journal": "Case reports in neurology",
"keywords": "Arrhythmias; Atrial fibrillation; Atrial fibrillation arrhythmia; Blood pressure; Hemorrhage; Heparin; Imaging; Ischemic; Ischemic stroke; Stroke; Tumor subject terms",
"medline_ta": "Case Rep Neurol",
"mesh_terms": null,
"nlm_unique_id": "101517693",
"other_id": null,
"pages": "388-393",
"pmc": null,
"pmid": "34248575",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "26346549;21111555;3629642;23267405;9174558;30935810;10927736;8018000;31992061;19762550;27100512;570666;27765728;26194057;22345142;22246443;20299623;30039053",
"title": "Heparin for Vertebral Intraluminal Thrombus Causing Retroperitoneal Hemorrhage from Occult Renal Angiomyolipoma.",
"title_normalized": "heparin for vertebral intraluminal thrombus causing retroperitoneal hemorrhage from occult renal angiomyolipoma"
} | [
{
"companynumb": "US-BAYER-2021A262142",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "Dr Susan Hou began her illustrious nephrology career at a time when pregnancy in women with chronic kidney disease (CKD) was hazardous and actively discouraged. Her pioneering research in women's health provided much of the early outcome data that shaped our current understanding of CKD and pregnancy. Although many uncertainties regarding optimal management of this vulnerable patient group remain, recent decades have witnessed important advances and renewed interest in improving care for pregnant women with CKD. Many nephrologists have been inspired by Dr Hou's lifetime of work and are grateful for her generous collaborations. In this In Practice Review, we honor her legacy by providing an update of current literature and clinical management guidance in the context of a clinical case vignette that challenges us to consider the many complex aspects to the counseling and care of women with CKD who desire a pregnancy.",
"affiliations": "Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan.;Department of Women and Children's Health, King's College London, London, United Kingdom; Department of Renal Medicine, King's College Hospital NHS Foundation Trust, London, United Kingdom.;Divisions of Nephrology and Obstetrics, Sunnybrook Health Sciences Center, University of Toronto, Toronto, Ontario, Canada. Electronic address: michelle.hladunewich@sunnybrook.ca.",
"authors": "Oliverio|Andrea L|AL|;Bramham|Kate|K|;Hladunewich|Michelle A|MA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1053/j.ajkd.2021.07.016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0272-6386",
"issue": "78(6)",
"journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation",
"keywords": "Chronic kidney disease (CKD); family planning; fertility; fetal outcomes; kidney failure; obstetrics; preconception counseling; pregnancy; reproductive health; review; sexual dysfunction",
"medline_ta": "Am J Kidney Dis",
"mesh_terms": null,
"nlm_unique_id": "8110075",
"other_id": null,
"pages": "865-875",
"pmc": null,
"pmid": "34656369",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Pregnancy and CKD: Advances in Care and the Legacy of Dr Susan Hou.",
"title_normalized": "pregnancy and ckd advances in care and the legacy of dr susan hou"
} | [
{
"companynumb": "US-009507513-2202USA004093",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LISINOPRIL"
},
"drugadditional": "4",
... |
{
"abstract": "Sickle cell disease (SCD) manifests itself with vaso-occlusive episodes leading to infarction. Placement of intravascular catheters provides a useful route for management of pain crises as well as other complications. However, catheter misuse is a commonly unrecognized problem, which can have lethal consequences. We present a case of fatal splenic sequestration/hyperhemolysis secondary to foreign body pulmonary and systemic embolization due to intravenous administration of hydromorphone pills in a young woman with SCD. Morphological identification of the embolized particles (crospovidone, microcrystalline cellulose, and hydrophilic polymer) was key in understanding the mechanism of death. Foreign particle deposition induced a granulomatous inflammatory response that resulted in obliteration and distortion of the microvasculature, thus triggering sickling with subsequent organ damage. Despite clinical evidence of asplenia and microscopic white pulp fibrosis with Gamna-Gandy body formation, unexpectedly for the patient's age, the spleen was enlarged by entrapped sickle cells. The findings support the possibility that loss of function can coexist with increased splenic activity under certain circumstances, an overlooked clinical phenotype of SCD. This case illustrates the teaching value of classic autopsy in addition to its crucial role in understanding the natural history of complex heterogeneous diseases.",
"affiliations": "From the Arkadi M. Rywlin, MD, Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL.",
"authors": "Febres-Aldana|Christopher A|CA|;Hernandez Howard|Lydia|L|",
"chemical_list": "D000701:Analgesics, Opioid; D013607:Tablets; D004091:Hydromorphone",
"country": "United States",
"delete": false,
"doi": "10.1097/PAF.0000000000000378",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0195-7910",
"issue": "39(2)",
"journal": "The American journal of forensic medicine and pathology",
"keywords": null,
"medline_ta": "Am J Forensic Med Pathol",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D000755:Anemia, Sickle Cell; D002408:Catheters, Indwelling; D017809:Fatal Outcome; D005260:Female; D005547:Foreign Bodies; D006461:Hemolysis; D006801:Humans; D004091:Hydromorphone; D009293:Opioid-Related Disorders; D011655:Pulmonary Embolism; D013163:Splenomegaly; D013607:Tablets",
"nlm_unique_id": "8108948",
"other_id": null,
"pages": "152-156",
"pmc": null,
"pmid": "29351102",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal Sickling Triggered by Massive Foreign Particle Embolism: A Case Report of Unrecognized Indwelling Venous Catheter Drug Abuse in Sickle Cell Disease.",
"title_normalized": "fatal sickling triggered by massive foreign particle embolism a case report of unrecognized indwelling venous catheter drug abuse in sickle cell disease"
} | [
{
"companynumb": "US-LANNETT COMPANY, INC.-US-2018LAN000598",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDROMORPHONE HYDROCHLORIDE"
},
... |
{
"abstract": "BACKGROUND\nPosterior fossa syndrome (PFS) is a rare manifestation of ponto-mesencephalic lesions frequently reported in post-surgical pediatric tumors, rarely described as a consequence of vascular, infective or inflammatory lesions.\n\n\nOBJECTIVE\nThe aim of this article is to report the clinical and neuroradiological characteristics of a patient with an acute PFS presentation as a relapse in relapsing-remitting MS, significantly responsive to Alemtuzumab treatment.\n\n\nMETHODS\n24-year-old patient affected by multiple sclerosis developed motor-cognitive and behavioral syndrome related to an extensive ponto-mesencephalic lesion under Fingolimod treatment.\n\n\nCONCLUSIONS\nOur case highlights the significant and rapid effect of Alemtuzumab therapy on both cognitive and motor symptoms occurring during a MS relapse with atypical neuroradiological localization.",
"affiliations": "Multiple Sclerosis Center, II Division of Neurology, University of Campania Luigi Vanvitelli, Naples, Italy. Electronic address: elisabetta.signoriello@unicampania.it.;Department of Advanced Biomedical Sciences, University of Naples \"Federico II\", Naples, Italy.;Multiple Sclerosis Center, II Division of Neurology, University of Campania Luigi Vanvitelli, Naples, Italy.;Department of Advanced Biomedical Sciences, University of Naples \"Federico II\", Naples, Italy.;Unit of Nephrology, Department of Translational Medical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy.;Alma Mater, Villa Camaldoli Hospital, Naples, Italy.;Multiple Sclerosis Center, II Division of Neurology, University of Campania Luigi Vanvitelli, Naples, Italy.;Multiple Sclerosis Center, II Division of Neurology, University of Campania Luigi Vanvitelli, Naples, Italy.;Unit of Nephrology, Department of Translational Medical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy.;Multiple Sclerosis Center, II Division of Neurology, University of Campania Luigi Vanvitelli, Naples, Italy.;Multiple Sclerosis Center, II Division of Neurology, University of Campania Luigi Vanvitelli, Naples, Italy.",
"authors": "Signoriello|E|E|;D'Amico|A|A|;Fratta|M|M|;Ugga|L|L|;Altobelli|C|C|;Conchiglia|G|G|;Barbarulo|A M|AM|;Di Pietro|A|A|;Anastasio|P|P|;Rossi|F|F|;Lus|G|G|",
"chemical_list": "D007155:Immunologic Factors; D000074323:Alemtuzumab; D000068876:Fingolimod Hydrochloride",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.msard.2019.101518",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2211-0348",
"issue": "38()",
"journal": "Multiple sclerosis and related disorders",
"keywords": "Alemtuzumab; Brainstem; Multiple sclerosis; Posterior fossa syndrome; Relapse",
"medline_ta": "Mult Scler Relat Disord",
"mesh_terms": "D000328:Adult; D000074323:Alemtuzumab; D001526:Behavioral Symptoms; D001927:Brain Diseases; D001933:Brain Stem; D060825:Cognitive Dysfunction; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007155:Immunologic Factors; D008279:Magnetic Resonance Imaging; D020529:Multiple Sclerosis, Relapsing-Remitting; D009155:Mutism; D012008:Recurrence; D066127:White Matter; D055815:Young Adult",
"nlm_unique_id": "101580247",
"other_id": null,
"pages": "101518",
"pmc": null,
"pmid": "31778927",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Alemtuzumab significantly improves posterior fossa syndrome presented as a relapse of multiple sclerosis.",
"title_normalized": "alemtuzumab significantly improves posterior fossa syndrome presented as a relapse of multiple sclerosis"
} | [
{
"companynumb": "NVSC2019IT059628",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FINGOLIMOD"
},
"drugadditional": "3",
"druga... |
{
"abstract": "BACKGROUND\nThe role of brentuximab peri-allogeneic transplantation in patients with relapsed and/or refractory CD30 positive lymphomas remains poorly defined.\n\n\nOBJECTIVE\nTo assess the outcome of use of brentuximab as a bridge to allogeneic stem cell transplantation (SCT) in patient with relapsed/refractory CD30+ classic Hodgkin lymphoma cHL and anaplastic large cell lymphoma (ALCL).\n\n\nMETHODS\nOutcomes of consecutive patients with relapsed/refractory cHL/ALCL treated with brentuximab as a bridge to SCT were determined by retrospective review of individual medical records. Survival analysis was measured from start of brentuximab treatment.\n\n\nRESULTS\nA total of 12 patients (10 cHL, 2 ALCL) had received brentuximab as a planned bridge to allogeneic SCT. Median age was 27 years (range 20-54 years); median prior lines of therapy was 4 (range 3-6) and all except one patient had undergone prior autologous SCT (92%). Patients received at median of 3 brentuximab doses pre-allogeneic SCT (range 1-4), with an overall response rate of 66.7%. At a median follow up of 30 months (range 6-52 months), 2 years progression free survival and overall survival post-allogeneic SCT is 58 and 92% respectively. Incidence of non-relapse mortality, grade 3-4 acute graft versus host disease and extensive stage chronic graft versus host disease is 8, 17 and 18% respectively. Of five patients who subsequently relapsed post-SCT, four remain alive with disease control post manipulation of immune-suppression.\n\n\nCONCLUSIONS\nOur experience suggests that brentuximab use pre-allogeneic SCT is not associated with any significant post-transplant toxicity, and is associated with a rapid response in a majority of patients with relapsed/refractory CD30 positive lymphomas. Brentuximab may thus provide a non-toxic bridge to allogeneic SCT for patients with relapsed/refractory CD30 positive cHL or ALCL.",
"affiliations": "Cancer Care Services, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.;Cancer Care Services, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.;Cancer Care Services, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.;Cancer Care Services, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.;Cancer Care Services, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.",
"authors": "Mediwake|Heshani|H|http://orcid.org/0000-0002-4521-7970;Morris|Kirk|K|;Curley|Cameron|C|;Butler|Jason|J|;Kennedy|Glen|G|",
"chemical_list": "D018796:Immunoconjugates; D000079963:Brentuximab Vedotin",
"country": "Australia",
"delete": false,
"doi": "10.1111/imj.13415",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1444-0903",
"issue": "47(5)",
"journal": "Internal medicine journal",
"keywords": "Hodgkin lymphoma; allogeneic stem cell transplantation; anaplastic large cell lymphoma",
"medline_ta": "Intern Med J",
"mesh_terms": "D000328:Adult; D000079963:Brentuximab Vedotin; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006689:Hodgkin Disease; D006801:Humans; D018796:Immunoconjugates; D017728:Lymphoma, Large-Cell, Anaplastic; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D016879:Salvage Therapy; D014184:Transplantation, Homologous; D055815:Young Adult",
"nlm_unique_id": "101092952",
"other_id": null,
"pages": "574-578",
"pmc": null,
"pmid": "28247950",
"pubdate": "2017-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Use of brentuximab vedotin as salvage therapy pre-allogeneic stem cell transplantation in relapsed/refractory CD30 positive lympho-proliferative disorders: a single centre experience.",
"title_normalized": "use of brentuximab vedotin as salvage therapy pre allogeneic stem cell transplantation in relapsed refractory cd30 positive lympho proliferative disorders a single centre experience"
} | [
{
"companynumb": "AU-SEATTLE GENETICS-2017SGN00438",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BRENTUXIMAB VEDOTIN"
},
"drugadditiona... |
{
"abstract": "Intensive monitoring of medical patients for adverse drug reactions (ADRs) to assess prevalence, incidence, risk factors and fatality of ADRs leading to hospital admission or occurring in the hospital.\n\n\n\nProspective cohort study on 1280 adult patients admitted to the medical wards of a tertiary institution over 12 months. Patients were assessed for ADRs during and throughout admission; causality and preventability of ADRs were assessed.\n\n\n\nSixty-seven (5.2%) patients had ADRs, 51 (3.9%) caused hospitalisation while 17(1.3%) occurred during hospitalisation, and 42 (62.7%) of total ADRs were preventable. Nonsteroidal anti-inflammatory drugs, 14 (20.3%), antidiabetics, 12 (17.4%) and antibacterial, 11 (15.8%) were the most implicated drug classes. Gastrointestinal tract (37%), central nervous system (30.2%), and skin (24.7%) were the most affected organ/systems, while upper gastrointestinal bleeding and hypoglycaemia were the most observed ADRs. ADRs led to deaths in 7 (10.4%) patients, with an overall case fatality rate of 0.5%. The highest number of deaths were among patients with Stevens-Johnson syndrome 2/7 (28.6%) and hepatotoxicity 2/7 (28.6%). Risk factors, adjusted odds ratio (AOR [95% confidence interval, CI]) for ADRs leading to hospitalisation was male sex 3.11 (1.11, 8.73) while for ADRs during hospitalisation were number of drugs used before admission (AOR [95% CI] = 6.67 [1.16, 38.47]) and comorbidities (AOR [95% CI] = 3.0 [1.13, 8.01]). Patients admitted with ADRs had prolonged hospital stay (AOR [95% CI] = 3.37 [1.11, 8.71]).\n\n\n\nPreventable ADRs are common and important causes of hospitalisation and inpatients' morbidity and mortality among medical patients in Nigeria. Upper gastrointestinal bleeding and hypoglycaemia, resulting from nonsteroidal anti-inflammatory drugs and antidiabetic drugs were the most observed ADRs.",
"affiliations": "Department of Pharmacology and Therapeutics, University of Ibadan, Ibadan, Oyo State, Nigeria.;Department of Pharmacology and Therapeutics, University of Ibadan, Ibadan, Oyo State, Nigeria.;Department of Family Medicine, University College Hospital, Ibadan, Ibadan, Nigeria.;Department of Chemical Pathology, College of Medicine, University College Hospital, Ibadan, Ibadan, Nigeria.",
"authors": "Adedapo|Aduragbenro D A|ADA|0000-0003-3858-6134;Adedeji|Waheed A|WA|0000-0003-2211-5442;Adedapo|Ifetoluwanimi A|IA|0000-0001-9071-9067;Adedapo|Kayode S|KS|0000-0002-0251-5636",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/bcp.14577",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0306-5251",
"issue": "87(4)",
"journal": "British journal of clinical pharmacology",
"keywords": "adverse drug reactions; preventability; prospective cohort study; risk factors",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D000328:Adult; D015331:Cohort Studies; D064420:Drug-Related Side Effects and Adverse Reactions; D006760:Hospitalization; D006801:Humans; D015994:Incidence; D008297:Male; D009549:Nigeria; D015995:Prevalence; D011446:Prospective Studies; D012307:Risk Factors; D062606:Tertiary Care Centers",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "1878-1889",
"pmc": null,
"pmid": "32991765",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cohort study on adverse drug reactions in adults admitted to the medical wards of a tertiary hospital in Nigeria: Prevalence, incidence, risk factors and fatality.",
"title_normalized": "cohort study on adverse drug reactions in adults admitted to the medical wards of a tertiary hospital in nigeria prevalence incidence risk factors and fatality"
} | [
{
"companynumb": "NG-GLAXOSMITHKLINE-NG2020GSK209354",
"fulfillexpeditecriteria": "1",
"occurcountry": "NG",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DICLOFENAC"
},
"drugadditional": "3"... |
{
"abstract": "Dexamethasone prolongs the duration of interscalene block, but the benefits of higher doses and perineural vs intravenous administration remain unclear.\n\n\n\nThis factorial design, double-blinded trial randomized 280 adult patients undergoing ambulatory arthroscopic shoulder surgery at a single centre in a 1:1:1:1 ratio. Patients received ultrasound-guided interscalene block with 30 mL 0.5% bupivacaine and 4 mg or 8 mg dexamethasone by either the perineural or intravenous route. The primary outcome (block duration measured as the time of first pain at the surgical site) and secondary outcomes (adverse effects, postoperative neurologic symptoms) were assessed by telephone. In this superiority trial, the predetermined minimum clinically important difference for comparisons between doses and routes was 3.0 hr.\n\n\n\nThe perineural route significantly prolonged the mean block duration by 2.0 hr (95% confidence interval [CI], 0.4 to 3.5 hr; P = 0.01), but 8 mg of dexamethasone did not significantly prolong the mean block duration compared with 4 mg (1.3 hr; 95% CI, -0.3 to 2.9 hr, P = 0.10), and there was no significant statistical interaction (P = 0.51). The mean (95% CI) block durations, in hours, were 24.0 (22.9 to 25.1), 24.8 (23.2 to 26.3), 25.4 (23.8 to 27.0), and 27.2 (25.2 to 29.3) for intravenous doses of 4 and 8 mg and perineural doses of 4 and 8 mg, respectively. There were no marked differences in side effects between groups. At 14 postoperative days, 57 (20.4%) patients reported neurologic symptoms, including dyspnea and hoarseness. At six months postoperatively, only six (2.1%) patients had residual symptoms, with four (1.4%) patients' symptoms unlikely related to interscalene block.\n\n\n\nCompared with the intravenous route, perineural dexamethasone prolongs the mean interscalene block duration by a small amount that may or may not be clinically significant, regardless of dose. However, the difference in mean block durations between 8 mg and 4 mg of dexamethasone is highly unlikely to be clinically important, regardless of the administration route.\n\n\n\nwww.clinicaltrials.gov (NCT02426736). Registered 14 April 2015.",
"affiliations": "Department of Anesthesia and Perioperative Medicine, University of Manitoba, Winnipeg, MB, R3E 0Z2, Canada.;Department of Anesthesia and Perioperative Medicine, University of Manitoba, Winnipeg, MB, R3E 0Z2, Canada.;Department of Anesthesia and Perioperative Medicine, University of Manitoba, Winnipeg, MB, R3E 0Z2, Canada.;Department of Anesthesia and Perioperative Medicine, University of Manitoba, Winnipeg, MB, R3E 0Z2, Canada.;Department of Anesthesia and Perioperative Medicine, University of Manitoba, Winnipeg, MB, R3E 0Z2, Canada.;Department of Anesthesia and Perioperative Medicine, University of Manitoba, Winnipeg, MB, R3E 0Z2, Canada.;Department of Anesthesia and Perioperative Medicine, University of Manitoba, Winnipeg, MB, R3E 0Z2, Canada.;Department of Orthopedic Surgery, University of Manitoba, Winnipeg, MB, Canada.;Department of Orthopedic Surgery, University of Manitoba, Winnipeg, MB, Canada.;Department of Orthopedic Surgery, University of Manitoba, Winnipeg, MB, Canada.;Department of Orthopedic Surgery, University of Manitoba, Winnipeg, MB, Canada.;Faculty of Health Sciences, George and Fay Yee Centre for Healthcare Innovation, University of Manitoba, Winnipeg, MB, Canada.;Department of Anesthesia and Perioperative Medicine, University of Manitoba, 2nd Floor, Harry Medovy House, 671 William Ave, Winnipeg, MB, R3E 0Z2, Canada. tmutter@exchange.hsc.mb.ca.",
"authors": "Holland|Darren|D|;Amadeo|Ryan J J|RJJ|;Wolfe|Scott|S|;Girling|Linda|L|;Funk|Faylene|F|;Collister|Mark|M|;Czaplinski|Emily|E|;Ferguson|Celeste|C|;Leiter|Jeff|J|;Old|Jason|J|;MacDonald|Peter|P|;Dufault|Brenden|B|;Mutter|Thomas C|TC|0000-0003-1614-7237",
"chemical_list": "D000779:Anesthetics, Local; D005938:Glucocorticoids; D003907:Dexamethasone; D002045:Bupivacaine",
"country": "United States",
"delete": false,
"doi": "10.1007/s12630-017-0989-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0832-610X",
"issue": "65(1)",
"journal": "Canadian journal of anaesthesia = Journal canadien d'anesthesie",
"keywords": null,
"medline_ta": "Can J Anaesth",
"mesh_terms": "D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000556:Ambulatory Surgical Procedures; D000779:Anesthetics, Local; D001182:Arthroscopy; D065527:Brachial Plexus Block; D002045:Bupivacaine; D003907:Dexamethasone; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D008297:Male; D008875:Middle Aged; D010149:Pain, Postoperative; D012785:Shoulder Joint; D013997:Time Factors; D018084:Ultrasonography, Interventional",
"nlm_unique_id": "8701709",
"other_id": null,
"pages": "34-45",
"pmc": null,
"pmid": "29127558",
"pubdate": "2018-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Effect of dexamethasone dose and route on the duration of interscalene brachial plexus block for outpatient arthroscopic shoulder surgery: a randomized controlled trial.",
"title_normalized": "effect of dexamethasone dose and route on the duration of interscalene brachial plexus block for outpatient arthroscopic shoulder surgery a randomized controlled trial"
} | [
{
"companynumb": "CA-PFIZER INC-2018000675",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUPIVACAINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "We report the case of a 75-year-old woman who died of liver failure following coronary artery bypass grafting. The possibility of an association with leflunomide is discussed.",
"affiliations": "Papworth Hospital, Papworth Everard, Cambridge, England. sarahthomasset@hotmail.com",
"authors": "Thomasset|Sarah C|SC|;Ong|Seok L|SL|;Large|Stephen R|SR|",
"chemical_list": "D007555:Isoxazoles; D000077339:Leflunomide",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.athoracsur.2003.08.022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4975",
"issue": "79(2)",
"journal": "The Annals of thoracic surgery",
"keywords": null,
"medline_ta": "Ann Thorac Surg",
"mesh_terms": "D000368:Aged; D001172:Arthritis, Rheumatoid; D001026:Coronary Artery Bypass; D017809:Fatal Outcome; D005260:Female; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D007555:Isoxazoles; D000077339:Leflunomide; D017093:Liver Failure",
"nlm_unique_id": "15030100R",
"other_id": null,
"pages": "698-9",
"pmc": null,
"pmid": "15680868",
"pubdate": "2005-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Post-coronary artery bypass graft liver failure: a possible association with leflunomide.",
"title_normalized": "post coronary artery bypass graft liver failure a possible association with leflunomide"
} | [
{
"companynumb": "GB-TAKEDA-THQ2010A03381",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
... |
{
"abstract": "Acquired thrombotic thrombocytopenic purpura (aTTP) is a thrombotic microangiopathy with a severe mortality and morbidity. Caplacizumab has recently been approved in the Netherlands as a new therapeutic option in patients with life-threatening organ failure due to aTTP. We describe the case of a 50 year old patient with aTTP who was referred to our hospital for treatment with caplacizumab. After undergoing treatment with plasmapheresis, prednisolone, rituximab and caplacizumab, her platelet count recovered and she was ready to be discharged. Unfortunately, before discharge she developed a fatal intra-cerebral hemorrhage. Fatal hemorrhage as an adverse event of caplacizumab has not been described before. Up to now there is no evidence-based treatment for caplacizumab induced heavy bleeding.",
"affiliations": "Department of Internal Medicine, Meander Medical Centre, Amersfoort, The Netherlands.;Department of Internal Medicine, Meander Medical Centre, Amersfoort, The Netherlands.;Department of Internal Medicine, Meander Medical Centre, Amersfoort, The Netherlands.",
"authors": "Ditzel|Kim|K|https://orcid.org/0000-0001-8303-3964;Mons|Dirk Jan|DJ|;Fijnheer|Rob|R|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/09537104.2021.1922883",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0953-7104",
"issue": null,
"journal": "Platelets",
"keywords": "Adverse drug event; bleeding; caplacizumab; cerebral hemorrhage; thrombotic thrombocytopenic purpura",
"medline_ta": "Platelets",
"mesh_terms": null,
"nlm_unique_id": "9208117",
"other_id": null,
"pages": "1-2",
"pmc": null,
"pmid": "33979560",
"pubdate": "2021-05-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Fatal cerebral hemorrhage in a patient with thrombotic thrombocytopenic purpura with a normal platelet count during treatment with caplacizumab.",
"title_normalized": "fatal cerebral hemorrhage in a patient with thrombotic thrombocytopenic purpura with a normal platelet count during treatment with caplacizumab"
} | [
{
"companynumb": "NL-NOVARTISPH-NVSC2022NL093958",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "4",
... |
{
"abstract": "BACKGROUND\nThe aggressive biological behavior and the lack of target therapy prompts the search for new therapeutic approaches for triple-negative breast cancers.\n\n\nMETHODS\nWe evaluated the efficacy in terms of Ki-67 variation and clinical response but also the toxicity of a neoadjuvant regimen based on metronomic principles including ECF (epidoxorubicin with cisplatin on day 1 with low-dose 5-fluorouracil in continuous infusion every 21 days for 4 courses) followed by paclitaxel (90 mg/m(2)) on day 1, 8, and 15 every 28 days for 3 courses in combination with metronomic oral cyclophosphamide 50 mg/d for 12 weeks in patients with HER2-negative breast cancer (T2-T4a-d, N0-3, M0) with estrogen receptor and progesterone receptor < 10%.\n\n\nRESULTS\nWe enrolled 34 patients from June 2009 to May 2013. All were considered evaluable on an intention-to treat basis. The mean difference between the percentage of Ki-67 positive cells evaluated in surgical resection specimens and in pretreatment tumor core biopsy was 41% (95% confidence interval [CI], 30-51; P < .0001) for the entire population, and 22% (95% CI, 7-38; P = .0097) in patients who did not achieve pathological complete response (pCR). Responses to the treatment were obtained in 31 patients [91%] of the patients, and 19 patients (56%; 95% CI, 35-70) had a pCR. Stable disease was observed in 3 patients and none had progressive disease. Grade ≥ 3 hematologic adverse events included leukopenia in 9% (3 of 34), neutropenia in 38% (13 of 34), and anemia in 3% (1 of 34) of patients. Nonhematologic Grade ≥ 3 toxicities included only stomatitis in 1 patient.\n\n\nCONCLUSIONS\nA neoadjuvant program with an ECF regimen followed by weekly paclitaxel with metronomic cyclophosphamide proved to be very effective, with high pCR rates, reduction of Ki-67, and it was associated with a low toxicity profile.",
"affiliations": "Division of Medical Senology, European Institute of Oncology, Milan, Italy. Electronic address: giuseppe.cancello@ieo.it.;Division of Epidemiology and Biostatistics, European Institute of Oncology, and Department of Statistics and Quantitative Methods, University of Milan-Bicocca, Milan, Italy.;Division of Medical Senology, European Institute of Oncology, Milan, Italy.;Division of Medical Senology, European Institute of Oncology, Milan, Italy.;Division of Medical Senology, European Institute of Oncology, Milan, Italy.;Division of Medical Senology, European Institute of Oncology, Milan, Italy.;Division of Medical Senology, European Institute of Oncology, Milan, Italy.;Department of Pathology, European Institute of Oncology, Milan, Italy; University of Milan School of Medicine, Milan, Italy.;Department of Pathology, European Institute of Oncology, Milan, Italy.;University of Milan School of Medicine, Milan, Italy; Division of Senology, European Institute of Oncology, Milan, Italy.;Division of Senology, European Institute of Oncology, Milan, Italy.;Division of Senology, European Institute of Oncology, Milan, Italy.;Program of Senology (Breast Health), European Institute of Oncology, Milan, Italy.;Division of Medical Senology, European Institute of Oncology, Milan, Italy.",
"authors": "Cancello|Giuseppe|G|;Bagnardi|Vincenzo|V|;Sangalli|Claudia|C|;Montagna|Emilia|E|;Dellapasqua|Silvia|S|;Sporchia|Andrea|A|;Iorfida|Monica|M|;Viale|Giuseppe|G|;Barberis|Massimo|M|;Veronesi|Paolo|P|;Luini|Alberto|A|;Intra|Mattia|M|;Goldhirsch|Aron|A|;Colleoni|Marco|M|",
"chemical_list": "D015251:Epirubicin; D003520:Cyclophosphamide; D017239:Paclitaxel; D002945:Cisplatin; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1526-8209",
"issue": "15(4)",
"journal": "Clinical breast cancer",
"keywords": "Chemotherapy; Ki-67; Metronomic therapy; Neoadjuvant; Pathological complete response",
"medline_ta": "Clin Breast Cancer",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin; D003520:Cyclophosphamide; D015251:Epirubicin; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D017239:Paclitaxel; D064726:Triple Negative Breast Neoplasms",
"nlm_unique_id": "100898731",
"other_id": null,
"pages": "259-65",
"pmc": null,
"pmid": "25933934",
"pubdate": "2015-08",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": null,
"title": "Phase II Study With Epirubicin, Cisplatin, and Infusional Fluorouracil Followed by Weekly Paclitaxel With Metronomic Cyclophosphamide as a Preoperative Treatment of Triple-Negative Breast Cancer.",
"title_normalized": "phase ii study with epirubicin cisplatin and infusional fluorouracil followed by weekly paclitaxel with metronomic cyclophosphamide as a preoperative treatment of triple negative breast cancer"
} | [
{
"companynumb": "IT-CIPLA LTD.-2015IT06538",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EPIRUBICIN"
},
"drugadditional": null,
... |
{
"abstract": "Trimethoprim-sulfamethoxazole, otherwise known as Bactrim or Septra, is a commonly prescribed antibiotic for soft tissue infections. Drug-induced thrombocytopenia is a rare but serious adverse reaction to sulfonamide antibiotics like Bactrim/Septra. A 34-year-old active duty marine male with no significant past medical history presented with a chief complaint of a rash on his lower extremities. The patient stated that 2 weeks earlier, he was prescribed Bactrim for cellulitis at the site of a new tattoo. The intern noted a petechial rash that was pathognomonic for thrombocytopenia. Laboratory testing confirmed the patient's thrombocytopenia with platelets of 2,000/μL on initial complete blood count, without pancytopenia or other coagulopathies. The blood smear indicated a profound lack of platelets but otherwise normal cell counts and morphology. In the emergency department, the patient was typed and crossed, platelets were ordered, and hematology-oncology was consulted. Once admitted to the internal medicine ward, he was administered glucocorticoids as well as platelet transfusions. He was monitored for 3 days and discharged with a diagnosis of resolved drug-induced thrombocytopenia. This case illustrates the importance of conducting a thorough review of systems and physical examination in stable and otherwise healthy patients. In this case, the seemingly benign rash was one of the only clinical signs of severe thrombocytopenia, with a high risk of spontaneous bleeding in clinically significant organ systems. It is important to recognize immune thrombocytopenic purpura as a potential complication of Bactrim/Septra, as this antibiotic is widely used by military providers in operational settings.",
"affiliations": "Department of Emergency Medicine, Naval Medical Center San Diego, San Diego, CA 92134, USA.;Department of Emergency Medicine, Naval Medical Center San Diego, San Diego, CA 92134, USA.;Department of Internal Medicine, Naval Medical Center San Diego, San Diego, CA 92134, USA.",
"authors": "Jahncke|Alexander|A|;Kay|Victoria|V|;Fiore|Benjamin|B|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/milmed/usab068",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0026-4075",
"issue": null,
"journal": "Military medicine",
"keywords": null,
"medline_ta": "Mil Med",
"mesh_terms": null,
"nlm_unique_id": "2984771R",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33608729",
"pubdate": "2021-02-20",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Tattoo Trouble: A Case of Drug-induced Thrombocytopenic Purpura.",
"title_normalized": "tattoo trouble a case of drug induced thrombocytopenic purpura"
} | [
{
"companynumb": "US-BAYER-2021-117199",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "A boy, aged 6 years and 11 months, was admitted due to nephrotic syndrome for 2 years, cough for 1 month, and shortness of breath for 15 days. The boy had a history of treatment with hormone and immunosuppressant. Chest CT after the onset of cough and shortness of breath showed diffuse ground-glass opacities in both lungs. Serum (1, 3)-beta-D glucan was tested positive, and the nucleic acid of cytomegalovirus was detected in respiratory secretions. After the anti-fungal and anti-viral treatment, the child improved temporarily but worsened again within a short period of time. Pneumocystis jirovecii was identified by Gomori's methenamine silver staining in bronchoalveolar lavage fluid. The child was diagnosed with severe pneumonia (Pneumocystis jirovecii and cytomegalovirus infection), acute respiratory distress syndrome, and nephrotic syndrome. After anti-infective therapy with sulfamethoxazole/trimethoprim and ganciclovir and respiratory support, the child still experienced progressive aggravation of dyspnea and tension pneumothorax, and extracorporeal membrane oxygenation (ECMO) was given on day 13 of invasive ventilation. Anti-infective therapy with sulfamethoxazole/trimethoprim, ganciclovir, and linezolid, anticoagulation therapy, sedation therapy, nutrition, and comprehensive management of the respiratory tract were given during ECMO. The child was successfully weaned from ECMO after 72 days, resulting in a length of hospital stay of 134 days. The child was followed up for 6 months after discharge, and there was a significant improvement on lung CT, without organ dysfunction. It is concluded that Pneumocystis jirovecii pneumonia is a potential lifethreatening infection for children with low immunity, and that ECMO can effectively improve the prognosis of children with severe respiratory distress syndrome.",
"affiliations": "Department of Pediatrics, Xiangya Hospital, Central South University, Changsha 410008, China.;Department of Pediatrics, Xiangya Hospital, Central South University, Changsha 410008, China.",
"authors": "Deng|Xiao-Lu|XL|;Zhao|Chun-Guang|CG|;Ma|Xin-Hua|XH|;Wang|Xia|X|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1008-8830",
"issue": "22(12)",
"journal": "Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics",
"keywords": null,
"medline_ta": "Zhongguo Dang Dai Er Ke Za Zhi",
"mesh_terms": "D002648:Child; D003371:Cough; D003586:Cytomegalovirus Infections; D004417:Dyspnea; D015199:Extracorporeal Membrane Oxygenation; D006801:Humans; D008297:Male; D009404:Nephrotic Syndrome; D011020:Pneumonia, Pneumocystis; D012128:Respiratory Distress Syndrome",
"nlm_unique_id": "100909956",
"other_id": null,
"pages": "1326-1330",
"pmc": null,
"pmid": "33328005",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": "30908288;29635251;16100140;30361119;30244544;24421306;10638515",
"title": "A school-aged boy with nephrotic syndrome with cough for one month and shortness of breath for half a month.",
"title_normalized": "a school aged boy with nephrotic syndrome with cough for one month and shortness of breath for half a month"
} | [
{
"companynumb": "CN-PFIZER INC-2020494666",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "A 47-year-old female patient presented nausea and vomiting for half a year and elevated serum creatinine for 3 days. Proximal renal tubular acidosis (RTA) complicated with anemiawas confirmed after admission. Secondary factors, such as autoimmune disease, drugs, poison, monoclonal gammopathy, were excluded. Renal biopsy revealed acute interstitial nephritis. The patient was administrated with daily prednisone 50 mg, sodium bicarbonate 4 g, 3 times per day, erythropoietin 3 000 U, 2 times per week, combined with potassium, calcium, and calcitriol tablets. Serum creatinine reduced to 90 μmol/L. However nausea and vomiting deteriorated with lactic acidosis. Bone marrow biopsy indicated the diagnosis of non-Hodgkin lymphoma, therefore the patient was treated with chemotherapy. Although metabolic acidosis improved gradually after chemotherapy, severe pneumocystis carinii pneumonia developed two weeks later. The patient refused further treatment and was discharged.",
"affiliations": "Department of Nephrology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.;Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.;Department of Nephrology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.",
"authors": "Chen|G|G|;Wu|D|D|;Li|M X|MX|",
"chemical_list": "D000970:Antineoplastic Agents; D004921:Erythropoietin; D017693:Sodium Bicarbonate; D003404:Creatinine; D011241:Prednisone",
"country": "China",
"delete": false,
"doi": "10.3760/cma.j.issn.0578-1426.2020.02.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0578-1426",
"issue": "59(2)",
"journal": "Zhonghua nei ke za zhi",
"keywords": "Acidosis, Lactic; Acidosis, renal tubular; Fanconi syndrome; Kidney failure; Lymphoma",
"medline_ta": "Zhonghua Nei Ke Za Zhi",
"mesh_terms": "D000140:Acidosis, Lactic; D000141:Acidosis, Renal Tubular; D000740:Anemia; D000970:Antineoplastic Agents; D001706:Biopsy; D003404:Creatinine; D004921:Erythropoietin; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008875:Middle Aged; D009325:Nausea; D011020:Pneumonia, Pneumocystis; D011241:Prednisone; D051437:Renal Insufficiency; D017693:Sodium Bicarbonate; D016312:Treatment Refusal; D014839:Vomiting",
"nlm_unique_id": "16210490R",
"other_id": null,
"pages": "165-168",
"pmc": null,
"pmid": "32074694",
"pubdate": "2020-02-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The 475th case: renal tubular acidosis, renal failure, anemia, and lactic acidosis.",
"title_normalized": "the 475th case renal tubular acidosis renal failure anemia and lactic acidosis"
} | [
{
"companynumb": "CN-NVP-000007",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CALCIUM"
},
"drugadditional": "3",
"drugadminis... |
{
"abstract": "Apixaban is a direct oral anticoagulant that works by inhibiting factor Xa. It has been associated with adverse bleeding outcomes including atraumatic splenic rupture. We present the case of an 86-year-old man who presented with features of left upper abdominal pain and hemorrhagic shock found to have atraumatic splenic rupture and hemoperitoneum on imaging.",
"affiliations": "Department of Medicine, Reading Hospital and Medical Center, West Reading, PA, USA.;Department of Medicine, Reading Hospital and Medical Center, West Reading, PA, USA.;Department of Medicine, Reading Hospital and Medical Center, West Reading, PA, USA.;Department of Medicine, Reading Hospital and Medical Center, West Reading, PA, USA.;Department of Medicine, Reading Hospital and Medical Center, West Reading, PA, USA.;Department of Medicine, Reading Hospital and Medical Center, West Reading, PA, USA.",
"authors": "Basnet|Sijan|S|https://orcid.org/0000-0002-8324-2827;Mohanty|Elan|E|;Mir|Izza|I|;Dhital|Rashmi|R|;Koirala|Ajay|A|;Tachamo|Niranjan|N|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2050313X19832490",
"fulltext": "\n==== Front\nSAGE Open Med Case RepSAGE Open Med Case RepSCOspscoSAGE Open Medical Case Reports2050-313XSAGE Publications Sage UK: London, England 10.1177/2050313X1983249010.1177_2050313X19832490Case ReportAtraumatic splenic rupture associated with apixaban https://orcid.org/0000-0002-8324-2827Basnet Sijan Mohanty Elan Mir Izza Dhital Rashmi Koirala Ajay Tachamo Niranjan Department of Medicine, Reading Hospital and Medical Center, West Reading, PA, USASijan Basnet, Department of Medicine, Reading Hospital and Medical Center, West Reading, PA 19611, USA. Email: sijan.basnet@towerhealth.org21 2 2019 2019 7 2050313X1983249022 12 2018 30 1 2019 © The Author(s) 20192019SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Apixaban is a direct oral anticoagulant that works by inhibiting factor Xa. It has been associated with adverse bleeding outcomes including atraumatic splenic rupture. We present the case of an 86-year-old man who presented with features of left upper abdominal pain and hemorrhagic shock found to have atraumatic splenic rupture and hemoperitoneum on imaging.\n\nApixabansplenic ruptureatraumaticcover-dateJanuary-December 2019\n==== Body\nIntroduction\nApixaban is a direct oral anticoagulant (DOAC) approved by the US Food and Drug Administration (FDA) for use in non-valvular atrial fibrillation for stroke prevention.1 DOACs are associated with an increased risk of bleeding. Recently, atraumatic splenic rupture has been reported with their increasing use.2–8 We present a case of a spontaneous splenic rupture with hemorrhagic shock requiring emergent splenic artery embolization and splenectomy in the setting of apixaban use.\n\nCase description\nAn 86-year-old gentleman presented to the emergency department (ED) after a fall due to orthostatic syncope. He had complained of left upper quadrant abdominal pain the night prior. According to his wife, he was restless overnight and had gone to the bathroom that morning when she heard him fall. The patient denied trauma prior to the onset of abdominal pain, recent sore throat, fever, chills, night sweats, weight loss, fatigue, reflux, or recent travel. His history was significant for atrial fibrillation, coronary artery disease, hypertension, hyperlipidemia, and type II diabetes mellitus. He did not have a history of bleeding or clotting disorders. His home medications included apixaban 5 mg two times daily, aspirin 81 mg daily, atorvastatin 40 mg daily, carvedilol 12.5 mg two times daily, hydrochlorothiazide 25 mg daily, lisinopril 10 mg daily, and metformin 500 mg two times daily. He was not on any medications with CYP3A4 or P-gp-inhibiting activity. On presentation, his temperature was 36.7°C (98.1°F), blood pressure was 107/67 mm Hg with nadir of 74/46 mm Hg, heart rate was 65/min, and respiratory rate was 16 breaths per minute. Physical examination was significant for diffuse bilateral abdominal tenderness without any guarding or rebound tenderness. He was lethargic and slow to follow commands. The remainder of the physical examination was normal.\n\nSerologic testing revealed his hemoglobin was 11.8 g/dL (reference range: 14.0–17.5 g/dL), down from a baseline of 14 g/dL. Coagulation panel revealed international normalized ratio (INR) of 1.2 (reference range: 0.9–1.1), prothrombin time (PT) of 14.9 s (reference range: 11.7–14.1 s), activated partial thromboplastin time (aPTT) of 28 s (reference range: 23–34 s), and platelets 146,000/µL (reference range: 130,000–400,000/µL). His random blood sugar was 268 mg/dL (reference range: 70–99 mg/dL). Computed tomography (CT) of the abdomen/pelvis with contrast showed active extravasation from the spleen with a large subcapsular hematoma and hemoperitoneum (Figure 1). CT head with cervical spine was negative for acute intracranial mass or hemorrhage, fracture, or focal bony lesions. He was given 2.5 L of normal saline to maintain his systolic blood pressure over 100 mg Hg. He received a unit of prothrombin complex concentrate (PCC), 2 units of packed red blood cells (PRBCs), and 2 units of fresh frozen plasma (FFP) in the ED to reverse his coagulopathy. The patient was taken for emergent splenic arteriography and embolization. Embolization was initially pursued to avoid the need for an exploratory laparotomy as his blood pressures stabilized with initial volume resuscitation. Images after contrast injection demonstrated a small area of extravasation from the inferior tip of the spleen in the area of the abnormality seen on CT scan. The proximal third of the splenic artery was successfully embolized with a 10-mm Amplatzer 2 plug device. Post procedure, the patient’s blood pressure improved to 154/47 mm Hg. He was then admitted to the surgical intensive care unit for close monitoring. Over the course of hours, the patient again deteriorated and was hypotensive with systolic blood pressure in the 80s. He was short of breath. Bedside focused assessment with sonography for trauma (FAST) scan showed a flat inferior vena cava and a large hemoperitoneum. With concern for ongoing bleed, the patient was transfused 2 units of PRBCs and was taken to the operating room for exploratory laparotomy and splenectomy for a ruptured subcapsular splenic hematoma. Around 1500 mL of bloody fluid was removed from the peritoneum. No retroperitoneal hematoma was noted. Splenic pathology revealed capsular disruption with associated subcapsular and intra-parenchymal hemorrhage, and numerous macrophages within the splenic parenchyma likely secondary to a reactive phenomenon. His hematoma was thought to be related to apixaban use in the absence of trauma or splenic pathology. Patient’s postoperative hospital stay was unremarkable. His hemoglobin was stable at 11.7 g/dL. He was discharged on day 5 with recommendations to resume apixaban and aspirin.\n\nFigure 1. CT scan of the abdomen/pelvis showing large subcapsular hematoma and active extravasation from the spleen with associated hemoperitoneum.\n\nDiscussion\nSpontaneous splenic rupture is a rare entity but has been noted to occur with infections such as infectious mononucleosis; hematologic neoplasms such as leukemia and lymphoma; non-infectious, inflammatory disorders such as amyloidosis and polyarteritis nodosa; medications; dialysis; and pregnancy.9,10 Orloff and Peskin11 established four criteria for spontaneous rupture of the normal spleen to which a fifth criterion was later added by Crate and Payne.12 In our case, the biopsy was negative for infiltrating atypical lymphocytes or monocytes that would be suggestive of infection, neoplasm, or inflammatory disorders. His renal function was unremarkable. Although he had a fall, this was preceded by left upper quadrant pain. Thus, we believe that his orthostatic syncope was a manifestation of low intravascular volume status from preceding splenic hemorrhage. We were not able to find an etiology for splenic rupture other than apixaban use.\n\nDOACs, apixaban, rivaroxaban, and dabigatran have all been associated with atraumatic splenic rupture in previous literature.2–8 This is the third case related to apixaban.7,8 Apixaban has anticoagulant properties by inhibiting free and bound form of factor Xa.1 Lowry and Goldner7 suggest that apixaban may worsen previously undetected microtrauma that may lead to splenic hemorrhage. Concomitant use of antiplatelets, p-glycoprotein, and CYP3A4-inhibiting medications and poor renal function all increase the risk of bleeding with DOACs.2 Our patient was not on any medications that were associated with p-glycoprotein and CYP3A4-inhibiting activity. Atraumatic splenic rupture was noted early after initiation of a DOAC. Splenic rupture was reported 1 day, 2 days, and 2 months after initiation of dabigatran,6 apixaban,8 and rivaroxaban,4 respectively. Left-sided abdominal pain that may radiate to the shoulder, declining hemoglobin levels, hypotension, and features of hemorrhagic shock all suggest splenic hemorrhage.6,7 Due to its non-specific clinical picture, it can easily be mistaken for peptic ulcer disease or cardiac disease in the absence of trauma. Diagnosis should especially be considered in a patient who is on anticoagulation.7\n\nBesides ultrasound can be urgently performed in these patients for rapid diagnosis,8 it can detect free fluid with 90% sensitivity and 99% specificity13 and can aid in early diagnosis and urgent consultations and guide treatment plans in cases with undifferentiated hypotension.14 CT scan is a recommended imaging modality for diagnosis, staging, and decision on surgical management.8 Initial management includes discontinuation of anticoagulants, volume resuscitation, and, if available, reversal of anticoagulation. Volume resuscitation with intravenous isotonic crystalloids offers the same benefit as colloids.15 PCC, FFP, and recombinant activated factor VII can be used in this setting despite lack of evidence.3 Current guidelines recommend RBC transfusion, platelet, and cryoprecipitate transfusion to maintain target hemoglobin >7 g/dL, platelet count >50,000/µL, and fibrinogen >100 mg/dL, respectively.15 With andexanet alfa being approved by FDA for reversal of anticoagulation in life-threatening or uncontrolled bleeding,16 it will be interesting to know its efficacy in patients with splenic hemorrhage. Surgical options for splenic rupture include conservative transcatheter arterial embolization and open surgical exploration.9 Spontaneous splenic hemorrhage can be managed conservatively with close monitoring if the patient is hemodynamically stable without signs of active hemorrhage or peritonitis.6,7 Embolization can be tried in hemodynamically stable patients with active contrast extravasation noted in CT angiography.17 Emergent laparotomy with splenectomy should be performed in hemodynamically unstable patients.7\n\nConclusion\nAtraumatic splenic hemorrhage is life-threatening, and high index of suspicion for this should be maintained in patients presenting with abdominal pain, features of hypotension, and hemorrhagic shock while on apixaban. We hope this case will bring forward more similar reports in the future.\n\nThis study was accepted for poster presentation at the “Society of Hospital Medicine 2018 Annual Meeting.”\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nEthical approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nInformed consent: Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article.\n\nORCID iD: Sijan Basnet \nhttps://orcid.org/0000-0002-8324-2827\n==== Refs\nReferences\n1 \n202155s000lbl.pdf , https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202155s000lbl.pdf (accessed 5 November 2018 ).\n2 \nHattab YA Speredelozzi D Bajwa O. \nRivaroxaban causing spontaneous splenic rupture C52 . Illustrative disease presentations in critical care I , https://www.atsjournals.org/doi/pdf/10.1164/ajrccm-conference.2015.191.1_MeetingAbstracts.A4632 (accessed 5 November 2018 ).\n3 \nNagaraja V Cranney G Kushwaha V. \nSpontaneous splenic rupture due to rivaroxaban . Drug Ther Bull \n2018 ; 56 (11 ): 136 –139 .30355723 \n4 \nGonzva J Patricelli R Lignac D. \nSpontaneous splenic rupture in a patient treated with rivaroxaban . Am J Emerg Med \n2014 ; 32 (8 ): 950 e3 .\n5 \nAmin A Safaya A Ronny F et al \nHemorrhagic shock from spontaneous splenic rupture requiring open splenectomy in a patient taking rivaroxaban . Am Surg \n2016 ; 82 (2 ): E54–E15.\n6 \nCarey R Nelatur V. \nSpontaneous splenic rupture secondary to dabigatran: the last in a series of unfortunate events . Clin Med \n2018 ; 18 (5 ): 406 –408 .\n7 \nLowry LE Goldner JA. \nSpontaneous splenic rupture associated with apixaban: a case report . J Med Case Rep \n2016 ; 10 (1 ): 217 .27506776 \n8 \nAbdelhady A Ahmed A Mohamed Y et al \nApixaban-associated spontaneous splenic rupture: a case report . Irish Med J , http://imj.ie/july-august-2018-c-r2-apixaban-associated-spontaneous-splenic-rupture/ (accessed 5 November 2018 ).\n9 \nRenzulli P Hostettler A Schoepfer AM et al \nSystematic review of atraumatic splenic rupture . Br J Surg \n2009 ; 96 (10 ): 1114 –1121 .19787754 \n10 \nDebnath D Valerio D. \nAtraumatic rupture of the spleen in adults . J R Coll Surg Edinb \n2002 ; 47 (1 ): 437 –445 .11874265 \n11 \nOrloff MJ Peskin GW. \nSpontaneous rupture of the normal spleen; a surgical enigma . Int Abstr Surg \n1958 ; 106 (1 ): 1 –11 .13495867 \n12 \nCrate ID Payne MJ. \nIs the diagnosis of spontaneous rupture of a normal spleen valid . J R Army Med Corps \n1991 ; 137 (1 ): 50 –51 .2023171 \n13 \nMa OJ Mateer JR Ogata M et al \nProspective analysis of a rapid trauma ultrasound examination performed by emergency physicians . J Trauma \n1995 ; 38 (6 ): 879 –885 .7602628 \n14 \nShokoohi H Boniface KS Pourmand A et al \nBedside ultrasound reduces diagnostic uncertainty and guides resuscitation in patients with undifferentiated hypotension . Crit Care Med \n2015 ; 43 (12 ): 2562 –2569 .26575653 \n15 \nTomaselli GF Mahaffey KW Cuker A et al \n2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American College of Cardiology Task Force on expert consensus decision pathways . J Am Coll Cardiol \n2017 ; 70 (24 ): 3042 –3067 .29203195 \n16 \nResearch C for BE and approved products—ANDEXXA (coagulation factor Xa (recombinant), inactivated-zhzo) , https://www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/approvedproducts/ucm606681.htm (accessed 6 November 2018 ).\n17 \nRaikhlin A Baerlocher MO Asch MR et al \nImaging and transcatheter arterial embolization for traumatic splenic injuries: review of the literature . Can J Surg \n2008 ; 51 (6 ): 464 –472 .19057735\n\n",
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"title": "Atraumatic splenic rupture associated with apixaban.",
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"abstract": "This report presents a rare case of recurrent urinary tract infections in a kidney transplant patient. Analysis revealed a ureteral stump calculus 31 years after bilateral nephrectomy which was disintegrated by means of flexible ureteroscopy and holmium laser. In case of unexplained recurrent urinary tract infections and abdominal pain, urolithiasis in the ureteral stumps should be considered.",
"affiliations": "a Department of Urology, University Medical Center Utrecht , Utrecht, The Netherlands.;a Department of Urology, University Medical Center Utrecht , Utrecht, The Netherlands.;a Department of Urology, University Medical Center Utrecht , Utrecht, The Netherlands.",
"authors": "Ten Donkelaar|Celine S|CS|;Wortel|Ruud C|RC|;Lock|M T W T|MTWT|",
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"title": "Rare case of urinary tract infections and the \"forgotten\" solution.",
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"abstract": "OBJECTIVE\nFluoroquinolones are antimicrobial agents with a broad spectrum of activity against gram-positive, gram-negative, and anaerobic organisms. They are widely used in surgical practice and are generally considered safe. Hypoglycemia because of use of levofloxacin is a rarely reported complication. This report of a case of a surgical patient highlights this potentially fatal complication.\n\n\nMETHODS\nAn elderly, non-diabetic patient with renal impairment presented with a possible duodenal perforation. After successful surgery, the patient developed recurrent hypoglycemic episodes in the post-operative period after use of levofloxacin. Delay in recognition of the cause of hypoglycemia led to irreversible brain damage and death.\n\n\nRESULTS\nThe calculated Naranjo adverse drug reaction probability scale criteria suggest the possibility that these episodes were related to levofloxacin. The mechanism of hypoglycemia with levofloxacin relates to the potential inhibition of the K(ATP) channel on the pancreatic beta cell by the drug.\n\n\nCONCLUSIONS\nThe case report highlights the need to be aware of this potentially fatal complication of a drug commonly used in surgical practice.",
"affiliations": "Department of Anesthesia and Critical Care, Christian Medical College and Hospital, Ludhiana, Punjab, 632004, India.",
"authors": "Singh|Madhurita|M|;Jacob|Jubbin Jagan|JJ|;Kapoor|Rajeev|R|;Abraham|John|J|",
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"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D000900:Anti-Bacterial Agents; D004359:Drug Therapy, Combination; D004381:Duodenal Ulcer; D017809:Fatal Outcome; D006801:Humans; D006946:Hyperinsulinism; D007003:Hypoglycemia; D007262:Infusions, Intravenous; D064704:Levofloxacin; D008297:Male; D015242:Ofloxacin; D010439:Peptic Ulcer Perforation; D010538:Peritonitis; D011182:Postoperative Care; D011183:Postoperative Complications; D012008:Recurrence",
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"title": "Fatal hypoglycemia with levofloxacin use in an elderly patient in the post-operative period.",
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"abstract": "A 55-year-old man treated with polycythemia vera visited our hospital, complaining of left abdominal pain and dyspnea. He had received minocycline infusions three weeks earlier for mycoplasma pneumonia. Contrast-enhanced computed tomography revealed pulmonary embolism and splenic infarction. Ultrasonography of the vein in the forearm revealed a thrombus filling the distal brachial veins to the radial veins on both sides. His condition improved after anticoagulant therapy, and right and left shunts were detected on transesophageal echocardiography. This suggested that thrombus in the forearm may have been the source of the embolism.",
"affiliations": "Department of Cardiology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Japan.;Department of Cardiology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Japan.;Department of Hematology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Japan.;Department of Respiratory, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Japan.;Department of Cardiology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Japan.;Department of Cardiology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Japan.;Department of Cardiology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Japan.;Department of Cardiology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Japan.",
"authors": "Takeuchi|Makoto|M|;Okada|Takenori|T|;Iwato|Kouji|K|;Kawamoto|Kazuma|K|;Ikegami|Yuki|Y|;Nakamoto|Yumiko|Y|;Idei|Naomi|N|;Ohashi|Norihiko|N|",
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"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918 1349-7235 The Japanese Society of Internal Medicine \n\n32921692\n10.2169/internalmedicine.5635-20\nCase Report\nPulmonary Embolism and Splenic Infarction after Minocycline Infusion in a Patient with Polycythemia Vera\nTakeuchi Makoto 1 Okada Takenori 1 Iwato Kouji 2 Kawamoto Kazuma 3 Ikegami Yuki 1 Nakamoto Yumiko 1 Idei Naomi 1 Ohashi Norihiko 1 \n1 Department of Cardiology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Japan\n\n2 Department of Hematology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Japan\n\n3 Department of Respiratory, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Japan\nCorrespondence to Dr. Makoto Takeuchi, mako0920take@outlook.jp\n\n\n12 9 2020 \n15 1 2021 \n60 2 275 279\n17 6 2020 20 7 2020 Copyright © 2021 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 55-year-old man treated with polycythemia vera visited our hospital, complaining of left abdominal pain and dyspnea. He had received minocycline infusions three weeks earlier for mycoplasma pneumonia. Contrast-enhanced computed tomography revealed pulmonary embolism and splenic infarction. Ultrasonography of the vein in the forearm revealed a thrombus filling the distal brachial veins to the radial veins on both sides. His condition improved after anticoagulant therapy, and right and left shunts were detected on transesophageal echocardiography. This suggested that thrombus in the forearm may have been the source of the embolism. \n\npolycythemia veraminocyclinepulmonary embolismparadoxical embolismsplenic infarction\n==== Body\nIntroduction\nIn patients with polycythemia vera (PV), cardiovascular conditions and hematological changes account for 45% and 13% of all deaths, respectively (1). Although PV is known to cause thrombosis, the rapid and long-term intravenous administration of minocycline is also associated with an increased risk of thrombophlebitis (2). While several cases of pulmonary embolism (PE) following superficial vein thrombosis (SVT) in the lower extremities have been reported (3), relatively few cases of PE following SVT in the upper extremities have been described (4, 5).\n\nWe herein report a rare case of PV with PE and paradoxical embolism after infusion of minocycline.\n\nCase Report\nA 55-year-old man with PV (diagnosed with JAK2V617F mutation-positive PV 8 years ago) was admitted to the Department of Hematology. Despite receiving treatment with hydroxyurea and aspirin, his control of PV gradually became poor. Two years ago, the treatment was changed to oral ruxolitinib, following which control was regained, and his spleen started to shrink. Myelofibrosis developed for a year, and the hemoglobin level was subsequently maintained at around 10.0 g/dL.\n\nHowever, on this occasion, he complained of a seven-day history of dyspnea and dry cough, and the symptoms persisted even once he was hospitalized. Mycoplasma pneumonia was strongly suspected based on chest computed tomography (CT), various investigations, and his clinical symptoms. Minocycline was infused for five days to treat the mycoplasma pneumonia. However, each intravenous dose caused vascular pain and was discontinued immediately after initiation. At this time, no pigmentation or induration was observed in either forearm. After the infusion of minocycline for two days, an increase in D-dimer levels was observed, and an ultrasound examination of the leg veins was performed; however, no thrombus was detected. During hospitalization, he developed two episodes of paroxysmal hypoxia but was discharged six days after admission due to improvement in inflammatory reaction and dyspnea.\n\nHe subsequently developed sudden left abdominal pain and dyspnea and visited our hospital again three weeks later. Contrast-enhanced CT revealed submassive PE (Fig. 1A), requiring emergency hospitalization. Splenic infarctions measuring 7.1 cm ×5.0 cm ×5.5 cm and 9.0 cm ×5.3 cm ×8.0 cm were observed in the upper and lower poles of the spleen, respectively (Fig. 1B). However, CT revealed no venous thrombosis in the lower extremities, and the source of the embolism could not be identified. After continuous intravenous administration of unfractionated heparin, we switched to edoxaban 60 mg that gradually improved the dyspnea and abdominal pain.\n\nFigure 1. Contrast-enhanced CT for complaints of left abdominal pain and dyspnea. (A) We diagnosed submassive pulmonary embolism. (B) Large splenic infarctions were observed, measuring 7.1 cm×5.0 cm×5.5 cm and 9.0 cm×5.3 cm×8.0 cm at the upper and lower poles of the spleen, respectively. (C) The right ventricle is pushing into the left ventricle, suggesting expansion of the right ventricle.\n\nAlong with the treatment, we looked for the source of the emboli. Although the presence of PV increases the risk of thrombus, blood tests obtained at the time of the visit did not reveal any congenital abnormalities of coagulation (Table).\n\nTable. Laboratory Data.\n\nComplete Blood Count\tCoagulation\t\nWBC\t7.0×103\t/µL\tPT-INR\t1.21\t\t\nRBC\t3.91×106\t/µL\tAPTT\t34.8\tsec\t\nHb\t11.9\tg/dL\tFibrinogen\t522\tmg/dL\t\nPLT\t209×103\t/µL\tFDP\t4.2\tµg/mL\t\nBiochemistry\tD-dimer\t4.2\tµg/mL\t\nAST\t76\tIU/L\tLAC DRVVT\t1.28\t\t\nALT\t94\tIU/L\tProtein C activity\t130\t\t\nLDH\t587\tIU/L\tProtein S antigen level\t132\t\t\nALP\t678\tIU/L\tLipoprotein(a)\t6.0\t\t\nCRP\t6.63\tmg/dL\tCardiolipin antibody IgG\t<8\t\t\n\t\t\tHomocysteine\t20.8\tnmol/mL\t\nBlood tests performed when the patient complained of left abdominal pain and dyspnea. D-dimer elevation was observed, but the tests did not reveal any further congenital abnormalities of coagulation. The hemoglobin level was maintained at around 10.0 g/dL while on ruxolitinib. The increased inflammatory response was thought to be due to splenic infarction.\n\nOn an examination, we found pigmentation along the blood vessels in the center of the left forearm (Fig. 2). The vein showed no dilation or swelling, but painless induration was noted. Both upper limbs showed mild swelling, but the swelling was not enough to depict fullness.\n\nFigure 2. Pigmentation along the blood vessels. (A) Right forearm. (B) Left forearm. We found pigmentation in the center of the left forearm.\n\nUltrasonography of the veins in the forearm revealed thrombi bilaterally, extending from the radial veins up to the distal brachial veins on both the sides (Fig. 3). The extent of the thrombi prior to the occurrence of the embolism is unknown, but at the time of the examination, no thrombus was found in the proximal portion of the brachial veins. Ultrasonography of the veins of the lower extremities and abdominal blood vessels also showed an absence of thrombi. He was never aware of any lower leg pain or any burning sensation during this period. After eight days of anticoagulant therapy, transesophageal echocardiography revealed right and left shunts in the patent foramen ovale (PFO). The bubble test was positive, showing moderate bubbles in the left heart system (Fig. 4). These results suggested that the intravenous administration of minocycline might have caused thrombosis in the upper extremities, which might have led to PE and splenic infarction through the PFO.\n\nFigure 3. Ultrasonography of the vein in the left forearm. We found a thrombus extending from the radial vein up to the distal brachial vein. On pressing with an echo probe, the blood vessels did not collapse. Similar findings were also found on the right forearm.\n\nFigure 4. (A) After 8 days of anticoagulant therapy, transesophageal echocardiography revealed right and left shunts in the patent foramen ovale. (B) The bubble test was positive, showing moderate bubbles in the left heart system.\n\nAs a result of the anticoagulant therapy for PE, transthoracic echocardiography showed an improvement in the right heart load findings and improved oxygenation. Lung perfusion scintigraphy taken after 15 days of anticoagulant therapy showed an improvement in the PE (Fig. 5). Pain and inflammation due to splenic infarction gradually improved with symptomatic treatment, and further definitive treatment, such as splenectomy, was not required. He was discharged home after 16 days of anticoagulant therapy.\n\nFigure 5. Lung perfusion scintigraphy conducted before anticoagulant therapy (A) and after 15 days of anticoagulant therapy (B). The left upper lung field improved, and the right lung tended to be slightly better overall.\n\nDiscussion\nPV is a clonal disease of hematopoietic stem cells, and the JAK2V617F gene mutation has recently been found to be a major mutation of this disease (6). According to a large-scale cohort study (1) of PV patients, thrombosis in PV is more commonly in arteries than in veins. Indeed, arteries accounted for 28.7% of the thromboses, resulting in the incidence of cerebral ischemic attacks (10.3%), cerebral embolism (8.9%), acute myocardial infarction (8.9%), and peripheral vascular thrombosis (5.5%). In contrast, veins accounted for 13.7% of the thromboses, resulting in the incidence of deep vein thrombosis (8.2%), superficial vein thrombosis (6.1%), and pulmonary embolism (2.4%). In addition, cases of thrombophlebitis caused by the injection of minocycline have also been reported (2). In the present case as well, 100 mg of minocycline was administered every 12 hours for ≥60 minutes, in keeping with the recommended dosage and rate of infusion. Although the standard minocycline administration technique was adhered to, PV itself may cause thrombosis, as described above, which may have caused this rare incident.\n\nRegarding the relationship between SVT of the upper limbs and PE, although several cases of PE following SVT in the lower extremities have been reported (3), relatively few cases of PE following SVT in the upper extremities have been reported (4, 5). In 1990, Sassu et al. (4) reported a patient with recurrent superficial thrombophlebitis of the left arm who developed right-sided (but not massive) PE. Although Barros et al. (5) described a case of post-traumatic superficial thrombophlebitis of the basilic vein complicated with PE, in that case as well, the PE was not massive but was limited to the basal posterior and lateral segments of the right inferior lobe of the lung. These reports suggested that the intravenous administration of minocycline might have caused thrombosis in the upper extremities, which might have led to PE. In the case of thrombophlebitis due to minocycline, the onset of PE was considered to be around the third day after the onset of pneumonia, when symptoms first occurred, along with the appearance of right heart overload on the 12-lead electrocardiogram and elevated D-dimer levels. When the paradoxical embolism occurred, about 20 days had passed since the onset of PE. We consider that there was more right heart load when paradoxical embolism occurred than when we performed transesophageal echocardiography (Fig. 1C). Right atrial pressure increased due to the right heart load, and there might have been more right and left shunts.\n\nWe also considered PFO catheter closure. Three meta-analyses investigated the efficacy of catheter-based closure for the treatment of a latent cerebral infarction with PFO (7-9). In addition, a study reported that 0.2% of patients who underwent closure of PFO developed device thrombosis (10). This patient was already at risk of device thrombosis because he had PV, which is characterized by spontaneous thrombosis. We suspected that treatment with edoxaban would be able to prevent the recurrence of venous thromboembolism. He was not treated with any intervention apart from edoxaban; however, he recovered without any deterioration.\n\nConclusion\nWe herein report a case in which the infusion of minocycline formed a thrombus in the forearm, which was thought to have resulted in embolism. We must bear in mind that drug-induced thrombophlebitis can lead to embolism. In addition, devising a better method of administering minocycline infusion may prevent thrombosis.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nMarchioli R , Finazzi G , Landolfi R , et al \nVascular and neoplastic risk in a large cohort of patients with polycythemia vera\n. J Clin Oncol \n23 : 2224 -2232\n, 2005 .15710945 \n2. \nGreig SL , Scott LJ \nIntravenous minocycline: a review in acinetobacter infections\n. Drugs \n76 : 1467 -1476\n, 2016 .27573640 \n3. \nKesteven P , Robinson B \nSuperficial thrombophlebitis followed by pulmonary embolism\n. J R Soc Med \n94 : 186 -187\n, 2001 .11317624 \n4. \nSassu GP , Chisholm CD , Howell JM , Huang E \nA rare etiology for pulmonary embolism: basilic vein thrombosis\n. J Emerg Med \n8 : 45 -49\n, 1990 .2351798 \n5. \nBarros FS , Sandri JL , Prezotti BB , et al \nPulmonary embolism in a rare association to a floating thrombus detected by ultrasound in the basilic vein at the distal arm\n. Rev bras Ecocardiogr Imagem Cardiovasc \n24 : 89 -92\n, 2011 .\n6. \nJames C , Ugo V , Le Couédic JP , et al \nA unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera\n. Nature \n434 : 1144 -1148\n, 2005 .15793561 \n7. \nSaver JL , Carroll JD , Thaler DE , et al \nLong-term outcomes of patent foramen ovale closure or medical therapy after stroke\n. N Engl J Med \n377 : 1022 -1032\n, 2017 .28902590 \n8. \nSøndergaard L , Kasner SE , Rhodes JF , et al \nPatent foramen ovale closure or antiplatelet therapy for cryptogenic stroke\n. N Engl J Med \n377 : 1033 -1042\n, 2017 .28902580 \n9. \nMas JL , Derumeaux G , Guillon B , et al \nPatent foramen ovale closure or anticoagulation vs. antiplatelets after stroke\n. N Engl J Med \n377 : 1011 -1021\n, 2017 .28902593 \n10. \nRigatelli G , Zuin M , Dell'Avvocata F , Roncon L , Vassilev D , Nghia N \nLight anti-thrombotic regimen for prevention of device thrombosis and/or thrombotic complications after interatrial shunts device-based closure\n. Eur J Intern Med \n74 : 42 -48\n, 2020 .31902564\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "60(2)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "minocycline; paradoxical embolism; polycythemia vera; pulmonary embolism; splenic infarction",
"medline_ta": "Intern Med",
"mesh_terms": "D006801:Humans; D008297:Male; D008875:Middle Aged; D008911:Minocycline; D011087:Polycythemia Vera; D011655:Pulmonary Embolism; D013159:Splenic Infarction; D013927:Thrombosis",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "275-279",
"pmc": null,
"pmid": "32921692",
"pubdate": "2021-01-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15793561;28902580;28902593;15710945;2351798;28902590;27573640;11317624;31902564",
"title": "Pulmonary Embolism and Splenic Infarction after Minocycline Infusion in a Patient with Polycythemia Vera.",
"title_normalized": "pulmonary embolism and splenic infarction after minocycline infusion in a patient with polycythemia vera"
} | [
{
"companynumb": "JP-TEVA-2021-JP-1912168",
"fulfillexpeditecriteria": "1",
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"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MINOCYCLINE HYDROCHLORIDE"
},
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"abstract": "We identified all patients with chronic lymphocytic leukemia at Mayo Clinic treated with ibrutinib outside the context of a clinical trial; timing and reasons for discontinuation were ascertained, as were symptoms, exam and radiographic findings, and laboratory changes following discontinuation. Of 202 patients who received ibrutinib, 52 discontinued therapy (estimated 1- and 2-year risk of discontinuation 18% and 28%, respectively). The most common reasons for discontinuation were toxicity (56%) and progression of disease (32%, including Richter's transformation in 15%). Rapid progression of disease within 4 weeks after discontinuation was observed in 9/36 (25%) patients with adequate records for review, mostly in those stopping ibrutinib for disease progression (n = 8) rather than toxicity (n = 1). This was evident by sudden worsening of disease-related symptoms (n = 9), exam/radiographic changes (n = 7), and laboratory changes (n = 8). An estimated one in every three patients discontinued ibrutinib by 2 years, with 25% developing rapid disease progression afterwards.",
"affiliations": "Department of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA.;Department of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA.;Department of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA.;Department of Health Sciences Research, Division of Biomedical Statistics & Informatics, Mayo Clinic, Rochester, MN, USA.;Department of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA.;Department of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA.;Department of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA.;Department of Hematology and Oncology, Mayo Clinic, Phoenix, AZ, USA.;Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA.;Department of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA.;Department of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA.;Department of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA.;Department of Health Sciences Research, Division of Biomedical Statistics & Informatics, Mayo Clinic, Rochester, MN, USA.;Department of Hematology, Stanford University Medical Center, Stanford, CA, USA.;Department of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA.;Department of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA.",
"authors": "Hampel|Paul J|PJ|0000-0003-1292-3024;Ding|Wei|W|;Call|Timothy G|TG|;Rabe|Kari G|KG|;Kenderian|Saad S|SS|;Witzig|Thomas E|TE|;Muchtar|Eli|E|0000-0003-2210-2174;Leis|Jose F|JF|;Chanan-Khan|Asher A|AA|;Koehler|Amber B|AB|;Fonder|Amie L|AL|;Schwager|Susan M|SM|;Slager|Susan L|SL|;Shanafelt|Tait D|TD|;Kay|Neil E|NE|;Parikh|Sameer A|SA|",
"chemical_list": "D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000225:Adenine",
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2019.1602268",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "60(11)",
"journal": "Leukemia & lymphoma",
"keywords": "Chronic lymphocytic leukemia (CLL); discontinuation; ibrutinib; progression",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000225:Adenine; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018450:Disease Progression; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D010818:Practice Patterns, Physicians'; D011379:Prognosis; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D012189:Retrospective Studies; D015996:Survival Rate; D028761:Withholding Treatment",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "2712-2719",
"pmc": null,
"pmid": "31014142",
"pubdate": "2019-11",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "25034748;24019783;17785570;27601462;20864406;23752116;23782158;29419429;29246803;28453705;28418267;28096090;25573991;26182309;28171709;29419435;27756834;22797152;28940587;29472352;25501025;28740693;27885886;29255067;29280186",
"title": "Rapid disease progression following discontinuation of ibrutinib in patients with chronic lymphocytic leukemia treated in routine clinical practice.",
"title_normalized": "rapid disease progression following discontinuation of ibrutinib in patients with chronic lymphocytic leukemia treated in routine clinical practice"
} | [
{
"companynumb": "US-ABBVIE-19K-163-3184494-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"activesubstance": {
"activesubstancename": "IBRUTINIB"
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... |
{
"abstract": "Atypical haemolytic uraemic syndrome is an ultra-rare, life-threatening disease. Causative variants in genes that encode complement factors can be identified in 40-70% of cases. We performed genetic analysis of 21 Czech children with atypical haemolytic uraemic syndrome. Genetic or acquired predisposition to the disease was identified in the majority of our patients: CFHR1 and CFHR3 deletions in 14/21 (67%; 13 of them were positive for anti-complement factor H antibodies), variants in complement genes or DGKE in 13/21 (62%). Multiple genetic findings were identified in eight patients (38%). The incidence of atypical haemolytic uraemic syndrome in the Czech paediatric population was estimated to be 0.092 (CI 0.053-0.131) cases per million inhabitants and 0.92 (CI 0.53-1.32) cases per 100,000 births for the entire reporting period. Ten patients were initially treated with plasma exchange and eight with eculizumab or with a combination of eculizumab and plasma exchange. At the last follow-up, 20 patients were alive and one patient had end-stage renal disease.Conclusion: The incidence of atypical haemolytic uraemic syndrome in the Czech paediatric population corresponds to the reported incidence in Europe. We detected the unusually high rate of CFHR1/CFHR3 deletions associated with anti-complement factor H antibodies in Czech paediatric patients. Treatment by eculizumab led to superior outcomes and prevention of the disease relapses compared with plasma exchange therapy. Our results may help to understand the polygenic nature of atypical haemolytic uraemic syndrome as a disease that results from a combination of various risk factors. What is Known: • Atypical haemolytic uraemic syndrome (aHUS) is considered a polygenic and multifactorial disease. Genetic predisposition to aHUS is identified in 40-70% of children. • Anti-complement factor H antibodies are usually found in 6-25% of affected children. What is New: • Potentially causative genetic or acquired factors were confirmed in the majority of patients. The prevailing finding was the unusually high rate of CFHR1/CFHR3 deletions associated with anti-complement factor H antibodies (62% of patients). • The incidence of aHUS in Czech children is 0.092 (CI 0.053-0.131) cases per million inhabitants and 0.92 (CI 0.53-1.32) cases per 100,000 births for the entire reporting period.",
"affiliations": "Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague, and Motol University Hospital, Prague, Czech Republic.;Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague, and Motol University Hospital, Prague, Czech Republic. martin.bezdicka@fnmotol.cz.;3rd Department of Medicine and MTA-SE Research Group of Immunology and Haematology, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.;3rd Department of Medicine and MTA-SE Research Group of Immunology and Haematology, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.;Institute of Haematology and Blood Transfusion, Prague, Czech Republic.;Department of Cardiovascular Surgery, 2nd Faculty of Medicine, Charles University in Prague, and Motol University Hospital, Prague, Czech Republic.;Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague, and Motol University Hospital, Prague, Czech Republic.;Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague, and Motol University Hospital, Prague, Czech Republic.;Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague, and Motol University Hospital, Prague, Czech Republic.",
"authors": "Štolbová|Šárka|Š|;Bezdíčka|Martin|M|http://orcid.org/0000-0001-6961-5853;Prohászka|Zoltán|Z|;Csuka|Dorottya|D|;Hrachovinová|Ingrid|I|;Burkert|Jan|J|;Šimánková|Naděžda|N|;Průhová|Štěpánka|Š|;Zieg|Jakub|J|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00431-020-03666-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-6199",
"issue": "179(11)",
"journal": "European journal of pediatrics",
"keywords": "Alternative complement pathway; Anti-complement factor H antibodies; Atypical haemolytic uraemic syndrome; Children; DGKE; Next-generation sequencing",
"medline_ta": "Eur J Pediatr",
"mesh_terms": "D065766:Atypical Hemolytic Uremic Syndrome; D002648:Child; D018153:Czech Republic; D005060:Europe; D006801:Humans; D010951:Plasma Exchange; D012307:Risk Factors",
"nlm_unique_id": "7603873",
"other_id": null,
"pages": "1739-1750",
"pmc": null,
"pmid": "32424742",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Molecular basis and outcomes of atypical haemolytic uraemic syndrome in Czech children.",
"title_normalized": "molecular basis and outcomes of atypical haemolytic uraemic syndrome in czech children"
} | [
{
"companynumb": "NVSC2020CZ142680",
"fulfillexpeditecriteria": "1",
"occurcountry": "CZ",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
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"drugadditional": "3",
"druga... |
{
"abstract": "Serious bleeding events have been frequently described in patients taking direct oral anticoagulants (DOAC). In secondary analyses of phase 3 trials, DOAC plasma concentrations were shown to correlate with bleeding outcomes. This study aimed to describe rivaroxaban plasma levels in patients admitted to the emergency department (ED) for bleeding events. For each patient, risk factors for experiencing bleeding events were also investigated.\nThis analysis was part of an observational study conducted in the ED of two teaching hospitals. Plasma samples from 10 rivaroxaban-treated patients admitted for bleeding events were collected. Rivaroxaban plasma concentrations were determined by calibrated chromogenic anti-Xa assay. The measured rivaroxaban levels were then extrapolated at trough using a published population pharmacokinetic (PopPK) model, and compared to on-therapy ranges observed in large clinical trials. For each patient, clinical, medication and ABCB1 genotype data were collected.\nRivaroxaban measurements varied from 5 to 358 ng/ml, with a post-intake delay ranging from 9 to 38 h. At trough, estimated plasma concentrations were between 12 and 251 ng/ml (median value 94 ng/ml). Four patients had higher-than-expected rivaroxaban levels. Inadequate dose regimen, excessive alcohol consumption and lack of treatment reassessment were observed in several patients. Half of patients were taking ≥1 drug with potential pharmacokinetics interactions (e.g. amiodarone, diltiazem), while half of patients were taking ≥1 drug increasing the risk of bleeding. All 3 patients with available genotyping data and higher-than-expected rivaroxaban levels were heterozygous or homozygous mutated for the ABCB1 1236C > T, 2677G > T, 3435 C > T and rs4148738 single nucleotide polymorphisms (SNP).\nRivaroxaban patients admitted to the ED for bleeding events showed highly variable plasma concentrations. This analysis underlines the usefulness of rapid DOAC measurement and the value of PopPK models to estimate concentrations at trough in a context where the post-intake delay is unmanageable. Close patient follow-up, including renal function assessment and drug interactions review, is essential for bleeding risk minimization.",
"affiliations": "1Louvain Drug Research Institute, Clinical Pharmacy Research Group, Université catholique de Louvain, Brussels, Belgium.;2CHU UCL Namur, Namur Thrombosis and Hemostasis Center, Department of Pharmacy, Université catholique de Louvain, Yvoir, Belgium.;3Namur Research Institute for LIfe Sciences, Namur Thrombosis and Hemostasis Center, Department of Pharmacy, University of Namur, Namur, Belgium.;4Louvain Drug Research Institute, Integrated PharmacoMetrics, PharmacoGenomics and PharmacoKinetics, Université catholique de Louvain, Brussels, Belgium.;4Louvain Drug Research Institute, Integrated PharmacoMetrics, PharmacoGenomics and PharmacoKinetics, Université catholique de Louvain, Brussels, Belgium.;5Center of Pharmacology, Therapeutic Drug Monitoring Unit, University Hospital of Cologne, Cologne, Germany.;6Center of Pharmacology, Clinical Pharmacology Unit, University Hospital of Cologne, Cologne, Germany.;3Namur Research Institute for LIfe Sciences, Namur Thrombosis and Hemostasis Center, Department of Pharmacy, University of Namur, Namur, Belgium.;1Louvain Drug Research Institute, Clinical Pharmacy Research Group, Université catholique de Louvain, Brussels, Belgium.;7CHU UCL Namur, Namur Thrombosis and Hemostasis Center, Hematology Laboratory, Université catholique de Louvain, Yvoir, Belgium.",
"authors": "Sennesael|Anne-Laure|AL|0000-0003-3499-1466;Larock|Anne-Sophie|AS|;Douxfils|Jonathan|J|;Elens|Laure|L|;Stillemans|Gabriel|G|;Wiesen|Martin|M|;Taubert|Max|M|;Dogné|Jean-Michel|JM|;Spinewine|Anne|A|;Mullier|François|F|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12959-018-0183-3",
"fulltext": "\n==== Front\nThromb JThromb JThrombosis Journal1477-9560BioMed Central London 18310.1186/s12959-018-0183-3ResearchRivaroxaban plasma levels in patients admitted for bleeding events: insights from a prospective study http://orcid.org/0000-0003-3499-1466Sennesael Anne-Laure +32 2 764 72 36anne-laure.sennesael@uclouvain.be 13Larock Anne-Sophie anne-sophie.larock@uclouvain.be 2Douxfils Jonathan jonathan.douxfils@unamur.be 3Elens Laure laure.elens@uclouvain.be 4Stillemans Gabriel gabriel.stillemans@uclouvain.be 4Wiesen Martin martin.wiesen@uk-koeln.de 5Taubert Max max.taubert@uk-koeln.de 6Dogné Jean-Michel jean-michel.dogne@unamur.be 3Spinewine Anne anne.spinewine@uclouvain.be 12Mullier François mullierfrancois@gmail.com 71 0000 0001 2294 713Xgrid.7942.8Louvain Drug Research Institute, Clinical Pharmacy Research Group, Université catholique de Louvain, Brussels, Belgium 2 0000 0001 2294 713Xgrid.7942.8CHU UCL Namur, Namur Thrombosis and Hemostasis Center, Department of Pharmacy, Université catholique de Louvain, Yvoir, Belgium 3 0000 0001 2242 8479grid.6520.1Namur Research Institute for LIfe Sciences, Namur Thrombosis and Hemostasis Center, Department of Pharmacy, University of Namur, Namur, Belgium 4 0000 0001 2294 713Xgrid.7942.8Louvain Drug Research Institute, Integrated PharmacoMetrics, PharmacoGenomics and PharmacoKinetics, Université catholique de Louvain, Brussels, Belgium 5 0000 0000 8852 305Xgrid.411097.aCenter of Pharmacology, Therapeutic Drug Monitoring Unit, University Hospital of Cologne, Cologne, Germany 6 0000 0000 8852 305Xgrid.411097.aCenter of Pharmacology, Clinical Pharmacology Unit, University Hospital of Cologne, Cologne, Germany 7 0000 0001 2294 713Xgrid.7942.8CHU UCL Namur, Namur Thrombosis and Hemostasis Center, Hematology Laboratory, Université catholique de Louvain, Yvoir, Belgium 12 11 2018 12 11 2018 2018 16 284 6 2018 21 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\nSerious bleeding events have been frequently described in patients taking direct oral anticoagulants (DOAC). In secondary analyses of phase 3 trials, DOAC plasma concentrations were shown to correlate with bleeding outcomes. This study aimed to describe rivaroxaban plasma levels in patients admitted to the emergency department (ED) for bleeding events. For each patient, risk factors for experiencing bleeding events were also investigated.\n\nMethods\nThis analysis was part of an observational study conducted in the ED of two teaching hospitals. Plasma samples from 10 rivaroxaban-treated patients admitted for bleeding events were collected. Rivaroxaban plasma concentrations were determined by calibrated chromogenic anti-Xa assay. The measured rivaroxaban levels were then extrapolated at trough using a published population pharmacokinetic (PopPK) model, and compared to on-therapy ranges observed in large clinical trials. For each patient, clinical, medication and ABCB1 genotype data were collected.\n\nResults\nRivaroxaban measurements varied from 5 to 358 ng/ml, with a post-intake delay ranging from 9 to 38 h. At trough, estimated plasma concentrations were between 12 and 251 ng/ml (median value 94 ng/ml). Four patients had higher-than-expected rivaroxaban levels. Inadequate dose regimen, excessive alcohol consumption and lack of treatment reassessment were observed in several patients. Half of patients were taking ≥1 drug with potential pharmacokinetics interactions (e.g. amiodarone, diltiazem), while half of patients were taking ≥1 drug increasing the risk of bleeding. All 3 patients with available genotyping data and higher-than-expected rivaroxaban levels were heterozygous or homozygous mutated for the ABCB1 1236C > T, 2677G > T, 3435 C > T and rs4148738 single nucleotide polymorphisms (SNP).\n\nConclusions\nRivaroxaban patients admitted to the ED for bleeding events showed highly variable plasma concentrations. This analysis underlines the usefulness of rapid DOAC measurement and the value of PopPK models to estimate concentrations at trough in a context where the post-intake delay is unmanageable. Close patient follow-up, including renal function assessment and drug interactions review, is essential for bleeding risk minimization.\n\nKeywords\nDirect oral anticoagulantsRivaroxabanBleedingDrug monitoringPharmacogenomicsPatient safetyissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nDirect oral anticoagulants (DOAC) are increasingly used in clinical practice, to prevent venous thrombosis or thrombus formation in non-valvular atrial fibrillation [1, 2]. However, serious bleeding events have been frequently described for patients taking DOACs. In 2013–2014, rivaroxaban and dabigatran were among the drugs most commonly implicated in emergency department (ED) admissions in the United States [3]. During phase 3 trials, risk of major bleeding of DOACs was similar to or lower than warfarin, whereas the risk of intracranial hemorrhage was substantially reduced [4, 5]. Recent observational studies have shown similar results in a real-life setting [6].\n\nAlthough DOACs do not require close therapeutic monitoring, their measurement remains useful in specific clinical situations such as major bleeding and emergency surgery [7]. Assessment of the individual response may also benefit patients with suspected drug accumulation or therapeutic failure. In secondary analyses of phase 3 trials, DOAC plasma concentrations were shown to correlate with bleeding outcomes [8–10]. Conversely, a recent observational study has highlighted the relationship between low DOAC levels, measured in the first month of treatment, and the occurrence of thromboembolic events [11]. However, a therapeutic range has not been defined yet for each DOAC.\n\nTo our knowledge, few studies have investigated the intensity of DOAC anticoagulation in patients presenting to the ED for bleeding events. In the RE-VERSE AD study, the median (unbound) dabigatran plasma concentration was 110 ng/ml in patients with uncontrollable or life-threatening bleeding, before the administration of idarucizumab [12]. Bouget and Oger described DOAC levels in 5 patients admitted for major bleeding [13]. However, measurements were not interpreted by taking into account the post-intake delay and other influencing individual factors.\n\nIn this study, we aimed to describe rivaroxaban levels in patients admitted to the ED for bleeding events. Measured plasma concentrations were extrapolated at trough using population pharmacokinetic (popPK) modeling, and compared to the expected on-therapy range. Several determinants of bleeding were previously reported in rivaroxaban-treated patients, including older age, renal impairment or drug interactions [14–17]. The inappropriate use of DOAC has also been highlighted in this respect [18, 19]. In addition, ABCB1 genetic polymorphisms have recently been suggested to contribute to high rivaroxaban levels in a patient admitted for gastrointestinal bleeding [20]. Therefore, a second objective was to investigate and discuss the presence of such risk factors for bleeding events in our rivaroxaban patients.\n\nMethods\nSetting and population\nThis analysis was part of a prospective observational cohort study, conducted in two teaching hospitals in Belgium to assess the preventability of serious adverse drug reactions related to the use of oral anticoagulants [21]. We collected plasma samples from rivaroxaban patients admitted to the ED for a bleeding event, between July 2015 and January 2016.\n\nRivaroxaban measurement\nBlood sampling was performed closely after management and inclusion of the patient in the study. Blood was taken by antecubital venipuncture and collected into 0.109 M sodium citrate (9:1 v/v) tubes. Platelet-poor plasma (PPP) was obtained from the supernatant fraction after double centrifugation for 15 min at 1500 g at room temperature. PPP was next aliquoted and frozen at − 80 °C without delay. Frozen plasma samples aliquots were thawed by heating to 37 °C for at least 5 min just before experiments.\n\nThe following routine clotting assay was performed: prothrombin time (PT) using RecombiPlasTin2G® (Werfen, Lexington, USA; normal range 12.4–14.5 s). Rivaroxaban plasma concentrations were estimated with the Biophen® Direct Factor Xa Inhibitors (Biophen®DiXaI, Hyphen BioMed, Neuville-Sur-Oise, France), a calibrated chromogenic anti-Xa assay. The procedure was performed on a STA-R® Evolution analyzer according to the manufacturer recommendations, using calibrators from Hyphen BioMed. Commercial rivaroxaban anti-Xa assays have previously demonstrated good accuracy (bias below 8%) and acceptable precision (inter-laboratory coefficients of variation (CV) 6–25%) [22]. A procedure dedicated to low concentrations was applied to rivaroxaban plasma concentrations < 50 ng/ml, where plasma samples were diluted 1:8 in buffer and low concentrations standards were used [23].\n\nWe extrapolated rivaroxaban plasma concentrations at trough (i.e. 12 h and 24 h after the last drug intake for twice daily and once daily regimen, respectively). To this end, we used a Pop PK model that was previously developed to predict adequate discontinuation intervals in a cohort of rivaroxaban patients scheduled for cardiac catheterization [24]. Residual rivaroxaban concentrations were described by a 2-compartment model with first-order absorption and elimination. Results were then compared to the expected on-therapy ranges at trough (5th–95th percentiles): 12–137 ng/ml (rivaroxaban 20 mg) and 18–136 ng/ml (rivaroxaban 15 mg) for stroke prevention in non-valvular atrial fibrillation (NVAF), and 6–87 ng/ml for treatment and secondary prevention of venous thromboembolism (VTE) [25].\n\nData collection\nA comprehensive medication history was performed with patients and/or relatives to collect sociodemographic, clinical and medication data (including dose regimen, indication and timing of the last rivaroxaban intake). Patient renal function was estimated based on serum creatinine on admission using Cockroft-Gault equation. We reviewed electronic medical records and contacted GPs, community pharmacists or relatives when necessary. Bleeding severity was assessed using the International Society on Thrombosis and Haemostasis definition. Patient follow-up was undertaken to assess 3-month mortality.\n\nAppropriateness of rivaroxaban prescribing was analyzed according to the Medication Appropriateness Index (MAI) [26]. We applied a DOAC-specific form, previously developed in a pilot study [27]. We documented the concomitant use of P-glycoprotein (P-gp) and CYP3A4 inhibitors or inducers. Regarding potential pharmacodynamics interactions, we considered other anticoagulants, antiplatelet therapy, non-steroidal anti-inflammatory drugs (NSAID), selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI). Patient adherence to anticoagulant therapy was evaluated during medication history using an adapted version of the Morisky Medication Adherence Scale [28].\n\nABCB1 genetic polymorphisms\nFor all patients except one (because of misunderstanding), an additional blood sample was drawn in EDTA tube and frozen at − 20 °C without delay until experiments. Genomic DNA was extracted from whole blood, using QIAamp DNA Blood Mini kit (Qiagen, CA, USA). The following single nucleotide polymorphisms (SNP) of ABCB1 were detected: rs1128503 (1236C > T, Gly412Gly), rs2032582 (2677G > T, Ala893Ser), rs1045642 (3435 C > T, Ile1145Ile) and rs4148738. Allelic discrimination was performed by TaqMan® (Applied Biosystems, CA, USA) Drug Metabolism Genotyping Assays (C___7586662_10, C_11711720C_30, C__15951365_20, C___1253813_10). Statistical analyses were performed using JMP Pro 13.2.0 (SAS Institute, Cary, NC, USA). Kruskal-Wallis tests were carried out to compare estimated trough concentrations between different genotypes. A p-value of less than 0.05 was considered statistically significant.\n\nResults\nStudy population\nPlasma samples from 10 rivaroxaban patients were included in this analysis. Median age of patients was 75 years, and 80% were female. Five patients had moderate renal impairment on admission (creatinine clearance < 60 ml/min). Indications of rivaroxaban therapy were stroke prevention in NVAF (6/10) and treatment and secondary prevention of VTE (4/10). Clinical characteristics are detailed in Table 1 for each patient. The most frequent adverse events were gastrointestinal bleeding (4/10). Half of bleeding events were considered major and half occurred spontaneously. Red blood cells transfusion and prothrombin complex concentrates administration were operated in 4 and 1 patients, respectively. All patients were alive at 3-month follow-up. Details of bleeding events are presented in Table 2.Table 1 Characteristics of rivaroxaban patients\n\nNo\tSex, age\n(years)\tWeight\n(kg)\tBMI\n(kg/m2)\tCLcr\n(ml/min)\tHb\n(g/dl)\tIndication\tDosage\tDuration\tCHA2DS2-VASC\tHAS-BLED\t\n1\tM, 83\t79\t23.1\t58\t13.7\tSPAF\t20 mg OD\t≤ 1 year\t5\t3\t\n2\tF, 70\tN/K\tN/K\tN/K\t3.1\tSPAF\t15 mg OD\t> 1 year\t3\t1\t\n3\tF, 87\t65\t25.7\t48\t6.4\tVTE\t20 mg OD\t< 30 days\tN/A\t2\t\n4\tF, 67\t80\t24.7\t53\t7.2\tSPAF\t20 mg OD\t> 1 year\t6\t2\t\n5\tF, 77\t63\t25.2\t61\t14.3\tSPAF\t15 mg OD\t> 1 year\t7\t3\t\n6\tM, 66\t100\t35\t86\t15.6\tSPAF\t20 mg OD\t≤ 1 year\t2\t2\t\n7\tF, 72\t66\t21.6\t46\t12.8\tVTE\t20 mg OD\t> 1 year\tN/A\t3\t\n8\tF, 90\t70\tN/K\t60\t13.8\tSPAF\t15 mg OD\tN/K\t6\t1\t\n9\tF, 86\t89\t31.2\t57\t14.9\tVTE\t15 mg BID\t< 30 days\tN/A\t1\t\n10\tF, 69\t73\t26.8\t76\t11.3\tVTE\t20 mg OD\t> 1 year\tN/A\t2\t\nBID twice-daily, BMI body mass index, CLcr creatinine clearance (Cockroft-Gault equation), Hb haemoglobin, OD once-daily, N/A not applicable, N/K not known, SPAF stroke prevention in atrial fibrillation, VTE venous thromboembolism\n\nTable 2 Characteristics, management and clinical outcomes of the 10 bleeding events\n\nNo\tSite of bleeding\tBleeding severity\tBleeding occurrence\tManagement\tLength of stay (days)\t90-day outcome\t\n1\tHematuria\tNMCR\tTrauma\t–\t0\tAlive\t\n2\tGastrointestinal\tMajor\tSpontaneous\tRBC (3 units)a\tN/K\tN/K\t\n3\tGastrointestinal\tMajor\tSpontaneous\tRBC (2 units)a\t3\tAlive\t\n4\tGastrointestinal\tMajor\tSpontaneous\tRBC (3 units)a\t1\tAlive\t\n5\tIntracranial\tMajor\tTrauma\tPCC (2500 IU)\t43\tAlive\t\n6\tGastrointestinal\tNMCR\tPost-intervention\t–\t0\tAlive\t\n7\tEpistaxis\tNMCR\tSpontaneous\t–\t2\tAlive\t\n8\tIntracranial\tMajor\tTrauma\t–\t1\tAlive\t\n9\tHematuria\tNMCR\tSpontaneous\t–\t0\tAlive\t\n10\tHematoma\tNMCR\tTrauma\t–\t0\tN/K\t\nN/K not known, NMCR non-major clinically relevant, PCC prothrombin complex concentrates, RBC red blood cells. aTransfusion before blood sampling\n\n\n\nRivaroxaban measurement\nMeasured rivaroxaban levels varied from 5 to 358 ng/ml, with a delay since the last drug intake ranging from 9 to 38 h. PT was above the normal range in all patients with rivaroxaban concentrations above 30 ng/ml (Table 3). When using PopPK model, estimated plasma concentrations at trough were between 12 and 251 ng/ml (median value 94 ng/ml). Elimination clearance (CL/F) was between 2.0 and 7.9 L/h (median value 3.3 L/h). Measured and extrapolated rivaroxaban concentrations are described in Table 3 for each patient, as well as the elimination clearance. Four patients had rivaroxaban levels at trough higher than the expected on-therapy range (No 2, 3, 5, 9).Table 3 Measurement of rivaroxaban plasma concentrations\n\nNo\tDelay (h)\tPT (sec)\tBiophen® DiXaI (ng/ml)\tEstimated cc at trough (ng/ml)\tClearance (L/h)\tPotential PK drug interactions\tPotential PD drug interactions\t\n1\t28\t18.7\t84.8\t98\t3.3\t–\tIbuprofen\t\n2\t22\t19.6\t237.5\t\n181\na\n\t2.0\tDiltiazem (↑), Clarithromycin (↑)\tEscitalopram\t\n3\t38\t15.4\t70.8\t\n125\na\n\t2.9\tSimvastatin (↑)\t/\t\n4\t27\t17.7\t58.3\t69\t3.9\t–\tDiclofenac, Escitalopram\t\n5\t27\tN/K\t139.4\t\n134\na\n\t2.4\tAmiodarone (↑)\tAspirin\t\n6\t26\t12.9\t4.9\t12\t7.9\tAmiodarone (↑)\t/\t\n7\t37\t14.4\t18.3\t44\t4.8\tDiltiazem (↑)\t/\t\n8\t27\t15.3\t86.5\t89\t3.0\t/\t/\t\n9\t9\t26.0\t357.8\t\n251\na\n\t3.2\t/\t/\t\n10\t13\tN/K\t184.7\t72\t3.9\t/\tDuloxetine, Paroxetine\t\nBiophen®DiXaI Biophen® Direct Factor Xa Inhibitors, cc concentration, N/K not known, PD pharmacodynamics, PK pharmacokinetics, PT prothrombin time (normal range: 12.4–14.5 s), ↑: increased plasma concentrations, ↓: decreased plasma concentrations\n\naEstimated trough concentration above the on-therapy range (we considered higher-than-expected rivaroxaban levels for patient 5, as measured concentration was higher than 136 ng/ml)\n\n\n\nAnalysis of risk factors for bleeding events\nThe analysis of rivaroxaban prescriptions revealed that at least one criterion of the MAI was inappropriate in 8 of 10 patients. Three patients received an inadequate dosing regimen: 20 mg OD instead of 15 mg OD (No 3, 7), and 15 mg BID instead of 20 mg OD (No 9). Two of them had estimated trough concentration above the on-therapy range. Three patients had an excessive alcohol consumption (≥ 2 units/day; No 1, 4, 7). Moreover, in two patients treated for VTE prevention, treatment indication had not been reassessed for years (No 3, 10).\n\nHalf of patients were taking at least 1 drug with potential pharmacokinetic interactions (Table 3). Three of them had higher-than-expected rivaroxaban plasma concentrations at trough. The most frequent interacting drugs were amiodarone and diltiazem. Moreover, half of patients were taking at least 1 drug increasing the risk of bleeding (Table 3). We mainly observed the concomitant use of SSRI (n = 3) and NSAID (n = 2). Regarding adherence to anticoagulant therapy, three patients reported forgetting to take their medicine in rare circumstances (No 1, 4, 7). One patient mentioned a variable time of intake (No 7).\n\nABCB1 genetic polymorphisms were analyzed in 9 of 10 patients. Genotyping data are presented in Table 4 for the ABCB1 1236C > T, 2677G > T, 3435 C > T and rs4148738 SNP. Of the four patients with higher-than-expected rivaroxaban trough levels, three carried at least one variant allele for each of these SNP (No 2, 3, 5 – blood sample not available for patient No 9). However, no clear association between ABCB1 genotype and estimated trough concentrations was observed (p > 0.05).Table 4 ABCB1 genotyping in 10 rivaroxaban patients with bleeding events\n\nNo\t1236C > T\t2677G > T\t3435C > T\trs4148738\t\n1\tCC\tGG\tCC\tAA\t\n2\t\nCT\n\t\nGT\n\t\nCT\n\t\nGA\n\t\n3\t\nCT\n\t\nGT\n\t\nCT\n\t\nGA\n\t\n4\tTT\tTT\tCT\tGG\t\n5\t\nCT\n\t\nGT\n\t\nTT\n\t\nGA\n\t\n6\tTT\tTT\tTT\tGG\t\n7\tCT\tGT\tTT\tGA\t\n8\tTT\tTT\tTT\tGG\t\n9\t\nN/K\n\t\nN/K\n\t\nN/K\n\t\nN/K\n\t\n10\tCC\tGG\tCT\tAA\t\nN/K not known. Patients with higher-than-expected rivaroxaban levels are shown in bold\n\n\n\nDiscussion\nIn this analysis of 10 patients admitted for bleeding events, we observed a large range of rivaroxaban levels. The application of a previously published PopPK model revealed that four patients had higher-than-expected plasma concentrations at trough. Several risk factors for bleeding were found at the individual level, including older age, inappropriate use of rivaroxaban and drug interactions.\n\nTo our knowledge, this is the first study to analyze in depth rivaroxaban measurements in the context of bleeding events. Inter-individual variability in DOAC exposure has been previously investigated in routine care, showing plasma levels outside the on-therapy range in 40% of rivaroxaban patients [29]. In four Italian anticoagulation clinics, rivaroxaban measurements varied nearly 15-fold among NVAF patients, with a mean trough level around 40 ng/ml [30]. This variability is in agreement with our results, although we estimated a higher median trough concentration (94 ng/ml). This reflects a delayed rivaroxaban clearance in our bleeding patients (median CL/F 3.3 L/h, compared to 4.9 L/h in patients scheduled for cardiac catheterization or 6.1 L/h in AF patients as previously reported) [24, 31]. Two recent cohort studies have shown median rivaroxaban levels of 124 ng/ml in patients with severe bleeding events, and 102 ng/ml in patients admitted for intracranial hemorrhage [32, 33]. Delay since the last drug intake was 12 h (median value) in the former case, and less than 24 h for most patients in the latter case.\n\nRivaroxaban measurement for bleeding management\nThe management of DOAC-related bleeding includes the temporary discontinuation of the oral anticoagulant, supportive measures and the administration of reversal agents, depending on the severity of the event [34, 35]. Andexanet alpha has recently been approved by the FDA to reverse the anticoagulant effect of rivaroxaban, while prothrombin complex concentrates were also suggested as an alternative [36–38]. In this context, rapid laboratory measurement may provide valuable assistance to warrant and monitor antidote administration, or manage urgent interventions [7].\n\nIn the present study, we observed that PT was prolonged in all patients with clinically relevant concentrations (> 30 ng/ml) of rivaroxaban. However, we employed a sensitive thromboplastin reagent (RecombiPlasTin 2G®) for the assay [39]. A nationwide Belgian survey has previously highlighted a wide variation in response to rivaroxaban according to the reagent used [40]. Commercial specific assays are currently available for all DOACs [41]. They are more accurate but require calibrators and controls. Turnaround times around 30 min have nevertheless been reported in a daily practice context [42, 43].\n\nFactors associated with an increased risk of bleeding\nSeveral risk factors for bleeding events were highlighted in our 10 rivaroxaban patients. First, half of them were older than 75 years, and half of them had moderate renal impairment. Older age and renal insufficiency were previously demonstrated as contributing factors to major bleeding in rivaroxaban patients [14]. Recently, glomerular filtration rates below 60 ml/min have been independently associated with higher-than-expected residual rivaroxaban levels in a perioperative setting [44]. This is not surprising since one third of the rivaroxaban dose is eliminated unchanged by the kidneys [25]. However, in our analysis, only two patients with moderate renal impairment had trough concentrations above the on-therapy range. Second, despite the highest convenience and fixed-dose regimen of DOAC, some of our patients did not receive the appropriate dose of rivaroxaban. In particular, one patient (No 9) was still taking rivaroxaban 15 mg BID while the 21-day treatment phase of VTE had been completed. Yao and colleagues highlighted that patients with indication for dose reduction were often potentially overdosed, leading to an increased risk of major bleeding [19].\n\nDrugs interactions with P-gp or CYP3A4 inhibitors were frequent in our patients, as previously reported [32, 45]. One patient (No 2) was taking diltiazem and clarithromycin, two inhibitors of both P-gp and CYP3A4. He had an estimated rivaroxaban level of 181 ng/ml at trough, exceeding the 95th percentile of the on-therapy range (136 ng/ml). In healthy volunteers, clarithromycin has been shown to promote a 2-fold increase in rivaroxaban exposure [46]. Similarly, we extrapolated a rivaroxaban trough concentration of 125 ng/ml in a patient taking simvastatin (No 3). This P-gp inhibitor has been associated with a higher risk of major bleeding in patients taking dabigatran [47]. Pharmacodynamic interactions were also widely observed. Aspirin has often no valid indication in anticoagulated patients, while combination therapy has been shown to increase the risk of major bleeding [16, 48]. A similar increase was associated with the addition of SSRIs, the most prescribed class of antidepressants [49].\n\nAn original aspect of this work was the investigation of several ABCB1 polymorphisms. All 3 patients with higher-than-expected rivaroxaban levels and available genotyping data were at least heterozygous mutated for the 1236C > T, 2677G > T, 3435C > T and rs4148738 SNP. Previous experiments have shown that the 1236 T–2677 T-3435 T variant haplotype decreased ABCB1 expression or transport towards several drugs such as anticancer agents [50–52]. These results support our observations, as a decreased efflux of rivaroxaban may have led to drug accumulation. However, in a recent study conducted in 60 healthy volunteers, the 1236 T–2677 T-3435 T haplotype was not a significant determinant of rivaroxaban pharmacokinetics [46]. This strengthens the need for additional studies to clarify the impact of ABCB1 polymorphisms on rivaroxaban transport. Indeed, our findings might also be due to the high frequency of the variant genotype 1236 T–2677 T-3435 T (up to 50% of the Caucasian population is expected to heterozygous mutated). Furthermore, these three patients were also receiving concomitant interacting medications, as previously discussed.\n\nThe study presents several limitations. First, statistical analysis was limited by the small number of plasma samples collected. However, this allowed an in-depth analysis of rivaroxaban measurements, including clinical, medication and genetic characteristics at the individual level. Second, three patients (No 2–4) were transfused with red blood cells (RBC) before sampling. For these patients, we cannot exclude that rivaroxaban measurements were not influenced by fluid volume or factor Xa content of packed RBC. However, Biophen®DiXaI was designed for minimizing the interference of plasma factors. Third, estimation of renal function was only based on serum creatinine on admission, as previous laboratory results performed in primary care were not available. Finally, the Pop PK model we used assumed no variability in the volume of distribution, while inter-individual variability in V/F was 18% in another Pop PK model from AF patients [31]. However, simulations were previously performed and showed the limited influence of this variability on predicted exposure estimates.\n\nConclusion\nIn conclusion, rivaroxaban patients admitted to the ED for bleeding events showed highly variable plasma concentrations and a delayed elimination clearance. This underlines the usefulness of rapid DOAC measurement to assess contribution to the adverse event, manage urgent procedures or warrant antidote administration. Close patient follow-up, including renal function assessment and drug interactions review, is essential for bleeding risk minimization. Further studies are needed to investigate the impact of ABCB1 polymorphisms on DOAC transport.\n\nAcknowledgements\nA.L. Sennesael is a Research Fellow of the Fonds National de la Recherche Scientifique (FNRS). The authors would like to thank the emergency departments of the Cliniques Universitaires Saint-Luc and CHU UCL Namur, Pr F. Verschuren, Dr. X. Muschart, Mrs. J. Baudar, Mrs. M. Guldenpfennig for their contributions to this work.\n\nAvailability of data and materials\nThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nALS, JD, JMD, AS and FM designed the research study. ALS and ASL contributed to plasma sample collection. LE, GS, MW, MT were responsible for the estimation of plasma concentrations at trough. ALS wrote the first draft of the manuscript and the final version. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThe study was approved by the Ethics Committees of the Cliniques Universitaires Saint-Luc (Brussels, Belgium) and the CHU UCL Namur (Yvoir, Belgium), and registered with clinicaltrials.gov (NCT02720328). Written informed consent was obtained from each patient.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Turpie AG Esmon C Venous and arterial thrombosis--pathogenesis and the rationale for anticoagulation Thromb Haemost 2011 105 586 596 10.1160/TH10-10-0683 21225099 \n2. Santos-Gallego CG Bayon J Badimon JJ Thrombi of different pathologies: implications for diagnosis and treatment Curr Treat Options Cardiovasc Med 2010 12 274 291 10.1007/s11936-010-0075-8 20842548 \n3. Shehab N Lovegrove MC Geller AI Rose KO Weidle NJ Budnitz DS. US emergency department visits for outpatient adverse drug events, 2013-2014 JAMA 2016 316 2115 2125 10.1001/jama.2016.16201 27893129 \n4. Ruff CT Giugliano RP Braunwald E Hoffman EB Deenadayalu N Ezekowitz MD Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials Lancet 2014 383 955 962 10.1016/S0140-6736(13)62343-0 24315724 \n5. van Es N, Coppens M, Schulman S, Middeldorp S, Buller HR. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood 2014; 124:1968–1975.\n6. Ntaios G Papavasileiou V Makaritsis K Vemmos K Michel P Lip GYH Real-world setting comparison of nonvitamin-K antagonist oral anticoagulants versus vitamin-K antagonists for stroke prevention in atrial fibrillation: a systematic review and meta-analysis Stroke 2017 48 2494 2503 10.1161/STROKEAHA.117.017549 28716982 \n7. Douxfils J Ageno W Samama CM Lessire S Ten Cate H Verhamme P Laboratory testing in patients treated with direct oral anticoagulants: a practical guide for clinicians J Thromb Haemost 2018 16 209 219 10.1111/jth.13912 29193737 \n8. Eikelboom JW Quinlan DJ Hirsh J Connolly SJ Weitz JI Laboratory monitoring of non-vitamin K antagonist oral anticoagulant use in patients with atrial fibrillation: a review JAMA Cardiol 2017 2 566 574 10.1001/jamacardio.2017.0364 28355459 \n9. Reilly PA Lehr T Haertter S Connolly SJ Yusuf S Eikelboom JW The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY trial (randomized evaluation of long-term anticoagulation therapy) J Am Coll Cardiol 2014 63 321 328 10.1016/j.jacc.2013.07.104 24076487 \n10. Ruff CT Giugliano RP Braunwald E Morrow DA Murphy SA Kuder JF Association between edoxaban dose, concentration, anti-factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial Lancet 2015 385 2288 2295 10.1016/S0140-6736(14)61943-7 25769361 \n11. Testa S Paoletti O Legnani C Dellanoce C Antonucci E Cosmi B Low drug levels and thrombotic complications in high-risk atrial fibrillation patients treated with direct oral anticoagulants J Thromb Haemost 2018 16 842 848 10.1111/jth.14001 29532628 \n12. Pollack CVJ, Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA, et al. Idarucizumab for dabigatran reversal — full cohort analysis. N Engl J Med. 2017. 10.1056/NEJMoa1707278.\n13. Bouget J Oger E Emergency admissions for major haemorrhage associated with direct oral anticoagulants Thromb Res 2015 136 1190 1194 10.1016/j.thromres.2015.10.036 26545315 \n14. Beyer-Westendorf J Forster K Pannach S Ebertz F Gelbricht V Thieme C Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry Blood 2014 124 955 962 10.1182/blood-2014-03-563577 24859362 \n15. Camm AJ Amarenco P Haas S Hess S Kirchhof P Kuhls S XANTUS: a real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation Eur Heart J 2016 37 1145 1153 10.1093/eurheartj/ehv466 26330425 \n16. Shah R Hellkamp A Lokhnygina Y Becker RC Berkowitz SD Breithardt G Use of concomitant aspirin in patients with atrial fibrillation: findings from the ROCKET AF trial Am Heart J 2016 179 77 86 10.1016/j.ahj.2016.05.019 27595682 \n17. Washam JB Hellkamp AS Lokhnygina Y Piccini JP Berkowitz SD Nessel CC Efficacy and safety of rivaroxaban versus warfarin in patients taking Nondihydropyridine Calcium Channel blockers for atrial fibrillation (from the ROCKET AF trial) Am J Cardiol 2017 120 588 594 10.1016/j.amjcard.2017.05.026 28645473 \n18. Whitworth MM Haase KK Fike DS Bharadwaj RM Young RB MacLaughlin EJ Utilization and prescribing patterns of direct oral anticoagulants Int J Gen Med 2017 10 87 94 10.2147/IJGM.S129235 28331354 \n19. Yao X Shah ND Sangaralingham LR Gersh BJ Noseworthy PA Non-Vitamin K Antagonist oral anticoagulant dosing in patients with atrial fibrillation and renal dysfunction J Am Coll Cardiol 2017 69 2779 2790 10.1016/j.jacc.2017.03.600 28595692 \n20. Ing Lorenzini K Daali Y Fontana P Desmeules J Samer C Rivaroxaban-induced hemorrhage associated with ABCB1 genetic defect Front Pharmacol 2016 7 494 10.3389/fphar.2016.00494 28066243 \n21. Sennesael AL, Larock AS, Devalet B, Mathieux V, Verschuren F, Muschart X, et al. Preventability of serious thromboembolic and bleeding events related to the use of oral anticoagulants: a prospective study. Br J Clin Pharmacol. 2018;84:1544–56.\n22. Gouin-Thibault I Freyburger G de Maistre E Susen S Delavenne X Golmard JL Evaluation of dabigatran, rivaroxaban and apixaban target-specific assays in a multicenter French study Thromb Res 2017 158 126 133 10.1016/j.thromres.2017.09.001 28892657 \n23. Lessire S Douxfils J Pochet L Dincq AS Larock AS Gourdin M Estimation of rivaroxaban plasma concentrations in the perioperative setting in patients with or without heparin bridging Clin Appl Thromb Hemost 2018 24 129 138 10.1177/1076029616675968 27811211 \n24. Wiesen MHJ Blaich C Taubert M Jennissen V Streichert T Pfister R Residual rivaroxaban exposure after discontinuation of anticoagulant therapy in patients undergoing cardiac catheterization Eur J Clin Pharmacol 2018 74 611 618 10.1007/s00228-018-2421-9 29376194 \n25. Mueck W Stampfuss J Kubitza D Becka M Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban Clin Pharmacokinet 2014 53 1 16 10.1007/s40262-013-0100-7 23999929 \n26. Hanlon JT Schmader KE Samsa GP Weinberger M Uttech KM Lewis IK A method for assessing drug therapy appropriateness J Clin Epidemiol 1992 45 1045 1051 10.1016/0895-4356(92)90144-C 1474400 \n27. Larock AS Mullier F Sennesael AL Douxfils J Devalet B Chatelain C Appropriateness of prescribing dabigatran etexilate and rivaroxaban in patients with nonvalvular atrial fibrillation: a prospective study Ann Pharmacother 2014 48 1258 1268 10.1177/1060028014540868 24982310 \n28. Wang Y Kong MC Ko Y Psychometric properties of the 8-item Morisky medication adherence scale in patients taking warfarin Thromb Haemost 2012 108 789 795 10.1160/TH12-05-0368 22836920 \n29. Gulilat M Tang A Gryn SE Leong-Sit P Skanes AC Alfonsi JE Interpatient variation in rivaroxaban and Apixaban plasma concentrations in routine care Can J Cardiol 2017 33 1036 1043 10.1016/j.cjca.2017.04.008 28754389 \n30. Testa S Tripodi A Legnani C Pengo V Abbate R Dellanoce C Plasma levels of direct oral anticoagulants in real life patients with atrial fibrillation: results observed in four anticoagulation clinics Thromb Res 2016 137 178 183 10.1016/j.thromres.2015.12.001 26672898 \n31. Girgis IG Patel MR Peters GR Moore KT Mahaffey KW Nessel CC Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with non-valvular atrial fibrillation: results from ROCKET AF J Clin Pharmacol 2014 54 917 927 10.1002/jcph.288 24668660 \n32. Albaladejo P Samama CM Sie P Kauffmann S Memier V Suchon P Management of Severe Bleeding in patients treated with direct oral anticoagulants: an observational registry analysis Anesthesiology 2017 127 111 120 10.1097/ALN.0000000000001631 28410272 \n33. Seiffge DJ Kagi G Michel P Fischer U Bejot Y Wegener S Rivaroxaban plasma levels in acute ischemic stroke and intracerebral hemorrhage Ann Neurol 2018 83 451 459 10.1002/ana.25165 29394504 \n34. Steffel J, Verhamme P, Potpara TS, Albaladejo P, Antz M, Desteghe L, et al. The 2018 European heart rhythm association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur heart J. 2018;39:1330–93.\n35. Tomaselli GF Mahaffey KW Cuker A Dobesh PP Doherty JU Eikelboom JW ACC expert consensus decision pathway on Management of Bleeding in patients on oral anticoagulants: a report of the American College of Cardiology Task Force on expert consensus decision pathways J Am Coll Cardiol 2017 2017 70 3042 3067 10.1016/j.jacc.2017.09.1085 \n36. Connolly SJ Milling TJ Jr Eikelboom JW Gibson CM Curnutte JT Gold A Andexanet alfa for acute major bleeding associated with factor Xa inhibitors N Engl J Med 2016 375 1131 1141 10.1056/NEJMoa1607887 27573206 \n37. Andexxa-An Antidote for Apixaban and Rivaroxaban JAMA 2018 320 399 400 10.1001/jama.2018.9257 30043058 \n38. Eerenberg ES Kamphuisen PW Sijpkens MK Meijers JC Buller HR Levi M Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled crossover study in healthy subjects Circulation 2011 124 1573 1579 21900088 \n39. Douxfils J Mullier F Loosen C Chatelain C Chatelain B Dogne JM Assessment of the impact of rivaroxaban on coagulation assays: laboratory recommendations for the monitoring of rivaroxaban and review of the literature Thromb Res 2012 130 956 966 10.1016/j.thromres.2012.09.004 23006523 \n40. Van Blerk M Bailleul E Chatelain B Demulder A Devreese K Douxfils J Influence of dabigatran and rivaroxaban on routine coagulation assays A nationwide Belgian survey Thromb Haemost 2015 113 154 164 10.1160/TH14-02-0161 25231101 \n41. Douxfils J Gosselin RC Laboratory assessment of direct oral anticoagulants Semin Thromb Hemost 2017 43 277 290 10.1055/s-0036-1597296 28249326 \n42. Seiffge DJ Traenka C Polymeris A Hert L Fisch U Peters N Feasibility of rapid measurement of rivaroxaban plasma levels in patients with acute stroke J Thromb Thrombolysis 2017 43 112 116 10.1007/s11239-016-1431-7 27696335 \n43. Dincq AS, Lessire S, Pirard G, Siriez R, Guldenpfennig M, Baudar J, et al. Reduction of the turn-around time for the measurement of rivaroxaban and apixaban: Assessment of the performance of a rapid centrifugation method. Int J Lab Hematol. 2018. 10.1111/ijlh.12870 .\n44. Kaserer A Schedler A Jetter A Seifert B Spahn DR Stein P Risk factors for higher-than-expected residual rivaroxaban plasma concentrations in real-life patients Thromb Haemost 2018 118 808 817 10.1055/s-0038-1639585 29614520 \n45. Jungbauer L Dobias C Stollberger C Weidinger F The frequency of prescription of P-glycoprotein-affecting drugs in atrial fibrillation J Thromb Haemost 2010 8 2069 2070 10.1111/j.1538-7836.2010.03943.x 20553377 \n46. Gouin-Thibault I Delavenne X Blanchard A Siguret V Salem JE Narjoz C Interindividual variability in dabigatran and rivaroxaban exposure: contribution of ABCB1 genetic polymorphisms and interaction with clarithromycin J Thromb Haemost 2017 15 273 283 10.1111/jth.13577 27893182 \n47. Antoniou T Macdonald EM Yao Z Hollands S Gomes T Tadrous M Association between statin use and ischemic stroke or major hemorrhage in patients taking dabigatran for atrial fibrillation CMAJ 2017 189 E4 e10 10.1503/cmaj.160303 28246253 \n48. Hernandez I Baik SH Pinera A Zhang Y Risk of bleeding with dabigatran in atrial fibrillation JAMA Intern Med 2015 175 18 24 10.1001/jamainternmed.2014.5398 25365537 \n49. Quinn GR Singer DE Chang Y Go AS Borowsky LH Udaltsova N Effect of selective serotonin reuptake inhibitors on bleeding risk in patients with atrial fibrillation taking warfarin Am J Cardiol 2014 114 583 586 10.1016/j.amjcard.2014.05.037 25001151 \n50. Dessilly G Panin N Elens L Haufroid V Demoulin JB Impact of ABCB1 1236C > T-2677G > T-3435C > T polymorphisms on the anti-proliferative activity of imatinib, nilotinib, dasatinib and ponatinib Sci Rep 2016 6 29559 10.1038/srep29559 27405085 \n51. Salama NN Yang Z Bui T Ho RJ MDR1 haplotypes significantly minimize intracellular uptake and transcellular P-gp substrate transport in recombinant LLC-PK1 cells J Pharm Sci 2006 95 2293 2308 10.1002/jps.20717 16883550 \n52. Hoffmeyer S Burk O von Richter O Arnold HP Brockmoller J Johne A Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo Proc Natl Acad Sci U S A 2000 97 3473 3478 10.1073/pnas.97.7.3473 10716719\n\n",
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"keywords": "Bleeding; Direct oral anticoagulants; Drug monitoring; Patient safety; Pharmacogenomics; Rivaroxaban",
"medline_ta": "Thromb J",
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"title": "Rivaroxaban plasma levels in patients admitted for bleeding events: insights from a prospective study.",
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"abstract": "We report a case of human herpesvirus-6 (HHV-6) encephalitis in a neutropenic patient who had undergone chemotherapy induction for acute myelogenous leukemia while on broad-spectrum antimicrobial therapy. The patient displayed symptoms of confusion, amnesia, and lethargy. Diagnosis was made via polymerase chain reaction analysis of cerebrospinal fluid. Electroencephalogram and magnetic resonance imaging of the brain were unremarkable. Following diagnosis, the patient was successfully treated with ganciclovir. HHV-6 encephalitis should be considered in immunocompromised patients who become encephalopathic.",
"affiliations": "Kansas City University of Medicine and Biosciences, Kansas City, MO, USA.;Department of Internal Medicine, University of Kansas School of Medicine - Wichita, Wichita, KS, USA.;Department of Infectious Disease, University of Kansas School of Medicine - Wichita, Wichita, KS, USA.",
"authors": "Frey|John W|JW|http://orcid.org/0000-0002-9106-3423;Cherabie|Joseph N|JN|;Assi|Maha A|MA|",
"chemical_list": "D000890:Anti-Infective Agents",
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"issue": "19(6)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "acute myelogenous leukemia; encephalitis; human herpesvirus-6; immunocompromised",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000368:Aged; D000890:Anti-Infective Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001706:Biopsy; D001853:Bone Marrow; D001921:Brain; D064146:Chemotherapy-Induced Febrile Neutropenia; D015179:Colorectal Neoplasms; D004569:Electroencephalography; D018792:Encephalitis, Viral; D015654:Herpesvirus 6, Human; D006801:Humans; D016867:Immunocompromised Host; D060828:Induction Chemotherapy; D015470:Leukemia, Myeloid, Acute; D008279:Magnetic Resonance Imaging; D008297:Male; D010198:Pancytopenia; D019349:Roseolovirus Infections; D014057:Tomography, X-Ray Computed",
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"pmid": "28746781",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Human herpesvirus-6 encephalitis following chemotherapy induction for acute myelogenous leukemia.",
"title_normalized": "human herpesvirus 6 encephalitis following chemotherapy induction for acute myelogenous leukemia"
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"abstract": "A patient with rheumatoid arthritis presented with increasing fatigue, fever, gingival bleeding, and petechial rash. Her symptoms started 1 week after the first injection of etanercept (Enbrel). Her only other medications (methotrexate and hydroxychloroquine) had been unchanged for years. Tests revealed severe pancytopenia and bone marrow aplasia. She recovered with supportive treatment within 12 days. The literature on serious blood dyscrasias associated with anti-tumor necrosis factor-α therapy is reviewed, an intriguing postulated mechanism is discussed, and selective patient monitoring is recommended.",
"affiliations": "Department of Medicine, Kaplan Medical Center, POB 1, Rehovot, 76100, Israel.",
"authors": "Kozak|Natasha|N|;Friedman|Joshua|J|;Schattner|Ami|A|",
"chemical_list": "D000900:Anti-Bacterial Agents; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor; D006886:Hydroxychloroquine; D000068800:Etanercept; D000069585:Filgrastim; D008727:Methotrexate",
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"fulltext": "\n==== Front\nDrugs R D\nDrugs R D\nDrugs in R&D\n1174-5886\n1179-6901\nSpringer International Publishing Cham\n\n24962606\n50\n10.1007/s40268-014-0050-z\nShort Communication\nEtanercept-Associated Transient Bone Marrow Aplasia: A Review of the Literature and Pathogenetic Mechanisms\nKozak Natasha\nFriedman Joshua\nSchattner Ami 972-8-939-0330 amiMD@clalit.org.il\n\nDepartment of Medicine, Kaplan Medical Center, POB 1, Rehovot, 76100 Israel\nThe Faculty of Medicine, Hebrew University and Hadassah, Jerusalem, Israel\n11 6 2014\n11 6 2014\n6 2014\n14 2 155158\n© The Author(s) 2014\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.\nA patient with rheumatoid arthritis presented with increasing fatigue, fever, gingival bleeding, and petechial rash. Her symptoms started 1 week after the first injection of etanercept (Enbrel). Her only other medications (methotrexate and hydroxychloroquine) had been unchanged for years. Tests revealed severe pancytopenia and bone marrow aplasia. She recovered with supportive treatment within 12 days. The literature on serious blood dyscrasias associated with anti-tumor necrosis factor-α therapy is reviewed, an intriguing postulated mechanism is discussed, and selective patient monitoring is recommended.\n\nissue-copyright-statement© Springer International Publishing Switzerland 2014\n==== Body\nIntroduction\n\nWith the increasing use of agents that block the action of tumor necrosis factor (TNF)-α in the treatment of rheumatoid arthritis (RA) and other chronic immune-mediated inflammatory conditions, recognition of serious adverse events assumes greater importance even when they are rare [1]. We report a patient with RA who presented with transient bone marrow (BM) aplasia associated with the first injection of etanercept, and review the literature on TNF-blocking agent-associated cytopenias.\n\nReport of a Case\n\nA 62-year-old woman was admitted with fatigue, fever (39 °C), gingival bleeding, and a rash over her legs.\n\nShe had a history of RA diagnosed 6 years prior when marked synovitis in more than ten large and small joints was found, associated with prolonged morning stiffness, elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and strongly positive rheumatoid factor and anti-citrullinated peptide antibodies (250 IU/ml and 76.6, respectively).\n\nHer recent treatment included methotrexate (22.5 mg once a week with daily folic acid) started on diagnosis, hydroxychloroquine (200 mg daily) and a single first injection of etanercept (Enbrel® 50 mg) administered subcutaneously into the thigh 23 days prior to admission.\n\nPrevious treatment with leflunomide and adalimumab (Humira®) had failed and been discontinued months before etanercept was started.\n\nNo other medications were used, and even methotrexate and hydroxychloroquine were discontinued by her rheumatologist when etanercept was commenced.\n\nOne week after the injection, she reported malaise, lassitude, and low-grade fever; those symptoms persisted over 2 weeks.\n\nA sudden appearance of high fever and rash led to her admission.\n\nOn admission, she was febrile and tachycardic but stable, with unrewarding examination except for gingival bleeding, a profuse petechial rash over both legs and polysynovitis, which was not new.\n\nLaboratory tests showed hemoglobin (Hb) 7.5 g/dl (normocytic), WBC 1.8 × 109/L with absolute neutrophil count (ANC) 0.7 × 109/L, platelets 3 × 109/L, ESR 172 mm/h, CRP 76.8 mg/dL (normal <6 mg/dL), albumin 26 g/L, and globulins 47 g/L (polyclonal). Serum creatinine, electrolytes, and liver enzymes were normal. Peripheral blood smear confirmed severe pancytopenia with absent reticulocytes (0.3 %). Bone marrow aspiration and biopsy revealed BM aplasia (Fig. 1). Methotrexate in serum was undetectable. Chest X-ray, urinalysis, and cultures were normal. Tests for other causes of cytopenias, including serology for Epstein–Barr virus (EBV), cytomegalovirus (CMV), hepatitis viruses, parvovirus B-19, and HIV were negative.Fig. 1 Patient’s bone marrow biopsy showing stroma and plasma cells (more resistant to drug toxicity) but absence of all other hematopoietic elements, consistent with transient aplasia\n\nThe patient was treated with platelets (four times), packed cells (4 U), granulocyte colony-stimulating factor (Neupogen®) over 5 days, and broad-spectrum antibiotics. She was discharged on the 12th hospital day, afebrile and stable (absolute neutrophil count [ANC] 10.5 × 109/L), for ambulatory follow-up.\n\nOne month later, the Hb was 12.4 g/dL, white blood count (WBC) 13.7 × 109/L, and platelets 149 × 109/L. The patient resumed methotrexate treatment uneventfully for more than 6 months of follow-up.\n\nDiscussion and Review of the Literature\n\nWhen serious adverse events (SAEs) associated with anti-TNFα therapy are considered, attention is usually focused on an increased risk of infections (in particular, reactivation of tuberculosis and opportunistic infections) and malignancy, though the latter remains an unresolved concern [2].\n\nHowever, anti-TNFα therapy-induced cytopenias constitute another SAE that are potentially life threatening and mandate better recognition. For example, neutropenia was reported in 14.3–18.8 % of patients receiving a TNFα inhibitor [3–5]. In most of the patients, neutropenia occurred after just 2 weeks of treatment, was mild (mean −1.1 × 109/L), transient, and showed spontaneous resolution, allowing the original treatment to be continued in most (81 %) patients. However, a few patients developed serious secondary infections (4/367, 1.1 %) [5]. Notably, asymptomatic drops in platelet counts (mean −28 × 109/L) were often associated [5]. Indeed, 19 patients with significant thrombocytopenia were identified in a recent review of the literature and, as in the case of neutropenia, almost all were due to either etanercept or infliximab [6]. No other concomitant medication was reported in most of the patients. Rarely, patients may develop both severe neutropenia and thrombocytopenia [7], whereas anemia is not usually a feature of this treatment. On the contrary, with amelioration of the underlying disease on anti-TNFα therapy, the often-present anemia of chronic inflammation frequently improves [8]. However, this therapy, especially etanercept and infliximab, may mediate a more life-threatening adverse event than neutropenia or thrombocytopenia, namely, aplastic anemia and pancytopenia. A few such patients have been identified in post-marketing reports, although the attribution of pancytopenia to the TNF inhibitor remains unclear [9]. The characteristics of all fully reported cases are summarized in Table 1. Thus, etanercept and infliximab have been linked so far to just one case of aplastic anemia each, and several patients had developed pancytopenia or aplastic anemia, which could well have been related to anti-TNFα therapy [11–16]. Most affected patients had RA, and the hematological SAE occurred predominantly after the first TNFα antagonist doses, becoming symptomatic soon after and usually responsive to drug discontinuation and supportive treatment (Table 1).Table 1 Potentially life-threatening non-malignant hematological complications associated with tumor necrosis factor-inhibitor therapy\n\nPatients\nReferences\tBackground\tTreatment\tOther potential drugs\tSAEs\tTime interval\tOutcome\tRemarks\t\n4/367 pts\n[5]\tVaried\tVaried\tUnlikely\tSevere neutropenia with serious infection\tNR\tRecovered\tBM ‘normal’ in 2 cases\t\n20M\n[10]\tCrohn’s spondylarthritis\tInfliximab [2nd]\tNone\tAgranulocytosis\tNR\tResolved, recurred after retreatment\tGranulocyte Bound Ab and neutrophil-specific bound Ab\t\n60F\n[7]\tRA\tInfliximab [3rd]\tUnlikely\tFever/chills and skin hemorrhages: profound neutropenia and thrombocytopenia\t7 weeks\tResolved\tBM Bx: hypoplasia\t\n2/61 pts\n[11]\tJuvenile Id. arthritis\tEtanercept [1st in 1 pt]\tUnlikely\tPancytopenia\t0.5; 12 months\tResolved\tOpen-label prospective study\t\n45F\n[12]\tScleroderma\tInfliximab [1st]\tNone\tSevere pancytopenia and candida peritonitis\t3 weeks\tDied\tTransient HS reaction at 6 days\t\n78M\n[13]\tRA\tEtanercept (>17th dose)\tUnlikely\tAplastic anemia and sepsis\t<3 months\tResolved over 3 weeks\tBM Bx+\t\n66M\n[14]\tRA\tInfliximab [1st]\tPossible\tSevere pancytopenia and BM hypoplasia with sepsis\t10 days\tResolved over 2 weeks\tBM Bx+\t\n32F\n[15]\tColitis\tInfliximab [1st]\tPossible (IV ATB)\tSevere pancytopenia\t6 days\tResolved over 2 weeks\t\t\n32NR\n[16]\tAnkylosing spondylitis\tInfliximab [1st]\tNone\tAplastic anemia\t4 days\tResolved over 16 days\tAssociated skin vasculitis BM Bx+\t\n62F\nCurrent\tRA\tEtanercept [1st]\tUnlikely\tTransient BM aplasia\t2 weeks\tResolved over 12 days\tBM Bx+\t\nAb antibodies, BM bone marrow, Bx biopsy, F female, HS hypersensitivity, Id. idiopathic, IV ATB intravenous antibiotics, M male, NR not reported, pt(s) patient(s), RA rheumatoid arthritis, SAE serious adverse event, + postive\n\nOur patient presented with symptoms and signs related to all three cytopenias: fatigue (due to anemia); fever that responded to broad spectrum antibiotics (due to severe neutropenia); and petechiae and gingival bleeding (due to severe thrombocytopenia). The absence of concomitant drugs (she had been receiving methotrexate and hydroxychloroquine for years) as well as the temporal relationship between the appearance of her symptoms and the first injection of etanercept, strongly suggest a causal link. Moreover, BM recovery from toxic injury corresponded to the discontinuation of etanercept, whereas methotrexate was later continued uneventfully for months. In contrast, in some of the other cases cited, drugs other than anti-TNFα could have been responsible.\n\nOther than listing all hitherto-reported cases of TNF blocking agent-associated aplastic anemia and pancytopenia, the literature review reveals the rarity of the association, considering that hundreds of thousands of patients have been treated. The other striking feature is the complexity of the pathogenesis. TNFα is a pleiotropic cytokine, part of a complex cytokine network that regulates hematopoiesis and may affect BM stem cells differently under different circumstances [17, 18]. On one hand, TNFα (and interferon γ) are overexpressed in the BM of patients with acquired aplastic anemia and can be involved in BM stem cell apoptosis and suppression of erythropoiesis [19, 20]. Thus, treatment with TNFα antagonists can be a useful approach to the treatment of refractory aplastic anemia [21–23]. On the other hand, under different conditions, TNFα interacting with other cytokines directly enhances the clonal growth of BM progenitors and suppresses hematopoietic stem cell apoptosis [17, 24]. Thus, its blockade can also exert a deleterious effect on hematopoiesis [6]. Since autoimmune mechanisms are believed to have a key role in the pathogenesis of idiopathic aplastic anemia [25], the association between TNF-targeted therapies and induction of autoimmune diseases (particularly, vasculitis and lupus predominantly with infliximab and etanercept) is also a tenable mechanism [26].\n\nIn conclusion, TNFα antagonists for the treatment of RA show significant benefit and are generally safe in comparison with other disease-modifying anti-rheumatic drugs [27–29]. BM suppression resulting in severe cytopenia, transient pancytopenia, or aplastic anemia is a well established but fortunately rare SAE of anti-TNFα therapy. Since a steadily increasing number of patients are being treated for longer periods, any serious adverse effect, however rare, may be encountered.\n\nMonitoring blood counts of patients starting treatment seems advisable, and we also suggest that patients should be instructed to consult their physician when unexplained fever, fatigue, or bleeding manifestations appear.\n\nConflict of interest\n\nThe authors confirm that they have no conflict of interest in connection with this manuscript.\n==== Refs\nReferences\n\n1. Hyrich KL Silman AJ Watson KD Symmons DPM Anti-tumour necrosis factor α therapy in rheumatoid arthritis: an update on safety Ann Rheum Dis 2004 63 1538 1543 10.1136/ard.2004.024737 15242866\n2. Burmester G Panaccione R Gordon KB Adalimumab: long-term safety in 23,458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn’s disease Ann Rheum Dis 2013 72 517 524 10.1136/annrheumdis-2011-201244 22562972\n3. Rajakulendran S Gadsby K Allen D Neutropenia while receiving anti-tumour necrosis factor treatment for rheumatoid arthritis Ann Rheum Dis 2006 65 1678 1679 10.1136/ard.2006.056176 17105865\n4. Bathon JM Martin RW Fleischmann RM A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis N Engl J Med 2000 343 1586 1593 10.1056/NEJM200011303432201 11096165\n5. Hastings R Ding T Butt S Neutropenia in patients receiving anti-tumor necrosis factor therapy Arthritis Care Res (Hoboken) 2010 62 764 769 10.1002/acr.20037 20535786\n6. Bessissow T Renard M Hoffman I Review article: non-malignant haematological complications of anti-tumour necrosis factor alpha therapy Aliment Pharmacol Ther 2012 36 312 323 10.1111/j.1365-2036.2012.05189.x 22725726\n7. Vidal F Fontova R Richart C Severe neutropenia and thrombocytopenia associated with infliximab Ann Intern Med 2003 139 E238 E239 10.7326/0003-4819-139-3-200308050-00021-w4\n8. Furst DE Kay J Wasko MC The effect of golimumab on haemoglobin levels in patients with rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis Rheumatology (Oxford) 2013 52 1845 1855 10.1093/rheumatology/ket233 23838027\n9. US FDA. Safety update on TNF-α antagonists: infliximab and etanercept. http://www.fda.gov/ohrms/dockets/ac/01/briefing/3779b2_01_cber_safety%20_revision2.pdf.\n10. Favalli EG Varenna M Sinigaglia L Drug-induced agranulocytosis during treatment with infliximab in enteropathic spondyloarthropathy Clin Exp Rheum 2005 23 247 250\n11. Quartier P Taupinv P Bourdeaut F Efficacy of etanercept for the treatment of juvenile idiopathic arthritis according to the onset type Arthritis Rheum 2003 48 1093 1101 10.1002/art.10885 12687553\n12. Menon Y Cucurulli E Espinoza LR Pancytopenia in a patient with scleroderma treated with infliximab Rheumatology 2003 42 1273 1274 10.1093/rheumatology/keg341 14508054\n13. Kuruvilla J Leitch HA Vickars L Aplastic anemia following administration of a tumor necrosis factor-α inhibitor Eur J Haematol 2003 71 396 398 10.1034/j.1600-0609.2003.00115.x 14667206\n14. Marchesoni A Arreghini M Panni B Battafarano N Uziel L Life-threatening bone marrow toxicity in a rheumatoid arthritis patient switched from leflunomide to infliximab Rheumatology 2003 42 193 194 10.1093/rheumatology/key051 12509641\n15. Seiderer J Goke B Ochsenkuhn T Safety aspects of infliximab in inflammatory bowel disease patients Digestion 2004 70 3 9 10.1159/000080075 15297773\n16. Ben-Salem C, Jeddi C, Fathalla N, et al. Infliximab-induced bone marrow aplasia and vasculitis. In: ISoP 9th annual Meeting, Reims, France, 2009, Abstract 10.\n17. Jacobsen SE Jacobsen FW Fahlman C Rusten LS TNF-alpha, the great imitator: role of p55 and p75 TNF receptors in hematopoiesis Stem Cells 1994 12 Suppl 1 111 126 7535144\n18. Schuettpelz LG, Link DC. Regulation of hematopoietic stem cell activity by inflammation. Front Immunol. 2013;4:204. doi:10.3389/fimmu.2013.00204. eCollection 2013.\n19. Dufour C Corcione A Svahn J Interferon gamma and tumour necrosis factor alpha are overexpressed in bone marrow T lymphocytes from paediatric patients with aplastic anaemia Br J Haematol 2001 115 1023 1031 10.1046/j.1365-2141.2001.03212.x 11843845\n20. Hara T Ando K Tsurumi H Moriwaki H Excessive production of tumor necrosis factor-alpha by bone marrow T lymphocytes is essential in causing bone marrow failure in patients with aplastic anemia Eur J Haematol 2004 73 10 16 10.1111/j.1600-0609.2004.00259.x 15182332\n21. Dufour C Ferretti E Bagnasco F Changes in cytokine profile pre- and post-immunosuppression in acquired aplastic anemia Haematologica 2009 94 1743 1747 10.3324/haematol.2009.007815 19586939\n22. Dufour C Giacchino R Ghezzi P Etanercept as a salvage treatment for refractory aplastic anemia Pediatr Blood Cancer 2009 52 522 525 10.1002/pbc.21886 19061218\n23. Fureder W Valent P Treatment of refractory or relapsed acquired aplastic anemia: review of established and experimental approaches Leuk Lymphoma 2011 52 1435 1445 10.3109/10428194.2011.568646 21635205\n24. Rezzoug F Huang Y Tanner MK TNF-alpha is critical to facilitate hemopoietic stem cell engraftment and function J Immunol 2008 180 49 57 10.4049/jimmunol.180.1.49 18097003\n25. Young NS Scheinberg P Calado RT Aplastic anemia Curr Opin Hematol 2008 15 162 168 10.1097/MOH.0b013e3282fa7470 18391779\n26. Ramos-Casals M Brito-Zeron P Munoz S Autoimmune diseases induced by TNF-targeted therapies Medicine 2007 86 242 251 10.1097/MD.0b013e3181441a68 17632266\n27. Wiens A Venson R Correr CJ Otuki MF Pontarolo R Meta-analysis of the efficacy and safety of adalimumab, etanercept, and infliximab for the treatment of rheumatoid arthritis Pharmacotherapy 2010 30 339 353 10.1592/phco.30.4.339 20334454\n28. Lethaby A, Lopez-Olivo MA, Maxwell L, et al. Etanercept for the treatment of rheumatoid arthritis. Cochrane Databases Syst Rev. 2013;(5):CD004525.\n29. Murdaca G Spano F Contratore M Efficacy and safety of etanercept in chronic immune-mediated disease Expert Opin Drug Saf 2014 13 649 661 10.1517/14740338.2014.899579 24654562\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1174-5886",
"issue": "14(2)",
"journal": "Drugs in R&D",
"keywords": null,
"medline_ta": "Drugs R D",
"mesh_terms": "D000741:Anemia, Aplastic; D000900:Anti-Bacterial Agents; D001172:Arthritis, Rheumatoid; D001853:Bone Marrow; D000068800:Etanercept; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D006886:Hydroxychloroquine; D007074:Immunoglobulin G; D008727:Methotrexate; D008875:Middle Aged; D010198:Pancytopenia; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "100883647",
"other_id": null,
"pages": "155-8",
"pmc": null,
"pmid": "24962606",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "18391779;12899609;17632266;15242866;12687553;15895899;22562972;15182332;7535144;19061218;15297773;14508054;11096165;14667206;20334454;23882270;21635205;18097003;11843845;19586939;20535786;12509641;24654562;22725726;23728649;23838027;17105865",
"title": "Etanercept-associated transient bone marrow aplasia: a review of the literature and pathogenetic mechanisms.",
"title_normalized": "etanercept associated transient bone marrow aplasia a review of the literature and pathogenetic mechanisms"
} | [
{
"companynumb": "IL-PFIZER INC-202101524595",
"fulfillexpeditecriteria": "2",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETANERCEPT"
},
"drugadditional": "3",
... |
{
"abstract": "Inflammatory myofibroblastic tumour (IMT) is a rare malignancy with limited responses to corticosteroids and chemotherapy. About half of cases have activating rearrangements in the ALK gene which could be targeted with ALK inhibitors. A 40-year-old man presented with a large right lung mass and nodal, trapezius and cerebral metastases. Biopsy confirmed IMT with TPM4-ALK fusion. He was treated with prednisolone without clinical benefit. He received the Trk/ROS1/ALK inhibitor entrectinib in a clinical trial but his disease progressed in less than 3 months. Ifosfamide and etoposide in addition to radiotherapy to the brain and chest were administered. Transient improvement in the radiotherapy-treated areas was observed but his disease progressed shortly afterwards on all sites including the development of new adrenal metastasis. Compassionate use of the third-generation ALK inhibitor lorlatinib resulted in excellent partial response on all disease sites after 2 months, followed by a further 6 months of disease stabilisation. Repeat imaging showed slight increase in size of the cerebral metastasis but stable disease elsewhere, for which he was given stereotactic radiotherapy. His disease progressed 3 months later and lorlatinib was substituted with another ALK inhibitor brigatinib but he deteriorated and died shortly afterwards. Our patient tolerated lorlatinib well for 11 months with minimal toxicities, although he developed unilateral right-sided lung consolidation that was probably related to a combination of infection, radiotherapy and lorlatinib, which needed treatment with antibiotics and corticosteroids. This case demonstrates a role of lorlatinib in the treatment of TPM4-ALK-rearranged IMT despite failure of entrectinib.",
"affiliations": "Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.",
"authors": "Wong|Han Hsi|HH|;Bentley|Helen|H|;Bulusu|Venkata Ramesh|VR|;Anyaegbu|Gloria|G|;Watkins|James|J|;Horan|Gail|G|;Hatcher|Helen|H|",
"chemical_list": "D000631:Aminopyridines; D001549:Benzamides; D007191:Indazoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; C501213:TPM4 protein, human; D014335:Tropomyosin; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C000607349:entrectinib; C000590786:lorlatinib",
"country": "England",
"delete": false,
"doi": "10.1097/CAD.0000000000000994",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-4973",
"issue": "31(10)",
"journal": "Anti-cancer drugs",
"keywords": null,
"medline_ta": "Anticancer Drugs",
"mesh_terms": "D000328:Adult; D000631:Aminopyridines; D000077548:Anaplastic Lymphoma Kinase; D001549:Benzamides; D050939:Gene Fusion; D006104:Granuloma, Plasma Cell; D006801:Humans; D007191:Indazoles; D007249:Inflammation; D007769:Lactams; D047029:Lactams, Macrocyclic; D008175:Lung Neoplasms; D008297:Male; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D017211:Treatment Failure; D014335:Tropomyosin",
"nlm_unique_id": "9100823",
"other_id": null,
"pages": "1106-1110",
"pmc": null,
"pmid": "32868646",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Lorlatinib for the treatment of inflammatory myofibroblastic tumour with TPM4-ALK fusion following failure of entrectinib.",
"title_normalized": "lorlatinib for the treatment of inflammatory myofibroblastic tumour with tpm4 alk fusion following failure of entrectinib"
} | [
{
"companynumb": "GB-TEVA-2021-GB-1980005",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nDespite the increasing cure rates for children with acute lymphoblastic leukemia (ALL), patients who relapse continue to have poor prognosis. The Children's Oncology Group (COG) conducted a limited institution Phase II trial of Campath-1H, a monoclonal antibody that targets CD52 on leukemic cells, in children with relapsed or refractory ALL.\n\n\nMETHODS\nFrom October 2005 to December 2006, 13 eligible patients were enrolled on the COG phase II study of Campath-1H (ADVL0222). Campath-1H was initially administered as an intravenous infusion over 2 hr, five times per week for 1 week, then three times per week for three additional weeks. Patients with stable disease or better on day 29 could continue on to combination therapy with Campath-1H, methotrexate, and 6-mercaptopurine for two additional cycles.\n\n\nRESULTS\nOne of 13 patients enrolled had a complete response to Campath-1H and 4 had stable disease. Dose limiting toxicity occurred in two out of nine fully evaluable patients (Grade IV pain and Grade III allergic reaction/hypersensitivity). No patients received combination therapy. Serum Campath-1H concentrations appeared to be somewhat lower in children with ALL compared with adult patients with chronic lymphocytic leukemia.\n\n\nCONCLUSIONS\nAlthough a single complete response was observed, activity of single agent Campath-1H appears limited. Our study does not support future single agent evaluation of Campath-1H in children with relapsed ALL.",
"affiliations": "Division of Oncology, Children's National Medical Center, Washington, District of Columbia 20010, USA. aangioli@cnmc.org",
"authors": "Angiolillo|Anne L|AL|;Yu|Alice L|AL|;Reaman|Gregory|G|;Ingle|Ashish M|AM|;Secola|Rita|R|;Adamson|Peter C|PC|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D000074323:Alemtuzumab",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.22209",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "53(6)",
"journal": "Pediatric blood & cancer",
"keywords": null,
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D016879:Salvage Therapy; D017211:Treatment Failure; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "978-83",
"pmc": null,
"pmid": "19637330",
"pubdate": "2009-12",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "12663634;15090452;11877305;17145843;16145065;17506867;11535503;11792397;12685828;16688777;18669463;15101704;16351633;12228210;11986207;17362994;18358930;17530018;17311819;16618945;16918530",
"title": "A phase II study of Campath-1H in children with relapsed or refractory acute lymphoblastic leukemia: a Children's Oncology Group report.",
"title_normalized": "a phase ii study of campath 1h in children with relapsed or refractory acute lymphoblastic leukemia a children s oncology group report"
} | [
{
"companynumb": "US-BAYER-200934993GPV",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALEMTUZUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Cystoisospora belli colitis is a rare complication of immunosuppression in solid organ transplant recipients. We describe a case of Cystoisospora belli infection with colitis following renal transplantation.",
"affiliations": "Department of Nephrology, Centro Hospitalar e Universitário Lisboa Central, Lisbon, Portugal.;Department of Nephrology, Centro Hospitalar e Universitário Lisboa Central, Lisbon, Portugal.;Department of Nephrology, Centro Hospitalar Universitário do Algarve, Faro, Portugal.;Department of Pathology, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal.;Department of Gastroenterology, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal.;Department of Gastroenterology, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal.;Department of Nephrology, Centro Hospitalar e Universitário Lisboa Central, Lisbon, Portugal.;Department of Nephrology, Centro Hospitalar e Universitário Lisboa Central, Lisbon, Portugal.;Department of Nephrology, Centro Hospitalar e Universitário Lisboa Central, Lisbon, Portugal.;Department of Nephrology, Centro Hospitalar e Universitário Lisboa Central, Lisbon, Portugal.",
"authors": "Marques|Joana|J|https://orcid.org/0000-0002-7216-8086;Menezes|Maria|M|;Mendes|Filipa|F|;Dutra|Eduardo|E|;Saiote|Joana|J|;Santos|Sara|S|;Cotovio|Patrícia|P|;Caeiro|Fernando|F|;Carvalho|Dulce|D|;Nolasco|Fernando|F|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13237",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "22(1)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "\nCystoisospora belli\n; colitis; eosinophilia; kidney transplant",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D003092:Colitis; D003967:Diarrhea; D006801:Humans; D016867:Immunocompromised Host; D007549:Isospora; D021865:Isosporiasis; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13237",
"pmc": null,
"pmid": "31884694",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A rare diarrheic parasite in a kidney transplant patient: Cystoisospora belli.",
"title_normalized": "a rare diarrheic parasite in a kidney transplant patient cystoisospora belli"
} | [
{
"companynumb": "PT-SA-2020SA110749",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
"d... |
{
"abstract": "Portal vein thrombosis is an unusual condition and its association with an acute cytomegalovirus (CMV) infection is known but rarely reported. We present here the case of a 24-year-old woman suffering from a symptomatic portal vein thrombosis, confirmed by CT angiography, and acute CMV-related hepatitis. Besides a second generation oral contraceptive with estrogen and progesterone, not associated with smoking, the acute CMV infection was the only cause found to have provoked the venous thrombosis; a myeloproliferative disorder or biological thrombophilia were ruled out. The patient rapidly recovered with vitamin K antagonists (VKA) anticoagulant treatment. Eighteen cases of splanchnic vein thrombosis complicating acute CMV infection were found in the literature. All patients had acute hepatitis. The outcome was usually favorable with warfarin therapy for a period lasting 3 to 7 months. Antiviral treatment (anti-CMV) was used in three cases of severe infection. The antiviral therapy was given only in immunosuppressed patients. For immunocompetent patients, CMV infection is usually asymptomatic and clinical signs are often non-specific and mild, not requiring treatment.\n\n\nCONCLUSIONS\nThis case report and the review of the literature recall the need to search for acute CMV infection in patients with portal thrombosis so a possible transient trigger for venous thromboembolism can be identified, avoiding extended anticoagulation.",
"affiliations": "Médecine vasculaire, hôpital européen Georges-Pompidou, 20, rue Leblanc, 75015 Paris, France. Electronic address: agalloula@gmail.com.;Médecine vasculaire, hôpital européen Georges-Pompidou, 20, rue Leblanc, 75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.;Médecine vasculaire, hôpital européen Georges-Pompidou, 20, rue Leblanc, 75015 Paris, France.;Équipe mobile d'infectiologie, hôpital européen Georges-Pompidou, 75015 Paris, France.;Médecine vasculaire, hôpital européen Georges-Pompidou, 20, rue Leblanc, 75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; Inserm U970, PARCC, 75015 Paris, France.;Médecine vasculaire, hôpital européen Georges-Pompidou, 20, rue Leblanc, 75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; Inserm U970, PARCC, 75015 Paris, France.",
"authors": "Galloula|A|A|;Rossi|A|A|;Gautier|V|V|;Minozzi|C|C|;Messas|E|E|;Mirault|T|T|",
"chemical_list": "D000925:Anticoagulants; D003277:Contraceptives, Oral, Combined; D003278:Contraceptives, Oral, Hormonal; D006495:Heparin, Low-Molecular-Weight; D004997:Ethinyl Estradiol; D014859:Warfarin; D016912:Levonorgestrel",
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0398-0499",
"issue": "39(3)",
"journal": "Journal des maladies vasculaires",
"keywords": "Cytomegalovirus infection; Infection à cytomégalovirus; Maladie thromboembolique veineuse; Portal vein; Veine porte; Venous thromboembolism",
"medline_ta": "J Mal Vasc",
"mesh_terms": "D000208:Acute Disease; D000925:Anticoagulants; D003277:Contraceptives, Oral, Combined; D003278:Contraceptives, Oral, Hormonal; D003586:Cytomegalovirus Infections; D004997:Ethinyl Estradiol; D005260:Female; D006495:Heparin, Low-Molecular-Weight; D006525:Hepatitis, Viral, Human; D006801:Humans; D016912:Levonorgestrel; D011169:Portal Vein; D020246:Venous Thrombosis; D014859:Warfarin; D055815:Young Adult",
"nlm_unique_id": "7707965",
"other_id": null,
"pages": "224-30",
"pmc": null,
"pmid": "24709282",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Portal vein thrombosis associated with an acute cytomegalovirus infection.",
"title_normalized": "portal vein thrombosis associated with an acute cytomegalovirus infection"
} | [
{
"companynumb": "FR-WATSON-2015-16232",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ETHINYL ESTRADIOL\\LEVONORGESTREL"
},
"drugadditio... |
{
"abstract": "A 29 year-old-man with Crohn's disease, who developed diffuse pulmonary infiltrates and hypoxemia two months following oral administration of mesalazine, was examined. Clinical findings and computed tomography were suggestive of, and lung histology was diagnostic of, bronchiolitis obliterans organizing pneumonia, also known as cryptogenic organizing pneumonia. Although the data did not allow for definitive conclusions, they did suggest that the pulmonary disease was an extraintestinal manifestation of Crohn's disease, rather than an adverse reaction to mesalazine. In fact, the patient showed clinical, radiological and functional improvements, despite the treatment with mesalazine and the withdrawal of steroid therapy.",
"affiliations": "University of Bari, Bari, Italy.",
"authors": "Carratú|Pierluigi|P|;Dragonieri|Silvano|S|;Nocerino|Maria Cristina|MC|;Trabucco|Senia Maria Rosaria|SM|;Lacedonia|Donato|D|;Parisi|Giuseppe|G|;Resta|Onofrio|O|",
"chemical_list": null,
"country": "Egypt",
"delete": false,
"doi": "10.1155/2005/784071",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1198-2241",
"issue": "12(8)",
"journal": "Canadian respiratory journal",
"keywords": null,
"medline_ta": "Can Respir J",
"mesh_terms": "D000328:Adult; D001706:Biopsy; D003424:Crohn Disease; D018549:Cryptogenic Organizing Pneumonia; D003937:Diagnosis, Differential; D006801:Humans; D008297:Male; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9433332",
"other_id": null,
"pages": "437-9",
"pmc": null,
"pmid": "16331316",
"pubdate": "2005",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of cryptogenic organizing pneumonia occurring in Crohn's disease.",
"title_normalized": "a case of cryptogenic organizing pneumonia occurring in crohn s disease"
} | [
{
"companynumb": "IT-ALLERGAN-1626581",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MESALAMINE"
},
"drugadditional": "2",
"dr... |
{
"abstract": "Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the digestive tract, followed by schwannomas, lipomas, leiomyomas, and vascular tumors. They arise more often in the stomach, followed by the small bowel, esophagus, and rectum. Imatinib mesylate, a tyrosine kinase inhibitor with activity against ABL, BCR-ABL, platelet-derived growth factor receptor-alpha (PDGFRA), and c-KIT (CD117), constitutes the cornerstone of treatment for inoperable or metastatic GIST. Cases showing disease progression or resistance to imatinib mesylate may retain their morphology or present unusual morphologic and immunohistochemical characteristics. We herein describe a case of a 67-year-old patient with a previous history of GIST of the stomach, with local recurrence, who was admitted with a workup of lung nodule on chest computed tomography as part of the routine follow-up. The nodule was resected which showed a malignant tumor composedof epithelioid cells, with an abrupt transition to chondrosarcoma. Epithelioid cells were immunostained for CD117, DOG1, and Vimentin, whereas chondrosarcomatous cells expressed only Vimentin. These findings were consistent with metachronous pulmonary metastasis of the previously diagnosed GIST with chondrosarcomatous dedifferentiation. No KIT or PDGFRA mutation was detected. A review of all accessible pertinent papers disclosed 26 similar cases with unusual morphological and immunohistochemical findings, either post-imatinib treatment or, less commonly, de novo, with heterogeneous differentiation. Awareness of the histological and immunohistochemical changes in GISTs post imatinib therapy is essential to avoid a severe diagnostic pitfall.",
"affiliations": "2nd Department of Pathology, National and Kapodistrian University of Athens, \"Attikon\" University Hospital, Athens, GRC.;2nd Department of Pathology, National and Kapodistrian University of Athens, \"Attikon\" University Hospital, Athens, GRC.;Department of Pathology, \"Vardakeion and Proion\" General Hospital of Syros, Hermoupolis, GRC.;Department of Thoracic Surgery, National and Kapodistrian University of Athens, \"Attikon\" University Hospital, Athens, GRC.;2nd Department of Internal Medicine - Propaedeutic, National and Kapodistrian University of Athens, \"Attikon\" University Hospital, Athens, GRC.;1st Department of Surgery, \"Laikon\" General University Hospital/National and Kapodistrian University of Athens, School of Medicine, Athens, GRC.;2nd Department of Pathology, National and Kapodistrian University of Athens, \"Attikon\" University Hospital, Athens, GRC.",
"authors": "Koufopoulos|Nektarios|N|;Zacharatou|Andriani|A|;Athanasiadou|Sophia|S|;Tomos|Periklis|P|;Ekonomopoulou|Panagiota|P|;Liakakos|Theodoros|T|;Panayiotides|Ioannis G|IG|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.17448",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.17448\nPathology\nGeneral Surgery\nOncology\nGastrointestinal Stromal Tumor With Chondrosarcomatous Dedifferentiation Following Imatinib Therapy\nMuacevic Alexander\nAdler John R\nKoufopoulos Nektarios 1\nZacharatou Andriani 1\nAthanasiadou Sophia 2\nTomos Periklis 3\nEkonomopoulou Panagiota 4\nLiakakos Theodoros 5\nPanayiotides Ioannis G 1\n1 2nd Department of Pathology, National and Kapodistrian University of Athens, “Attikon” University Hospital, Athens, GRC\n2 Department of Pathology, “Vardakeion and Proion” General Hospital of Syros, Hermoupolis, GRC\n3 Department of Thoracic Surgery, National and Kapodistrian University of Athens, “Attikon” University Hospital, Athens, GRC\n4 2nd Department of Internal Medicine - Propaedeutic, National and Kapodistrian University of Athens, “Attikon” University Hospital, Athens, GRC\n5 1st Department of Surgery, “Laikon” General University Hospital/National and Kapodistrian University of Athens, School of Medicine, Athens, GRC\nNektarios Koufopoulos koufonektar@yahoo.com\n25 8 2021\n8 2021\n13 8 e1744825 8 2021\nCopyright © 2021, Koufopoulos et al.\n2021\nKoufopoulos et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/68237-gastrointestinal-stromal-tumor-with-chondrosarcomatous-dedifferentiation-following-imatinib-therapy\nGastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the digestive tract, followed by schwannomas, lipomas, leiomyomas, and vascular tumors. They arise more often in the stomach, followed by the small bowel, esophagus, and rectum. Imatinib mesylate, a tyrosine kinase inhibitor with activity against ABL, BCR-ABL, platelet-derived growth factor receptor-alpha (PDGFRA), and c-KIT (CD117), constitutes the cornerstone of treatment for inoperable or metastatic GIST. Cases showing disease progression or resistance to imatinib mesylate may retain their morphology or present unusual morphologic and immunohistochemical characteristics.\n\nWe herein describe a case of a 67-year-old patient with a previous history of GIST of the stomach, with local recurrence, who was admitted with a workup of lung nodule on chest computed tomography as part of the routine follow-up. The nodule was resected which showed a malignant tumor composedof epithelioid cells, with an abrupt transition to chondrosarcoma. Epithelioid cells were immunostained for CD117, DOG1, and Vimentin, whereas chondrosarcomatous cells expressed only Vimentin. These findings were consistent with metachronous pulmonary metastasis of the previously diagnosed GIST with chondrosarcomatous dedifferentiation. No KIT or PDGFRA mutation was detected. A review of all accessible pertinent papers disclosed 26 similar cases with unusual morphological and immunohistochemical findings, either post-imatinib treatment or, less commonly, de novo, with heterogeneous differentiation.\n\nAwareness of the histological and immunohistochemical changes in GISTs post imatinib therapy is essential to avoid a severe diagnostic pitfall.\n\ngastrointestinal stromal tumor\ndedifferentiation\nstomach\ncd117\nmetastasis\nimatinib\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\npmcIntroduction\n\nGastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. They originate from or differentiate into interstitial cells of Cajal, which function as pacemaker cells [1]. They usually arise from the stomach, followed by the small bowel, esophagus, and rectum [2]; less often, GISTs have been reported in the gallbladder and appendix [1]. Moreover, so-called extra-gastrointestinal GISTs (E-GISTs) have been reported in the prostate, mesentery, omentum, retroperitoneum, scrotum, bladder, ovary, pancreas, and vagina [3]. Imatinib mesylate (IM), an oral tyrosine kinase inhibitor (TKI) targeting c-KIT (CD117), platelet-derived growth factor receptor-alpha (PDGFRA), and the fusion protein BCR-ABL [3] constitutes first-line standard treatment for locally advanced or metastatic GISTs. Patients with GIST treated with IM show a remarkable initial benefit followed, in the majority of patients, by disease progression or secondary resistance due to acquired mutations in c-KIT or PDGFRA [4]. Disease progression is manifested as general tumor expansion, resistant nodules, or new metastatic lesions [5, 6]. The majority of tumors during disease progression retain their original morphological features, while in a few cases they may develop heterogeneous differentiation [7].\n\nPost-IM treatment dedifferentiation of a spindle cell GIST, demonstrating an abrupt transition to a high-grade sarcoma with loss of CD117 and CD34 expression in the dedifferentiated component, was first described by Pauwels et al. in 2005 [5]; in 2013, Antonescu et al. described de novo GIST dedifferentiation in TKI naïve tumors [8]. Twenty-six cases of dedifferentiated GIST have so far been described [5-16], displaying a wide morphologic and immunophenotypic spectrum of dedifferentiation.\n\nWe herewith describe a case of a gastric GIST with metachronous pulmonary metastasis showing heterologous differentiation after therapy with IM; our case is the first (to our best knowledge) with chondrosarcomatous histology, thus adding another morphologic facet to GIST dedifferentiation.\n\nCase presentation\n\nA 67-year-old male was admitted to the Department of Thoracic Surgery in July 2019. Past medical history was significant for a previously (2005) operated, 10 cm large gastric GIST with metastasis to two regional lymph nodes. The patient received adjuvant therapy with IM for 24 months. Surgical resection of a recurrent tumor was performed in 2009, with a further 12-month adjuvant treatment with IM. His clinical course was uneventful until 2018 when a small lesion adjacent to the tail of the pancreas was found on abdominal computed tomography (CT). This lesion was stable until 2019 when a 1 cm tumor was found in the left lung's lower lobe on chest CT, consistent with either metastasis or a second primary (Figures 1A, 1B). Wedge resection of the lung tumor was performed.\n\nFigure 1 Chest CT revealed a 1 cm lesion in the lower lobe of the left lung (red arrows).\n\nThe resection specimen was fixed in 10% buffered formalin for 24 hours. On gross examination, a well-circumscribed, solid, gray-white, 1.3-cm-large tumor was found; it was embedded in toto. Both hematoxylin and eosin (H&E) stained and immunostained sections from the previously operated gastric tumor were retrieved from the files of the Department of Pathology and compared to those of the lung tumor. This consisted of two components: an epithelioid one, with a solid architecture, high-grade atypia, and numerous mitotic figures, with an abrupt transition to an atypical chondrogenic component, consistent with chondrosarcoma (Figures 2A-2C). Thus, whereas the primary gastric tumor was a spindle-cell GIST, the recurrent tumor had both an epithelioid and a chondrosarcomatous component. The epithelioid component expressed DOG-1 (Figure 2D) and CD117 (Figure 2E), whereas both components were immunostained for Vimentin (Figure 2F); CKAE1/AE3, CK5/6, p63, TTF1, Napsin A, and CD99 immunostains were uniformly negative. Analysis through immunostains performed at the initial diagnosis showed both the primary gastric tumor and the recurrence to be positive for CD117, CD34, and Vimentin and negative for CKAE1/AE3 SMA, Desmin, and S100 protein. A diagnosis of a malignant pulmonary neoplasm with morphological and immunohistochemical features consistent with metastasis of the previously diagnosed gastric GIST, with heterologous chondrosarcomatous dedifferentiation, was rendered.\n\nFigure 2 The lung metastasis showed a biphasic appearance consisting of epithelioid and chondrosarcomatous components (A-C). Epithelioid areas stained diffusely for DOG1 (D) and CD117 (E), while Vimentin showed uniform staining in all tumors cells (F).\n\nMutational analysis with real-time PCR technique was performed on samples from the primary tumor, the local recurrence, and both differentiated and dedifferentiated areas of the pulmonary tumor, revealing no KIT or PDGFRA mutation. IM treatment was resumed. Four months later, abdominal CT showed a decrease in the size of the juxtapancreatic tumor. The patient is currently still on IM.\n\nDiscussion\n\nGISTs are the commonest mesenchymal tumors of the digestive tract, usually displaying spindle cell morphology, with epithelioid or mixed patterns being less frequent. All subtypes have uniform nuclei and usually display low mitotic activity [1].\n\nImmunostaining for CD117, DOG1, and CD34 clinches the diagnosis of GIST; CD117 stains ca 95% of tumors, DOG1 75%-100%, and CD34 60%-70% of tumors [1]. Neoplastic cells may less often be decorated for SMA, S-100 protein, desmin, or keratin [17].\n\nMost GISTs have KIT gene mutations, most commonly located in exon 11 and less often in exons 9, 13, or 17 [18-20]. PDGFRA gene mutations occur less frequently (10%-15% of GISTs) involving exons 12, 14, or 18 [21]. KRAS mutations have been reported in 5% of GISTs and may be related to a possible novel mechanism of primary resistance to IM [22]. Wild type KIT/PDGFRA/RAS GISTs may harbor succinate dehydrogenase deficiencies [23] or BRAF exon 15 V600E mutations [24,25].\n\nFew cases of GIST dedifferentiation have previously been reported: a review of the pertinent English literature yielded 12 papers describing 26 cases with unusual morphological and/or immunohistochemical findings, either de novo or after therapy with TKIs [5-16]. Four papers described eight, five, three, and two cases, respectively, whereas the remaining eight were single case reports. Patient ages ranged from 23 to 75 years (median 55 years); 20 patients were male and six female. The primary tumor was located in the stomach (15 cases), small bowel (seven cases), colon (two cases), and rectum (one case), with a single retroperitoneal E-GIST. Demographic and clinicopathological data of all cases are summarized in Table 1.\n\nTable 1 Demographic and clinical data of dedifferentiated GISTs\n\nM: male, F: female, LNs: lymph nodes, LR: local recurrence, NA: not available, NM: not mentioned, DOD: died of disease, AWD: alive with disease, ANED: Alive with no evidence of disease, mo: months, * tumors with de novo dedifferentiation, **previous IM treatment for chronic myeloid leukemia.\n\nCase\tAuthor\tYear\tAge\tSex\tTumor size\tTumor location\tMetastases at presentation\tLR/ Metachronous Metastases\tOutcome (mo)\t\n1\tPauwels et al. [5]\t2005\t37\tM\tNA\tStomach\tNo\tAbdominal, disseminated\tDOD\t\n2\tPauwels et al. [5]\t2005\t46\tM\t17 cm\tSmall bowel\tNo\tLiver\tANED 31\t\n3\tPauwels et al. [5]\t2005\t73\tM\t7.5 cm\tRectum\tNo\tLiver, peritoneum\t AWD 88\t\n4\tLiegl et al. [9]\t2009\t53\tM\t15 cm\tSmall bowel\tNo\tLiver, abdominal\tDOD 87\t\n5\tLiegl et al. [9]\t2009\t39\tF\t6 cm\tSmall bowel\tLiver, pancreas\tPeritoneal, retroperitoneal, right ovary, left lung, para-aortic LNs, L1 vertebral body\tDOD 22\t\n6\tLiegl et al. [9]\t2009\t35\tF\t10 cm\tStomach\tNo\tAbdominal, pelvic\tAWD 65\t\n7\tLiegl et al. [9]\t2009\t57\tM\t16 cm\tStomach\tNo\tAbdominal\tAWD 33\t\n8\tLiegl et al. [9]\t2009\t66\tM\t20 cm\tStomach\t No\tPeritoneal\tANED 33\t\n9\tVassos et al. [10]\t2011\t62\tF\t20 cm\tStomach\tNo\tNo\tANED 28\t\n10\tMartz et al. [11]\t2013\t65\tM\t13 cm\tSmall bowel**\tRetroperitoneal LNs\tLiver, omental, LNs\tNM\t\n11\tAntonescu et al. [8]\t2013\t23\tM\tNA\tStomach\tLiver\tLiver, peritoneal\tNM\t\n12\tAntonescu et al. [8]\t2013\t40\tF\t8 cm\tStomach*\tPeritoneum\tPeritoneal\t NM\t\n13\tAntonescu et al. [8]\t2013\t55\tM\t18 cm\tStomach*\tNo\tNo\t NM\t\n14\tAntonescu et al. [8]\t2013\t48\tM\t5.5 cm\tStomach*\tPeritoneum\tLiver, peritoneal\t NM\t\n15\tAntonescu et al. [8]\t2013\t58\tM\t6 cm\tRectum*\tNo\tNo\t NM\t\n16\tAntonescu et al. [8]\t2013\t53\tM\t7 cm\tStomach*\tLocoregional LNs\tPeritoneal\t NM\t\n17\tAntonescu et al. [8]\t2013\t60\tM\t7.5 cm\tSmall bowel\tNo\tLiver, peritoneal\t NM\t\n18\tAntonescu et al. [8]\t2013\t65\tM\t25 cm\tColon\tNo\tPeritoneal\t NM\t\n19\tJung et al. [12]\t2013\t51\tM\t11 cm\tStomach*\tLocoregional LNs, liver\tNo\tANED 10\t\n20\tChoi et al. [13]\t2014\t52\tF\t30 cm\tSmall bowel*\tNo\tNo\tNM\t\n21\tJiang et al. [6]\t2015\t47\tM\t14 cm\tStomach\tPelvis\tPelvic\tAWD 48\t\n22\tZhu et al. [7]\t2015\t57\tM\t12 cm\tRetroperitoneum\tNo\tLR after 15 mo\tDOD 42\t\n23\tJung et al. [14]\t2017\t72\tM\t7 cm\tStomach\tLiver\tLiver\tAWD 72\t\n24\tJung et al. [14]\t2017\t67\tF\t10 cm\tStomach\tNo\tNo\tANED 58\t\n25\tLi et al. [15]\t2019\t75\tM\t9.3 cm\tStomach\tNo\tNo\tANED 20\t\n26\tShah et al. [16]\t2021\t64\tM\t8cm\tSmall bowel *\tNo\tNM\tNM\t\n27\tPresent case\t2021\t52\tM\t10 cm\tStomach\tLocoregional LNs\tLR after 60 mo, lung\tAWD 190\t\n\nPretreatment specimens were available in 18 cases: 16 had spindle-cell and the remaining two epithelioid morphology. The post-treatment aspect showed a well-differentiated spindle cell proliferation consistent with GIST next to a dedifferentiated high-grade malignancy, most frequently rhabdomyosarcomatous (eight cases) [6,9,15,16], with six cases showing epithelioid/pleomorphic differentiation [5,10,13], five cases nondescript anaplastic features [8] and one each showing epithelioid/tubulopapillary [5], undifferentiated pleomorphic sarcoma [12], and angiosarcomatous [8] features. The retroperitoneal E-GIST showed rhabdomyosarcomatous and chondrosarcomatous differentiation [7], whereas two cases showed changes in the immunophenotype without corresponding morphological alterations [14]. A case that deserves separate mention presented initially as a high-grade sarcoma of the small bowel, following long-term treatment with IM for chronic myeloid leukemia [11]. The diagnosis was confirmed by the molecular demonstration of a KIT exon 11 WK557-8 deletion [8].\n\nIn cases with available pretreatment samples, tumors showed almost always positive staining for CD117 and DOG1 and less often for CD34. In post-treatment tumors, the aforementioned markers were usually expressed in areas with GIST morphology and were lost or only focally retained in the dedifferentiated component. The expression of immunohistochemical markers in de novo dedifferentiated GISTs was similar to the post-treatment samples.\n\nThe case presented by Martz et al. showed strong diffuse staining for Vimentin, scattered positivity for CD34 and CAM5.2, MNF116, and multifocal positivity for EMA, CD117, DOG1, INI-1, ERG, and desmin. Lymphoid and melanoma markers were negative.\n\nRegarding molecular findings, the three IM-resistant cases presented by Pauwels et al. had KIT exon 11 mutations [5]. In GISTs with rhabdomyoblastic differentiation, KIT exon 11 deletions [9], KIT exon 11 point mutation [6,9,15], and PDGFR exon 18 deletions [9] were detected in both components, without secondary mutations in the dedifferentiated component [9,14].\n\nThe molecular mechanism of tumor progression was investigated in three IM-treated and five IM-naïve tumors in the case series presented by Antonescu et al. [8]. Four of them had wild-type KIT, PDGFRA, and BRAF genes in both conventional and dedifferentiated components. Loss of a KIT gene copy due to haploinsufficiency was found in the dedifferentiated components of the three KIT-negative imatinib-resistant GISTs. KIT mutations in exons 11 were present in the two cases described by Jung et al. [14]. KIT mutations in exons 11 and 13 were present in two IM-treated tumors. Loss of heterozygosity or low-level KIT amplification was the most common finding in the dedifferentiated components [8]. KIT and KRAS mutations were found in the CD117, DOG1, and CD34 negative GIST with anaplastic dedifferentiation presented by Martz et al. [11].\n\nSeven tumors with de novo dedifferentiation have been described [8,12,13]. Antonescu et al. found KIT mutations on exon 11 in three out of five cases. The other two tumors were wild-type with lower levels of KIT amplification as compared to that of the KIT-positive component with classic GIST morphology. KIT exon 11 mutation was detected in the case reported by Jung et al. [12]. GISTs of the small intestine reported by Choi et al. and Shah et al. were wild type [13,16].\n\nThe above findings suggest that dedifferentiation with loss of KIT expression may not be related to additional mutations in the original driver oncogene; dedifferentiation could result from alternative escape mechanisms driven by KIT-independent signaling pathways [1].\n\nFollow-up information was available in 15 cases, ranging from 10 to 87 months. Six patients were alive with no evidence of disease, five were alive with disease, and four died of the disease.\n\nGIST dedifferentiation might cause diagnostic problems for the inexperienced pathologist. Malignant \"Triton\" tumor, dedifferentiated liposarcoma, desmoid fibromatosis, or collision tumors are significant diagnostic problems. In difficult or doubtful cases, extensive sampling, detailed morphological analysis, appropriate use of immunohistochemical markers, and mutational analysis are the key to the correct diagnosis.\n\nIn our case, due to the biphasic (epithelioid and chondrosarcomatous) morphology, the differential diagnosis included sarcomatoid carcinoma of the lung; immunopositivity of neoplastic cells for CD117, DOG1, and negative staining for epithelial markers as well as for TTF1, Napsin A, and p63 resolved the diagnostic problem.\n\nConclusions\n\nWe herein present the first (to our best knowledge) case of dedifferentiated GIST with heterologous, chondrosarcomatous differentiation, after treatment with IM. Awareness of the histological and immunohistochemical changes in GISTs, usually post-IM treatment, is essential to avoid severe diagnostic pitfalls. Furthermore, precise early diagnosis of dedifferentiation will lead to correct therapeutic decisions.\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 Dedifferentiated gastrointestinal stromal tumor: recent advances Ann Diagn Pathol Karakas C Christensen P Baek D Jung M Ro JY 118 124 39 2019 30661742\n2 Gastrointestinal stromal tumors and leiomyosarcomas J Surg Oncol Katz SC DeMatteo RP 350 359 97 2008 18286477\n3 Primary prostatic extragastrointestinal stromal tumor: a case report and literature review J Int Med Res You YH Zhang Y 4343 4349 46 2018 30152251\n4 Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor J Clin Oncol Heinrich MC Maki RG Corless CL 5352 5359 26 2008 18955458\n5 Changing phenotype of gastrointestinal stromal tumours under imatinib mesylate treatment: a potential diagnostic pitfall Histopathology Pauwels P Debiec-Rychter M Stul M De Wever I Van Oosterom AT Sciot R 41 47 47 2005 15982322\n6 Rhabdomyosarcomatous transformation of a gastrointestinal stromal tumor following treatment with iImatinib Case Rep Oncol Med Jiang X Anderson HB Guy CD Mosca PJ Riedel RF Cardona DM 317493 2015 2015 25694839\n7 Recurrent retroperitoneal extra-GIST with rhabdomyosarcomatous and chondrosarcomatous differentiations: a rare case and literature review Int J Clin Exp Pathol Zhu P Fei Y Wang Y Ao Q Wang G 9655 9661 8 2015 26464733\n8 Dedifferentiation in gastrointestinal stromal tumor to an anaplastic KIT-negative phenotype: a diagnostic pitfall: morphologic and molecular characterization of 8 cases occurring either de novo or after imatinib therapy Am J Surg Pathol Antonescu CR Romeo S Zhang L 385 392 37 2013 23348204\n9 Rhabdomyosarcomatous differentiation in gastrointestinal stromal tumors after tyrosine kinase inhibitor therapy: a novel form of tumor progression Am J Surg Pathol Liegl B Hornick JL Antonescu CR Corless CL Fletcher CD 218 226 33 2009 18830121\n10 An unusual and potentially misleading phenotypic change in a primary gastrointestinal stromal tumour (GIST) under imatinib mesylate therapy Virchows Arch Vassos N Agaimy A Schlabrakowski A Hohenberger W Schneider-Stock R Croner RS 363 369 458 2011 21191613\n11 High-grade KIT-negative sarcoma of the small bowel in a patient with chronic myeloid leukemia receiving long-term tyrosine kinase inhibitors J Clin Oncol Martz J Jain S Vahdat LT Qin L Mosquera JM Antonescu CR Popa EC 0 5 31 2013\n12 Gastrointestinal stromal tumor with dedifferentiation to undifferentiated pleomorphic sarcoma Pathol Int Jung JH Im S Choi HJ Lee YS Jung ES 479 482 63 2013 24200161\n13 Dedifferentiated gastrointestinal stromal tumor arising de novo from the small intestine Pathol Res Pract Choi JJ Sinada-Bottros L Maker AV Weisenberg E 264 266 210 2014 24484970\n14 Gastrointestinal stromal tumor of unusual phenotype after imatinib treatment: a case report and diagnostic utility of ETV1 mRNA in situ hybridization Medicine (Baltimore) Jung M Park SH Jeon YK Won JK Yang HK Kim WH 0 96 2017\n15 Case report of rhabdomyosarcomatous transformation of a primary gastrointestinal stromal tumor (GIST) BMC Cancer Li L Khalili M Johannes G 913 19 2019 31514735\n16 Rare case of a duodenal de novo dedifferentiated gastrointestinal stromal tumour BMJ Case Rep Shah PA Babu R Uthaiah SB Patil S 0 14 2021\n17 Diagnosis of gastrointestinal stromal tumors: a consensus approach Hum Pathol Fletcher CD Berman JJ Corless C 459 465 33 2002 12094370\n18 Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors Science Hirota S Isozaki K Moriyama Y 577 580 279 1998 9438854\n19 Biology of gastrointestinal stromal tumors J Clin Oncol Corless CL Fletcher JA Heinrich MC 3813 3825 22 2004 15365079\n20 Frequent KIT mutations in human gastrointestinal stromal tumors Sci Rep Xu Z Huo X Tang C 5907 4 2014 25080996\n21 Analysis of mutation of the c-Kit gene and PDGFRA in gastrointestinal stromal tumors Exp Ther Med Xu CW Lin S Wang WL 1045 1051 10 2015 26622437\n22 KRAS and BRAF mutations predict primary resistance to imatinib in gastrointestinal stromal tumors Clin Cancer Res Miranda C Nucifora M Molinari F 1769 1776 18 2012 22282465\n23 Succinate dehydrogenase - Assembly, regulation and role in human disease Mitochondrion Rutter J Winge DR Schiffman JD 393 401 10 2010 20226277\n24 BRAF mutation status in gastrointestinal stromal tumors Am J Clin Pathol Hostein I Faur N Primois C 141 148 133 2010 20023270\n25 V600E BRAF mutations are alternative early molecular events in a subset of KIT/PDGFRA wild-type gastrointestinal stromal tumours J Clin Pathol Agaimy A Terracciano LM Dirnhofer S Tornillo L Foerster A Hartmann A Bihl MP 613 616 62 2009 19561230\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(8)",
"journal": "Cureus",
"keywords": "cd117; dedifferentiation; gastrointestinal stromal tumor; imatinib; metastasis; stomach",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e17448",
"pmc": null,
"pmid": "34589354",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports",
"references": "9438854;21191613;30152251;18955458;15982322;31514735;29245294;23439757;33962926;30661742;26622437;15365079;20023270;25080996;18830121;23348204;20226277;22282465;24200161;12094370;19561230;18286477;25694839;26464733;24484970",
"title": "Gastrointestinal Stromal Tumor With Chondrosarcomatous Dedifferentiation Following Imatinib Therapy.",
"title_normalized": "gastrointestinal stromal tumor with chondrosarcomatous dedifferentiation following imatinib therapy"
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"abstract": "To investigate the incidence and predictors of macular atrophy during treatment with aflibercept for neovascular age-related macular degeneration in Japanese patients.\n\n\n\nThis study included patients with treatment-naive subfoveal neovascular age-related macular degeneration treated from December 2012 through January 2015. Patients were treated with bi-monthly aflibercept injections after 3 monthly loading injections for the first year. Diagnosis of retinal pigment epithelial atrophy was made based on color fundus photography, spectral-domain optical coherence tomography, and fundus autofluorescence. Baseline characteristics and morphological features were analyzed for their association with the development of macular atrophy.\n\n\n\nThis study included 123 eyes that had no baseline macular atrophy and treated with aflibercept injections for 12 months. Thirteen eyes (10.6%) developed new macular atrophy at 12 months. Logistic regression analysis showed that the presence of intraretinal fluid and thinner subfoveal choroidal thickness at baseline were associated with the development of macular atrophy after aflibercept treatment.\n\n\n\nMacular atrophy developed in about 10% of eyes with neovascular age-related macular degeneration during 12 months of treatment with a fixed regimen of aflibercept. Intraretinal fluid and subfoveal choroidal thickness seem to be predictors for development of macular atrophy after anti-vascular endothelial growth factor (VEGF) therapy.",
"affiliations": "Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.",
"authors": "Kuroda|Yoshimasa|Y|;Yamashiro|Kenji|K|;Ooto|Sotaro|S|;Tamura|Hiroshi|H|;Oishi|Akio|A|;Nakanishi|Hideo|H|;Miyata|Manabu|M|;Hata|Masayuki|M|;Takahashi|Ayako|A|;Wakazono|Tomotaka|T|;Yoshimura|Nagahisa|N|;Tsujikawa|Akitaka|A|",
"chemical_list": "D011993:Recombinant Fusion Proteins; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor",
"country": "United States",
"delete": false,
"doi": "10.1097/IAE.0000000000001765",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0275-004X",
"issue": "38(9)",
"journal": "Retina (Philadelphia, Pa.)",
"keywords": null,
"medline_ta": "Retina",
"mesh_terms": "D000368:Aged; D004305:Dose-Response Relationship, Drug; D005260:Female; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D005654:Fundus Oculi; D006801:Humans; D058449:Intravitreal Injections; D008266:Macula Lutea; D008297:Male; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins; D012189:Retrospective Studies; D013997:Time Factors; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D057135:Wet Macular Degeneration",
"nlm_unique_id": "8309919",
"other_id": null,
"pages": "1743-1750",
"pmc": null,
"pmid": "28691937",
"pubdate": "2018-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "MACULAR ATROPHY AND MACULAR MORPHOLOGY IN AFLIBERCEPT-TREATED NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.",
"title_normalized": "macular atrophy and macular morphology in aflibercept treated neovascular age related macular degeneration"
} | [
{
"companynumb": "JP-REGENERON PHARMACEUTICALS, INC.-2017-19313",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AFLIBERCEPT"
},
"drugaddi... |
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"abstract": "BACKGROUND\nLatent tuberculosis infection (LTBI) describes the dormant state of tuberculosis (TB), in which persistent immune-related interaction between TB and T-cells maintain its state. Cabazitaxel (CBZ) is reported to improve overall survival in patients with castration-resistant prostate cancer (CRPC) after progression observed in regimens including docetaxel. CBZ is known for severe myelosuppression; however there is no recommendation for the treatment of LTBI before CBZ treatment. To the authors' knowledge, this is the first report to describe reactivation of LTBI induced by CBZ.\nA 75-year-old Japanese male with a medical history of TB since 16 years of age had been treated for prostate cancer (PC) (initial prostate-specific antigen 532 ng/ml; cT4N1M1b; Gleason score4+4) with androgen deprivation therapy, abiraterone, and docetaxel. Calcified nodules and radiological findings of LTBI were present in the upper right lobe since the diagnosis of PC. After progression was observed during these treatments, CBZ was administered combined with pegfilgrastim, long-acting granulocyte colony-stimulating factor (G-CSF). Seven days after the third course of CBZ, he was admitted to the authors' hospital to treat febrile neutropenia (FN). High fever persisted even after myelosuppression had recovered. Computed tomography (CT) revealed distribution of small nodules in the bilateral lungs, for which miliary TB was included in the differential diagnosis. T-Spot, interferon-gamma-release assay, and bronchoscopy yielded no significant findings; however, sputum and urine culture confirmed the diagnosis of TB.\n\n\nMETHODS\nCT, sputum and urine culture confirmed the diagnosis of miliary TB.\n\n\nMETHODS\nThe patient was treated with anti-bacterial therapy (cefepime) on hospital admission, which was not effective. After the diagnosis of miliary TB was confirmed, anti-TB drugs, including isoniazid, rifampicin, pyrazinamide and ethambutol, were administered.\n\n\nRESULTS\nDespite anti-TB therapy, high fever persisted and radiological findings worsened. Fifty days after the third course of CBZ, the patient died of respiratory dysfunction caused by progression of miliary TB.\n\n\nCONCLUSIONS\nManagement of LTBI is needed in cases of radiographic findings of LTBI and medical history of TB before CBZ treatment, despite the rarity of LTBI reactivation in patients with PC.",
"affiliations": "Department of Urology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.",
"authors": "Hashimoto|Mamoru|M|;Minami|Takafumi|T|;Hamaguchi|Mamoru|M|;Fujimoto|Saizo|S|;Takahashi|Tomoki|T|;Kikuchi|Takashi|T|;Adomi|Shogo|S|;Banno|Eri|E|;Ohzeki|Takayuki|T|;Shimizu|Nobutaka|N|;Mori|Yasunori|Y|;Nozawa|Masahiro|M|;Nose|Kazuhiro|K|;Yoshimura|Kazuhiro|K|;Uemura|Hirotsugu|H|",
"chemical_list": "D000995:Antitubercular Agents; D043823:Taxoids; C552428:cabazitaxel",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000018436",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31861013MD-D-19-0505010.1097/MD.0000000000018436184367300Research ArticleClinical Case ReportReactivation of latent tuberculosis infection induced by cabazitaxel in a patient with prostate cancer A case reportHashimoto Mamoru MDMinami Takafumi MD, PhDHamaguchi Mamoru MDFujimoto Saizo MDTakahashi Tomoki MDKikuchi Takashi MDAdomi Shogo MDBanno Eri MD, PhDOhzeki Takayuki MDShimizu Nobutaka MD, PhDMori Yasunori MDNozawa Masahiro MD, PhDNose Kazuhiro MD, PhDYoshimura Kazuhiro MD, PhDUemura Hirotsugu MD, PhD∗NA. Department of Urology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.∗ Correspondence: Hirotsugu Uemura, Department of Urology, Kindai University Faculty of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan (e-mail: huemura@med.kindai.ac.jp).12 2019 20 12 2019 98 51 e1843628 6 2019 28 10 2019 14 11 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nLatent tuberculosis infection (LTBI) describes the dormant state of tuberculosis (TB), in which persistent immune-related interaction between TB and T-cells maintain its state. Cabazitaxel (CBZ) is reported to improve overall survival in patients with castration-resistant prostate cancer (CRPC) after progression observed in regimens including docetaxel. CBZ is known for severe myelosuppression; however there is no recommendation for the treatment of LTBI before CBZ treatment. To the authors’ knowledge, this is the first report to describe reactivation of LTBI induced by CBZ.\n\nPatient concerns:\nA 75-year-old Japanese male with a medical history of TB since 16 years of age had been treated for prostate cancer (PC) (initial prostate-specific antigen 532 ng/ml; cT4N1M1b; Gleason score4+4) with androgen deprivation therapy, abiraterone, and docetaxel. Calcified nodules and radiological findings of LTBI were present in the upper right lobe since the diagnosis of PC. After progression was observed during these treatments, CBZ was administered combined with pegfilgrastim, long-acting granulocyte colony-stimulating factor (G-CSF). Seven days after the third course of CBZ, he was admitted to the authors’ hospital to treat febrile neutropenia (FN). High fever persisted even after myelosuppression had recovered. Computed tomography (CT) revealed distribution of small nodules in the bilateral lungs, for which miliary TB was included in the differential diagnosis. T-Spot, interferon-gamma-release assay, and bronchoscopy yielded no significant findings; however, sputum and urine culture confirmed the diagnosis of TB.\n\nDiagnosis:\nCT, sputum and urine culture confirmed the diagnosis of miliary TB.\n\nInterventions:\nThe patient was treated with anti-bacterial therapy (cefepime) on hospital admission, which was not effective. After the diagnosis of miliary TB was confirmed, anti-TB drugs, including isoniazid, rifampicin, pyrazinamide and ethambutol, were administered.\n\nOutcomes:\nDespite anti-TB therapy, high fever persisted and radiological findings worsened. Fifty days after the third course of CBZ, the patient died of respiratory dysfunction caused by progression of miliary TB.\n\nLessons:\nManagement of LTBI is needed in cases of radiographic findings of LTBI and medical history of TB before CBZ treatment, despite the rarity of LTBI reactivation in patients with PC.\n\nKeywords\ncabazitaxelcalcified nodulelatent tuberculosis infectionprostate cancerreactivationOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nThe term LTBI has been used since the American Thoracic Society and Centers for Disease Control and Prevention issued recommendations for targeted screening and treatment of LTBI intended to eradicate TB. They supported the concept of concentrating resources for screening and treatment of LTBI in individuals with significant risk factors for reactivation of LTBI. Risk factors included several cancers (hematological malignancies, lung cancer, and head and neck cancers), immune suppressive states (HIV-positivity, uncontrolled diabetes mellitus, organ transplant, substantial and long-term administration of steroids), and nodules and fibrotic scars on chest radiography, which are signs of former TB infection; however PC was not included.[1] CBZ has been reported to improve overall survival in patients with CRPC after progression observed in regimens including docetaxel.[2] CBZ is known for adverse events such as severe neutropenia, and grade 3–4 lymphopenia has been reported in up to 69% of patients.[3] LTBI is the dormant state of TB, with T-cells playing a key role in maintaining dormancy. T-cells activated in the presence of TB mediate several types of immune cells, which then form granulomas and confine TB. These immune cells constantly infiltrate the granuloma, if the balance is disturbed by certain immune suppression, disintegration of the granuloma results. Radiographic findings of LTBI are reflected by the formation of granuloma; therefore these findings may be included as risk factors.[1,4,5] Thus, careful management of LTBI in patients with typical radiological findings of former TB infection is needed before initiation of CBZ therapy, despite PC not being a risk factor. To our knowledge, we report the first case of reactivation of LTBI induced by CBZ. The patient had a history of TB in his teens, and radiological findings of the former TB infection were evident since the diagnosis of his PC. Patient has provided written informed consent for publication of the case before the administration of CBZ.\n\n2 Case report\nA 75-year-old Japanese male (height, 157 cm; body weight, 50 kg; body surface area, 1.48 m2) with a medical history of TB since 16 years of age had been treated for PC (initial prostate-specific antigen 532 ng/ml; cT4N1M1b; Gleason score 4+4) with androgen deprivation therapy, abiraterone, and docetaxel. He smoked 20 cigarettes per day since he was 20 years of age. After a total of 7 courses of monthly docetaxel (75 mg/m2), CBZ was administered at full dose (25 mg/m2). Pegfilgrastim (3.6 mg), G-CSF medication with long-acting effectiveness, was co-administered the day after each CBZ treatment. The dosage of CBZ was reduced from full to three-quarters since the beginning of second course due to FN. Despite the reduction in dosage, he was admitted to hospital to treat his FN 7 days after the third course of CBZ. Three-weekly schedule of CBZ could not be maintained due to the adverse event. Blood tests revealed white blood cell count of 580/L, with grade 4 neutropenia and grade 3 lymphopenia (160/L and 340/L, respectively). Anti-bacterial therapy (cefepime) was started to treat his FN. High fever persisted for an extended period, even after myelosuppression recovered. Compared with the chest CT before CBZ treatment (Fig. 1A), small nodular shadows distributed around the bilateral lungs emerged 15 days after the third course of CBZ (Fig. 1B), at which time miliary TB was included in the differential diagnosis. A total of 3 sputum Ziehl-Neelsen (ZN) stains performed every 24 hours for the detection of mycobacterium were all negative. High fever (approximately 39°C) persisted; therefore CT was performed once again 23 days after the third course of CBZ. Results revealed progression of a small nodular shadow and pleural effusion emerged (Fig. 1C). Bronchoscopy with bronchoalveolar lavage (BAL) performed by a pulmonologist yielded no significant findings in the respiratory tract (Fig. 1D) and ZN stain of BAL fluid was negative. T-Spot, interferon-gamma-release assay, was also negative. However, polymerase chain reaction testing of BAL fluid was positive, and mycobacterium culture of sputum and urine submitted several days previously, confirmed the diagnosis of TB with sensitivity to anti-TB drugs. Anti-TB drugs, including isoniazid, rifampicin, pyrazinamide and ethambutol were started 30 days after the third course of CBZ to treat miliary TB. Fifty days after the third course of CBZ, the patient died of respiratory dysfunction caused by progression of miliary TB. CT findings of calcified nodules, a typical finding in LTBI, were observed since the diagnosis of PC (Fig. 2).\n\nFigure 1 Compared with the findings of chest computed tomography before cabazitaxel treatment (A), small nodules distributed around the bilateral lungs (white arrows) emerged 15 days after the third course of cabazitaxel therapy (B). Findings of diffusely distributed small nodules worsened (white arrows) and pleural effusion (black arrow) was newly observed 23 days after the third course of cabazitaxel therapy (C). Bronchoscopy of the respiratory system did not yield any significant findings (D).\n\nFigure 2 Computed tomography revealing calcified nodule (white arrow) in the right upper lobe of the lung, long before or, at least since, the diagnosis of prostate cancer.\n\n3 Discussion\nTo our knowledge, there have been no reports of reactivation of LTBI caused by CBZ; the same is similarly true for docetaxel, another approved chemotherapy for the treatment of PC. Cancers such as hematological malignancies, lung cancer, and head and neck cancers, have been categorized as risk factors for reactivation of LTBI; however, PC has not been included.[1] Despite the lack of evidence, we encountered a case involving reactivation of LTBI induced by CBZ and the patient died of activated TB. Dose escalation of CBZ is reported to be linked to severe myelosuppression.[6] Despite dose reduction of CBZ and combined use of pegfilgrastim, our patient developed FN and reactivation of LTBI. The reservoir of hematopoietic stem cells is reported to malfunction in elderly individuals.[7] As such, management of LTBI is especially important for elderly individuals who undergo CBZ treatment. In terms of diagnosis of TB, CT findings of distributed nodules around the bilateral lungs, highly suspicious for miliary TB, were observed; however ZN-staining and T-Spot assay were negative. Although T-Spot is a useful method, which only requires a simple blood sample, the results are not totally reliable due to its sensitivity and specificity.[8] In patients with miliary TB, urine culture is often reported to be positive,[9] and was one of the definitive findings in our case. Therefore, in addition to sputum culture, urine culture should be performed as early as possible if miliary TB is suspected.\n\nCBZ was developed to resolve the problem of resistance of tumor cells to the other taxanes, namely, docetaxel, and paclitaxel. One of the drug-resistance features of the taxanes is explained by overexpression of P-glycoprotein 1 (P-gp), which involves efflux of the drug through an ATP-binding cassette. The poor affinity of CBZ to P-gp results in its remaining inside cancer cells and exerts its antitumor effects stronger than the other taxanes.[3,6] However, its toxicity especially severe myelosuppression, should be managed cautiously, similar to severe neutropenia managed with the use of G-CSF.[10] Grade 3–4 lymphopenia has been reported in 69% of patients treated with CBZ.[3] Moreover, pharmacodynamics of the prolonged half-life of CBZ (mean half-life, 77.3 ± 45.5 hours) expose patients to immunosuppressive states for extended periods.[6] However, management options for lymphopenia, such as G-CSF are not available. TB enters the respiratory system and is phagocytosed by macrophages that present antigens to T cells. Sensitized T cells secrete interferon-gamma, which play a central role in the formulation and maintenance of granulomas, maintain TB in a dormant state for decades.[4] Radiological findings of previous TB infection, nodules and scars on chest radiography, are included as risk factors for reactivation of LTBI.[1] These findings could reflect the formation of granuloma developed by TB. Thus, intervention for LTBI should also be considered before or during CBZ treatment, especially in patients with radiological findings of previous infection, similar to the individual described in the present report.[1,5] If the mediation of granuloma by T-cells were disturbed by immunosuppression, TB could be activated from inside the granuloma. Other immunosuppressive states, such as organ transplantation, uncontrolled diabetes mellitus, HIV positivity and anti-tumor necrosis-alpha therapy for rheumatoid arthritis, have been included as risk factors for the reactivation of LTBI.[1,11]\n\nIn Japan, the number of LTBI notification was reported to be 7255 cases in 2017, which remained virtually unchanged over the previous 5 years. Among the newly identified LTBI cases in 2017, patients 65 to 74 years of age accounted for the largest proportion (1199/7255 [16.5%]), followed by those 45 to 54 (1111/7255 [15.3%]), and 55 to 64 (1018/7255 [14.0%]) years of age.[12] A previous report describing the age distribution of PC reported that the incidence of PC turned upward at 50 years of age, which persisted until reaching a peak in the eighth decade of life.[13] Thus, these reports showed that the age distribution of LTBI and PC in elderly individuals overlapped. As such, caution should be exercised in PC patients undergoing chemotherapy with strong myelosuppressive drugs such as CBZ.\n\n4 Conclusion\nIn conclusion, careful management of LTBI before initiation of CBZ is needed because of its severe myelosuppressive properties and the incidence of LTBI overlapping with that of PC in elderly individuals.\n\nAuthor contributions\nSupervision: Kazuhiro Yoshimura, Hirotsugu Uemura.\n\nVisualization: Eri Banno, Yasunori Mori.\n\nWriting – original draft: Mamoru Hashimoto, Takafumi Minami.\n\nWriting – review & editing: Mamoru Hamaguchi, Saizo Fujimoto, Tomoki Takahashi, Takashi Kikuchi, Shogo Adomi, Takayuki Ohzeki, Nobutaka Shimizu, Masahiro Nozawa, Kazuhiro Nose.\n\nAbbreviations: BAL = bronchoalveolar lavage, CBZ = cabazitaxel, CRPC = castration-resistant prostate cancer, CT = computed tomography, FN = febrile neutropenia, G-CSF = granulocyte colony-stimulating factor, LTBI = latent tuberculosis infection, PC = prostate cancer, P-gp = P-glycoprotein 1, TB = tuberculosis, ZN = Ziehl-Neelsen.\n\nHow to cite this article: Hashimoto M, Minami T, Hamaguchi M, Fujimoto S, Takahashi T, Kikuchi T, Adomi S, Banno E, Ohzeki T, Shimizu N, Mori Y, Nozawa M, Nose K, Yoshimura K, Uemura H. Reactivation of latent tuberculosis infection induced by cabazitaxel in a patient with prostate cancer: a case report. Medicine. 2019;98:51(e18436).\n\nThe authors report no conflicts of interest.\n==== Refs\nReferences\n[1] Targeted tuberculin testing and treatment of latent tuberculosis infection. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. This is a Joint Statement of the American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC). This statement was endorsed by the Council of the Infectious Diseases Society of America. (IDSA), September 1999, and the sections of this statement . Am J Respir Crit Care Med \n2000 ;161 :S221 –47 .10764341 \n[2] de Bono JS Oudard S Ozguroglu M \nPrednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial . Lancet \n2010 ;376 :1147 –54 .20888992 \n[3] Nightingale G Ryu J \nCabazitaxel (jevtana): a novel agent for metastatic castration-resistant prostate cancer . P T \n2012 ;37 :440 –8 .23091336 \n[4] Mack U Migliori GB Sester M \nLTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement . Eur Respir J \n2009 ;33 :956 –73 .19407047 \n[5] Jonathan W. Uzorka Lucia J.M. Kroft Jaap A. Bakker \nAbnormalities suggestive of latent tuberculosis infection on chest radiography; how specific are they? \nJ Clin Tuberc Other Mycobact Dis \n2019 ;15 :100089 .31720416 \n[6] Mita AC Denis LJ Rowinsky EK \nPhase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors . Clin Cancer Res \n2009 ;15 :723 –30 .19147780 \n[7] Balducci L Hardy CL Lyman GH \nHemopoietic reserve in the older cancer patient: clinical and economic considerations . Cancer Control \n2000 ;7 :539 –47 .11088062 \n[8] Whitworth HS Badhan A Boakye AA \nClinical utility of existing and second-generation interferon-γ release assays for diagnostic evaluation of tuberculosis: an observational cohort study . Lancet Infect Dis \n2019 ;19 :193 –202 .30655049 \n[9] Yokoyama T Kinoshita T Okamoto M \nHigh detection rates of urine mycobacterium tuberculosis in patients with suspected miliary tuberculosis . Intern Med \n2017 ;56 :895 –902 .28420836 \n[10] Schouten HC \nNeutropenia management . Ann Oncol \n2006 ;17 Suppl 10 :x85 –9 .17018758 \n[11] Xie X Li F Chen JW \nRisk of tuberculosis infection in anti-TNF-α biological therapy: from bench to bedside . J Microbiol Immunol Infect \n2014 ;47 :268 –74 .23727394 \n[12] Department of Epidemiology and Clinical Research, the Research Institute of Tuberculosis , Kawatsu L Izumi K Uchimura K \nTuberculosis in Japan-annual report 2018 . 2018 .\n[13] Baade PD Youlden DR Cramb SM \nEpidemiology of prostate cancer in the Asia-Pacific region . Prostate Int \n2013 ;1 :47 –58 .24223402\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "98(51)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000368:Aged; D000995:Antitubercular Agents; D017809:Fatal Outcome; D006801:Humans; D055985:Latent Tuberculosis; D008297:Male; D011471:Prostatic Neoplasms; D043823:Taxoids; D014391:Tuberculosis, Miliary",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e18436",
"pmc": null,
"pmid": "31861013",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "31720416;17018758;30655049;10764341;20888992;23091336;11088062;19407047;23727394;19147780;24223402;28420836",
"title": "Reactivation of latent tuberculosis infection induced by cabazitaxel in a patient with prostate cancer: A case report.",
"title_normalized": "reactivation of latent tuberculosis infection induced by cabazitaxel in a patient with prostate cancer a case report"
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"companynumb": "JP-SAKK-2019SA147915AA",
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"activesubstancename": "PREDNISOLONE"
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{
"abstract": "OBJECTIVE\nTo report a case of panhypopituitarism in a patient receiving long-term intrathecal opioids.\n\n\nMETHODS\nThis is a case study and review of current medical literature. There is a 7-year follow-up time.\n\n\nMETHODS\nOne adult male clinic patient with pituitary dysfunction.\n\n\nMETHODS\nIntrathecal opioids may lead to pituitary dysfunction.\n\n\nRESULTS\nIntrathecal opioid pain management may produce some generalized effects, as well as pituitary hypofunction, as evidenced by this case. This patient experienced simultaneous suppression of multiple anterior pituitary hormones, which persisted with chronic oral opioid therapy following cessation of an intrathecal opioid pump.\n\n\nCONCLUSIONS\nAll hypothalamic pituitary axes, seem potentially vulnerable to therapy with intrathecal opioids. When patients are receiving these medications, symptoms need to be critically evaluated with appropriate laboratory assessments for suspected pituitary dysfunction. Further studies are required in order to create formal recommendations for routine patient surveillance during intrathecal opioid therapy.",
"affiliations": "PGY-3, Marianjoy Rehabilitation Hospital, Frankfort, Illinois.",
"authors": "Xenidis|Melissa|M|;Pandya|Naushira|N|;Hames|Elizabeth|E|",
"chemical_list": "D000701:Analgesics, Opioid; D009020:Morphine",
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"issue": "14(11)",
"journal": "Pain medicine (Malden, Mass.)",
"keywords": "Chronic Pain; Opioids",
"medline_ta": "Pain Med",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D006801:Humans; D007018:Hypopituitarism; D015918:Infusion Pumps, Implantable; D060186:Infusions, Spinal; D008297:Male; D009020:Morphine; D010902:Pituitary Gland",
"nlm_unique_id": "100894201",
"other_id": null,
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"pubdate": "2013-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Effects of intrathecal opioid administration on pituitary function.",
"title_normalized": "effects of intrathecal opioid administration on pituitary function"
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"companynumb": "US-MYLANLABS-2015M1007751",
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"abstract": "Although endometrial cancer, the most common gynecologic malignancy, is most often diagnosed in postmenopausal women, it affects young women who wish to preserve fertility. The purpose of this article is to describe 2 cases of stage IA endometrial cancer managed conservatively by a combination of hysteroscopic surgery and medical therapy for fertility-sparing purposes, one of which achieved successful pregnancy using assisted reproductive technology, and review the existing literature on the use of hysteroscopic resection in conservative management of endometrial cancer to preserve fertility. The addition of hysteroscopic resection to conservative management of early-stage endometrial carcinoma may be a way to improve response and recurrence rates in women wishing to preserve fertility and can offer other additional benefits, such as a shorter time period to remission and a faster return to fertility. Key factors to success with this approach include an interdisciplinary approach, thorough patient counseling, and the availability of a team experienced in hysteroscopic resection.",
"affiliations": "Department of Obstetrics and Gynecology, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada. Electronic address: kristina.arendas@gmail.com.;Department of Obstetrics and Gynecology, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada.;Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada.;Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Ottawa, Ottawa, Ontario, Canada.;Department of Obstetrics and Gynecology, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada.",
"authors": "Arendas|Kristina|K|;Aldossary|Mona|M|;Cipolla|Amanda|A|;Leader|Arthur|A|;Leyland|Nicholas A|NA|",
"chemical_list": "D018931:Antineoplastic Agents, Hormonal; D017258:Medroxyprogesterone Acetate",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1553-4650",
"issue": "22(1)",
"journal": "Journal of minimally invasive gynecology",
"keywords": "Conservative management; Endometrial cancer; Fertility preservation; Hysteroscopy",
"medline_ta": "J Minim Invasive Gynecol",
"mesh_terms": "D000328:Adult; D018931:Antineoplastic Agents, Hormonal; D024221:Antineoplastic Protocols; D002277:Carcinoma; D004107:Dilatation and Curettage; D019468:Disease Management; D016889:Endometrial Neoplasms; D005260:Female; D059247:Fertility Preservation; D006801:Humans; D015907:Hysteroscopy; D017258:Medroxyprogesterone Acetate; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011247:Pregnancy; D016896:Treatment Outcome",
"nlm_unique_id": "101235322",
"other_id": null,
"pages": "34-9",
"pmc": null,
"pmid": "25196160",
"pubdate": "2015-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Hysteroscopic resection in the management of early-stage endometrial cancer: report of 2 cases and review of the literature.",
"title_normalized": "hysteroscopic resection in the management of early stage endometrial cancer report of 2 cases and review of the literature"
} | [
{
"companynumb": "CA-BAYER-2015-014005",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEVONORGESTREL"
},
"drugadditional": null,
... |
{
"abstract": "Although end-organ damage caused by AL amyloidosis historically portends a poor prognosis, advances in therapy in combination with solid organ transplantation can lead to significant improvements in survival. Immunomodulatory agents (IMiDs), such as lenalidomide and pomalidomide, are an effective class of drugs in the treatment of AL amyloidosis. However, there is growing concern that these agents may precipitate acute transplant rejection via upregulation of interleukin-2 and inhibition of immune tolerance. This case series describes three patients who underwent orthotopic heart transplantation for AL amyloidosis and later had progression of their underlying plasma cell dyscrasia, leading to treatment with IMiD therapy. Two patients subsequently developed acute allograft rejection, including the first reported case of pomalidomide-associated allograft rejection. The third patient tolerated long-term therapy without signs of rejection: the first reported case of IMiD tolerability after heart transplant. These cases, together with a review of the literature, demonstrate variable outcomes and elucidate the potential risk of organ rejection associated with the use of IMiDs. When treatment with IMiDs is necessary, close surveillance and modification of immunosuppression may mitigate risks of rejection and complications.",
"affiliations": "Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.;Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.;Amyloidosis Center, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts.;Amyloidosis Center, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts.",
"authors": "Qualls|David A|DA|0000-0001-5297-9685;Lewis|Gregory D|GD|0000-0001-8108-8240;Sanchorawala|Vaishali|V|0000-0002-6307-2445;Staron|Andrew|A|0000-0003-1638-4873",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.15499",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "19(11)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "AL amyloidosis; heart transplant; immunomodulatory agents; lenalidomide; pomalidomide",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000328:Adult; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D016027:Heart Transplantation; D006801:Humans; D000075363:Immunoglobulin Light-chain Amyloidosis; D056747:Immunomodulation; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012307:Risk Factors",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "3185-3190",
"pmc": null,
"pmid": "31207062",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Orthotopic heart transplant rejection in association with immunomodulatory therapy for AL amyloidosis: A case series and review of the literature.",
"title_normalized": "orthotopic heart transplant rejection in association with immunomodulatory therapy for al amyloidosis a case series and review of the literature"
} | [
{
"companynumb": "US-CELGENEUS-USA-20190611269",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nSalmonellosis is a relatively rare complication in kidney transplant recipients that cannot be clinically distinguished from other forms of enteritis. Among kidney transplant patients, it varies broadly in intensity, and is highly associated with extra-intestinal disease, bacteremia, and, in this case, a high mortality rate.\n\n\nMETHODS\nHere we describe a clinical case of ciprofloxacin resistant salmonellosis in a kidney transplant patient.\n\n\nCONCLUSIONS\nThis case illustrates how immunosuppressed patients can be exposed to rare forms of infection, often clinically difficult to identify, and possibly with severe clinical courses and poor outcomes despite evidence-based empiric antibiotic therapy.",
"affiliations": "Universidade Federal de Juiz de Fora, Brazil.;Universidade Federal de Juiz de Fora, Brazil.;Universidade Federal de Juiz de Fora, Brazil.",
"authors": "Mendes|Matheus Miranda|MM|;Carminatti|Moisés|M|;Pinheiro|Hélady Sanders|HS|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin",
"country": "Brazil",
"delete": false,
"doi": "10.5935/0101-2800.20170014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0101-2800",
"issue": "39(1)",
"journal": "Jornal brasileiro de nefrologia : 'orgao oficial de Sociedades Brasileira e Latino-Americana de Nefrologia",
"keywords": null,
"medline_ta": "J Bras Nefrol",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin; D024881:Drug Resistance, Bacterial; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D011183:Postoperative Complications; D012475:Salmonella; D012480:Salmonella Infections; D018805:Sepsis",
"nlm_unique_id": "9426946",
"other_id": null,
"pages": "82-85",
"pmc": null,
"pmid": "28355394",
"pubdate": "2017-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe sepsis from a Ciprofloxacin resistant salmonellosis in a kidney transplant recipient.",
"title_normalized": "severe sepsis from a ciprofloxacin resistant salmonellosis in a kidney transplant recipient"
} | [
{
"companynumb": "BR-BAYER-2017-067482",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "BRASH (bradycardia, renal failure, atrioventricular-node blockers, shock, and hyperkalemia) syndrome is a recently coined term for a condition that describes the severe bradycardia and shock associated with hyperkalemia in patients on atrioventricular (AV)-node blocking agents. The proposed pathophysiology involves a precipitating event that exacerbates renal dysfunction with resulting AV-node blocker and potassium accumulation that act synergistically to precipitate bradycardia and hypotension. This syndrome may be refractory to the usual management of bradycardia. This case describes BRASH syndrome precipitated by trimethoprim/sulfamethoxazole.",
"affiliations": "Desert Regional Medical Center, Department of Emergency Medicine, Palm Springs, California.;Desert Regional Medical Center, Department of Emergency Medicine, Palm Springs, California.",
"authors": "Diribe|Nnaemeka|N|;Le|Jacqueline|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.5811/cpcem.2019.5.43118",
"fulltext": "\n==== Front\nClin Pract Cases Emerg MedClin Pract Cases Emerg MedClinical Practice and Cases in Emergency Medicine2474-252XUniversity of California Irvine, Department of Emergency Medicine publishing Western Journal of Emergency Medicine 3140310310.5811/cpcem.2019.5.43118cpcem-3-282Case ReportTrimethoprim/Sulfamethoxazole-Induced Bradycardia, Renal Failure, AV-Node Blockers, Shock and Hyperkalemia Syndrome Diribe Nnaemeka DOLe Jacqueline MDDesert Regional Medical Center, Department of Emergency Medicine, Palm Springs, CaliforniaAddress for Correspondence: Nnaemeka Diribe, DO, Desert Regional Medical Center, Department of Emergency Medicine, 1180 N. Indian Canyon Dr. Suite E418, Palm Springs, CA 92262. Email: nnaemeka.diribe@tenethealth.com.8 2019 22 7 2019 3 3 282 285 17 3 2019 06 5 2019 20 5 2019 Copyright: © 2019 Diribe et al2019This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) License. See: http://creativecommons.org/licenses/by/4.0/BRASH (bradycardia, renal failure, atrioventricular-node blockers, shock, and hyperkalemia) syndrome is a recently coined term for a condition that describes the severe bradycardia and shock associated with hyperkalemia in patients on atrioventricular (AV)-node blocking agents. The proposed pathophysiology involves a precipitating event that exacerbates renal dysfunction with resulting AV-node blocker and potassium accumulation that act synergistically to precipitate bradycardia and hypotension. This syndrome may be refractory to the usual management of bradycardia. This case describes BRASH syndrome precipitated by trimethoprim/sulfamethoxazole.\n==== Body\nINTRODUCTION\nSevere hyperkalemia can present as reversible bradycardia that mimics atrioventricular (AV) block.1 However, hyperkalemia in the setting of concomitant AV-node blocker usage can precipitate refractory bradycardia and hemodynamic instability even without a critically elevated potassium level or sizeable ingestion of AV-node blocking agents. This syndrome termed BRASH – bradycardia, renal failure, AV-node blockers, shock and hyperkalemia –is a cycle of synergy between hyperkalemia and AV-blockade that can result in cardiovascular collapse.2 It would generally be expected that the prevalence of such a condition be higher among the elderly who may be more likely to be on AV-node blocking medications and have a greater likelihood of events that precipitate renal failure.3 We report a case of BRASH syndrome occurring in a relatively young patient following a course of trimethoprim/sulfamethoxazole (TMP/SMX).\n\nCASE REPORT\nA 51-year-old male with past medical history of pituitary carcinoma with resection, metastasis to the liver, Cushing’s syndrome, hypertension, hyperlipidemia, hypothyroidism, insulin dependent diabetes mellitus, and renal insufficiency presented to the emergency department (ED) after a syncopal episode at the office of his primary care physician (PCP). He was found to have a pulse of 20 beats per minute (bpm) and blood pressure of 60/30 millimeters of mercury (mmHg) by paramedics who immediately initiated transcutaneous pacing and transported him to the ED. On arrival, the patient was somnolent but arousable, paced at 90 bpm at 70 milliamps, and persistently hypotensive with blood pressure of 80/60 mm Hg. Pacer capture was poor. His electrocardiogram (ECG) revealed third-degree AV block and marked bradycardia with heart rate of 39 bpm, peaked T waves, and widened QRS of 173 milliseconds (Image). The patient’s bradycardia was refractory to atropine, and pacing was resumed. Initial laboratory data was significant for elevated serum potassium of 8.6 millimoles per liter (mmol/L) (reference range 3.5 – 4.9 mmol/L), blood urea nitrogen (BUN) of 51 milligrams per deciliter (mg/dL) (reference range 8 – 26 mg/dL), and creatinine of 3.3 mg/dL (reference range 0.6 – 1.3 mg/dL).\n\nAccording to his PCP, his baseline creatinine level was 1.7 mg/dL. Sodium was low at 130 mmol/L (reference range 138 – 146 mmol/L), and troponin I was normal at 0.010 ng/mL (reference range 0.000 – 0.080ng/mL). Intravenous (IV) calcium chloride, insulin with dextrose, and albuterol were administered to treat his hyperkalemia. IV hydrocortisone was additionally given for potential adrenal crisis. With treatment, his heart rate and blood pressure improved to 97 bpm and 140/52 mmHg, respectively. His level of consciousness likewise was restored. Nephrology was contacted for possible dialysis, and the patient was admitted to the intensive care unit.\n\nIt was later discovered that the patient’s medications included the beta-blocker carvedilol (6.25 mg twice daily) and eplerenone (25 mg daily), a potassium-sparing diuretic. He denied any recent dosage changes or attempted overdose. Interestingly, he had been started on TMP/SMX for otitis media a week prior to presentation and had developed progressive weakness and fatigue three days after his first dose. He was being evaluated on an outpatient basis for said weakness when he had the syncopal episode. His hospital course consisted of continued therapy with additional diuresis and sodium polystyrene sulfonate, resulting in the down trending of serum potassium levels and improvement of his renal function and urine output. Within 24 hours, his potassium level corrected to 5.0 mmol/L, and therefore dialysis was not initiated. Upon discharge three days later, his potassium was 4.1 mmol/L, BUN 31 mg/dL, and creatinine 1.4 mg/dL. He was instructed to stop taking his eplerenone and was discharged in stable condition with scheduled outpatient follow-up.\n\nCPC-EM Capsule\nWhat do we already know about this clinical entity?\n\nAtrioventricular-node blockers and hyperkalemia may act in synergy to precipitate bradycardia and shock that may be refractory to usual individual therapy.\n\nWhat makes this presentation of disease reportable?\n\nThis case highlights bradycardia, renal failure, AV-node blockers, shock and hyperkalemia (BRASH) syndrome and the potentially grave risk associated with prescribing medications that can cause hyperkalemia.\n\nWhat is the major learning point?\n\nBradycardia and shock from BRASH syndrome require intervention at multiple physiologic fronts that individually may not be grossly abnormal.\n\nHow might this improve emergency medicine practice?\n\nAlgorithmic and heuristic recognition of this syndrome could aid rapid intervention by the emergency physician and improve potential morbidity and mortality.\n\nDISCUSSION\nHyperkalemia is a well-known reversible cause of heart block, arrhythmia, and syncope.3 It can be precipitated and worsened by multiple factors including medications, renal failure, mineralocorticoid deficiency, tissue necrosis, metabolic derangement and exogenous intake.4 Risk factors for medication-induced hyperkalemia include diabetes mellitus, renal insufficiency, hypoaldosteronism, and age greater than 60 years.5 There have been multiple documented cases of hyperkalemia precipitated by TMP/SMX as sole therapy6,7 or in combination with other medications.8 In fact, hyperkalemia and acute renal dysfunction have been documented with onset after therapy initiation in as quickly as 24 hours, particularly in patients with baseline renal insufficiency.9 This is due to the direct activity of the trimethoprim component of TMP/SMX in inhibiting potassium excretion by reversibly disrupting sodium reabsorption by cells in the distal nephron.10\n\nThere may also be elements of renal toxicity driven by sulfamethoxazole crystal deposition.11 Moreover, eplerenone is an aldosterone antagonist that inhibits renal secretion of potassium and sodium reabsorption, whereas carvedilol is a beta blocker that suppresses catecholamine-driven renin release while impairing cellular potassium uptake.4 Our patient was therefore on several prescribed medications with the potential to drive and worsen hyperkalemia. Particularly interesting is the notion that beta blockers can act in synergy with hyperkalemia to induce bradycardia even with only mild hyperkalemia present.3 This is achieved by the dual role beta blockers play as direct AV-node blockers in addition to maintaining higher serum potassium levels by reducing potassium excretion and impairing cellular uptake of serum potassium.4 This cycle is propagated as bradycardia worsens renal perfusion leading to a spiral of worsening hyperkalemia, renal failure and bradycardic shock, which can sometimes be refractory to usual therapy.2\n\nGiven the pathophysiology described above, it is reasonable to expect that the population most susceptible to this syndrome would include the elderly who are often on multiple medications with potential to block the AV node or depress renal function, as well as patients with baseline renal insufficiency or heart block.3,4 It is important to note that patients presenting with BRASH syndrome may be adherent to the prescribed doses of the AV-node blocker and have not ingested additional significant quantities of the medication. There may be, however, a precipitating event such as the addition of a new medication with the potential to cause hypovolemia or exacerbate baseline renal insufficiency. In this case, the initiation of antibiotic therapy with TMP/SMX worsened our patient’s already-known renal insufficiency and on top of the eplerenone and carvedilol he was taking, contributed to his overall marked hyperkalemia and bradycardia. Furthermore, a stress corticosteroid was not used during the treatment of his ear infection.\n\nManagement of BRASH syndrome involves supportive care, treatment of shock, and expeditious correction of electrolyte abnormalities (Figure). As is standard with severe symptomatic hyperkalemia, membrane stabilization must be initiated with IV administration of calcium, insulin and dextrose, beta-agonist therapy and diuresis or dialysis as needed. Volume status must be evaluated carefully and addressed since acutely anuric patients can experience fluid overload while others may be fluid depleted. Patients may require support with vasopressors if shock remains despite other therapies, in which case epinephrine and isoproterenol could be reasonable choices given their beta-receptor activity.2\n\nCONCLUSION\nBRASH – bradycardia, renal failure, AV-node blockers, shock and hyperkalemia – is a syndrome of severe bradycardic shock that is likely propagated by a synergy between AV-node blockade and hyperkalemia. The patients are generally on only prescribed doses of the AV-node blocker and present with severe bradycardia and hypotension after a precipitating event that worsens renal function. In some cases, such as the one presented here, the shock is severe enough to cause syncope. Mindfulness of the populations most likely to develop BRASH syndrome is recommended to help avoid prescribing medications that can potentially worsen renal function and predispose an already vulnerable patient to this syndrome. Immediate recognition of BRASH syndrome is likewise imperative to ensure prompt and aggressive management.\n\nSection Editors: Joel Moll, MD and Rick A. McPheeters, DO\n\nFull text available through open access at http://escholarship.org/uc/uciem_cpcem\n\nDocumented patient informed consent and/or Institutional Review Board approval has been obtained and filed for publication of this case report.\n\nConflicts of Interest: By the CPC-EM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The authors disclosed none.\n\nImage Initial electrocardiogram of 51-year-old male showing third-degree atrioventricular block with a ventricular escape rhythm. There is marked bradycardia (39 beats/minute), peaked T waves, and widened QRS (173 milliseconds).\n\nFigure Management considerations for BRASH – bradycardia, renal failure, atrioventricular-node blockers, shock, and hyperkalemia – syndrome.\n==== Refs\nREFERENCES\n1 Unterman A Moscavitch SD The silence of the atria Isr Med Assoc J 2008 10 7 556 18751643 \n2 Farkas J BRASH syndrome: bradycardia, renal failure, AV blocker, shock, hyperkalemia Available at: https://emcrit.org/pulmcrit/brash-syndrome-bradycardia-renal-failure-av-blocker-shock-hyperkalemia/ Accessed July 15, 2018 \n3 Ahmad NH Tan TL Correlation of iatrogenic mild hyperkalaemia and bradyarrhythmia: a problem of polypharmacy in elderly Med & Health 2017 12 2 329 34 \n4 Aziz EF Javed F Korniyenko A Mild hyperkalemia and low eGFR a tedious recipe for cardiac disaster in the elderly: an unusual reversible cause of syncope and heart block Heart Int 2011 6 2 e12 22049311 \n5 Ponce SP Jennings AE Madias NE Drug-induced hyperkalemia Medicine (Baltimore) 1985 64 6 357 70 2865667 \n6 Velazquez H Perazella MA Wright FS Renal mechanism of trimethoprim-induced hyperkalemia Ann Intern Med 1993 119 4 296 301 8328738 \n7 Greenberg S Reiser IW Chou SY Trimethoprim-sulfamethoxazole induces reversible hyperkalemia Ann Intern Med 1993 119 4 291 5 8328737 \n8 Antoniou T Gomes T Juurlink DN Trimethoprim-sulfamethoxazole–induced hyperkalemia in patients receiving inhibitors of the renin-angiotensin system: a population-based study Arch Intern Med 2010 170 12 1045 9 20585070 \n9 Nucera G Raffaelli V Caliari L Trimethoprim/sulfamethoxazole-induced acute renal failure: a case report 2017 Available at: http://journalhss.com/wp-content/uploads/jhhs22_215-220.pdf Accessed July 15, 2018 \n10 Choi MJ Fernandez PC Patnaik A Brief report: trimethoprim-induced hyperkalemia in a patient with AIDS N Engl J Med 1993 328 10 703 6 8433730 \n11 Shrishrima K Wesson J Sulfamethoxazole crystalluria Am J Kidney Dis 2011 58 3 492 3\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2474-252X",
"issue": "3(3)",
"journal": "Clinical practice and cases in emergency medicine",
"keywords": null,
"medline_ta": "Clin Pract Cases Emerg Med",
"mesh_terms": null,
"nlm_unique_id": "101718968",
"other_id": null,
"pages": "282-285",
"pmc": null,
"pmid": "31403103",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports",
"references": "18751643;20585070;21856494;22049311;2865667;8328737;8328738;8433730",
"title": "Trimethoprim/Sulfamethoxazole-Induced Bradycardia, Renal Failure, AV-Node Blockers, Shock and Hyperkalemia Syndrome.",
"title_normalized": "trimethoprim sulfamethoxazole induced bradycardia renal failure av node blockers shock and hyperkalemia syndrome"
} | [
{
"companynumb": "US-ACCORD-152770",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
"drugadditional": "... |
{
"abstract": "Pneumatosis cystoides intestinalis is characterized by multiple air-filled cysts in the intestine wall. A perforation causes pneumoperitoneum, frequently with minimal clinical affectation and do not require surgery at first in most cases. Recently, some cancer treatments, mainly molecular targeted therapy, have been associated with this complication. For this reason, radiologic findings of intestinal pneumatosis and/or secondary perforation during patient follow-up should be carefully interpreted. The clinical-analytical findings should always be considered. We report a case associated with the use of tyrosine kinase inhibitors in order to illustrate this point.",
"affiliations": "Aparato Digestivo, Complejo Hospitalario de Granada, España.;Radiodiagnóstico, Hospital General Universitario, Ciudad Real.;Medicina Interna, Hospital Virgen de Altagracia de Manzanares.",
"authors": "Martín-Lagos Maldonado|Alicia|A|;Lozano Cejudo|Cristina|C|;Sáenz Lozano|Antonio|A|",
"chemical_list": "D000970:Antineoplastic Agents; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib",
"country": "Spain",
"delete": false,
"doi": "10.17235/reed.2018.5588/2018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1130-0108",
"issue": "110(8)",
"journal": "Revista espanola de enfermedades digestivas : organo oficial de la Sociedad Espanola de Patologia Digestiva",
"keywords": null,
"medline_ta": "Rev Esp Enferm Dig",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D002292:Carcinoma, Renal Cell; D006801:Humans; D007191:Indazoles; D007680:Kidney Neoplasms; D008297:Male; D011006:Pneumatosis Cystoides Intestinalis; D011027:Pneumoperitoneum; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9007566",
"other_id": null,
"pages": "531-532",
"pmc": null,
"pmid": "29900744",
"pubdate": "2018-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A pneumoperitoneum due to intestinal cystic pneumatosis associated with a tyrosine kinase inhibitor.",
"title_normalized": "a pneumoperitoneum due to intestinal cystic pneumatosis associated with a tyrosine kinase inhibitor"
} | [
{
"companynumb": "PHHY2018ES183601",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PAZOPANIB"
},
"drugadditional": "1",
"drugad... |
{
"abstract": "We describe a patient with dystonia and psychotic symptoms treated with standard doses of antipsychotics, who developed neuroleptic malignant syndrome (NMS). A 16-year-old male with a history of misuse of dextromethorphan and pseudoephedrine for recreational purpose presented with dystonia and a psychotic episode. Following continuous treatment with olanzapine (10 mg/day), repeated injections of levomepromazine (37.5 mg/day), and a single injection of haloperidol (2.5 mg), the patient developed NMS. Muscular rigidity, fever (up to 41 °C), hypotension (100/70 mmHg), tachycardia (120 beats per minute), tachypnea (26 breaths per minute), elevated leukocyte count (up to 16.6 × 10(3)/μL), and elevated serum creatinine phosphokinase (CPK) (up to 15,255 U/L) were observed. A diagnosis of NMS was made according to the DSM-IV TR criteria. Genotyping revealed that he was homozygous for a non-functional CYP2D6*4 allele. The case highlights the importance of therapeutic drug monitoring in identification and differentiation of drug-induced effects in psychiatric disorder to prevent NMS and its complications. In addition, genotyping of CYP2D6 might be considered in patients with symptoms suggestive of drug toxicity who are treated with neuroleptics metabolized via the CYP2D6 pathway, as carriage of one or more non-functional alleles may increase the risk for adverse reactions, such as NMS.",
"affiliations": "Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, PO Box 281, 171 77, Stockholm, Sweden, agnieszka.butwicka@ki.se.",
"authors": "Butwicka|Agnieszka|A|;Krystyna|Szymańska|S|;Retka|Włodzimierz|W|;Wolańczyk|Tomasz|T|",
"chemical_list": "D004247:DNA; D019389:Cytochrome P-450 CYP2D6",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00431-013-2208-z",
"fulltext": "\n==== Front\nEur J Pediatr\nEur J Pediatr\nEuropean Journal of Pediatrics\n0340-6199\n1432-1076\nSpringer Berlin Heidelberg Berlin/Heidelberg\n\n24253372\n2208\n10.1007/s00431-013-2208-z\nCase Report\nNeuroleptic malignant syndrome in an adolescent with CYP2D6 deficiency\nButwicka Agnieszka +46-8-52482428 +46-8-314975 agnieszka.butwicka@ki.se\n\n12\nKrystyna Szymańska 2\nRetka Włodzimierz 3\nWolańczyk Tomasz 2\n1 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, PO Box 281, 171 77 Stockholm, Sweden\n2 Department of Child Psychiatry, Medical University of Warsaw, 24 Marszałkowska St., 00-575 Warsaw, Poland\n3 Department of Paediatric Anaesthesia, Medical University of Warsaw, Warsaw, Poland\n20 11 2013\n20 11 2013\n2014\n173 12 16391642\n21 8 2013\n25 10 2013\n© The Author(s) 2013\nOpen Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.\nWe describe a patient with dystonia and psychotic symptoms treated with standard doses of antipsychotics, who developed neuroleptic malignant syndrome (NMS). A 16-year-old male with a history of misuse of dextromethorphan and pseudoephedrine for recreational purpose presented with dystonia and a psychotic episode. Following continuous treatment with olanzapine (10 mg/day), repeated injections of levomepromazine (37.5 mg/day), and a single injection of haloperidol (2.5 mg), the patient developed NMS. Muscular rigidity, fever (up to 41 °C), hypotension (100/70 mmHg), tachycardia (120 beats per minute), tachypnea (26 breaths per minute), elevated leukocyte count (up to 16.6 × 103/μL), and elevated serum creatinine phosphokinase (CPK) (up to 15,255 U/L) were observed. A diagnosis of NMS was made according to the DSM-IV TR criteria. Genotyping revealed that he was homozygous for a non-functional CYP2D6*4 allele. The case highlights the importance of therapeutic drug monitoring in identification and differentiation of drug-induced effects in psychiatric disorder to prevent NMS and its complications. In addition, genotyping of CYP2D6 might be considered in patients with symptoms suggestive of drug toxicity who are treated with neuroleptics metabolized via the CYP2D6 pathway, as carriage of one or more non-functional alleles may increase the risk for adverse reactions, such as NMS.\n\nKeywords\n\nAdverse drug reactions\nPharmacogenetics\nCYP2D6\nPoor metabolizer\nNeuroleptic malignant syndrome\nissue-copyright-statement© Springer-Verlag Berlin Heidelberg 2014\n==== Body\nIntroduction\n\nThe use of atypical antipsychotic has increased rapidly in recent years in pediatric populations worldwide [1]. Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal complication of treatment with antipsychotics. Clinical features of NMS include muscle rigidity, hyperpyrexia, autonomic instability, mental status changes, and evidence of muscle catabolism [2]. One of the hypotheses regarding its etiology postulates that susceptibility to NMS may be associated with variation in genes that code for metabolic enzymes [7]. We report on a pediatric patient who developed NMS while being treated with standard doses of antipsychotics due to an acute psychotic episode. Clinical observation suggested drug toxicity due to impaired drug metabolism. Genotyping of the CYP2D6 gene confirmed the carriage of two dysfunctional alleles.\n\nCase report\n\nIn September 2009, a 16-year-old male (weight: 65.5 kg, height: 1.83 m, BMI = 19.6 kg/m2) was admitted to a pediatric neurology unit due to dystonia. A month before, the patient became withdrawn and developed insomnia and twisting movements of the left extremities. These symptoms began after a 1-month period of using medication containing dextromethorphan and pseudoephedrine for recreational purpose. Upon admission to the pediatric neurology unit, he was well oriented and followed instructions. Neurological examination showed no alteration except for sustained twisting of the left extremities. Results of laboratory tests, electroencephalography (EEG), and computed tomography of the head and neck were normal. During hospitalization his mental status deteriorated. He became confused and illogical. The consulting psychiatrist diagnosed a psychotic episode and transferred the patient to the adolescent inpatient psychiatric unit.\n\nAt the time of this transfer, the patient was awake and revealed delusional thoughts and hallucinations. Treatment with orally administered olanzapine (10 mg/day) and lorazepam (as required) with intramuscular injections of first-generation antipsychotic medication—levomepromazine (25 mg/day)—was initiated. The next day, levomepromazine was increased to 37.5 mg/day. During the course of treatment, dystonic movement worsened. Opisthotonic trunk extension, intermittent, sustained extension movements of the arms, and incomprehensible screaming were observed. The patient had no verbal communication with the medical staff, was agitated, unable to sleep, and refused to eat and drink. Intravenous fluids were administered for dehydration. In 2 weeks of treatment, he became drowsy with decreased physical activity. Due to recurrent episodes of agitation, the patient received 1–3 mg/day of lorazepam. An episode of aggression towards medical staff required one intramuscular injection with haloperidol (2.5 mg). The timeline of presented symptoms and administered medications is displayed in Fig. 1. At the 16th day of treatment with antipsychotics, the patient was transferred to the University Child Psychiatry Department.Fig. 1 Timeline of presented symptoms and administered medication prior to admission to the intensive care unit\n\nAt the time of this transfer, the patient was unconscious and showed muscular rigidity and extrapyramidal symptoms. Fever (up to 41 °C), hypotension (100/70 mmHg), tachycardia (120 beats per minute), and tachypnea (26 breaths per minute) were noted. Laboratory analysis revealed a leukocyte count (WBC) of 13.40 × 103/μL, serum creatinine phosphokinase (CPK) level of 639 U/L, and normal liver and renal function tests.\n\nOn the following day, the patient became diaphoretic, with a Glasgow Coma Scale of 7 points (range 3–15 points) indicating a state of coma. CPK increased to 2,458 U/L, WBC to 16.6 × 103/μL, creatinine (SCC) to 1.70 mg/dL, and blood urea nitrogen (BUN) to 79.0 mg/dL. The patient was transferred to an intensive care unit (ICU), intubated and mechanically ventilated because of respiratory insufficiency. Generalized tonic–clonic seizures were observed. Acyclovir was administered for potential herpes encephalitis and dantrolene to counter potential NMS. Electrocardiogram revealed elevation of the ST segment with T wave inversion. Elevated troponin levels and myoglobin detected in urine suggested myocardial injury. An echocardiogram showed left ventricular hypokinesis. Serum CPK levels continued to rise over the following 6 days and reached a peak of 15,255 U/L. BUN and SCC also increased for 3 days, up to 79.6 and 2.1 mg/dL, respectively. Organic pathology of the brain was ruled out after repeatedly normal magnetic resonance images and cerebrospinal fluid examination (glucose concentration 70.0 mg/dL, protein concentration 34 mg/dL, and an absence of cells). Polymerase chain reaction (PCR) ruled out herpes simplex virus infection, and acyclovir was discontinued. Six weeks after the last administration of neuroleptics, urine toxicology was done. The presence of haloperidol was detected, but not olanzapine. The presence of levomepromazine was not measured. There was no test performed to measure any plasma drug concentration. Real-time PCR showed that the genotype of CYP2D6 was *4/*4. These findings indicated lack of CYP2D6 activity.\n\nAs other conditions were excluded, the diagnosis of NMS was made based on symptoms of muscle rigidity, elevated temperature, and leukocytosis. After 10 weeks of hospitalization in the ICU, the patient was readmitted to the psychiatric unit. His weight had decreased to 41 kg (BMI = 12.2 kg/m2). At the time of readmission, he was agitated and visually hallucinating. Extrapyramidal symptoms were present. Disturbance of mental status fluctuated during the course of the day with worseness of agitation in the nights. The diagnosis of delirium was stated. Secondary generalized tonic–clonic seizures were noted every second day. Agitation was treated with ziprasidone, and gabapentin was introduced for seizures. During the subsequent 6-month hospitalization, the patient's condition gradually improved, and he gained 12.5 kg (weight: 53.5 kg, height: 1.83 m, BMI = 16.0 kg/m2). In June 2010, he was discharged from inpatient center with diagnosis of schizophreniform disorder complicated by neuroleptic malignant syndrome according to DSM-IV TR criteria. He remained under regular review in the outpatient psychiatric clinic. Control EEGs performed 6 and 12 weeks after the above episode were normal. Ziprasidone and gabapentin were gradually withdrawn, and no other medications were required. In September 2010, he went back to school. However, due to learning difficulties, he had to repeat the class. After 2.5 years of outpatient follow-up, he still shows persistent mild memory and concentration impairment and emotional lability. There has been no further evidence of psychotic symptoms or seizures.\n\nDiscussion\n\nThis is the first report of a pediatric patient with NMS and confirmed CYP2D6 deficiency. Symptoms presented by the patients such as fever, rigidity, tachycardia, leukocytosis, diaphoresis, abnormal blood pressure, tachypnea, altered mental status, and elevated CK level are consistent with clinical presentations of other patients with NMS [11]. Remarkably, the development of NMS was preceded by catatonic symptoms such as mutism, refusal of food and fluid intake, and decreased and excesive motor activity. There are reports suggesting that neuroleptic-induced catationa may be a stage progressing to NMS [9]. In the presented case, catatonic symptoms occurred after introduction of neutroleptics, and further treatment even worsen the mental state of the patient (Fig. 1).\n\nThis case illustrates a multifactorial cause of NMS. The primary risk factors are probable disproportionally high drug concentrations - which were unfortunetely not measured - and toxicity resulting from repeated administration of oral and intramuscular medication in a patient with dysfunctional metabolic pathways. This patient received repeated daily doses of olanzapine. The role of olanzapine and its combination with levomepromazine in the development of NMS has been previously described [5, 8]. The plasma level of olanzapine should not have exceed therapeutic levels as it is mainly metabolized by CYP1A2 and to a lesser extent by CYP2D6. However, the clinical presentation, with the lack of improvement and sedation on adequate doses of medications combined with worseness of catatonia, suggests drug toxicity. Metabolism of levomepromazine and haloperidol is catalyzed by CYP2D6 and if given to the patient with lack activity of this enzyme might have induced adverse effects even on standard doses [3]. Furthermore, nonfunctional alleles of CYP2D6 have been suggested to affect vulnerability to NMS in Japanese population [6]. Other factors such as dehydration, malnutrition, and severe clinical presentation with agitation may also contribute to the development of NMS. Initial symptoms of the patient might be also related to the abuse of dextromethorphan- and pseudoepedrine-containing remedies as both medications are metabolized by CYP2D6 and known to cause dystonia and psychotic symptoms [10].\n\nOur report highlights the need for therapeutic drug monitoring (TDM) [4]. TDM is economically reasonable and can detect different pharmacokinetic problems, not limited to CYP polymorphisms. Unfortunately, in Poland, TDM of neuroleptics was not implemented in the clinical routine and even if recommended remains unavailable in psychiatric centers. Described patient had several indications for measuring plasma concentration of medication such as possible medication-related onset of symptoms, adverse effects on standard doses of medication, suspected impaired drug metabolism, and being an adolescent patient. Plasma levels of drugs involved in this case would have been helpful to evaluate the origin of symptoms, modify the treatment, and avoid dramatic complication.\n\nAbbreviations\n\nBUN Blood urea nitrogen\n\nCPK Serum creatinine phosphokinase\n\nDSM-IV TR Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision\n\nEEG Electroencephalography\n\nICU Intensive care unit\n\nNMS Neuroleptic malignant syndrome\n\nPCR Polymerase chain reaction\n\nSCC Creatinine\n\nTDM Therapeutic drug monitoring\n\nWBC Leukocyte count\n\nWe thank Dr. Sameer Jauhar from the Institute of Psychiatry, King's College London for his constructive comments and proofreading.\n\nConflict of interest\n\nWe report no conflict of interest.\n==== Refs\nReferences\n\n1. Clavenna A Rossi E DeRosa M Bonati M Use of psychotropic medications in Italian children and adolescents Eur J Pediatr 2007 166 4 339 347 10.1007/s00431-006-0244-7 17028883\n2. Croarkin PE Emslie GJ Mayes TL Neuroleptic malignant syndrome associated with atypical antipsychotics in pediatric patients: a review of published cases J Clin Psychiatry 2008 69 7 1157 1165 10.4088/JCP.v69n0716 18572981\n3. Fang J Baker GB Silverstone PH Coutts RT Involvement of CYP3A4 and CYP2D6 in the metabolism of haloperidol Cell Mol Neurobiol 1997 17 2 227 233 10.1023/A:1026317929335 9140699\n4. Hiemke C Baumann P Bergemann N Conca A Dietmaier O Egberts K Fric M Gerlach M Greiner C Grunder G Haen E Havemann-Reinecke U Jaquenoud Sirot E Kirchherr H Laux G Lutz UC Messer T Muller MJ Pfuhlmann B Rambeck B Riederer P Schoppek B Stingl J Uhr M Ulrich S Waschgler R Zernig G AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011 Pharmacopsychiatry 2011 44 6 195 235 10.1055/s-0031-1286287\n5. Jarventausta K Leinonen E Neuroleptic malignant syndrome during olanzapine and levomepromazine treatment Acta Psychiatr Scand 2000 102 3 231 233 10.1034/j.1600-0447.2000.102003231.x 11008860\n6. Kato D Kawanishi C Kishida I Furuno T Suzuki K Onishi H Hirayasu Y Effects of CYP2D6 polymorphisms on neuroleptic malignant syndrome Eur J Clin Pharmacol 2007 63 11 991 996 10.1007/s00228-007-0355-8 17701031\n7. Kishida I Kawanishi C Furuno T Kato D Ishigami T Kosaka K Association in Japanese patients between neuroleptic malignant syndrome and functional polymorphisms of the dopamine D(2) receptor gene Mol Psychiatry 2004 9 3 293 298 10.1038/sj.mp.4001422 15094790\n8. Kontaxakis VP Havaki-Kontaxaki BJ Christodoulou NG Paplos KG Olanzapine-associated neuroleptic malignant syndrome Prog Neuropsychopharmacol Biol Psychiatry 2002 26 5 897 902 10.1016/S0278-5846(02)00202-6 12369263\n9. Luchini F Lattanzi L Bartolommei N Cosentino L Litta A Kansky C Mauri M Cassano GB Fagiolini A Casamassima F Catatonia and neuroleptic malignant syndrome: two disorders on a same spectrum? Four case reports J Nerv Ment Dis 2013 201 1 36 42 10.1097/NMD.0b013e31827ab24b 23274293\n10. Soutullo CA Cottingham EM Keck PE Jr Psychosis associated with pseudoephedrine and dextromethorphan J Am Acad Child Adolesc Psychiatry 1999 38 12 1471 1472 10.1097/00004583-199912000-00004 10596243\n11. van Maidegem BT Smit LME Touw DJ Gemke RJBJ Neuroleptic malignant syndrome in a 4-year-old girl associated with alimemazine Eur J Pediatr 2002 161 5 259 261 10.1007/s00431-002-0956-2 12012220\n\n",
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"journal": "European journal of pediatrics",
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"medline_ta": "Eur J Pediatr",
"mesh_terms": "D000293:Adolescent; D019389:Cytochrome P-450 CYP2D6; D004247:DNA; D003937:Diagnosis, Differential; D005500:Follow-Up Studies; D005820:Genetic Testing; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008297:Male; D009459:Neuroleptic Malignant Syndrome; D060888:Real-Time Polymerase Chain Reaction; D013997:Time Factors",
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"title": "Neuroleptic malignant syndrome in an adolescent with CYP2D6 deficiency.",
"title_normalized": "neuroleptic malignant syndrome in an adolescent with cyp2d6 deficiency"
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"abstract": "OBJECTIVE\nSmall cell cancer of the esophagus (SCCE) is an extremely rare entity with an aggressive clinical course, thus early diagnosis and treatment are important for improved survival.\n\n\nMETHODS\nA 35-year-old male presented with dysphagia, loss of appetite and weight loss. Diagnostic workup revealed an esophageal mass, which was diagnosed as primary non-Hodgkin lymphoma (NHL) on initial biopsy. Despite receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy for 3 months, there was an interval increase in the size of the esophagus mass, which unveiled underlying SCCE. A re-review of the previous biopsy specimen with immunohistochemical staining confirmed the initial diagnosis as SCCE as well. Despite 4 cycles of platinum-based chemotherapy and radiotherapy, the malignancy progressed and proved fatal.\n\n\nCONCLUSIONS\nSCCE and non-Hodgkin lymphomas are rare entities, whose morphologies can be diagnostically challenging, hence they require special immunostaining for accurate diagnosis. Prompt diagnosis and initiation of treatment can confer better quality of life and survival.",
"affiliations": "Department of Medicine, Allegheny Health Network, Pittsburgh, PA, U.S.A.;Department of Medicine, Allegheny Health Network, Pittsburgh, PA, U.S.A.;Department of Medicine, Allegheny Health Network, Pittsburgh, PA, U.S.A.; adeel.nasrullah@ahn.org adeel.shifa@gmail.com.;Departement Pathology, Allegheny Health Network, Pittsburgh, PA, U.S.A.;Department of Medicine, Allegheny Health Network, Pittsburgh, PA, U.S.A.;Department of Pulmonology and Critical Care, Allegheny Health Network, Pittsburgh, PA, U.S.A.;Department of Pulmonology and Critical Care, Allegheny Health Network, Pittsburgh, PA, U.S.A.",
"authors": "Sarma|Deeksha|D|;Karna|Rahul|R|;Nasrullah|Adeel|A|;Zhang|Qiuhong|Q|;Javed|Anam|A|;Ashraf|Obaid|O|;Arshad|Hammad|H|",
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"issue": "41(6)",
"journal": "Anticancer research",
"keywords": "Small cell carcinoma; extrapulmonary small cell cancer; non-Hodgkin lymphomas",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001706:Biopsy; D018288:Carcinoma, Small Cell; D059248:Chemoradiotherapy; D003937:Diagnosis, Differential; D004938:Esophageal Neoplasms; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D049268:Positron-Emission Tomography",
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"title": "Primary Esophageal Small Cell Carcinoma Masquerading as Non-Hodgkin Lymphoma in a Young Patient.",
"title_normalized": "primary esophageal small cell carcinoma masquerading as non hodgkin lymphoma in a young patient"
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"abstract": "Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by urticarial plaques and/or vesicles and tense bullae. A unique presentation of BP can occur during pregnancy, the postpartum period after delivery, or with the initiation of contraception, in which case it is referred to as pemphigoid gestationis (PG). In rare instances, newborns born to mothers with PG may also present with blisters due to transplacental passage of maternal anti-bullous pemphigoid 180 (BP180) or 230 (BP230) immunoglobulin G (IgG). In this report, we present an unusual case of neonatal PG in an infant born to an asymptomatic mother without a previous diagnosis of PG.",
"affiliations": "School of Medicine, University of Utah, Salt Lake City, Utah, USA.;Department of Dermatology, University of Utah, Salt Lake City, Utah, USA.;Department of Dermatology, University of Utah, Salt Lake City, Utah, USA.;Department of Dermatology, University of Utah, Salt Lake City, Utah, USA.;Department of Dermatology, University of Utah, Salt Lake City, Utah, USA.;Department of Dermatology, University of Utah, Salt Lake City, Utah, USA.",
"authors": "Jimenez|Amber|A|https://orcid.org/0000-0002-6408-5504;Blain|Kimberly|K|;Khalighi|Mazdak|M|;Clarke|Jennie T|JT|;Snook|Jeremy|J|;Cipriano|Sarah D|SD|https://orcid.org/0000-0003-0888-1458",
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"pmid": "34713489",
"pubdate": "2021-10-29",
"publication_types": "D016428:Journal Article",
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"title": "Neonatal pemphigoid gestationis: An atypical presentation of a rare disease.",
"title_normalized": "neonatal pemphigoid gestationis an atypical presentation of a rare disease"
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"abstract": "We report a case of peritoneal dissemination of gastric cancer in which the QOL was maintained with a less-than-optimum dose of anticancer agent. A 64-year-old man underwent total gastrectomy for corpus gastric cancer without distant metastasis performedas an open-laparotomy. Peritoneum disseminations were observed in the left sub-diaphragmatic space and back side of the mesocolon, andthe tumor passedd irectly to the superior mesenteric vein of transverse mesocolon. As a first- line chemotherapy, G-SOX therapy(S-1 80mg/day/body and oxaliplatin 100mg/m2)was administered for 15 courses. After these courses, the disease was categorized as PD. Next, RAM/PTX(ramucirumab 8mg/kg andpaclitaxel 80mg/m2) were administered as second-line chemotherapy. However, the PTX, especially causedprolongedad verse effects such as G4- leveledbloodtoxicity andsevere general fatigue. Therefore, we administereda lower dose of PTX than the original optimal minimum dose. This lower dose chemotherapy resulted in effective changes such as decreased pain and general fatigue and resolution of the bloodtoxicity. As a result, the patient's QOL improved, and his condition has been maintained as SD for 2 years after the operation. For these reasons, this ordinary chemotherapy may be used as a palliative chemotherapy.",
"affiliations": "Dept. of Surgery, Suita Municipal Hospital.",
"authors": "Yamamura|Noriyuki|N|;Ebisui|Chikara|C|;Minoji|Takayuki|T|;Tamai|Koki|K|;Takabatake|Hiroyuki|H|;Kitahara|Tomohiro|T|;Watanabe|Noriyuki|N|;Okamura|Shu|S|;Fukuchi|Nariaki|N|;Yokouchi|Hideoki|H|;Kinuta|Masakatsu|M|",
"chemical_list": null,
"country": "Japan",
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"issue": "46(4)",
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"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D005743:Gastrectomy; D006801:Humans; D008297:Male; D010537:Peritoneum; D010538:Peritonitis; D013274:Stomach Neoplasms",
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"references": null,
"title": "Role of Palliative Chemotherapy for Peritonitis Carcinomatosa of Inoperable Advanced Gastric Cancer.",
"title_normalized": "role of palliative chemotherapy for peritonitis carcinomatosa of inoperable advanced gastric cancer"
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"companynumb": "JP-PFIZER INC-2019289749",
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"abstract": "Fungal infections like Paecilomyces keratitis have emerged in childhood recently. The diagnosis and treatment of Paecilomyces keratitis is difficult and the outcome is usually poor. Corneal culture should be performed on fungal media such as Sabouraud glucose neopeptone agar (SDA) as soon as possible for diagnosis. We report a rare case of Paecilomyces keratitis in an immunocompetent child, which was unresponsive to amphotericin B. The case was managed by a multidisciplinary approach involving the departments of ophthalmology, microbiology and pediatric infectious diseases. We want to draw attention once again that fungal keratitis caused by unusual agents are increasing. Physicians should consider fungal causes of keratitis, in patients with some predisposing factors like ocular surgery and prolonged use of topical corticosteroids.",
"affiliations": "Istanbul University, Istanbul Faculty of Medicine, Department of Ophthalmology, Pendik, Istanbul, Turkey.;The Council of Forensic Medicine, Department of Microbiology, Istanbul, Turkey.;Marmara University Medical Faculty, Department of Pediatric Infectious Diseases, Pendik, Istanbul, Turkey.;Marmara University Medical Faculty, Department of Pediatric Infectious Diseases, Pendik, Istanbul, Turkey.;Bezmialem Vakif University, Department of Pediatric Infectious Diseases, Istanbul, Turkey.;Boston Childrens Hospital, Department of Pediatric/Urgent Care, USA.;Istanbul University, Istanbul Faculty of Medicine, Department of Ophthalmology, Pendik, Istanbul, Turkey.;Marmara University Medical Faculty, Department of Microbiology, Istanbul, Turkey.;Marmara University Medical Faculty, Department of Pediatric Infectious Diseases, Pendik, Istanbul, Turkey.;Marmara University Medical Faculty, Department of Pediatric Infectious Diseases, Pendik, Istanbul, Turkey.",
"authors": "Toker|Ebru|E|;Ziyade|Nihan|N|;Atici|Serkan|S|;Eda|Kepenekli Kadayifçi|KK|;Türel|Özden|Ö|;Toprak|Demet|D|;Oray|Merih|M|;Cerikcioglu|Nilgün|N|;Soysal|Ahmet|A|;Bakir|Mustafa|M|",
"chemical_list": "D000935:Antifungal Agents; D000666:Amphotericin B",
"country": "Uganda",
"delete": false,
"doi": "10.11604/pamj.2016.24.317.9772",
"fulltext": "\n==== Front\nPan Afr Med JPan Afr Med JPAMJThe Pan African Medical Journal1937-8688The African Field Epidemiology Network PAMJ-24-31710.11604/pamj.2016.24.317.9772Case ReportPostoperative keratitis due to Paecilomyces: a rare pediatric case Toker Ebru 1Ziyade Nihan 2Atici Serkan 3Eda Kepenekli Kadayifçi 3Türel Özden 4Toprak Demet 5Oray Merih 6Cerikcioglu Nilgün 7Soysal Ahmet 3&Bakir Mustafa 31 Istanbul University, Istanbul Faculty of Medicine, Department of Ophthalmology, Pendik, Istanbul, Turkey2 The Council of Forensic Medicine, Department of Microbiology, Istanbul, Turkey3 Marmara University Medical Faculty, Department of Pediatric Infectious Diseases, Pendik, Istanbul, Turkey4 Bezmialem Vakif University, Department of Pediatric Infectious Diseases, Istanbul, Turkey5 Boston Childrens Hospital, Department of Pediatric/Urgent Care, USA6 Istanbul University, Istanbul Faculty of Medicine, Department of Ophthalmology, Pendik, Istanbul, Turkey7 Marmara University Medical Faculty, Department of Microbiology, Istanbul, Turkey& Corresponding author: Ahmet Soysal, Marmara University Medical Faculty, Department of Pediatric Infectious Diseases, Pendik, Istanbul, Turkey18 8 2016 2016 24 31702 5 2016 19 6 2016 © Ebru Toker et al.2016The Pan African Medical Journal - ISSN 1937-8688. This is an Open Access article distributed under the terms of the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Fungal infections like Paecilomyces keratitis have emerged in childhood recently. The diagnosis and treatment of Paecilomyces keratitis is difficult and the outcome is usually poor. Corneal culture should be performed on fungal media such as Sabouraud glucose neopeptone agar (SDA) as soon as possible for diagnosis. We report a rare case of Paecilomyces keratitis in an immunocompetent child, which was unresponsive to amphotericin B. The case was managed by a multidisciplinary approach involving the departments of ophthalmology, microbiology and pediatric infectious diseases. We want to draw attention once again that fungal keratitis caused by unusual agents are increasing. Physicians should consider fungal causes of keratitis, in patients with some predisposing factors like ocular surgery and prolonged use of topical corticosteroids.\n\nFungal infectionpaecilomycesvoriconazole\n==== Body\nIntroduction\nPaecilomyces species are saprobic filamentous fungi and mainly cause ocular infections that frequently followed intraocular lens implantation, trauma and ocular surgery [1]. This fungus can be found in air, soil, wood and decaying vegetation. It is a rare but potentially serious pathogen that causes of filamentous fungal keratitis in children. Paecilomyces species are resistant to many antifungal agents, hence Paecilomyces keratitis treatment is frequently difficult and usually results poor outcome [2]. We report an unusual pediatric case of postoperative Paecilomyces keratitis that required vigorous antifungal treatment-systemic, topical and intracameral, and healed with a vascularized scar. We want to emphasize that corneal sample should performed on fungal media such as Sabouraud glucose neopeptone agar (SDA) as soon as possible in suspected fungal cases. Case management is important for prevent further complications.\n\nPatient and observation\nA-14-year-old boy with a history of acute hydrops due to keratoconus in the right eye was treated by keratoplasty. Prednisolone acetate 1% and ciprofloxacin 0.3% eye drops were given postoperatively. On the 30th day after the surgery he complained of severe pain, redness and decreasing vision in the right eye and admitted to hospital. On slit lamp examination, there was a 3x3 mm central abscess on the graft involving all layers of the cornea in the right eye; the left eye examination was normal (Figure 1 A). Corneal scraping was performed and material was obtained for smears and cultures. Corticosteroid eye drop was discontinued and broad-spectrum topical antibiotic therapy with fortified vancomycine (50 mg/ml) and gentamicine (14 mg/ml) was initiated. Treatment was subsequently switched to topical (2%, 6 times a day) and systemic (6 mg/kg intravenous, once a day) fluconazole and topical (0.3%, 6 times a day) amphotericin B since microscopic examination of the corneal scrapings revealed septate branching fungal hyphal structures (Figure 2 A). Amphotericin B was also injected intracamerally at a dosage of 0.005 mg/0.1mL. After 1 week of treatment, the clinical picture deteriorated with elevation of the abscess and impending perforation. The viral and bacterial investigations were negative. In the meantime, mold colonies appeared on SDA (first week of incubation). On examination of fungal culture, the colony was flat, powdery, velvety and yellowish in the obverse side and white to pinkish color in the reverse side. The fungal isolate was identified as a Paecilomyces species by the microbiology laboratory (Figure 2 B). Antifungal therapy was modified to oral terbinafine (250 mg once a day) plus topical (1%, 6 times a day) and systemic (6 mg/kg twice on day 1 and 4 mg/kg twice on the following days, intravenous) voriconazole. Repeat fungal cultures were negative. Clinical improvement was observed and the corneal lesion healed with the vascularized scar tissue (Figure 1 B). Terbinafine and voriconazole were discontinued after, respectively (Figure 1 C, D).\n\nFigure 1 On slit lamp examination (right eye): A) the central corneal abscess with corneal edema and hypopyon on admission; B) healing with vascularized scar on cornea after voriconazole and terbinafine treatment at day 4; C) day 8; D) day 15\n\nFigure 2 A) microscopic examination of corneal scrapings revealed a septate and branching fungal hyphae; B) branching conidiophores arising from infrequent septate hyphae with tapering phialides and chains of conidia characterise Paecilomyces spp (Lactophenol cotton blue stain)\n\nDiscussion\nFungal infections are important cause of morbidity and mortality in childhood. More than 70 genera of filamentous fungi and yeasts have been reported to cause fungal keratitis. The reports of fungal ocular infections related with the impared host defense mechanisms have been increased in recent years [3]. Ocular surgery and prolonged use of topical corticosteroids were stated to be the major risk factors associated with fungal keratitis. Paecilomyces species are saprobic, filamentous fungi which belong to hyphomycetes class. All hyaline hyphomycetes, including species of Aspergillus, Scedosporium, Fusarium, Acremonium and Paecilomyces, exhibit similar appearances in clinical specimens on microscopic examination of the infected tissue. Their septate, nonpigmented acute branching (about 45° angles) hyphae render them indistinguishable from each other on microscopic examination. Correlation with culture results and macroscopic morphology is needed for definitive identification at least at the genus level. Once isolated, molds are primarily identified according to their macroscopic morphology on culture media and type of reproductive structures observed microscopically [4]. Paecilomyces species usually cause keratitis, endocarditis, sinusitis, fungemia, pulmonary, cutaneous and subcutaneous infections in an immunocompromised host and similar infections in an immunocompetent host are very rare.\n\nPaecilomyces infections have been reported in patients with or without predisposing factors. About 100 cases of these infections have been reported related to the surgical procedure or immunocompromised hosts [5]. Although Paecilomyces keratitis caused by lilacinus strain is more common, other Paecilomyces strains such as farinosus, marquandii, variotti and viridis keratitis were reported in the literature [6]. A review study showed that 31% of 42 Paecilomyces keratitis cases were associated with chronic keratopathy or previous ocular surgery, 26% appeared following a corneal trauma and 24% occurred in soft contact lens wearers. Other causes were endogenous endophthalmitis and infectious scleritis [7]. Fungal cultures should be obtained as early as possible for diagnosis. Correct identification for fungal pathogen is important for appropriate treatment and to prevent further complications. Antifungal susceptibility tests are not performed routinely for saprobic molds because of difficulties in standardization and reading of the end points.\n\nThis case was managed by a multidisciplinary approach involving the departments of ophthalmology, microbiology and pediatric infectious diseases. Experience in the treatment of keratitis due to Paecilomyces species is limited and the optimal antifungal treatment remains unknown. There has been a trend toward using voriconazole, which has the broadest spectrum of the azole antifungals, for the treatment of fungal keratitis. Although P. Lilacinus keratitis is resistant to many antifungal agents, voriconazole has been found effective for treatment. Voriconazole has an excellent topical and oral bioavailability and therapeutic aqueous and vitreous levels are achieved after the topical and oral administration of voriconazole [8, 9]. Terbinafine belongs to the allylamine group of antifungals and inhibits squalene epoxidase, an enzyme involved in sterol metabolism of the cell membrane. Terbinafine and voriconazole combination was synergistic against all tested strains of Paecilomyces [10]. We combined terbinafine with voriconazole to treat and prevent further complications. Anderson et al. also reported a case of Paecilomyces keratitis associated with a retained intracorneal hair that was resistant to routine antifungal agents but was successfully treated with terbinafine and voriconazole combination therapy [3]. Although a treatment algorithm for Paecilomyces keratitis has not been defined, it may be described with additional experiences in the future.\n\nConclusion\nWe want to draw attention once again that fungal keratitis caused by unusual agents are increasing. Physicians should consider fungal causes of keratitis, in patients with some predisposing factors like ocular surgery and prolonged use of topical corticosteroids. We also suggest that corneal cultures should be performed. Voriconazole was effective in treatment for keratitis caused by Paecilomyces species.\n\nAcknowledgements\nThis study is financially supported by the Turkish Academy of Sciences.\n\nCompeting interests\nThe authors declare no competing interest.\n\nAuthors’ contributions\nAll authors interested in management, treatment and outcome the patient. All authors have been involved in drafting the manuscript or revising critically for important intellectual content. All authors read and approved the final manuscript.\n==== Refs\nReferences\n1 Monden Y Sugita M Yamakawa R Nishimura K Clinical experience treating Paecilomyces lilacinus keratitis in four patients Clin Ophthalmol. 2012 6 949 53 22791978 \n2 McLintock CA Lee GA Atkinson G Management of recurrent Paecilomyces lilacinus keratitis Clin Exp Optom. 2013 96 3 343 5 22925066 \n3 Anderson KL Mitra S Salouti R Pham TA Taylor HR Fungal keratitis caused by Paecilomyces lilacinus associated with a retained intracorneal hair Cornea. 2004 23 5 516 21 15220739 \n4 Costa SF Alexander BD Diagnosis and treatment of Scedosporium infection http://www.uptodate.com/contents/diagnosis-and-treatment-of-scedosporium-infection . Accessed 7 September 2014 \n5 Hilmarsdottir I Thorsteinsson SB Asmundsson P Bödvarsson M Arnadottir M Cutaneous infection by Paecilomyces lilacinus in a renal transplant: treatment with voriconazole Scand J Infect Dis. 2000 32 3 331 2 10879613 \n6 McLintock CA Lee GA Atkinson G Management of recurrent Paecilomyces lilacinus keratitis Clin Exp Optom. 2013 96 3 343 5 22925066 \n7 Yuan X Wilhelmus KR Matoba AY Alexandrakis G Miller D Huang AJW Pathogenesis and outcome of Paecilomyces keratitis Am J Ophthalmol. 2009 147 4 691 6 19195638 \n8 Vemulakonda GA Hariprasad SM Mieler WF Prince RA Shah GK Van Gelder RN Aqueous and vitreous concentrations following topical administration of 1% voriconazole in humans Arch Ophthalmol. 2008 126 1 18 22 18195213 \n9 Hariprasad SM Mieler WF Holz ER Gao H Kim JE Chi J Prince RA Determination of vitreous, aqueous and plasma concentration of orally administered voriconazole in humans Arch Ophthalmol. 2004 122 1 42 7 14718293 \n10 Ortoneda M Capilla J Pastor FJ Pujol I Yustes C Serena C Guarro J In vitro interactions of approved and novel drugs against Paecilomyces spp Antimicrob Agents Chemother. 2004 48 7 2727 9 15215136\n\n",
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"issue": "24()",
"journal": "The Pan African medical journal",
"keywords": "Fungal infection; paecilomyces; voriconazole",
"medline_ta": "Pan Afr Med J",
"mesh_terms": "D000293:Adolescent; D000666:Amphotericin B; D000935:Antifungal Agents; D003315:Cornea; D015821:Eye Infections, Fungal; D006801:Humans; D007634:Keratitis; D008297:Male; D013508:Ophthalmologic Surgical Procedures; D010143:Paecilomyces; D011183:Postoperative Complications",
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"title": "Postoperative keratitis due to Paecilomyces: a rare pediatric case.",
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"abstract": "The comparative cardiovascular risk profiles of available hormone therapies for the treatment of prostate cancer is not known.\n\n\n\nWe queried the U.S. Food and Drug Administration Adverse Event Reporting System, a retrospective, pharmacovigilance database, for cardiovascular adverse event reports in men with prostate cancer receiving gonadotropin releasing hormone (GnRH) agonists, GnRH antagonists, androgen receptor antagonists, and/or androgen synthesis inhibitors from January 2000 to April 2020.\n\n\n\nCardiovascular adverse events accounted for 6,231 reports (12.6%) on hormone monotherapy and 1,793 reports (26.1%) on combination therapy. Arterial vascular events were reported most commonly, followed by arrhythmias, heart failure, and venous thromboembolism. Compared to GnRH agonists, GnRH antagonists were associated with fewer cardiovascular adverse event reports as monotherapy (adjusted reporting odds ratio [ROR]=0.70 [95% CI 0.59-0.84], p <0.001) and as combination therapy (ROR=0.47 [0.34-0.67], p <0.0001), driven by reductions in arterial vascular events. Second generation androgen receptor antagonists and abiraterone were associated with more reports of hypertension requiring hospitalization (ROR=1.21 [1.03-1.41], p=0.02 and ROR=1.19 [1.01-1.40], p=0.03, respectively), and more heart failure events when used in combination with GnRH antagonists (ROR=2.79 [1.30-6.01], p=0.009 and ROR=2.57 [1.12-5.86], p=0.03).\n\n\n\nIn this retrospective analysis of a pharmacovigilance database, arterial vascular events were the most commonly reported cardiovascular adverse events in men on hormone therapy for prostate cancer. GnRH antagonists were associated with fewer reports of overall cardiovascular events and arterial vascular events than GnRH agonists. Additional study is needed to identify optimal strategies to reduce cardiovascular morbidity among men with prostate cancer receiving hormone therapy.",
"affiliations": "Cardio-Oncology Center of Excellence, Cardiovascular Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.;Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.;Department of Urology, Case Western Reserve University School of Medicine, Cleveland, Ohio.;Cardio-Oncology Center of Excellence, Division of Cardiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.;Department of Urology, Case Western Reserve University School of Medicine, Cleveland, Ohio.;Division of Oncology, Seidman Cancer Center, Cleveland, Ohio.;Department of Population and Quantitative Health Sciences, Case Comprehensive Cancer Center, Cleveland, Ohio.;Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri.;Cardio-Oncology Program, Division of Cardiology, The Ohio State University Wexner Medical Center, Columbus, Ohio.;Cardio-Oncology Program, Division of Cardiology, The Ohio State University Wexner Medical Center, Columbus, Ohio.;Cardio-Oncology Service, Barts Heart Centre, St. Bartholomew's Hospital West Smithfield, London, United Kingdom.;Cardio-Oncology Center of Excellence, Cardiovascular Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.;Cardiovascular Medicine Section, Yale School of Medicine, New Haven, Connecticut.;Division of Cardiovascular Medicine, Augusta University, Augusta, Georgia.;Harrington Heart and Vascular Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio.",
"authors": "Zhang|Kathleen W|KW|;Reimers|Melissa A|MA|;Calaway|Adam Christopher|AC|;Fradley|Michael G|MG|;Ponsky|Lee|L|;Garcia|Jorge A|JA|;Cullen|Jennifer|J|;Baumann|Brian C|BC|;Addison|Daniel|D|;Campbell|Courtney M|CM|;Ghosh|Arjun K|AK|;Lenihan|Daniel J|DJ|;Desai|Nihar R|NR|;Weintraub|Neal|N|;Guha|Avirup|A|",
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"title": "Cardiovascular Events in Men with Prostate Cancer Receiving Hormone Therapy: An Analysis of the FDA Adverse Event Reporting System (FAERS).",
"title_normalized": "cardiovascular events in men with prostate cancer receiving hormone therapy an analysis of the fda adverse event reporting system faers"
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"abstract": "A well-documented (by ECG as well as autopsy) case of fatal ventricular asystole secondary to intravenous administration of sodium diphenylhydantoin is presented. The possible role of ventricular conduction disturbances, hypoxemia, and metabolic abnormalities as precipitating factors are discussed.",
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"title": "Sudden death following intravenous sodium diphenylhydantoin.",
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"abstract": ": There are limited data on the effectiveness of dolutegravir (DTG)-based combination antiretroviral therapy (ART) in real-life settings in southern Africa where HIV-1 subtype C predominates. We report a patient infected with HIV-1 subtype C on DTG-based ART previously exposed to raltegravir who developed multidrug resistance mutations to four antiretroviral classes. There is need for drug resistance monitoring and clinical vigilance to ensure effectiveness of HIV treatment programs even in the era of DTG-based ART.",
"affiliations": "Botswana Harvard AIDS Institute Partnership.;Ministry of Health and Wellness, Gaborone, Botswana.;Botswana Harvard AIDS Institute Partnership.;Botswana Harvard AIDS Institute Partnership.;Botswana Harvard AIDS Institute Partnership.;Botswana Harvard AIDS Institute Partnership.;Botswana Harvard AIDS Institute Partnership.;Department of Immunology & Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.;Ministry of Health and Wellness, Gaborone, Botswana.;Botswana Harvard AIDS Institute Partnership.;Department of Medical Laboratory Sciences, Faculty of Health Sciences.;Botswana Harvard AIDS Institute Partnership.",
"authors": "Seatla|Kaelo K|KK|;Avalos|Ava|A|;Moyo|Sikhulile|S|;Mine|Madisa|M|;Diphoko|Thabo|T|;Mosepele|Mosepele|M|;Gaolatlhe|Tendani|T|;Rowley|Christopher F|CF|;Ramaabya|Dinah|D|;Jarvis|Joseph N|JN|;Kasvosve|Ishmael|I|;Gaseitsiwe|Simani|S|",
"chemical_list": "D019380:Anti-HIV Agents; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; C562325:dolutegravir",
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"mesh_terms": "D019380:Anti-HIV Agents; D001902:Botswana; D024921:Drug Resistance, Multiple, Viral; D005838:Genotype; D015658:HIV Infections; D015497:HIV-1; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones",
"nlm_unique_id": "8710219",
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"references": "28121707;28362063;29207000;24446523;23596273;27404185;21115794;21767103;18066037",
"title": "Four-class drug-resistant HIV-1 subtype C in a treatment experienced individual on dolutegravir-based antiretroviral therapy in Botswana.",
"title_normalized": "four class drug resistant hiv 1 subtype c in a treatment experienced individual on dolutegravir based antiretroviral therapy in botswana"
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"abstract": "Direct oral anticoagulants have suggested a favorable profile compared with vitamin K antagonists. However, the lack of treatment to reverse the effect of direct oral anticoagulants has limited its use in some patients who require rapid reversal of anticoagulation, as those included in the transplant waiting list. Idarucizumab is a recently approved drug to reverse the anticoagulant effect of dabigatran. However, the clinical experience when using this drug is scarce. Herein, we present a clinical case on anticoagulation reversal with idarucizumab to perform heart and lung transplantation in a patient with Eisenmenger syndrome.",
"affiliations": "Heart Failure and Transplantation Unit, Cardiology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain.;Heart Failure and Transplantation Unit, Cardiology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain.;Heart Failure and Transplantation Unit, Cardiology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain.;Physiotherapy Department, University of Valencia, Valencia, Spain.;Adult Congenital Heart Disease Unit, Cardiology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain.;Heart Failure and Transplantation Unit, Cardiology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain.",
"authors": "López-Vilella|R|R|;Sanz-Sánchez|J|J|;Sánchez-Lázaro|I|I|;Marques-Sule|E|E|;Rueda-Soriano|J|J|;Almenar-Bonet|L|L|",
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"fulltext": "\n==== Front\nInt J Organ Transplant MedInt J Organ Transplant MedIjotmInternational Journal of Organ Transplantation Medicine2008-64822008-6490Avicenna Organ Transplantation Institute Shiraz, Iran ijotm-7-097Case ReportIdarucizumab in High-risk Thoracic Surgery López-Vilella R. 1*Sanz-Sánchez J. 1Sánchez-Lázaro I. 1Marques-Sule E. 2Rueda-Soriano J. 3Almenar-Bonet L. 1\n1 Heart Failure and Transplantation Unit, Cardiology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain\n2 Physiotherapy Department, University of Valencia, Valencia, Spain\n3 Adult Congenital Heart Disease Unit, Cardiology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain* Correspondence: Raquel López Vilella, MD, Heart Failure and Transplantation Unit, Cardiology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain, E-mail: lopez_raqvil@gva.es2018 1 5 2018 9 2 97 100 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Direct oral anticoagulants have suggested a favorable profile compared with vitamin K antagonists. However, the lack of treatment to reverse the effect of direct oral anticoagulants has limited its use in some patients who require rapid reversal of anticoagulation, as those included in the transplant waiting list. Idarucizumab is a recently approved drug to reverse the anticoagulant effect of dabigatran. However, the clinical experience when using this drug is scarce. Herein, we present a clinical case on anticoagulation reversal with idarucizumab to perform heart and lung transplantation in a patient with Eisenmenger syndrome.\n\nKey Words\nHeart-lung transplantationAnticoagulantsIdarucizumab\n==== Body\nINTRODUCTION\nDabigatran is a direct thrombin inhibitor with favorable effectiveness and safety profile when compared with vitamin K antagonists (VKAs). Before idarucizumab’s approval, VKAs were the main therapy for patients waiting for transplantation who required long-term oral anticoagulation, as antidotes for direct acting oral anticoagulants (DOACs) were not available. Idarucizumab is the first targeted reversal agent specific for dabigatran. It is approved for emergency surgery/urgent procedures or for life-threatening or uncontrolled bleeding in patients taking dabigatran. We present a patient with a very high risk of hemorrhage receiving dabigatran who required heart and lung transplantation.\n\nCASE PRESENTATION\nOur patient was a 33-year-old man with congenitally corrected transposition of the great arteries and ventricular septal defect (VSD). Cardiac MRI showed a dilated right ventricle with an indexed end-diastolic volume of 165 mL/m2 on the left side, and moderate systolic dysfunction, having an ejection fraction (EF) of 36%. In addition, morphologically, left subpulmonary ventricle was observed on the right side with moderate depression (EF of 37%). The VSD was subpulmonary and presented a pulmonary/systemic flow rate (Qp/Qs) of 1.8. Right cardiac catheterization showed severe pulmonary hypertension (mean pulmonary arterial pressure of 92 mm Hg, systolic pulmonary arterial pressure of 109 mm Hg, and diastolic pulmonary arterial pressure of 70 mm Hg). Considering these findings, an implantable cardioverter defibrillator (ICD) was provided as the primary prevention for the sudden death, and treatment with bosentan was started. One year later the patient’s functional condition worsened; the maximal oxygen uptake in the exercise testing was 41% of the theoretical. Bosentan was replaced by sildenafil, but due to poor tolerance to sildenafil, Ambrisentan was prescribed.\n\nFive months later, the patient was hospitalized for atrial flutter. During electrophysiological study, atrial fibrillation (AF) was induced, and cavotricuspid isthmus ablation and isolation of pulmonary veins were performed. The patient was then discharged in sinus rhythm and anticoagulated with 110 mg of dabigatran every 12 hours. Nevertheless, his clinical status progressively worsened in the following months, with limiting dyspnea and symptoms of low cardiac output. An upgrade from ICD to cardiac resynchronization therapy was performed, since the patient presented a high percentage of ventricular stimulation and reduced ejection fraction. A risk assessment study for heart and lung transplantation (HLT) was carried out. The echocardiogram showed severe biventricular dysfunction with severe tricuspid regurgitation. Right cardiac catheterization confirmed pulmonary hypertension; he had a mean pulmonary arterial pressure of 90 mm Hg, systolic pulmonary arterial pressure of 104 mm Hg, diastolic pulmonary arterial pressure of 72 mm Hg, pulmonary capillary wedge pressure of 36 mm Hg, pulmonary vascular resistance of 9 Wood units, and cardiac output of 2.92 L/min. No absolute contraindications for HLT were detected. The patient was included in the waiting list for transplantation and was discharged with anticoagulation therapy (dabigatran), after checking idarucizumab was available.\n\nIn October 2016, an optimal donor was found. The patient was admitted to the hospital 7 hours after the last dose of dabigatran (110 mg). Two ampoules of intravenous idarucizumab 2.5 mg were given over 5 minutes each, with an interval of 15 minutes between the first and second doses. Since the antidote is a non-competitive inhibitor, the onset of inhibition of the anticoagulant action of dabigatran is practically instantaneous. Therefore, the drug was administered once it was confirmed the donor was suitable and the transplant could be performed. Dabigatran mainly prolongs the activated partial thromboplastin time (APTT) and, to a lesser extent, the prothrombin time (PT). However, idarucizumab routine monitoring is not necessary due to its stable and predictable pharmacokinetics [1]. The patient’s APTT and PT before CPT was 41 and 14.3 seconds, respectively. HLT was performed without hemorrhagic, intra-operative or post-operative complications. \n\nDISCUSSION\nHLT is a surgical treatment for patients with end-stage cardiac or pulmonary diseases when they coexist with severe pulmonary or cardiac involvement, respectively [2]. Hospital mortality is high, close to 50% in some series [3], and it is related, to a great extent, to the high incidence of hemorrhagic complications and reinterventions for bleeding. The available data reveal the difficulty and relevance of hemostasis in patients undergoing HLT. These are terminal patients who require prolonged extracorporeal circulation, with hypothermia, and who undergo transplantation in a limited situation regarding the function of their vital organs, with early or established renal and hepatic failure.\n\nIn our patient, the etiological diagnosis was Eisenmenger syndrome. These patients have a pro-hemorrhagic condition because they frequently have thrombocytopenia [4], increased platelet volume and a significant reduction of platelet aggregation. Circulating platelets in peripheral blood are formed by fragmentation of the megakaryocytes produced in the bone marrow. This fragmentation occurs in the pulmonary vascular bed, but in patients with a right-to-left shunt, part of the venous blood flow passes directly to the arterial circulation without passing through the lungs. These patients present with increased number of megakaryocytes in the peripheral blood and decreased number of platelets, inversely proportional to the hematocrit and to the size of the shunt. Moreover, not only is there a decrease in the number of platelets, but their function might also be altered. A deficiency of vitamin K-dependent coagulation factors (II, VII, IX, X) and factor V have also been detected, as well as increased fibrinolytic activity and a deficiency of von Willebrand factor. Therefore, hemorrhagic complications in Eisenmenger syndrome are frequent [5, 6], as well as thrombotic complications. Despite this situation, it is common that patients with congenital heart disease have an indication for anticoagulation, for instance when presenting with arrhythmias, especially AF or atrial flutter, as in our patient. In this regard, direct-acting anticoagulants have proven to be at least as effective as anti-vitamin K (AVK) drugs for the prevention of cardioembolic stroke in patients with non-valvular AF. Moreover, direct-acting anticoagulants have proven to be safer than AVK drugs, since they present less frequently significant hemorrhages, especially intracranial hemorrhages [7]. Nevertheless, the absence of antidotes with a fast, effective and safe mechanism of action for reversal of anticoagulation has been one of the potential drawbacks for a greater use. Until now, when including a patient in a heart or heart-lung transplant waiting list, it was necessary to change the usual treatment for acenocoumarol, in order to effectively reverse anticoagulation prior to transplantation. Our patient was being treated with dabigatran, a direct thrombin inhibitor used to prevent embolic events in patients with non-valvular AF [7]. It was decided to maintain treatment with the direct-acting anticoagulant when including the patient in the waiting list because idarucizumab was available. Idarucizumab is a specific reversal agent for dabigatran therapy, and has recently been approved by the US Food and Drug Administration and the European Medicines Agency [8-12]. It is a humanized monoclonal antibody fragment that specifically binds to dabigatran and its metabolites with high affinity, with 300-fold stronger binding affinity to thrombin than dabigatran. The idarucizumab-dabigatran complex, with no intrinsic procoagulant activity, is characterized by a fast association constant and an extremely slow dissociation constant, resulting in a very stable complex.\n\nThe results of the phase III RE-VERSE AD study showed that idarucizumab neutralizes the effect of dabigatran in a matter of minutes in patients with severe bleeding, or in those who are undergoing emergency procedures [13]. Due to the mechanism of action of the antidote (non-competitive inhibitor), the onset of inhibition of the anticoagulant action of dabigatran is practically instantaneous. It should be noted that the specificity of the reversing agent is exclusively by dabigatran, so effects are only observed in thrombin bounded to the reversible agent. Therefore, there are no side effects derived from the actions of thrombin on platelets, fibrinogen or on the own ability to generate thrombin. Therefore, there are no procoagulant or anticoagulant effects intrinsic to idarucizumab. Routine monitoring of idarucizumab administration is not necessary, because of its stable and predictable pharmacokinetics [1]. HLT was performed without complications, since no hemorrhagic, intra-operative or post-operative complications were reported. \n\nThe availability of a specific reversal agent is an important factor to consider when choosing an anticoagulant in clinical practice. There are some clinical cases or short series of published cases about the use of idarucizumab. Ours was the first case of reversal of anticoagulation with idarucizumab for an elective HLT. Firstly, a rapid reversal of the anticoagulant effect after administration is demonstrated. Secondly, efficacy and ease of use are illustrated, as well as the role in patient safety when a rapid reversal of the anticoagulant effect of dabigatran is required.\n\nCONFLICTS OF INTEREST:\nNone declared.\n\nFINANCIAL SUPPORT:\nNone.\n==== Refs\nReferences\n1 Eikelboom JW Quinlan DJ van Ryn J Idarucizumab The antidote for reversal of dabigatran Circulation 2015 132 2412 22 26700008 \n2 Monguió E Castedo E Segovia J Heart and lung transplantation: 8 years of experience Cir Cardiov 2007 14 119 24 \n3 Morales P Almenar L Torres JJ Heart and lung transplantation: experience of a lung transplant group Transplant Proc 2003 35 1954 6 12962861 \n4 Liu A Saman H Pusalkar P Massive epistaxis in a patient with Eisenmenger syndrome: illustrating the clot-versus-bleed conundrum BMJ Case Reports 2011 2011 bcr0220113812 \n5 Jensen AS Versen K Vejlstrup NG Images in cardiovascular medicine Pulmonary artery thrombosis and hemoptysis in Eisenmenger syndrome Circulation 2007 115 e632 4 17576876 \n6 Remková A Šimková I Valkovičová T Platelet abnormalities in adults with severe pulmonary arterial hypertension related to congenital heart defects (Eisenmenger syndrome) Blood Coagul Fibrinolysis 2016 27 925 9 26829363 \n7 Huisman MV Rothman KJ Paquette M Antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation: the GLORIA-AF registry, phase II Am J Med 2015 128 1306 13 26239094 \n8 Glund S Stangier J Schmohl M Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebocontrolled, double-blind phase 1 trial Lancet 2015 386 680 90 26088268 \n9 Honickel M Treutler S van Ryn J Reversal of dabigatran anticoagulation ex vivo: porcine study comparing prothrombin complex concentrates and idarucizumab Thromb Haemost 2015 113 728 40 25567155 \n10 Glund S Moschetti V Norris S A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran Thromb Haemost 2015 113 943 51 25789661 \n11 Huisman MV Fanikos J Idarucizumab and factor Xa reversal agents: role in hospital guidelines and protocols Am J Emerg Med 2016 34 46 51 27697438 \n12 Syed YY Idarucizumab: A Review as a Reversal Agent for Dabigatran Am J Cardiovasc Drugs 2016 16 297 304 27388764 \n13 Pollack CV Reilly PA Eikelboom J Idarucizumab for dabigatran reversal N Engl J Med 2015 373 511 20 26095746\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2008-6482",
"issue": "9(2)",
"journal": "International journal of organ transplantation medicine",
"keywords": "Anticoagulants; Heart-lung transplantation; Idarucizumab",
"medline_ta": "Int J Organ Transplant Med",
"mesh_terms": null,
"nlm_unique_id": "101535773",
"other_id": null,
"pages": "97-100",
"pmc": null,
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"pubdate": "2018",
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"title": "Idarucizumab in High-risk Thoracic Surgery.",
"title_normalized": "idarucizumab in high risk thoracic surgery"
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"abstract": "Biologic immunotherapies have transformed the treatment landscape of multiple sclerosis. Such therapies include recombinant proteins (interferon beta), as well as monoclonal antibodies (natalizumab, alemtuzumab, daclizumab, rituximab and ocrelizumab). Monoclonal antibodies show particular efficacy in the treatment of the inflammatory phase of multiple sclerosis. However, the immunological perturbations caused by biologic therapies are associated with significant immunological adverse reactions. These include development of neutralising immunogenicity, secondary immunodeficiency and secondary autoimmunity. These complications can affect the balance of risks and benefits of biologic agents, and 2018 saw the withdrawal from the market of daclizumab, an anti-CD25 monoclonal antibody, due to concerns about the development of severe, unpredictable autoimmunity. Here we review established and emerging risks associated with multiple sclerosis biologic agents, with an emphasis on their immunological adverse effects. We also discuss the specific challenges that multiple sclerosis biologics pose to drug safety systems, and the potential for improvements in safety frameworks.",
"affiliations": "Anne Rowling Clinic, University of Edinburgh, Edinburgh, UK.;Anne Rowling Clinic, University of Edinburgh, Edinburgh, UK.;Anne Rowling Clinic, University of Edinburgh, Edinburgh, UK. david.hunt@igmm.ed.ac.uk.",
"authors": "Soleimani|Babak|B|0000-0002-8630-4595;Murray|Katy|K|;Hunt|David|D|",
"chemical_list": "D001688:Biological Products",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40264-019-00799-1",
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"issn_linking": "0114-5916",
"issue": "42(8)",
"journal": "Drug safety",
"keywords": null,
"medline_ta": "Drug Saf",
"mesh_terms": "D001688:Biological Products; D006801:Humans; D007167:Immunotherapy; D009103:Multiple Sclerosis",
"nlm_unique_id": "9002928",
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"pages": "941-956",
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"pubdate": "2019-08",
"publication_types": "D016428:Journal Article; D016454:Review",
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"title": "Established and Emerging Immunological Complications of Biological Therapeutics in Multiple Sclerosis.",
"title_normalized": "established and emerging immunological complications of biological therapeutics in multiple sclerosis"
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"abstract": "Bradycardia may occur during spinal anesthesia with atropine commonly used as a treatment. A 44-year-old female with no known history of any underlying diseases, developed a coronary spasm following ventricular tachycardia when 0.5 mg of atropine was injected intravenously to treat bradycardia during spinal anesthesia. The imbalance caused by atropine in the sympathovagal activity may predispose the coronary artery to develop spasms with ventricular tachycardia. Therefore prudent use of atropine should be accompanied by close monitoring.",
"affiliations": "Department of Anesthesiology and Pain Medicine, Daegu Fatima Hospital, Daegu, Korea.",
"authors": "Lee|Joon-Ho|JH|;Seok|Ji-Hye|JH|;Kim|Young-Lok|YL|;Lee|Ji-Hyang|JH|;Lee|Sang-Gon|SG|;Kim|Eun-Ju|EJ|;Seo|Da-Mi|DM|",
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"country": "Korea (South)",
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"doi": "10.4097/kjae.2013.65.1.66",
"fulltext": "\n==== Front\nKorean J AnesthesiolKorean J AnesthesiolKJAEKorean Journal of Anesthesiology2005-64192005-7563The Korean Society of Anesthesiologists 10.4097/kjae.2013.65.1.66Case ReportAtropine injection followed by coronary artery spasm with ventricular tachycardia during spinal anesthesia -A case report- Lee Joon-Ho Seok Ji-Hye Kim Young-Lok Lee Ji-Hyang Lee Sang-Gon Kim Eun-Ju Seo Da-Mi Department of Anesthesiology and Pain Medicine, Daegu Fatima Hospital, Daegu, Korea.Corresponding author: Ji-Hyang Lee, M.D., Department of Anesthesiology and Pain Medicine, Daegu Fatima Hospital, 576-31, Sinam-dong, Dong-gu, Daegu 701-600, Korea. Tel: 82-53-940-7434, Fax: 82-53-954-7417, lovehan3@yahoo.co.kr7 2013 19 7 2013 65 1 66 70 14 8 2012 10 9 2012 12 9 2012 Copyright © the Korean Society of Anesthesiologists, 20132013This 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.Bradycardia may occur during spinal anesthesia with atropine commonly used as a treatment. A 44-year-old female with no known history of any underlying diseases, developed a coronary spasm following ventricular tachycardia when 0.5 mg of atropine was injected intravenously to treat bradycardia during spinal anesthesia. The imbalance caused by atropine in the sympathovagal activity may predispose the coronary artery to develop spasms with ventricular tachycardia. Therefore prudent use of atropine should be accompanied by close monitoring.\n\nAtropineBradycardiaCoronary artery spasmSpinal anesthesiaVentricular tachycardia\n==== Body\nSpinal anesthesia has long been considered a relatively safe technique. However, bradycardia may occasionally occur during spinal anesthesia. Sudden and severe bradycardia and asystolic cardiac arrest are considered to be infrequent, but they are certainly the most serious of complications in spinal anesthesia.\n\nAtropine, an anti-muscarinic drug, is commonly used for the treatment of bradyarrythmias.\n\nThus, we report one such case of a patient experiencing a coronary spasm following ventricular tachycardia (VT) after atropine during spinal anesthesia.\n\nCase Report\nA 44-year-old female, height and weight of 158 cm; 53 kg, was scheduled for a varicosectomy and a communicating vein ligation of the bilateral varicose veins.\n\nThe patient's family history, past history, obstetric history, and social history were unremarkable.\n\nUpon admission, vital signs were stable with a normal physical examination. The electrocardiogram (ECG) displayed a normal sinus rhythm at 57 beats per minute at normal intervals (Fig. 1).\n\nThe patient's vital signs on arrival to the operation room showed a blood pressure of 134/72 mmHg and heart rate of 90-93 beats/min.\n\nWith the patient in the lateral decubitus position, spinal anesthesia was administered using a 25-gauge Quincke-type needle with 12 mg of bupivacaine (Marcaineheavy®) at the L3-L4 interspace.\n\nThe patient was placed in the supine position for 10 minutes, where the blood pressure lowered to 120/70 mmHg and the heart rate decreased to 82-85 beats/min. The maximal level of the sensory block to cold temperature was T8.\n\nThereafter, 2.5 mg of midazolam were given intravenously\nfor the sedation and resolution of anxiety.\n\nThe patient's blood pressure was then stabilized to 110-90/65-45 mmHg. After one hour since the start of the operation, the patient's heart rate began to gradually decrease. However, since the patient's blood pressure was stable and she was successfully sedated, we decided to observe and no supplementary evaluation of block level was performed. Two hours after the administration of the spinal anesthesia, the heart rate dropped to 42-45 beats/min, and 0.5 mg of atropine was injected intravenously. The patient's heart rate rose to 60 beats per minute within 5 minutes. Shortly after, premature ventricular contraction occurred in the ECG followed by ventricular tachycardia, where the patient's heart rate increased to 140 beats per minute and the blood pressure to 120/60 mmHg (Fig. 2 and 3). The patient complained of chest discomfort, but was capable of communication and cooperation. At that time, the upper sensory block level to cold temperature was T10. The patient was given 10 mg of esmolol intravenously. After 2-3 minutes, the patient's ECG presented an elevation in the ST with a heart rate of 62 beats/min (Fig. 4). After the termination of the operation, the patient was transferred to the intensive care unit. Laboratory tests at the moment of ventricular tachycardia were nonspecific. The CPK-MB was 19.7 ng/ml; and Troponin I peaked at 6.38 ng/ml, where both subsequently returned back to normal within 2 days. Thyroid function test and fasting lipid profile were within normal limits.\n\nCoronary angiography (CAG) that was performed after the operation showed luminal stenosis of up to 40% at the middle left anterior descending coronary artery (mLAD), while left circumflex artery (LCX) and right coronary artery (RCA) showed no significant signs of luminal stenosis. Ultrasonic cardiography (UCG) that was performed after the operation showed an ejection fraction of 40%, akinesia at the LCX territory with mild left ventricle (LV) systolic dysfunction, and impaired relaxation. According to the CAG and UCG results that were obtained by the consultation of the department of cardiology, the patient was diagnosed with VT due to vasospasm. After the administration of calcium channel blockers, the patient was discharged 3 days later without any further symptoms.\n\nDiscussion\nAlthough spinal anesthesia has long been considered a safe technique, it is known to have several side effects - such as hypotension, bradycardia, dysrhythmia, nausea and vomiting. Carpenter et al reported that the incidence of bradycardia (heart rate < 60 beats/min) during spinal anesthesia (SA) is 13%, with variables conferring to increased odds of developing bradycardia include a baseline heart rate < 60 beats/min (odds ratio 4.9, P < 0.001), the ASA physical status status classification of 1 versus 3 or 4 (3.5, P < 0.001), current therapy with β-adrenergic blocking drugs (2.9, P < 0.001), and peak block height ≥ T5 (1.7, P = 0.02). Three simple factors (baseline heart rate, ASA physical status, and β-blockade) have a stronger correlation than the peak block height. These findings suggest that the imbalance between the sympathetic and parasympathetic tone may play an important role in the susceptibility to the development of bradycardia during spinal anesthesia [1]. Abrupt, extreme bradycardia and/or asystolic cardiac arrest during spinal anesthesia seldom occurs, but can be life-threatening when they appear [2]. In order to prevent such side effects, atropine is used to treat bradycardia with heartbeat rates below 50 beats/min [3,4]. In our patient, atropine was injected intravenously when the patient's heart rate was between 42-45 beats/min, although the blood pressure was stable.\n\nAtropine, a potent cardiac parasympatholytic blocking agent, increases the heart rate and is widely used to treat bradycardia. There are three distinct phases of atropine action on the heart, which include an initial vagotonic effect, a transient period of vagal imbalance at different levels of the conduction system, and a final prolonged period of parasympathetic blockage [5].\n\nThe influence of atropine on the autonomic nervous system which controls the heart is studied via spectral analysis of the heart rate variability (HRV). The spectral analysis of the HRV can distinguish the parasympathetic from the sympathetic influence to the heart. The low frequency (LF) component of the spectral HRV reflects the sympathetic activity with some influence from the vagal activity, whereas the high frequency (HF) component is almost exclusively mediated by the vagal activity. The LF/HF ratio has been used as an index for the sympathovagal balance of the heart, with its increase suggesting sympathetic predominance as a result of increased sympathetic or decreased parasympathetic drive to the heart, or a combination of both [6]. In a report of atropine-induced ventricular tachycardia, atropine is thought to initially decrease parasympathetic activity and then provoke unopposed sympathetic activity [7]. This enhanced sympathetic activity probably contributed to the provocation of the coronary artery spasm in our case.\n\nThe coronary arteries are innervated by both sympathetic and parasympathetic neurons, and alterations to either nervous system may cause coronary artery spasms. There are many factors involved in the occurrence of perioperative coronary artery spasms - activated sympathetic activity, activated parasympathetic activity, alkalosis, and calcium drugs, etc. Spinal anesthesia by itself can be the cause of coronary artery spasms. It has been shown that a spinal or extradural blockade denervates the sympathetic nervous system by two to three segments above the level of the somatic block. Above the level of the sympathetic blockade, compensatory vasoconstriction is observed, presumably in an effort to offset the reduction in the peripheral resistance caused by the block. This sympathetic activity reflex involves the cardiac sympathetic nerves causing coronary vasoconstriction and the consequent ischemia [8]. It is likely, in this current case, that a combination of an activated sympathetic nervous system by atropine and spinal anesthesia may be responsible for the coronary artery spasm. Therefore, anesthesiologists should be aware that atropine may provoke coronary artery spasms, especially during spinal anesthesia.\n\nThere are some reports of ventricular tachycardia that are induced by atropine in the presence of significant ischemic heart disease [9,10]. These reports warned of the side effects of atropine administration in patients with ischemic myocardium. In this case, an absence of a preoperative diagnosis of ischemic heart disease (IHD) allowed us to administer atropine. However, as postoperative evaluation showed that the results suggested IHD, the susceptibility to coronary spasms through atropine may be relatively high for this patient.\n\nAlthough there are currently no established guidelines for the treatment of bradycardia, it is widely believed that a heart rate below 50 beats per minute after the induction of SA requires treatment. However, further considerations should be taken in regards to the benefits found from the use of atropine in bradycardia, which is not accompanied by hypotension. As in this case, administration of atropine in patients with previously undiagnosed IHD may cause adverse outcomes, such as coronary spasms or ventricular arrhythmia. Therefore, it appears that the administration of atropine should be used with caution and on a flexible basis when bradycardia without hypotension occurs after SA during clinical practice.\n\nFig. 1 Preoperative electrocardiogram shows normal sinus rhythm.\n\nFig. 2 Premature ventricular complexes and ventricular tachycar appearing five minutes after the administration of atropine.\n\nFig. 3 Electrocardiogram showing ventricular tachycardia.\n\nFig. 4 After disappearance of ventricular tachycardia, electrocardiogram show ST elevation.\n==== Refs\n1 Carpenter RL Caplan RA Brown DL Stephenson C Wu R Incidence and risk factors for side effects of spinal anesthesia Anesthesiology 1992 76 906 916 1599111 \n2 Løvstad RZ Granhus G Hetland S Bradycardia and asystolic cardiac arrest during spinal anaesthesia: a report of five cases Acta Anaesthesiol Scand 2000 44 48 52 10669271 \n3 Park SK Kim YK Chung SL Chin JH Lee C Lee YM Effects of Patient's Position on blood pressure and heart rate during spinal anesthesia for Axillo-femoral bypass surgery Korean J Anesthesiol 2006 51 675 679 \n4 Kim SH Cho MJ Shin YS Lee JS Lee JW Yoon KB Spinal anesthesia with 3.75 mg of 0.25% hyperbaric bupivacaine for diabetic foot surgery Korean J Anesthesiol 2009 56 273 279 \n5 Averill KH Lamb LE Less commonly recognized actions of atropine on cardiac rhythm Am J Med Sci 1959 237 304 318 13626971 \n6 Hayashi H Fujiki A Tani M Mizumaki K Shimono M Inoue H Role of sympathovagal balance in the initiation of idiopathic ventricular tachycardia originating from the right ventricular outflow tract Pacing Clin Electrophysiol 1997 20 2371 2377 9358475 \n7 Gujja K Pai VM Aslam AF Saponieri C Vasavada B Atropine-induced polymorphic ventricular tachycardia: a rare and bygone occurrence revisited Am J Ther 2010 17 e175 e178 19535970 \n8 Krantz EM Viljoen JF Gilbert MS Prinzmetal's variant angina during extradural anaesthesia Br J Anaesth 1980 52 945 949 7437231 \n9 Massumi RA Mason DT Amsterdam EA DeMaria A Miller RR Scheinman MM Ventricular fibrillation and tachycardia after intravenous atropine for treatment of bradycardias N Engl J Med 1972 287 336 338 5041702 \n10 Goel VK Mehrotra TN Gupta SK Ventricular tachyarrhythmias: complication of atropine therapy in acute myocardial infarction Indian Heart J 1981 33 301 302 7341405\n\n",
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"issn_linking": "2005-6419",
"issue": "65(1)",
"journal": "Korean journal of anesthesiology",
"keywords": "Atropine; Bradycardia; Coronary artery spasm; Spinal anesthesia; Ventricular tachycardia",
"medline_ta": "Korean J Anesthesiol",
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"nlm_unique_id": "101502451",
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"pages": "66-70",
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"title": "Atropine injection followed by coronary artery spasm with ventricular tachycardia during spinal anesthesia -A case report-.",
"title_normalized": "atropine injection followed by coronary artery spasm with ventricular tachycardia during spinal anesthesia a case report"
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... |
{
"abstract": "We report a patient who developed chronic myelogenous leukemia (CML) at 12 months of age. She was treated aggressively with stem cell transplant (SCT), interferon, donor lymphocytes and imatinib, with subsequent molecular progression. She received dasatinib, achieving a complete molecular response. Dasatinib was discontinued at 3 years but she had a molecular recurrence. Dasatinib was restarted and continued for 5 additional years with a second major molecular remission (MMR). While on dasatinib therapy she suffered growth failure and was treated with concurrent growth hormone (GH). After discontinuing dasatinib and GH, catch-up growth continues and she remains in MMR. Discontinuation of TKI therapy and the toxicity of long-term TKI therapy is discussed.",
"affiliations": "MD Anderson Cancer Center, University of Texas, Houston, Texas, USA.;MD Anderson Cancer Center, University of Texas, Houston, Texas, USA.;MD Anderson Cancer Center, University of Texas, Houston, Texas, USA.;MD Anderson Cancer Center, University of Texas, Houston, Texas, USA.;MD Anderson Cancer Center, University of Texas, Houston, Texas, USA.",
"authors": "Triche|Lisa|L|http://orcid.org/0000-0001-5016-7245;Yarbrough|Angela|A|;Roth|Michael|M|;Ying|Anita|A|;Wells|Robert|R|",
"chemical_list": "D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D000069439:Dasatinib",
"country": "England",
"delete": false,
"doi": "10.1080/08880018.2020.1751755",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0888-0018",
"issue": "37(5)",
"journal": "Pediatric hematology and oncology",
"keywords": "Chronic myeloid leukemia; growth hormone; major molecular remission; tyrosine kinase inhibitor",
"medline_ta": "Pediatr Hematol Oncol",
"mesh_terms": "D002657:Child Development; D000069439:Dasatinib; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D007223:Infant; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D009364:Neoplasm Recurrence, Local; D047428:Protein Kinase Inhibitors; D012074:Remission Induction; D016896:Treatment Outcome; D028761:Withholding Treatment",
"nlm_unique_id": "8700164",
"other_id": null,
"pages": "375-379",
"pmc": null,
"pmid": "32347770",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sustained molecular response following a failed attempt of tyrosine kinase inhibitor discontinuation & the effects on growth in a child with chronic myeloid leukemia: not always a short story.",
"title_normalized": "sustained molecular response following a failed attempt of tyrosine kinase inhibitor discontinuation the effects on growth in a child with chronic myeloid leukemia not always a short story"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-038879",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DASATINIB"
},
"drugaddi... |
{
"abstract": "Fulminant type 1 diabetes mellitus (T1DM) is thought to be partly caused by virus infection.\n\n\n\nThis study investigated the mechanism of β cell destruction in fulminant T1DM after drug-induced hypersensitivity syndrome (DIHS).\n\n\n\nWe determined the localization of human cytomegalovirus (HCMV), human herpesvirus 6 (HHV-6), and Epstein-Barr virus (EBV) and the expression of interferon regulatory factor 3 (IRF3) and viral receptors of Z-DNA binding protein 1 (ZBP1) and retinoic acid-inducible gene I (RIG-I), together with inflammatory cells, by immunohistochemistry of the autopsy pancreas of a patient with fulminant T1DM with DIHS and in seven subjects with normal glucose tolerance who underwent pancreatectomy.\n\n\n\nHCMV-positive cells were detected in islets and exocrine areas in the patient with fulminant T1DM. Greater numbers of macrophages and CD4+ and CD8+ T lymphocytes had infiltrated into HCMV-positive islets than into HCMV-negative islets, and 52.6% of HCMV-positive cells were also positive for IRF3. α Cells expressed IRF3, ZBP1, or RIG-I. No HCMV-positive cells were detected in the control subjects. HHV-6-positive, but not EBV-positive, cells were present in the patient and the control subjects.\n\n\n\nThese findings indicate that the immunoresponse caused by HCMV infection was associated with β cell injury.",
"affiliations": "Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita \"565-0871\", Japan.;Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita \"565-0871\", Japan.;Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita \"565-0871\", Japan.;Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita \"565-0871\", Japan.;Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita \"565-0871\", Japan.;Internal Medicine, Konan Hospital, Kobe \"658-0064\", Japan.;Internal Medicine, Konan Hospital, Kobe \"658-0064\", Japan.;Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita \"565-0871\", Japan.;Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita \"565-0871\", Japan.",
"authors": "Yoneda|Sho|S|;Imagawa|Akihisa|A|;Fukui|Kenji|K|;Uno|Sae|S|;Kozawa|Junji|J|;Sakai|Makoto|M|;Yumioka|Toshiki|T|;Iwahashi|Hiromi|H|;Shimomura|Iichiro|I|",
"chemical_list": "D004268:DNA-Binding Proteins; D050838:Interferon Regulatory Factor-3; D016601:RNA-Binding Proteins; C485731:ZBP1 protein, human",
"country": "United States",
"delete": false,
"doi": "10.1210/jc.2016-4029",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-972X",
"issue": "102(7)",
"journal": "The Journal of clinical endocrinology and metabolism",
"keywords": null,
"medline_ta": "J Clin Endocrinol Metab",
"mesh_terms": "D000368:Aged; D001707:Biopsy, Needle; D016022:Case-Control Studies; D002478:Cells, Cultured; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D004268:DNA-Binding Proteins; D003922:Diabetes Mellitus, Type 1; D006801:Humans; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells; D050838:Interferon Regulatory Factor-3; D008297:Male; D016601:RNA-Binding Proteins; D012016:Reference Values; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D014775:Virus Activation",
"nlm_unique_id": "0375362",
"other_id": null,
"pages": "2394-2400",
"pmc": null,
"pmid": "28398495",
"pubdate": "2017-07-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Histological Study of Fulminant Type 1 Diabetes Mellitus Related to Human Cytomegalovirus Reactivation.",
"title_normalized": "a histological study of fulminant type 1 diabetes mellitus related to human cytomegalovirus reactivation"
} | [
{
"companynumb": "JP-TEVA-807106ROM",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALLOPURINOL"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Ramucirumab-an IgG1 vascular endothelial growth factor receptor 2 antagonist-plus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial.\n\n\n\nWe did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m2 (60 mg/m2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues.\n\n\n\nBetween July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7·4 months (IQR 3·5-13·9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4·1 months [95% CI 3·3-4·8] vs 2·8 months [2·6-2·9]; HR 0·696 [95% CI 0·573-0·845]; p=0·0002). Median overall survival was 9·4 months (95% CI 7·9-11·4) in the ramucirumab group versus 7·9 months (7·0-9·3) in the placebo group (stratified HR 0·887 [95% CI 0·724-1·086]; p=0·25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group.\n\n\n\nAdditional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population.\n\n\n\nEli Lilly and Company.",
"affiliations": "Yale School of Medicine, Yale University, New Haven, CT, USA. Electronic address: daniel.petrylak@yale.edu.;Erasmus MC Cancer Institute, Rotterdam, Netherlands.;British Columbia Cancer Agency, Vancouver, BC, Canada.;David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.;San Camillo and Forlanini Hospitals, Rome, Italy.;University of Tsukuba, Tsukuba, Ibaraki, Japan.;Hospital Universitario 12 de Octubre (CiberOnc), Madrid, Spain.;Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield, UK.;Centre Léon Bérard, Lyon, France.;National and Kapodistrian University of Athens, Athens, Greece.;University of Washington, Seattle, WA, USA.;Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands.;National Cancer Center Hospital East, Chiba, Japan.;P.A. Herzen Moscow Oncological Research Institute, Moscow, Russia.;Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy.;National Institute of Oncology, Budapest, Hungary.;Tungs' Taichung Metro Harbor Hospital, Taichung, Taiwan.;Akdeniz University School of Medicine, Antalya, Turkey.;Institute of Clinical Medicine, College of Medicine, National Cheng Kung University & Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.;Department of Urology, University of Tübingen, Tübingen, Germany.;Department of Urology, University of Tübingen, Tübingen, Germany; Pediatric Urology, Julius Maximillians University, Würzburg, Germany.;Florida Cancer Specialists, Port Charlotte, FL, USA.;Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.;Division of Medical Oncology, Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, Turin, Italy.;RBHI Ivanovo Regional Oncology Dispensary, Ivanovo, Russia.;Centre Oscar Lambret, Lille, France.;Rambam Health Care Campus, Haifa, Israel.;University of Verona and Azienda Ospedaliera Universitaria Integrata, Verona, Italy.;Tatarstan Regional Cancer Center, Kazan, Russia.;Institut Català d'Oncologia L'Hospitalet, Institut d'Investigacio Biomedica de Bellvitge, University of Barcelona, Barcelona, Spain.;Hospital del Mar, Barcelona, Spain.;Trakya University, Edirne, Turkey.;Inonu University, Malatya, Turkey.;New York-Presbyterian/Weill Cornell Medical Center, New York, NY, USA.;Karmanos Cancer Institute, Detroit, MI, USA.;Inova Schar Cancer Institute, Fairfax, VA, USA.;Eli Lilly and Company, Indianapolis, IN, USA.;Eli Lilly and Company, Indianapolis, IN, USA.;Eli Lilly and Company, Indianapolis, IN, USA.;Eli Lilly and Company, Indianapolis, IN, USA.;Eli Lilly and Company, Indianapolis, IN, USA.;Eli Lilly and Company, Indianapolis, IN, USA.;Eli Lilly and Company, Indianapolis, IN, USA.;Eli Lilly and Company, Indianapolis, IN, USA.;Barts Cancer Institute, Queen Mary University of London, London, UK.",
"authors": "Petrylak|Daniel P|DP|;de Wit|Ronald|R|;Chi|Kim N|KN|;Drakaki|Alexandra|A|;Sternberg|Cora N|CN|;Nishiyama|Hiroyuki|H|;Castellano|Daniel|D|;Hussain|Syed A|SA|;Fléchon|Aude|A|;Bamias|Aristotelis|A|;Yu|Evan Y|EY|;van der Heijden|Michiel S|MS|;Matsubara|Nobuaki|N|;Alekseev|Boris|B|;Necchi|Andrea|A|;Géczi|Lajos|L|;Ou|Yen-Chuan|YC|;Coskun|Hasan Senol|HS|;Su|Wen-Pin|WP|;Bedke|Jens|J|;Gakis|Georgios|G|;Percent|Ivor J|IJ|;Lee|Jae-Lyun|JL|;Tucci|Marcello|M|;Semenov|Andrey|A|;Laestadius|Fredrik|F|;Peer|Avivit|A|;Tortora|Giampaolo|G|;Safina|Sufia|S|;Garcia Del Muro|Xavier|X|;Rodriguez-Vida|Alejo|A|;Cicin|Irfan|I|;Harputluoglu|Hakan|H|;Tagawa|Scott T|ST|;Vaishampayan|Ulka|U|;Aragon-Ching|Jeanny B|JB|;Hamid|Oday|O|;Liepa|Astra M|AM|;Wijayawardana|Sameera|S|;Russo|Francesca|F|;Walgren|Richard A|RA|;Zimmermann|Annamaria H|AH|;Hozak|Rebecca R|RR|;Bell-McGuinn|Katherine M|KM|;Powles|Thomas|T|;|||",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000077143:Docetaxel; D010984:Platinum; C543333:ramucirumab",
"country": "England",
"delete": false,
"doi": "10.1016/S1470-2045(19)30668-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-2045",
"issue": "21(1)",
"journal": "The Lancet. Oncology",
"keywords": null,
"medline_ta": "Lancet Oncol",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D002295:Carcinoma, Transitional Cell; D000077143:Docetaxel; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010984:Platinum; D011379:Prognosis; D016879:Salvage Therapy; D015996:Survival Rate; D014571:Urologic Neoplasms",
"nlm_unique_id": "100957246",
"other_id": null,
"pages": "105-120",
"pmc": null,
"pmid": "31753727",
"pubdate": "2020-01",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "20048182;28408175;9816139;19687335;16515971;28988769;19536904;27571927;16682719;26952546;29268948;26926681;9823778;7539869;28833869;28131785;25326055;22819172;28601352;25096609;10022687;28916371;11156246;28817753;26487582;28212060;28375787;7530131;29867230;23341513;31301962;22370319",
"title": "Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial.",
"title_normalized": "ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum based therapy range overall survival and updated results of a randomised double blind phase 3 trial"
} | [
{
"companynumb": "US-PFIZER INC-2019517812",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": "3",
... |
{
"abstract": "A double-blind crossover study was conducted in four CYP2C19 genotype-defined metabolizer groups to assess whether increase in clopidogrel dosing can overcome reduced pharmacodynamic response in CYP2C19 poor metabolizers (PMs). Ten healthy subjects in each of four metabolizer groups were randomized to a clopidogrel regimen of a 300-mg loading dose (LD) and a 75-mg/day maintenance dose (MD) for 4 days followed by 600-mg LD and 150 mg/day MD, or vice versa. The exposure levels of clopidogrel's active metabolite H4 (clopi-H4) in PMs were 71% lower on the 75-mg/day regimen and 64% lower on the 150-mg/day regimen than the corresponding exposure levels in extensive metabolizers (EMs). In PMs, the maximal platelet aggregation (MPA) induced by adenosine diphosphate (ADP) 5 µmol/l was 10.5% lower on the 75-mg/day regimen and 7.9% lower on the 150-mg/day regimen than the corresponding values in EMs. PMs who were on the clopidogrel regimen of 600-mg LD/150 mg/day MD showed clopi-H4 exposure and MPA levels similar to those in EMs who were on the regimen of 300-mg LD/75 mg/day MD. In a pooled analysis evaluating CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A5, CYP2D6, ABCB1, and P2RY12 polymorphisms (N = 396 healthy subjects), only CYP2C19 had a significant impact on antiplatelet response. In healthy CYP2C19 PMs, a clopidogrel regimen of 600-mg LD/150 mg/day MD largely overcomes diminished clopi-H4 exposure and antiplatelet response, as assessed by MPA levels.",
"affiliations": "Department of Clinical Pharmacology, Assistance Publique-Hôpitaux de Paris, CHU Saint-Antoine and Université Pierre et Marie Curie, Paris, France. abassome.simon@sat.aphp.fr",
"authors": "Simon|T|T|;Bhatt|D L|DL|;Bergougnan|L|L|;Farenc|C|C|;Pearson|K|K|;Perrin|L|L|;Vicaut|E|E|;Lacreta|F|F|;Hurbin|F|F|;Dubar|M|M|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine",
"country": "United States",
"delete": false,
"doi": "10.1038/clpt.2011.127",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-9236",
"issue": "90(2)",
"journal": "Clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Clin Pharmacol Ther",
"mesh_terms": "D000244:Adenosine Diphosphate; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D000077144:Clopidogrel; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors; D011110:Polymorphism, Genetic; D013988:Ticlopidine; D055815:Young Adult",
"nlm_unique_id": "0372741",
"other_id": null,
"pages": "287-95",
"pmc": null,
"pmid": "21716274",
"pubdate": "2011-08",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Genetic polymorphisms and the impact of a higher clopidogrel dose regimen on active metabolite exposure and antiplatelet response in healthy subjects.",
"title_normalized": "genetic polymorphisms and the impact of a higher clopidogrel dose regimen on active metabolite exposure and antiplatelet response in healthy subjects"
} | [
{
"companynumb": "CH-JNJFOC-20150710769",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OMEPRAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Background. Catatonia is caused by a variety of psychiatric and organic conditions. The onset, clinical profile, and response to treatment may vary depending on the underlying cause. Catatonia is more likely to be associated with neurotic and psychotic disorders, but some psychiatric symptoms are key components in the clinical presentation of other medical conditions. Case Report. We report the case of a woman who started showing paroxysmal recurrent episodes since the age of 57 years, characterized by surrounding disconnection, disorientation, and muscle spasm (myoclonus), followed by a postictal state. In the following months, the symptoms evolved to akinetic mutism, catatonia, and rapidly progressive vision and audition loss. She underwent a battery of tests, most of them inconclusive, until a neoplastic meningoencephalitis was diagnosed after more than two years of symptoms. Numerous medical conditions can mimic psychiatric disorders. This uncommon presentation may lead to a late diagnosis and treatment initiation, increasing significantly morbidity and mortality. A differential diagnosis with infectious, autoimmune, and neoplastic etiologies should always be carried out.",
"affiliations": "Psychiatry Department, Hospital Clínico San Cecilio, Granada, Spain.;Internal Medicine Department, Hospital Clínico San Cecilio, Granada, Spain.;Department of Psychiatry, University of Granada, Granada, Spain.",
"authors": "de Jaime Ruiz|Pilar|P|;García-Fogeda Romero|Jose Luis|JL|;Gutiérrez-Rojas|Luis|L|https://orcid.org/0000-0003-0082-2189",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/5936673",
"fulltext": "\n==== Front\nCase Rep Psychiatry\nCase Rep Psychiatry\nCRIPS\nCase Reports in Psychiatry\n2090-682X\n2090-6838\nHindawi\n\n10.1155/2021/5936673\nCase Report\nCatatonia and Mutism: Neurotic, Psychotic, or Organic Disorder?\nde Jaime Ruiz Pilar 1\nGarcía-Fogeda Romero Jose Luis 2\nhttps://orcid.org/0000-0003-0082-2189\nGutiérrez-Rojas Luis gutierrezrojasl@hotmail.com\n3\n1Psychiatry Department, Hospital Clínico San Cecilio, Granada, Spain\n2Internal Medicine Department, Hospital Clínico San Cecilio, Granada, Spain\n3Department of Psychiatry, University of Granada, Granada, Spain\nAcademic Editor: Erik J nsson\n\n2021\n28 10 2021\n2021 593667319 4 2021\n5 10 2021\nCopyright © 2021 Pilar de Jaime Ruiz et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground. Catatonia is caused by a variety of psychiatric and organic conditions. The onset, clinical profile, and response to treatment may vary depending on the underlying cause. Catatonia is more likely to be associated with neurotic and psychotic disorders, but some psychiatric symptoms are key components in the clinical presentation of other medical conditions. Case Report. We report the case of a woman who started showing paroxysmal recurrent episodes since the age of 57 years, characterized by surrounding disconnection, disorientation, and muscle spasm (myoclonus), followed by a postictal state. In the following months, the symptoms evolved to akinetic mutism, catatonia, and rapidly progressive vision and audition loss. She underwent a battery of tests, most of them inconclusive, until a neoplastic meningoencephalitis was diagnosed after more than two years of symptoms. Numerous medical conditions can mimic psychiatric disorders. This uncommon presentation may lead to a late diagnosis and treatment initiation, increasing significantly morbidity and mortality. A differential diagnosis with infectious, autoimmune, and neoplastic etiologies should always be carried out.\n==== Body\npmc1. Introduction\n\nEven though catatonia can be caused by a variety of psychiatric and organic conditions, ranging from neurologic to systemic diseases, it is more likely to be associated with neurotic and psychotic disorder [1]. Catatonia is found in 10% of psychiatric inpatients and is more common in patients with mood disorders, especially mania, than in patients with schizophrenia [2]. The diversity of symptoms often leads to a delay in diagnosis and treatment initiation, increasing morbidity and mortality significantly. Albeit catatonia and akinetic mutism are commonly related to psychiatric diseases, numerous medical conditions can mimic psychiatric disorders [3]. A differential diagnosis with infectious, autoimmune, and paraneoplastic encephalitis should always be carried out [4].\n\nIn this report, we describe the case of a patient who consulted due to a two-year history of paroxysmal recurrent episodes, with surrounding disconnection, disorientation, and muscle spasm (myoclonus), followed by a postictal state. Eventually, she ended up in a catatonic state, with rapidly progressive vision and audition loss and almost surrounding disconnection. The patient died seven months later.\n\nThe purpose of this report is to describe a case of psychomotor impairment and catatonia due to a neoplastic meningoencephalitis associated with an unknown primary tumor. We also aim to create a differential diagnosis, which should lead us to investigate other causes apart from mental illnesses, and to enumerate the general principles of a comprehensive assessment.\n\n2. Case\n\nThe patient, Ms. A., was a 57-year-old married woman and mother to a son. She had no relevant medical history. As surgical background, she had undergone surgery of groin hernia, varicosities in lower limbs, appendectomy, and tonsillectomy. Ms. A. was an ex-smoker (who quitted at the age of 39 years). She had a family history of breast cancer in her mother and her sister.\n\nAs for her psychiatric history, she suffered from depressive mood after her father's death, when the patient was 49 years old. She was treated with individual support psychotherapy and venlafaxine 150 mg/day for one year, showing good response and clinical remission.\n\n2.1. First Episodes\n\nIn March, 2015, Ms. A. attended the emergency room presenting with a confused state, spatial disorientation, inability to recognize her relatives, and a slurred speech. Due to the patient's mental condition, the information was provided by her family.\n\nIn July, 2015, Ms. A. had a new episode, this time characterized of hyperventilation and upper and lower intermittent shakes. The patient was conscious, and she linked the episode with some stressful familiar situations. In both these episodes, Ms. A. was assessed by a neurologist, who performed blood tests, a computed tomography (CT) scan, an electroencephalogram (EEG), a sleep-deprived EEG, and a brain magnetic resonance imaging (MRI) scan but no abnormalities were detected.\n\nBoth neurologist and psychiatrist assessed the patient. Since physical tests were unremarkable, Ms. A. was diagnosed initially with a conversion/dissociative disorder.\n\nWe referred Ms. A. to neurology and psychiatry departments in outpatient visits. After performing neurological and psychiatric assessments with the consent and collaboration of the patient and her relatives, she was started on an anticonvulsant (levetiracetam 1000 mg/day), an antidepressant (desvenlafaxine 50 mg/day), and a benzodiazepine (alprazolam sustained release tablets 1 mg/day).\n\n2.2. New Episodes Two Years Later\n\nBetween July, 2015, and December, 2016, episodes as described above continued, but they were less frequent and self-limiting. From January, 2017, the episodes started to be more severe and disabling. In March 2017, Ms. A. presented to the hospital's emergency room by her relatives with a new episode of confusion, spatial disorientation, myoclonus seizures, and stereotypies (such as lip smacking), during which she remained unconscious for ten minutes. Afterwards, she recovered by herself, but drowsiness and spatial disorientation persisted. After recovering, when we tried to establish contact with Ms. A. and elucidate what had happened, she could not remember the episode. According to her relatives at that time, she was taking desvenlafaxine 50 mg/day, alprazolam sustain-released tablets 0.5 mg/day, and olanzapine 5 mg/day. In order to rule out any iatrogenic cause, we replaced alprazolam 0.5 mg/day with diazepam 5 mg/8 h (as a muscle relaxer) and quitted desvenlafaxine.\n\nIn April, 2017, Ms. A. started to display migraine-like symptoms, drowsiness, and being increasingly more excited, up to the point that she could barely breathe, suffering from trismus and emitting gibberish sounds. Furthermore, she also presented with muscle contractions and claw digits. In our physical examination, she was neither cooperative nor resistant, but she appeared to be indifferent. We requested additional tests in order to rule out other organic conditions. Brain CT scan, EEG, and pulmonary scan (in order to rule out a pulmonary thromboembolism), as well as laboratory test results, were unremarkable, again. A psychiatric orientation was then reassumed as a key component of this clinical profile. At that time, we added quetiapine 25 mg/8 h replacing olanzapine for the purpose of reducing a long-term anxious mental state, which was the patient's most remarkable clinical manifestation during those episodes.\n\n2.3. Clinical Worsening and Hospitalization\n\nIn May 2017, within a few weeks, the patient developed hyperventilation, muscle stiffness, lockjaw, walking difficulty, falls, and psychiatric symptoms consisting on visual hallucinations, bizarre behaviour, and some abnormal gestures such as trying to grab nonexistent objects in the air. This initial presentation was followed by an acute course towards a catatonic state, mutism, rapidly progressive vision and audition loss (initially, she could not recognize colours, and then, she lost visual and audition acuity), frequent seizures, muscle rigidity, and facial dyskinesia. The patient was eventually admitted to a psychiatric inpatient unit, as our initial presumptive diagnosis had been, until that point, a mental disorder. There, she was started on intravenous diazepam 5 mg/8 h and haloperidol 5 mg/8 h. We did not observe any response, so we went further with physical evaluation.\n\nA new brain MRI scan was performed, showing linear hyperintensities in basal segments and the VIII, VII, V, and III cranial nerves in FLAIR sequence, in the walls of both lateral ventricles in T2 sequences, as well as subtle communicant hydrocephalus (see Figures 1 and 2). A lumbar puncture showed very high cerebrospinal fluid (CSF) pressure (55 mmHg, normal value 10-15 mmHg), notable hyperproteinorrachy (470 mg/dL, normal value 15-15 mg/dL), with normal glucose levels and cell account. Gram stain cultures and C-reactive protein (CRP) test for bacteria and viruses were also negative.\n\nEventually, CSF cytology detected tumor cells. These cells were compatible with a metastatic breast adenocarcinoma, according to immunohistochemical stain. However, we never found any primary tumor after performing body CT scan, mammography, and positron emission tomography- (PET-) CT. The clinical course was very aggressive, with refractory catatonia and rigidity, and the patient died few weeks later.\n\n2.4. Final Diagnosis\n\nThe final diagnosis was carcinomatous meningoencephalitis, probable breast cancer as primary tumor.\n\n3. Discussion\n\nCatatonia is a neuropsychiatric syndrome easily identifiable by the clinician. However, an etiological diagnosis is not always easy. The Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) [5] recognizes that many cases are secondary to an organic disorder, under the heading of catatonic disorder due to a general medical condition (CD-GMC). The fifth DSM edition (DSM-5) recognizes that catatonia can occur in the context of another mental disorder or as a disorder due to another medical condition. Despite the amount of evidence, there are not many publications available regarding characteristics of organic catatonia.\n\nMany acute cases are attended at emergency departments, where the catatonias are often attributed to psychiatric problems, instead of medical and neurological conditions [1, 6]. This means delays in diagnosis and initial management, which are associated with increased morbidity and complications; some of these are serious and life-threatening. Many of these complications are related to decreased dietary and liquid intake and others to hospitalization and immobilization, such as rhabdomyolysis, deep vein thrombosis, pulmonary thromboembolism, and aspiration pneumonia, among others [6].\n\n3.1. Differential Diagnosis\n\nApart from psychiatric disorders, catatonia is secondary to numerous medical and neurological conditions. In a cohort of patients from a single institution [7], no reports of any psychiatric condition and a previous history of seizures were found in a greater proportion in the group of CD-GMC. Nonetheless, in clinical practice, there is a great deal of overlap between neurological and psychiatric processes. Thus, our approach is to rule out organic disease always, even when mental illness is the main suspicion.\n\nIn the study cited above, 21% of the cases were attributable to CD-GMC [7]. Cortical processes and encephalitis were the most common etiologies. Encephalitis was also observed to be among the most common etiologies of CD-GMC in a systematic literature review [8]. On this line, anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis might be the paradigm of CD-GMC [9]. Since it was identified just a little more than a decade ago, a lot of researches have been done; this rare condition receives a lot of interest among clinicians and investigators. It is believed that for many decades, anti-NMDAR encephalitis remained underdiagnosed, and a substantial number of patients were mistakenly categorized as having a psychiatric disorder. Even nowadays, distinguishing the disease from a primary psychiatric disorder is challenging.\n\nThe differential diagnosis of CD-GMC also includes other autoimmune and inflammatory mechanisms, as well as infectious, neoplastic, metabolic, toxic, and other causes. Table 1 provides a comprehensive list of etiologies [1].\n\n3.2. General Principles for Etiologic Assessment\n\nAfter syndrome categorization, it is necessary to focus on etiological diagnosis. It is essential to make a comprehensive clinical history, including patient's past medical, surgical, psychiatric, and drug/toxic history and symptoms of the current episode. Most patients are not able to perform an interview due to their catatonic state, so questioning accompanying persons is recommended.\n\nConsidering physical and psychiatric examinations, catatonic signs and symptoms in patients with CD-GMC and in psychiatric patients are mostly indistinguishable [10]. This was the conclusion of a retrospective chart review of 47 cases, which found a slightly higher prevalence of negativism and higher frequency of echo phenomena in patients with CD-GMC, but in general with a similar distribution of catatonic signs regardless of the etiology.\n\nThe appropriate evaluation [1, 6] would consist of a basic blood test with biochemical and haematological parameters. Specific investigations, such us drug blood/urine screen, viral serology, or nuclear autoantibodies, will be done depending on the clinical history, symptoms, and subsequent results in initial tests. Neuroimaging is necessary to rule out structural abnormalities; MRI may be more sensitive than CT. EEG can identify abnormal epileptiform activity seen, which is mostly related to nonconvulsive epileptic status.\n\nLumbar puncture was found to be the most useful procedure to make final diagnosis in CD-GMC [7, 8]. Therefore, analysis of CSF, including biochemical parameters, cell count, culture, and cytology, may probably be obligatory in all circumstances.\n\n3.3. Summary\n\nIn this case, the patient underwent a remarkable great number of tests; unfortunately, most of them were inconclusive. In fact, a first MRI was completely normal, and no abnormalities were found until a second MRI was performed two years later. Although prognosis of metastatic infiltration of CNS is bleak, a more rapid diagnosis may have been made if CSF had been analysed in an earlier stage.\n\nThis highlights how psychiatric symptoms often lead to a psychiatric diagnosis straightaway, with other possibilities seldom being considered. Although catatonia and akinetic mutism are commonly related to psychiatric diseases, several medical conditions can mimic psychiatric disorders [1, 5, 6, 10]. Cancer is just one of them, which can induce neurological and behavioural disturbances. Encephalitis is also an important differential diagnosis [9].\n\nThe correct diagnostic subcategorization of catatonia is critical for proper prognostication, identification of disease-specific acute therapies, and long-term therapeutic management of the underlying disease state. Delays are linked to poorer outcomes [6]. We strongly suggest to always rule out an organic condition as cause. We also recommend the use of lumbar puncture and CSF analyses for patients with catatonic disorder of unclear etiology [7, 8]. Focus should be placed on patients with neurological symptoms and recurrent bizarre episodes of undetermined origin with partial response to the treatment, as these patients may be at higher risk of any organic condition, and a complete differential diagnosis should be carried out.\n\nConflicts of Interest\n\nThe authors declare that they have no conflicts of interest.\n\nAuthors' Contributions\n\nThe authors of this paper were responsible for conceiving and designing the evaluation, clinical data collection, clinical data interpretation, and drafting the manuscript.\n\nFigure 1 Brain MRI showing linear hyperintensities in basal segments and VIII, VII, V, and III cranial nerves (FLAIR sequence) (please see the arrow).\n\nFigure 2 T2 sequence revealing hyperintensity in the walls of both lateral ventricles, as well as subtle communicant hydrocephalus (please see the arrow).\n\nTable 1 Causes of catatonia (adapted from Jaimes-Albornoz and Serra-Mestres [1]).\n\nPsychiatric and neurodevelopmental\n(i) Mania and depression (bipolar disorder), unipolar depression, late-onset depression, schizophrenia, and chronic psychoses\n(ii) Anxiety disorder, dissociative disorder and Ganser syndrome, adjustment disorders, acute stress reactions, obsessive-compulsive disorder, Prader–Willi syndrome, autistic spectrum disorders, and Gilles de la Tourette syndrome\t\n\t\nNeurological\n(i) Cerebrovascular disease, haemorrhagic infarcts\n(ii) Neoplasms, paraneoplastic encephalopathy, and malignant and benign central nervous system tumors\n(iii) Encephalitis (including anti-NMDAR, herpes, human immunodeficiency virus (HIV), postimmunisation, and encephalitis lethargica), meningitis, and cerebral abscesses\n(iv) Postencephalitic states, especially with parkinsonism, progressive multifocal encephalopathy\n(v) Epilepsy (absence seizures, complex nonconvulsive partial seizures, generalised and complex partial (focal) status epilepticus, postictal states)\n(vi) Neurosyphilis, other central nervous system infections: typhoid fever, tuberculosis, borreliosis, malaria, trypanosomiasis, hidatidosis\n(vii) Parkinson's disease, Lewy body disease, frontotemporal dementia, Alzheimer's disease, vascular dementia, Creutzfeldt-Jakob disease, fatal familial insomnia\n(viii) Motor neuron disease, Wilson's disease, Huntington's disease, multiple sclerosis, progressive supranuclear palsy\n(ix) Brain trauma acute and squeal, Wernicke's encephalopathy, hepatic encephalopathy, central pontine myelinolysis\n(x) Insomnia, narcolepsy, Tay-Sachs disease, tuberous sclerosis\n(xi) Hydrocephalus\t\n\t\nMetabolic and endocrine, haematological, and immune\n(i) Diabetic ketoacidosis, hypercalcemia, renal failure, liver failure\n(ii) Acute intermittent porphyria, homocystinuria, membranous glomerulonephritis, hyponatremia, hypernatremia\n(iii) Lysosomal disease, hypothyroidism, hyperthyroidism, hyperparathyroidism, hypoglycemia, Sheehan's syndrome\n(iv) Addison's disease, Cushing's disease, syndrome of inappropriate antidiuretic hormone secretion (SIADH)\n(v) Vitamin B12 deficiency, nicotinic acid deficiency, pellagra\n(vi) Systemic lupus erythematosus, pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS)\n(vii) Antiphospholipid syndrome, renal and hepatic transplant, Langerhans carcinoma\t\n\t\nPharmacological, toxic, and other\n(i) Typical and atypical antipsychotics (use and withdrawal) including clozapine, levodopa, amantadine, serotonergic drugs (selective serotonin reuptake inhibitors (SSRIs), trazodone, venlafaxine, etc.), lithium, acetyl-cholinesterase inhibitors\n(ii) Cephalosporins, ciprofloxacin, levofloxacin, azithromycin, levetiracetam, sodium valproate, gabapentin\n(iii) Disulfiram, paracetamol, aspirin, tramadol, hydroxyzine, antiretroviral, adrenocorticotropic hormone (ACTH), steroids\n(iv) Cyclosporine, chlorphenamine, methylphenidate, morphine, methadone, meperidine, allopurinol\n(v) Benzodiazepine withdrawal, cocaine, cannabis, lysergic acid diethylamide (LSD), mescaline, ketamine, phencyclidine, amphetamines, organophosphates, ethylene, carbon monoxide, severe burns\n==== Refs\n1 Serra-Mestres J. Jaimes-Albornoz W. Recognizing catatonia in medically hospitalized older adults: why it matters Geriatrics 2018 3 3 p. 37 10.3390/geriatrics3030037\n2 Usman D. M. Olubunmi O. A. Taiwo O. Taiwo A. Rahman L. Oladipo A. Comparison of catatonia presentation in patients with schizophrenia and mood disorders in Lagos, Nigeria Iranian Journal of Psychiatry 2011 6 7 11 22952514\n3 Desarkar P. Blumberger D. Daskalakis Z. J. Case report: successful use of the combination of electroconvulsive therapy and clozapine in treating treatment-resistant schizophrenia and catatonia in an adult with intellectual disability Journal of Autism and Developmental Disorders 2018 48 10 3637 3640 10.1007/s10803-018-3589-7 2-s2.0-85046031003 29696528\n4 Roldan Urgoiti G. Sinnarajah A. Hussain S. Hao D. Paraneoplastic neuropsychiatric syndrome presenting as delirium BMJ Supportive & Palliative Care 2017 7 2 218 220 10.1136/bmjspcare-2015-001043 2-s2.0-85020792179\n5 First M. B. Tasman A. DSM-IV-TR Mental Disorders: Diagnosis, Etiology, and Treatment 2004 Hoboken, NJ Wiley\n6 Jaimes-Albornoz W. Serra-Mestres J. Catatonia in the emergency department: Table 1 Emergency Medicine Journal 2012 29 11 863 867 10.1136/emermed-2011-200896 2-s2.0-84868150476 22389352\n7 Smith J. H. Smith V. D. Philbrick K. L. Kumar N. Catatonic disorder due to a general medical or psychiatric condition The Journal of Neuropsychiatry and Clinical Neurosciences 2012 24 2 198 207 10.1176/appi.neuropsych.11060120 2-s2.0-84865137262 22772668\n8 Carroll B. T. Anfinson T. J. Kennedy J. C. Yendrek R. Boutros M. Bilon A. Catatonic disorder due to general-medical conditions The Journal of Neuropsychiatry and Clinical Neurosciences 1994 6 2 122 133 10.1176/jnp.6.2.122 2-s2.0-0028326559 8044033\n9 Dalmau J. Armangué T. Planagumà J. An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models The Lancet Neurology 2019 18 11 1045 1057 10.1016/S1474-4422(19)30244-3 2-s2.0-85072867959 31326280\n10 Carroll B. T. Kennedy J. C. Goforth H. W. Catatonic signs in medical and psychiatric catatonias CNS Spectrums 2000 5 7 66 69 10.1017/S1092852900013420 2-s2.0-0033884838\n\n",
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"title": "Catatonia and Mutism: Neurotic, Psychotic, or Organic Disorder?",
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"abstract": "BACKGROUND\nWe report a case of post COVID-19 Sino-orbital Mucormycosis infection caused by Rhizopus oryzae and its management.\n\n\nMETHODS\nThe patient was diagnosed with COVID-19 and treated according to the persisting protocols. Following recovery, on the 18th day, the patient developed chemosis and pain in the left eye. A diagnosis of mucormycosis was established after Magnetic Resonance Imaging (MRI) and Functional Endoscopic Sinus Surgery (FESS). Initially, conservative management with intravenous (IV) Fluconazole & Amphotericin B was done and later on with surgical debridement. The patient recovered with minimal residual deformity.\n\n\nCONCLUSIONS\nMucormycosis generally develops secondary to immunosuppression or debilitating diseases. In Head and Neck cases, the mold usually gains entry through the respiratory tract involving the nose and sinuses, with possible further progression into the orbital and intracranial structures. Hence, an early diagnosis and intervention is required for a good prognosis, decreasing the morbidity. This can be achieved on the basis of clinical picture and direct smears.\n\n\nCONCLUSIONS\nResearch needs to be carried out in COVID-19 patients for better prevention and management of opportunistic infections in order to reduce its incidence and morbidity. Prophylactic treatment protocols need to be established, along with rational use of corticosteroids.",
"affiliations": "Department Of Oral and Maxillofacial Surgery, D. Y. Patil University, Sector 7 Nerul, Navi Mumbai 400706, India.;Department Of Oral and Maxillofacial Surgery, D. Y. Patil University, Sector 7 Nerul, Navi Mumbai 400706, India. Electronic address: dr.gauravtom@gmail.com.;Unit Head - Head and Neck Oncology & Associate Professor Oral and Maxillofacial Surgery, School of Medicine D. Y. Patil University, Sector 7 Nerul, Navi Mumbai, India.;Department Of Oral and Maxillofacial Surgery, D. Y. Patil University, Sector 7 Nerul, Navi Mumbai 400706, India.;Department Of Oral and Maxillofacial Surgery, D. Y. Patil University, Sector 7 Nerul, Navi Mumbai 400706, India.;Department Of Oral and Maxillofacial Surgery, D. Y. Patil University, Sector 7 Nerul, Navi Mumbai 400706, India.",
"authors": "Maini|Aastha|A|;Tomar|Gaurav|G|;Khanna|Deepak|D|;Kini|Yogesh|Y|;Mehta|Hardik|H|;Bhagyasree|V|V|",
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"doi": "10.1016/j.ijscr.2021.105957",
"fulltext": "\n==== Front\nInt J Surg Case Rep\nInt J Surg Case Rep\nInternational Journal of Surgery Case Reports\n2210-2612\nElsevier\n\nS2210-2612(21)00459-4\n10.1016/j.ijscr.2021.105957\n105957\nCase Report\nSino-orbital mucormycosis in a COVID-19 patient: A case report\nMaini Aastha a\nTomar Gaurav dr.gauravtom@gmail.com\na⁎\nKhanna Deepak b\nKini Yogesh a\nMehta Hardik a\nBhagyasree V. a\na Department Of Oral and Maxillofacial Surgery, D. Y. Patil University, Sector 7 Nerul, Navi Mumbai 400706, India\nb Unit Head - Head and Neck Oncology & Associate Professor Oral and Maxillofacial Surgery, School of Medicine D. Y. Patil University, Sector 7 Nerul, Navi Mumbai, India.\n⁎ Corresponding author. dr.gauravtom@gmail.com\n04 5 2021\n5 2021\n04 5 2021\n82 1059579 4 2021\n27 4 2021\n28 4 2021\n© 2021 The Authors. Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.\n2021\n\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nIntroduction\n\nWe report a case of post COVID-19 Sino-orbital Mucormycosis infection caused by Rhizopus oryzae and its management.\n\nPresentation of case\n\nThe patient was diagnosed with COVID-19 and treated according to the persisting protocols. Following recovery, on the 18th day, the patient developed chemosis and pain in the left eye. A diagnosis of mucormycosis was established after Magnetic Resonance Imaging (MRI) and Functional Endoscopic Sinus Surgery (FESS). Initially, conservative management with intravenous (IV) Fluconazole & Amphotericin B was done and later on with surgical debridement. The patient recovered with minimal residual deformity.\n\nDiscussion\n\nMucormycosis generally develops secondary to immunosuppression or debilitating diseases. In Head and Neck cases, the mold usually gains entry through the respiratory tract involving the nose and sinuses, with possible further progression into the orbital and intracranial structures. Hence, an early diagnosis and intervention is required for a good prognosis, decreasing the morbidity. This can be achieved on the basis of clinical picture and direct smears.\n\nConclusion\n\nResearch needs to be carried out in COVID-19 patients for better prevention and management of opportunistic infections in order to reduce its incidence and morbidity. Prophylactic treatment protocols need to be established, along with rational use of corticosteroids.\n\nHighlights\n\n• Sino-orbital Mucormycosis post COVID-19\n\n• Opportunistic infections in COVID-19\n\n• Immuno-suppressants need to be more judicious\n\n• Early diagnosis and management reduces morbidity and mortality.\n\nKeywords\n\nCovid-19\nMucormycosis\nAmphotericin B\nFungal infection\nOpportunistic infection\nCase report\n==== Body\n1 Introduction\n\nThe outbreak of coronavirus disease (COVID-19) has spread rapidly on a global scale [1,2]. Despite great efforts, there is no definitive treatment of the disease. However, prevention and symptomatic management are the best options.\n\nSecondary infections are a well-described phenomenon in influenza, SARS, MERS, and other respiratory viral illnesses. But super-infections and co-infections in COVID-19 pneumonia are still under exploration [3]. Secondary infections are reportedly common in hospitalized, severely ill Covid-19 patients, encompassing between 10 and 30% of cases, fungal being 10 times more common [3]. As the nature of the disease is still not completely unveiled, it can't be confirmed if it's a complication of the disease or its management.\n\nDrugs like Corticosteroids i.e., Methylprednisolone and Dexamethasone are believed to modulate inflammation mediated lung injury and thereby reduce progression of respiratory failure [4] in Covid-19. There side effects include increased secondary infections, immune modulation, manifestation of latent diabetes mellitus, dizziness, weight gain, mood changes, insomnia and muscle weakness [5].\n\nMucormycosis is amongst the most fulminant form of Zygormycosis caused by Mucorales species of the phylum Zygomycota [6] described as a potentially lethal infection occurring mostly in immunocompromised hosts, particularly in those with diabetes mellitus, leukemia and lymphoma [7].\n\nThe incidence rate of mucormycosis globally varies from 0.005 to 1.7 per million population [8]. Whereas, in Indian population its prevalence is 0.14 per 1000, which is about 80 times higher than developed countries [9]. The fatality rate of mucormycosis is 46% globally [10]. However, factors like intracranial or orbital involvement, irreversible immune suppression increases fatality to as high as 50% to 80% [11]. A high suspicion for this disease must be considered in patients who are immunocompromised. Tissue necrosis, a hallmark of mucormycosis is often a late sign [10].\n\nMucormycosis is difficult to diagnosis which affects outcome and results in poor prognosis. Early diagnosis and treatment is essential. Delay of a week often doubles the 30-day mortality from 35% to 66%. Despite early aggressive combined surgical and medical therapy, the prognosis of mucormycosis is poor [10].\n\n2 Presentation of case\n\nA 38-year-old male was admitted to our Hospital, a tertiary care center with a history of fever for 4 days, on 2nd September 2020. He presented with a high grade fever, body ache, cough and shortness of breath. Nasopharyngeal swab was sent for RT-PCR which came positive and a diagnosis of COVID-19 was confirmed. The patient had no history of diabetes or any other debilitating conditions and no relevant family history. On admission, the derranged investigations were: Neutrophil count 83.1% (35–66%), Lymphocyte count 9.5% (24–44%), Fasting blood sugar (FBS) 98 mg/dL (70-110 mg/dL), Post-prandial blood sugar (PPBS) 146 mg/dL (110-140 mg/dL), HbA1c 6.3% (<6%), Serum Interleukin-6 37.93 pg/mL (<6.4 pg/mL), CRP 17.84 mg/L (0–6 mg/L), D-Dimer 460 ng/mL (0–500 ng/mL).\n\nHe was monitored in the Intensive Care Unit for 5 days and was started on Inj.Remdesivir IV with a loading dose of 200 mg, followed by 100 mg daily for 11 days. Methylprednisolone was given by IV infusion, 80 mg/day in 240 mL saline at 10 mL/h for 18 days. Also Inj.Dexamethasone 4 mg twice daily was given for 12 days as a part of COVID-19 management. Post-treatment FBS 125 mg/dL, PPBS 352 mg/dL and HbA1c 12.3%.\n\nAfter 18 days, the patient complaint of swelling and pain in the left eye. He was referred to the Department of Head and Neck Oncology for the same. On clinically examination, there was malaise, proptosis, chemosis, periorbital cellulitis and restricted medial gaze. Visual acuity was 6/6 with partial opthalmoplegia and no nasal discharge was seen (Fig. 1). The work has been reported in line with the SCARE 2020 criteria [12].Fig. 1 Preoperative photograph showing left eye exopthalmous and chemosis.\n\nFig. 1\n\n2.1 Management and follow-up\n\nMRI brain & orbit was done showing an ill-defined heterogenous soft tissue signal intensity (hypointense on T1W-imaging), polyploidal mucosal thickening involving left maxillary and ethmoid sinuses was seen. A breach was seen in the posterior portion of left lamina paprycea with altered signal intensity involving conal and extra-conal infero-medial portion of the left orbit. There was displacement of adjacent medial and inferior rectus. Retrobulbar soft tissue fat stranding and edema with resultant displacement of left eye ball anteriorly leading to proptosis was seen. It was also found to be closely abutting the left optic nerve (Fig. 2).Fig. 2 (A) Coronal Section of MRI T1 weighted image and (B) Axial Section of MRI T2 weighted image showing extension of the lesion.\n\nFig. 2\n\nFESS was done for right & left maxillary sinus and left ethmoid sinus. Crusting was noted over posterior aspect of inferior turbinate, septum and conchae. The sinuses were debrided and the specimen obtained was sent for culture sensitivity and histopathology. Inj.Piptaz 4.5 g-8hourly, Inj.Metronidazole 500 mg-8hourly and Inj.Fluconazole 200 mg-12hourly was started postoperatively. On histopathology examination, aseptate broad based hyphae and gram positive bacilli were seen and hence Mucormycosis suspected. The medical regime changed to Inj.Amphotericin B 300 mg/day, eyedrops Tobramycin BD and Nepalact TDS. The swelling and chemosis reduced slightly, but no improvement in extraocular movements was seen after 3 days of treatment.\n\nSurgical debridement was planned under general anesthesia. Lateral canthotomy and inferior cantholysis was done. Inferior fornix incision was taken, septum incised and orbit was approached along the medial wall. Inferior and medial rectus muscles were tagged and intraconal space was entered. Debridement and Amphotericin B lavage (1 mg/mL) was done (Fig. 3, Fig. 4). Closure was done with 6-0 resorbable suture. Monocef 1 g–12hourly was added to the pre-existing regime.Fig. 3 (A) Inferior fornix incision marked and retraction sutures taken. (B) Inferior fornix incision taken, lateral canthotomy and inferior cantholysis done. (C) Dissection done in preseptal plane (D) Septum incised and orbit approached along the medial wall. Inferior and medial rectus muscles tagged. (E) Intraconal space entered between the two muscles. (F) Debridement of Intraconal space.\n\nFig. 3\n\nFig. 4 Necrotic tissue removed during debridement.\n\nFig. 4\n\nPost-operative MRI orbit showed mucosal thickening of the paranasal sinuses. The left medial and inferior rectus appear mildly bulky. No obvious residual lesion seen.\n\nTotal hospitalization for the patient was 38 days. On discharge, Inj.Amphotericin B 300 mg/day 18 days, followed by Tab.Fluconazole 200 mg was prescribed.\n\nOn a 7 day follow up, chemosis was present and the eye movements were sluggish on medial and lateral movement. On a 2 month follow up, minimal residual deformity was seen along with normal eye movements as compared to the other eye. FBS, PPBS and HbA1c levels dropped to 100 mg/dL, 124 mg/dL and 7.4% respectively. Patient was satisfied with treatment and outcome.\n\n2.2 Microbiology\n\nMicrobiological studies were performed on tissue biopsies, inoculated on Sabouraud's agar, incubated at 30 °C and the sample was examined microscopically. Fungal growth was studied macroscopically at 37 °C and 45 °C after staining with lactofuchsin. After 4 days, colonies of Rhizopus oryzae were seen growing on the media. Special stains for fungal hyphae: PAS and GMS were positive.\n\nAseptate, branching broad based fungal hyphae, areas of necrosis along with epitheloid cell granulomas comprising of epitheloid cells, multinucleated giant cells and chronic inflammatory cell infiltrate were seen (Fig. 5).Fig. 5 Lactofuchsin stained section showing typical aseptate, branching broad based fungal hyphae, areas of necrosis, epitheloid cell granulomas, multinucleated giant cells and chronic inflammatory cell infiltrate. (A) 100× (B) 10×.\n\nFig. 5\n\n3 Discussion\n\nThe nomenclature of Mucormycosis is suggested by anatomic site localization rather than by mycologic classification. For the head and neck region, they can be classified into isolated nasal, rhino-orbital or rhino-orbital-cerebral Mucormycosis. Other accepted forms are pulmonary, disseminated, cutaneous, gastrointestinal and miscellaneous [13]. Fungi of the genus Rhizopus account for the majority of clinical isolates.\n\nMucoraceae are ubiquitous saprophytic fungi and are common inhabitants of decaying matter also found in bread, soil, air, dust and hospital ward rooms [[13], [14], [15]]. Seasonal variance could theoretically be related to use of air conditioners. The organisms are potent in the temperate climates [7].\n\nThe most common risk factors being diabetes mellitus, immunosuppressive therapy, leukemias, neutropenias [7]. Patients with neutrophil dysfunction, hematopoetic stem cell transplantation, diabetic ketoacidosis, iron-overload and HIV/AIDs are some identifiable risk factors.\n\nThe mold usually gains entry into the host through the respiratory tract and exhibits a remarkable affinity for arteries and grows along internal elastic lamina causing thrombosis and infarction [16,17]. The progression of the disease from nose and sinuses is either direct or through vascular occlusion. Intracranial involvement also occurs by invasion through superior orbital fissure, ophthalmic vessels, cribriform plate [18], carotid artery or possibly via a perineural route [19].\n\nWaiting for cultures is impractical and may lead to delay in initiation of treatment. If clear clinical picture of mucormycosis exists, positive direct smears may be sufficient for initiating treatment [7].\n\nDiagnosis is classically dependent on clinical features, pathological findings and imaging plays an important role in defining the extent of involvement [11]. Early establishement of the diagnosis and prompt surgical intervention aids in controlling the extent and severity of the disease.\n\nThe primary guideline for treating the disease is to correct the underlying cause, but this cannot be achieved in patients dependent on high dose steroid therapy like in COVID-19. The two mainstays of treatment are medical treatment with Amphotericin B and surgical debridement. Hyperbaric oxygen therapy and local treatment with Amphotericin B are adjunctive modalities. Amphotericin B is a fungistatic agent rather than fungicidal, which leads to longer treatment duration.\n\nPrognosis is dependent on multiple factors and early initiation of treatment is an important element. Once the diagnosis is confirmed, conservative management is started for the patient. Orbital exenteration remains the most difficult decision in rhino-orbital cases, due to concerns about disability and disfigurement. Although, exenteration is the last resort but can be life-saving at the price of mutilating procedure.\n\n4 Conclusion\n\nThe question still prevails about the cause and origin of enhanced prevalence in post COVID-19 patients. Research is needed for better prevention and management of opportunistic infections in COVID-19 patients. The use of prophylactic treatment protocols for the same needs to be assessed and guidelines need to established in order to reduce morbidity. Moreover, use of Immuno-suppressants should be more judicious along with continuous monitoring.\n\nSources of funding\n\nNo source of funding.\n\nEthical approval\n\nNot applicable.\n\nConsent\n\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nAuthor contribution\n\nDr. Aastha Maini: Analysis and interpretation of data, drafting the article, final approval of the version to be submitted.\n\nDr. Gaurav Tomar: Analysis and interpretation of data, drafting the article, final approval of the version to be submitted.\n\nDr. Deepak Khanna: Analysis and interpretation of data, drafting the article, final approval of the version to be submitted.\n\nDr. Yogesh Kini: Analysis and interpretation of data, drafting the article, final approval of the version to be submitted.\n\nDr. Hardik Mehta: Analysis and interpretation of data, drafting the article, final approval of the version to be submitted.\n\nDr. V. Bhagyasree: Analysis and interpretation of data, drafting the article, final approval of the version to be submitted.\n\nResearch registration (for case reports detailing a new surgical technique or new equipment/technology): NOT APPLICABLE.\n\nGuarantor\n\nDr. Aastha Maini.\n\nDr. Gaurav Tomar.\n\nProvenance and peer review\n\nNot commissioned, externally peer-reviewed.\n\nDeclaration of competing interest\n\nNone.\n==== Refs\nReferences\n\n1 Jayaweera M. Perera H. Gunawardana B. Manatunge J. Transmission of COVID-19 virus by droplets and aerosols: a critical review on the unresolved dichotomy Environ. Res. 188 2020 Sep 109819 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293495/ 32569870\n2 Modes of transmission of virus causing COVID-19: implications for IPC precaution recommendations https://www.who.int/news-room/commentaries/detail/modes-of-transmission-of-virus-causing-covid-19-implications-for-ipc-precaution-recommendations\n3 Superinfections and coinfections in COVID-19 MedPage Today. https://www.medpagetoday.com/infectiousdisease/covid19/86192.\n4 RECOVERY Collaborative Group Horby P. Lim W.S. Dexamethasone in Hospitalized Patients with Covid-19 N. Engl. J. Med. 384 8 2021 Feb 693 704 10.1056/nejmoa2021436 32678530\n5 Methylprednisolone for patients with COVID-19 severe acute respiratory syndrome - full text view ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04323592\n6 Sugar A.M. Mucormycosis Clin. Infect. Dis. 14 1992 S126 S129 Available from: https://www.jstor.org/stable/4456403 1562684\n7 Talmi Y.P. Goldschmied-Reouven A. Bakon M. Barshack I. Wolf M. Horowitz Z. Rhino-orbital and rhino-orbito-cerebral mucormycosis Otolaryngol. Head Neck Surg. 127 1 2002 Jul 1 22 31 Available from 10.1067/mhn.2002.1265874 12161726\n8 Jeong W. Keighley C. Wolfe R. The epidemiology and clinical manifestations of mucormycosis: a systematic review and meta-analysis of case reports Clin. Microbiol. Infect. 25 2019 26 34 30036666\n9 Chander J. Kaur M. Singla N. Punia R. Singhal S. Attri A. Guarro J. Mucormycosis: battle with the deadly enemy over a five-year period in India J. Fungi 4 2 2018 46 10.3390/jof4020046\n10 Werthman-Ehrenreich A. Mucormycosis with orbital compartment syndrome in a patient with COVID-19 Am. J. Emerg. Med. 42 2021 264.e5 264.e8 10.1016/j.ajem.2020.09.032\n11 Deutsch P.G. Whittaker J. Prasad S. Invasive and non-invasive fungal rhinosinusitis—a review and update of the evidence Medicina 55 2019 1 14\n12 Agha R.A. Franchi T. Sohrabi C. Mathew G. for the SCARE Group The SCARE 2020 guideline: updating consensus Surgical CAse REport (SCARE) guidelines Int. J. Surg. 84 2020 226 230 33181358\n13 Safi M. Ang M.J. Patel P. Silkiss R.Z. Rhino-orbital-cerebral mucormycosis (ROCM) and associated cerebritis treated with adjuvant retrobulbar amphotericin B Am. J. Ophthalmol. Case Rep. 19 2020 100771 10.1016/j.ajoc.2020.100771 32551404\n14 Kolekar J.S. Rhinocerebral mucormycosis: a retrospective study Indian J. Otolaryngol. Head Neck Surg. 67 1 2015 93 96 10.1007/s12070-014-0804-5 25621242\n15 Camara-Lemarroy C.R. González-Moreno E.I. Rodríguez-Gutiérrez R. Rendón-Ramírez E.J. Ayala-Cortés A.S. Fraga-Hernández M.L. García-Labastida L. Galarza-Delgado D.Á. Clinical features and outcome of mucormycosis Interdiscip. Perspect. Infect. Dis. 2014 2014 562610 10.1155/2014/562610 25210515\n16 Gupta S. Goyal R. Kaore N.M. Rhino-orbital-cerebral mucormycosis: battle with the deadly enemy Indian J. Otolaryngol. Head Neck Surg. 72 1 2020 104 111 10.1007/s12070-019-01774-z 32158665\n17 Groote C.A. Rhinocerebral phycomycosis Arch. Otolaryngol. 92 3 1970 Sep 1 288 292 https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/603163 4993724\n18 Bawankar P. Lahane S. Pathak P. Gonde P. Singh A. Central retinal artery occlusion as the presenting manifestation of invasive rhino-orbital-cerebral mucormycosis Taiwan J. Ophthalmol. 10 1 2020 62 65 10.4103/tjo.tjo_72_18 32309127\n19 Parsi K. Itgampalli R.K. Vittal R. Kumar A. Perineural spread of rhino-orbitocerebral mucormycosis caused by Apophysomyces elegans Ann. Indian Acad. Neurol. 16 3 2013 Jul 1 414 https://www.annalsofian.org/article.asp?issn=0972-2327;year=2013;volume=16;issue=3;spage=414;epage=417;aulast=Parsi;type=0 24101833\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2210-2612",
"issue": "82()",
"journal": "International journal of surgery case reports",
"keywords": "Amphotericin B; Case report; Covid-19; Fungal infection; Mucormycosis; Opportunistic infection",
"medline_ta": "Int J Surg Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101529872",
"other_id": null,
"pages": "105957",
"pmc": null,
"pmid": "33964720",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Sino-orbital mucormycosis in a COVID-19 patient: A case report.",
"title_normalized": "sino orbital mucormycosis in a covid 19 patient a case report"
} | [
{
"companynumb": "IN-BAUSCH-BL-2021-018617",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "Heparin-induced thrombocytopenia (HIT) is a serious and life-threatening complication that occurs in five per cent of patients exposed to heparin. It should be considered in patients with a platelet count <100×109cells/l or a >50% decrease from baseline count in association with heparin therapy. Thromboembolic complications develop in 50% of patients. Bleeding is rare as the platelet count nadir typically does not drop below 20×109cells/l. Up to 12% of dialysis patients develop HIT, named haemodialysis-related-heparin-induced thrombocytopenia (HD-HIT), as they are a risk group with continuous exposure to heparin. The definition of HD-HIT is less strict, in the range of a platelet count decrease of 30% and below 150×109cells/l due to the intermittent use of heparin. Heparin cessation and alternative anticoagulation are the key interventions in patients with HIT. In dialysis patients, citrate anticoagulation, heparin-free dialysis or peritoneal dialysis are options that must be considered. The authors describe the presentation, diagnosis, treatment and outcomes of five cases of HD-HIT, and emphasize the importance of an accurate diagnosis and early intervention in order to reduce the mortality risk, which can be as high as 20 per cent.",
"affiliations": "Division of Nephrology and Renal Transplantation, Department of Medicine, Centro Hospitalar Lisboa Norte, EPE, Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal. Electronic address: joana.estrelagameiro@gmail.com.;Division of Nephrology and Renal Transplantation, Department of Medicine, Centro Hospitalar Lisboa Norte, EPE, Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal.;Division of Nephrology and Renal Transplantation, Department of Medicine, Centro Hospitalar Lisboa Norte, EPE, Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal.",
"authors": "Gameiro|Joana|J|;Jorge|Sofia|S|;Lopes|José António|JA|",
"chemical_list": "D000925:Anticoagulants; D006493:Heparin",
"country": "Spain",
"delete": false,
"doi": "10.1016/j.nefro.2018.02.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2013-2514",
"issue": "38(5)",
"journal": "Nefrologia",
"keywords": "Dialysis; Diálisis; Heparin; Heparina; Thrombocytopenia; Trombocitopenia",
"medline_ta": "Nefrologia (Engl Ed)",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D005260:Female; D006493:Heparin; D006801:Humans; D008297:Male; D006435:Renal Dialysis; D013921:Thrombocytopenia",
"nlm_unique_id": "101778581",
"other_id": null,
"pages": "551-557",
"pmc": null,
"pmid": "29871769",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Haemodialysis-related-heparin-induced thrombocytopenia: Case series and literature review.",
"title_normalized": "haemodialysis related heparin induced thrombocytopenia case series and literature review"
} | [
{
"companynumb": "PT-B. BRAUN MEDICAL INC.-2059690",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": ... |
{
"abstract": "OBJECTIVE\nThe purpose of this review is to educate the reader about the one of the most common vasculitides of childhood: Henoch-Schonlein purpura. Although the disease has been described for over a century, the etiology has yet to be discovered. Adult-onset Henoch-Schonlein purpura is unusual, but through case studies, this review examines some of the common manifestations of this presentation of disease. Long-term outcome studies are still defining how this disease affects a small but significant percentage of patients afflicted with Henoch-Schonlein purpura.\n\n\nRESULTS\nThis article will summarize recent work in molecular biology and genetics evaluating predisposing factors in the development of Henoch-Schonlein purpura. Further illustrations of the various complications of Henoch-Schonlein purpura will be reviewed. Recent long-term studies of outcomes of patients with renal disease from Henoch-Schonlein purpura will be summarized.\n\n\nCONCLUSIONS\nAfter reading this review, the clinician will be able to elucidate the manifestations of Henoch-Schonlein purpura, determine appropriate treatment of the disease, and, most importantly, give the patient information about long-term consequences of Henoch-Schonlein purpura.",
"affiliations": "Indiana University School of Medicine, Indianapolis 46202, USA. sballing@iupui.edu",
"authors": "Ballinger|Susan|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/00002281-200309000-00012",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1040-8711",
"issue": "15(5)",
"journal": "Current opinion in rheumatology",
"keywords": null,
"medline_ta": "Curr Opin Rheumatol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D006801:Humans; D011695:IgA Vasculitis; D009393:Nephritis; D011379:Prognosis",
"nlm_unique_id": "9000851",
"other_id": null,
"pages": "591-4",
"pmc": null,
"pmid": "12960486",
"pubdate": "2003-09",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Henoch-Schonlein purpura.",
"title_normalized": "henoch schonlein purpura"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201708493",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ONDANSETRON"
},
"drugadditional": null,
... |
{
"abstract": "A patient with rheumatoid arthritis presented with pancytopenia 3 weeks after initiation of low-dose methotrexate administered orally. She had minimal renal insufficiency and hypoalbuminemia prior to initiation of methotrexate therapy, and had received a nonsteroidal anti-inflammatory drug concurrently. Bone marrow recovery occurred within 3 weeks. Patients receiving low-dose methotrexate therapy for rheumatoid arthritis require early monitoring for bone marrow injury, especially those who have risk factors for possible methotrexate toxicity.",
"affiliations": "Department of Medicine, University of Kansas Medical Center, Kansas City 66103.",
"authors": "Doolittle|G C|GC|;Simpson|K M|KM|;Lindsley|H B|HB|",
"chemical_list": "D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-9926",
"issue": "149(6)",
"journal": "Archives of internal medicine",
"keywords": null,
"medline_ta": "Arch Intern Med",
"mesh_terms": "D001172:Arthritis, Rheumatoid; D005260:Female; D006801:Humans; D008727:Methotrexate; D008875:Middle Aged; D010198:Pancytopenia; D013997:Time Factors",
"nlm_unique_id": "0372440",
"other_id": null,
"pages": "1430-1",
"pmc": null,
"pmid": "2730263",
"pubdate": "1989-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Methotrexate-associated, early-onset pancytopenia in rheumatoid arthritis.",
"title_normalized": "methotrexate associated early onset pancytopenia in rheumatoid arthritis"
} | [
{
"companynumb": "US-PFIZER INC-2016531937",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": "3",... |
{
"abstract": "BACKGROUND\nLenalidomide is an immunomodulatory agent with multiple mechanisms of action, and treatment with lenalidomide is associated with adverse events such as thrombosis and abdominal pain; nonetheless, other rarer adverse events do exist, with few knowledge from physicians and pharmacists. For such adverse events, pharmacovigilance databases are of great interest.\n\n\nMETHODS\nA 71-year-old patient with no rheumatologic history, in complete remission of a mantle-cell lymphoma following rituximab, doxorubicin, vincristine, cyclophosphamide, and prednisone induction, received a maintenance treatment with rituximab and lenalidomide. After each course of lenalidomide and with no other new medication, the patient presented with fever and high inflammatory markers level, and a scapular-belt arthritis.\nThe patient was managed with non-steroidal anti-inflammatory drugs and colchicine, with symptomatology and inflammation improvement. After discontinuation of lenalidomide, he had no arthritis relapse; it was then concluded that the patient had a lenalidomide-induced arthritis. We interrogated the national and international (VigiBase®) pharmacovigilance databases and found that arthritis in the context of lenalidomide exposure is a rare finding, with only three reported cases in France; 0.13% of adverse events reported with lenalidomide in the international database VigiBase® were arthritis.\n\n\nCONCLUSIONS\nOur case then reports an uncommon finding, of which both pharmacists and physicians should be aware due to the wide and increasing use of lenalidomide.",
"affiliations": "Department of Medical and Clinic Pharmacology, 36760CHU de Toulouse, France.;Department of Medical and Clinic Pharmacology, 36760CHU de Toulouse, France.;Department of Hematology, 54909Institut Universitaire du Cancer-Oncopole, France.;Department of Medical and Clinic Pharmacology, 36760CHU de Toulouse, France.;Department of Hematology, 54909Institut Universitaire du Cancer-Oncopole, France.",
"authors": "Icard|Charlotte|C|;Mocquot|Pauline|P|https://orcid.org/0000-0001-7181-3525;Nogaro|Jean-Claude|JC|;Despas|Fabien|F|;Gauthier|Martin|M|https://orcid.org/0000-0001-5338-2071",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/10781552211038001",
"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": "Pharmacovigilance; adverse drug reaction; lenalidomide; mantle-cell lymphoma",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": null,
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "10781552211038001",
"pmc": null,
"pmid": "34590522",
"pubdate": "2021-09-30",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Lenalidomide-induced arthritis: A case report and review of literature and pharmacovigilance databases.",
"title_normalized": "lenalidomide induced arthritis a case report and review of literature and pharmacovigilance databases"
} | [
{
"companynumb": "FR-drreddys-LIT/FRA/22/0147347",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"drugadditional": "1",
... |
{
"abstract": "Eribulin is an antineoplastic agent used in advanced breast cancer refractory to anthracycline and taxane treatment regimens. A wide variety of side effects with unclear mechanisms have been noted, but encephalopathy has not been widely reported. Here we describe the case of a middle-aged woman treated with eribulin for advanced breast cancer who subsequently developed central nervous system drug-induced toxicity but improved promptly with steroid administration.\nEribulin-induced encephalopathy is a diagnosis of exclusion and should be included in the differential diagnosis of patients treated with eribulin and presenting with altered mental status.Eribulin can cross the blood-brain barrier.Steroids and drug cessation should be the mainstay of treatment in cases of eribulin-induced encephalopathy.",
"affiliations": "Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA.;Department of Gastroenterology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.;Department of Internal Medicine, Shifa College of Medicine, Islamabad, Pakistan.;Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA.",
"authors": "Sheikh|Abu Baker|AB|;Perisetti|Abhilash|A|;Javed|Nismat|N|;Shekhar|Rahul|R|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2020_001708",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2284-2594",
"issue": "7(9)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Eribulin; breast cancer; encephalopathy",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "001708",
"pmc": null,
"pmid": "32908828",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "26956105;30041177;31753013;21324687;28056400",
"title": "Eribulin and Confusion: A Previously Unknown Drug Side-Effect.",
"title_normalized": "eribulin and confusion a previously unknown drug side effect"
} | [
{
"companynumb": "US-EISAI MEDICAL RESEARCH-EC-2019-059222",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ERIBULIN"
},
"drugadditional":... |
{
"abstract": "Neonatal abstinence syndrome (NAS) refers to a constellation of signs occurring in newborn infants who were exposed to opioids or opiates in utero. These manifestations include poor feeding, gastrointestinal disorders, abnormal sleep patterns, and neurological signs such as jitteriness, tremors, and seizures (1, 2). Myoclonus, jitteriness, and tremors often may be interpreted as seizures and therefore treated as epileptic seizures. Objective: To determine whether seizure like activity observed in infants with NAS correlate with electroencephalogram (EEG) findings. Design/ Method: We reviewed the standard EEG or video electroencephalogram (VEEG) of infants with NAS who were admitted because of seizure-like clinical activity. The exclusion criteria were major neurological anomalies, hypoxic ischemic encephalopathy, metabolic disorders, or with clinical diagnosis other than NAS. Results: Forty neonates met study criteria; 28 had standard EEG recordings and 18 had VEEG. Mean gestational age was 38.5 weeks. The onset of seizure-like clinical activity was as early as day 1 and as late as day 16 of life. The clinical seizure-like activity described at the referring hospital were jerking, rhythmic movement of the extremities, or tremors. Only three (7.5%) neonates had epileptic seizures. There were increased sharp transients in frontal, central, temporal, and or occipital regions. VEEG showed disturbed non-rapid eye movement (REM) sleep with frequent arousal, jittery movements, or sleep myoclonus. Conclusion: Clinical seizure-like activity correlates poorly with epileptic seizures in infants with NAS. In neonates with NAS, a VEEG would be useful to determine if the clinical seizure-like activity is of epileptic origin or not, prior to initiation of anti-seizure medications.",
"affiliations": "Division of Neonatology, Department of Pediatrics, University of Kentucky, Lexington, KY, United States.;Division of Neonatology, Department of Pediatrics, University of Kentucky, Lexington, KY, United States.;Division of Neonatology, Department of Pediatrics, University of Kentucky, Lexington, KY, United States.;Division of Neonatology, Department of Pediatrics, University of Kentucky, Lexington, KY, United States.",
"authors": "Palla|Murali Reddy|MR|;Khan|Gulam|G|;Haghighat|Zahra M|ZM|;Bada|Henrietta|H|",
"chemical_list": null,
"country": "Switzerland",
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"doi": "10.3389/fped.2019.00111",
"fulltext": "\n==== Front\nFront PediatrFront PediatrFront. Pediatr.Frontiers in Pediatrics2296-2360Frontiers Media S.A. 10.3389/fped.2019.00111PediatricsOriginal ResearchEEG Findings in Infants With Neonatal Abstinence Syndrome Presenting With Clinical Seizures Palla Murali Reddy *Khan Gulam Haghighat Zahra M. Bada Henrietta Division of Neonatology, Department of Pediatrics, University of Kentucky, Lexington, KY, United StatesEdited by: Eugene Dempsey, University College Cork, Ireland\n\nReviewed by: Anne Smits, University Hospitals Leuven, Belgium; Liam Mahoney, Southmead Hospital, United Kingdom\n\n*Correspondence: Murali Reddy Palla mpa229@uky.eduThis article was submitted to Neonatology, a section of the journal Frontiers in Pediatrics\n\n29 3 2019 2019 7 11106 9 2018 07 3 2019 Copyright © 2019 Palla, Khan, Haghighat and Bada.2019Palla, Khan, Haghighat and BadaThis 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.Neonatal abstinence syndrome (NAS) refers to a constellation of signs occurring in newborn infants who were exposed to opioids or opiates in utero. These manifestations include poor feeding, gastrointestinal disorders, abnormal sleep patterns, and neurological signs such as jitteriness, tremors, and seizures (1, 2). Myoclonus, jitteriness, and tremors often may be interpreted as seizures and therefore treated as epileptic seizures.\n\nObjective: To determine whether seizure like activity observed in infants with NAS correlate with electroencephalogram (EEG) findings.\n\nDesign/ Method: We reviewed the standard EEG or video electroencephalogram (VEEG) of infants with NAS who were admitted because of seizure-like clinical activity. The exclusion criteria were major neurological anomalies, hypoxic ischemic encephalopathy, metabolic disorders, or with clinical diagnosis other than NAS.\n\nResults: Forty neonates met study criteria; 28 had standard EEG recordings and 18 had VEEG. Mean gestational age was 38.5 weeks. The onset of seizure-like clinical activity was as early as day 1 and as late as day 16 of life. The clinical seizure-like activity described at the referring hospital were jerking, rhythmic movement of the extremities, or tremors. Only three (7.5%) neonates had epileptic seizures. There were increased sharp transients in frontal, central, temporal, and or occipital regions. VEEG showed disturbed non-rapid eye movement (REM) sleep with frequent arousal, jittery movements, or sleep myoclonus.\n\nConclusion: Clinical seizure-like activity correlates poorly with epileptic seizures in infants with NAS. In neonates with NAS, a VEEG would be useful to determine if the clinical seizure-like activity is of epileptic origin or not, prior to initiation of anti-seizure medications.\n\nseizuresneonatal abstinence syndromeelectroencephalographyprenatal opiate exposuresleep myoclonus\n==== Body\nIntroduction\nNeonatal abstinence syndrome (NAS) is a clinical diagnosis, and a consequence of the abrupt discontinuation of chronic fetal exposure to substances, specifically opiates or opioids used by the mother during pregnancy. The prolonged half-life of opioids in the infants and the ease with which opioids can cross the fetal blood-brain barrier of the fetus may increase the severity of withdrawal manifestations in infants with NAS (3). Furthermore, accumulation of the drug in the fetus may result in the increased production of various neurotransmitters through a cascade of enzymatic activities (4). Locus coeruleus is the most important center of activity in opioid withdrawal. This is the principal noradrenergic nucleus of the brain and is extremely sensitive to opioid status (5), i.e., withdrawal of the inhibitory effect of opiate on the adrenergic neurons results in the hyperactivity of these neurons (6). Most infant with NAS manifests with central nervous system irritability, autonomic over reactivity, and gastrointestinal tract dysfunction. Central nervous system manifestations reported with NAS are tremors, exaggerated Moro reflex, hypertonia, and myoclonic jerks (7). These can mimic seizures and therefore, an EEG may be required for confirmation prior to treatment.\n\nOf neonates with NAS, 2–11% manifest with seizures (8). The underlying cause of seizures in NAS is not known, although the threshold for seizure activity may be decreased due to upregulation of sodium channels as a result of receptor instability (9). NAS may involve a short intense initial phase, consisting of tremors, seizures, irritability, feeding problems, vomiting, diarrhea, hyperthermia, and other systemic signs which lasts for upto 1–2 weeks. Later initial phase may be followed by a long chronic and relapsing course that includes hyperirritability, sleep disturbances, hyperphagia, and other neurologic and autonomic signs (lasting for a few weeks to a few months) (10). NAS symptoms depend on the type of drug exposure. In intrauterine opioids exposure, such as heroin is associated with earlier onset and shorter duration of withdrawal, compared to methadone or buprenorphine, which is associated with late onset and prolonged withdrawal. In the nonopioids class, methamphetamine exposure is associated with early withdrawal symptoms (11).\n\nThe jerking movement in NAS may be interpreted as seizures, thus an indication for anti-convulsant therapy. However, these jerking movements may represent benign neonatal sleep myoclonus (BNSM), which has been reported in neonates with NAS (1). Benign neonatal sleep myoclonus (BNSM) is a phenomenon typically observed in newborns during the first 4 weeks of life. This condition is not associated with abnormal EEG. BNSM does not need treatment and does not affect neurodevelopmental outcome (12–14).\n\nSince clinical observation of myoclonus, jitteriness, or tremors can be misinterpreted as epileptic seizures, it prompted us to explore the association between myoclonus, jitteriness, tremors, and or seizure-like activity and EEG findings in babies with NAS.\n\nMethods\nThis retrospective study had approval by the Institutional Review Board (IRB) and met compliance with the Health Insurance Portability and Accountability Act. The IRB waived informed consent procedure for this study. Inclusion criteria included admission to the neonatal intensive care unit, history of intrauterine opioid exposure with or without other substances, seizure-like activity reported as a clinical manifestation, and the infant having had routine EEG or VEEG. Opioid exposure refers to a mother admitting use during pregnancy or had a positive urine test for opioids or the baby had positive urine or meconium drug test. Seizure-like manifestation was described as jerking or rhythmic movement of extremities, myoclonus during sleep, apnea, and/or tremors. The exclusion criteria were major neurological anomalies, hypoxic ischemic encephalopathy, metabolic disorders, or with clinical diagnosis other than NAS. Interval assessment or monitoring of these infants used the Finnegan Neonatal Abstinence Scoring System (2). Oxygen saturation monitored by pulse oximetry, blood glucose; sodium, potassium, and calcium were monitored. All infants were monitored with Finnegan scoring system. If 3 consecutive scores were ≥8 or 2 consecutive scores of ≥12, infants were treated with morphine escalated and weaned according to the unit protocol. If infants had electrographic seizures, they were treated as per our neonatal intensive care unit (NICU) guidelines.\n\nThe EEG and VEEG were reviewed by one of the investigators (GK), a pediatric epileptologist. Routine EEG was done for 1 h and VEEG was done for 48 h. The Xltek EEG/PSG System (Natus Neuro Inc., Pleasanton, CA) was used for both EEG and VEEG; it has components needed for EEG and VEEG. The EEG and VEEG waveforms were assessed for the background activity, sharp transients, and electrographic seizures. Background activity is considered normal if there is no focal slowing and no prolonged “trace alternant” (in term neonates 6–8 s is normal). Sharp transients are normally present in newborn infants but disappear by 50 weeks of post conceptional age. Sharp transients that are repetitive in same area with slow background and increased frequency are considered abnormal (15). Neonatal electrographic seizure refers to a sudden, repetitive, evolving, and stereotyped event of abnormal electrographic pattern with amplitude of at least 2 μV and a minimum duration of 10 s (16). Descriptive statistics were used and no EEG scoring system was used.\n\nResults\nForty neonates with NAS were admitted to our level IV neonatal intensive care unit (NICU) for seizure-like manifestation during January 2010- November 2015. The patient characteristics are shown in Table 1. There were 23 males and 17 females. The mean (SD) gestational age was 37.5 (1.9) weeks and mean (SD) birth weight was 2,843 (620) grams. All infants were exposed to tobacco during pregnancy and of whom 29 infants were exposed to opioids only. The remaining 11 infants were exposed to more than one drug (marijuana, benzodiazepines, methamphetamines, and/or gabapentin).The onset of seizure-like manifestation was as early as day 1 and as late as day 16 of life, mean (SD) of 4.1 (4) days. Twenty-seven neonates were treated for seizure-like clinical sign at the referring hospital before EEG was performed; 23 were treated with phenobarbital, two with morphine, and one with levetiracetam. In these patients, seizure like clinical activity were described as jerking or rhythmic movement of extremities, myoclonus during sleep, apnea, and/or tremors. Based on review of the EEG or VEEG, only three neonates had epileptic seizure. Findings on EEG are shown in Table 2. Most of the neonates (72.5%) had normal background activity and 27.5% had mildly slow activity. Three neonates (7.5%) with epileptic seizures also had mildly slow background activity. There were sharp transients in frontal, central, temporal, and or occipital regions. Additionally, in the 18 (45%) neonates who had continuous video monitoring, detailed review showed disturbed non-REM sleep with frequent arousal pattern, jittery movements, and sleep myoclonus. BNSM was seen in 13/18 (72%) neonates and 5/18 (28%) had increased arousal pattern. Oxygen saturation monitored by pulse oximetry, blood glucose, sodium, potassium, and calcium were within normal limits (Table 3).\n\nTable 1 Patient characteristics.\n\nTotal number of subjects\t40\t\nMales\t23 (57.5%)\t\nFemales\t17 (42.5%)\t\nMean gestational age (SD)\t37.5 weeks (1.9)\t\nMean birth weight (SD)\t2,843 g (620)\t\nIntrauterine exposure to single drug\t29 (72.5%)\t\nIntrauterine exposure to poly drugs\t11 (27.5%)\t\nDay of life onset of reported seizure, mean (SD)\t4.1 (4)\t\nDay of life onset of reported seizure, median (range)\t2.5 (1–16)\t\nNumber of Pts treated for clinical seizures with anti-seizure medications before admission/EEG\t23 (57.5%)\t\nNot treated for clinical seizures\t17 (42.5%)\t\nTable 2 Electroencephalographic findings in infants with neonatal abstinence syndrome observed to manifest with clinical seizures.\n\nRoutine EEG and VEEG (n = 40)\tn (%)\t\nBACKGROUND ACTIVITY\t\t\nNormal\t29 (72.5)\t\nMildly slow\t11 (27.5)\t\nSHARP TRANSIENTS\t\t\nFronto- centro-temporal (FCT)\t21 (52.5)\t\nFronto centro temporal occipital (FCTO)\t8 (20)\t\nCentro temporal (CT)\t7 (17.5)\t\nCentro temporal occipital (CTO)\t2 (5)\t\nNo transient spikes\t2 (5)\t\nSEIZURES\t\t\nNo seizures\t37 (92.5)\t\nSeizures present\t3 (7.5)\t\nVEEG (n\n=\n18)\t\t\nBenign neonatal sleep myoclonus (BNSM)\t13 (72)\t\nIncreased arousal pattern\t5 (28)\t\nTable 3 Oxygen saturations and biochemical parameters on admission.\n\nParameters\tMean and standard deviation (SD)\t\nOxygen saturations, %\t96.65 (1.57)\t\nBlood glucose, mg/dL\t81 (16.69)\t\nSodium, mmol/L\t139 (3.38)\t\nPotassium, mmol/L\t4.7 (0.72)\t\nCalcium, mmol/L\t9.4 (0.94)\t\nDiscussion\nWe report EEG findings in neonates with NAS, who were admitted for clinical seizure like activity. The neurological examination was normal, except for the irritability, tremors, and increased tone, which are not unusual findings in babies with NAS.\n\nHerzlinger and co-investigators reported an incidence of 5.9% of documented seizures in neonates with NAS (8). In our study, of infants with NAS who presented with seizure-like activity, majority (92.5%) had no electroencephalographic seizures; only three or 7.5% had seizures consistent with the EEG pattern. Our findings suggest that seizures if confirmed by EEG studies occur at a much lower incidence than in previous reports based on clinical findings. Our findings on EEG were consistent with disturbed non-REM sleep with frequent arousal, Jittery movements, or sleep myoclonus (1, 17). Benign neonatal sleep myoclonus or (BNSM) is a distinctive disorder characterized by rhythmic myoclonic jerks, which occur when the child is asleep and stop when the child is awakened. BNSM may appear on the first day of life and persist for several weeks to months. BNSM is often mistaken for epilepsy but the EEGs are always normal. The pathophysiological mechanism of BNSM is not fully elucidated (18). It may a result of a benign discharge in the reticular activating system, where the initiation and synchronization of normal sleep is controlled (19). Another possibility is that BNSM is related to transient immaturity or imbalance of the serotoninergic system (20). Because of the spontaneous resolution with age, BNSM it is likely related to brain maturation. Previously reported clinical seizures in NAS could at least in part have been myoclonic jerks (12). An earlier study showed around 67% of infants with NAS and had EEG procedure had BNSM (1). In our study of 18 neonates with VEEG, BNSM was seen in a comparable incidence (13/18 or 72%). Five or 28% had increased arousal pattern. In children and adults, the most specific interictal electrographic signs of the seizure activity are spikes and sharp waves. The neonatal situation is more complex, since some sharp transients are commonly seen in their EEG (21). Further, in healthy neonates, sharp EEG transients usually appear against a normal background and which do not signify the presence of encephalopathy nor support the presence of seizures. The clinical significance of sharp wave transients on neonatal electroencephalographic (EEG) recordings remains controversial (22). Rowe et al. stressed that EEG background abnormalities are a more accurate independent predictor of neurodevelopmental outcome rather than sharp wave transients. In our study there were increased sharp transients in frontal, central, temporal, and occipital regions, but with normal background activity (23). EEG background activity was normal in 72.5% of our patients; none of them had electrical seizures. Eleven or 27.5% had mildly slow pattern background; the three with electrical seizures were among those with mildly slow background activity.\n\nFew studies examined sleep in NAS. Opiate-exposed newborns have shown a significant increase in active sleep and a reciprocal decrease in quiet sleep than controls (23–26). O'Brien and Jeffery reported on a reduction of quiet sleep in infants with NAS compared to their control group (8). Also, adult and preclinical studies demonstrated that sleep is altered in opiate withdrawal (27–30). The mechanisms behind sleep disturbances during NAS remain unclear, but could be due to changes to the central nervous system (CNS) during opiate dependency in utero, and due to hyperactivity of the CNS during withdrawal (23, 25). In our study, the neonates who had VEEG, 28% did have increased arousal pattern.\n\nLimitations\nOur study merely focused on infants with NAS admitted for seizure-like clinical manifestation. VEEG was not performed in all study subjects. The small number of infants in our study precluded analysis of any correlation between the EEG findings and the type of opioids or other drugs to which the infants were exposed. The impact of medication used to treat NAS (or seizures) on the EEG was not analyzed.\n\nConclusion\nClinical manifestation of seizure-like activity correlates poorly with epileptic seizures in infants with NAS. In infants with a history of intrauterine drug exposure mainly opioids presenting with seizure like activity with no other medical conditions, obtaining a video EEG would be ideal to determine if the seizure-like manifestation is of epileptic origin, before starting anti-seizure medication. If available, a VEEG is a preferred modality to be able to correlate abnormal movements with electroencephalographic findings.\n\nEthics Statement\nStudy was approved by University of Kentucky Institutional Review Board.\n\nAuthor Contributions\nMP reviewed the charts, EEG along with pediatric neurologists. ZH did the chart review and EEG review. GK did review of EEG's. HB guided through the project.\n\nConflict of Interest Statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n1. Held-Egli K Rüegger C Das-Kundu S Schmitt B Bucher HU . Benign neonatal sleep myoclonus in newborn infants of opioid dependent mothers . Acta Paediatr. (2009 ) 98 :69 –73 . 10.1111/j.1651-2227.2008.01010.x 18803624 \n2. Finnegan LP Kron JR Connaughton EF Emich JP . Assessment and treatment of abstinence in the infant of the drug dependent mother . Int J Clin Pharmacol. (1975 ) 12 :19 –32 . 1100537 \n3. Scott CS Riggs KW Ling EW Fitzgerald CE Hill ML Grunau RV . Morphine pharmacokinetics and pain assessment in premature newborns . J Pediatr. (1999 ) 135 :423 –9 . 10.1016/S0022-3476(99)70163-0 10518075 \n4. Rehni AK Jaggi AS Singh N . Opioid withdrawal syndrome: emerging concepts and novel therapeutic targets . CNS Neurol Disord Drug Targets. (2013 ) 12 :112 –25 . 10.2174/1871527311312010017 23244430 \n5. Scavone JL Sterling RC Van Bockstaele EJ . Cannabinoid and opioid interactions: implications for opiate dependence and withdrawal . Neuroscience. (2013 ) 248 :637 –54 . 10.1016/j.neuroscience.2013.04.034 23624062 \n6. Aghajanian GK . Tolerance of locus coeruleus neurones to morphine and suppression of withdrawal response by clonidine . Nature. (1978 ) 276 :186 –188 . 10.1038/276186a0 216919 \n7. Gaalema DE Scott TL Heil SH Coyle MG Kaltenbach K Badger GJ . Differences in the profile of neonatal abstinence syndrome signs in methadone- versus buprenorphine-exposed neonates . Addiction. (2012 ) 107 (suppl. 1 ):53 –62 . 10.1111/j.1360-0443.2012.04039.x 23106927 \n8. Herzlinger RA Kandall SR Vaughan HG Jr . Neonatal seizures associated with narcotic withdrawal . J Pediatr. (1977 ) 91 :638 –41 . 10.1016/S0022-3476(77)80523-4 908988 \n9. Feng Y He X Yang Y Chao D Lazarus LH Xia Y . Current research on opioid receptor function . Curr Drug Targets. (2012 ) 13 :230 –46 . 10.2174/138945012799201612 22204322 \n10. Kocherlakota P . Neonatal Abstinence Syndrome . Pediatrics. (2014 ) 134 :e547 . 10.1542/peds.2013-3524 25070299 \n11. Hudak ML Tan RC Committee on Drugs Committee on Fetus and Newborn American Academy of Pediatrics Clinical Report . Neonatal drug withdrawal . Pediatrics. (2012 ) 129 :e540 –60 . 10.1542/peds.2011-3212 22291123 \n12. Blennow G . Benign infantile nocturnal myoclonus . Acta pediatr Scand. (1985 ) 74 :505 –7 . 4024921 \n13. Goraya JS Poddar B Parmar VR . Benign neonatal sleep myoclonus . Ind Pediatr. (2001 ) 38 :81 –3 . 11175939 \n14. Egger J Grossmann G Auchterlonie IA . Benign sleep myoclonus in infancy mistaken for epilepsy . BMJ. (2003 ) 326 :975 –6 . 10.1136/bmj.326.7396.975 12727774 \n15. Eisermann M kaminska A Moutard ML Soufflet C Plouin P . Normal EEG in childhood: from neonates to adolescents . Clin Neurophysiol. (2013 ) 43 :35 –65 . 10.1016/j.neucli.2012.09.091 23290174 \n16. Abend N Wusthoff C . Neonatal seizures and status epilepticus . J Clin Neurophysiol. (2012 ) 29 :441 –8 . 10.1097/WNP.0b013e31826bd90d 23027101 \n17. O'Brien CM Jeffery HE . Sleep deprivation, disorganization and fragmentation during opiate withdrawal in newborns . J Paediatr Child Health. (2002 ) 38 :66 –71 . 11869404 \n18. Halliday AM \nThe neurophysiology of myoclonic jerking . In: Charlton MD editor. Myoclonic Seizures. Princeton, NJ, Excepta Medica (1975 ), p. 1 –29 .\n19. Coulter DL Allen RJ \nBenign neonatal sleep myoclonus . Arch Neurol. (1982 ) 32 :191 –92 . 10.1001/archneur.1982.00510150061016 \n20. Resnick TJ Moshe SL Perotta L Chambers HJ \nBenign neonatal sleep myoclonus. Relation to sleep states . Arch Neurol. (1986 ) 43 :266 –68 . 10.1001/archneur.1986.00520030056014 3080981 \n21. Robert R \nClancy. Interictal Sharp EEG Transients in Neonatal Seizures . J Child Neurol. (1989 ) 4 :30 –8 . 10.1177/088307388900400105 2918208 \n22. Scher MS Bova JM Dokianakis SG Steppe DA \nPhysiological significance of sharp wave transients on EEG recordings of healthy pre-term and full-term neonates. Electroencephalography and clinical \nNeurophysiology. (1994 ) 90 :179 –85 . 10.1016/0013-4694(94)90089-2 \n23. Rowe RJ Holmes GL Hafford J Baboval D Robinson S Phillips T \nPrognostic value of electroencephalogram in term and pre- term infants following neonatal seizures . Electroenceph Clin Neurophysiol. (1985 ) 6 :183 –96 . 10.1016/0013-4694(85)90030-6 \n24. Pinto F Torrioli M Tempesta E Fundaro C . Sleep in babies born to chronically heroin addicted mothers. A follow up study . Drug Alcohol Depend. (1988 ) 21 :43 –7 . 10.1016/0376-8716(88)90009-9 3366054 \n25. Schulman C \nAlterations in sleep cycle in heroin and suspect newborn . Neuropädiatrie. (1969 ) 1 :89 –100 . 10.1055/s-0028-1091866 4330029 \n26. Dinges D Davis M Glass P . Fetal exposure to narcotics: Neonatal sleep as a measure of nervous system disturbance . Science. (1980 ) 209 :619 –21 . 10.1126/science.7190326 7190326 \n27. Lewis S Oswald I Evans J Akindele M Tompsett S \nHeroin and human sleep . Electroencephalogr Clin Neurophysiol. (1970 ) 28 :374 –81 . 10.1016/0013-4694(70)90230-0 4191189 \n28. Oyefeso A Sedgwick P Ghodse H \nSubjective sleep-wake para- meters in treatment- seeking opiate addicts . Drug Alcohol Depend. (1997 ) 48 :9 –16 . 10.1016/S0376-8716(97)00097-5 9330916 \n29. Howe R Hegge F Phillips J . Acute heroin abstinence in man. I. Changes in behavior and sleep . Drug Alcohol Depend. (1980 ) 5 :341 –56 . 10.1016/0376-8716(80)90160-X \n7371499 \n30. Sisson T Wickler M Tsai P Rao I \nEffect of narcotic withdrawal on neonatal sleep patterns . Pediatr Res. (1974 ) 8 :451 \n10.1203/00006450-197404000-00664\n\n",
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"title": "EEG Findings in Infants With Neonatal Abstinence Syndrome Presenting With Clinical Seizures.",
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"abstract": "OBJECTIVE\nTo describe a case of nivolumab-induced ulcerative keratitis rapidly recovering on topical steroid treatment and to determine changes in cytokine levels in the tear fluid caused by nivolumab.\n\n\nMETHODS\nWe report a 34-year-old man receiving nivolumab for metastasized melanoma with severe dry eye symptoms and a persistent corneal epithelial defect. Levels of cytokine and matrix metalloproteinase in tear fluid were measured by multiplex immunoassays.\n\n\nRESULTS\nThe corneal epithelial defect failed to recover for antiviral and lubrication therapy but resolved within 48 hours after topical steroid therapy was initiated. No recurrence of corneal ulceration was observed with intermittent topical steroid therapy during the remaining period of nivolumab treatment. No Sjögren disease-related autoantibodies were detected in the patient's serum. The levels of inflammatory cytokines and matrix metalloproteinases in the tear fluid were markedly elevated after nivolumab treatment.\n\n\nCONCLUSIONS\nOur observations suggest that nivolumab treatment induces a local autoimmune ocular surface disorder resulting in corneal ulceration that promptly resolves using steroid eye drops. The integrity of the corneal epithelial layer can be sustained using intermittent topical steroid therapy in patients receiving nivolumab.",
"affiliations": "Department of Ophthalmology, Zuyderland-Eyescan BV, Zuyderland Hospital, Sittard-Geleen, the Netherlands; and.;University Eye Clinic Maastricht, Maastricht University Medical Center, Maastricht, the Netherlands.;University Eye Clinic Maastricht, Maastricht University Medical Center, Maastricht, the Netherlands.",
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"abstract": "We report five women who presented with scleroderma due to taxanes, mimicking systemic sclerosis. All five patients had received taxane chemotherapy for the treatment of metastatic breast cancer. Marked oedema began first, followed by skin sclerosis occurring mainly at the distal ends of the extremities 6-12 months after the administration of taxane in all patients. Skin biopsies showed full-layer dermal fibrosis with thickened collagen bundles, and perivascular monocytic cell infiltration. These cases resemble systemic sclerosis in terms of their clinical course and histological findings. However, clinical findings including Raynaud's phenomenon and pulmonary fibrosis as well as immunological abnormalities associated with systemic sclerosis were not detected in any of the patients. Although the mechanisms have not been clarified, it should be noted that taxane is causally involved in the formation of scleroderma-like skin conditions.",
"affiliations": "Department of Dermatology, The Jikei University School of Medicine, 3-25-8 Nishishimbashi, Tokyo, Japan. seafowl@jikei.ac.jp",
"authors": "Itoh|M|M|;Yanaba|K|K|;Kobayashi|T|T|;Nakagawa|H|H|",
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"title": "Taxane-induced scleroderma.",
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"abstract": "BACKGROUND\nHigh-dose therapy (HDT) with stem-cell support is the reference treatment for relapsed lymphoma, but is not appropriate for all patients. Conventional salvage chemotherapies have been used with limited efficacy and significant toxicity. Rituximab, gemcitabine and oxaliplatin are active as single agents in relapsed or refractory lymphoma, and have demonstrated synergistic effects in vitro and in vivo.\n\n\nMETHODS\nForty-six patients with relapsed or refractory B-cell lymphoma received up to eight cycles of R-GemOx (rituximab 375 mg/m(2) on day 1, gemcitabine 1000 mg/m(2) and oxaliplatin 100 mg/m(2) on day 2). The majority (72%) had diffuse large B-cell lymphoma.\n\n\nRESULTS\nAfter four cycles of R-GemOx, the overall response rate was 83% [50% complete response (CR)/unconfirmed CR (CRu)]. High CR/CRu rates were observed in all histological subtypes. In patients who had previously received rituximab, the CR/CRu rate after eight cycles was 65%. The 2-year event-free and overall survival rates (median follow-up of 28 months) were 43% and 66%, respectively. Among responders, the probability of being disease free for 2 years was 62%. Treatment was generally well tolerated.\n\n\nCONCLUSIONS\nR-GemOx shows promising activity with acceptable toxicity in patients with relapsed/refractory B-cell lymphoma who are not eligible for HDT.",
"affiliations": "Department of Clinical Hematology, Henri Mondor Hospital, Assistance Publique-Hôpitaux de Paris, Paris XII University, Créteil, France.",
"authors": "El Gnaoui|T|T|;Dupuis|J|J|;Belhadj|K|K|;Jais|J-P|JP|;Rahmouni|A|A|;Copie-Bergman|C|C|;Gaillard|I|I|;Diviné|M|M|;Tabah-Fisch|I|I|;Reyes|F|F|;Haioun|C|C|",
"chemical_list": "D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000069283:Rituximab; C056507:gemcitabine",
"country": "England",
"delete": false,
"doi": "10.1093/annonc/mdm133",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0923-7534",
"issue": "18(8)",
"journal": "Annals of oncology : official journal of the European Society for Medical Oncology",
"keywords": null,
"medline_ta": "Ann Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D016393:Lymphoma, B-Cell; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000069283:Rituximab; D016879:Salvage Therapy; D015996:Survival Rate",
"nlm_unique_id": "9007735",
"other_id": null,
"pages": "1363-8",
"pmc": null,
"pmid": "17496309",
"pubdate": "2007-08",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Rituximab, gemcitabine and oxaliplatin: an effective salvage regimen for patients with relapsed or refractory B-cell lymphoma not candidates for high-dose therapy.",
"title_normalized": "rituximab gemcitabine and oxaliplatin an effective salvage regimen for patients with relapsed or refractory b cell lymphoma not candidates for high dose therapy"
} | [
{
"companynumb": "FR-ROCHE-1845623",
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"occurcountry": "FR",
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"activesubstance": {
"activesubstancename": "DEXCHLORPHENIRAMINE"
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{
"abstract": "Clozapine is a second-generation antipsychotic medication, which is mostly used in patients with treatment resistant schizophrenia. It is considered to be associated with lower incidence of extrapyramidal side-effects. Akathisia is considered to be a rare side-effect of clozapine. In this report, we describe a patient who developed akathisia while receiving clozapine and review the literature. Existing literature suggests that except for few initial reports, data suggests that clozapine is in general associated with lower incidence of akathisia compared to first generation antipsychotics. Data comparing clozapine with other atypical antipsychotics is equivocal.",
"affiliations": "Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh, India.",
"authors": "Grover|Sandeep|S|;Sahoo|Swapnajeet|S|",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine",
"country": "India",
"delete": false,
"doi": "10.4103/0253-7613.153441",
"fulltext": "\n==== Front\nIndian J PharmacolIndian J PharmacolIJPharmIndian Journal of Pharmacology0253-76131998-3751Medknow Publications & Media Pvt Ltd India IJPharm-47-23410.4103/0253-7613.153441Drug WatchClozapine induced akathisia: A case report and review of the evidence Grover Sandeep Sahoo Swapnajeet Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh, IndiaCorrespondence to: Dr. Sandeep Grover, E-mail: drsandeepg2002@yahoo.comMar-Apr 2015 47 2 234 235 28 3 2014 21 11 2014 25 2 2015 Copyright: © Indian Journal of Pharmacology2015This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Clozapine is a second-generation antipsychotic medication, which is mostly used in patients with treatment resistant schizophrenia. It is considered to be associated with lower incidence of extrapyramidal side-effects. Akathisia is considered to be a rare side-effect of clozapine. In this report, we describe a patient who developed akathisia while receiving clozapine and review the literature. Existing literature suggests that except for few initial reports, data suggests that clozapine is in general associated with lower incidence of akathisia compared to first generation antipsychotics. Data comparing clozapine with other atypical antipsychotics is equivocal.\n\nKEY WORDS\nAkathisiaclozapineextrapyramidal side effects\n==== Body\nIntroduction\nAkathisia is understood as a subjective feeling of motor restlessness, which manifests as a pressing need to be in constant movement. Compared to the first generation antipsychotic (FGA), in general, second-generation antipsychotic (SGA) have been reported to be associated with lower incidence of akathisia.[1]\n\nSome reports also suggest a beneficial effect of clozapine on persistent akathisia too.[2] However, few reports have also linked acute akathisia with use of clozapine but literature is still limited. We describe a case of acute akathisia associated with clozapine and review the existing literature linking clozapine with acute akathisia.\n\nCase Report\nA 32-year-old, male presented with a history suggestive of schizophrenia of 9 years duration. To start with he developed symptoms in the form of auditory hallucinations, suspiciousness, fearfulness, decreased interaction with family members and social withdrawal. Three months after the onset of the illness he was treated with T. haloperidol 10 mg/day along with clonazepam 3 mg/day with which his positive symptoms subsided, but negative symptoms continued. However, he discontinued the medications and after few months had a relapse of symptoms and was again started on treatment. Over the years, he developed a pattern in which he would have florid positive symptoms for 3–6 months, following which treatment would be started with which his positive symptoms would resolve, but negative symptoms would persist. After taking medications (olanzapine 20 mg/day or risperidone 3 mg/day) for 3–4 months after improvement of positive symptoms he would discontinue the medications and then remain in the same deficit state for varying periods of 6 months to 2 years. About 4 months prior to presentation at our center, following one of the relapses, he was started on clozapine by a psychiatrist with which he improved over the period of 3 weeks. However, at the dose of clozapine 200 mg/day he started to complaint of feeling restless and would have tingling sensation in his feets and hands; continuously feel an urge to move about and would not be able to sit at a place. While sitting at one place would keep on moving his feet and keep on shifting positions. He presented to our center with these symptoms. At the time of presentation his physical examination did not reveal any evidence of rigidity, tremors and orofacial movements. In the mental status examination he was restless throughout the interview, kept on moving his both upper and lower limbs after every few minutes and often got up while being interviewed and on inquiry reported inner restlessness and an urge to move his limbs.\n\nOn the basis of available information, a diagnosis of undifferentiated schizophrenia with akathisia (possibly clozapine induced) was considered. On Barnes Akathisia Rating Scale, his total score was 11. His routine investigations did not reveal any abnormality and magnetic resonance imaging of the brain did not reveal any abnormality. Initially tablet propranolol 40 mg/day was added but with this he did not perceive any improvement. After 2 weeks of introduction of propranolol, the dose of clozapine was slowly reduced to 150 mg/day with close monitoring of psychopathology. Reduction of clozapine led to subsidence of akathisia with Barnes Akathisia Rating Scale scores coming down to 0 after 3 weeks of reduction of clozapine to 150 mg/day. According to the WHO-UMC causality criteria, association of akathisia with clozapine was rated as “probable.”\n\nDiscussion\nClozapine is an atypical antipsychotic, which binds to both dopamine and serotonin receptors, and it acts as an antagonist at the 5HT2A and D4 receptors.[1] Data linking clozapine and akathisia are available from two sources: Data arising from case reports and data arising from clinical efficacy trials, which have evaluated various side-effects of neuroleptic medications.\n\nIn one of the first studies, authors compared the rates of akathisia associated with clozapine and chlorpromazine concluded that the rates are equivalent and are in the range of 40%.[3] However, over the years data accumulated from trials comparing clozapine with other antipsychotic suggests the contrary. Two reviews have evaluated the data emerging from the clinical trials.[14] Kane et al.[1] concluded that existing data suggest that incidence of akathisia with clozapine is lower than FGAs, and the results are equivocal with regard to SGA with some studies reporting no difference and others reporting lower incidence of akathisia with clozapine.[1] The recent meta-analysis, which included 15 trials, which compared various other SGAs with clozapine suggested that rate of akathisia with clozapine was more than the ziprasidone but was similar to that seen with olanzapine and risperidone.[4]\n\nIn terms of spontaneous case report's authors have described acute and tardive nocturnal akathisia, akathisia in children and akathisia on augmentation of clozapine with amisulpride (for details see).[5] Our case description adds to these findings.\n\nIn addition, a large patient cohort data set suggests that only 0.28% of patients receiving clozapine develop akathisia and in most of the cases akathisia develop during the 1st month of clozapine therapy.[6]\n\nIn the patient described by us acute akathisia was seen during the initial phase of treatment and was dose related, as reduction in dose of clozapine from 200 mg/day to 150 mg/day led to resolution of akathisia. From the available literature and the association seen in the index case, it can be said that akathisia can occur with clozapine too.\n\nFrom the existing literature, it can be concluded that akathisia is a rare side-effect of clozapine and our case description suggests that clinicians should consider reduction in the dose of clozapine while managing clozapine associated akathisia, besides using other strategies.\n\nSource of Support: Nil\n\nConflict of Interest: No.\n==== Refs\n1 Kane JM Fleischhacker WW Hansen L Perlis R Pikalov A 3rd Assunção-Talbott S Akathisia: An updated review focusing on second-generation antipsychotics J Clin Psychiatry 2009 70 627 43 19389331 \n2 Chengappa KN Shelton MD Baker RW Schooler NR Baird J Delaney J The prevalence of akathisia in patients receiving stable doses of clozapine J Clin Psychiatry 1994 55 142 5 7915271 \n3 Claghorn J Honigfeld G Abuzzahab FS Sr Wang R Steinbook R Tuason V The risks and benefits of clozapine versus chlorpromazine J Clin Psychopharmacol 1987 7 377 84 3323261 \n4 Rummel-Kluge C Komossa K Schwarz S Hunger H Schmid F Kissling W Second-generation antipsychotic drugs and extrapyramidal side effects: A systematic review and meta-analysis of head-to-head comparisons Schizophr Bull 2012 38 167 77 20513652 \n5 Ray A Munshi S Augmenting amisulpride with clozapine had led to unmasking of akathisia Ind Psychiatry J 2012 21 152 4 24250050 \n6 eHealthMe Personalized Health Information Last accessed on 2014 Mar 27 Available from:\nhttp://www.ehealthme.com/ds/clozapine/akathisia\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0253-7613",
"issue": "47(2)",
"journal": "Indian journal of pharmacology",
"keywords": "Akathisia; clozapine; extrapyramidal side effects",
"medline_ta": "Indian J Pharmacol",
"mesh_terms": "D000328:Adult; D017109:Akathisia, Drug-Induced; D014150:Antipsychotic Agents; D003024:Clozapine; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D012559:Schizophrenia; D012565:Schizophrenic Psychology; D016896:Treatment Outcome",
"nlm_unique_id": "7902477",
"other_id": null,
"pages": "234-5",
"pmc": null,
"pmid": "25878393",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "3323261;24250050;20513652;7915271;19389331",
"title": "Clozapine induced akathisia: a case report and review of the evidence.",
"title_normalized": "clozapine induced akathisia a case report and review of the evidence"
} | [
{
"companynumb": "IN-MYLANLABS-2017M1002200",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
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{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "CLOZAPINE"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nEplerenone is claimed to be a more selective blocker of the mineralocorticoid receptor than spironolactone being associated with fewer antiandrogenic side-effects. We compared the efficacy, safety and tolerability of eplerenone versus spironolactone in patients with hypertension associated with primary aldosteronism.\n\n\nMETHODS\nThe study was multicentre, randomized, double-blind, active-controlled, and parallel group design. Following a single-blind, placebo run-in period, patients were randomized 1: 1 to a 16-week double-blind, treatment period of spironolactone (75-225 mg once daily) or eplerenone (100-300 mg once daily) using a titration-to-effect design. To be randomized, patients had to meet biochemical criteria for primary aldosteronism and have a seated DBP at least 90 mmHg and less than 120 mmHg and SBP less than 200 mmHg. The primary efficacy endpoint was the antihypertensive effect of eplerenone versus spironolactone to establish noninferiority of eplerenone in the mean change from baseline in seated DBP.\n\n\nRESULTS\nChanges from baseline in DBP were less on eplerenone (-5.6 ± 1.3 SE mmHg) than spironolactone (-12.5 ± 1.3 SE mmHg) [difference, -6.9 mmHg (-10.6, -3.3); P<0.001]. Although there were no significant differences between eplerenone and spironolactone in the overall incidence of adverse events, more patients randomized to spironolactone developed male gynaecomastia (21.2 versus 4.5%; P=0.033) and female mastodynia (21.1 versus 0.0%; P=0.026).\n\n\nCONCLUSIONS\nThe antihypertensive effect of spironolactone was significantly greater than that of eplerenone in hypertension associated with primary aldosteronism.",
"affiliations": "Department of Cardiology, Papworth Hospital, Cambridge, UK.",
"authors": "Parthasarathy|Hari K|HK|;Ménard|Joel|J|;White|William B|WB|;Young|William F|WF|;Williams|Gordon H|GH|;Williams|Bryan|B|;Ruilope|Luis Miguel|LM|;McInnes|Gordon T|GT|;Connell|John M|JM|;MacDonald|Thomas M|TM|",
"chemical_list": "D000959:Antihypertensive Agents; D010919:Placebos; D013148:Spironolactone; D000077545:Eplerenone",
"country": "England",
"delete": false,
"doi": "10.1097/HJH.0b013e3283455ca5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0263-6352",
"issue": "29(5)",
"journal": "Journal of hypertension",
"keywords": null,
"medline_ta": "J Hypertens",
"mesh_terms": "D000328:Adult; D000959:Antihypertensive Agents; D004311:Double-Blind Method; D000077545:Eplerenone; D005260:Female; D006801:Humans; D006929:Hyperaldosteronism; D008297:Male; D008875:Middle Aged; D010919:Placebos; D011788:Quality of Life; D013148:Spironolactone",
"nlm_unique_id": "8306882",
"other_id": null,
"pages": "980-90",
"pmc": null,
"pmid": "21451421",
"pubdate": "2011-05",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A double-blind, randomized study comparing the antihypertensive effect of eplerenone and spironolactone in patients with hypertension and evidence of primary aldosteronism.",
"title_normalized": "a double blind randomized study comparing the antihypertensive effect of eplerenone and spironolactone in patients with hypertension and evidence of primary aldosteronism"
} | [
{
"companynumb": "GB-PFIZER INC-2020225083",
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"occurcountry": "GB",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EPLERENONE"
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"drugadditional": "3",
... |
{
"abstract": "Coexistence of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and inflammatory bowel disease (IBD) is rare (Sy et al. in Semin Arthritis Rheum 45:475-482, 2016). Nevertheless, we present a case of an AAV in a 53-year-old female with enteropathic spondylarthritis previously treated with tumor necrosis factor α inhibitors (TNFi). Management of vasculitis in a patient with IBD may be problematic due to the difficulty in distinguishing if the vasculitis is an extraintestinal manifestation of the IBD or a new coexistent entity. Moreover, in our report, the previous treatment with TNFi is a possible confounding factor due to the paradoxical effects induced by TNFi, including vasculitis (Ramos-Casals et al. in Curr Rheumatol Rep 10:442-448, 2008). The reported case alerts to the complexity in the management of patients with enteropathic spondylarthritis and vasculitis, as well as discusses the diversity of differential diagnosis in this particular clinical scenario.",
"affiliations": "Rheumatology Department, Unidade Local de Saúde do Alto Minho, Largo Conde Bertiandos, 4990-041, Ponte de Lima, Portugal. francisca.guimaraes92@gmail.com.;Rheumatology Department, Unidade Local de Saúde do Alto Minho, Largo Conde Bertiandos, 4990-041, Ponte de Lima, Portugal.;Rheumatology Department, Unidade Local de Saúde do Alto Minho, Largo Conde Bertiandos, 4990-041, Ponte de Lima, Portugal.;Rheumatology Department, Unidade Local de Saúde do Alto Minho, Largo Conde Bertiandos, 4990-041, Ponte de Lima, Portugal.;Rheumatology Department, Unidade Local de Saúde do Alto Minho, Largo Conde Bertiandos, 4990-041, Ponte de Lima, Portugal.;Rheumatology Department, Hospital de Braga, Braga, Portugal.;Nephrology Department, Hospital de Braga, Braga, Portugal.;Nephrology Department, Hospital de Braga, Braga, Portugal.;Rheumatology Department, Unidade Local de Saúde do Alto Minho, Largo Conde Bertiandos, 4990-041, Ponte de Lima, Portugal.;Rheumatology Department, Unidade Local de Saúde do Alto Minho, Largo Conde Bertiandos, 4990-041, Ponte de Lima, Portugal.;Rheumatology Department, Unidade Local de Saúde do Alto Minho, Largo Conde Bertiandos, 4990-041, Ponte de Lima, Portugal.;Rheumatology Department, Unidade Local de Saúde do Alto Minho, Largo Conde Bertiandos, 4990-041, Ponte de Lima, Portugal.",
"authors": "Guimarães|Francisca|F|http://orcid.org/0000-0003-4983-0833;Santos-Faria|Daniela|D|;Azevedo|Soraia|S|;Ramos Rodrigues|Joana|J|;Leite Silva|Joana|J|;Esperança-Almeida|Diogo|D|;Ribeiro|Bárbara|B|;Vaz|Raquel|R|;Teixeira|Filipa|F|;Tavares-Costa|José|J|;Afonso|Carmo|C|;Peixoto|Daniela|D|",
"chemical_list": "D019268:Antibodies, Antineutrophil Cytoplasmic",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10067-021-05612-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0770-3198",
"issue": "40(8)",
"journal": "Clinical rheumatology",
"keywords": "ANCA vasculitis; Enteropathic spondylarthritis; Granulomatosis with polyangiitis; Inflammatory bowel disease",
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D019268:Antibodies, Antineutrophil Cytoplasmic; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases; D008875:Middle Aged; D025241:Spondylarthritis",
"nlm_unique_id": "8211469",
"other_id": null,
"pages": "3351-3355",
"pmc": null,
"pmid": "33517484",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "26223844;31093814;26315859;26106214;16954966;26873008;23345025;19007533;10979362;24316902",
"title": "ANCA-associated vasculitis in a patient with enteropathic spondylarthritis: a case report and literature review.",
"title_normalized": "anca associated vasculitis in a patient with enteropathic spondylarthritis a case report and literature review"
} | [
{
"companynumb": "PT-TEVA-2021-PT-1952289",
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"occurcountry": "PT",
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"activesubstance": {
"activesubstancename": "SULFASALAZINE"
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... |
{
"abstract": "Agranulocytosis as a side effect of clozapine has been reported to be associated with initial phases of treatment, i.e., first six months. Agranulocytosis with clozapine during the initial phases of treatment has been linked to genetic vulnerability in the form of variations in the human leukocyte-antigen haplotypes. However, there is limited literature on late onset agranulocytosis with clozapine and this has very rarely been linked to human leukocyte-antigen haplotypes vulnerability. In this report we review the existing data on late onset agranulocytosis with clozapine and describe the case of a young man, who developed agranulocytosis with clozapine after 35 months of treatment and was found to have genetic vulnerability in form of being positive for HLA DR4. This case highlights underlying autoimmune immune mechanism in clozapine-induced agranulocytosis and the need for frequent blood count monitoring on clozapine even after the initial 6 months of starting treatment especially in patients with genetic vulnerability to develop this condition.",
"affiliations": "Department of Psychiatry, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Psychiatry, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India.",
"authors": "Singh|Aakanksha|A|;Grover|Sandeep|S|;Malhotra|Pankaj|P|;Varma|Subhash C|SC|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.9758/cpn.2016.14.2.212",
"fulltext": "\n==== Front\nClin Psychopharmacol NeurosciClin Psychopharmacol NeurosciClinical Psychopharmacology and Neuroscience1738-10882093-4327Korean College of Neuropsychopharmacology 2712143410.9758/cpn.2016.14.2.212cpn-14-212Case ReportLate Onset Agranulocytosis with Clozapine Associated with HLA DR4 Responding to Treatment with Granulocyte Colony-stimulating Factor: A Case Report and Review of Literature Singh Aakanksha 1Grover Sandeep 1Malhotra Pankaj 2Varma Subhash C. 21 Department of Psychiatry, Post Graduate Institute of Medical Education and Research, Chandigarh, \nIndia2 Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, \nIndiaAddress for correspondence: Sandeep Grover, MD, Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India, Tel: +91-172-2756807, Fax: +91-172-2756807, E-mail: drsandeepg2002@yahoo.com5 2016 31 5 2016 14 2 212 217 08 6 2015 12 8 2015 01 9 2015 Copyright © 2016, Korean College of Neuropsychopharmacology2016This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Agranulocytosis as a side effect of clozapine has been reported to be associated with initial phases of treatment, i.e., first six months. Agranulocytosis with clozapine during the initial phases of treatment has been linked to genetic vulnerability in the form of variations in the human leukocyte-antigen haplotypes. However, there is limited literature on late onset agranulocytosis with clozapine and this has very rarely been linked to human leukocyte-antigen haplotypes vulnerability. In this report we review the existing data on late onset agranulocytosis with clozapine and describe the case of a young man, who developed agranulocytosis with clozapine after 35 months of treatment and was found to have genetic vulnerability in form of being positive for HLA DR4. This case highlights underlying autoimmune immune mechanism in clozapine-induced agranulocytosis and the need for frequent blood count monitoring on clozapine even after the initial 6 months of starting treatment especially in patients with genetic vulnerability to develop this condition.\n\nClozapineAgranulocytosisNeutropenia\n==== Body\nINTRODUCTION\nSince the beginning of its use, the heamatological side effects of clozapine in the form of agranulocytosis and neutropenia have been an important issue with the patients and clinicians.1,2) Available data suggests that overall the incidence rate of agranulocytosis is 0.38% among patients receiving clozapine.1) Most of the evidence suggests that whenever neutropenia occurs with clozapine, it usually occurs during the early phase of treatment, i.e., highest in first 6 weeks to 18 months after the onset of treatment.1,3) Due to this, more intense monitoring is suggested during the initial phase of the treatment, i.e., first 18 weeks.3) However, there are few reports of late onset neutropenia with clozapine after as long as 19 years of use of clozapine.4–17) Studies have attempted to find out the factors associated with clozapine induced neutropenia. Among the various factors reported to be associated with clozapine induced neutropenia, there is some data to suggest that genetic vulnerability in the form of variations in the human leukocyte-antigen haplotypes predisposes a person to develop neutropenia.18)\n\nIn this report, we present a case of late onset neutropenia with clozapine who on investigation was found positive for human leukocyte antigen (HLA) DR4.\n\nCASE\nA male patient, University Graduate, smoker, suffering from treatment resistant schizophrenia was started on clozapine at the age of 32 years. Initially he tolerated the dose of clozapine well and showed partial response to clozapine 450 mg/day. Later in view of partial response, trifluoperazine was added and he was stabilized on clozapine 450 mg/day and trifluoperazine 20 mg/day after 9 months of initiation of clozapine. Regular weekly hematological monitoring was done during initial 5 months, followed by monitoring at monthly intervals. He maintained well with this combination for next 26 months. However after this on one occasion he all of a sudden developed high grade fever, which was not associated with any specific systemic signs and symptoms. A haemogram was ordered and it revealed a total leucocyte count of 1,100/mm3 with neutrophils count of zero. The differential count showed 98% lymphocytes, 1% monocytes and 1% eosinophils, along with hemoglobin level of 13.5 g/dL and platelet count of 1.5/μl. There was no history of administration of any antibiotics, chemotherapeutic agent, radiotherapy, anti-epileptic medications.\n\nHe was immediately hospitalized, all psychotropics were stopped. Physical examination revealed a small ulcer on the prepuce and a tender swelling in his right axilla. He was investigated for possible causes of leucopenia and neutropenia in the form of heamatological malignancies, systemic lupus erythematous, Crohn’s disease, rheumatoid arthritis, infections (bacterial, tubercular and viral in the form of human immunodeficiency virus, Epstein-Barr virus (EBV), cytomegalus virus, hepatitis). Investigations in form of serum electrolytes, renal function test, liver function tests, chest X-ray, urine examination (routine and culture sensitivity), blood culture for bacteria and fungus, electrocardiogram and echocardiography did not reveal any abnormality. Serum calcium was 8.24 mg/dl, hepatitis B antigen and hepatitis C antibody were negative. EBV immunoglobulin M antibody (IgM Ab), Widal test, dengue serology (IgM Ab), smear for malaria parasite and ultrasound abdomen did not reveal any abnormality. Venereal Disease Research Laboratory test was found to be negative. The fine needle aspiration cytology of the mass in the axilla was positive for Proteus mirabilis which was sensitive to piperacillin and tazobactum. Fever improved after antibiotic treatment was started.\n\nIn view of no other detectable cause, the leucopenia and neutropenia were attributed clozapine and the infection was considered to be secondary to the neutropenia. He was further investigated and was found positive for HLA DR4 (DRB1*04) and HLA DQB1*02:01, 1*02:02, 1*03:02. He was managed with granulocyte colony-stimulating factor (G-CSF) at the dose of 5 μg/kg/day for 7 days, along with broad-spectrum antibiotics. Over the period of one week his leucocyte and neutrophil count normalized. In view of the genetic vulnerability clozapine re-challenge was not done and he was managed with a combination of antipsychotics (trifluoperazine and olanzapine) over next one year, with which he showed partial response in terms of improvement in psychotic symptoms.\n\nDISCUSSION\nWe searched the PubMed search engine and available data suggests that there is limited literature in the form of case reports of late onset neutropenia and late onset agranulocytosis associated with clozapine,4–17) with one of the reports showing the association after 19 years of use of clozapine.5) In a review of literature, authors reported 16 case reports available prior to 2012.4,8–11,13,16,19–25) The authors themselves reported the 17th case. In our literature search of PubMed, we came across 3 more cases.10,17,26) The data of all the cases is presented in Table 1. In majority of the case reports, patients were receiving concomitant medications along with clozapine, with valproate (5 cases), risperidone (7 cases) and haloperidol (3 cases) being the commonly used concomitant medications.4,6,10,13,15–17) In other cases concomitant medication use involved use of antidepressants, anti-tubercular drugs, etc.7,8,12,15) In 6 cases, late onset agranulocytosis/neutropenia was seen with clozapine monotherapy. In most of these cases, the patients were not rechallenged with clozapine.4,5,7,9,15,17) Our case developed agranulocytosis while on clozapine for 35 months. In terms of concomitant medication our patient was receiving trifluoperazine, for about 1.5 years prior to development of agranulocytosis. Accordingly it can be concluded that trifluoperazine would not have contributed to agranulocytosis. Our case adds to the limited literature of late onset agranulocytosis/neutropenia and suggests that regular haematological monitoring should be done in patients receiving clozapine. In our case neutropenia improved rapidly over the period of 1 week. The rapid resolution of neutropenia after stoppage of clozapine possibly suggests that the neutropenia was due immune mediated destruction of neutrophils, which resolved with stoppage of offending agent. The Naranjo probability score for our case was 7, indicative of probable association.27)\n\nOver the years few researchers have attempted to find the risk factors associated with development of clozapine-induced agranulocytosis. The factors identified to have some association with clozapine-induced agranulocytosis include HLA class III genes for tumor necrosis factor (TNF) and heat shock proteins (HSP), increased expression of proapoptotic genes bax α, p53, and bik and presence of certain HLA phenotypes. With regard to the HLA class III genes for TNF and HSP it is proposed that the formation of oxidized clozapine intermediates may decrease the survival of granulocytes in individuals who carry clozapine-induced agranulocytosis susceptibility-associated HSP or TNF variants.28) Increased expression of proapoptotic genes bax α, p53, and bik has been linked to oxidative mitochondrial stress in neutrophils of clozapine-treated patients and suggest that free radicals and oxidative stress possibly up-regulate proapoptotic genes and contribute to the induction of apoptosis and clozapine-induced agranulocytosis.29) There is lack of consensus for type of HLA phenotype associated with clozapine-induced agranulocytosis. Lieberman et al.30) reported that Ashkenazi Jews exhibiting the phenotype HLA B38, DR4, DQW3 are at an increased risk of agranulocytosis, as are non-Jewish individuals with HLA phenotype B7, DR2, DQ2. They also suggested that specific gene products encoded in the major histocompatibility complex may be involved in mediating drug toxicity. Yunis et al.,31) in an extension of the findings of Lieberman et al.,30) observed that in Ashkenazi patients the susceptibility class II haplotype is DRB1*0402, DQB1*0302, and in non-Jewish patients, DRB1*02, DQB1*0502 and DQA1*0102 were associated with vulnerability to develop clozapine-induced agranulocytosis. However, in another study involving 103 patients with a history of clozapine induced agranulocytosis no significant association was noted between HLA-A, -B, -C, -DR, -DQ, number of neutrophil-specific alloantigens and susceptibility to clozapine-induced agranulocytosis.32) However, these results were later questioned when emphasis was placed on statistical methodology used for statistical analysis of simultaneous occurrence of multiple HLAs, in an attempt to predict vulnerability to clozapine-induced agranulocytosis.33) Another study on Israeli Jewish patients showed that HLA B38 conferred susceptibility for clozapine-induced agranulocytosis.33) Further on combining the data of Lieberman et al.30) and Yunis et al.31), the authors proposed that the gene susceptible for clozapine induced agranulocytosis was located in the HLA-B locus rather than in the DR/DQ region.34) Recent report has associated increased risk of developing clozapine-induced agranulocytosis in patients with DQB1 genotype.35) Our case was found positive for HLA DR4 (DRB1*04) and HLA DQB1*02:01, 1*02:02, 1*03:02, suggesting that late onset neurotropenia also may be related to HLA gene susceptibility. In a recent largest study which included, 163 cases authors found association between clozapine induced agranulocytosis and HLA-DQB1 and HLA-B especially two amino acids sequences, i.e., HLA-DQB1 126Q and HLA-B 158T. However, the authors concluded that they could not distinguish as to whether these amino acids had causal role or just conferred risk.36)\n\nBesides the genetic vulnerability other factors which have been considered as risk factors for bone marrow suppression with clozapine include increased age (i.e., more than 40 years), female gender, African race, and concomitant medications,3,37,38) eosinophilia antedating the onset of neutropenia.39)\n\nThe hematopoietic growth factors, G-CSF and granulocyte macrophage colony stimulating factor increase the proliferation and differentiation of myeloid precursor cells. The recombinant human granulocyte growth factor G-CSF (filgrastim) is approved for the correction of severe clozapine-related neutropenia.40–42) In our patient, immediate discontinuation of clozapine upon diagnosis, prompt initiation of antibiotic therapy, and G-CSF titration managed the early increase in the neutrophil count and the improvement of the patient’s clinical presentation.\n\nTable 1 Published case reports on late onset neutropenia/agranulocytosis with clozapine\n\nAuthor\tAge (yr)/sex\tDiagnosis\tDose of clozapine (mg/d)\tType of heamatological abnormality\tDuration of clozapine use prior to neutropenia/agranulocytosis\tConcomitant medications\tConcomitant physical illness and clozapine associated complications\tRemarks\tOutcome\t\nVoulgari et al.26)\t33/F\tSchizoaffective disorder\t400\tTLC: 100\nANC: zero\t24 months\tLevothyroxine 125 μg/d\tStreptococcus pneumonia\nVenous thromboembolism\nAllergic vasculitis\tG-CSF given\tRechallenge done\nNo complication\t\nVelayudhan and Kakkan17)\t44/F\tParanoid schizophrenia\t150\tTLC: 6,700→700\nANC: 4,690→<100\nOver 7 days\t60 months\tRisperidone 6 mg/d\nTrihexyphenidyl 4 mg/d\tFever, rigor, swelling of right hand, sore throat, deep vein thrombosis right upper limb\tContinued on risperidone 8 mg/d\nChlorpromazine 150 mg/d\nTrihexyphenidyl 2 mg/d\nPartial remission\tPartial remission\nNo rechallenge\t\nCohen and Monden5)\t42/M\tParanoid schizophrenia\nOpium abuse\t250\tTwo months\nTLC: 2,500→1,900\nANC: 1,000→600\t228 months\t±Lorazepam 2.5 mg/d\tFever, laryngitis\tAripiprazole 45 mg/d\nLorazepam 5 mg/d\nFull remission\tCell count recovery in one week\nNo rechallenge\t\nRaveendranathan et al.10)\t31/F\tParanoid schizophrenia\t325\tTLC: 2,820→2,200\nANC: 1,111→198\nOver two weeks\t24 months (of rechallenge with 325 mg dose)\tRisperidone 6 mg/d\tNil\tHistory of neutropenia in past within 3 wks of clozapine dose 325 mg/d\nTLC: 10,100→6,500\nANC (details NA): rechallenge→2nd time agranulocytosis→risperidone 8 mg/d, HPL 30 mg/d, lithium 900 mg/d\tRechallenge (after neutropenia)\nTreated with G-CSF (in 2nd episode), count normalised in 2 wks\t\nRaja et al.9)\t65/M\tSchizoaffective disorder\t450\tOver 7 months, progreesive neutropenia\t120 months\tMetformin 500 mg/d\tNil\tRisperidone 6 mg/d →olanzapine 10 mg/d+ quetiapine 150 mg/d\tCell count recovery in next week\nNo rechallenge\t\nTourian and Margolese16)\t41/F\tParanoid schizophrenia\nTobacco dependence\t100\tThree months (corresponding to increase in lamotrigine dose)\t84 months\tRisperidone 1 mg/d\nLamotrigine 100 mg/d\tTreated with stoppage of clozapine, lamotrigine; G-CSF +\tAgranulocytosis associated with increase in lamotrigine dose\tRechallenge done\nNo agranulocytosis\t\nMcKnight et al.35)\t33/F\tSchizoaffective disorder\t96\t300\tDetails NA\tSodium valproate 1,500 mg/d\nQuetiapine 4,000 mg/d\tNil\tHLA – DQB1 testing done\tRechallenge\nDone\nNo complication after rechallenge\t\nPanesar et al.8)\t37/M\tSchizoaffective disorder\t108\tDetail NA\tTLC: 2,700\nANC: 500\tAnti-tuberular medication\tNil\tWhile on anti-tubercular drugs (duration detail NA)\tClozapine rechallenge 500 mg/d\nNo complication after rechallenge\t\nGhaznavi et al.6)\t55/M\tParanoid schizophrenia\t168\t750\tANC: 2,556→1,620, over one month\tValproic acid 1,500\nDonepezil (dose NA)\tNil\tWithin one month of starting donepezil\tRechallenge in one week→clozapine increased 500 mg/d in 20 days; donepezil stopped, ANC 2,762→850 in 20 days, risperidone 6 mg/d\t\nManfredi and Sabbatani7)\t36/M\tSevere depressive disorders\nPersonality disturbances\nSuicidal behaviour\tNA\t16 weeks\nSevere leukopenia sudden onset (TLC: 1,050 ANC: 36 cells/μL)\t96 HPL\tLithium carbonate 600 mg/d\nCitalopram 40 mg/d\nClomipramine 75 mg/d\nLorazepam 2.5 mg/d\tFever (pyrexia of unknown origin)\tG-CSF\tNo rechallenge\t\nSmall et al.13)\t45/F\tSchizophrenia\nMild mental retardation\nTobacco dependence\t72\t500\tSudden, 4,000→1,800, ANC: 2,000→198\tOlanzapine 10 mg/d\nHPL 150 mg/3 wk\nBenzopril hydrochloride 20 mg/d\tNil\tClozapine rechallenge 800 mg/d, slow titration over 5 months\nLithium added later→increase in TLC, ANC\tNo complication after rechallenge\t\nThompson et al.15)\t34/M\tParanoid schizophrenia\t36\t250\tANC: 1,500/μL\nTLC: 5,840/μL\tSod valproate 1,000 mg/d\nSertraline 50 mg/d\tNil\tWhile on valproate, SSRI\tNo rechallenge\t\nBhanji et al.4)\t48/M\tUndiff. schizophrenia\t550\tFall in TLC (7,600→2,900)\nDrop in neutrophil count (3,000 →1,000)\t17 months (abrupt drop)\tRisperidone 5 mg/d\nOlanzapine 15 mg/d\nValproate 750 mg/d\nQuetiapine 50 mg/d\tNil\tQuetiapine associated with idiosyncratic leukopenic reactions - additive toxicity\tClozapine stopped→recovery in 8 days\nNo rechallenge\t\nSilvestrini et al.12)\t29/F\tUndiff. schizophrenia\t300\tTLC: 2,600\nANC: 1,340/mm3\t60 months\tClomipramine 75 mg/d\tInsomnia, shivering, hot flushes, sense of tremor, symptoms of common cold, dry mouth\tThioridazine 350 mg/d olanzapine 20 mg/d, valproate 1,500\n→ more 2 months\nClozapine rechallenge\tCell count-recovery in 2 days\nClozapine 500 mg/d\nClomipramine 150 mg/d\t\nM, male; F, female; TLC, total leucocyte count; Nil, no comorbid physical illness; ANC, absolute neutrophil count; G-CSF, granulocyte colony stimulating factor; SSRI, selective serotonin reuptake inhibitors; HLA, human leukocyte antigen; NA, not available; Undiff., undifferentiated; HPL, haloperidol.\n==== Refs\nREFERENCES\n1 Alvir JM Lieberman JA Safferman AZ Schwimmer JL Schaaf JA Clozapine-induced agranulocytosis. Incidence and risk factors in the United States N Engl J Med 1993 329 162 167 10.1056/NEJM199307153290303 8515788 \n2 Hummer M Kurz M Barnas C Saria A Fleischhacker WW Clozapine-induced transient white blood count disorders J Clin Psychiatry 1994 55 429 432 7961519 \n3 Atkin K Kendall F Gould D Freeman H Liberman J O’Sullivan D Neutropenia and agranulocytosis in patients receiving clozapine in the UK and Ireland Br J Psychiatry 1996 169 483 488 10.1192/bjp.169.4.483 8894200 \n4 Bhanji NH Margolese HC Chouinard G Turnier L Lateonset agranulocytosis in a patient with schizophrenia after 17 months of clozapine treatment J Clin Psychopharmacol 2003 23 522 523 10.1097/01.jcp.0000088917.02635.7a 14520134 \n5 Cohen D Monden M White blood cell monitoring during long-term clozapine treatment Am J Psychiatry 2013 170 366 369 10.1176/appi.ajp.2012.12081036 23545791 \n6 Ghaznavi S Nakic M Rao P Hu J Brewer JA Hannestad J Rechallenging with clozapine following neutropenia: treatment options for refractory schizophrenia Am J Psychiatry 2008 165 813 818 10.1176/appi.ajp.2008.07111823 18593787 \n7 Manfredi R Sabbatani S Clozapine-related agranulocytosis associated with fever of unknown origin, protective hospitalisation, and multiple adverse events related to the administration of empiric antimicrobial treatment Pharmacoepidemiol Drug Saf 2007 16 1285 1289 10.1002/pds.1476 17879354 \n8 Panesar N Pai N Valachova I Late onset neutropenia with clozapine Aust N Z J Psychiatry 2011 45 684 10.3109/00048674.2011.581645 21561237 \n9 Raja M Azzoni A Maisto G Late onset neutropenia associated with clozapine J Clin Psychopharmacol 2011 31 780 781 10.1097/JCP.0b013e318234eec2 22051920 \n10 Raveendranathan D Sharma E Venkatasubramanian G Rao MG Varambally S Gangadhar BN Late-onset clozapine-induced agranulocytosis in a patient with comorbid multiple sclerosis Gen Hosp Psychiatry 2013 35 574.e5 6 10.1016/j.genhosppsych.2012.07.001 22902258 \n11 Sedky K Shaughnessy R Hughes T Lippmann S Clozapine-induced agranulocytosis after 11 years of treatment Am J Psychiatry 2005 162 814 10.1176/appi.ajp.162.4.814 15800170 \n12 Silvestrini C Arcangeli T Biondi M Pancheri P A second trial of clozapine in a case of granulocytopenia Hum Psychopharmacol 2000 15 275 279 10.1002/1099-1077(200006)15:4<275::AID-HUP171>3.0.CO;2-3 12404322 \n13 Small JG Weber MC Klapper MH Kellams JJ Rechallenge of late-onset neutropenia with clozapine J Clin Psychopharmacol 2005 25 185 186 10.1097/01.jcp.0000155831.72154.bc 15738753 \n14 Tamam L Kulan E Ozpoyraz N Late onset neutropenia during clozapine treatment Psychiatry Clin Neurosci 2001 55 547 548 10.1046/j.1440-1819.2001.904(1).x 11555354 \n15 Thompson A Girishchandra B Castle D Orr K Late onset neutropenia with clozapine Can J Psychiatry 2004 49 647 648 15503747 \n16 Tourian L Margolese HC Late-onset agranulocytosis in a patient treated with clozapine and lamotrigine J Clin Psychopharmacol 2011 31 665 667 10.1097/JCP.0b013e31822c29db 21881454 \n17 Velayudhan R Kakkan S Late onset clozapine induced agranulocytosis Indian J Psychol Med 2014 36 425 427 10.4103/0253-7176.140738 25336778 \n18 Corzo D Yunis JJ Yunis EJ Howard A Lieberman JA HSP70-2 9.0 kb variant is in linkage disequilibrium with the HLA-B and DRB1* alleles associated with clozapine-induced agranulocytosis J Clin Psychiatry 1994 55 Suppl B 149 152 7961560 \n19 Godleski LS Sernyak MJ Agranulocytosis after addition of risperidone to clozapine treatment Am J Psychiatry 1996 153 735 736 10.1176/ajp.153.5.735b 8615431 \n20 Kutscher EC Robbins GP Kennedy WK Zebb K Stanley M Carnahan RM Clozapine-induced leukopenia successfully treated with lithium Am J Health Syst Pharm 2007 64 2027 2031 10.2146/ajhp060319 17893412 \n21 Nongpiur A Praharaj SK Sarkar S Das B Delayed onset of clozapine-induced leucopenia Am J Ther 2012 19 e118 e119 10.1097/MJT.0b013e3181ebb268 20724912 \n22 Sénéchal A Landry P Deschamps R Lessard M Neutropenia in a patient treated with clozapine in combination with other psychotropic drugs Encephale 2002 28 567 569 Dutch 12506270 \n23 Patel NC Dorson PG Bettinger TL Sudden late onset of clozapine-induced agranulocytosis Ann Pharmacother 2002 36 1012 1015 10.1345/aph.1A417 12022904 \n24 Peacock L Gerlach J Clozapine treatment in Denmark: concomitant psychotropic medication and hematologic monitoring in a system with liberal usage practices J Clin Psychiatry 1994 55 44 49 8077154 \n25 Latif Z Malik MA Jabbar F Ahmed Y McDonough C Clozapine-induced late leukopenia Ir J Med Sci 2012 181 139 141 10.1007/s11845-010-0587-y 20872253 \n26 Voulgari C Giannas R Paterakis G Kanellou A Anagnostopoulos N Pagoni S Clozapine-induced late agranulocytosis and severe neutropenia complicated with Streptococcus pneumonia, venous thromboembolism, and allergic vasculitis in treatment-resistant female psychosis Case Rep Med 2015 2015 703218 25755670 \n27 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 245 10.1038/clpt.1981.154 7249508 \n28 Husain Z Almeciga I Delgado JC Clavijo OP Castro JE Belalcazar V Increased FasL expression correlates with apoptotic changes in granulocytes cultured with oxidized clozapine Toxicol Appl Pharmacol 2006 214 326 334 10.1016/j.taap.2006.01.008 16510162 \n29 Fehsel K Loeffler S Krieger K Henning U Agelink M Kolb-Bachofen V Clozapine induces oxidative stress and proapoptotic gene expression in neutrophils of schizophrenic patients J Clin Psychopharmacol 2005 25 419 426 10.1097/01.jcp.0000177668.42640.fe 16160616 \n30 Lieberman JA Yunis J Egea E Canoso RT Kane JM Yunis EJ HLA-B38, DR4, DQw3 and clozapine-induced agranulocytosis in Jewish patients with schizophrenia Arch Gen Psychiatry 1990 47 945 948 10.1001/archpsyc.1990.01810220061007 2222133 \n31 Yunis JJ Corzo D Salazar M Lieberman JA Howard A Yunis EJ HLA associations in clozapine-induced agranulocytosis Blood 1995 86 1177 1183 7620171 \n32 Claas FH Abbott PA Witvliet MD D’Amaro J Barnes PM Krupp P No direct clinical relevance of the human leucocyte antigen (HLA) system in clozapine-induced agranulocytosis Drug Saf 1992 7 Suppl 1 3 6 10.2165/00002018-199200071-00004 1503675 \n33 Abt K Gülich A Krupp P Reinberg W HLA-associations in Leponex/Clozaril (clozapine)-induced granulocytopenia and agranulocytosis. Statistical viewpoints Drug Saf 1992 7 Suppl 1 10 16 10.2165/00002018-199200071-00006 1503672 \n34 Valevski A Klein T Gazit E Meged S Stein D Elizur A HLA-B38 and clozapine-induced agranulocytosis in Israeli Jewish schizophrenic patients Eur J Immunogenet 1998 25 11 13 10.1046/j.1365-2370.1998.00091.x 9587740 \n35 McKnight C Guirgis H Votolato N Clozapine rechallenge after excluding the high-risk clozapine-induced agranulocytosis genotype of HLA-DQB1 6672G>C Am J Psychiatry 2011 168 1120 10.1176/appi.ajp.2011.11020202 21969051 \n36 Goldstein JI Jarskog LF Hilliard C Alfirevic A Duncan L Fourches D Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles Nat Commun 2014 5 4757 10.1038/ncomms5757 25187353 \n37 Baldessarini RJ Frankenburg FR Clozapine. A novel anti-psychotic agent N Engl J Med 1991 324 746 754 10.1056/NEJM199103143241107 1671793 \n38 Lekhakula A Swasdikul D Drug-induced agranulocytosis: experience in two university hospitals J Med Assoc Thai 1991 74 121 130 1861127 \n39 Hummer M Sperner-Unterweger B Kemmler G Falk M Kurz M Oberbauer H Does eosinophilia predict clozapine induced neutropenia? Psychopharmacology (Berl) 1996 124 201 204 10.1007/BF02245622 8935817 \n40 Nielsen H Recombinant human granulocyte colony-stimulating factor (rhG-CSF; filgrastim) treatment of clozapine-induced agranulocytosis J Intern Med 1993 234 529 531 10.1111/j.1365-2796.1993.tb00789.x 7693847 \n41 Sedky K Lippmann S Psychotropic medications and leukopenia Curr Drug Targets 2006 7 1191 1194 10.2174/138945006778226642 17017894 \n42 Whiskey E Taylor D Restarting clozapine after neutropenia: evaluating the possibilities and practicalities CNS Drugs 2007 21 25 35 10.2165/00023210-200721010-00003 17190527\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1738-1088",
"issue": "14(2)",
"journal": "Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology",
"keywords": "Agranulocytosis; Clozapine; Neutropenia",
"medline_ta": "Clin Psychopharmacol Neurosci",
"mesh_terms": null,
"nlm_unique_id": "101207332",
"other_id": null,
"pages": "212-7",
"pmc": null,
"pmid": "27121434",
"pubdate": "2016-05-31",
"publication_types": "D002363:Case Reports",
"references": "25755670;7961519;15800170;1861127;17893412;21969051;7961560;21881454;8894200;8935817;1671793;2222133;23545791;18593787;7620171;12404322;14520134;1503675;11555354;15503747;22902258;17017894;8515788;12506270;7693847;16510162;16160616;8077154;8615431;9587740;7249508;20872253;20724912;17879354;25336778;15738753;12022904;25187353;21561237;22051920;1503672;17190527",
"title": "Late Onset Agranulocytosis with Clozapine Associated with HLA DR4 Responding to Treatment with Granulocyte Colony-stimulating Factor: A Case Report and Review of Literature.",
"title_normalized": "late onset agranulocytosis with clozapine associated with hla dr4 responding to treatment with granulocyte colony stimulating factor a case report and review of literature"
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"abstract": "Multidrug-resistant (MDR) cytomegalovirus (CMV) emerged after transient responses to ganciclovir, foscarnet, and cidofovir in a CMV-seropositive recipient who underwent allogeneic hematopoietic stem cell transplantation from a CMV-seronegative donor. Experimental treatments using leflunomide and artesunate failed. Re-transplantation from a CMV-seropositive donor supported by adoptive transfer of pp65-specific T cells and maribavir was followed by lasting suppression. This case illustrates that successful MDR CMV therapy may require individualized multidisciplinary approaches.",
"affiliations": "Infection Biology Laboratory, Department of Biomedicine, University and University Hospital of Basel, Basel, Switzerland.;Division of Hematology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.;Division of Hematology, Department of Biomedicine and Clinical Research, University Hospital of Basel, Basel, Switzerland.;Infection Biology Laboratory, Department of Biomedicine, University and University Hospital of Basel, Basel, Switzerland.;Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Basel, Basel, Switzerland.;Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Basel, Basel, Switzerland.;Division of Hematology, Department of Biomedicine and Clinical Research, University Hospital of Basel, Basel, Switzerland.;Division of Hematology, Department of Biomedicine and Clinical Research, University Hospital of Basel, Basel, Switzerland.;Division of Hematology, Department of Biomedicine and Clinical Research, University Hospital of Basel, Basel, Switzerland.;Division of Hematology, Department of Biomedicine and Clinical Research, University Hospital of Basel, Basel, Switzerland.;Division of Hematology, Department of Biomedicine and Clinical Research, University Hospital of Basel, Basel, Switzerland.;Division of Hematology, Department of Biomedicine and Clinical Research, University Hospital of Basel, Basel, Switzerland.;Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Basel, Basel, Switzerland.;Transplantation & Clinical Virology, Department of Biomedicine, University of Basel, Basel, Switzerland.;Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Basel, Basel, Switzerland.;Infection Biology Laboratory, Department of Biomedicine, University and University Hospital of Basel, Basel, Switzerland.",
"authors": "Stuehler|C|C|http://orcid.org/0000-0002-0926-3427;Stüssi|G|G|;Halter|J|J|;Nowakowska|J|J|;Schibli|A|A|;Battegay|M|M|;Dirks|J|J|;Passweg|J|J|;Heim|D|D|;Rovo|A|A|;Kalberer|C|C|;Bucher|C|C|;Weisser|M|M|;Dumoulin|A|A|;Hirsch|H H|HH|;Khanna|N|N|",
"chemical_list": "D000998:Antiviral Agents",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12435",
"fulltext": null,
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"issn_linking": "1398-2273",
"issue": "17(5)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "adoptive T-cell transfer; allogeneic hematopoietic stem cell transplantation; cytomegalovirus; maribavir; multidrug resistance",
"medline_ta": "Transpl Infect Dis",
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"abstract": "Phlegmonous proctitis is a rare condition; it was first described in 1940. We report the case of an elderly woman who presented with acute severe lower abdominal pain, tenesmus, and fever. A computed tomography of the whole abdomen revealed a long segment of circumferential wall thickening of the rectum and rectosigmoid colon. Colonoscopy was done subsequently and showed marked edematous and erythematous rectal mucosa. When rectal tissue biopsy was performed, a large amount of pus came out at the biopsy site, which led to the diagnosis of phlegmonous proctitis.",
"affiliations": "Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand.",
"authors": "Kaewdech|Apichat|A|;Sripongpun|Pimsiri|P|",
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"fulltext": "\n==== Front\nCase Rep GastroenterolCase Rep GastroenterolCRGCase Reports in Gastroenterology1662-0631S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000489302crg-0012-0254Case and ReviewPhlegmonous Proctitis: A Rare Entity of the Presentation of Proctitis Kaewdech Apichat *Sripongpun Pimsiri Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand*Apichat Kaewdech, MD, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Kanchanavanich Road, Hat Yai, Songkhla 90110 (Thailand), E-Mail apichatka@hotmail.comMay-Aug 2018 15 6 2018 15 6 2018 12 2 254 259 19 3 2018 17 4 2018 Copyright © 2018 by S. Karger AG, Basel2018This 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.Phlegmonous proctitis is a rare condition; it was first described in 1940. We report the case of an elderly woman who presented with acute severe lower abdominal pain, tenesmus, and fever. A computed tomography of the whole abdomen revealed a long segment of circumferential wall thickening of the rectum and rectosigmoid colon. Colonoscopy was done subsequently and showed marked edematous and erythematous rectal mucosa. When rectal tissue biopsy was performed, a large amount of pus came out at the biopsy site, which led to the diagnosis of phlegmonous proctitis.\n\nKeywords\nPhlegmonous proctitisRectumRectosigmoid colonColonoscopyBiopsy\n==== Body\nIntroduction\nPhlegmonous proctitis is an uncommon condition; it was first described in 1940 by Yaker [1], and there was no other case report since then. The first case was a woman who had postpartum rectal pain. The author hypothesized that the cause of phlegmonous proctitis might be the chemical irritation following paraldehyde and soap enema [1]. This is the second case report of phlegmonous proctitis. There is little knowledge about this condition. Like in phlegmonous gastritis, which is a suppurative bacterial infection of the gastric wall, the clinical course is rapidly worsening and results in a high mortality [2].\n\nCase Presentation\nA 68-year-old Thai woman with type 2 diabetes had Child-Turcotte-Pugh B cirrhosis suspected to be due to nonalcoholic steatohepatitis and adjustment disorder. Her current medications were omeprazole 20 mg/day, aspirin 81 mg once daily, multivitamin twice daily, lactulose p.r.n., and glicazide 30 mg once daily. She presented with severe lower abdominal pain for 12 h. Two days prior to admission, she had lower abdominal pain with cramping and tenesmus. She tried to defecate several times, but no fecal material came out. She also had agitation and fever with chills, but no other organ-specific symptom was observed. Her daughter then brought her to the emergency department. On physical examination, her body temperature was 38.4°C, pulse rate was 84 beats per minute, blood pressure was 140/60 mm Hg, and respiratory rate was 24 breaths per minute. Abdominal examination revealed marked abdominal distension, low midline surgical scar, normal bowel sound, and moderate tenderness with voluntary guarding at the lower abdomen, especially at the left lower quadrant; liver and spleen were not palpable. Mucous bloody stool was obtained from digital rectal examination. The laboratory test revealed hematocrit 27.3%, white blood cell count 13.2 × 109/L, PMN 92%, band 5%, and platelet count 58 × 109/L, as well as stable hematocrit and platelet count compared to the previous follow-up visit. The electrolytes showed wide anion metabolic acidosis and hyperlactatemia level of 7 mmol/L. Hemoculture was taken but showed no growth of bacteria. Stool exam showed numerous white blood cells without trophozoite of Entamoeba histolytica on iodine stain as well as negative rectal culture for bacteria. She underwent computed tomography of the whole abdomen which showed a long segment of circumferential wall thickening, about 0.9–2.0 cm in thickness, involving the rectum, surrounded by moderate fat reticulation (Fig. 1). Ceftriaxone and metronidazole were given intravenously. Colonoscopy was subsequently performed 2 days later since there was no significant improvement of her clinical condition. The colonoscopic findings were severe edematous, erythematous mucosa with multiple small ulcers and exudation at the top of the rectum; the rest of the colon, including the terminal ileum, were normal (Fig. 2). A biopsy was taken at the rectum, and there was a large amount of pus discharge from the biopsy site. A rectal tissue culture was obtained and revealed Escherichia coli and Klebsiella pneumoniae ESBL strain organisms.\n\nThe histopathology of the biopsy specimens was consistent with debris and ulcer with crypt abscess at the rectum (Fig. 3). Hence, phlegmonous proctitis was diagnosed from a combination of her imaging and colonoscopic findings and the histopathological report. After drainage of pus discharge by biopsy of the rectal mucosa, accompanied by continued ceftriaxone and metronidazole treatment, her clinical condition gradually improved, the fever was gone, and there was no more abdominal pain; normal bowel movement then followed. The follow-up computed tomography of the abdomen 3 weeks after treatment showed marked improvement of circumferential wall thickening at the rectum (Fig. 4).\n\nDiscussion\nPhlegmonous proctitis is a rare entity that was mentioned for the first time in 1940 by Yaker [1]. We carried out a bibliographic search using the PubMed database with the keyword “phlegmonous proctitis.” There was no other case report since then; we here describe the second case of phlegmonous proctitis.\n\nThe first case report by Yaker [1] described a woman who presented with postpartum rectal pain and purulent feces after using paraldehyde and soap enema in labor pain and after postpartum. He followed up the patient and found a rectal stricture after that. The hypothesis was that the cause of phlegmonous proctitis might be the chemical irritation and injury of the rectal mucosa. Our case is totally different from the first case in terms of underlying clinical conditions, and no previous history of rectal enema was present in our case. Nonetheless, the pain in the rectum and lower abdomen were similar.\n\n“Phlegmonous” is a term that means mass-like forming of the gastrointestinal tract that is caused by suppurative bacterial infection. Among various sites of the gastrointestinal tract, the term “phlegmonous gastritis,” the suppurative infection of the gastric wall [3], is the most well-known and widely described. The presentation of phlegmonous gastritis is nonspecific; typical clinical manifestations are epigastric pain, vomiting, and fever [3, 4]. The diagnosis was difficult in the early phase according to nonspecific manifestations. Risk factors include postprocedures (such as esophagoduodenoscopy with biopsy, endoscopic submucosal resection), alcohol consumption, immunosuppression, chronic gastritis, drugs, and mucosal injury [2, 5]. However, the risk factors of phlegmonous proctitis are unclear. In the first case, chemical irritation from rectal enema was presumably the cause of this condition, but in our case, there was no such history of enema. We hypothesize that our patient's medical history of diabetes and cirrhosis may have led to an immunocompromised status and might have been a risk factor for developing phlegmonous proctitis.\n\nThe diagnosis of phlegmonous proctitis was made with comprehensive modalities, including computed tomography of the abdomen, colonoscopy, and histopathological study. There are no data regarding the common microbiology of this condition. In phlegmonous gastritis, the common pathogens found were Streptococcus spp. (57%) and Enterococcus (10%) [2]. In our case, tissue cultures were positive for Escherichia coli and Klebsiella pneumoniae ESBL strain; nevertheless, these organisms could not be the only colonization since the patient had a good response to ceftriaxone and metronidazole, to which these organisms are not sensitive. The follow-up computed tomography of the abdomen 3 weeks after treatment showed marked improvement of phlegmonous proctitis. The causative organisms may be gram-negative bacteria and anaerobes.\n\nStatement of Ethics\nInformed consent was obtained for this case report.\n\nDisclosure Statement\nThe authors have no conflicts of interest to disclose.\n\nFunding Sources\nThere are no funding sources to report.\n\nAuthor Contributions\nBoth authors participated in writing the manuscript. A. Kaewdech is the article guarantor.\n\nFig. 1 Computed tomography of the abdomen, axial view (a) and coronal view (b), showing circumferential wall thickening at the rectum.\n\nFig. 2 a Colonoscopy showing severe edematous, erythematous mucosa with multiple ulcers and exudate at the rectum. b Pus discharge at the biopsy site.\n\nFig. 3 HE stain showing acute inflammation of mucosa and neutrophilic abscess in submucosa of the rectum (×100).\n\nFig. 4 Computed tomography of the abdomen, axial view (a) and coronal view (b), after 3 weeks of antibiotics treatment showing marked improvement of phlegmonous proctitis.\n==== Refs\nReferences\n1 Yaker DN Phlegmonous proctitis Am J Surg 1940 8 49 (2) 393 5 \n2 Rada-Palomino A Muñoz-Duyos A Pérez-Romero N Vargas-Pierola H Puértolas-Rico N Ruiz-Campos L Phlegmonous gastritis: a rare entity as a differential diagnostic of an acute abdomen. Description of a case and a bibliographic review Rev Esp Enferm Dig 2014 6 106 (6) 418 24 25361454 \n3 Schultz MJ van der Hulst RW Tytgat GN Acute phlegmonous gastritis Gastrointest Endosc 1996 7 44 (1) 80 3 8836724 \n4 Lawrence JS Phlegmonous Gastritis Boston Med Surg J 1926 195 (17) 800 3 \n5 Kato K Tominaga K Sugimori S Nagami Y Kamata N Yamagami H Successful Treatment of Early-Diagnosed Primary Phlegmonous Gastritis Intern Med 2015 54 (22) 2863 6 26567999\n\n",
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"keywords": "Biopsy; Colonoscopy; Phlegmonous proctitis; Rectosigmoid colon; Rectum",
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"title": "Phlegmonous Proctitis: A Rare Entity of the Presentation of Proctitis.",
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"abstract": "Quetiapine is a dopamine D2 and serotonin 5-HT2 antagonist with antipsychotic and mood-stabilizing properties. Recent studies suggest that higher doses of quetiapine combine superior therapeutic efficacy with good tolerability. We present five patients, in whom treatment with higher doses of quetiapine was associated with constipation. Our observations raise the question of dose-dependent constipation under treatment with quetiapine.",
"affiliations": "Department of Psychiatry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. traedler@uke.uni-hamburg.de",
"authors": "Raedler|Thomas J|TJ|;Reimer|Jens|J|;Wiedemann|Klaus|K|",
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"abstract": "We analyzed ammonium levels and acute central nervous complications in adult patients receiving chemotherapy for acute lymphoblastic leukemia with or without asparaginase (l-asp). Twenty patients with a median age of 40.3 years were included. Ammonium-levels were measured during 88 chemotherapy cycles, 60 cycles (68%) with l-asp, and 28 cycles (32%) without l-asp. Ammonium was elevated in 87% of all l-asp containing cycles, with median ammonium levels of 169 μmol/l (interquartile range (IQR) 91-269 μmol/l). These values were higher when compared to ammonium levels at baseline (31.5 μmol/l, IQR 24-40 μmol/l, p < .001), and when compared to levels in cycles without l-asp (30 μmol/l, IQR 19-41 μmol/l, p < .001). Acute hyperammonemic encephalopathy was diagnosed in one patient, and encephalopathy for other reasons, but with hyperammonemia as a possible contributing factor in four patients. In conclusion, ammonium levels are elevated in all adult patients receiving l-asparaginase, but only some patients will present symptoms of encephalopathy.",
"affiliations": "a Department of Hematology and Oncology, Division of Hematology , University and University Hospital Zurich , Zurich , Switzerland.;a Department of Hematology and Oncology, Division of Hematology , University and University Hospital Zurich , Zurich , Switzerland.;a Department of Hematology and Oncology, Division of Hematology , University and University Hospital Zurich , Zurich , Switzerland.;a Department of Hematology and Oncology, Division of Hematology , University and University Hospital Zurich , Zurich , Switzerland.;a Department of Hematology and Oncology, Division of Hematology , University and University Hospital Zurich , Zurich , Switzerland.;a Department of Hematology and Oncology, Division of Hematology , University and University Hospital Zurich , Zurich , Switzerland.",
"authors": "Strickler|Nicole|N|;Balabanov|Stefan|S|;Casauro|Katharina|K|;Schanz|Urs|U|;Manz|Markus G|MG|;Gerber|Bernhard|B|",
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"keywords": "Asparaginase; acute lymphoblastic leukemia; adult; ammonium; encephalopathy",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000328:Adult; D064751:Ammonium Compounds; D000971:Antineoplastic Combined Chemotherapy Protocols; D001215:Asparaginase; D005260:Female; D006801:Humans; D022124:Hyperammonemia; D008297:Male; D008875:Middle Aged; D020258:Neurotoxicity Syndromes; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012189:Retrospective Studies",
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"title": "Acute central nervous system complications and ammonium levels in adult patients with acute lymphoblastic leukemia receiving l-asparaginase.",
"title_normalized": "acute central nervous system complications and ammonium levels in adult patients with acute lymphoblastic leukemia receiving l asparaginase"
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"abstract": "T-cell receptor sequencing (TCRseq) enables tracking of T-cell clonotypes recognizing the same antigen over time and across biological compartments. TCRseq has been used to test if cross-reactive antitumor T cells are responsible for development of immune-related adverse events (irAEs) following immune checkpoint blockade. Prior studies have interpreted T-cell clones shared among the tumor and irAE as evidence supporting this, but interpretations of these findings are challenging, given the constraints of TCRseq. Here we capitalize on a rare opportunity to understand the impact of potential confounders, such as sample size, tissue compartment, and collection batch/timepoint, on the relative proportion of shared T-cell clones between an irAE and tumor specimens. TCRseq was performed on tumor-involved and -uninvolved tissues, including an irAE, that were obtained throughout disease progression and at the time of rapid autopsy from a patient with renal cell carcinoma treated with programmed death-1 (PD-1) blockade. Our analyses show significant effects of these confounders on our ability to understand T-cell receptor overlap, and we present mitigation strategies and study design recommendations to reduce these errors. Implementation of these strategies will enable more rigorous TCRseq-based studies of immune responses in human tissues, particularly as they relate to antitumor T-cell cross-reactivity in irAEs following checkpoint blockade.",
"affiliations": "Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.;Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, MD, USA.;Department of Biostatistics, Johns Hopkins University, Baltimore, Maryland, USA.;Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.;Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, MD, USA.;Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, MD, USA.;Department of Radiology, Johns Hopkins School of Medicine, Baltimore, MD, USA.;Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.;Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.;Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, MD, USA.;Department of Biostatistics, Johns Hopkins University, Baltimore, Maryland, USA.;Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.;Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, MD, USA ksmit228@jhmi.edu.",
"authors": "Cottrell|Tricia|T|;Zhang|Jiajia|J|;Zhang|Boyang|B|;Kaunitz|Genevieve J|GJ|;Burman|Poromendro|P|;Chan|Hok-Yee|HY|;Verde|Franco|F|;Hooper|Jody E|JE|;Hammers|Hans|H|;Allaf|Mohamad E|ME|;Ji|Hongkai|H|;Taube|Janis|J|;Smith|Kellie N|KN|",
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"fulltext": "\n==== Front\nJ Immunother Cancer\nJ Immunother Cancer\njitc\njitc\nJournal for Immunotherapy of Cancer\n2051-1426\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\njitc-2021-002642\n10.1136/jitc-2021-002642\nCase Report\n1506\n2518\n1619\nEvaluating T-cell cross-reactivity between tumors and immune-related adverse events with TCR sequencing: pitfalls in interpretations of functional relevance\nCottrell Tricia 123\nZhang Jiajia 245\nZhang Boyang 6\nKaunitz Genevieve J 7\nBurman Poromendro 245\nChan Hok-Yee 245\nVerde Franco 8\nHooper Jody E 1\nHammers Hans 49\nAllaf Mohamad E 24\nJi Hongkai 6\nTaube Janis 12410\nSmith Kellie N 24510\n1 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA\n2 Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, MD, USA\n3 Queen's Cancer Research Institute at Queens University, Kingston, Ontario, Canada\n4 Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA\n5 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA\n6 Department of Biostatistics, Johns Hopkins University, Baltimore, Maryland, USA\n7 Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA\n8 Department of Radiology, Johns Hopkins School of Medicine, Baltimore, MD, USA\n9 Harold C. Simmons Comprehensive Cancer Center, Dallas, TX, USA\n10 The Mark Foundation Center for Advanced Genomics and Imaging, Baltimore, MD, USA\nCorrespondence to Dr Kellie N Smith; ksmit228@jhmi.edu\n2021\n6 7 2021\n9 7 e00264202 6 2021\n© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.\n\nT-cell receptor sequencing (TCRseq) enables tracking of T-cell clonotypes recognizing the same antigen over time and across biological compartments. TCRseq has been used to test if cross-reactive antitumor T cells are responsible for development of immune-related adverse events (irAEs) following immune checkpoint blockade. Prior studies have interpreted T-cell clones shared among the tumor and irAE as evidence supporting this, but interpretations of these findings are challenging, given the constraints of TCRseq. Here we capitalize on a rare opportunity to understand the impact of potential confounders, such as sample size, tissue compartment, and collection batch/timepoint, on the relative proportion of shared T-cell clones between an irAE and tumor specimens. TCRseq was performed on tumor-involved and -uninvolved tissues, including an irAE, that were obtained throughout disease progression and at the time of rapid autopsy from a patient with renal cell carcinoma treated with programmed death-1 (PD-1) blockade. Our analyses show significant effects of these confounders on our ability to understand T-cell receptor overlap, and we present mitigation strategies and study design recommendations to reduce these errors. Implementation of these strategies will enable more rigorous TCRseq-based studies of immune responses in human tissues, particularly as they relate to antitumor T-cell cross-reactivity in irAEs following checkpoint blockade.\n\nimmunotherapy\nreceptors\nimmunologic\nt-lymphocytes\nimmunologic techniques\nbiostatistics\nLung Cancer Foundation of America http://dx.doi.org/10.13039/100000054 National Cancer Institute R37 CA251447 IASLC Foundation http://dx.doi.org/10.13039/100002192 LUNGevity Foundation Kimmel Institute for Cancer Immunotherapy, Bloomberg Philanthropies Bloomberg~Kimmel Institute for Cancer Immunotherapy NIH/NHGRI R01HG009518 NIH T32 CA193145 http://dx.doi.org/10.13039/100004436 Commonwealth Foundation http://dx.doi.org/10.13039/100014599 Mark Foundation For Cancer Research special-featureunlocked\n==== Body\nIntroduction\n\nPD(L)-1 checkpoint blockade is complicated by the development of immune-related adverse events (irAEs) in 5%–20% of treated patients.1 Severe irAEs have been reported in up to 10% of patients and can result in hospitalization, interruption or discontinuation of therapy, and rarely, death.1 Notably, irAEs increase in prevalence and severity with combination immunotherapy, an approach likely required to improve disappointingly low response rates.2 Prediction, prevention, and treatment of irAEs will require delineation of etiological mechanisms. One hypothesis is that irAEs are the result of cross-reactivity of an antigen-specific antitumor immune response. Supporting this hypothesis, improvements in response rates and survival in patients who develop irAEs have been observed in studies across tumor types.3–6 T-cell repertoire profiling with T-cell receptor sequencing (TCRseq) enables tracking of individual T-cell clones recognizing the same antigen.7 Multiple case series have identified shared T-cell clones in tumor and irAE tissues, thereby providing a foundation for shared antigen specificity between the tumor and irAE.8–10 Unfortunately, these types of analyses may be subject to several sources of confounding that are rarely considered and are often difficult to address in the context of human immune-oncology.\n\nThe current study evaluates notable sources of confounding in the analysis of T-cell receptor (TCR) repertoire overlap between tumor-involved and irAE specimens in a patient who developed a refractory irAE (dermatitis) while receiving PD-1 blockade for metastatic renal cell carcinoma (RCC). We demonstrate how these analytical pitfalls could lead to erroneous interpretation of TCRseq data obtained from distinct biological compartments and timepoints within the same patient. These factors have previously been considered as potentiators of confoundment in large-scale genomic datasets11 but have not been evaluated or implemented in TCR studies.\n\nCase report\n\nA woman in her early 70s underwent radical nephrectomy for clear cell RCC followed by systemic therapy, including anti-PD-1. The patient’s clinical course, including development of an irAE in the form of a lichenoid dermatitis (LD),12–16 and biospecimen collection are shown in figure 1. The immune-related LD (irAE) persisted despite two treatment breaks and systemic prednisone (figure 1). Anti-PD-1 therapy was discontinued because of the severity of the irAE. Progressing metastases in the small bowel and a new brain metastasis were confirmed by biopsy. The patient died approximately 2 months after cessation of anti-PD-1 therapy and a rapid autopsy was performed. Findings included metastatic RCC involving the brain (specimen TM1), jejunum (specimen TM2), and mesentery (specimen TM3). Of the three mediastinal lymph nodes (LNs) sampled, one was histologically unremarkable (LN1); one showed multiple large fibrotic nodules (LN2); and one showed multiple small subcapsular fibrotic nodules (LN3). An inflamed seborrheic keratosis (benign skin lesion) was sampled from the skin (SK) as well as uninvolved normal tissues from the left kidney and normal small bowel (NSB).\n\nFigure 1 Clinical course and assessment of TCR repertoire overlap among tumor specimens and the irAE. (A) Timeline shows the clinical course from RCC resection to autopsy. Therapies included pazopanib (yellow bar), nivolumab (green bar), and prednisone (blue bars), with treatment dates shown below the bars. Radiographical assessments (gray boxes) included mediastinal metastases with partial response to nivolumab followed by PD in the bowel and brain. Tissue specimens collected (blue boxes) included the resected RCC (photomicrograph shown), biopsies of the immune-related lichenoid dermatitis (irAE), and multiple specimens collected at the time of rapid autopsy (see online supplemental table S1). The anatomical sites of the collected specimens are illustrated, including the primary renal tumor (black diamond), two sites of irAE (black pentagons), mediastinal LNs at the site of tumor regression (green circles) and progressing lesions in the jejunum, mesentery, and brain (red circles). (B) Intravenous contrast-enhanced CT of the chest demonstrated right lower paratracheal adenopathy which resolves after nivolumab treatment (red arrow). (C) A photograph (left) and photomicrograph (right) of the irAE, the latter showing the brisk lichenoid lymphocytic infiltrate and necrotic keratinocytes. (D) Diagram illustrating two hypotheses for the development of irAEs following immune checkpoint blockade: (i) the cross-reactivity hypothesis proposed that T cells activated as part of the antitumor immune response cross-react at the site of the irAE; this would be supported by detection of overlapping TCR repertoire signatures between the tumor and irAE; (ii) in contrast, if the irAE and antitumor immune responses were independent of each other, it was unlikely significant TCR repertoire overlap between the two sites would be detected. All photomicrographs at ×400 magnification, scale bars 50 um. (E) Proposed approaches to maximize interpretive value and minimize confounding in TCR sequencing data analysis, including (i) the MI for quantifying global TCR repertoire sharing among multiple specimens in a sample size-independent manner, (ii) proportional downsampling for library size normalization to enable relative interpretations of clonal sharing, and (iii) normalization to relative clonal abundance in each specimen to assess relative sharing among the most abundant T-cell clones across multiple specimens. (F) The Morita index demonstrates that the three metastatic lesions consistently showed a greater degree of sharing with the Tp (MI median 0.014, range 0.012–0.088) relative to the normal control tissues (NSB MI 0.004, NK MI 0.003). (G) Chord diagram illustrates TCR repertoire overlap among the Tp and multiple post-treatment progressing metastases (red). Non-tumor specimens are shown in gray. (H) Following library size normalization, a metastasis (TM2, left), LN (LN2, middle), and NSB (right) were evaluated for T-cell repertoire overlap with the primary tumor (TP). Clonal expansion of clones shared with TM2 is suggested by 9.1% of shared TP clonotypes representing 27.1% of TP reads. Subsampled comparisons are indicated (*) and the 95% CIs for shared TP clones were 5.2% to 6.8% for LN2 (middle, representing 4.9%–15.8% total TP reads) and 3.3% to 4.3% for NSB (right, representing 3.5%–14.7% total TP reads). (I) The Morita Index demonstrates an overall low degree of TCR repertoire between the irAE and the other specimens, although the relative sharing with two of the three metastatic lesions (MI median 0.02, range 0.0003–0.026) and the three regression site LNs (MI median 0.025, range 0.021–0.027) was higher than with the normal tissues (NSB MI 0.00004, NK MI 0.003). (J) Chord diagram highlighting sharing with the irAE as assessed by the MI in red (sharing among other specimens shown in gray for reference). (K) Following library size normalization, pairwise quantification of shared clones shows that while 4.7% of irAE clones were shared with the primary tumor and a regression site LN (LN2, 95% CI 4.6% to 5.9% irAE clones), the shared clones were not expanded in the irAE (representing 4.5% and 4.7%, 95% CI 4.7% to 6.4% of the total irAE reads, respectively). Sharing between the irAE and NSB shown for comparison, 1.6% shared clones (95% CI 1.3% to 2.2%) represent 1.8% total irAE reads (95% CI 1.3% to 2.2%). Subsampled comparisons are indicated (*). (L) The GLIPH2 clustering algorithm was used to detect and quantify potential specificity clusters based on TCR CDR3 sequencing information. Motif clusters were included in downstream analysis if there were ≥3 unique CDR3s, ≥10 reads for each CDR3, a vb score <0.05, and a length score of <0.05. The barplot shows the clonal abundance of the significantly enriched ‘SSQD’ motif in the dermatitis and respective clonal abundance in other tissue compartments. GLIPH2, grouping lymphocyte interactions by paratope hotspots 2; irAE, immune-related adverse event; LN, lymph node; MI, Morisita Overlap Index; NK, normal tissues from the left kidney; NSB, normal small bowel; PD, progressive disease; RCC, renal cell carcinoma; SK, skin; TCR, T-cell receptor; Tp, pretreatment primary tumor.\n\n10.1136/jitc-2021-002642.supp1 Supplementary data\n\nTo test for possible T-cell cross-reactivity among the tumor and irAE (figure 1D), TCR Vβ CDR3 sequencing was performed on all specimens (online supplemental table S1).17 18 The irAE shared 147 unique clonotypes (4.7%) with the pretreatment primary tumor (Tp) and 118 unique clonotypes (3.7%) with jejunal metastasis (TM2) (online supplemental figure S1A, B). In total, 127 unique T-cell clones present in the irAE (4.0%) were also found in at least one tumor specimen and absent in all healthy, non-lymphoid specimens (online supplemental figure S1C). We next tested if library size (the total number of productive sequencing reads) influences T-cell repertoire overlap among specimens. The number of clones shared with a given specimen was highly correlated with library size, illustrated for the irAE (Spearman’s rho, R=0.7, p=0.031; online supplemental figure S1D, left) and LN2 (R=0.78, p=0.012; online supplemental figure S1D, right). Random subsampling weighted by clonal abundance within each specimen was used to equalize library sizes to eliminate this confounding (online supplemental figure S1E).7 11 Not surprisingly, a strong correlation was observed between library size and the number of unique clonotypes (R=0.93, p<2.2e−16; online supplemental figure S2). The degree of clonal sharing was also correlated with the number of unique clonotypes in each specimen (R=0.85 and p=0.0035 for the irAE, and R=0.92 and p=0.00047 for LN2; online supplemental figure S3A). Using weighted downsampling,7 11 we normalized specimens to the same library size, which eliminated the correlation between the number of unique clonotypes in a specimen and clonal sharing (online supplemental figure S3B). Therefore, we used weighted downsampling for the remainder of our analyses.\n\nTumor-specific T cells can be detected in paired uninvolved tissue, even when the normal tissue is collected 10–15 cm from the tumor itself.19–21 Likewise, clonotype sharing analyses could be confounded by bypassing viral-specific T cells. We performed a reanalysis of a previously published functional assay20 21 and found that viral-specific T-cell clones showed notable clonotype sharing across multiple tissue compartments, including the tumor, in a patient with non-small cell lung cancer. A similar pattern was previously observed with neoantigen-specific T-cell clones,20 21 suggesting that T cells can traffic across tumor involved/uninvolved compartments regardless of the presence of antigen (online supplemental figure S4A, B). Indeed, after mapping the TCRs from our present study to a public TCR database with annotated antigen specificity (vdjdb, https://vdjdb.cdr3.net/), we found an Epstein-Barr Virus (EBV)-specific clone that was detected in tumor-involved tissues from our study participant (online supplemental figure S4C–D). This emphasizes that clonotype sharing alone is not necessarily associated with biological relevance. Additional abundance measurement and antigen specificity analyses are warranted to assist further interpretation. The SK and LN outliers in online supplemental figure S1D (red arrows) also indicate increased T-cell repertoire sharing between specimens from the same tissue compartment, even when collected at different locations and timepoints (ie, the irAE and SK). Tissue compartment confounding—a greater degree of T-cell repertoire overlap between specimens collected from the same tissue site—is illustrated with pairwise comparisons in online supplemental figure S5A, B. While T-cell repertoire sharing is reduced in samples from different tissue compartments, shared clones are still detected between seemingly unrelated specimens. These could reflect circulating clones at the time of tissue collection and are not necessarily reflective of biologically meaningful clonal sharing, (ie, batch effect confounding). We used the Morisita Overlap Index (MI), which incorporates relative clonal abundance and is not influenced by library size in our dataset (online supplemental figure S6A), to calculate the overlap between the irAE and all other specimens. The relative clonal sharing among all specimens is illustrated in a chord diagram (online supplemental figure S6B), in which the width of the bands is proportional to the MI values. The highest MI was observed between specimens collected from the same batch and from the same tissue compartment (online supplemental figure S6C). These population-level comparisons likely capture a combination of biological and batch effects, which cannot be distinguished in this dataset.\n\nWe next tested for evidence of cross-reactive T cells in the tumor and irAE while accounting for the sources of confounding identified previously (figure 1E). Within the limitations of specimen availability, tissue compartment and batch effect were considered in selecting comparator specimens for meaningful analyses. First, the T-cell repertoire overlap between the primary tumor and the metastases was quantified using MI, which demonstrated a significantly higher overlap among the progressing metastases relative to the mediastinal LNs and normal tissues (p=0.044; figure 1F, G). A chord diagram highlights population-level sharing among all tumor specimens (figure 1G), with the greatest TCR repertoire overlap observed between the metastases from the brain (TM1) and mesentery (TM3, MI 0.47). Although batch effect is a potential confounder, this degree of overlap is not observed with the small bowel metastasis (TM2, MI 0.03 and 0.04 with TM1 and TM3, respectively), also collected at autopsy. Since the primary tumor and metastases were collected at different time points and from different tissue sites, batch and tissue compartment effects could not be confounders in this analysis. We recognize that a small sample size limits interpretation of the aforementioned findings, given that TM1 and TM3 have the smallest library sizes (online supplemental table S1), even though they satisfied our criteria for inclusion. Consequently, we focused on the metastasis with the largest library size (TM2, 6945 reads) for additional analyses.\n\nFollowing library size normalization, 9.1% of unique primary tumor clonotypes are shared with TM2 relative to 5.8% (95% CI 5.2% to 6.8%) and 3.7% (95% CI 3.3% to 4.3%) of Tp clonotypes shared with LN2 and NSB, respectively (figure 1H). Clonal expansion of shared clones in the primary tumor was greatest for those shared with TM2, with shared clones representing 27.1% of total primary tumor reads. The TCR repertoire overlap between the primary tumor and LN2 may suggest an antitumor signature in the mediastinal LNs, a site of radiographical tumor regression. The same approach was used to evaluate TCR repertoire overlap between the irAE and tumor specimens. The irAE repertoire was most similar to TM3, TM1, and the regression site LNs (figure 1I), with intermediate overlap with Tp and the least overlap with the normal control specimens. Although the relative degrees of overlap with the irAE potentially suggest a biologically relevant pattern, the magnitude of population-level TCR repertoire sharing is quite small relative to values observed among other specimens (figure 1J).\n\nSpecimen libraries were then normalized to allow direct pairwise comparison of clonal sharing with the irAE. Sharing between the irAE and Tp (largest library size of 12,588 reads) was compared with LN2 and NSB. A similar degree of irAE clonotype sharing was observed in Tp and LN2, which was greater than that observed for NSB (figure 1K). There was no evidence of clonal proliferation in the irAE or Tp (figure 1K). Finally, we evaluated the most abundant clonotypes in each specimen for overlap with the irAE, given that prior studies have implicated the highest-frequency intratumor clonotypes in mediating antitumor immunity.22 There was no enrichment of irAE-shared clones in the tumor relative to the non-tumor specimens (online supplemental figure S7).\n\nBased on observations that antigen specificity may be determined by limited contact sites in the TCR CDR3, we applied the grouping lymphocyte interactions by paratope hotspots 2 (GLIPH2) algorithm23 24 to identify and cluster TCR sequences into possible antigen specificity groups. In order to be included in downstream analyses, clusters had to contain ≥3 unique CDR3s, ≥10 reads for each CDR3, a variable gene beta (vb) score of <0.05, and a length score <0.05. One cluster with significant enrichment in the irAE was identified. Notably, the primary tumor (3.66%) had the highest abundance of T-cell clones in the ‘SSQD’ CDR3 motif cluster (figure 1L), followed by the irAE (2.42%), which were both higher than representation of this motif in non-diseased TCR repertoires from four healthy donors (range: 0.03%–1.67%, online supplemental figure S8).25 Though the human leukocyte antigen (HLA) information is unknown, three of the four healthy donors had common clonotypes shared with the patient in our study, indicating that at least one HLA allele was shared among them. By querying additional published skin/tumor-reactive TCR data, the specific motif SSQD was reported in a T-cell clone recognizing an epitope derived from Maspin, which functions as a tumor suppressor gene in epithelial cells.26 Collectively, this indicates that, though analyses of the total TCR repertoire and a subset of high abundance clones do not show a signature of enriched sharing between the irAE and tumor specimens relative to non-tumor specimens at the clonotype level, more ‘antigen-driven’ approaches may be useful to identify potential specificity clusters, especially when coupled with functional assays to confirm antigen specificity and cross-reactivity between irAEs and tumors.\n\nDiscussion\n\nAs immune checkpoint blocking agents become first-line and second-line therapies for a growing number of tumor types, we are faced with an increasing number of diverse irAEs that may develop during or after treatment. The association of cutaneous irAEs with clinical benefit in some patients suggests that there may be a common antigen that may underlie both durable antitumor responses and clinically significant irAEs. It is conceivable that T cells with a common TCR could mediate both tumor regression and irAE development and progression, as has been evidenced by prior studies evaluating clonal overlap of TCR clonotypes between tumor and irAE tissues8–10 and that expansion of peripheral blood T-cell clones prior to irAE onset positively correlates with irAE severity during checkpoint blockade treatment.27\n\nThe large number and circulating nature of T cells predispose these studies to detecting false positive signals, that is, detection of differential or statistically significant clonal overlap that is not necessarily of pathogenic relevance. Biological differences exacerbate this issue, including variation in T-cell numbers and clonality in different tissue types. In addition, due to differences in sampling, clonotype detection can be limited, particularly for rare/low-frequency clonotypes. The analysis pitfalls and mitigation strategies identified in this study are summarized in table 1, and we present considerations for prospective specimen collection in online supplemental figure S9. Many of these factors are already considered as a standard part of large-scale genomic analyses, but they are not yet routinely applied to immune receptor sequencing datasets and, to date, no studies have demonstrated the differential outcomes when these important sources of confounding are not acknowledged. Strengths of this study include the rare opportunity to analyze the TCR repertoire in the same patient across time, tissue compartments, and disease states, and the ability to compare with published tumor-reactive/skin-reactive TCRs and non-irAE skin TCRs. We recognize that we are limited in our ability to comprehensively dissect all potential sources of confounding owing to limited sample availability. Lastly, the data-driven recommendations made in this study highlight the scientific value of rapid autopsy to answer complex questions using human tissue specimens.\n\nTable 1 Mitigating pitfalls and approaches for interpretation of TCRseq data\n\nPotential confounders\tPitfall\tMitigation\t\nBatch effect\tCirculating T-cell clones may be ‘shared’ by multiple specimens collected at the same time point.\tControl normal tissue(s) collected at the same timepoint can be used to identify these background clones.\t\nBlood\tDuring active immune responses,* both relevant and non-relevant clones circulate in blood.\tFunctional assays enable identification of disease-relevant clones (vs batch background).\t\nTissue compartment effect\tSpecimens from the same organ share tissue resident T cells, including antitumor clones.19\tClonotype sharing with ‘paired’ normal tissue does not preclude biological relevance. Measurements such as abundance and antigen specificity (antigen-driven clustering/functional assays) are needed for further discernment.\t\nLibrary size variation\tIncreased read count→more clones sampled→a larger proportion of shared clones\tAnalyses must correct for sample size variation (eg, Morisita Overlap Index, normalization, etc)\t\nLNs/lymphoid-rich tissues\tIncreased probability of repertoire overlap given large, diverse T-cell populations\tAvoid analysis of background lymphoid tissue in LN metastases; interpret LN data with caution.\t\nInterpretation\tDefinition\tApproach\t\nClonal abundance\n(relative read count)\tRelative proportion of sequencing reads for a unique clonotype (surrogate for clonal proliferation)\tAssess for signals of clonal proliferation in relevant tissues to suggest functional relevance.†\t\nLow abundance\tMeaningful threshold for exclusion of ‘background’ clones has not been rigorously defined\tExclude specimens with <1000 reads. Sample size informs interpretation of low-read clones.\t\nHigh abundance\tIncreasing abundance suggests clonal proliferation (and antigen exposure) in a given tissue.*\tProliferation of shared clones in disease-relevant tissues supports potential mechanistic overlap.\t\nTCR repertoire sharing\tMechanistic interpretations of TCR repertoire overlap are limited by several confounders.\tMultispecimen analyses, antigen-driven clustering (such as GLIPH2), and functional assays maximize interpretability of TCRseq data.\t\n*During tumor killing (early in treatment) or active autoimmunity (immune-related adverse events).\n\n†Assuming systemic clonal proliferation (batch effect) has been excluded.\n\nGLIPH2, grouping lymphocyte interactions by paratope hotspots 2; LN, lymph node; TCR, T-cell receptor; TCRseq, T-cell receptor sequencing.\n\nMethods\n\nCase selection\n\nSpecimens from the underlying primary tumor and/or metastatic site and from skin affected by the cutaneous irAE were collected from the Johns Hopkins Hospital surgical pathology archives and the Rapid Autopsy program and Franklin Square Hospital. Overall patient response to anti-PD-1 therapy was classified according to Response Evaluation Criteria in Solid Tumors V.1.1.\n\nTCRseq and bioinformatic analysis\n\nDNA extraction from formalin-fixed paraffin-embedded (FFPE)-preserved tumor and skin biopsy specimens was performed using the DNeasy Blood and Tissue Kit (Qiagen). The TCR-B locus was amplified and sequenced using the ImmunoSEQ assay (Adaptive Biotechnologies). Non-productive TCR CDR3 sequences (premature stop or frameshift), sequences with amino acid length less than 7, and sequences not starting with ‘C’ or ending with ‘F/W’ were excluded from the final analyses. Specimens with at least 1000 reads were included in the final analysis. To focus on T cells recognizing the same antigen, we analyzed amino acid clonotypes exclusively.\n\nThe degree of clonality for each specimen was assessed by the productive clonality matrix, which is defined as 1-Pielou’s evenness.28 Values near one represent samples with one or a few predominant clones (monoclonal or oligoclonal samples), whereas values near 0 represent a polyclonal population.\n\nA random subsampling approach weighted by clonal abundance was used to equalize library sizes for relative comparisons of TCR repertoire overlap. For subsampling, each clonotype at amino acid level was treated as a sample and specimens were randomly sampled with replacement and weighted by clonal abundance (or frequency) until the total read count equaled that of the comparator library. To account for subsampling variation, the procedure was repeated 100 times and the 95%CIs for all subsampled comparisons are reported.\n\nThe degree of T cell clone overlap at the species level was evaluated using the Morisita overlap index.29 30 This measurement accounts for differences in library size and diversity per specimen, values near one the species occur in the same proportion in both samples, whereas values near 0 implies the two samples do not overlap in terms of species. Clonotypic sharing at the individual clone level was assessed in pairwise biological compartments before and after normalization to the same library size. Clones that were copresented in any of the compartment pairs are defined as shared clones. Based on the clonal frequency distributions (online supplemental figure 4), we assessed the top 40 clones in each specimen for overlap with the irAE repertoire. GLIPH223 24 was used for antigen-specific clustering. The motif significantly-enriched in the irAE was queried in a published dataset of tumor-reactive/skin-reactive TCRs in lung cancer26 and in a dataset of dermal/epidermal TCRs from healthy donors.25\n\nStatistical analysis\n\nStatistical analysis was performed using R software. The Mann Whitney U test was used for comparison of 2-group data. For analysis of >2 group data, Kruskal-Wallis was used. Spearman’s rho correlation was used to determine correlation significance. TCR preprocessing was performed using tcR package. Chord diagram was performed using the circlize package.31 32 p<0.05 was considered significant.\n\nData and code availability\n\nBulk TCR Vβ sequencing data generated by Adaptive Biotechnologies are available in the Adaptive Biotechnologies ImmuneACCESS repository at DOI: 10.21417/TRCJZ2021JITC. The code to perform downsampling of the TCR repertoire to the same library size and relevant figures are available online (https://github.com/BKI-immuno/dermatitis/).\n\nWe thank the patient and the patient’s family for participation in this study, members of our research and administrative teams who contributed to this study, and also Fiamma Berner and Lukas Flatz for generous and prompt tumor-reactive/skin-reactive T-cell receptor sequencing data sharing.\n\nEthics statements\n\nPatient consent for publication\n\nNot required.\n\nEthics approval\n\nThis study was approved by the institutional review board (IRB) at Johns Hopkins University (JHU) and was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. The patient described in this study provided written informed consent as approved by the IRB of JHU.\n\nTwitter: @jihk99, @SmithImmunology\n\nTC and JZ contributed equally.\n\nContributors: TC, GJK, and H-YC conceived of and conducted the experiments. KNS and JT oversaw the study design, data interpretation, and manuscript preparation. JZ, BZ, PB, and HJ led the bioinformatic analyses. FV, JEH, HH, and MEA oversaw the clinical care of the patient and led the specimen acquisition. All authors contributed to and edited the manuscript.\n\nFunding: KNS was supported by the Lung Cancer Foundation of America, the IASLC Foundation, Swim Across America, and The Commonwealth Foundation. KNS, JT, JZ, and BZ were supported by the Mark Foundation for Cancer Research. HJ was partially supported by the National Institutes of Health (NIH)/National Human Genome Research Institute (grant R01HG009518). TC was supported by NIH (T32 CA193145). KNS and HJ were supported by R37 CA251447. This research was funded in part through the Bloomberg-Kimmel Institute for Cancer Immunotherapy, Bloomberg Philanthropies, and P30CA006973.\n\nCompeting interests: HH has received clinical research funding from Bristol-Myers Squibb and Merck and serves in an advisory role for Pfizer, Merck, and Bristol-Myers Squibb. JT receives research funding from Bristol-Myers Squibb and serves a consulting/advisory role for Bristol-Myers Squibb, Merck, and Astra Zeneca. KNS has received travel support/honoraria from Illumina, Inc., receives research funding from Bristol-Myers Squibb, Enara Bio, and Astra Zeneca, and owns founder’s equity in manaT Bio. The terms of all these arrangements are being managed by the investigators’ respective institutions in accordance with their conflict of interest policies.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nSupplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.\n==== Refs\nReferences\n\n1 Martins F , Sofiya L , Sykiotis GP , et al . Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol 2019;16 :563–80. 10.1038/s41571-019-0218-0 31092901\n2 Haslam A , Prasad V . Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. JAMA Netw Open 2019;2 :e192535. 10.1001/jamanetworkopen.2019.2535 31050774\n3 Weber JS , Kähler KC , Hauschild A . Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 2012;30 :2691–7. 10.1200/JCO.2012.41.6750 22614989\n4 Freeman-Keller M , Kim Y , Cronin H , et al . Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res 2016;22 :886–94. 10.1158/1078-0432.CCR-15-1136 26446948\n5 Das S , Johnson DB . Immune-Related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. J Immunother Cancer 2019;7 :306. 10.1186/s40425-019-0805-8 31730012\n6 Xing P , Zhang F , Wang G , et al . Incidence rates of immune-related adverse events and their correlation with response in advanced solid tumours treated with NIVO or NIVO+IPI: a systematic review and meta-analysis. J Immunother Cancer 2019;7 . 10.1186/s40425-019-0779-6\n7 Rosati E , Dowds CM , Liaskou E , et al . Overview of methodologies for T-cell receptor repertoire analysis. BMC Biotechnol 2017;17 :61. 10.1186/s12896-017-0379-9 28693542\n8 Läubli H , Koelzer VH , Matter MS , et al . The T cell repertoire in tumors overlaps with pulmonary inflammatory lesions in patients treated with checkpoint inhibitors. Oncoimmunology 2018;7 :e1386362. 10.1080/2162402X.2017.1386362 29308309\n9 Johnson DB , Balko JM , Compton ML , et al . Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med 2016;375 :1749–55. 10.1056/NEJMoa1609214 27806233\n10 Berner F , Bomze D , Diem S , et al . Association of checkpoint Inhibitor–Induced toxic effects with shared cancer and tissue antigens in Non–Small cell lung cancer. JAMA Oncol 2019;5 :1043. 10.1001/jamaoncol.2019.0402 31021392\n11 Zhang J , Ji Z , Smith KN . Analysis of TCR β CDR3 sequencing data for tracking anti-tumor immunity. Methods Enzymol 2019;629 :443–64. 10.1016/bs.mie.2019.08.006 31727253\n12 Chou S , Hwang SJE , Carlos G , et al . Histologic assessment of lichenoid dermatitis observed in patients with advanced malignancies on Antiprogramed cell death-1 (anti-PD-1) therapy with or without ipilimumab. Am J Dermatopathol 2017;39 :23–7. 10.1097/DAD.0000000000000587 28045749\n13 Curry JL , Tetzlaff MT , Nagarajan P , et al . Diverse types of dermatologic toxicities from immune checkpoint blockade therapy. J Cutan Pathol 2017;44 :158–76. 10.1111/cup.12858 27859479\n14 Hwang SJE , Carlos G , Wakade D , et al . Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: A single-institution cohort. J Am Acad Dermatol 2016;74 :455–61. 10.1016/j.jaad.2015.10.029 26793994\n15 Schaberg KB , Novoa RA , Wakelee HA , et al . Immunohistochemical analysis of lichenoid reactions in patients treated with anti-PD-L1 and anti-PD-1 therapy. J Cutan Pathol 2016;43 :339–46. 10.1111/cup.12666 26762844\n16 Tetzlaff MT , Nagarajan P , Chon S , et al . Lichenoid dermatologic toxicity from immune checkpoint blockade therapy: a detailed examination of the clinicopathologic features. Am J Dermatopathol 2017;39 :121–9. 10.1097/DAD.0000000000000688 28134729\n17 Robins HS , Campregher PV , Srivastava SK , et al . Comprehensive assessment of T-cell receptor beta-chain diversity in alphabeta T cells. Blood 2009;114 :4099–107. 10.1182/blood-2009-04-217604 19706884\n18 Carlson CS , Emerson RO , Sherwood AM , et al . Using synthetic templates to design an unbiased multiplex PCR assay. Nat Commun 2013;4 :2680. 10.1038/ncomms3680 24157944\n19 Zhang J , Ji Z , Caushi JX , et al . Compartmental analysis of T-cell clonal dynamics as a function of pathologic response to neoadjuvant PD-1 blockade in resectable non-small cell lung cancer. Clin Cancer Res 2020;26 :1327–37. 10.1158/1078-0432.CCR-19-2931 31754049\n20 Danilova L , Anagnostou V , Caushi JX , et al . The mutation-associated neoantigen functional expansion of specific T cells (MANAFEST) assay: a sensitive platform for monitoring antitumor immunity. Cancer Immunol Res 2018;6 :888–99. 10.1158/2326-6066.CIR-18-0129 29895573\n21 Forde PM , Chaft JE , Smith KN , et al . Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med 2018;378 :1976–86. 10.1056/NEJMoa1716078 29658848\n22 Zhang J , Ji Z , Caushi JX , et al . Compartmental analysis of T-cell clonal dynamics as a function of pathologic response to neoadjuvant PD-1 blockade in resectable non-small cell lung cancer. Clin Cancer Res 2019 10.1158/1078-0432.CCR-19-2931\n23 Huang H , Wang C , Rubelt F , et al . Analyzing the Mycobacterium tuberculosis immune response by T-cell receptor clustering with GLIPH2 and genome-wide antigen screening. Nat Biotechnol 2020;38 :1194–202. 10.1038/s41587-020-0505-4 32341563\n24 Glanville J , Huang H , Nau A , et al . Identifying specificity groups in the T cell receptor repertoire. Nature 2017;547 :94–8. 10.1038/nature22976 28636589\n25 Cheuk S , Schlums H , Gallais Sérézal I , et al . CD49a expression defines tissue-resident CD8+ T cells poised for cytotoxic function in human skin. Immunity 2017;46 :287–300. 10.1016/j.immuni.2017.01.009 28214226\n26 Berner F , Bomze D , Diem S , et al . Association of checkpoint inhibitor-induced toxic effects with shared cancer and tissue antigens in non-small cell lung cancer. JAMA Oncol 2019;5 :1043–7. 10.1001/jamaoncol.2019.0402 31021392\n27 Subudhi SK , Aparicio A , Gao J , et al . Clonal expansion of CD8 T cells in the systemic circulation precedes development of ipilimumab-induced toxicities. Proc Natl Acad Sci U S A 2016;113 :11919–24. 10.1073/pnas.1611421113 27698113\n28 Kirsch I , Vignali M , Robins H . T-cell receptor profiling in cancer. Mol Oncol 2015;9 :2063–70. 10.1016/j.molonc.2015.09.003 26404496\n29 Wolda H . Similarity indices, sample size and diversity. Oecologia 1981;50 :296–302. 10.1007/BF00344966 28309044\n30 Morisita M . Measuring of the dispersion and analysis of distribution patterns. In: Memoires of the faculty of science. Kyushu University, 1959.\n31 Gu Z , Gu L , Eils R , et al . circlize implements and enhances circular visualization in R. Bioinformatics 2014;30 :2811–2. 10.1093/bioinformatics/btu393 24930139\n32 Nazarov VI , Pogorelyy MV , Komech EA , et al . tcR: an R package for T cell receptor repertoire advanced data analysis. BMC Bioinformatics 2015;16 :175. 10.1186/s12859-015-0613-1 26017500\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2051-1426",
"issue": "9(7)",
"journal": "Journal for immunotherapy of cancer",
"keywords": "biostatistics; immunologic; immunologic techniques; immunotherapy; receptors; t-lymphocytes",
"medline_ta": "J Immunother Cancer",
"mesh_terms": null,
"nlm_unique_id": "101620585",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34230111",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "29658848;28309044;27806233;31092901;26446948;31801636;29895573;31727253;26762844;22614989;27698113;26404496;29308309;26793994;28134729;28693542;26017500;19706884;28214226;27859479;28636589;24157944;31730012;24930139;32341563;31050774;28045749;31754049;31021392",
"title": "Evaluating T-cell cross-reactivity between tumors and immune-related adverse events with TCR sequencing: pitfalls in interpretations of functional relevance.",
"title_normalized": "evaluating t cell cross reactivity between tumors and immune related adverse events with tcr sequencing pitfalls in interpretations of functional relevance"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-071356",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "BACKGROUND\nTools are lacking to assess the individual risk of severe toxicity from chemotherapy. Such tools would be especially useful for older patients, who vary considerably in terms of health status and functional reserve.\n\n\nMETHODS\nThe authors conducted a prospective, multicentric study of patients aged ≥70 years who were starting chemotherapy. Grade 4 hematologic (H) or grade 3/4 nonhematologic (NH) toxicity according to version 3.0 of the Common Terminology Criteria for Adverse Events was defined as severe. Twenty-four parameters were assessed. Toxicity of the regimen (Chemotox) was adjusted using an index to estimate the average per-patient risk of chemotherapy toxicity (the MAX2 index). In total, 562 patients were accrued, and 518 patients were evaluable and were split randomly (2:1 ratio) into a derivation cohort and a validation cohort.\n\n\nRESULTS\nSevere toxicity was observed in 64% of patients. The Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score was constructed along 2 subscores: H toxicity and NH toxicity. Predictors of H toxicity were lymphocytes, aspartate aminotransferase level, Instrumental Activities of Daily Living score, lactate dehydrogenase level, diastolic blood pressure, and Chemotox. The best model included the 4 latter predictors (risk categories: low, 7%; medium-low, 23%; medium-high, 54%; and high, 100%, respectively; P(trend) < .001). Predictors of NH toxicity were hemoglobin, creatinine clearance, albumin, self-rated health, Eastern Cooperative Oncology Group performance, Mini-Mental Status score, Mini-Nutritional Assessment score, and Chemotox. The 4 latter predictors provided the best model (risk categories: 33%, 46%, 67%, and 93%, respectively; P(trend) < .001). The combined risk categories were 50%, 58%, 77%, and 79%, respectively; P(trend) < .001). Bootstrap internal validation and independent sample validation demonstrated stable risk categorization and P(trend) < .001.\n\n\nCONCLUSIONS\nThe CRASH score distinguished several risk levels of severe toxicity. The split score discriminated better than the combined score. To the authors' knowledge, this is the first score systematically integrating both chemotherapy and patient risk for older patients and has a potential for future clinical application.",
"affiliations": "Senior Adult Oncology Program, Moffitt Cancer Center, University of South Florida, Tampa, Florida 33612, USA. martine.extermann@moffitt.org",
"authors": "Extermann|Martine|M|;Boler|Ivette|I|;Reich|Richard R|RR|;Lyman|Gary H|GH|;Brown|Richard H|RH|;DeFelice|Joseph|J|;Levine|Richard M|RM|;Lubiner|Eric T|ET|;Reyes|Pablo|P|;Schreiber|Frederic J|FJ|;Balducci|Lodovico|L|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "United States",
"delete": false,
"doi": "10.1002/cncr.26646",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-543X",
"issue": "118(13)",
"journal": "Cancer",
"keywords": null,
"medline_ta": "Cancer",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D006801:Humans; D008297:Male; D011446:Prospective Studies; D018570:Risk Assessment",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "3377-86",
"pmc": null,
"pmid": "22072065",
"pubdate": "2012-07-01",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Predicting the risk of chemotherapy toxicity in older patients: the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score.",
"title_normalized": "predicting the risk of chemotherapy toxicity in older patients the chemotherapy risk assessment scale for high age patients crash score"
} | [
{
"companynumb": "US-ROCHE-1958412",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "The association between Helicobacter pylori and chronic spontaneous urticaria (CSU) is controversial. Therefore, we aimed to directly diagnose H pylori by polymerase chain reaction (PCR) in gastric tissue from patients with CSU and to investigate the association between H pylori eradication therapy and CSU remission.\n\n\n\nTwenty-seven of 72 patients with CSU who were positive for H pylori stool antigen and PCR in gastric biopsy specimens were randomized to receive either anti-H pylori treatment or placebo.\n\n\n\nPatients with H pylori were found to have significantly lower hemoglobin concentrations with microcytic hypochromic anemia and a significantly higher occurrence of dyspepsia symptoms. All H pylori-treated patients (except two) showed significant improvement of the urticaria itching and red wheals after 2 weeks of therapy compared with the placebo group (P < .001). The response rate to treatment was 85.7% (12 patients; 95% confidence interval, 64.3%-100.0%). The two patients who failed to eradicate H pylori had an H pylori strain resistant to amoxicillin.\n\n\n\nAn association was observed between CSU and presence of H pylori infection in the gastric tissue. Whether this is a causal relationship or not remains to be discovered, but treatment of H pylori can significantly improve the symptoms of CSU.",
"affiliations": "Tropical Medicine and Infectious Diseases Department, Tanta, Egypt.;Clinical Pathology Department, Tanta, Egypt.;Dermatology and Venereology Department, Faculty of Medicine, Tanta University, Tanta, Egypt.;Public Health and Community Medicine Department, Faculty of Medicine, Menoufia University, Shebin Elkom, Egypt.",
"authors": "Elhendawy|Mohammed|M|;Hagras|Maha M|MM|;Soliman|Shaimaa S|SS|;Shaker|Engi Seif E|ESE|",
"chemical_list": "D000900:Anti-Bacterial Agents; D054328:Proton Pump Inhibitors; D000658:Amoxicillin; D017291:Clarithromycin; D009853:Omeprazole",
"country": "England",
"delete": false,
"doi": "10.1093/ajcp/aqaa134",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9173",
"issue": "155(3)",
"journal": "American journal of clinical pathology",
"keywords": "\n Helicobacter pylori\n ; Amoxicillin; PCR; Resistant strains; Spontaneous urticaria; Stool Ag",
"medline_ta": "Am J Clin Pathol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000658:Amoxicillin; D000900:Anti-Bacterial Agents; D000080223:Chronic Urticaria; D017291:Clarithromycin; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D016481:Helicobacter Infections; D016480:Helicobacter pylori; D006801:Humans; D008297:Male; D008875:Middle Aged; D009853:Omeprazole; D010865:Pilot Projects; D054328:Proton Pump Inhibitors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0370470",
"other_id": null,
"pages": "405-411",
"pmc": null,
"pmid": "32940336",
"pubdate": "2021-02-11",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Positive Effect of Helicobacter pylori Treatment on Outcome of Patients With Chronic Spontaneous Urticaria.",
"title_normalized": "positive effect of helicobacter pylori treatment on outcome of patients with chronic spontaneous urticaria"
} | [
{
"companynumb": "EG-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-294778",
"fulfillexpeditecriteria": "1",
"occurcountry": "EG",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OMEPRAZOLE"
},
"drug... |
{
"abstract": "The clinical benefit of second-line chemotherapy in advanced biliary tract cancers is currently unknown. We investigated the role of platinum re-challenge in a selected cohort of patients who progressed after first-line gemcitabine/cisplatin (GemCis) chemotherapy. We retrospectively analysed seventy-four patients treated between January 2008 and September 2012 at Nottingham University Hospitals. Demographics, treatment data, radiological response and survival data were captured. Univariate and multivariate analysis of survival outcomes were evaluated. Platinum sensitive disease was defined as tumours that progress after 12 weeks of completion of first-line GemCis chemotherapy. Seventy-four patients (median age = 67 years) had received first-line chemotherapy (gemcitabine alone = 21/74, Gem/Cis combination = 53/74). Best response to GemCis chemotherapy was as follows; partial response (PR) (17 %), stabilisation of disease (SD) (39.6 %), disease control rate (DCR) (56.6 %) and disease progression (43.4 %). 18/74 patients received second-line chemotherapy [GemCis (12/18), 5-FU/cisplatin (4/18), gemcitabine (2/8)]. Best response to GemCis second-line chemotherapy was as follows: PR (33.3 %), SD (33.3 %) and DCR (66.6 %). The median overall survival in patients who received second-line chemotherapy was 29 months compared to 10.6 months in patients who received first-line therapy only (p = 0.00001). The data suggest that patients who progress after 12 weeks of completion of first-line therapy may remain platinum sensitive and benefit from second-line platinum re-challenge. Prospective multicentre studies are warranted to explore this possibility further.",
"affiliations": "Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, Nottingham University Hospitals, University of Nottingham, Nottingham, NG51PB, UK.",
"authors": "Adhikaree|Jason|J|;Madhusudan|Srinivasan|S|",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine; D002945:Cisplatin; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1007/s12032-014-0046-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1357-0560",
"issue": "31(7)",
"journal": "Medical oncology (Northwood, London, England)",
"keywords": null,
"medline_ta": "Med Oncol",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001661:Biliary Tract Neoplasms; D002945:Cisplatin; D003841:Deoxycytidine; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome",
"nlm_unique_id": "9435512",
"other_id": null,
"pages": "46",
"pmc": null,
"pmid": "24913810",
"pubdate": "2014-07",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "21742554;20358256;20628385;20607585;22947649;24140396;20375404",
"title": "Is there a role for second-line platinum re-challenge in advanced biliary tract cancers?",
"title_normalized": "is there a role for second line platinum re challenge in advanced biliary tract cancers"
} | [
{
"companynumb": "GB-HQ SPECIALTY-GB-2015INT000581",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
... |
{
"abstract": "To describe the successful treatment of epithelial ingrowth using combined surgical excision with intracameral adjuvant 5-fluorouracil (5-FU) followed by Descemet-stripping automated endothelial keratoplasty (DSAEK). A 71-year-old man presented with epithelial ingrowth after clear corneal phacoemulsification. He underwent surgical excision of the membrane together with pars plana vitrectomy, air fluid exchange, and intracameral 5-FU. This treatment resulted in corneal decompensation for which DSAEK was performed 6 months later. Despite interface haze, the postoperative corrected distance visual acuity returned to 20/40 three months after DSAEK. There was no clinical evidence of recurrence of the epithelial ingrowth 9 months after the surgical removal. Intracameral 5-FU can be used in conjunction with surgical excision and subsequent DSAEK to successfully treat epithelial ingrowth.",
"affiliations": "Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. Electronic address: skoenig@mcw.edu.;Weill Cornell Medical College, New York, New York, USA.;Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.;Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.",
"authors": "Koenig|Steven B|SB|;Koenig|Lisa R|LR|;Connor|Thomas B|TB|;Simons|Kenneth B|KB|",
"chemical_list": "D000963:Antimetabolites; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jcrs.2018.12.030",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0886-3350",
"issue": "45(5)",
"journal": "Journal of cataract and refractive surgery",
"keywords": null,
"medline_ta": "J Cataract Refract Surg",
"mesh_terms": "D000368:Aged; D000867:Anterior Chamber; D000963:Antimetabolites; D003131:Combined Modality Therapy; D003315:Cornea; D003316:Corneal Diseases; D057111:Descemet Stripping Endothelial Keratoplasty; D019573:Epithelium, Corneal; D005472:Fluorouracil; D006801:Humans; D008297:Male; D018918:Phacoemulsification; D000072776:Slit Lamp Microscopy",
"nlm_unique_id": "8604171",
"other_id": null,
"pages": "690-693",
"pmc": null,
"pmid": "30853320",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful management of epithelial ingrowth after sequential intracameral 5-fluorouracil and Descemet-stripping automated endothelial keratoplasty.",
"title_normalized": "successful management of epithelial ingrowth after sequential intracameral 5 fluorouracil and descemet stripping automated endothelial keratoplasty"
} | [
{
"companynumb": "US-TEVA-2019-US-1059225",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "3",
... |
{
"abstract": "This study evaluated the risk of heart failure hospitalization in a 1:1 matched pair sample of sitagliptin ever and never users derived from the Taiwan's National Health Insurance. A total of 85,859 ever users and 85,859 never users matched on 8 digits of propensity score were followed for the first event of heart failure hospitalization until December 31, 2011. The treatment effect (for ever versus never users, and for tertiles of cumulative duration of therapy) was estimated by Cox regression incorporated with the inverse probability of treatment weighting using propensity score. Additionally, adjusted hazard ratios for heart failure were estimated for the baseline characteristics in sitagliptin ever users. Results showed that the incidence of heart failure hospitalization was 1,020.16 and 832.54 per 100,000 person-years, respectively, for ever and never users, with an overall hazard ratio (95% confidence intervals) of 1.262 (1.167-1.364). While compared to never users, the respective hazard ratio for the first, second, and third tertile of cumulative duration < 3.7, 3.7-10.3 and >10.3 months was 2.721 (2.449-3.023), 1.472 (1.318-1.645) and 0.515 (0.447-0.594). Older age, longer diabetes duration, male sex, and use of insulin, sulfonylurea, calcium channel blockers, aspirin, ticlopidine, clopidogrel and dipyridamole were significantly associated with a higher risk in sitagliptin users, but dyslipidemia and use of metformin and statin were protective. In conclusion, sitagliptin increases the risk of heart failure hospitalization within one year of its use, but reduces the risk thereafter. Some factors predisposing to sitagliptin-related heart failure are worthy of attention in clinical practice.",
"affiliations": "Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.",
"authors": "Tseng|Chin-Hsiao|CH|",
"chemical_list": "D007004:Hypoglycemic Agents; D000068900:Sitagliptin Phosphate",
"country": "United States",
"delete": false,
"doi": "10.18632/oncotarget.10507",
"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 274096761050710.18632/oncotarget.10507Clinical Research PaperSitagliptin and heart failure hospitalization in patients with type 2 diabetes Tseng Chin-Hsiao 1231 Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan2 Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan3 Division of Environmental Health and Occupational Medicine of the National Health Research Institutes, Zhunan, TaiwanCorrespondence to:Chin-Hsiao Tseng,ccktsh@ms6.hinet.net20 9 2016 9 7 2016 7 38 62687 62696 25 4 2016 17 6 2016 Copyright: © 2016 Tseng2016This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This study evaluated the risk of heart failure hospitalization in a 1:1 matched pair sample of sitagliptin ever and never users derived from the Taiwan's National Health Insurance. A total of 85,859 ever users and 85,859 never users matched on 8 digits of propensity score were followed for the first event of heart failure hospitalization until December 31, 2011. The treatment effect (forever versus never users, and for tertiles of cumulative duration of therapy) was estimated by Cox regression incorporated with the inverse probability of treatment weighting using propensity score. Additionally, adjusted hazard ratios for heart failure were estimated for the baseline characteristics in sitagliptin ever users. Results showed that the incidence of heart failure hospitalization was 1,020.16 and 832.54 per 100,000 person-years, respectively, for ever and never users, with an overall hazard ratio (95% confidence intervals) of 1.262 (1.167-1.364). While compared to never users, the respective hazard ratio for the first, second, and third tertile of cumulative duration < 3.7, 3.7-10.3 and >10.3 months was 2.721 (2.449-3.023), 1.472 (1.318-1.645) and 0.515 (0.447-0.594). Older age, longer diabetes duration, male sex, and use of insulin, sulfonylurea, calcium channel blockers, aspirin, ticlopidine, clopidogrel and dipyridamole were significantly associated with a higher risk in sitagliptin users, but dyslipidemia and use of metformin and statin were protective. In conclusion, sitagliptin increases the risk of heart failure hospitalization within one year of its use, but reduces the risk thereafter. Some factors predisposing to sitagliptin-related heart failure are worthy of attention in clinical practice.\n\nheart failurehospitalizationincretinsitagliptinTaiwan\n==== Body\nINTRODUCTION\nTwo clinical trials published in 2013 brought to public concern a possible risk of heart failure associated with the use of dipeptidyl-peptidase 4 (DPP-4) inhibitors in the treatment of type 2 diabetes mellitus. The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53 trial (SAVOR-TIMI53) showed an unexpectedly higher risk of heart failure hospitalization in patients treated with saxagliptin vs. placebo [3.5% vs. 2.8%; hazard ratio 1.27, 95% confidence interval (CI): 1.07-1.51, P = 0.007] [1]. Although not significant, more patients treated with alogliptin were diagnosed with heart failure than patients taking placebo, as demonstrated in the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) [2, 3]. In the meta-analysis by Monami et al. when these two clinical trials were pooled together, the estimated Mantel-Haenszel odds ratio was 1.24 (95% CI: 1.07-1.45, P = 0.004) [3]. However, such an increased risk of heart failure was not similarly observed in the more recently published Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), which suggested a neutral risk association between sitagliptin use and placebo, with an estimated hazard ratio of 1.00 (95% CI: 0.83-1.20, P = 0.98) [4].\n\nFour independent meta-analyses published in 2014 did not make a consistent conclusion. Iqbal et al. estimated a pooled incidence rate ratio (95% CI) of 0.55 (0.27-1.12) for heart failure associated with saxagliptin from 20 clinical trials [5]. Monami et al. estimated a Mantel-Haenszel odds ratio of 1.19 (95% CI: 1.03-1.37, P = 0.015) for DPP-4 inhbitors from 84 randomized trials up to October 1, 2013 [3]. When different DPP-4 inhibitors were estimated separately, the Mantel-Haenszel odds ratio (95% CI) was 0.99 (0.44-2.24), 0.55 (0.20-1.53), 1.22 (1.03-1.45), 1.56 (0.66-3.65) and 1.18 (0.89-1.56), respectively, for sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin [3]. Savarese et al. included 94 randomized trials in their meta-analysis and found that long-term (29 weeks or more) use of DPP-4 inhibitors (not specified) was associated with a significantly higher risk of heart failure (relative risk 1.158, 95% CI: 1.011-1.326, P = 0.034), but this was not observed in short-term users (relative risk 0.668, 95% CI: 0.318-1.400, P = 0.285) [6].\n\nIn the fourth meta-analysis, Clifton included 4 cohort studies and 5 randomized trials (including SAVOR-TIMI53 and EXAMINE) published since October 2013 and estimated an odds ratio of 1.148 (95% CI: 1.025-1.287, P = 0.017) for DPP-4 inhibitors [7]. When cohort studies and clinical trials were analyzed separately, only the odds ratio derived from the 5 clinical trials was significant (1.239, 95% CI: 1.078-1.424, P = 0.002), and that derived from the 4 cohort studies was not (1.099, 95% CI: 0.913-1.323, P = 0.317) [7].\n\nIt is worthy to note that the studies included in the fourth meta-analysis were restricted to recent publications and only one cohort study by Weir et al. was focused on the effect of sitagliptin by using a nested case-control design to analyze the US claims database from a nationally based commercial insurance [8]. They showed that sitagliptin increased the risk of heart failure hospitalization among diabetic patients with pre-existing heart failure (12.5% vs. 9.0%), with an adjusted odds ratio of 1.84 (95% CI: 1.16-2.92) [8].\n\nSitagliptin was the first DPP4 inhibitor approved in Taiwan on July 13, 2007, while the other DPP4 inhibitors (i.e., saxagliptin, vildagliptin and linagliptin) were not approved until after 2009 [9]. A recent study by Wang et al. used a 1:1 matched pairs of users and non-users of sitagliptin in the reimbursement database of the National Health Insurance (NHI) in Taiwan [10]. They showed that the adjusted hazard ratio for the first event of heart failure hospitalization for sitagliptin was 1.21 (95% CI 1.04-1.42, P = 0.017) [10].\n\nTherefore, whether the most commonly used DPP-4 inhibitor, sitagliptin, may increase the risk of heart failure is under-investigated and inconclusive. While the meta-analysis by Monami et al. [3] including 11 randomized trials suggested a null association, the two analyses of insurance databases showed a significantly higher risk [8, 10]. Because not many of these studies evaluated heart failure risk with regards to exposure duration, the present study aimed at evaluating whether sitagliptin use would affect the risk differently among different groups of exposure duration by using the reimbursement database of the NHI. Other incretins were not evaluated because they were not used commonly during the study period. In addition, a new-user design was used to minimize the potential “prevalent user bias” [11]. To reduce the potential risk of “immortal time bias” (the initial period of follow-up during which the outcome can not occur) [12, 13], patients included into the study should have been prescribed antidiabetic drugs for at least two times. To avoid the potential confounding from the differences in baseline characteristics associated with treatment allocation in non-random observational studies, a 1:1 matched-pair sample based on 8 digits of propensity score (PS) was used according to the methods described by Parsons [14]. Calculation of standardized difference for each baseline characteristic as recommended by Austin and Stuart [15] was used as a formal test for balance diagnostics. To obtained unbiased estimates, Cox regression models were created by incorporation with the inverse probability of treatment weighting (IPTW) using PS as recommended by Austin [16].\n\nRESULTS\nTable 1 compares the baseline characteristics between ever users and never users of sitagliptin in the matched-pair sample. Although 15 among the 30 variables were significantly different between ever and never users with P < 0.05, none of the variables had a standardized difference > 10%, suggesting that residual confounding from the baseline characteristics might not be remarkable [15].\n\nTable 1 Baseline characteristics of sitagliptin never users and ever users\nVariables\tSitagliptin\tP\tStandardized difference\t\n\tNever users (n = 85859)\tEver users (n = 85859)\t\t\t\n\tn\t%\tn\t%\t\t\t\nAge (years)*\t54.90 ± 13.30\t54.96 ± 12.15\t0.3214\t0.43\t\nDiabetes duration (years)*\t3.20 ± 2.64\t3.27 ± 2.69\t<0.0001\t2.81\t\nSex (men)\t47171\t54.94\t46687\t54.38\t0.0190\t−1.22\t\nHypertension\t54094\t63.00\t54568\t63.56\t0.0176\t1.02\t\nChronic obstructive pulmonary disease\t29728\t34.62\t30187\t35.16\t0.0201\t1.18\t\nStroke\t14109\t16.43\t14271\t16.62\t0.2926\t0.50\t\nNephropathy\t11901\t13.86\t12067\t14.05\t0.2477\t0.60\t\nIschemic heart disease\t25359\t29.54\t25784\t30.03\t0.0249\t1.09\t\nPeripheral arterial disease\t10892\t12.69\t11031\t12.85\t0.3148\t0.49\t\nObesity\t4434\t5.16\t4531\t5.28\t0.2927\t0.48\t\nDyslipidemia\t53409\t62.21\t53775\t62.63\t0.0682\t0.85\t\nAcute pancreatitis\t2248\t2.62\t2205\t2.57\t0.5138\t−0.32\t\nAlcohol-related diagnoses\t3939\t4.59\t3878\t4.52\t0.4801\t−0.38\t\nCancer\t54\t0.06\t65\t0.08\t0.3131\t0.47\t\nSulfonylurea\t60850\t70.87\t60309\t70.24\t0.0042\t−1.67\t\nMetformin\t60705\t70.70\t60099\t70.00\t0.0014\t−1.82\t\nMeglitinides\t10284\t11.98\t10327\t12.03\t0.7495\t0.11\t\nAcarbose\t13887\t16.17\t14292\t16.65\t0.0083\t1.15\t\nPioglitazone\t5917\t6.89\t6599\t7.69\t<0.0001\t2.93\t\nRosiglitazone\t11975\t13.95\t12513\t14.57\t0.0002\t1.70\t\nInsulin\t9320\t10.86\t9023\t10.51\t0.0203\t−1.01\t\nStatin\t34256\t39.90\t34671\t40.38\t0.0410\t0.90\t\nFibrate\t23894\t27.83\t24267\t28.26\t0.0451\t0.91\t\nAngiotensin converting enzyme inhibitor\t34804\t40.54\t35156\t40.95\t0.0838\t0.75\t\nAngiotensin receptor blocker\t27222\t31.71\t27685\t32.24\t0.0166\t1.08\t\nCalcium channel blocker\t37362\t43.52\t37589\t43.78\t0.2694\t0.47\t\nAspirin\t35529\t41.38\t35942\t41.86\t0.0432\t0.95\t\nTiclopidine\t2079\t2.42\t2158\t2.51\t0.2191\t0.60\t\nClopidogrel\t3336\t3.89\t3327\t3.87\t0.9105\t−0.04\t\nDipyridamole\t22728\t26.47\t22943\t26.72\t0.2403\t0.56\t\n* Age and diabetes duration are compared by Student's t test and expressed as mean and standard deviation, other variables are compared by Chi square test.\n\nTable 2 shows the incidence of heart failure hospitalization by sitagliptin exposure and the hazard ratios comparing sitagliptin exposed to unexposed. During follow-up, a total of 2,988 never users and 1,134 ever users developed first events of heart failure hospitalization, with respective incidence of 832.54 and 1,020.16 per 100,000 person-years. The overall hazard ratio was 1.262 (1.167-1.364). For the tertiles of cumulative duration of sitagliptin therapy, significantly increased risk was observed for the first and second tertiles, but the risk was significantly reduced in the third tertiles.\n\nTable 2 Incidence of heart failure hospitalization by sitagliptin exposure and the hazard ratios comparing sitagliptin exposed to unexposed\nSitagliptin use\tCase number followed\tIncident cases of heart failure hospitalization\tPerson-years\tIncidence rate of heart failure hospitalization (per 100,000 person-years)\tHazard ratio (95% confidence interval)\tP\t\nNever users\t85859\t2988\t358903.58\t832.54\t1.000\t\t\nEver users\t85859\t1134\t111158.84\t1020.16\t1.262 (1.167-1.364)\t<0.0001\t\nCumulative duration (months)\t\nNever users\t85859\t2988\t358903.58\t832.54\t1.000\t\t\n<3.7\t26643\t498\t20635.73\t2413.29\t2.721 (2.449-3.023)\t<0.0001\t\n3.7-10.3\t30491\t418\t35868.65\t1165.36\t1.472 (1.318-1.645)\t<0.0001\t\n>10.3\t28725\t218\t54654.47\t398.87\t0.515 (0.447-0.594)\t<0.0001\t\nTable 3 shows the adjusted hazard ratios for heart failure hospitalization for all baseline characteristics in patients ever treated with sitagliptin. Older age, longer diabetes duration, male sex, and use of insulin, sulfonylurea, calcium channel blockers, aspirin, ticlopidine, clopidogrel and dipyridamole were significantly associated with a higher risk, but dyslipidemia and use of metformin and statin were associated with a significantly lower risk.\n\nTable 3 Adjusted hazard ratios for heart failure hospitalization in patients ever treated with sitagliptin\nVariable\tInterpretation\tHazard ratio (95% confidence interval)\tP\t\nAge\tEvery 1-year increment\t1.051 (1.045-1.057)\t<0.0001\t\nDiabetes duration\tEvery 1-year increment\t1.171 (1.039-1.320)\t0.0098\t\nSex\tMen versus women\t1.033 (1.007-1.061)\t0.0145\t\nHypertension\tYes versus no\t0.918 (0.761-1.107)\t0.3713\t\nChronic obstructive pulmonary disease\tYes versus no\t1.028 (0.910-1.162)\t0.6534\t\nStroke\tYes versus no\t1.009 (0.875-1.164)\t0.9049\t\nNephropathy\tYes versus no\t1.276 (1.105-1.472)\t0.9049\t\nIschemic heart disease\tYes versus no\t1.093 (0.952-1.255)\t0.2082\t\nPeripheral arterial disease\tYes versus no\t1.077 (0.926-1.252)\t0.3348\t\nObesity\tYes versus no\t1.103 (0.820-1.483)\t0.5174\t\nDyslipidemia\tYes versus no\t0.768 (0.666-0.885)\t0.0003\t\nAcute pancreatitis\tYes versus no\t1.214 (0.852-1.729)\t0.2827\t\nAlcohol-related diagnoses\tYes versus no\t1.325 (1.010-1.739)\t0.0419\t\nCancer\tYes versus no\t2.831 (0.703-11.405)\t0.1433\t\nSulfonylurea\tYes versus no\t1.286 (1.085-1.526)\t0.0038\t\nMetformin\tYes versus no\t0.791 (0.678-0.923)\t0.0030\t\nMeglitinides\tYes versus no\t1.126 (0.958-1.323)\t0.1489\t\nAcarbose\tYes versus no\t1.049 (0.901-1.220)\t0.5386\t\nPioglitazone\tYes versus no\t1.021 (0.832-1.254)\t0.8407\t\nRosiglitazone\tYes versus no\t0.983 (0.834-1.158)\t0.8386\t\nInsulin\tYes versus no\t1.483 (1.264-1.739)\t<0.0001\t\nStatin\tYes versus no\t0.831 (0.723-0.955)\t0.0089\t\nFibrate\tYes versus no\t0.963 (0.837-1.108)\t0.6009\t\nAngiotensin converting enzyme inhibitor\tYes versus no\t1.115 (0.964-1.289)\t0.1442\t\nAngiotensin receptor blocker\tYes versus no\t1.129 (0.986-1.293)\t0.0783\t\nCalcium channel blocker\tYes versus no\t1.193 (1.020-1.394)\t0.0269\t\nAspirin\tYes versus no\t1.199 (1.040-1.383)\t0.0125\t\nTiclopidine\tYes versus no\t1.256 (0.981-1.608)\t0.0707\t\nClopidogrel\tYes versus no\t1.468 (1.190-1.812)\t0.0003\t\nDipyridamole\tYes versus no\t1.333 (1.166-1.525)\t<0.0001\t\nDISCUSSION\nThe present study confirmed the findings of an overall increased risk of heart failure hospitalization associated with sitagliptin use as observed in a previous analysis that also used the reimbursement database of the NHI [10]. The estimated overall hazard ratio of 1.262 (95% CI 1.167-1.364) in the present study (Table 2) was very close to the estimated 1.21 (95% CI 1.04-1.42) observed in the previous study [10]. Besides, the present study suggested that such an increased risk was mainly observed during a short duration of its use, i.e., with a cumulative duration of therapy < 1 year (Table 2). After long-term use, the risk was actually significantly reduced (Table 2). The present study also identified some predictive and some protective factors in association with heart failure hospitalization in sitagliptin users (Table 3). The predictive factors included an older age, a longer diabetes duration, male sex and use of insulin, sulfonylurea, calcium channel blockers and anti-platelet drugs (Table 3). On the other hand, the protective factors included dyslipidemia and use of metformin and statin (Table 3).\n\nA significantly higher risk of heart failure hospitalization associated with short-term rather than long-term use of sitagliptin (Table 2) was contradictory to the finding in the meta-analysis by Savarese et al. [6], which showed a significantly higher risk associated with long-term use of DPP-4 inhibitors for 29 weeks or more. Because this meta-analysis did not consider separate DPP-4 inhibitors, it is not known whether the discrepant findings could be due to the undifferentiation of the DPP-4 inhibitors in the meta-analysis.\n\nThe lower risk associated with sitagliptin after a longer duration of its exposure (Table 2) suggested a potentially protective effect of sitagliptin on heart failure. Such a protective effect could be supported by a recent study by dos Santos et al. conducted in human and experimental heart failure [17]. The investigators showed an increase of approximately 130% in circulating DPP-4 activity in patients with heart failure and an inverse correlation between serum DPP-4 activity and left ventricular ejection fraction in patients with heart failure [17]. Furthermore, long-term sitagliptin treatment for 6 weeks significantly improved cardiac performance and mitigated the development and progression of heart failure in rats [17]. Such a beneficial effect of sitagliptin on heart failure could also be demonstrated in another study using pigs as a model [18], but could not be similarly shown when vildagliptin was used in rats [19], suggesting that the protective effect of sitagliptin on heart failure might not be a class effect of DPP-4 inhibitors. However, the observed “protective effect” of sitagliptin after its long-term use may also be explained by reasons not directly related to a real protective effect of the drug on heart failure. First, the reduced risk of heart failure after long-term use might be resulted from the better long-term diabetes control in the users. Second, the lower risk after long-term sitagliptin therapy could be explained by a depletion of susceptible cases. Patients who were predisposed to heart failure might have exhibited the event soon after their use of sitagliptin, leaving the remaining in the cohort of long-term therapy less susceptible to heart failure.\n\nOn the other hand, the significantly higher risk of heart failure hospitalization within a short-term exposure to sitagliptin might either be due to the drug per se or due to some other reasons not necessarily indicating a cause-effect relationship. First, the care-givers would be more cautious in the search of severe adverse events when they prescribed a new drug to their patients, leading to a possible detection bias among new users. However, possible detection bias due to the awareness and alertness of heart failure related to the use of DPP-4 inhibitors was less likely because the two clinical trials (i.e., SAVOR-TIMI53 and EXAMINE) reporting an unexpectedly higher risk of heart failure hospitalization related to the use of saxagliptin and alogliptin were published in 2013 [1, 2] and the follow-up of the present study cohort was actually ended before this year. Second, although all standardized differences were < 10% and did not suggest a residual confounding from the differences in the baseline characteristics, 15 out of the 30 variables were significantly different between ever and never users of sitagliptin (Table 1). It is worthy to point out that many of the ever users of sitagliptin were characterized by significantly higher prevalence of risk factors of heart failure such as ischemic heart disease, chronic obstructive pulmonary disease, hypertension and use of thiazolidinediones (Table 1). Therefore, it is not known whether residual confounding from these potential risk factors or from some unmeasured risk factors could exert an effect on the observation of a significantly higher risk of heart failure in short-term users of sitagliptin (Table 2).\n\nThe discrepant risk association with regards to exposure duration is an interesting finding that has not been reported previously. Estimating an overall risk by lumping together all drug users into an exposure group without considering different durations of exposure would not provide full information and might not be adequate in data analyses. Studies mainly including patients within the first year of sitagliptin use may overestimate an overall risk, but studies including more patients with longer duration of exposure might find an attenuated relative risk and concluded with a neutral or even a protective effect.\n\nThe discrepant findings between the present study and the recently published TECOS clinical trial which showed a lack of increased risk of heart failure in the sitagliptin group [4] are worthy of discussion. First, the TECOS study is a clinical trial and the generalization of the findings should be limited to patients fitting the inclusion and exclusion criteria set in the trial. On the other hand, the present study mainly reflected a real world scenario. For example, in the TECOS, patients were recruited with a glycated hemoglobin level of 6.5% to 8.0% at enrollment [4]. However, in clinical practice in Taiwan, sitagliptin is mainly used as a second or third line therapy because of its higher cost in relative to other preexisting oral antidiabetic drugs. As a result, most patients would be prescribed sitagliptin only when other treatment modalities could not adequately control the blood glucose level, say with a glycated hemoglobin level of > 8.0%. Therefore, the observed outcomes derived from a clinical trial may not be necessarily the same when a medication is widely used in clinical practice in the real world. This discrepancy can also be supported by other observational studies previously conducted in Taiwan [10] and in the USA [8], both reporting a significantly higher risk of heart failure associated with sitagliptin use. Second, ethnicity difference may also partly explain the discrepant findings between the TECOS and the present study. While the present study recruited a more homogeneous group of patients, the TECOS trial was conducted mainly in a mixture of different ethnicities (67.9% white, 22.3% Asian, 3.0% black and 6.8% others). It has already been known that DPP-4 inhibitors may have a better efficacy on blood glucose lowering in the Asian populations than in the western people [20], suggesting that the adverse effects related to incretin-based therapy may also show ethnicity difference.\n\nThe identification of predictive and protective factors associated with heart failure hospitalization in sitgaliptin users may have some clinical implications. The predictive factors suggested that sitagliptin use should be closely observed for the potential risk of heart failure in patients with an older age, a longer diabetes duration, male sex and use of insulin, sulfonylurea, calcium channel blockers and anti-platelet drugs (Table 3). On the other hand, dyslipidemia and use of metformin and statin might show a protective effect (Table 3). It is not known whether the lower risk of heart failure associated with dyslipidemia could be due to the protective effect of statin, a lipid-lowering drug with well recognized cardiac protective effects commonly used in diabetic patients. Currently it remained difficult to say whether the positive association with some medications and the negative association with others could be due to the direct pharmacological effects of the medications or due to the indications or different disease severities related to their use. More studies are required to clarify the underlying mechanisms or explanations for the relationship with these baseline characteristics.\n\nIt is interesting that our previous studies also suggested that sitagliptin may increase the risk of acute pancreatitis [21], pancreatic cancer [22] and thyroid cancer [23] within one or two years of its initiation. The potential risk of these adverse outcomes associated with sitagliptin use have been previously reported and therefore a higher reporting rate might be expected due to clinical awareness and alertness, resulting in a detection bias. However, this could not be applied to the present study because the study period ended by the end of 2011, preceding the publication of most of the reports suggesting a potentially higher risk. There could also be a speculation on the reliability of the database on higher reporting rates of all types of cancer among patients who were initiated with sitagliptin. However, our unpublished analyses did not find such a significantly overall higher risk of other cancers among sitagliptin users, neither within one or two years after its initiation. Therefore, all of these pointed to a true link between sitagliptin use and the adverse outcomes including acute pancreatitis, pancreatic cancer, thyroid cancer and heart failure, especially during the initial period of its use. A similar observation of risk attenuation of these adverse outcomes after a longer duration of sitagliptin use [21–23] might be partly due to the depletion of susceptible cases.\n\nThere are some strengths in the study. First, we included all longitudinal data to cover the whole period since the availability of the database in 1996. Second, the large sample size representing the whole nation rendered the generalization of the findings to the whole population in a real world scenario. Third, the use of medical records reduced the bias related to self-reporting.\n\nThe limitations include a lack of laboratory data to support the diagnosis of heart failure. However, because the diagnosis of heart failure was made during hospitalization, the reimbursement for such hospitalization should be supported by laboratory data. Second, because no laboratory data were available to define the severity of heart failure, patients hospitalized with such a diagnosis might have represented those with more severe clinical symptoms. Third, the diabetes duration observed from the database may be underestimated because many patients with type 2 diabetes mellitus may remain undiagnosed for several years during the early phase of diabetes. Fourth, we did not have biochemical data such as blood levels of glucose and lipid profiles for evaluating their impacts. Fifth, this study could not evaluate the effects of other DPP4 inhibitors because only the sample size of sitagliptin users was large enough for evaluation.\n\nIn conclusions, the present study suggests a biphasic pattern in the association between sitagliptin use and heart failure hospitalization. Users with a cumulative duration < 1 year may show a significantly higher risk, but a significantly reduced risk can be seen in users with longer duration of exposure. This is the first study pointing out the potential protective effect of sitagliptin on heart failure after long-term use, suggesting that patients who have been using sitagliptin with a cumulative duration > 1 year should be kept on the medication to be benefited from its potentially protective effect on heart failure. Because spurious association could not be excluded among the short-term users, it remains to be clarified whether the significantly higher risk of heart failure among short-term users can be due to detection bias or residual confounding from the high prevalence of known risk factors of heart failure in the ever users of sitagliptin. The identification of some predictive and some protective baseline characteristics associated with sitagliptin-related heart failure is helpful for the physicians when they prescribe sitagliptin for blood glucose control to their patients.\n\nMATERIALS AND METHODS\nAn ethic review board of the National Health Research Institutes (NHRI) approved the study (approval number 99274). The identification information of each patient was scrambled, and written informed consent was not required according to local regulations.\n\nThe NHI was implemented since March 1995 and covers more than 99% of the Taiwanese population, with contracts covering 98% of the hospitals nationwide. The database keeps detailed records of the insurants' information of principal and secondary diagnostic codes, prescription orders, and claimed expenses from outpatient visits, emergency department visits, and hospital admission.\n\nFigure 1 shows the flowchart for creating a cohort of 1:1 matched pair sample of sitagliptin ever and never users from the NHI. The NHRI created a cohort of 120,000 newly diagnosed diabetic patients in each calendar year for a 12-year period from 1999 to 2010 from the whole nation. The longitudinal reimbursement records of these patients from 1996 to 2011 can be provided for academic research. A patient should not have a diagnosis of diabetes in the previous years when he/she was randomly selected into the cohort for each specific year. The definition of diabetes was based on one of the following two criteria: 1) Diagnosis of diabetes during an admission to the hospital or having been prescribed with antidiabetic drugs during hospitalization; or 2) In an outpatient setting within one year, a patient has been diagnosed as having diabetes for two or more times, or diagnosed as having diabetes for one time plus prescribed with antidiabetic drugs for one time. As a result, a total of 1,440,000 patients with newly diagnosed diabetes were available within these 12 years.\n\nFigure 1 Flowchart showing the procedures followed in creating a cohort of 1:1 matched pair sample of sitagliptin ever and never users from the NHI for the study\nNHRI: National Health Research Institutes, NHI: National Health Insurance.\n\nIn consideration that some patients might have been given insulin or oral antidiabetic drugs during an admission for some medical conditions but they might not be real cases of diabetes, patients who were recruited based on the criterion of having been prescribed with antidiabetic drugs during hospitalization but had not been followed at the outpatient clinics with a diagnosis of diabetes or had not received antidiabetic drugs at outpatient follow-up were first excluded. This resulted in a sample size of 1,183,187 patients. Patients who were alive on January 1, 2007 were recruited into the study by the following selection procedures. After exclusion of patients with duplicated identification number (n = 2,534), withdrawn from the NHI (n = 896), with a diagnosis of type 1 diabetes (n = 3,879), died before 2007 (n = 47,117), with a diagnosis of any cancer before 2007 (n = 150,824), with a diagnosis of heart failure before 2007 (n = 60,369), and ever use of saxagliptin (n = 3,884), vildagliptin (n = 2,540) and exenatide (n = 151, linagliptin and liraglutide were not available in Taiwan during the study period). As a result, a total of 924,823 patients were available. Among them, 85,859 patients had been newly prescribed with sitagliptin (ever users). To create a 1:1 matched pair sample of 85,859 patients who had not been treated with sitagliptin (never users), the methods described by Parsons based on 8 digits of PS derived from baseline characteristics by logistic regression were used [14]. These methods have also been used in our recently published papers [23, 24].\n\nThe International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) has been used during the study period and diabetes was coded 250.XX. Information of the first event of heart failure hospitalization (ICD-9-CM: 398.91, 402.11, 402.91, 404.11, 404.13, 404.91, 404.93 and 428) was linked from the hospitalization database.\n\nThe ICD-9-CM codes for the comorbidities were [25–29]: hypertension 401-405, chronic obstructive pulmonary disease (a surrogate for smoking) 490-496, stroke 430-438, nephropathy 580-589, ischemic heart disease 410-414, peripheral arterial disease 250.7, 785.4, 443.81 and 440-448, obesity 278, dyslipidemia 272.0-272.4, acute pancreatitis 577.0, alcohol-related diagnosis 291, 303, 535.3, 571.0-571.3, 980.0, and cancer 140-208. Medications included sulfonylurea, metformin, meglitinide, acarbose, pioglitazone, rosiglitazone, insulin, statin, fibrate, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, aspirin, ticlopidine, clopidogrel, and dipyridamole.\n\nThe baseline characteristics of sitagliptin never users and ever users were compared by Student's t test for age and diabetes duration and by Chi-square test for others. The crude incidence density of heart failure hospitalization was calculated for sitagliptin ever users and never users and for the tertiles of cumulative duration of sitagliptin therapy (months). The numerator for the incidence was the number of patients with the first event of heart failure hospitalization during follow-up, and the denominator was the person-years of follow-up. Follow-up started on January 1, 2007 and ended on December 31, 2011, at the time of the first event of heart failure hospitalization, or at the date of the last reimbursement record. In the lack of information on the mortality or migration status of the patients, the last reimbursement record may serve as a surrogate because these patients should be withdrawn from the NHI in Taiwan. Standardized difference for each baseline characteristic was calculated according to the recommendation of Austin and Stuart and a value of > 10% may indicate meaningful imbalance with potential confounding [15].\n\nThe treatment effect was estimated by using PS-weighting with the IPTW approach incorporated into a Cox regression [16]. Hazard ratios were estimated forever users versus never users, and for each tertile of cumulative duration of sitagliptin therapy compared to never users as referent.\n\nTo identify the predictive and protective characteristics related to sitagliptin-associated heart failure, patients ever treated with sitagliptin were selected for a Cox regression model. In this model heart failure hospitalization was treated as the dependent variable and independent variables included all baseline characteristics.\n\nAnalyses were conducted using SAS statistical software, version 9.3 (SAS Institute, Cary, NC). P < 0.05 was considered statistically significant.\n\nThe study is based in part on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health and managed by National Health Research Institutes (Registered number 99274). The interpretation and conclusions contained herein do not represent those of Bureau of National Health Insurance, Department of Health or National Health Research Institutes. The author wishes to thank Ms. Ting-Ting Chang for her excellent help in the conduction of statistical analyses.\n\nCONFLICTS OF INTERESTS\n\nNone.\n\nFUNDINGS\n\nThe study was supported by the Ministry of Science and Technology (MOST 103-2314-B-002-187-MY3) of Taiwan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n==== Refs\nREFERENCES\n1 Scirica BM Bhatt DL Braunwald E Steg PG Davidson J Hirshberg B Ohman P Frederich R Wiviott SD Hoffman EB Cavender MA Udell JA Desai NR SAVOR-TIMI 53 Steering Committee Investigators Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus N Engl J Med 2013 369 1317 26 23992601 \n2 White WB Cannon CP Heller SR Nissen SE Bergenstal RM Bakris GL Perez AT Fleck PR Mehta CR Kupfer S Wilson C Cushman WC Zannad F EXAMINE Investigators Alogliptin after acute coronary syndrome in patients with type 2 diabetes N Engl J Med 2013 369 1327 35 23992602 \n3 Monami M Dicembrini I Mannucci E Dipeptidyl peptidase-4 inhibitors and heart failure: a meta-analysis of randomized clinical trials Nutr Metab Cardiovasc Dis 2014 24 689 97 24793580 \n4 Green JB Bethel MA Armstrong PW Buse JB Engel SS Garg J Josse R Kaufman KD Koglin J Korn S Lachin JM McGuire DK Pencina MJ Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes N Engl J Med 2015 373 232 42 26052984 \n5 Iqbal N Parker A Frederich R Donovan M Hirshberg B Assessment of the cardiovascular safety of saxagliptin in patients with type 2 diabetes mellitus: pooled analysis of 20 clinical trials Cardiovasc Diabetol 2014 13 33 24490835 \n6 Savarese G Perrone-Filardi P D'Amore C Vitale C Trimarco B Pani L Rosano GM Cardiovascular effects of dipeptidyl peptidase-4 inhibitors in diabetic patients: A meta-analysis Int J Cardiol 2014 181C 239 44 \n7 Clifton P Do Dipeptidyl Peptidase IV (DPP-IV) Inhibitors Cause Heart Failure? Clin Ther 2014 36 2072 9 25453730 \n8 Weir DL McAlister FA Senthilselvan A Minhas-Sandhu JK Eurich DT Sitagliptin use in patients with diabetes and heart failure: a population-based retrospective cohort study JACC Heart Fail 2014 2 573 82 24998080 \n9 Tseng CH Lee KY Tseng FH An updated review on cancer risk associated with incretin mimetics and enhancers J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 2015 33 67 124 25803196 \n10 Wang KL Liu CJ Chao TF Huang CM Wu CH Chen SJ Yeh CM Chen TJ Lin SJ Chiang CE Sitagliptin and the risk of hospitalization for heart failure: A population-based study Int J Cardiol 2014 177 86 90 25499347 \n11 Ray WA Evaluating medication effects outside of clinical trials: new-user designs Am J Epidemiol 2003 158 915 20 14585769 \n12 Stricker BH Stijnen T Analysis of individual drug use as a time-varying determinant of exposure in prospective population-based cohort studies Eur J Epidemiol 2010 25 245 51 20358262 \n13 Suissa S Immortal time bias in pharmaco-epidemiology Am J Epidemiol 2008 167 492 9 18056625 \n14 Parsons LS Performing a 1:N case-control match on propensity score http://www.google.com.tw/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&ved=0CBsQFjAAahUKEwibi7HllcnIAhUDoJQKHVeZA9A&url=http%3A%2F%2Fwww2.sas.com%2Fproceedings%2Fsugi29%2F165-29.pdf&usg=AFQjCNFOHGWYu8E8Bn4-Bo1TUiJKtT987Q (last accessed October 17, 2015) \n15 Austin PC Stuart EA Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies Stat Med 2015 34 3661 79 26238958 \n16 Austin PC The performance of different propensity score methods for estimating marginal hazard ratios Stat Med 2013 32 2837 49 23239115 \n17 dos Santos L Salles TA Arruda-Junior DF Campos LC Pereira AC Barreto AL Antonio EL Mansur AJ Tucci PJ Krieger JE Girardi AC Circulating dipeptidyl peptidase IV activity correlates with cardiac dysfunction in human and experimental heart failure Circ Heart Fail 2013 6 1029 38 23894014 \n18 Gomez N Touihri K Matheeussen V Mendes Da Costa A Mahmoudabady M Mathieu M Baerts L Peace A Lybaert P Scharpé S De Meester I Bartunek J Vanderheyden M Dipeptidyl peptidase IV inhibition improves cardiorenal function in overpacing-induced heart failure Eur J Heart Fail 2012 14 14 21 22045924 \n19 Yin M Silljé HH Meissner M van Gilst WH de Boer RA Early and late effects of the DPP-4 inhibitor vildagliptin in a rat model of post-myocardial infarction heart failure Cardiovasc Diabetol 2011 10 85 21955567 \n20 Cho YM Incretin physiology and pathophysiology from an Asian perspective J Diabetes Investig 2015 6 495 507 \n21 Tseng CH Sitagliptin increases acute pancreatitis risk within 2 years of its initiation: A retrospective cohort analysis of the National Health Insurance database in Taiwan Ann Med 2015 47 561 9 26426676 \n22 Tseng CH Sitagliptin and pancreatic cancer risk in patients with type 2 diabetes Eur J Clin Invest 2016 46 70 9 26584246 \n23 Tseng CH Sitagliptin use and thyroid cancer risk in patients with type 2 diabetes Oncotarget 2016 3 28 10.18632/oncotarget.8399 [Epub ahead of print] \n24 Tseng CH Metformin may reduce oral cancer risk in patients with type 2 diabetes Oncotarget 2016 7 2000 8 10.18632/oncotarget.6626 26683519 \n25 Tseng CH Pioglitazone and bladder cancer: a population-based study of Taiwanese Diabetes Care 2012 35 278 80 22210574 \n26 Tseng CH Rosiglitazone may reduce thyroid cancer risk in patients with type 2 diabetes Ann Med 2013 45 539 44 24215589 \n27 Tseng CH Treatment with human insulin does not increase thyroid cancer risk in patients with type 2 diabetes Eur J Clin Invest 2014 44 736 42 24931333 \n28 Tseng CH Metformin significantly reduces incident prostate cancer risk in Taiwanese men with type 2 diabetes mellitus Eur J Cancer 2014 50 2831 7 25201464 \n29 Tseng CH Diabetes but not insulin increases the risk of lung cancer: a Taiwanese population-based study PLoS One 2014 9 e101553 24991802\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "7(38)",
"journal": "Oncotarget",
"keywords": "Taiwan; heart failure; hospitalization; incretin; sitagliptin",
"medline_ta": "Oncotarget",
"mesh_terms": "D000328:Adult; D000368:Aged; D015331:Cohort Studies; D048909:Diabetes Complications; D003924:Diabetes Mellitus, Type 2; D005260:Female; D006333:Heart Failure; D006760:Hospitalization; D006801:Humans; D007004:Hypoglycemic Agents; D015994:Incidence; D007348:Insurance, Health; D008297:Male; D008875:Middle Aged; D011336:Probability; D016016:Proportional Hazards Models; D012044:Regression Analysis; D000068900:Sitagliptin Phosphate; D013624:Taiwan",
"nlm_unique_id": "101532965",
"other_id": null,
"pages": "62687-62696",
"pmc": null,
"pmid": "27409676",
"pubdate": "2016-09-20",
"publication_types": "D016428:Journal Article",
"references": "26426676;23992601;25201464;23894014;14585769;24490835;22210574;24215589;23239115;26417406;25803196;24931333;26584246;26683519;27029076;22045924;20358262;23992602;18056625;26238958;26052984;25528528;21955567;24991802;25453730;24793580;24998080;25499347",
"title": "Sitagliptin and heart failure hospitalization in patients with type 2 diabetes.",
"title_normalized": "sitagliptin and heart failure hospitalization in patients with type 2 diabetes"
} | [
{
"companynumb": "TW-009507513-1607TWN008963",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SITAGLIPTIN PHOSPHATE"
},
"drugadditional": ... |
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