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"abstract": "OBJECTIVE\nTo assess the safety, maximum-tolerated dose (MTD), and dose-limiting toxicities (DLT), of motexafin gadolinium (MGd), given in combination with doxorubicin, in patients with advanced solid tumors.\n\n\nMETHODS\nThe combination of MGd and doxorubicin was administered every 28 days (cycle 1) and then every 21 days (subsequent cycles). The dose of MGd, given daily for 3 days, was escalated from 1.0 mg/kg/d to 3.3 mg/kg/d, while the dose of doxorubicin was held at 30 mg/m².\n\n\nRESULTS\nFifteen patients received 37 cycles of treatment, for a median of 2 cycles per patient (range 0-6 cycles). Three patients (20%) completed 6 cycles of therapy. The MTD was identified as MGd, 2 mg/kg/day and doxorubicin, 30 mg/m². Dose limiting toxicities included grade 3 hypertension, pneumonia, bacteremia, and elevated GGT. Serious adverse events also included pulmonary embolism and urinary tract infection requiring hospitalization. There was no exacerbation of cardiac toxicity. No patients attained a response to treatment. Six patients (54%) had stable disease. The median time to disease progression, or to last assessment, was 49 days (range 8-195 days).\n\n\nCONCLUSIONS\nThe combination of MGd and doxorubicin was fairly well tolerated. However, due to emerging preclinical data suggesting that MGd inhibits ribonucleotide reductase, further development of the combination of MGd plus doxorubicin is not recommended.",
"affiliations": "University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, WI 53792, USA. amt@medicine.wisc.edu",
"authors": "Traynor|Anne M|AM|;Thomas|James P|JP|;Ramanathan|Ramesh K|RK|;Mody|Tarak D|TD|;Alberti|Dona|D|;Wilding|George|G|;Bailey|Howard H|HH|",
"chemical_list": "D000970:Antineoplastic Agents; D008665:Metalloporphyrins; C437683:motexafin gadolinium; D004317:Doxorubicin",
"country": "United States",
"delete": false,
"doi": "10.1007/s10637-009-9364-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-6997",
"issue": "29(2)",
"journal": "Investigational new drugs",
"keywords": null,
"medline_ta": "Invest New Drugs",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D003710:Demography; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin; D005260:Female; D006801:Humans; D008297:Male; D008665:Metalloporphyrins; D008875:Middle Aged; D009369:Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "8309330",
"other_id": null,
"pages": "316-22",
"pmc": null,
"pmid": "19997959",
"pubdate": "2011-04",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "16481328;18760875;17112739;15627019;15867382;15388578;16146732;12829672;11595717;2845993;18977094;11283141;19121624;7388791;15990023;15315800",
"title": "Phase I trial of motexafin gadolinium and doxorubicin in the treatment of advanced malignancies.",
"title_normalized": "phase i trial of motexafin gadolinium and doxorubicin in the treatment of advanced malignancies"
} | [
{
"companynumb": "US-JNJFOC-20151010857",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MOTEXAFIN GADOLINIUM"
},
"drugadditional": null,
... |
{
"abstract": "This retrospective study investigated the role of antivascular endothelial growth factor agents (VEGF), ranibizumab, bevacizumab and pegaptanib sodium in patients with iris neovascularisation (INV), in which 9 eyes received intraocular injections for various ischaemic ocular conditions. Ocular sequelae included recurrence of rubeosis (n=2) and hyphaema (n=2). Systemic complication included one case of cerebrovascular accident. INV regressed in all cases from day one. INV recurrence occurred in 2 cases. The mean intraocular pressure of the study eyes decreased from 25.3 mmHg to 18.3 mmHg at one month. Five eyes are medication free. Visual acuity improved in 5 eyes. Four eyes achieved a Snellen visual acuity of 6/24 or better. We conclude that the use of intraocular anti-VEGF agents are safe and effective for inducing the regression of INV. Patients with multiple systemic risk factors should be counseled on stroke risk.",
"affiliations": "Universiti Kebangsaan Malaysia, Ophthalmology, Department of Ophthalmology, Hospital UKM, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Kuala Lumpur, Malaysia. maelynnbdr@gmail.com.",
"authors": "Bastion|M L C|ML|;Then|K Y|KY|;Faridah|H A|HA|;Mushawiahti|M|M|;Othmaliza|O|O|;Wong|H S|HS|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D042461:Vascular Endothelial Growth Factor A",
"country": "Malaysia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-5283",
"issue": "66(1)",
"journal": "The Medical journal of Malaysia",
"keywords": null,
"medline_ta": "Med J Malaysia",
"mesh_terms": "D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D006801:Humans; D007498:Iris; D008296:Malaysia; D012189:Retrospective Studies; D042461:Vascular Endothelial Growth Factor A",
"nlm_unique_id": "0361547",
"other_id": null,
"pages": "10-4",
"pmc": null,
"pmid": "23765135",
"pubdate": "2011-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The Adjunctive Use of Anti-vascular Endothelial Growth Factor Agents in the Management of Iris Neovascularisation in Malaysia.",
"title_normalized": "the adjunctive use of anti vascular endothelial growth factor agents in the management of iris neovascularisation in malaysia"
} | [
{
"companynumb": "MY-ROCHE-1760563",
"fulfillexpeditecriteria": "1",
"occurcountry": "MY",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RANIBIZUMAB"
},
"drugadditional": null,
"dru... |
{
"abstract": "Cor triatriatum sinistrum (CTS) is a congenital anomaly where the left atrium is divided into two compartments by a fibromuscular membrane. This report aims to add to the literature on a rare cardiac condition that can cause neurological morbidity. We report a case of a 19-year-old female with an infarct in the right middle cerebral artery (MCA) territory initially maintained on aspirin. Eighteen months later, she had recurrence of weakness, for which repeat transthoracic echocardiography (TTE) and re-evaluation of the first TTE demonstrated a hyperechoic membrane spanning the width of the left atrium, clinching the diagnosis of CTS. Despite anticoagulation with apixaban, she was admitted for a third stroke where she succumbed to hospital-acquired pneumonia. Among cases of CTS associated with stroke, anticoagulation and surgery were the main modes of treatment. This case has the longest follow-up and the first to demonstrate failure of antiplatelet therapy and anticoagulation.",
"affiliations": "Department of Neurosciences, Philippine General Hospital, University of the Philippines, Manila, Philippines.;Department of Medicine, Philippine General Hospital, University of the Philippines Manila, Manila, Philippines.;Department of Medicine, Philippine General Hospital, University of the Philippines Manila, Manila, Philippines.;Department of Neurology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA.;Department of Neurosciences, Philippine General Hospital, University of the Philippines, Manila, Philippines.;Department of Neurosciences, Philippine General Hospital, University of the Philippines, Manila, Philippines.",
"authors": "Diestro|Jose Danilo Bengzon|JDB|http://orcid.org/0000-0001-8450-2021;Regaldo|Joseph Justin Hipolito|JJH|;Gonzales|Eddieson Masangcay|EM|;Dorotan|Maria Kristina Casanova|MKC|;Espiritu|Adrian Isidro|AI|;Pascual|Jose Leonard Rivera|JLR|",
"chemical_list": "D000925:Anticoagulants; D001241:Aspirin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-219763",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "Cardiovascular Medicine; Neurology; Stroke",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000925:Anticoagulants; D001241:Aspirin; D003310:Cor Triatriatum; D004452:Echocardiography; D017809:Fatal Outcome; D005260:Female; D006325:Heart Atria; D006801:Humans; D020244:Infarction, Middle Cerebral Artery; D018810:Magnetic Resonance Angiography; D020768:Middle Cerebral Artery; D014057:Tomography, X-Ray Computed; D055815:Young Adult",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28790049",
"pubdate": "2017-08-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10524744;10979010;12807866;14261744;14777837;15148800;15360112;16946152;17882376;18143913;18984443;19571448;20656504;21029431;21560829;2222044;23949551;24354423;24630764;26597113;3762855;455431;5805986;7486462;8001302;9068919;9227708",
"title": "Cor triatriatum and stroke.",
"title_normalized": "cor triatriatum and stroke"
} | [
{
"companynumb": "PH-SUN PHARMACEUTICAL INDUSTRIES LTD-2017RR-152362",
"fulfillexpeditecriteria": "1",
"occurcountry": "PH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": null,
"drugadditional": "3",
"drugadministrationroute": "0... |
{
"abstract": "Approximately 15-20% of ulcerative colitis patients and 20-40% of those with Crohn's disease experience extraintestinal manifestations (EIMs) of their inflammatory bowel disease (IBD). Clinicians who treat IBD must manage EIMs affecting multiple organs that variably correlate with intestinal disease activity. Vedolizumab is a monoclonal antibody for the treatment of IBD with a gut-selective mechanism of action.\n\n\n\nThis report evaluates whether vedolizumab is an effective treatment of EIMs, given its gut-specific mechanism of action.\n\n\n\nWe report 8 case studies of patients with various EIMs, including pyoderma gangrenosum, peripheral arthralgia/arthritis, axial arthropathies, erythema nodosum, and uveitis, who received vedolizumab therapy.\n\n\n\nVedolizumab therapy was effective for pyoderma gangrenosum in ulcerative colitis, uveitis, erythema nodosum, polyarticular arthropathy, and ankylosing spondylitis/sacroiliitis but did not provide sustained benefit for the treatment of pyoderma gangrenosum in a patient with Crohn's disease.\n\n\n\nThese cases demonstrate the potential of vedolizumab as a treatment of EIMs in patients with IBD.",
"affiliations": "Borland-Groover Clinic, Jacksonville, FL, USA.;Lund University, Lund, Sweden.;University of Washington, Seattle, WA, USA.;Mount Sinai Hospital, New York, NY, USA.;Johns Hopkins Hospital, Baltimore, MD, USA.;Division of Gastroenterology, Department of Medicine, Lenox Hill Hospital, New York, NY, 10075, USA.;Robarts Clinical Trials, Robarts Research Institute, Western University, 100 Dundas Street, Suite 200, London, ON, N6A 5B6, Canada. Brian.feagan@robartsinc.com.",
"authors": "Fleisher|Mark|M|;Marsal|Jan|J|;Lee|Scott D|SD|;Frado|Laura E|LE|;Parian|Alyssa|A|;Korelitz|Burton I|BI|;Feagan|Brian G|BG|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D005765:Gastrointestinal Agents; C543529:vedolizumab",
"country": "United States",
"delete": false,
"doi": "10.1007/s10620-018-4971-1",
"fulltext": "\n==== Front\nDig Dis SciDig. Dis. SciDigestive Diseases and Sciences0163-21161573-2568Springer US New York 497110.1007/s10620-018-4971-1ReviewEffects of Vedolizumab Therapy on Extraintestinal Manifestations in Inflammatory Bowel Disease Fleisher Mark mfleisher@bgclinic.com 1Marsal Jan jan.marsal@med.lu.se 2Lee Scott D. leesd@uw.edu 3Frado Laura E. fradol@gmail.com 4Parian Alyssa aparian1@jhmi.edu 5Korelitz Burton I. 212-434-2063bkorelitzmd@gmail.com 6Feagan Brian G. (226) 270-7675Brian.feagan@robartsinc.com 71 Borland-Groover Clinic, Jacksonville, FL USA 2 0000 0001 0930 2361grid.4514.4Lund University, Lund, Sweden 3 0000000122986657grid.34477.33University of Washington, Seattle, WA USA 4 grid.416167.3Mount Sinai Hospital, New York, NY USA 5 0000 0001 2192 2723grid.411935.bJohns Hopkins Hospital, Baltimore, MD USA 6 0000 0001 2215 7314grid.415895.4Division of Gastroenterology, Department of Medicine, Lenox Hill Hospital, New York, NY 10075 USA 7 0000 0004 1936 8884grid.39381.30Robarts Clinical Trials, Robarts Research Institute, Western University, 100 Dundas Street, Suite 200, London, ON N6A 5B6 Canada 26 2 2018 26 2 2018 2018 63 4 825 833 3 10 2017 8 2 2018 © The Author(s) 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Background\nApproximately 15–20% of ulcerative colitis patients and 20–40% of those with Crohn’s disease experience extraintestinal manifestations (EIMs) of their inflammatory bowel disease (IBD). Clinicians who treat IBD must manage EIMs affecting multiple organs that variably correlate with intestinal disease activity. Vedolizumab is a monoclonal antibody for the treatment of IBD with a gut-selective mechanism of action.\n\nAims\nThis report evaluates whether vedolizumab is an effective treatment of EIMs, given its gut-specific mechanism of action.\n\nMethods\nWe report 8 case studies of patients with various EIMs, including pyoderma gangrenosum, peripheral arthralgia/arthritis, axial arthropathies, erythema nodosum, and uveitis, who received vedolizumab therapy.\n\nResults\nVedolizumab therapy was effective for pyoderma gangrenosum in ulcerative colitis, uveitis, erythema nodosum, polyarticular arthropathy, and ankylosing spondylitis/sacroiliitis but did not provide sustained benefit for the treatment of pyoderma gangrenosum in a patient with Crohn’s disease.\n\nConclusions\nThese cases demonstrate the potential of vedolizumab as a treatment of EIMs in patients with IBD.\n\nKeywords\nInflammatory bowel diseaseCrohn’s diseaseUlcerative colitisExtraintestinal manifestationsTakeda Pharmaceuticals U.S.A., Inc.issue-copyright-statement© Springer Science+Business Media, LLC, part of Springer Nature 2018\n==== Body\nIntroduction\nInflammatory bowel disease (IBD), which comprises ulcerative colitis (UC) and Crohn’s disease (CD), is characterized by chronic intestinal inflammation that results in mucosal ulceration and tissue damage [1]. Although the etiology of IBD is not yet fully elucidated, multiple factors including genetic susceptibility, environmental influences, the intestinal microbiota, and defective host defense mechanisms contribute to the pathological process [2]. Failure to adequately control inflammation frequently leads to bowel damage and disability [3], and many patients will eventually require surgery [4].\n\nEarly introduction of highly effective anti-inflammatory therapy has been shown to prevent IBD-related complications in both UC and CD [5]. In CD, treatment with tumor necrosis factor (TNF) antagonists has demonstrated increased rates of mucosal healing and clinical remission [6–8] and decreased rates of hospitalization and surgery [3]. Similar results have been obtained with infliximab therapy in UC. These findings have led to a fundamental change in the treatment paradigm for both diseases such that the recent STRIDE (Selecting Therapeutic Targets in Inflammatory Bowel Disease) guidelines have incorporated endoscopy, an objective marker of inflammation, as a treatment target in both conditions [9].\n\nExtraintestinal Manifestations\nDespite this nascent emphasis on controlling inflammation, little attention has been paid to the treatment of extraintestinal manifestations (EIMs) in IBD. Prevalence estimates currently suggest that EIMs are present in 15–20% of UC patients and 20–40% of CD patients [10]. EIMs adversely affect quality of life, and some EIMs, such as primary sclerosing cholangitis or venous thromboembolism, can be life-threatening [11].\n\nCurrently, the pathophysiology of EIMs is poorly understood; however, possible mechanisms include antigen leakage from the gut resulting in immune complex-mediated small vessel vasculitis and molecular mimicry, whereby shared epitopes between intestinal bacteria and antigens of the joints and skin trigger immune responses at extraintestinal sites [12]. Although the relationship between EIMs and intestinal disease activity varies depending on the type of EIM, in general, effective treatment of the local intestinal inflammation should control many EIMs of IBD.\n\nThe musculoskeletal, dermatologic, ocular, hepatopancreatobiliary, renal, and hematologic systems are common organ systems affected (Table 1); and of those, musculoskeletal EIMs are the most common [13]. Peripheral arthralgia/arthritis, which occurs with an estimated prevalence of 5–20% [14], can be classified as type 1 (pauciarticular) or type 2 (polyarticular). Type 1 disease mainly affects large joints, including the knees, ankles, wrists, and elbows, and usually correlates with IBD activity [14]. Type 2 mainly affects small joints with a symmetrical distribution, including the metacarpophalangeal and interphalangeal joints, and generally does not correlate with luminal inflammation [14].Table 1 Common extraintestinal manifestations\n\nSite\tPrevalence\tManifestation\tCorrelates with bowel inflammation?\t\nMusculoskeletal\t5–20% [14]\tPeripheral arthralgia/arthritis\tType 1 (large joints)\tYes [14]\t\nType 2 (small joints)\tNo [14]\t\n5–12% [15]\tAxial arthropathies\tAnkylosing spondylitis\tNo [16]\t\nIsolated sacroiliitis\tNo [16]\t\nDermatologic\t2–34% [13]\tErythema nodosum\tYes [25]\t\n\tPyoderma gangrenosum\tNo [25]\t\n13% [20]\tHidradenitis suppurativa\tYes [20]\t\nOcular\t0.3–5% [13]\tEpiscleritis\tYes [25]\t\n\tUveitis\tCase dependent [28]\t\nHepatopancreatobiliary\t30% [11]\tAbnormal liver chemistry\tCase dependent [11]\t\n13–34% [13]\tGallstones\tNo [11]\t\n2–5% [13]\tPrimary sclerosing cholangitis\nBile duct carcinoma\nDrug-induced liver injury\nPancreatitis\tCase dependent [25]\t\nMetabolic\t20–50% [11]\tLow bone mass/osteoporosis\tCase dependent [11]\t\nRenal\t6–23% [13]\tKidney stones\tCase dependent [13]\t\nHematologic\t1.4–3.3% [11]\tThromboembolism\tYes [11]\t\n\n\n\nAxial arthropathies, a second type of musculoskeletal EIM, have a prevalence between 5 and 12% (Table 1) [15]. Axial arthropathies include ankylosing spondylitis, a systemic inflammatory disease that affects the sacroiliac joints, the spine, and potentially other joints, but may also present as isolated sacroiliitis. Both versions usually do not correlate with intestinal IBD activity [16]. TNF antagonists are highly effective treatment for ankylosing spondylitis [17]. Although the European Crohn’s and Colitis Organization (ECCO) currently recommends that TNF antagonist therapy be used early in IBD patients with axial arthritis and for other musculoskeletal EIMs that are refractory to nonsteroidal anti-inflammatory drugs [11], only a few studies have investigated the use of these agents in IBD-related arthritides. A sub-analysis of the CHARM trial, including 420 CD patients with arthritis and arthralgia symptoms at baseline, showed that 70 of the 281 patients (24.9%) treated with adalimumab were free of arthritis and arthralgia after 56 weeks of therapy compared with 11 of the 139 patients (7.9%) treated with placebo [18].\n\nDermatologic EIMs include a broad spectrum of skin diseases, and it is not uncommon for patients to develop multiple manifestations concurrently during the natural course of IBD. Two major immune-mediated forms of dermatologic EIMs are erythema nodosum (EN) and pyoderma gangrenosum (PG) [19]. In addition, hidradenitis suppurativa affects about 13% of IBD patients and is characterized by painful, inflamed skin follicles commonly found in the axillae, inguinal, and anogenital areas [20]. Psoriasis is another skin disease that is common among IBD patients. The prevalence of psoriasis in the general population is approximately 1.5% [21], and patients with IBD have a sixfold risk of developing the disease [22]. As is the case for spondyloarthropathies, TNF antagonists are highly effective therapy for psoriasis. However, some patients develop psoriasiform lesions, typically on the scalp, hands, and feet following prolonged treatment with these drugs. In many cases, treatment requires withdrawal of the TNF antagonist and switching to another class of agent, typically ustekinumab or vedolizumab.\n\nEN, which affects 15% of CD and 10% of UC patients [23], is a small vessel vasculitis that results in panniculitis. The lesions typically present as inflamed nodules of 1 cm to 5 cm in diameter on the lower limbs and occasionally on the arms and trunk [23]. Treatment of EN usually consists of corticosteroids and intensification of medical therapy to control intestinal disease. A strong correlation exists between the presence of EN and intestinal disease activity.\n\nPG is less common, occurring in 0.4–2% of IBD patients, and is usually more severe than EN [24]. Pathologically, PG is characterized by full thickness necrosis of the skin due to vasculitis. The disease manifests as nodules that evolve into deep ulcerations typically on the shins but can develop anywhere on the skin [23]. PG is more common in UC than CD. Unlike EN, PG is normally independent of luminal IBD disease activity [25]. Although ECCO guidelines suggest corticosteroids as a first-line therapy for PG, severe cases require treatment with immunosuppressives such as azathioprine, TNF antagonists, or calcineurin inhibitors [11]. A small (n = 13) randomized controlled trial for the treatment of PG showed 6 (46%) of the infliximab treated patients improved compared with only 1 of 17 (6%) patients assigned to placebo [26].\n\nOcular complications include episcleritis and uveitis and are often present concurrently with other EIMs [27]. Episcleritis, which is more common in CD than in UC, often correlates with intestinal disease activity [25] and presents with hyperemia, irritation, burning, and tenderness [28]. Uveitis is less common than episcleritis, and the association with IBD activity is variable. Patients with uveitis present with ocular pain, blurred vision, photophobia, and headaches [28]. While some cases of episcleritis are self-limiting, the risk of blindness associated with uveitis mandates ophthalmologic referral and prompt initiation of therapy [28]. ECCO guidelines currently recommend topical corticosteroids for symptomatic treatment and systemic corticosteroids or immunosuppressives, including biologics, in severe or resistant cases [11, 29].\n\nVedolizumab for the Treatment of EIMs\nVedolizumab is unique among biologics used to treat IBD because it specifically targets the gastrointestinal tract [30]. Vedolizumab binds to the α4β7 integrin that is expressed on activated gut-homing T lymphocytes, and blocks the interaction of α4β7 and mucosal addressin cell adhesion molecule 1 (MAdCAM-1) [31]. MAdCAM-1 is preferentially expressed on the endothelium of blood vessels in the gastrointestinal tract. The gastrointestinal tract-specific interaction between α4β7 integrins and MAdCAM-1 allows for gut-targeted therapy, thereby likely reducing side effects associated with systemic immunosuppression.\n\nThe gut-selective mode of action of vedolizumab has demonstrated efficacy in the treatment of UC and CD in the phase 3 GEMINI 1 [32] and GEMINI 2 [33] studies, respectively. An integrated summary of 6 phase 2 and phase 3 vedolizumab trials also provided evidence for the safety of vedolizumab, which included a low incidence of the infectious side effects that are typically associated with non-selective treatments [34].\n\nAlthough the GEMINI studies were not powered to assess EIMs, post hoc analyses of the GEMINI 2 CD data indicated a potential benefit with vedolizumab in resolving symptoms of arthralgias. In these analyses, EIMs were evaluated post hoc and defined by the CD Activity Index (CDAI) complications component as the presence of arthritis/arthralgia, iritis/uveitis, EN, PG, aphthous stomatitis, or fever. Resolution of EIMs was defined by the absence of CDAI complications at each post-baseline study visit during the 52-week study [35]. Kaplan–Meier estimates for the resolution of these events were 18% at week 26 and 43% at week 52 in vedolizumab-treated patients (compared with 4 and 23% in those assigned to placebo, respectively) with a hazard ratio of 1.84 (95% confidence interval, 0.91–3.71) [35]. Analysis of these data also revealed that patients who received vedolizumab were 32% more likely to achieve sustained resolution of arthritis/arthralgia and 21% less likely to have a worsening or new occurrence than those assigned to placebo [36]; however, few descriptions regarding the efficacy of vedolizumab on EIMs based on real-world clinical experience have been published.\n\nHerein, we present 8 cases describing our clinical experience with vedolizumab for the treatment of IBD patients who present with various EIMs including peripheral arthralgia/arthritis, axial arthropathies, PG, EN, and uveitis (Table 2).Table 2 Cases\n\n\tAge\tIBD\tEIM\tCorrelates with IBD?\tConcomitant medications\tOutcome of vedolizumab treatment\t\nCase 1\t50\tCD\tAnkylosing spondylitis and sacroiliitis\tNo\tNone\tResolved 5 months into vedolizumab treatment\t\nCase 2\t44\tCD\tPolyarthritis (back and knees)\tYes\tBudesonide\tResolved 4 months into vedolizumab treatment\n2 years into vedolizumab treatment, knee pain remains resolved, back pain has returned\t\nCase 3\t34\tUC\tJoint and back pain\tYes\tNone\tResolved 1 month into vedolizumab treatment\t\nCase 4\t18\tUC\tPolyarticular arthropathy\tNo\tMesalamine\tResolved after third dose of vedolizumab\t\nCase 5\t46\tCD\tEN\tYes\tMesalamine\tResolved after third dose of vedolizumab\t\nCase 6\t24\tUC\tPG\tNo\tNone\tResolved after sixth dose of vedolizumab\t\nCase 7\t87\tCD\tPG\tNo\tMethotrexate\tPG improved but not resolved after 6 months\nPG resolved after 4 months of increasing infusion frequency to every 4 weeks\nRecurrent PG 9 months after increasing infusion frequency\nPG at pre-vedolizumab severity 12 months after increasing infusion frequency\nVedolizumab discontinued, PG resolved after treatment with ustekinumab\t\nCase 8\t24\tUC\tUveitis\tCase dependent\tMesalamine\tResolved after third dose of vedolizumab\t\nCD Crohn’s disease, EIM extraintestinal manifestation, EN erythema nodosum, IBD inflammatory bowel disease, PG pyoderma gangrenosum, UC ulcerative colitis\n\n\n\n\nCases\nCase 1\nA 50-year-old male with CD diagnosed in 1992 developed ankylosing spondylitis and sacroiliitis in 2002. The sacroiliitis presented with edema in the lowest sacral segment and the highest coccyx segment (Fig. 1). Prior treatment consisted of infliximab from 2002 to 2014, prednisolone for 2 months between 2012 and 2013, and azathioprine from 2007 to 2014. Infliximab and azathioprine were discontinued in 2014 because of recurrent peritonsillar abscesses, infectious keratoconjunctivitis, acne causing skin abscesses, and failure to achieve symptomatic remission. The patient then initiated treatment with vedolizumab. At the time, the patient had 3–4 bowel movements per day with some mucus, a fecal calprotectin concentration of 722 mg/kg, and primary symptoms of back pain, stiffness, and joint pain. Five months after initiation of treatment with vedolizumab, these symptoms resolved, and the patient had 1 bowel movement per day without mucus and a fecal calprotectin concentration that had decreased to 33 mg/kg. Overall, CD symptoms improved and were well controlled throughout vedolizumab treatment. One year after resolution of symptoms, the patient experienced acne-like skin lesions on the face, which were diagnosed as rosacea that immediately resolved with tetracycline treatment.Fig. 1 MRI findings of the 50-year-old male in case 1 before treatment. Arrows in the axial MR image of the sacroiliac joints indicate articular irregularities and periarticular edema as signs of sacroiliitis\n\n\n\nCase 2\nA 44-year-old male with CD initially diagnosed in 2009 developed polyarthritis in 2010. He had also been experiencing back pain since 1991. Prior treatments included prednisolone for 2 months in 2009 and 1 month in 2010, budesonide for 1 month in 2009 and 2 months in 2015, methotrexate for 2 months in 2010 (discontinued because of diffuse skin rash), azathioprine for 1 week in 2009 (discontinued because of pancreatitis), adalimumab for 1 month in 2010 (discontinued because of swollen and painful joints), sulfasalazine for 1 month in 2011 (discontinued because of lack of response), and natalizumab from 2011 to 2014.\n\nNatalizumab was effective in controlling both the luminal symptoms and the polyarthritis; however, it was discontinued for safety concerns because the patient was positive for antibodies to the John Cunningham (JC) virus. After discontinuation, the patient presented with back pain likely caused by degenerative changes and knee pain from arthritis. Intestinal symptoms included 4–5 bowel movements per day with a small amount of blood and mucus and moderate abdominal pain. Vedolizumab treatment was initiated in 2014, and 4 months later all of his arthritic complaints had resolved. Although some back pain returned 2 years after initiation of treatment, the patient’s knee pain remained resolved. Furthermore, the patient’s stool frequency had improved to 2 loose stools per day with no blood or abdominal pain. It is noteworthy that this patient developed a perianal abscess that was drained in 2015 and a perianal fistula that was resected in 2016. It is unclear whether a causal relationship exists between vedolizumab and these events.\n\nCase 3\nA 34-year-old male with UC diagnosed in 2012 presented with joint and back pain in 2013. The pain mainly affected his back; however, he also had peripheral arthritis type 1 with severe pain in his hips, knees, and muscles. No diagnosis of sacroiliitis was confirmed despite MR imaging of the lumbosacral spine and pelvis. Prior treatments included prednisolone for 2 months in 2013, mesalamine for 1 week in 2013 (discontinued because of myocarditis), infliximab for 14 months between 2013 and 2014 (discontinued because of lack of efficacy and development of antidrug antibodies), and golimumab for 7 months between 2014 and 2015 (discontinued because of insomnia and migraine).\n\nVedolizumab treatment was initiated in 2015, and after 1 month the patient’s back and joint pain resolved. However, for the first 5 months he received vedolizumab, the patient experienced arthralgias in both his back and peripheral joints approximately 5 days before the vedolizumab infusions. One year after resolution of symptoms, the patient developed pityriasis rosea on his abdomen, which resolved spontaneously within 2 months without treatment. The patient continues to be in remission on vedolizumab therapy.\n\nCase 4\nAn 18-year-old female with UC diagnosed in 2014 had polyarticular arthropathy diagnosed in 2016. At the time of presentation, the patient was being treated with mesalamine and was naïve to corticosteroids.\n\nAlthough a definitive diagnosis of UC was not made until 2016, the patient had been experiencing arthralgias in her hands and knees since her initial presentation. Colonoscopy showed no active disease, and her C-reactive protein (CRP) and fecal calprotectin concentrations were normal; however, random colon biopsies revealed mildly active histopathologic disease. Although the entire colon appeared to be normal on endoscopic examination, histological evaluation revealed mild-to-moderate active disease. Characteristics of mild-to-moderate chronic disease, including cryptitis, crypt abscesses, mild-to-moderate mucosal ulceration, and moderate crypt architectural distortion, were observed. The patient opted to initiate vedolizumab after being offered the options of treatment with corticosteroid, immunosuppressives, or TNF antagonists. The patient noted that the joint pains resolved completely after the third induction dose of vedolizumab.\n\nCase 5\nA 46-year-old female with CD diagnosed in 2005 received multiple courses of corticosteroid therapy resulting in initiation of azathioprine. However, this agent was discontinued because pancreatitis developed within 2 weeks of treatment. Although infliximab monotherapy was started, it was not possible to provide continuous treatment for insurance reasons. In 2015, the patient experienced a rash and shortness of breath following re-initiation of infliximab and the medication was discontinued.\n\nIn 2016, the patient presented with right lower quadrant pain and increasingly frequent non-bloody stools. Physical examination revealed right lower quadrant tenderness and a questionable mass. Tender, raised red nodules of EN were present on the extensor surfaces of both tibias. Her white blood cell (WBC) count was 14.6 × 109/L, erythrocyte sedminentation rate (ESR) was 34 mm/h, and the serum CRP concentration was 6 mg/L. Stool calprotectin concentrations were elevated. Magnetic resonance enterography showed active inflammation of the terminal ileum. A colonoscopy to the terminal ileum revealed a normal colon examination, but multiple ulcers were present in the terminal ileum. Biopsies from the ileum were consistent with active CD, with a single non-caseating granuloma demonstrated.\n\nTreatment with vedolizumab was initiated, and resolution of the skin lesions followed the third infusion of the drug. The abdominal pain resolved completely after the fifth dose. The CRP, ESR, and stool calprotectin values were also normal after the fifth dose. The patient continued treatment with vedolizumab, and mesalamine was discontinued. Repeat endoscopy revealed a normal colon and ileum; however, the ileocecal valve was noted to be deformed and mildly stenotic. Biopsies of the colon and valve were normal, and biopsies of the ileum revealed mild enteritis.\n\nCase 6\nA 24-year-old male with comorbid osteoporosis and diabetes, who was diagnosed with UC in 1998, presented with PG in 2016. Prior treatments were 6-mercaptopurine, mesalamine, corticosteroids, and multiple TNF antagonists. The patient underwent a colectomy and permanent ileostomy in 2012.\n\nIn 2016, the patient presented with a peristomal ulceration. The lesion had irregular borders and was diagnosed by a dermatologist as PG. The patient was positive for anti-saccharomyces cerevisiae antibodies (ASCA) and anti-neutrophil cytoplasmic antibodies (ANCA). The patient deferred corticosteroid treatment because of his osteoporosis. Small bowel was normal by endoscopy and video capsule endoscopy. The patient began vedolizumab therapy in 2016, and the lesion resolved after the sixth dose. The patient remains on vedolizumab and has been lesion free for 1 year.\n\nCase 7\nAn 87-year-old patient with a history of CD underwent an end ileostomy in 1972, and in 2014, he developed peristomal PG. The patient was treatment naïve since surgery, CD symptoms were well controlled, and luminal disease was not present at the time of PG presentation. Treatment with infliximab and methotrexate was commenced in 2015, leading to improvement in PG. However, 6 months after initiation of treatment, the patient developed a diffuse rash and infliximab was discontinued. Subsequently, the peristomal ulcer worsened. After a period without any biologic therapy, the patient began treatment with vedolizumab and continued methotrexate. Six months later, the PG had improved but was not resolved. Although PG improved with maintenance infusions dosed every 8 weeks, it began to worsen 4–5 weeks after each infusion. In response, treatment was intensified to an infusion every 4 weeks, which led to complete healing of PG after 4 months.\n\nNine months into the adjusted vedolizumab infusion schedule, the patient began to experience recurrent PG. Three months later, PG worsened to the severity level exhibited before the initiation of vedolizumab. The patient discontinued vedolizumab and began treatment with ustekinumab in 2017 and achieved complete healing.\n\nCase 8\nA 24-year-old male with UC diagnosed in 2014, following presentation with bloody diarrhea that required hospitalization, developed uveitis in 2016. After intravenous corticosteroid induction therapy, the patient received mesalamine for maintenance or remission, which was successful for 2 years. In 2016, the patient presented with headaches, bilateral ocular pain, and blurred vision without symptoms of bloody diarrhea or abdominal cramps. Although the stool fecal calprotectin concentration was within the normal range, the CRP concentration was 14 mg/L and ESR was 64 mm/h. An initial colonoscopy revealed moderately active pancolitis, and biopsies confirmed the endoscopic findings. The patient’s ophthalmologic assessment revealed anterior chamber uveitis. Treatment with oral prednisone 40 mg daily for 2 weeks was initiated with tapering by 5 mg weekly. The patient developed recurrent symptoms when the prednisone dose was reduced to 15 mg. At this time, a colonoscopy revealed mild disease of the rectum and sigmoid, which was confirmed by biopsies.\n\nSubsequently, treatment with vedolizumab was initiated. Corticosteroid tapering was resumed after the third dose of vedolizumab. The patient had no recurrence of uveitis and was off prednisone 1 year later, when a repeat colonoscopy showed a normal mucosa. Biopsies confirmed the absence of active histopathologic inflammation.\n\nDiscussion\nThe occurrence of EIMs with IBD is an important challenge for clinicians who treat IBD. These entities are relatively common and contribute substantially to the burden of illness of both CD and UC. Very little high-quality research has been conducted into the pathogenesis, epidemiology, or therapy of these conditions. Consequently, many important gaps exist in our approach to the management of EIMs. Although conventional wisdom is that some of the individual EIMs, such as arthralgias, track closely with the presence of luminal disease activity, whereas others, such as sacroiliitis, follow an independent course, this dogma can be challenged.\n\nIn keeping with this notion, some of the cases presented in this paper describe patients with quiescent gastrointestinal tract disease and continuing symptoms of arthralgias. Alternatively, cases of uveitis and sacroiliitis are depicted that resolve with more intense management of intestinal disease. Even though these cases cannot be considered strong scientific evidence to refute the established relationships between EIMs and disease activity, the classic studies that have previously evaluated this question did not rigorously evaluate patients’ luminal disease activity by endoscopy, nor did they assess EIMs using objective or qualitative measures. These cases are valuable in that they underscore the need to further examine the relationship between intestinal disease activity and EIM severity using rigorous methodologies.\n\nTNF antagonists are thought to be effective for the treatment of EIMs, and a systematic review that included 9 interventional, 7 open-label, and 13 noninterventional studies concluded that they are beneficial for the treatment of musculoskeletal, cutaneous, and ocular manifestations [37]. Data from the CARE study, a large multicenter open-label phase 3 trial in patients with moderately to severely active CD, show that after 20 weeks of adalimumab treatment in 497 patients with baseline EIMs, 79% had resolution of at least one EIM and 51% were free of EIM signs and symptoms [38]. A multinational phase 3 trial has also shown that adalimumab is effective in treating idiopathic uveitis by reducing both inflammation and visual impairment [13]. For PG, specifically, infliximab demonstrated complete healing of skin lesions in a retrospective study of 13 patients with IBD and medically refractory PG; 3 patients had a complete response to only induction infliximab therapy, while 10 patients required infusions every 4–12 weeks for maintained PG healing [26, 39].\n\nAlthough TNF antagonists are beneficial for the management of EIMs, these agents are not uniformly effective, are poorly tolerated in some patients, and frequently become ineffective owing to sensitization or other poorly defined mechanisms. Our observations here suggest that vedolizumab may be an effective treatment option for the management of EIMs, especially those that track closely with luminal disease. In this case series, vedolizumab therapy was effective for PG in UC, uveitis, EN, polyarticular arthropathy, and ankylosing spondylitis/sacroiliitis, but did not provide sustained benefit for the treatment of PG in CD. Notably, most of these patients had good control of their luminal IBD, which suggests that control of intestinal inflammation may be critical for the management of EIMs. The efficacy of vedolizumab in treating EIMs that are known to correlate with disease is not surprising, as analysis of the GEMINI 2 clinical trial data showed that patients treated with vedolizumab were 32% more likely to achieve sustained resolution of arthritis/arthralgia compared with placebo [40]. However, the cases described herein of patients with EIMs that were traditionally thought to be independent of bowel disease, such as PG and axial spondyloarthritis (SpA), are interesting. These results are consistent with a recent study conducted by Orlando and colleagues [41] in 53 patients with IBD-associated SpA, the majority of whom had failed to respond to a TNF antagonist and were corticosteroid dependent. Of the 14 patients with active SpA in this study, 6 patients demonstrated a strong clinical benefit after initiation of vedolizumab treatment. In another observational study, a correlation was shown between an improvement in symptoms and decrease in MR-defined bone marrow edema and gut inflammation in patients with active SpA [42].\n\nIn summary, the findings of these cases highlight the need to further examine the relationship between intestinal disease activity and EIMs and suggest that vedolizumab has a role in the management of these patients. Given the limited data available, large-scale cohort studies and randomized controlled trials that employ objective measures of inflammation are needed before these questions can be answered definitively.\n\nMedical writing assistance was provided by Michael D’Ecclessis, Ph.D., and Martina Schwarzkopf, Ph.D., of inVentiv Medical Communications and funded by Takeda Pharmaceuticals U.S.A., Inc.\n\nCompliance with ethical standards\nConflict of interest\nDr. Feagan has received grant support from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Roche, Genentech, J&J, Janssen, Millennium, Pfizer, Receptos, Tillotts, and UCB and served as a consultant or advisory board member for AbbVie, ActoGeniX, Akros, Albireo, Amgen, AstraZeneca, Avaxia Biologics, Avir Pharma, Baxter Healthcare Corp, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, enGene, Ferring Pharmaceuticals, Galapagos, Genentech/Roche, GiCare Pharma, Gilead, Given Imaging, GSK, Inception IBD Inc, Ironwood Pharmaceuticals, J&J, Janssen, Japan Tobacco, Kyowa Hakko Kirin Co Ltd, Lexicon, Lilly, Lycera Biotech, Merck, Mesoblast Ltd, Millennium, Nektar, Nestlé, Novartis, Novo Nordisk, Pfizer, Prometheus Therapeutics & Diagnostics, Protagonist, Receptos, Salix, Shire, Sigmoid Pharma, Synergy Pharmaceuticals Inc, Takeda, Teva Pharmaceutical Industries Ltd, TiGenix, Tillotts, UCB Pharma, Vertex Pharmaceuticals, VHsquared Ltd, Warner Chilcott, Wyeth, Zealand Pharma, and Zyngenia. Dr. Marsal has received grants from the Healthcare Region of Southern Sweden, Skane University Hospital, and the Swedish government; grants and personal fees from Abbvie, Ferring, Hospira; and personal fees from Bristol-Myers Squibb, Takeda and Tillotts. Dr. Lee has received grant and research support from AbbVie, Arena, Atlantic, Celgene, Gilead Sciences, Janssen, Pfizer, Salix, Shield, Takeda, Tetherex, UCB Pharma and has performed consulting for Arena, Celgene, Celltrion Healthcare, Cornerstones, Eli Lilly and Company, Janssen, Mesoblast, Pfizer, Salix, Takeda, and UCB Pharma. Dr. Fleisher has served on the speaker bureau for Janssen and Takeda. Drs. Korelitz, Frado, and Parian have nothing to disclose.\n\nInformed consent\nA written informed consent was obtained from patient cases 1, 2, 3, 4, 5, 6, and 8. Case 7 was de-identified and was in compliance with University of Washington Medical Center’s IRB, which does not require an informed consent for single case reports of de-identified patients.\n==== Refs\nReferences\n1. Dulai PS Singh S Casteele NV Boland BS Sandborn WJ How will evolving future therapies and strategies change how we position the use of biologics in moderate to severely active inflammatory bowel disease Inflamm Bowel Dis 2016 22 998 1009 10.1097/MIB.0000000000000661 26835982 \n2. Silva FA Rodrigues BL Ayrizono ML Leal RF The immunological basis of inflammatory bowel disease Gastroenterol Res Pract 2016 2016 2097274 10.1155/2016/2097274 28070181 \n3. Colombel JF Narula N Peyrin-Biroulet L Management strategies to improve outcomes of patients with inflammatory bowel diseases Gastroenterology 2017 152 351–361 e355 \n4. Frolkis AD Dykeman J Negron ME Risk of surgery for inflammatory bowel diseases has decreased over time: a systematic review and meta-analysis of population-based studies Gastroenterology 2013 145 996 1006 10.1053/j.gastro.2013.07.041 23896172 \n5. Moss AC Optimizing the use of biological therapy in patients with inflammatory bowel disease Gastroenterol Rep (Oxf) 2015 3 63 68 10.1093/gastro/gou087 25567472 \n6. Colombel JF Sandborn WJ Reinisch W Infliximab, azathioprine, or combination therapy for Crohn’s disease N Engl J Med 2010 362 1383 1395 10.1056/NEJMoa0904492 20393175 \n7. Colombel JF Rutgeerts PJ Sandborn WJ Adalimumab induces deep remission in patients with Crohn’s disease Clin Gastroenterol Hepatol 2014 12 414 422.e5 10.1016/j.cgh.2013.06.019 23856361 \n8. Schreiber S Reinisch W Colombel JF P178 early Crohn’s disease shows high levels of remission to therapy with adalimumab: sub-analysis of CHARM J Crohn’s Colitis Suppl 2007 1 49 10.1016/S1873-9954(07)70190-8 \n9. Peyrin-Biroulet L Sandborn W Sands BE Selecting therapeutic targets in inflammatory bowel disease (STRIDE): Determining therapeutic goals for treat-to-target Am J Gastroenterol 2015 110 1324 1338 10.1038/ajg.2015.233 26303131 \n10. Lakatos PL Lakatos L Kiss LS Peyrin-Biroulet L Schoepfer A Vavricka S Treatment of extraintestinal manifestations in inflammatory bowel disease Digestion 2012 86 Suppl 1 28 35 10.1159/000341950 23051724 \n11. Harbord M Annese V Vavricka SR The first European evidence-based consensus on extra-intestinal manifestations in inflammatory bowel disease J Crohns Colitis 2016 10 239 254 10.1093/ecco-jcc/jjv213 26614685 \n12. Bhagat S Das KM A shared and unique peptide in the human colon, eye, and joint detected by a monoclonal antibody Gastroenterology 1994 107 103 108 10.1016/0016-5085(94)90066-3 8020652 \n13. Levine JS Burakoff R Extraintestinal manifestations of inflammatory bowel disease Gastroenterol Hepatol (NY) 2011 7 235 241 \n14. Orchard TR Wordsworth BP Jewell DP Peripheral arthropathies in inflammatory bowel disease: their articular distribution and natural history Gut 1998 42 387 391 10.1136/gut.42.3.387 9577346 \n15. Voulgari PV Rheumatological manifestations in inflammatory bowel disease Ann Gastroenterol 2011 24 173 180 24713717 \n16. Atzeni F Ardizzone S Bertani L Antivalle M Batticciotto A Sarzi-Puttini P Combined therapeutic approach: inflammatory bowel diseases and peripheral or axial arthritis World J Gastroenterol 2009 15 2469 2471 10.3748/wjg.15.2469 19468996 \n17. van der Heijde D Kivitz A Schiff MH Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, placebo-controlled trial Arthritis Rheum 2006 54 2136 2146 10.1002/art.21913 16802350 \n18. Schwartz D Lofberg R Pollack P Adalimumab-treated patients with moderate to severe Crohn’s disease experienced reductions in extraintestinal manifestations data from CHARM Am J Gastroenterol 2009 104 S465 10.1038/ajg.2009.518 \n19. Zippi M Pica R De Nitto D Paoluzi P Biological therapy for dermatological manifestations of inflammatory bowel disease World J Clin Cases 2013 1 74 78 10.12998/wjcc.v1.i2.74 24303470 \n20. Principi M Cassano N Contaldo A Hydradenitis suppurativa and inflammatory bowel disease: an unusual, but existing association World J Gastroenterol 2016 22 4802 4811 10.3748/wjg.v22.i20.4802 27239107 \n21. Nevitt GJ Hutchinson PE Psoriasis in the community: prevalence, severity and patients’ beliefs and attitudes towards the disease Br J Dermatol 1996 135 533 537 10.1111/j.1365-2133.1996.tb03826.x 8915141 \n22. Stolwijk C van Tubergen A Castillo-Ortiz JD Boonen A Prevalence of extra-articular manifestations in patients with ankylosing spondylitis: a systematic review and meta-analysis Ann Rheum Dis 2015 74 65 73 10.1136/annrheumdis-2013-203582 23999006 \n23. Greenstein AJ Janowitz HD Sachar DB The extra-intestinal complications of Crohn’s disease and ulcerative colitis: a study of 700 patients Medicine (Baltimore) 1976 55 401 412 10.1097/00005792-197609000-00004 957999 \n24. Bernstein CN Blanchard JF Rawsthorne P Yu N The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study Am J Gastroenterol 2001 96 1116 1122 10.1111/j.1572-0241.2001.03756.x 11316157 \n25. Vavricka SR Schoepfer A Scharl M Lakatos PL Navarini A Rogler G Extraintestinal manifestations of inflammatory bowel disease Inflamm Bowel Dis 2015 21 1982 1992 10.1097/MIB.0000000000000392 26154136 \n26. Brooklyn TN Dunnill MG Shetty A Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo controlled trial Gut 2006 55 505 509 10.1136/gut.2005.074815 16188920 \n27. Korelitz BI Coles RS Uveitis (iritis) associated with ulcerative and granulomatous colitis Gastroenterology 1967 52 78 82 6018375 \n28. Rothfuss KS Stange EF Herrlinger KR Extraintestinal manifestations and complications in inflammatory bowel diseases World J Gastroenterol 2006 12 4819 4831 10.3748/wjg.v12.i30.4819 16937463 \n29. Jaffe GJ Dick AD Brezin AP Adalimumab in patients with active noninfectious uveitis N Engl J Med 2016 375 932 943 10.1056/NEJMoa1509852 27602665 \n30. Wyant T Fedyk E Abhyankar B An overview of the mechanism of action of the monoclonal antibody vedolizumab J Crohns Colitis 2016 10 1437 1444 10.1093/ecco-jcc/jjw092 27252400 \n31. Pijls PA Gilissen LP Vedolizumab is an effective alternative in inflammatory bowel disease patients with anti-TNF-alpha therapy-induced dermatological side effects Dig Liver Dis 2016 48 1391 1393 10.1016/j.dld.2016.08.122 27639825 \n32. Feagan BG Rutgeerts P Sands BE Vedolizumab as induction and maintenance therapy for ulcerative colitis N Engl J Med 2013 369 699 710 10.1056/NEJMoa1215734 23964932 \n33. Sandborn WJ Feagan BG Rutgeerts P Vedolizumab as induction and maintenance therapy for Crohn’s disease N Engl J Med 2013 369 711 721 10.1056/NEJMoa1215739 23964933 \n34. Colombel JF Sands BE Rutgeerts P The safety of vedolizumab for ulcerative colitis and Crohn’s disease Gut 2017 66 839 851 10.1136/gutjnl-2015-311079 26893500 \n35. Rubin D Feagan B Dryden G The effect of vedolizumab on extraintestinal manifestations in patients with Crohn’s disease in GEMINI 2 Crohn’s Colitis Found Am 2016 22 S42 S43 \n36. Feagan BG Rubin DT Danese S Efficacy of vedolizumab induction and maintenance therapy in patients with ulcerative colitis, regardless of prior exposure to tumor necrosis factor antagonists Clin Gastroenterol Hepatol 2017 15 229 239.e5 10.1016/j.cgh.2016.08.044 27639327 \n37. Peyrin-Biroulet L Van Assche G Gomez-Ulloa D Systematic review of tumor necrosis factor antagonists in extraintestinal manifestations in inflammatory bowel disease Clin Gastroenterol Hepatol 2017 15 25 36.e27 10.1016/j.cgh.2016.06.025 27392760 \n38. Lofberg R Louis EV Reinisch W Adalimumab produces clinical remission and reduces extraintestinal manifestations in Crohn’s disease: results from CARE Inflamm Bowel Dis 2012 18 1 9 10.1002/ibd.21663 21351211 \n39. Regueiro M Valentine J Plevy S Fleisher MR Lichtenstein GR Infliximab for treatment of pyoderma gangrenosum associated with inflammatory bowel disease Am J Gastroenterol 2003 98 1821 1826 10.1111/j.1572-0241.2003.07581.x 12907338 \n40. Feagan BG Sandborn WJ Colombel JF DOP019 Effect of vedolizumab treatment on extraintestinal manifestations in patients with Crohn’s disease: a GEMINI 2 post hoc analysis Gastroenterology 2017 152 S597 10.1016/S0016-5085(17)32137-6 \n41. Orlando A Orlando R Ciccia F Clinical benefit of vedolizumab on articular manifestations in patients with active spondyloarthritis associated with inflammatory bowel disease Ann Rheum Dis 2017 76 e31 10.1136/annrheumdis-2016-211011 28096071 \n42. Van Praet L Jans L Carron P Degree of bone marrow oedema in sacroiliac joints of patients with axial spondyloarthritis is linked to gut inflammation and male sex: results from the GIANT cohort Ann Rheum Dis 2014 73 1186 1189 10.1136/annrheumdis-2013-203854 24276368\n\n",
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"issue": "63(4)",
"journal": "Digestive diseases and sciences",
"keywords": "Crohn’s disease; Extraintestinal manifestations; Inflammatory bowel disease; Ulcerative colitis",
"medline_ta": "Dig Dis Sci",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D015212:Inflammatory Bowel Diseases; D008297:Male; D008875:Middle Aged; D055815:Young Adult",
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"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
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"title": "Effects of Vedolizumab Therapy on Extraintestinal Manifestations in Inflammatory Bowel Disease.",
"title_normalized": "effects of vedolizumab therapy on extraintestinal manifestations in inflammatory bowel disease"
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"abstract": "BACKGROUND Autoimmune encephalitis might coexist in patients with autoimmune demyelinating disorders. CASE REPORT We report on a case of a 45-year-old female multiple sclerosis (MS) patient presenting with acute onset short-term memory loss, altered mental status, inflammatory cerebrospinal fluid (CSF) findings and an MRI lesion on the left temporal lobe. An extensive panel for neuronal autoantibodies proved negative. Neuropsychological symptoms gave a prompt response to immunotherapy but nevertheless control MRI showed left hippocampal atrophy. CONCLUSIONS Several recent reports of concurrent emergence of autoimmune encephalitis and MS suggest a common mechanism for these disorders. Since autoimmune encephalitis and MS share certain common CSF and neuroimaging findings, an increased understanding of overlapping autoimmune brain disorders is required to avoid misdiagnosis especially in antibody negative autoimmune encephalitis cases.",
"affiliations": "Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.;Department of Neurology, Haydarpaşa Numune Training and Research Center, Istanbul, Turkey.;Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.;Department of Neurology, Haydarpaşa Numune Training and Research Center, Istanbul, Turkey.;Department of Neurology, Haydarpaşa Numune Training and Research Center, Istanbul, Turkey.",
"authors": "Karaaslan|Zerrin|Z|;Mercan|Özlem|Ö|;Tüzün|Erdem|E|;Mısırlı|Handan|H|;Türkoğlu|Recai|R|",
"chemical_list": "D001323:Autoantibodies",
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"doi": "10.12659/ajcr.901391",
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"issn_linking": "1941-5923",
"issue": "18()",
"journal": "The American journal of case reports",
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"medline_ta": "Am J Case Rep",
"mesh_terms": "D001323:Autoantibodies; D001327:Autoimmune Diseases; D001921:Brain; D005260:Female; D006801:Humans; D020363:Limbic Encephalitis; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009103:Multiple Sclerosis; D013577:Syndrome",
"nlm_unique_id": "101489566",
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"pages": "64-66",
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"pmid": "28096524",
"pubdate": "2017-01-18",
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"references": "27420299;21387374;20803970;25340058;25972873;24935858;24700511;22152786;26906964;26892983",
"title": "A Case of Seronegative Limbic Encephalitis with Multiple Sclerosis: A Possible Overlapping Syndrome.",
"title_normalized": "a case of seronegative limbic encephalitis with multiple sclerosis a possible overlapping syndrome"
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"companynumb": "TR-BAYER-2017-045528",
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"abstract": "In multiple sclerosis (MS), chronic active lesions, which previously could only be detected at autopsy, can now be identified on susceptibility-based magnetic resonance imaging (MRI) in vivo as non-gadolinium-enhancing lesions with paramagnetic rims. Pathologically, they feature smoldering inflammatory demyelination at the edge, remyelination failure, and axonal degeneration. To our knowledge, the prospect of long-term in vivo monitoring makes it possible for the first time to determine their contribution to disability and value as a treatment target.\n\n\n\nTo assess whether rim lesions are associated with patient disability and long-term lesion outcomes.\n\n\n\nWe performed 3 studies at the National Institutes of Health Clinical Center: (1) a prospective clinical/radiological cohort of 209 patients with MS (diagnosis according to the 2010 McDonald revised MS criteria, age ≥18 years, with 7-T or 3-T susceptibility-based brain MRI results) who were enrolled from January 2012 to March 2018 (of 209, 17 patients [8%] were excluded because of uninterpretable MRI scans); (2) a radiological/pathological analysis of expanding lesions featuring rims; and (3) a retrospective longitudinal radiological study assessing long-term lesion evolution in 23 patients with MS with yearly MRI scans for 10 years or more (earliest scan, 1992).\n\n\n\n(1) Identification of chronic rim lesions on 7-T or 3-T susceptibility-based brain MRI in 192 patients with MS and the association of rim counts with clinical disability (primary analysis) and brain volume changes (exploratory analysis). (2) Pathological characterization of 10 expanding lesions from an adult with progressive MS who came to autopsy after 7 years of receiving serial in vivo MRI scans. (3) Evaluation of annual lesion volume change (primary analysis) and T1 times (exploratory analysis) in 27 rim lesions vs 27 rimless lesions.\n\n\n\nOf 209 participants, 104 (50%) were women and 32 (15%) were African American. One hundred seventeen patients (56%) had at least 1 rim lesion regardless of prior or ongoing treatment. Further, 84 patients (40%) had no rims (mean [SD] age, 47 [14] years), 66 (32%) had 1 to 3 rims (mean [SD] age, 47 [11] years), and 42 (20%) had 4 rims or more (mean [SD] age, 44 [11] years). Individuals with 4 rim lesions or more reached motor and cognitive disability at an earlier age. Normalized volumes of brain, white matter, and basal ganglia were lower in those with rim lesions. Whereas rimless lesions shrank over time (-3.6%/year), rim lesions were stable in size or expanded (2.2%/year; P < .001). Rim lesions had longer T1 times, suggesting more tissue destruction, than rimless lesions. On histopathological analysis, all 10 rim lesions that expanded in vivo had chronic active inflammation.\n\n\n\nChronic active lesions are common, are associated with more aggressive disease, exert ongoing tissue damage, and occur even in individuals treated with effective disease-modifying therapies. These results prompt the planning of MRI-based clinical trials aimed at treating perilesional chronic inflammation in MS.",
"affiliations": "Translational Neuroradiology Section, Division of Neuroimmunology and Neurovirology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.;Translational Neuroradiology Section, Division of Neuroimmunology and Neurovirology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.;Translational Neuroradiology Section, Division of Neuroimmunology and Neurovirology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.;Translational Neuroradiology Section, Division of Neuroimmunology and Neurovirology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.;Translational Neuroradiology Section, Division of Neuroimmunology and Neurovirology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.;Translational Neuroradiology Section, Division of Neuroimmunology and Neurovirology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.;Translational Neuroradiology Section, Division of Neuroimmunology and Neurovirology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.;Translational Neuroradiology Section, Division of Neuroimmunology and Neurovirology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.;Translational Neuroradiology Section, Division of Neuroimmunology and Neurovirology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.;Translational Neuroradiology Section, Division of Neuroimmunology and Neurovirology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.",
"authors": "Absinta|Martina|M|;Sati|Pascal|P|;Masuzzo|Federica|F|;Nair|Govind|G|;Sethi|Varun|V|;Kolb|Hadar|H|;Ohayon|Joan|J|;Wu|Tianxia|T|;Cortese|Irene C M|ICM|;Reich|Daniel S|DS|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1001/jamaneurol.2019.2399",
"fulltext": null,
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"issn_linking": "2168-6149",
"issue": "76(12)",
"journal": "JAMA neurology",
"keywords": null,
"medline_ta": "JAMA Neurol",
"mesh_terms": "D000328:Adult; D001921:Brain; D015331:Cohort Studies; D018450:Disease Progression; D017352:Echo-Planar Imaging; D005260:Female; D006801:Humans; D021621:Imaging, Three-Dimensional; D007249:Inflammation; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis; D009929:Organ Size; D011379:Prognosis",
"nlm_unique_id": "101589536",
"other_id": null,
"pages": "1474-1483",
"pmc": null,
"pmid": "31403674",
"pubdate": "2019-12-01",
"publication_types": "D016428:Journal Article; D052060:Research Support, N.I.H., Intramural; D013485:Research Support, Non-U.S. Gov't",
"references": "27270171;19204159;29735982;20625086;6685237;15824338;23813441;29320652;9663568;25888557;20644149;29441412;27988845;26250739;22313379;27796537;24639479;25697158;21387374;25662351;19107998;26939635;24964187;27125632;25748099;19766196;28541408;27339071;23297322;25007244;25137340;22641301;30561514;22407571;22084205;29856910;29724768;19022862;22171355;26239536",
"title": "Association of Chronic Active Multiple Sclerosis Lesions With Disability In Vivo.",
"title_normalized": "association of chronic active multiple sclerosis lesions with disability in vivo"
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"abstract": "Two HIV-infected individuals on second-line atazanavir-based antiretroviral therapy presented with neuropsychiatric symptoms. Cerebrospinal fluid HIV RNA was higher than plasma HIV RNA and antiretroviral regimens' optimization led to prompt resolution of symptoms in one. Patients on second-line atazanavir-based antiretroviral therapy with documented previous treatment failure may be at risk of symptomatic cerebrospinal fluid escape.",
"affiliations": "Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda.;College of Health Sciences, Makerere University, Kampala, Uganda.;Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda.;Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda.;Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda.;Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda.;Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Torino, Italy.",
"authors": "Ssebambulidde|Kenneth|K|0000-0002-8125-0698;Segawa|Ivan|I|;Laker|Eva|E|;Lamorde|Mohammed|M|;Castelnouvo|Barbara|B|;Nakasujja|Noeline|N|;Calcagno|Andrea|A|0000-0003-2534-8815",
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"doi": "10.1093/omcr/omy132",
"fulltext": "\n==== Front\nOxf Med Case ReportsOxf Med Case ReportsomcrOxford Medical Case Reports2053-8855Oxford University Press 10.1093/omcr/omy132omy132Case ReportSymptomatic cerebrospinal fluid HIV-1 escape in two patients on second-line antiretroviral therapy in Uganda http://orcid.org/0000-0002-8125-0698Ssebambulidde Kenneth 1Segawa Ivan 2Laker Eva 1Lamorde Mohammed 1Castelnouvo Barbara 1Nakasujja Noeline 12http://orcid.org/0000-0003-2534-8815Calcagno Andrea 31 Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda2 College of Health Sciences, Makerere University, Kampala, Uganda3 Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Torino, ItalyCorrespondence address. Department of Research, Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda. Tel: +256-41-453-0020; E-mail: kssebambulidde@idi.co.ug2 2019 16 2 2019 16 2 2019 2019 2 omy13212 8 2018 17 11 2018 04 1 2019 © The Author(s) 2019. Published by Oxford University Press.2019This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License(http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nTwo HIV-infected individuals on second-line atazanavir-based antiretroviral therapy presented with neuropsychiatric symptoms. Cerebrospinal fluid HIV RNA was higher than plasma HIV RNA and antiretroviral regimens’ optimization led to prompt resolution of symptoms in one. Patients on second-line atazanavir-based antiretroviral therapy with documented previous treatment failure may be at risk of symptomatic cerebrospinal fluid escape.\n==== Body\nINTRODUCTION\nCerebrospinal fluid (CSF) HIV escape in individuals on antiretroviral therapy (ART) is defined as a detectable CSF HIV RNA with a concurrent undetectable plasma level, or CSF HIV RNA higher (any level, 0.5 or 1 log) than plasma HIV RNA. It has been reported in 0.7–27.4% asymptomatic HIV-infected individuals on ART [1].\n\nSymptomatic CSF escape has been described in more than 100 individuals but never in limited resource countries. Patients usually present with subacute neurological symptoms, CSF HIV RNA higher than plasma levels and with resistance associated mutations (RAMs). Risk factors include low nadir CD4 cell count, incomplete plasma viral suppression and poor adherence [2, 3]. Two recent case series from India and one large cohort suggest that it may be more frequent in patients on protease inhibitors (PIs), but this may be biased by the presence of RAMs [4–6]. Treatment is usually with optimization of ART through choosing drugs according to genotype resistance test results and their central nervous system penetration/effectiveness score (CPE).\n\nHere; we describe two Ugandan patients on PIs based second line ART for at least 7 years at the time of presentation with neuropsychiatric symptoms associated with uncontrolled central nervous system HIV compartmental replication.\n\nCASE 1\nA 62-year-old male, HIV-infected on second-line ART for 7 years with a nadir CD4 T-cell count of 158 cells/μL. He was referred to the Infectious Diseases Institute, Kampala from a mental health unit for further assessment of his neurocognitive decline. He had been well till 8 months prior to his referral when he started having; memory impairment, visual hallucinations, sleepiness, unstable gait and being scared of falling. He had no history of headache or head trauma. He was taking Donepezil 2.5 mg daily for early onset dementia for 8 months by the time of his referral. He had no history of substance abuse and no family history of mental illness. His cognitive decline had impaired his daily activities. He stopped working due to memory impairment and was unable to move unsupported. He needed help for his daily activities including; washing himself, dressing up and ambulation. He could not recognize anyone in his family including his wife and children.\n\nHe initiated ART 18 years prior to his referral. The antiretroviral regimen he had taken for the first 4 years was unknown after which he was switched to tenofovir, lamivudine and efavirenz which he took with inconsistent adherence for 7 years before being switched to second line therapy due to viral failure (plasma HIV RNA; 4014 copies/mL). His second line regimen consisted of zidovudine, lamivudine and ritonavir-boosted atazanavir. He achieved plasma virological suppression (HIV RNA < 75 copies/mL) in the first 5 years of this second line regimen. He had no prior history of an AIDS-defining opportunistic illness.\n\nClinically, he was slightly overweight (BMI 26 kg/m2), afebrile, the blood pressure was 158/96 mmHg and a pulse of 96 beats per minute; his speech was characterized by confabulating, challenges in maintaining attention, had intentional tremors and a shuffling gait.\n\nA lumbar puncture was performed as part of his investigations for his neurocognitive decline. CSF had normal opening pressure at 11cmH2O, with a normal white cell count (<5 cells/μL), normal total protein (12 mg/dL), an elevated glucose level of 11.7 mmol/L as compared to plasma 7.6 mmol/L and the veneral disease research laboratory (VDRL) test was negative. The CSF HIV RNA was 4 895 copies/mL (3.69 log units) and plasma HIV RNA was 277 copies/mL. Other laboratory findings included; CD4 T-cell count of 503 cells/μL normal renal and liver function tests, hyponatremia (127 mmol/L), HbA1C 6.6%, and elevated fasting triglycerides (2.2 mmol/L).\n\nHe had a normal brain CT scan. However, magnetic resonance imaging (MRI) of his brain showed neuroparenchymal atrophy and hyperintensities involving bilateral periventricular white matter; features suggestive of HIV encephalitis (Fig. 1).\n\nFigure 1: Magnetic resonance image of the brain: symmetric T2/FLAIR hyperintensities involving bilateral periventricular white matter, fronto-temporo-parietal sub-cortical white matter and centrum semiovale. Neuroparenchymal atrophy. Dilated and prominent cerebral ventricles, sulci and cisterns. Features usually representative of HIV associated encephalitis.\n\nPlasma drug sensitivity tests done showed several RAMs: I50L and others (L10V, I13V, K14R, I15V, E35D, M36I, R41K, R57K, I64V, H69K, T74A, L89M) in the protease gene, several mutations in the reverse transcriptase gene both for NRTIs (T215F, K219E, D67H, K70R, L74I, M184V) and NNRTIs (K103N, V179T, P225H). CSF HIV drug sensitivity testing was not available.\n\nBasing on the resistance profile results, his ART regimen was changed to dolutegravir, lamivudine and ritonavir boosted lopinavir. This increased his central nervous penetration effectiveness score from 5 to 8. He is registering on-going improvement in his subsequent follow-up visits. Gait normalizing, memory impairment resolving within 2 months of follow up. His sodium improved to 137 mmol/L. His plasma HIV RNA was suppressed within a month of ART change. He was now able to move without support and recognize family members. He returned to work with no one escorting him in his third month of ART change. Donepezil was tapered off.\n\nCASE 2\n A 58-year-old female diagnosed with HIV and cryptococcal meningitis 12 years prior to her admission to Mulago National Referral Hospital. Her initial ART regimen included zidovudine, lamivudine and nevirapine and had a nadir CD4 T-cell count of 263 cell/μL (current). Nine years following ART initiation, she was diagnosed with sputum positive pulmonary tuberculosis for which she received anti-tuberculous therapy for 6 months and was declared cured. Following her pulmonary tuberculosis treatment, she was found to have virologic failure (plasma HIV RNA of 170 694 copies/mL) and was switched to tenofovir, lamivudine and ritonavir boosted atazanavir. Plasma HIV RNA was <75 copies/mL a year after her switch, and low viremia 2 years after the switch (HIV RNA; 251 copies/mL) and an elevated fasting blood sugar (8.9 mmol/L) was found for which metformin 500 mg daily was added to her treatment.\n\nShe was admitted to Mulago National Referral Hospital with urinary incontinence and irritability but no constitutional symptoms. Of note, she had progressively had lower limb weakness over a year resulting in inability to move, and had been bedridden for 3 months. This was associated with short term memory loss and abnormal picking on herself articles that were never seen by other individuals and unusual posturing of her neck (mannerisms). She was always in and out of confusion for over 2 months.\n\nClinically, she had an axillary temperature of 36.2°C, fast regular normal volume pulse of 111 bpm, normal blood pressure 104/88 mmHg, saturating at 98% on room air, respiratory rate of 20 bpm. She had mannerisms and poor eye contact. She was paraplegic with a staggering gait on moving with support.\n\nA lumbar puncture was performed; CSF was under normal opening pressure at 14 cmH2O with normal CSF protein 48 mg/dL, elevated white cell count 220 cells/μL 100% lymphocytes. Negative gram stain, cryptococcal antigen, MTB/Rif GeneXpert and ultra Xpert and no fungal or bacterial or mycobacterial growth on culture. Her CSF HIV RNA was 31 896 copies/mL (4.50 log units) with a plasma HIV RNA of 1804 copies/mL (3.26 log units). She was diagnosed with symptomatic CSF HIV escape. We await her plasma HIV drug sensitivity test results to optimize her ART.\n\nDISCUSSION\nWe here report the first two cases of symptomatic CSF HIV escape from Uganda; it should be noted that CSF HIV RNA is not usually measured in the routine work up for unexplained neurological symptoms in HIV-infected individuals. In many resource limited countries, the application of World Health Organization guidelines may result into the ‘perfect’ scenario for the compartmental replication of HIV. The use of low genetic barrier first-line therapy, delayed antiretroviral switch due to infrequent viral load monitoring and at a higher cut off (1000 copies/mL) as well as the recycling of some nucleotide reverse transcriptase inhibitors (NRTIs) for second line treatment might favour selection of RAMs.\n\nOf the PIs routinely available in Uganda, atazanavir has the least CPE score of 2 compared to lopinavir and darunavir each with a CPE score of 3 [7]. Atazanavir has been associated with more reports of CSF HIV escape than lopinavir [8]. In Uganda, however, atazanavir is preferred to lopinavir for second line antiretroviral regimens due to its affordability, gastrointestinal tolerability and reduced pill burden [9]. The presence of several RAMs may therefore expose patients to atazanavir monotherapy. Several studies reported the possibility of symptomatic CSF escape in patients with low nadir CD4 T-cell count on PI monotherapy. Low CD4 nadir seems the strongest risk factor for symptomatic CSF escape: in one the two Indian studies its incidence was 9.5 per 10 000 person-months in patients with nadir CD4 cell count below 200/μL versus 0.49 per 10 000 person-months in those ones with higher levels [4]. However, CSF escape is rare in individuals on robust highly active ART with atazanavir as one of the drugs unless they also have RAMs.\n\nThe two patients described had their HIV diagnoses 18 and 12 years ago with current CD4 counts of 504 and 263, respectively. They were both on ritonavir boosted atazanavir based ART. Their characteristics are similar to other patients previously described with CSF HIV escape [5, 10]. Cases 1 and 2 had a CSF/plasma HIV RNA log difference of 1.25 log units and 1.24 log units respectively characteristic of CSF HIV escape.\n\nSymptomatic neurocognitive impairment has been reported in 35.1% of individuals with CSF HIV escape [11]. The more commonly described symptoms in individuals with CSF HIV escape include; memory impairment, gait disturbances, sleep disorders and inability to concentrate. These symptoms were noted in both patients we have described. Case 2 had worse symptoms compared to case 1. This could be as a result of overwhelming inflammation from the higher CSF HIV RNA level noted compared to that found in case 1.\n\nIn a setting where adults with HIV infection, even with ART, are more likely to have cognitive dysfunction than those without HIV infection [12], it is only prudent that CSF HIV RNA evaluation is added to their routine diagnostic evaluation. This will facilitate optimization of their ART to better central nervous system penetrating/effective regimens.\n\nACKNOWLEDGEMENTS\nWe acknowledge Drs Noela Orwawo, Ddungu Ahmed and Lumu Ivan for clinical advice. Opio Patrick and Babirye Dorothy for providing prompt laboratory services. We thank the patients’ families.\n\nCONFLICT OF INTEREST STATEMENT\nNone declared.\n\nFUNDING\nNo funding was got for this work.\n\nCONSENT\nSurrogate informed consent was sought from the next of kin of each of the patients described above.\n==== Refs\nREFERENCES\n1 \nJoseph J , Cinque P , Colosi D , Dravid A , Ene L , Fox H , et al \nHighlights of the Global HIV-1 CSF Escape Consortium Meeting, 9 June 2016, Bethesda, MD, USA . J virus Erad 2016 ;2 :243 –50 .27781109 \n2 \nPeluso MJ , Ferretti F , Peterson J , Lee E , Fuchs D , Boschini A , et al \nCerebrospinal fluid HIV escape associated with progressive neurologic dysfunction in patients on antiretroviral therapy with well controlled plasma viral load . AIDS 2012 ;26 :1765 –74 .22614889 \n3 \nCanestri A , Jaureguiberry S , Moulignier A , Amiel C , Peytavin G , Tubiana R , et al \nDiscordance between cerebral spinal fluid and plasma HIV replication in patients with neurological symptoms who are receiving suppressive antiretroviral therapy . Clin Infect Dis 2010 ;50 :773 –8 .20100092 \n4 \nPatel AK , Patel KK , Gohel S , Kumar A , Letendre S \nIncidence of symptomatic CSF viral escape in HIV infected patients receiving atazanavir/ritonavir (ATV/r)-containing ART: a tertiary care cohort in western India . J Neurovirol 2018 ;4 :498 –505 .\n5 \nMukerji SS , Misra V , Lorenz D , Cervantes-Arslanian AM , Lyons J , Chalkias S , et al \nTemporal patterns and drug resistance in CSF viral escape among ART-experienced HIV-1 infected adults . J Acquir Immune Defic Syndr 2017 ;75 :246 –55 .28328546 \n6 \nDravid AN , Natrajan K , Kulkarni MM , Saraf CK , Mahajan US , Kore SD , et al \nDiscordant CSF/plasma HIV-1 RNA in individuals on virologically suppressive antiretroviral therapy in Western India . Medicine 2018 ;97 .\n7 \nLetendre S \nLetendre 2011 HAND and HAART . Top Antivir Med [Internet] 2011 ;19 :137 –42 . Available from: http://www.ncbi.nlm.nih.gov/pubmed/22156215.\n8 \nSmurzynski M , Wu K , Letendre S , Robertson K , Bosch RJ \nEffects of central nervous system antiretroviral penetration on cognitive functioning in the ALLRT cohort . AIDS 2011 ;25 :357 –65 .21124201 \n9 \nUganda Ministry of Health \nConsolidated Guidelines for Prevention and Treatment of HIV in Uganda\n2018 ; April. https://www.prepwatch.org/wp-content/uploads/2017/08/consolidated_guidelines_hiv_prevention_uganda.pdf\n10 \nBingham R , Ahmed N , Rangi P , Johnson M , Tyrer M , Green J \nHIV encephalitis despite suppressed viraemia: a case of compartmentalized viral escape . Int J STD AIDS 2011 ;22 :608 –9 .21998185 \n11 \nMukerji SS , Misra V , Lorenz DR , Uno H , Morgello S , Franklin D , et al \nImpact of antiretroviral regimens on CSF viral escape in a prospective multicohort study of ART-experienced HIV-1 infected adults in the United States . Clin Infect Dis [Internet] 2018 ;2018 :1 –14 . Available from: https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciy267/4959767.\n12 \nNakasujja N , Allebeck P , Agren H , Musisi S , Katabira E \nCognitive dysfunction among HIV positive and HIV negative patients with psychosis in Uganda . PLoS One 2012 ;7 :1 –5 .\n\n",
"fulltext_license": "CC BY-NC",
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"references": "20100092;21124201;21998185;22156215;22614889;22970214;27781109;28328546;29465595;29691760",
"title": "Symptomatic cerebrospinal fluid HIV-1 escape in two patients on second-line antiretroviral therapy in Uganda.",
"title_normalized": "symptomatic cerebrospinal fluid hiv 1 escape in two patients on second line antiretroviral therapy in uganda"
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"abstract": "In order to survive, Aspergillus fumigatus must adapt to specific niche environments. Adaptation to the human host includes modifications facilitating persistent colonisation and the development of azole resistance. The aim of this study is to advance understanding of the genetic and physiological adaptation of A. fumigatus in patients during infection and treatment. Thirteen A. fumigatus strains were isolated from a single chronic granulomatous disease patient suffering from persistent and recurrent invasive aspergillosis over a period of 2 years. All strains had identical microsatellite genotypes and were considered isogenic. Whole genome comparisons identified 248 non-synonymous single nucleotide polymorphisms. These non-synonymous mutations have potential to play a role in in-host adaptation. The first 2 strains isolated were azole susceptible, whereas later isolates were itraconazole, voriconazole and/or posaconazole resistant. Growth assays in the presence and absence of various antifungal stressors highlighted minor changes in growth rate and stress resistance, with exception of one isolate showing a significant growth defect. Poor conidiation was observed in later isolates. In certain drug resistant isolates conidiation was restored in the presence of itraconazole. Differences in virulence were observed as demonstrated in a Galleria mellonella infection model. We conclude that the microevolution of A. fumigatus in this patient has driven the emergence of both Cyp51A-independent and Cyp51A-dependent, azole resistance mechanisms, and additional phenotypes that are likely to have promoted fungal persistence.",
"affiliations": "Medical Research Council Centre for Medical Mycology at the University of Aberdeen, Aberdeen Fungal Group, Institute of Medical Sciences, Aberdeen, UK.;Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen, The Netherlands; Centre of Expertise in Mycology, Radboudumc/CWZ, Nijmegen, The Netherlands.;Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen, The Netherlands; Centre of Expertise in Mycology, Radboudumc/CWZ, Nijmegen, The Netherlands.;Medical Research Council Centre for Medical Mycology at the University of Aberdeen, Aberdeen Fungal Group, Institute of Medical Sciences, Aberdeen, UK.;Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen, The Netherlands; Centre of Expertise in Mycology, Radboudumc/CWZ, Nijmegen, The Netherlands.;Medical Research Council Centre for Medical Mycology at the University of Aberdeen, Aberdeen Fungal Group, Institute of Medical Sciences, Aberdeen, UK. Electronic address: a.warris@abdn.ac.uk.",
"authors": "Ballard|Eloise|E|;Melchers|Willem J G|WJG|;Zoll|Jan|J|;Brown|Alistair J P|AJP|;Verweij|Paul E|PE|;Warris|Adilia|A|",
"chemical_list": "D000935:Antifungal Agents; D001393:Azoles; D005656:Fungal Proteins; D003577:Cytochrome P-450 Enzyme System",
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"fulltext": "\n==== Front\nFungal Genet BiolFungal Genet. BiolFungal Genetics and Biology1087-18451096-0937Academic Press S1087-1845(18)30025-210.1016/j.fgb.2018.02.003ArticleIn-host microevolution of Aspergillus fumigatus: A phenotypic and genotypic analysis Ballard Eloise aMelchers Willem J.G. bcZoll Jan bcBrown Alistair J.P. aVerweij Paul E. bcWarris Adilia a.warris@abdn.ac.uka⁎a Medical Research Council Centre for Medical Mycology at the University of Aberdeen, Aberdeen Fungal Group, Institute of Medical Sciences, Aberdeen, UKb Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen, The Netherlandsc Centre of Expertise in Mycology, Radboudumc/CWZ, Nijmegen, The Netherlands⁎ Corresponding author. a.warris@abdn.ac.uk1 4 2018 4 2018 113 1 13 11 12 2017 6 2 2018 21 2 2018 © 2018 The Author(s)2018This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Highlights\n• Description of in-host adaptation of A. fumigatus promoting fungal persistence.\n\n• Significant in-host microevolution was identified in 13 consecutive A. fumigatus isolates from a single patient.\n\n• Emerging azole resistance, fungal growth, conidiation and virulence differences were observed.\n\n• 248 non-synonymous single nucleotide polymorphisms developed throughout series.\n\n\n\nIn order to survive, Aspergillus fumigatus must adapt to specific niche environments. Adaptation to the human host includes modifications facilitating persistent colonisation and the development of azole resistance. The aim of this study is to advance understanding of the genetic and physiological adaptation of A. fumigatus in patients during infection and treatment. Thirteen A. fumigatus strains were isolated from a single chronic granulomatous disease patient suffering from persistent and recurrent invasive aspergillosis over a period of 2 years. All strains had identical microsatellite genotypes and were considered isogenic. Whole genome comparisons identified 248 non-synonymous single nucleotide polymorphisms. These non-synonymous mutations have potential to play a role in in-host adaptation. The first 2 strains isolated were azole susceptible, whereas later isolates were itraconazole, voriconazole and/or posaconazole resistant. Growth assays in the presence and absence of various antifungal stressors highlighted minor changes in growth rate and stress resistance, with exception of one isolate showing a significant growth defect. Poor conidiation was observed in later isolates. In certain drug resistant isolates conidiation was restored in the presence of itraconazole. Differences in virulence were observed as demonstrated in a Galleria mellonella infection model. We conclude that the microevolution of A. fumigatus in this patient has driven the emergence of both Cyp51A-independent and Cyp51A-dependent, azole resistance mechanisms, and additional phenotypes that are likely to have promoted fungal persistence.\n\nKeywords\nAspergillus fumigatusIn-host microevolutionAzole-resistanceFungal growthWhole genome sequencing\n==== Body\n1 Introduction\nAspergillus fumigatus is a ubiquitous saprophytic fungus. Its ecological niche is soil, where it plays a key role in carbon and nitrogen recycling by degradation of organic biomass (O’Brien et al., 2005, Tedersoo et al., 2014). Various characteristics enable A. fumigatus to survive in this harsh environment, including rapid germination, growth at higher temperatures and nutritional metabolic flexibility (Mullins et al., 1976). This versatility enables A. fumigatus to be a successful pathogen in human, animal and plant populations (Armstrong-James et al., 2016, Fisher et al., 2012).\n\nIn humans, A. fumigatus is the causative agent of aspergillosis, which ranges from allergic syndromes to life-threatening invasive aspergillosis (Latgé, 2001, Warris, 2014). Azole antifungal agents hold great importance in the treatment of aspergillosis, as they are the only orally available anti-Aspergillus agents (Patterson et al., 2016, Peyton et al., 2015, Warris, 2014). The primary target of azoles is cytochrome P450 14α-sterol demethylase (Cyp51A), which catalyses the demethylation of ergosterol precursors in the ergosterol biosynthetic pathway (Bosschef et al., 1995, Ghannoum and Rice, 1999, Shapiro et al., 2011). Azoles competitively inhibit Cyp51A by binding to the haem active site (Gollapudy et al., 2004, Xiao et al., 2004).\n\nIn order to survive and thrive in-host, A. fumigatus must adapt to specific niche environments (Verweij et al., 2016). Genetic adaptation can be defined as the acquisition of heritable modifications, via either spontaneous mutation or recombination, which enable survival and reproduction in the environment (Schoustra et al., 2005). Examples of adaptation include adaptation to enable persistent infection and azole resistance development (Fedorova et al., 2008, Hagiwara et al., 2014, Kano et al., 2015, Valsecchi et al., 2015, Verweij et al., 2016). The in-host acquisition of resistance has previously been described within aspergillomas in chronic pulmonary aspergillosis (Howard et al., 2013).\n\nSince the first report of itraconazole resistance in A. fumigatus in 1997 (Denning et al., 1997), azole resistance is increasingly reported globally. A range of molecular mechanisms conferring azole resistance have been described. Specific non-synonymous point mutations in cyp51A have been shown to confer azole resistance by altering the ligand entry channel structure; examples include G54, P216, G138 and M220 (Albarrag et al., 2011, Garcia-Effron et al., 2005, Mann et al., 2003, Mellado et al., 2004, Mellado et al., 2003, Snelders et al., 2010). A tandem repeat of 34 bp in the promoter region of cyp51A has also been shown to confer itraconazole resistance by increasing cyp51A gene expression in combination with an L98H mutation within cyp51A (Mellado et al., 2007, Snelders et al., 2008). In contrast to cyp51A-mediated resistance mechanisms, relatively few non cyp51A-mediated mechanisms have been described. One example is a P88L substitution in the CCAAT-binding transcription factor complex subunit HapE, which has been shown to confer itraconazole resistance by enhancing cyp51A expression (Camps et al. 2012). Overexpression of efflux transporters AtrF and Cdr1B has been associated with azole resistance (Fraczek et al., 2013, Slaven et al., 2002) but further research is required to validate the role of these pumps in azole resistance. Mutation in components of mitochondrial complex I, RamA (farnesyltransferase β-subunit), overexpression of cyp51B and deletion of cytochrome b5 CybE have also been described to result in azole resistance (Bromley et al., 2016, Buied et al., 2013, Misslinger et al., 2017, Norton et al., 2017).\n\nCyp51A-mediated resistance mechanisms are not thought to be associated with fitness costs (Lackner et al., 2017, Valsecchi et al., 2015). In contrast, the HapE itraconazole resistance mechanism is associated with a growth defect (Camps et al. 2012). Interestingly, specific azole resistant isolates are hypothesised to be ‘azole addicted’ whereby they exhibit enhanced growth in the presence of azole antifungals (Anderson, 2005, Schoustra et al., 2006).\n\nStudies investigating the dynamics of in-host adaptation and persistent infection are scarce. Here we performed a detailed phenotypic and genotypic analysis of 13 A. fumigatus isolates consecutively cultured over a period of 2 years with increasing azole resistance in a chronic granulomatous disease (CGD) patient with chronic and recurrent aspergillosis. Whole genome sequencing was used to assess the genomic dynamics. Phenotypic analysis including growth in liquid and on solid media and conidiation assays were used to investigate physiological adaptation. An invertebrate infection model was used to assess differences in virulence.\n\n2 Materials and methods\n2.1 Origin and characterisation of fungal isolates\nThe 13 isolates used in this study were cultured from a 36-year-old male diagnosed with X-linked chronic granulomatous disease with severe chronic obstructive pulmonary disease (Gold IV) and allergic bronchopulmonary aspergillosis (Verweij et al., 2016). The patient suffered from 3 episodes of invasive aspergillosis and developed an aspergilloma, which could not be surgically removed due to his poor respiratory condition. The patient was treated prophylactically with interferon-gamma, trimethoprim-sulphamethoxazole and itraconazole. Between June and December 2011, the patient was treated with itraconazole followed by combination therapy consisting of voriconazole and an echinocandin (caspofungin, anidulafungin). Isolate V130-15 was collected on 22/11/11 and isolates V130-14, V130-18 and V130-54 were collected on 25/11/11. Between December 2011 and January 2013 the patient was treated consecutively with liposomal amphotericin B, itraconazole, anidulafungin in combination with voriconazole. Between August and December 2013, the patient was treated with posaconazole monotherapy, followed by combination therapy with micafungin. Despite these efforts, eradication of the fungus was not achieved. Isolates V157-39, V157-40, V157-47, V157-48 and V157-62 were collected on 9/12/13. Isolates V157-59, V157-60 and V157-61 were collected on 12/12/13; and isolate V157-80 was collected on 19/12/13. Unfortunately the patient died from his infection.\n\nThe 13 A. fumigatus isolates were cultured and morphologically identified as A. fumigatus at Radboud University Medical Centre (Verweij et al., 2016). In vitro susceptibility testing of the isolates was performed according to the EUCAST broth microdilution reference method (Subcommittee on Antifungal Susceptibility Testing of the ESCMID European Committee for Antimicrobial Susceptibility Testing (EUCAST), 2015). Isolates were tested at a final drug concentration rage of 0.0312–16 mg/L itraconazole (Sigma Aldrich, UK), 0.0312–16 mg/L voriconazole (Pfizer, UK) and 0.0156–8 mg/L posaconazole (Sigma Aldrich, UK). A no growth end point was determined by eye. Short tandem repeat (STR) typing was performed as described previously using microsatellite loci STRAf 3A, 3B, 3C, 4A, 4B and 4C (de Valk et al., 2005). Repeat numbers at each loci were determined by PCR and subsequent sequencing.\n\n2.2 Conidial suspension preparation\nA. fumigatus conidia were spread onto diluted Sabouraud dextrose agar in T75 culture flasks (Greiner Bio-One, Germany) and incubated at 37 °C for 7 d. Diluted Sabouraud dextrose agar was selected to promote sporulation. Conidia were harvested via immersion in 30 mL phosphate buffered saline (PBS) (Thermo Fisher Scientific, UK) containing 0.05% Tween-80 (Thermo Fisher Scientific, UK). Conidial suspensions were passed through a sterile 40 µm strainer to remove hyphal fragments, washed twice using PBS and then counted using a Neubauer improved haemocytometer (Petrikkou et al., 2001). For all experiments, suspensions were diluted as required in RPMI (RPMI 1640 + Glutamax, Fisher Scientific, UK).\n\n2.3 Whole genome sequencing\nDNA was extracted from either conidia or mycelium. Conidia were suspended in TE buffer (pH 8, 1% SDS, 2% Triton X100, 100 mM NaCl). The suspension was shaken for 30 min at 70 °C. DNA was extracted using phenol/chloroform extraction and purified using the QIAamp DNA Blood Mini kit (Qiagen, Germany). A fragmented genomic DNA library was prepared using a Nextera XT DNA sample preparation kit (Illumina, USA). Subsequent sequencing was conducted in a paired end 2 × 150 bp mode using an Illumina NextSeq 500 machine (Illumina, USA).\n\n2.4 Bioinformatics analysis\nRaw reads were quality checked using FastQC (version 0.11.5, Babraham Institute). Reads containing adapter sequences and/or with a Phred score <30 were removed using Trimmomatic (Galaxy version 0.32.3) (Bolger et al., 2014, Giardine et al., 2005). Reads were mapped to the Af293 reference genome (release 31, EnsemblFungi) using the very sensitive local align preset mode in Bowtie2 (Garcia-Alcalde et al., 2012). Mapping quality was assessed using Qualimap (Garcia-Alcalde et al., 2012, Okonechnikov et al., 2015). Single nucleotide polymorphism (SNP) detection was conducted using FreeBayes (Garrison and Marth, 2012). VCFtools vcf-isec was used to assess patterns amongst SNPs and to filter SNPs with a minimum coverage of 5 and a minimum probability of 0.8 (Danecek et al., 2011). EnsemblFungi Variant Effect Predictor was used to assess the impact of non-synonymous SNPs (Flicek et al., 2014). Both synonymous and non-synonymous SNPs were considered for phylogenetic analysis using the SNPhylo pipeline (Lee et al., 2014), which utilises vcftools (Danecek et al., 2011), Phylip (University of Washington, USA) and Muscle (Edgar, 2004) to generate phylogenetic trees by the maximum likelihood method. Integrated Genomics Viewer and Tablet were utilised for visualisation of sequence data (Boyaval et al., 2007, Milne et al., 2013, Thorvaldsdóttir et al., 2013).\n\n2.5 Growth assays\n2.5.1 Liquid medium\nFlat-bottomed 96-well plates (Nunc microwell 96F, Thermo Fischer Scientific, UK) were seeded with 1.9 × 105 conidia in RPMI. Selected wells were supplemented with specific concentrations of posaconazole (POS 0.5–1 mg/L), voriconazole (VORI 1–4 mg/L) or 2.5 mM tert-Butyl hydroperoxide (tBOOH) (Sigma Aldrich, UK). Plates were incubated at 37 °C for 48 h inside a spectrophotometric plate reader (FLUOstar OPTIMA, BMG Labtech, Germany). Optical density at 450 nm was automatically measured every 20 min with 5 s shaking before every reading. Each condition was performed in triplicate wells and repeated twice. Due to the lipophilic properties of itraconazole (ITR), specific concentrations were unable to be determined in liquid media; solid media assays were consequently used for studying the impact of ITR on growth.\n\n2.5.2 Solid medium\nSabouraud dextrose agar plates were spot-inoculated with 5 × 102 conidia. Selected plates were supplemented with specific concentrations of either ITR (between 1 and 8 mg/L) or 2.5 mM tBOOH. Supplements were added to the medium at ∼50 °C before solidification. Plates were incubated at 37 °C for 96 h, colony diameters were measured every 24 h. Each condition was performed in triplicate.\n\n2.5.3 Environmental zinc depletion\nA. fumigatus conidia were spread onto glucose minimal agar lacking zinc in T75 culture flasks and incubated at 37 °C for 7 d. Conidia were harvested and counted as described. Zinc depletion experiments were performed by spot inoculating 5 × 102 conidia on glucose minimal media in the absence and presence of 1 mM zinc at pH 4.5 and 7.5 (Amich et al., 2010). Plates were incubated at 37 °C for 96 h, colony diameters were measured every 24 h. Each condition was performed in triplicate.\n\n2.5.4 Conidiation quantification\nT75 culture flasks containing Sabouraud dextrose agar were inoculated with 1 × 105 conidia and incubated at 37 °C for 7 d. Selected flasks were supplemented with 4 mg/L ITR. Conidial suspensions were prepared and counted as described above. Where sterile hyphae were produced, a 1 cm3 section of hyphae was excised using a sterile plastic loop, re-plated and incubated at 37 °C for an additional 7 d. Conidial suspensions were subsequently prepared and counted as described. Each condition was performed in duplicate.\n\n2.6 Galleria mellonella virulence assays\nSimilar sized G. mellonella larvae (Livefood Ltd, UK) were selected for use in experiments. All larval injections were performed in the last pro-leg using a 0.33 mm Micro-Fine needle (BD, UK). Groups of 10 larvae were infected with 6 × 103 conidia. Control groups of larvae were included in each experiment; 10 unmanipulated larvae and 10 larvae injected with 10 µl PBS. Larvae were incubated at 37 °C for 6 d. Larval death was characterised by lack of movement and melanisation (Gomez-Lopez et al., 2014, Renwick et al., 2006, Slater et al., 2011). Virulence assays were performed in duplicate.\n\n2.7 Statistical analysis\nStatistical significance was assessed using a two-tailed Students T-test. Survival curves comparisons were performed using a log-rank Mantel-Cox test. A p value of <0.05 was considered significant.\n\n3 Results\n3.1 Initial characterisation of the A. Fumigatus isolates\n3.1.1 Validation of genetic relatedness\nMicrosatellite typing was performed in order to verify genetic relatedness between the 13 isolates (de Valk et al., 2005). STRAf loci 3A, 3B, 3C, 4A, 4B and 4C were assessed. All isolates showed identical repeat numbers at all loci except for 3C and 4A. Isolates showed 26 repeats at 3A, 9 repeats at 3B, 12 repeats at 4B and 8 repeats at 4C. At locus 3C isolates showed 16 repeats, with the exception of isolates V130-15 and V130-18 which showed 17 repeats. At locus 4A isolates showed 9 repeats, with the exception of isolates V157-39, V157-40 and V157-80 which showed 8 repeats. As repeat numbers at these loci differed by only one single repeat the isolates are considered isogenic.\n\n3.1.2 Development of triazole resistance\nAccording to the EUCAST clinical resistance breakpoints, isolates V130-15 and V130-14 were azole susceptible, while isolate V130-54 was itraconazole (ITR) resistant. Furthermore, isolates V130-18, V157-62, V157-59, V157-60 and V157-61 were pan-azole resistant, whereas isolates V157-39, V157-40, V157-47, V157-48 and V157-80 were ITR and posaconazole (POS) resistant (Table 1).Table 1 Minimum inhibitory concentrations of the A. fumigatus isolates in the series.\n\nIsolation date\tStrain\tCyp51A SNP\tMinimum inhibitory concentration (MIC; mg/L)\t\nItraconazole\tVoriconazole\tPosaconazole\t\n22/11/11\tV130-15\t\t1\t1\t0.25\t\n25/11/11\tV130-14\t\t1\t1\t0.25\t\n25/11/11\tV130-18\t\t4\t4\t0.5\t\n25/11/11\tV130-54\t\t>16\t1\t0.125\t\n09/12/13\tV157-39\tG54R\t>16\t1\t>16\t\n09/12/13\tV157-40\tG54V\t>16\t1\t>16\t\n09/12/13\tV157-47\tP216L\t>16\t2\t>16\t\n09/12/13\tV157-48\tP216L\t>16\t2\t>16\t\n09/12/13\tV157-62\tM220R\t>16\t8\t>16\t\n12/12/13\tV157-59\tM220R\t>16\t4\t>16\t\n12/12/13\tV157-60\tM220R\t>16\t4\t>16\t\n12/12/13\tV157-61\tM220R\t>16\t4\t>16\t\n19/12/13\tV157-80\tP216L\t>16\t1\t>16\t\nBold indicates a MIC exceeding the EUCAST clinical resistance breakpoint; which are defined as itraconazole >2 mg/L, voriconazole >2 mg/L and posaconazole >0.25 mg/L.\n\n\n\n3.1.3 Differences in colony morphology\nColony morphology differed hugely between isolates. The first 5 isolates (V130-15, V130-14, V130-18, V130-54, V157-39 and V157-40) produced wild-type green colonies whereas subsequent isolates produced predominantly white, sterile hyphae. Remarkably, the final isolate collected (V157-80) produced green1 colonies again (Fig. 1).Fig. 1 Observed colony morphology of the series. Sabouraud dextrose agar plates were spot inoculated with 5 × 102 conidia and incubated at 37 °C for 96 h.\n\n\n\n3.2 In depth characterisation of the isolates\n3.2.1 Whole genome comparisons between isolates\nAf293 was used as the reference genome based on assessment of mapping quality and coverage statistics; mean coverage across the series was 65X and mean mapping quality was 40 (Table A.1). SNP-based full genome phylogenetic analysis was performed (Lee et al., 2014). The sequences of various unrelated isolates were included in the phylogenetic analysis; a clinical isolate from Japan (IFM59361-1) (Hagiwara et al., 2014), a clinical isolate from the UK (09-7500806) (Abdolrasouli et al., 2015), an environmental isolate from the Netherlands (08-19-02-61) (Abdolrasouli et al., 2015) and a clinical isolate from India (Afu 1042/09) (Abdolrasouli et al., 2015). Fig. 2A highlights the genetic closeness of the series, as unrelated isolates showed greater genetic distance and diversity. In agreement with microsatellite typing results, whole genome sequencing verified the isolates to be isogenic (Fig. 2A). The first strain to be isolated (V130-15) was verified to be the precursor to the series (Fig. 2B). Later isolates appear to take on independent lineages of microevolution from the precursor isolate.Fig. 2 Phylogenetic tree based on whole genome sequences of the A. fumigatus series. (A) Single nucleotide polymorphism based phylogenetic tree was constructed using the SNPhylo pipeline and the whole genome sequences of the entire series as well as unrelated isolates IFM59361-1, 09-7500806, 08-19-02-61 and Afu 1042/09. (B) Unrooted phylogenetic tree of the series constructed using the SNPhylo pipeline. Tree scale represents nucleotide substitutions per site.\n\n\n\nA total of 248 non-synonymous SNPs, absent in early isolates V130-15 and V130-14, were identified in later isolates (Table A.2). These SNPs are predicted to have developed during the course of infection and in-host microevolution of the precursor strain (V130-15). SNPs of particular interest were identified based on their occurrence in multiple isolates or being localised in genes encoding proteins considered to play an important role in fungal cell metabolism and growth (Table 2). The genes identified were located across all 8 chromosomes and encoded a range of proteins including phospholipases (AFUA_3G07940 phosphoinositide phospholipase C), protein kinases (AFUA_2G01700 Snf1) and cell division control proteins (AFUA_3G10250 Cdc15). Cyp51A SNPs were identified in 9 isolates in the series. V157-39 harboured G54R; V157-40 harboured G54V; isolates V157-47, V157-48 and V157-80 harboured P216L; isolates V157-59, V157-60, V157-62 and V157-61 harboured M220R. SNPs were also identified in a range of uncharacterised proteins. For example, V204A SNP in AFUA_4G08100 was demonstrated in isolates V157-39, V157-48, V157-59, V157-60, V157-62, V157-61 and V157-80. A wide range of Cyp51A SNPs were identified, supporting the prediction that the isolates took on independent lineages of microevolution (Fig. 2B).Table 2 Non synonymous single nucleotide polymorphisms of particular interest present in isolates within the series.\n\nGene\tDescription\tV130-18\tV130-54\tV157-39\tV157-40\tV157-47\tV157-48\tV157-59\tV157-60\tV157-62\tV157-61\tV157-80\t\nAFUA_1G09270\tTransmembrane glycoprotein\t\t\t\t\t\tS772N\tS772N\tS772N\tS772N\tS772N\tS772N\t\nAFUA_1G12540\tTMEM1 family protein\t\t\t\t\t\t\tF879C\tF879C\tF879C\tF879C\t\t\nAFUA_2G01700\tCarbon catabolite Derepressing protein kinase Snf1\t\t\t\t\t\t\tR188Q\tR188Q\tR188Q\tR188Q\t\t\nAFUA_2G02320\tHsp70 chaperone (BiP)\t\t\t\t\t\t\t\t490*\t\t490*\t\t\nAFUA_2G08040\tC6 finger domain protein\t\t\tD347Y\t\t\tD347Y\tD347Y\tD347Y\tD347Y\tD347Y\tD347Y\t\nAFUA_3G07940\tPhosphoinositide phospholipase C\t\t\t\t\t\t\tKSS213KS\tKSS213KS\tKSS213KS\tKSS213KS\t\t\nAFUA_3G08990\tCell surface protein\tF141S\tF141S\t\t\t\t\t\t\t\t\t\t\nAFUA_3G10250\tCell division control protein (Cdc15)\t\t\tD220G\tD220G\t\tD220G\tD220G\tD220G\tD220G\tD220G\tD220G\t\nAFUA_3G11940\tChromatin modification-related protein\t\t\t154X\t\t\t\t292*\t292*\t292*\t292*\t154X\t\nAFUA_4G06890\tCyp51A\t\t\tG54R\tG54V\tP216L\tP216L\tM220R\tM220R\tM220R\tM220R\tP216L\t\nAFUA_4G08100\tUncharacterised protein\t\t\tV204A\t\t\tV204A\tV204A\tV204A\tV204A\tV204A\tV204A\t\nAFUA_4G13800\tExo-alpha-sialidase\t\t\t\t\t\t\tT214K\tT214K\tT214K\tT214K\t\t\nAFUA_4G14310\tUncharacterised protein\t\t\t\tA207I V209I\t\t\t\tA207I V209I\tA207I V209I\tA207I V209I\tA207I V209I\t\nAFUA_5G03760\tEndochitinase A1\tS438P\tS438P V436I\t\t\t\t\t\t\t\t\t\t\nAFUA_5G04050\tScramblase family protein\t\t\t128*\t\t\t\t128*\t128*\t128*\t128*\t128*\t\nAFUA_6G00530\tUncharacterised protein\t\t\t\t\t\tY380H\tY380H\tY380H\tY380H\tY380H\tY380H\t\nAFUA_6G10050\tSmall oligopeptide transporter, OPT family\t\t\tG428S\tG428S\t\tG428S\tG428S\tG428S\tG428S\tG428S\tG428S\t\nAFUA_6G10620\tNuclear pore complex subunit\t\t\tD43N\tD43N\t\tD43N\tD43N\tD43N\tD43N\tD43N\tD43N\t\nAFUA_6G14720\tTelomere-associated RecQ helicase\tI1077V\tI1077V P1152L R984C\tG1119R\tR984C A994V S996N\t\t\tD123N\t\t\tT969A\t\t\nIsolates V130-15 and V130-14 have been excluded from this table as they were defined as references, and therefore did not contain any substitutions.\n\n\n\nOf the SNPs identified, of particular interest was F125L in ZrfC alkaline zinc transporter (AFUA_4G09560) in the last isolate of the series, V157-80. F125L lies in the highly conserved ETFCND motif, which is C-terminal of a zinc-binding motif (Macpherson et al., 2005). The strict conservation of this motif indicates importance (Macpherson et al., 2005). Zinc depletion assays were performed in order to assess whether this isolate possessed any growth differences as a result of this SNP in zinc-limiting environments, much like the human host.\n\nIsolate V157-40 was selected as a control strain with a similar genetic background; both V157-40 and V157-80 possessed MICs > 16 mg/L for both ITR and POS. There were no significant growth differences between isolates V157-40 and V157-80 in the presence and absence of 1 mM zinc at pH 4.5 and 7.5. Both isolates exhibited significantly enhanced colony growth in the absence of zinc at pH 7.5 in comparison to pH 4.5 (p < 0.05). In the presence of zinc, growth differences between pH 4.5 and 7.5 were negligible in both isolates (Fig. 3). In summary, the SNP observed in ZrfC does not appear affect the ability to scavenge zinc under the conditions tested.Fig. 3 Comparison of mycelial growth of A. fumigatus isolates V157-40 and V157-80 in the presence and absence of zinc at pH 4.5 and 7.5. Isolates were pre-cultured on glucose minimal media lacking zinc for 7 d at 37 °C. Conidia were harvested via immersion in 30 mL PBS containing 0.05% Tween-80 and counted. Glucose minimal media plates lacking zinc or containing 1 mM zinc at pH 4.5 and 7.5 were spot inoculated with 5 × 102 conidia. Every 24 h for 96 h colony diameter was measured; results at 96 h are shown. Data was obtained in triplicate and mean values ± SD are shown (*p < 0.05; two-tailed Students T-test).\n\n\n\n3.2.2 Phenotypic analysis\nThe isolates showed variations in their growth kinetics in control liquid and solid media. The mean OD450 after 48 h growth in liquid media ranged from 0.666 (V130-18) to 0.818 (V157-48) (p = NS). All isolates cultured on solid media for 96 h showed growth colony diameters of between 30.2 (V130-14) and 37.5 mm (V157-39) (p = NS). Isolate V157-62 was an exception to this range. This isolate possessed a significantly decreased mean 96 h colony diameter of 16.2 mm (p = 0.003 compared to the mean of isolates V130-15, V157-39, V157-47 and V157-59). This represents a mycelial growth rate 52% slower than the other isolates (Fig. 1, Fig. 4). Specific isolates (V130-15, V157-39, V157-47, V157-62 and V157-59) were selected for detailed phenotypic analyses to assess their response to antifungal stressors. These isolates were considered representative of the different azole resistance profiles, Cyp51A mutations and growth rates observed in the series. As shown in Table 1, V130-15 was azole susceptible without Cyp51A SNPs; V157-39 harboured G54R in Cyp51A and was ITR and POS resistant; V157-47 harboured P216L in Cyp51A and was ITR and POS resistant; V157-62 had a growth defect, harboured M220R in Cyp51A and was ITR, VORI and POS resistant; V157-59 harboured M220R in Cyp51A and was ITR, VORI and POS resistant. As anticipated, in both solid and liquid media, isolates were unable to grow in the presence of a mould-active azole at a concentration higher than its MIC. Resistant isolates exhibited a concentration dependent decrease in growth in the presence of azole antifungal agents in both solid and liquid media (Fig. 4, Fig. 5). None of the isolates exhibited enhanced growth in comparison to control conditions in the presence of azole antifungals.Fig. 4 Comparison of mycelial growth of selected A. fumigatus isolates on solid media with increasing concentrations of itraconazole. Sabouraud dextrose agar plates were spot inoculated with 5 × 102 conidia and incubated at 37 °C. Colony diameter was measured every 24 h for 96 h; results for 96 h are shown. Data was obtained in triplicate and mean values ± SD are shown (*p = 0.003 compared to mean of V130-15, V157-39, V157-47 and V157-59; two-tailed Students T-test).\n\nFig. 5 Growth kinetics of selected A. fumigatus isolates in liquid media. Flat-bottomed 96-well plates were seeded with 1 × 105 conidia in RPMI with or without voriconazole (A) or posaconazole (B) in various concentrations. Plates were incubated at 37 °C for 48 h inside a spectrophotometric plate reader; the optical density at 450 nm was automatically measured every 20 min with 5 s shaking before every reading. Optical density at 48 h is shown. Data was obtained in duplicate, mean values ± SD are shown. No significant differences were observed between isolates under the same condition.\n\n\n\nThe series of strains were isolated from a CGD patient. This group of patients possess a defect in the nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase complex, this results in a failure to mount a phagocyte respiratory burst and produce superoxide (King et al., 2016). In order to assess whether the isolates displayed enhanced sensitivity to oxidative stress, as a result of adaptation in the CGD host, growth in the presence of tBOOH was assessed in both liquid and on solid media. Growth of all 5 isolates was fully inhibited by the presence of 2.5 mM tBOOH (data not shown). All 5 isolates grew normally at lower concentrations, indicating normal sensitivity to oxidative stress (Emri et al., 2015).\n\nIn order to further investigate the growth and development of the isolates, conidiation levels were quantified (Fig. 6). Under control conditions, specific resistant isolates (V157-39, V157-40, V157-47, V157-48, V157-62, V157-59, V157-60, V157-61, and V157-80) produced on average 5-fold less conidia than earlier isolates (V130-15, V130-14, V157-18 and V157-54) (p = 0.038). Conidia production in ITR resistant isolates (V157-39, V157-40, V157-47, V157-62, V157-60 and V157-80) increased on average 7-fold in the presence of 4 mg/L ITR (p = 0.041). Isolates V157-39 and V157-62 produced 5-fold (p = 0.023) and 3-fold (p = 0.0009) more conidia respectively in the presence of 4 mg/L ITR than susceptible isolates under control conditions. In summary, the majority of resistant isolates displayed increased levels of conidiation in the presence of 4 mg/L ITR. Isolates V157-48, V157-59 and V157-61 did not display this trend. However, upon passaging sterile hyphae onto 4 mg/L ITR, enhanced sporulation was observed.Fig. 6 Comparison of amount of conidia produced by the A. fumigatus strains throughout the series. T75 culture flasks containing Sabouraud dextrose agar with or without the addition of 4 mg/L itraconazole, were inoculated with 1x105 conidia and incubated at 37 °C for 7 d. Conidial suspensions were prepared via immersion in 30 mL PBS containing 0.05% Tween-80 and counted. Data was obtained in duplicate and mean values ± SD are shown (*p = 0.023, **p = 0.0009; two-tailed Students T-test).\n\n\n\n3.2.3 Differences in virulence between isolates\nIn order to assess associated changes in virulence in the series, survival studies were performed using the well-established invertebrate model of systemic infection, Galleria mellonella (Gomez-Lopez et al., 2014, Renwick et al., 2006, Slater et al., 2011). Clear differences in mortality rates were observed for the isolates tested (Fig. 7). The percentage survival at 6 d ranged from 10% (isolate V157-39) to 60% (isolate V157-62). The percentage survival at 6 d was 40% after infection with the first isolate (V130-15). Survival after infection with isolate V157-62, the only isolate with a growth defect, was significantly higher than after infection with isolate V130-15 (p = 0.037). Survival after infection with isolate V157-39 was significantly lower than after infection with isolate V130-15 (p = 0.01). No associations between virulence and conditions levels and/or resistance profile could be made.Fig. 7 Survival of Galleria mellonella larvae infected with specific isolates. Groups of 10 G. mellonella larvae were infected with 6 × 103 conidia in the last pro-leg using a 0.33 mm Micro-Fine needle. Two control groups of larvae were included in each experiment; 10 unmanipulated larvae and 10 larvae injected with phosphate-buffered saline. Larvae were monitored for 6 d; larval death was characterised by lack of movement and melanisation. Survival after infection with isolate V157-62 or V135-39 was significantly higher in comparison to isolate V130-15 (*p < 0.05; two-tailed Students T-test).\n\n\n\n4 Discussion\nIn this study we investigated the dynamics of both physiological and genetic adaptation in A. fumigatus throughout chronic and recurrent infection. Central to this study was our series of 13 isolates obtained from a single chronic granulomatous disease patient over a period of 2 years. Using this unique series, we identified large numbers of genetic changes thought to have occurred throughout infection and disease. These non-synonymous mutations identified have potential to play a role in adaptation to the human host under antifungal therapy. Additionally, we identified one isolate that displays a severe growth defect. We also observed significant differences in the ability of the isolates to produce conidia. Isolates were demonstrated to exhibit varying levels of virulence and be more equipped to cope with zinc depletion at pH 7.5 in comparison to pH 4.5, which is consistent with previous findings (Amich et al., 2010).\n\nIt is hypothesised that advantageous SNPs, which have developed during natural random mutation, are selected for during exposure to in-host stressors, such as azoles and effectors of the innate immunity. Subsequent natural selection is thought to enable survival. Here, we identified 248 SNPs predicted to have arisen during the course of infection in one host. Specific proteins were mutated in multiple isolates in the series. The identified proteins are involved in a wide range of cellular activities, indicating the stressors present in-host to be equally wide ranging. It is expected that the identified proteins play a role in in-host adaptation. Azole target Cyp51A is a hotspot for mutations conferring azole resistance (Zoll et al., 2016). Nine isolates within our series contained a SNP in Cyp51A. As the initial susceptible isolates lacked Cyp51A SNPs it can be concluded that these SNPs developed in-host, presumably as a result of azole pressure. Isolates contained either G54R, G54V, P216L or M220R SNPs, all of which have previously been proven to result in azole resistance to varying degrees (Bellete et al., 2010, Bueid et al., 2010, Chen et al., 2005, Garcia-Effron et al., 2005, Hodiamont et al., 2009, Howard et al., 2009, Kuipers et al., 2011, Mann et al., 2003, Mellado et al., 2003, Mellado et al., 2007, Mellado et al., 2004, Snelders et al., 2010, Xiao et al., 2004). In most cases the Cyp51A SNP present did not fully explain the resistance profile observed, indicating the presence of additional non-cyp51A mediated resistance mechanisms. As an example, isolate V157-39 was highly resistant to both POS and ITR. This isolate possessed a G54R substitution in Cyp51A, which has previously been shown to confer ITR resistance (Mellado et al., 2003). The POS resistance of this isolate is as yet unexplained.\n\nFour isolates possessed SNP R188Q in Snf1 kinase; this protein is known to be involved in nutrient limitation and salt stress responses in Saccharomyces cerevisiae (Hsu et al., 2015, Sanz, 2003). It is possible that R188Q alters Snf1 functionality, potentially enhancing the ability of the isolates to cope with these stresses, which could enable persistence of infection. Furthermore, 7 isolates possessed SNP D347Y in C6 finger domain protein (AFUA_2G08040). This protein possesses RNA polymerase II transcription factor activity and is zinc ion binding (Bateman et al., 2015). Interestingly, Hagiwara et al also reported a mutation (Y958) in this C6 finger domain protein, predicted to have developed throughout infection in an invasive pulmonary aspergillosis patient (Hagiwara et al., 2014). This supports our hypothesis that the identified proteins are involved in in-host adaptation.\n\nFitness losses in clinical azole resistant A. fumigatus isolates are frequently reported (Hagiwara et al., 2014, Valsecchi et al., 2015). Various methods of assessing fitness are described in A. fumigatus (Arendrup et al., 2010, Lackner et al., 2017, Valsecchi et al., 2015). In this study we performed liquid and solid media growth assays. These growth assays were selected to represent different forms of in vivo growth. Liquid assays were deemed a basic representation of growth in human tissue, where conidiation does not occur. Solid media assays were chosen to crudely represent growth with sporulation, which occurs when the fungus is in contact with the air, as on the epithelial lining of the airways. Isolate V157-62 was shown to harbour defects in both conidiation and growth on solid media. This isolate contains a M220R Cyp51A mutation. Previous in vivo competition studies, using both immunocompetent and immunosuppressed mice, have shown that M220 SNPs are not associated with fitness costs (Lackner et al., 2017, Valsecchi et al., 2015). It is possible that other SNPs gained as a result of adaptation are the cause of this fitness defect. These SNPs could be either beneficial and associated with a fitness cost or simply disadvantageous. Clues can be obtained using whole genome sequencing however further research is required to definitively associate specific SNPs, or combinations thereof, with this phenotype.\n\nLater isolates were shown to produce significantly fewer conidia than earlier more susceptible isolates. Conidiation in specific isolates was restored in the presence of itraconazole. This could be classified as azole addiction, where the fungus has adapted to grow in the presence of azole and as a result requires it for specific aspects of growth. These isolates do not share an isolation date or resistance profile, but perhaps shared localisation within the lung and therefore adapted similarly. As the majority of isolates possessed normal mycelial growth rates, the defect lies directly in the isolates’ ability to form conidia. In agreement with our findings, Hagiwara et al also reported a sporulation defect in serially isolated clinical strains from individual patients (Hagiwara et al., 2014). It can be hypothesised that the virulence of the poorly sporulating isolates is unaffected by this defect as conidiation is rarely observed in human tissue and is not required for invasive disease pathogenesis. However, the environmental spread of resistant isolates with this defect is likely to be limited.\n\nInterestingly, under zinc depletion isolates grew better at pH 7.5 in comparison to pH 4.5. ZrfC is central to this behaviour. This zinc transporter is capable of functioning under alkaline zinc limiting conditions due to its N-terminus, which is also predicted to scavenge Zn2+ from host tissues (Amich et al., 2014, Wilson et al., 2012). It is probable that these strains have evolved in host and are therefore more adapted to scavenge zinc and thrive at physiological pH in host. Survival in acidic conditions is perhaps driven by adaptation to the ecological niche of A. fumigatus in soil. The SNP identified by us in the ZrfC in V157-80 did not influence the capability to grow in alkaline zinc limiting conditions and seems not to play a role in in-host adaptation.\n\nThe phenotypic and genotypic changes observed in the series may be associated with the virulence differences observed in our experimental G. mellonella model. Isolates exhibited both increased and decreased virulence in comparison to the precursor isolate (V130-15). The isolate determined to have a growth defect in vitro (V157-62) showed attenuated virulence in comparison to V130-15. This could be a direct impact of its slower mycelial growth. Another azole resistant isolate (V157-39) showed enhanced virulence in comparison to V130-15. In agreement with previous findings, no associations could be made between resistance development and changes in virulence (Lackner et al., 2017, Valsecchi et al., 2015). Furthermore, no associations could be made between conidiation levels and virulence. As mycelial growth drives invasion in-host rather than conidiation, it is possible that differences in conidiation ability have minimal impact on ability to cause infection. It is likely that microevolution has driven both increases and decreases in virulence. Attenuated virulence may well be a cost associated with another yet unidentified adaptation mechanism. Increases in virulence are regarded as direct adaptation to enable persistence.\n\n5 Conclusions\nIn summary, A. fumigatus undergoes substantial in-host adaptation. This adaptation occurs on both a physiological and genetic level as illustrated by our results, and is hypothesised to enable persistence of infection in some cases. Genetic changes reported here are wide ranging, suggesting that the stressors driving adaptation are equally wide ranging. It should be noted that as this study involves a series of isolates from a single chronic granulomatous disease patient, adaptation dynamics reported may not be representative of other patient groups and/or other patients with chronic granulomatous disease. However, this study is the first to provide in depth analysis into the genetic and physiological changes that occur in A. fumigatus during adaptation to the human host.\n\nAppendix A\nTable A.1Table A1 Mean coverage and mapping quality of whole genome sequence data sets to Af293 reference.\n\nStrain\tMean coverage (X)\tMean mapping quality\t\nV130-15\t69\t40\t\nV130-14\t85\t39\t\nV130-18\t118\t39\t\nV130-54\t69\t39\t\nV157-39\t62\t40\t\nV157-40\t76\t41\t\nV157-47\t20\t37\t\nV157-48\t25\t37\t\nV157-62\t53\t41\t\nV157-59\t77\t40\t\nV157-60\t58\t41\t\nV157-61\t61\t39\t\nV157-80\t71\t41\t\n\n\n\t\nMean across series\t65\t40\t\n\n\nTable A.2Table A2 Non synonymous single nucleotide polymorphisms identified to have developed throughout the course of infection in the series of isolates.\n\nGene\tDescription\tV130-18\tV130-54\tV157-39\tV157-40\tV157-47\tV157-48\tV157-59\tV157-60\tV157-62\tV157-61\tV157-80\t\nAFUA_1G00220\tUncharacterised protein\t\t\t\t\t\t\t\t\t\tA430V T437I 348 S493L\t\nAFUA_1G00230\tUncharacterised protein\t\t\t\t748*\t\tL756A\t\t748*\t\t\t\t\nAFUA_1G00550\tUncharacterised protein\tA430V\t\t\tT11M\t\tV369L\t\t\tS168L M170I V173I D175N R176C T182C T182I\t\t\nAFUA_1G00750\tUncharacterised protein\t\t\t\t\t\t\t171 A170T M162I P155L M153I S152L\t\t\t\t\nAFUA_1G12130\tTranslation initiation factor eIF4E\t\t\t\t\t\t\tV160A\t\t\t\t\t\nAFUA_1G06060\tUncharacterised protein\t\t\tA786T G608V S772N\t\t\t\t\t\t\t\t\t\nAFUA_1G08920\tIQ calmodulin-binding motif domain protein\t\t\t\t\t\tA189V\t\t\t\t\t\t\nAFUA_1G09270\tTransmembrane glycoprotein\t\t\t\t\t\tS772N\tS772N\tS772N\tS772N\tS772N\tS772N\t\nAFUA_1G12540\tTMEM1 family protein\t\t\t\t\t\t\tF879C\tF879C\tF879C\tF879C\t\t\nAFUA_1G15940\tAuxin Efflux Carrier superfamily\t\t\t\t\t\tG318GGGS\t\t\t\tG281C\t\t\nAFUA_2G00230\tAmid-like NADH oxidoreductase\t\t\tE240A\t\t\t\t\t\t\t\t\t\nAFUA_2G01700\tCarbon catabolite derepressing protein kinase Snf1\t\t\t\t\t\t\tR188Q\tR188Q\tR188Q\tR188Q\t\t\nAFUA_2G02320\tHsp70 chaperone (BiP)\t\t\t\t\t\t\t\t490*\t\t490*\t\t\nAFUA_2G04290\tCytochrome P450 monooxygenase\t\t\t\tN176S\t\t\t\t\t\t\t\t\nAFUA_2G07450\tPX domain protein\t\t\t\t\t\t\t\t\t\tL282F\t\t\nAFUA_2G08040\tC6 finger domain protein\t\t\tD347Y\t\t\tD347Y\tD347Y\tD347Y\tD347Y\tD347Y\tD347Y\t\nAFUA_2G09710\tProtein kinase (NpkA)\t\t\t\t\t\t\t\t\t\t\tP414L\t\nAFUA_2G11570\tF-box domain protein\t\t\tG204V\t\t\t\t\t\t\t\t\t\nAFUA_2G12360\tWD repeat protein\t\t\t\tE942K\t\t\t\t\t\t\t\t\nAFUA_2G13500\tUncharacterised protein\t\t\t\t\t\t\tT\t\t\t\t\t\nAFUA_2G13770\tC2H2 conidiation transcription factor FlbC\t\t\t\t\t\t\t\t218*\t\t\t\t\nAFUA_2G16170\tDNA-directed RNA polymerase III RPC4\t\tR16A\t\t\t\t\t\t\t\t\t\t\nAFUA_2G13960\tTafazzin\t\t\t\tL157F\t\t\t\t\t\t\t\t\nAFUA_2G16830\tEndonuclease/exonuclease/phosphatase family protein\t\t\t\t\t\t\t\t\tG190R\t\t\t\nAFUA_2G17000\tPT repeat family protein\tE1362K\t\t\t\t\t\t\t\t\t\t\t\nAFUA_2G17600\tConidial pigment polyketide synthase PksP/Alb1\t\t\t\tS1197Y\t\t\t\t\t\t\t\t\nAFUA_2G18100\tTelomere-associated RecQ helicase\t\t\t\t\t\t\t\t\t\t\t\t\nAFUA_3G02550\tUncharacterised protein\t\t\t\t\t\t\t\t\t\tY33F S34L\t\t\nAFUA_3G02640\tNucleoside-diphosphate-sugar epimerase family protein\t\t\t\t\t\t\t\t\t\t237 A243T T248C\t\t\nAFUA_3G03852\tC2H2 type zinc finger domain protein\t\t\t\tC292Y\t\t\t\t\t\t\t\t\nAFUA_3G04300\tActin cytoskeleton organization and biogenesis protein\t\t\t\tP1125H\t\t\t\t\t\t\t\t\nAFUA_3G07080\tUPF0016 domain protein\t\t\t\tV470M\t\t\t\t\t\t\t\t\nAFUA_3G07940\tPhosphoinositide phospholipase C\t\t\t\t\t\t\tKSS213KS\tKSS213KS\tKSS213KS\tKSS213KS\t\t\nAFUA_3G08570\tUncharacterised protein\t\t\t\t\t\t\t\t\t\t\tV54L\t\nAFUA_3G08990\tCell surface protein\tF141S\tF141S\t\t\t\t\t\t\t\t\t\t\nAFUA_3G10250\tCell division control protein (Cdc15)\t\t\tD220G\tD220G\t\tD220G\tD220G\tD220G\tD220G\tD220G\tD220G\t\nAFUA_3G10290\tUncharacterised protein\t\t\t\t\t\t\t\t\tR198W\t\t\t\nAFUA_3G10450\tUncharacterised protein\t\t\t\tR718C\t\t\t\t\t\t\t\t\nAFUA_3G11940\tChromatin modification-related protein\t\t\t154X\t\t\t\t292*\t292*\t292*\t292*\t154X\t\nAFUA_3G14445\tBromodomain associated domain protein\t\t\t\tR223C\t\t\t\t\t\t\t\t\nAFUA_3G14510\tRhamnogalacturonan acetylesterase RgaE\t\t\t\t\t\t\t\t\tP186L\t\t\t\nAFUA_3G14700\tPolyketide synthase\t\t\t\t\t\t\t\t\t\tA1923G\t\t\nAFUA_4G04760\tInositol kinase kinase (UvsB)\t\t\tE485Q\t\t\t\t\t\t\t\t\t\nAFUA_4G06890\tCyp51A\t\t\tG54R\tG54V\tP216L\tP216L\tM220R\tM220R\tM220R\tM220R\tP216L\t\nAFUA_4G07530\tUncharacterised protein\t\t\t\t\t\t288HDD\t\t\t\t\t\t\nAFUA_4G08100\tUncharacterised protein\t\t\tV204A\t\t\tV204A\tV204A\tV204A\tV204A\tV204A\tV204A\t\nAFUA_4G08360\tMediator of RNA polymerase II transcription subunit 8\t\tE188V\t\t\t\t\t\t\t\t\t\t\nAFUA_4G09560\tZIP Zinc transporter\t\t\t\t\t\t\t\t\t\t\tF125L\t\nAFUA_4G12050\tThermoresistant gluconokinase family protein\t\t\tL196V\t\t\t\t\t\t\t\t\t\nAFUA_5G12440\tCell cycle control protein (Cwf23)\t\t\t\t\tA242V\t\t\t\t\t\t\t\nAFUA_4G13000\tLysine-specific histone demethylase Aof2\t\t\t\tE2D\t\t\t\t\t\t\t\t\nAFUA_4G13800\tExo-alpha-sialidase\t\t\t\t\t\t\tT214K\tT214K\tT214K\tT214K\t\t\nAFUA_4G14310\tUncharacterised protein\t\t\t\tA207I V209I\t\t\t\tA207I V209I\tA207I V209I\tA207I V209I\tA207I V209I\t\nAFUA_5G02390\tAuxin Efflux Carrier superfamily\t\t\t\tV403D\t\t\t\t\t\t\t\t\nAFUA_5G03760\tEndochitinase A1\tS438P\tS438P V436I\t\t\t\t\t\t\t\t\t\t\nAFUA_5G04050\tScramblase family protein\t\t\t128*\t\t\t\t128*\t128*\t128*\t128*\t128*\t\nAFUA_5G07140\tTranslation elongation factor G2\t\t\t\tA542S\t\t\t\t\t\t\t\t\nAFUA_5G08330\tRNA binding protein\t\t\t\t\t\t\t\t\t\t\tT209S\t\nAFUA_5G08390\tResponse regulator\t\t\tV706F\t\t\t\t\t\t\t\t\t\nAFUA_5G11820\tSurvival factor 1\t\t\t\t\t\t\t\t\t213*\t\t\t\nAFUA_5G14920\tUncharacterised protein\tW372S\t\t\t\t\t\t\t\t\t\t\t\nAFUA_5G14865\tUncharacterised protein\t\t\t\t\t\t\t\t\t\t301*\t\t\nAFUA_6G00530\tUncharacterised protein\t\t\t\t\t\tY380H\tY380H\tY380H\tY380H\tY380H\tY380H\t\nAFUA_6G04080\tUncharacterised protein\t\t\t\tA1393T\t\t\t\t\t\t\t\t\nAFUA_6G05280\tMeiosis protein MEI2\t\t\t\tK417N\t\t\t\t\t\t\t\t\nAFUA_6G06335\tHistone-lysine N-methyltransferase, H3 lysine-4 specific\t\t\tR578C\t\t\t\t\t\t\t\t\t\nAFUA_6G07660\tUncharacterised protein\t\t\t\t\t\t\t\t\t\tE169K\t\t\nAFUA_6G10050\tSmall oligopeptide transporter, OPT family\t\t\tG428S\tG428S\t\tG428S\tG428S\tG428S\tG428S\tG428S\tG428S\t\nAFUA_6G10380\tCullin binding protein CanA\t\t\t\t\t\t\t\t\tL91V\t\t\t\nAFUA_6G10490\tUncharacterised protein\t\t\t\t\t\t\t\t\t\t\tY365C\t\nAFUA_6G10620\tNuclear pore complex subunit\t\t\tD43N\tD43N\t\tD43N\tD43N\tD43N\tD43N\tD43N\tD43N\t\nAFUA_6G12950\tAlpha, alpha-trehalose-phosphate synthase (UDP-forming)\t\t\t\t\t\t\t\t\tV265A\t\t\t\nAFUA_6G13660\tUncharacterised protein\t\t\t\t\t\t\t\t\t\tP865L\t\t\nAFUA_6G13800\tIntegral membrane protein Pth11-like\t\t\t\t\t\t\t\tW148C\t\t\t\t\nAFUA_6G13900\tUncharacterised protein\t\t\t\t\t\t\t\t\t\t\tK413N\t\nAFUA_6G14720\tTelomere-associated RecQ helicase\tI1077V\tI1077V P1152L R984C\tG1119R\tR984C A994V S996N\t\t\tD123N\t\t\tT969A\t\t\nAFUA_7G00720\tUncharacterised protein\tA311T\t\t\t\t\tA311T\t\t\t\tA311T\t\t\nAFUA_7G01290\tUncharacterised protein\t\t\t\t\tG51R\t\t\t\t\t\t\t\nAFUA_7G01310\tC6 transcription factor\t\t\t\t\t\t\t\t\t\t\tQ538H\t\nAFUA_7G01960\tUncharacterised protein\t\t\t\t\t\t\t\t\t167*\t\t\t\nAFUA_7G04180\tAmine oxidase\t\t\t\tR614P\t\t\t\t\t\t\t\t\nAFUA_7G05220\tMitochondrial carrier protein\t\t\t\t\t\t\t\t\t\t\tV639L\t\nAFUA_7G05960\tC2H2 finger domain protein\t\t\t\tG792D\t\t\t\t\t\t\t\t\nAFUA_7G08250\tC6 finger domain protein\tS749G\t\t\t\t\t\t\tS749G\t\t\t\t\nAFUA_7G08630\tUncharacterised protein\t\t\t\t\t\t\t\t\t\t\t\t\nAFUA_8G00750\tC2H2 transcription factor\tQ429K\t\tC45Y\t\t\t\t\t\t\t\t\t\nAFUA_8G01820\tUncharacterised protein\t\t\t\t\t\tGX\t\t\t\t\t\t\nAFUA_8G02420\tUncharacterised protein\t\t\t\tE\t\t\t\t\t\t\t\t\nAFUA_8G02850\tActin binding protein\t\t\t\t\t\t\t\t\t\t\tS505T\t\nAFUA_8G04520\tCytoskeleton assembly control protein Sla1\t\t\tQ257K\t\t\t\t\t\t\t\t\t\nAFUA_8G05780\tNACHT and Ankyrin domain protein\t\t\t\t\tK618E Q622H\t\t\t\t\t\t\t\nAFUA_8G06132\tFluG domain protein\tG81R M90I A135I E142K R79H T82M\tA135I\t\t\t\t\t\t\t\t\t\t\nAFUA_8G06140\tSensor histidine kinase/response regulator\tA231I F232L M222D S223N T218A\t\t\t\t\t\t\t\t\t\t\nAFUA_8G06210\tMetalloreductase transmembrane component\t\t\t\tR479Y\t\t\t\t\t\t\t\nAFUA_8G06220\tUncharacterised protein\t\tS238L V245I\t\t\t\t\t\t\t\tS238L 239 V245I 249 V249M G252S 253\t\nAFUA_8G06230\tUncharacterised protein\t\t\tV50M\t\t\t\t\t\t\t\t\nIsolates V130-15 and V130-14 have been excluded from this table as they were defined as references, and therefore did not contain any substitutions.\n\n\n\nAcknowledgments\nWe are thankful to Kenny Ntwari Nindorera for performing the G. mellonella survival studies. EB, AB and AW are supported by the Wellcome Trust Strategic Award (grant 097377), the MRC Centre for Medical Mycology (grant MR/N006364/1) at the University of Aberdeen. AB was also supported by the Biotechnology and Biological Research Council (BB/K017365/1) and the Medical Research Council (MR/M026663/1). The work in this paper is funded by a BBSRC EASTBIO grant. The funders had no role in study design, data interpretation, or the decision to submit the work for publication.\n\n1 For interpretation of color in Fig. 1, the reader is referred to the web version of this article.\n==== Refs\nReferences\nAbdolrasouli A. Rhodes J. Beale M.A. Hagen F. Rogers T.R. Chowdhary A. Meis J.F. Armstrong-James D. Fisher M.C. Genomic context of azole resistance mutations in Aspergillus fumigatus determined using whole-genome sequencing MBio 6 2015 e00536 15 26037120 \nAlbarrag A.M. Anderson M.J. Howard S.J. Robson G.D. Warn P.A. Sanglard D. Denning D.W. Interrogation of related clinical pan-azole-resistant Aspergillus fumigatus strains: G138C, Y431C, and G434C single nucleotide polymorphisms in cyp51A, upregulation of cyp51A, and integration and activation of transposon Atf1 in the cyp51A promoter Antimicrob. Agents Chemother. 55 2011 5113 5121 21876055 \nAmich J. Vicentefranqueira R. Leal F. Calera J.A. Aspergillus fumigatus survival in alkaline and extreme zinc-limiting environments relies on the induction of a zinc homeostasis system encoded by the zrfc and aspf2 genes Eukaryot. Cell 9 2010 424 437 20038606 \nAmich J. Vicentefranqueira R. Mellado E. Ruiz-Carmuega A. Leal F. Calera J.A. The ZrfC alkaline zinc transporter is required for Aspergillus fumigatus virulence and its growth in the presence of the Zn/Mn-chelating protein calprotectin Cell. Microbiol. 16 2014 548 564 24245710 \nAnderson J.B. Evolution of antifungal-drug resistance: mechanisms and pathogen fitness Nat. Rev. Microbiol. 3 2005 547 556 15953931 \nArendrup M.C. Mavridou E. Mortensen K.L. Snelders E. Frimodt-Møller N. Khan H. Melchers W.J.G. Verweij P.E. Development of azole resistance in aspergillus fumigatus during azole therapy associated with change in virulence PLoS One 5 2010 \nArmstrong-James D. Meintjes G. Brown G.D. A neglected epidemic: fungal infections in HIV/AIDS Trends Microbiol. 22 2016 120 127 \nBateman A. Martin M.J. O’Donovan C. Magrane M. Apweiler R. Alpi E. Antunes R. Arganiska J. Bely B. Bingley M. Bonilla C. Britto R. Bursteinas B. Chavali G. Cibrian-Uhalte E. Da Silva A. De Giorgi M. Dogan T. Fazzini F. Gane P. Castro L.G. Garmiri P. Hatton-Ellis E. Hieta R. Huntley R. Legge D. Liu W. Luo J. Macdougall A. Mutowo P. Nightingale A. Orchard S. Pichler K. Poggioli D. Pundir S. Pureza L. Qi G. Rosanoff S. Saidi R. Sawford T. Shypitsyna A. Turner E. Volynkin V. Wardell T. Watkins X. Zellner H. Cowley A. Figueira L. Li W. McWilliam H. Lopez R. Xenarios I. Bougueleret L. Bridge A. Poux S. Redaschi N. Aimo L. Argoud-Puy G. Auchincloss A. Axelsen K. Bansal P. Baratin D. Blatter M.C. Boeckmann B. Bolleman J. Boutet E. Breuza L. Casal-Casas C. De Castro E. Coudert E. Cuche B. Doche M. Dornevil D. Duvaud S. Estreicher A. Famiglietti L. Feuermann M. Gasteiger E. Gehant S. Gerritsen V. Gos A. Gruaz-Gumowski N. Hinz U. Hulo C. Jungo F. Keller G. Lara V. Lemercier P. Lieberherr D. Lombardot T. Martin X. Masson P. Morgat A. Neto T. Nouspikel N. Paesano S. Pedruzzi I. Pilbout S. Pozzato M. Pruess M. Rivoire C. Roechert B. Schneider M. Sigrist C. Sonesson K. Staehli S. Stutz A. Sundaram S. Tognolli M. Verbregue L. Veuthey A.L. Wu C.H. Arighi C.N. Arminski L. Chen C. Chen Y. Garavelli J.S. Huang H. Laiho K. McGarvey P. Natale D.A. Suzek B.E. Vinayaka C.R. Wang Q. Wang Y. Yeh L.S. Yerramalla M.S. Zhang J. UniProt: A hub for protein information Nucleic Acids Res. 43 2015 D204 D212 25348405 \nBellete B. Raberin H. Morel J. Flori P. Hafid J. Manhsung R.T. Acquired resistance to voriconazole and itraconazole in a patient with pulmonary aspergilloma Med. Mycol. 48 2010 197 200 20055745 \nBolger A.M. Lohse M. Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data Bioinformatics 30 2014 2114 2120 24695404 \nBosschef H Vanden Koymans L. Moereels H. P450 inhibitors of use in medical treatment: focus on of action mechanisms Science 67 1995 79 100 \nBoyaval P. Moineau S. Romero D.A. Horvath P. CRISPR provides acquired resistance against viruses in prokaryotes Science 315 2007 1709 1712 17379808 \nBromley M. Johns A. Davies E. Fraczek M. Gilsenan J.M. Mitochondrial complex I is a global regulator of secondary metabolism, virulence and azole sensitivity in fungi PLoS One 2016 e0158724 27438017 \nBueid A. Howard S.J. Moore C.B. Richardson M.D. Harrison E. Bowyer P. Denning D.W. Azole antifungal resistance in Aspergillus fumigatus: 2008 and 2009 J. Antimicrob. Chemother. 65 2010 2116 2118 20729241 \nBuied A. Moore C.B. Denning D.W. Bowyer P. High-level expression of cyp51B in azole-resistant clinical aspergillus fumigatus isolates J. Antimicrob. Chemother. 68 2013 512 514 23208831 \nCamps S.M.T. Dutilh B.E. Arendrup M.C. Rijs A.J.M.M. Snelders E. Huynen M.A. Verweij P.E. Melchers W.J.G. Discovery of a hapE mutation that causes azole resistance in aspergillus fumigatus through whole genome sequencing and sexual crossing PLoS One 7 2012 e50034 23226235 \nChen J. Li H. Li R. Bu D. Wan Z. Mutations in the cyp51A gene and susceptibility to itraconazole in Aspergillus fumigatus serially isolated from a patient with lung aspergilloma J. Antimicrob. Chemother. 55 2005 31 37 15563516 \nDanecek P. Auton A. Abecasis G. Albers C.A. Banks E. DePristo M.A. Handsaker R.E. Lunter G. Marth G.T. Sherry S.T. McVean G. Durbin R. The variant call format and VCFtools Bioinformatics 27 2011 2156 2158 21653522 \nde Valk H. Meis J.F.G.M. Curfs I.M. Muehlethaler K. Mouton J.W. Corné H.W. Use of a novel panel of nine short tandem repeats for exact and high-resolution fingerprinting of aspergillus fumigatus isolates J. Clin. Microbiol. 43 2005 4112 4120 16081958 \nDenning D.W. Venkateswarlu K. Oakley K.L. Anderson M.J. Manning N.J. Stevens D.A. Warnock D.W. Kelly S.L. Itraconazole resistance in Aspergillus fumigatus Antimicrob. Agents Chemother. 41 1997 1364 1368 9174200 \nEdgar R.C. MUSCLE: multiple sequence alignment with high accuracy and high throughput Nucleic Acids Res. 32 2004 1792 1797 15034147 \nEmri T. Szarvas V. Orosz E. Antal K. Park H. Han K.-H. Yu J.-H. Pócsi I. Core oxidative stress response in Aspergillus nidulans BMC Genomics 16 2015 478 26115917 \nFedorova N.D. Khaldi N. Joardar V.S. Maiti R. Amedeo P. Anderson M.J. Crabtree J. Silva J.C. Badger J.H. Albarraq A. Angiuoli S. Bussey H. Bowyer P. Cotty P.J. Dyer P.S. Egan A. Galens K. Fraser-Liggett C.M. Haas B.J. Inman J.M. Kent R. Lemieux S. Malavazi I. Orvis J. Roemer T. Ronning C.M. Sundaram J.P. Sutton G. Turner G. Venter J.C. White O.R. Whitty B.R. Youngman P. Wolfe K.H. Goldman G.H. Wortman J.R. Jiang B. Denning D.W. Nierman W.C. Genomic islands in the pathogenic filamentous fungus Aspergillus fumigatus PLoS Genet. 4 2008 e1000046 18404212 \nFisher M.C. Henk D.A. Briggs C.J. Brownstein J.S. Madoff L.C. McCraw S.L. Gurr S.J. Emerging fungal threats to animal, plant and ecosystem health Nature 484 2012 186 194 22498624 \nFlicek P. Amode M.R. Barrell D. Beal K. Billis K. Brent S. Carvalho-Silva D. Clapham P. Coates G. Fitzgerald S. Gil L. Girón C.G. Gordon L. Hourlier T. Hunt S. Johnson N. Juettemann T. Kähäri A.K. Keenan S. Kulesha E. Martin F.J. Maurel T. McLaren W.M. Murphy D.N. Nag R. Overduin B. Pignatelli M. Pritchard B. Pritchard E. Riat H.S. Ruffier M. Sheppard D. Taylor K. Thormann A. Trevanion S.J. Vullo A. Wilder S.P. Wilson M. Zadissa A. Aken B.L. Birney E. Cunningham F. Harrow J. Herrero J. Hubbard T.J.P. Kinsella R. Muffato M. Parker A. Spudich G. Yates A. Zerbino D.R. Searle S.M.J. Variant effect predictor Nucleic Acids Res. 2014 \nFraczek M.G. Bromley M. Buied A. Moore C.B. Rajendran R. Rautemaa R. Ramage G. Denning D.W. Bowyer P. The cdr1B efflux transporter is associated with non-cyp51a-mediated itraconazole resistance in Aspergillus fumigatus J. Antimicrob. Chemother. 68 2013 1486 1496 23580559 \nGarcia-Alcalde F. Okonechnikov K. Carbonell J. Cruz L.M. Gotz S. Tarazona S. Dopazo J. Meyer T.F. Conesa A. Qualimap: evaluating next-generation sequencing alignment data Bioinformatics 28 2012 2678 2679 22914218 \nGarcia-Effron G. Mellado E. Gomez-Lopez A. Alcazar-Fuoli L. Cuenca-Estrella M. Rodriguez-Tudela J.L. Differences in interactions between azole drugs related to modifications in the 14-α sterol demethylase gene (cyp51A) of Aspergillus fumigatus Antimicrob. Agents Chemother. 49 2005 2119 2121 15855543 \nGarrison, E., Marth, G., 2012. Haplotype-based variant detection from short-read sequencing. arXiv Prepr. arXiv1207.3907 9. doi: arXiv:1207.3907 [q-bio.GN].\nGhannoum, M.A., Rice, L.B., 1999. Antifungal Agents : Mode of Action, Mechanisms of Resistance, and Correlation of These Mechanisms with Bacterial Resistance 12, pp. 501–517. doi: 10.1.1.322-6182.\nGiardine B. Riemer C. Hardison R.C. Burhans R. Elnitski L. Shah P. Zhang Y. Blankenberg D. Albert I. Taylor J. Miller W. Kent W.J. Nekrutenko A. Galaxy: a platform for interactive large-scale genome analysis Genome Res. 15 2005 1451 1455 16169926 \nGollapudy R. Ajmani S. Kulkarni S.A. Modeling and interactions of Aspergillus fumigatus lanosterol 14-α demethylase “A” with azole antifungals Bioorganic Med. Chem. 12 2004 2937 2950 \nGomez-Lopez A. Forastiero A. Cendejas-Bueno E. Gregson L. Mellado E. Howard S.J. Livermore J.L. Hope W.W. Cuenca-Estrella M. An invertebrate model to evaluate virulence in Aspergillus fumigatus: the role of azole resistance Med. Mycol. 52 2014 311 319 24577012 \nHagiwara D. Takahashi H. Watanabe A. Takahashi-Nakaguchi A. Kawamoto S. Kamei K. Gonoi T. Whole-genome comparison of aspergillus fumigatus strains serially isolated from patients with aspergillosis J. Clin. Microbiol. 52 2014 4202 4209 25232160 \nHodiamont C.J. Dolman K.M. Ten Berge I.J.M. Melchers W.J.G. Verweij P.E. Pajkrt D. Multiple-azole-resistant Aspergillus fumigatus osteomyelitis in a patient with chronic granulomatous disease successfully treated with long-term oral posaconazole and surgery Med. Mycol. 47 2009 217 220 19101840 \nHoward S.J. Cerar D. Anderson M.J. Albarrag A. Fisher M.C. Pasqualotto A.C. Laverdiere M. Arendrup M.C. Perlin D.S. Denning D.W. Frequency and evolution of azole resistance in Aspergillus fumigatus associated with treatment failure Emerg. Infect. Dis. 15 2009 1068 1076 19624922 \nHoward S.J. Pasqualotto M.J. Anderson H. Leatherbarrow A.M. Albarrag A.M. Harrison E. Gregson L. Bowyer P. Denning D.W. Major variations in Aspergillus fumigatus arising within aspergillomas in chronic pulmonary aspergillosis Mycoses 56 2013 434 441 23369025 \nHsu J. Chen K. Lee F.S. Snf1/AMP-activated protein kinase activates Arf3p to promote invasive yeast growth via a non-canonical GEF domain Nat. Commun. 6 2015 7840 26198097 \nKano R. Sobukawa H. Murayama S.Y. Hirose D. Tanaka Y. Kosuge Y. Hasegawa A. Kamata H. In vitro resistance of Aspergillus fumigatus to azole farm fungicide J. Infect. Chemother. 22 2015 133 136 26711232 \nKing J. Henriet S. Warris A. Aspergillosis in Chronic Granulomatous Disease J. Fungi 2 2016 15 \nKuipers S. Brüggemann R.J.M. De Sévaux R.G.L. Heesakkers J.P.F.A. Melchers W.J.G. Mouton J.W. Verweij P.E. Failure of posaconazole therapy in a renal transplant patient with invasive aspergillosis due to Aspergillus fumigatus with attenuated susceptibility to posaconazole Antimicrob. Agents Chemother. 55 2011 3564 3566 21502625 \nLackner M. Jukic E. Sartori B. Fritz J. Seger C. Hagleitner M. Speth C. Lass-fl C. Azole-resistant and -susceptible Aspergillus fumigatus isolates show comparable fitness and azole treatment outcome in immunocompetent mice Med. Mycol. 2017 1 8 27994098 \nLatgé J.P. The pathobiology of aspergillus fumigatus Trends Microbiol. 9 2001 382 389 11514221 \nLee T.-H. Guo H. Wang X. Kim C. Paterson A.H. SNPhylo: a pipeline to construct a phylogenetic tree from huge SNP data BMC Genom. 15 2014 162 \nMacpherson S. Akache B. Deken X. De Turcotte B. Candida albicans zinc cluster protein Upc2p confers resistance to antifungal drugs and is an activator of ergosterol biosynthetic genes Antimicrob. Agents Chemother. 49 2005 1745 1752 15855491 \nMann P.A. Parmegiani R.M. Wei S.Q. Mendrick C.A. Li X. Loebenberg D. DiDomenico B. Hare R.S. Walker S.S. McNicholas P.M. Mutations in Aspergillus fumigatus resulting in reduced susceptibility to posaconazole appear to be restricted to a single amino acid in the cytochrome P450 14a-demethylase Antimicrob. Agents Chemother. 47 2003 577 581 12543662 \nMellado E. Cuenca-Estrella J.M. Rodriguez-Tudela J.L. A Point mutation in the 14α-Sterol Demethylase Gene cyp51A Contributes to Itraconazole Resistance in Aspergillus fumigatus a point mutation in the 14α-sterol demethylase Gene cyp51A contributes to itraconazole resistance in aspergillus fumigatus Antimicrob. Agents Chemother. 47 2003 1120 1125 12604551 \nMellado E. Garcia-Effron G. Alcazar-Fuoli L. Cuenca-Estrella M. Rodriguez-Tudela J.L. Substitutions at methionine 220 in the 14α-sterol demethylase (cyp51A) of Aspergillus fumigatus are responsible for resistance in vitro to azole antifungal drugs Antimicrob. Agents Chemother. 48 2004 2747 2750 15215142 \nMellado E. Garcia-Effron G. Alcázar-Fuoli L. Melchers W.J.G. Verweij P.E. Cuenca-Estrella M. Rodriguez-Tudela J.L. A new Aspergillus fumigatus resistance mechanism conferring in vitro cross-resistance to azole antifungals involves a combination of cyp51A alterations Antimicrob. Agents Chemother. 51 2007 1897 1904 17371828 \nMilne I. Stephen G. Bayer M. Cock P.J.A. Pritchard L. Cardle L. Shawand P.D. Marshall D. Using tablet for visual exploration of second-generation sequencing data Brief. Bioinform. 14 2013 193 202 22445902 \nMisslinger M. Gsaller F. Hortschansky P. Mu C. Bracher F. Bromley M.J. Haas H. The cytochrome b5 CybE is regulated by iron availability and is crucial for azole resistance in A. fumigatus Metallomics 9 2017 1655 1665 29072765 \nMullins J. Harvey R. Seaton A. Sources and incidence of airborne Aspergillus fumigatus Clin. Allergy 6 1976 209 221 780000 \nNorton T.S. Abdallah Q. Al Hill A.M. Lovingood R.V. Fortwendel J.R. Norton T.S. Abdallah Q. Al Hill A.M. Lovingood R.V. Tiffany F. Norton S. Abdallah Q. Al Amy M. Lovingood R.V. Jarrod R. The Aspergillus fumigatus farnesyltransferase β – subunit, RamA, mediates growth, virulence, and antifungal susceptibility Virulence 8 2017 1401 1416 28489963 \nO’Brien H.E. Parrent J.L. Jackson J.A. Moncalvo J. Vilgalys R. Fungal community analysis by large-scale sequencing of environmental samples Appl. Environ. Microbiol. 71 2005 5544 5550 16151147 \nOkonechnikov, K., Conesa, A., García-alcalde, F., 2015. Qualimap 2 : advanced multi-sample quality control for high-throughput sequencing data, pp. 1–3.\nPatterson T.F. Thompson George R. III Denning D.W. Fishman J.A. Hadley S. Herbrecht R. Kontoyiannis D.P. Marr K.A. Morrison V.A. Nguyen M.H. Segal B.H. Steinbach W.J. Stevens D.A. Walsh T.J. Wingard J.R. Young J.-A.H. Bennett J.E. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the infectious diseases society of America Clin. Infect. Dis. 63 2016 e1 e60 27365388 \nPetrikkou E. Rodri J.L. Gómez A. Molleja A. Cuenca-estrella M. Molleja A.N. Mellado E. Inoculum standardization for antifungal susceptibility testing of filamentous fungi pathogenic for humans inoculum standardization for antifungal susceptibility testing of filamentous fungi pathogenic for humans J. Clin. Microbiol. 39 2001 1345 1347 11283054 \nPeyton L.R. Gallagher S. Hashemzadeh M. Triazole antifungals: a review Drugs Today 51 2015 705 718 26798851 \nRenwick J. Daly P. Reeves E.P. Kavanagh K. Susceptibility of larvae of Galleria mellonella to infection by Aspergillus fumigatus is dependent upon stage of conidial germination Mycopathologia 161 2006 377 384 16761185 \nSanz P. Snf1 protein kinase: a key player in the response to cellular stress in yeast Biochem. Soc. Trans. 31 2003 178 181 12546680 \nSchoustra S.E. Debets A.J.M. Slakhorst M. Hoekstra R.F. Reducing the cost of resistance; experimental evolution in the filamentous fungus Aspergillus nidulans J. Evol. Biol. 19 2006 1115 1127 16780512 \nSchoustra S.E. Slakhorst M. Debets A.J.M. Hoekstra R.F. Comparing artificial and natural selection in rate of adaptation to genetic stress in Aspergillus nidulans J. Evol. Biol. 18 2005 771 778 16033548 \nShapiro R.S. Robbins N. Cowen L.E. Regulatory circuitry governing fungal development, drug resistance, and disease Microbiol. Mol. Biol. Rev. 75 2011 213 267 21646428 \nSlater J.L. Gregson L. Denning D.W. Warn P.A. Pathogenicity of Aspergillus fumigatus mutants assessed in Galleria mellonella matches that in mice Med. Mycol. 49 Suppl 1 2011 S107 S113 20950221 \nSlaven J.W. Anderson M.J. Sanglard D. Dixon G.K. Bille J. Roberts I.S. Denning D.W. Increased expression of a novel Aspergillus fumigatus ABC transporter gene, atrF, in the presence of itraconazole in an itraconazole resistant clinical isolate Fungal Genet. Biol. 36 2002 199 206 12135575 \nSnelders E. Karawajczyk A. Schaftenaar G. Verweij P.E. Melchers W.J.G. Azole resistance profile of amino acid changes in Aspergillus fumigatus CYP51A based on protein homology modeling Antimicrob. Agents Chemother. 54 2010 2425 2430 20385860 \nSnelders E. Van Der Lee H.A.L. Kuijpers J. Rijs A.J.M.M. Varga J. Samson R.A. Mellado E. Donders A.R.T. Melchers W.J.G. Verweij P.E. Emergence of azole resistance in Aspergillus fumigatus and spread of a single resistance mechanism PLoS Med. 5 2008 1629 1637 \nSubcommittee on Antifungal Susceptibility Testing of the ESCMID European Committee for Antimicrobial Susceptibility Testing (EUCAST), 2015. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi. Clin. Microbiol. Infect. 14, pp. 982–984.\nTedersoo L. Bahram M. Polme S. Koljalg U. Yorou S. Wardle D.A. Lindahl B.D. Global diversity and geography of soil fungi Science 346 2014 1052 1053 25430752 \nThorvaldsdóttir H. Robinson J.T. Mesirov J.P. Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration Brief. Bioinform. 14 2013 178 192 22517427 \nValsecchi I. Mellado E. Beau R. Raj S. Latgé J.P. Fitness studies of azole-resistant strains of Aspergillus fumigatus Antimicrob. Agents Chemother. 59 2015 7866 7869 26416854 \nVerweij P.E. Zhang J. Debets A.J.M. Meis J.F. van de Veerdonk F.L. Schoustra S.E. Zwaan B.J. Melchers W.J.G. In-host adaptation and acquired triazole resistance in Aspergillus fumigatus: a dilemma for clinical management Lancet Infect. Dis. 3099 2016 1 10 \nWarris A. The biology of pulmonary aspergillus infections J. Infect. 69 2014 S36 S41 25135079 \nWilson D. Citiulo F. Hube B. Zinc exploitation by pathogenic fungi PLoS Pathog. 8 2012 12 15 \nXiao L. Madison V. Chau A.S. Loebenberg D. Palermo R.E. McNicholas P.M. Three-dimensional models of wild-type and mutated forms of cytochrome P450 14α-sterol demethylases from aspergillus fumigatus and candida albicans provide insights into posaconazole binding Antimicrob. Agents Chemother. 48 2004 568 574 14742211 \nZoll J. Snelders E. Verweij P.E. Melchers W.J.G. Next-generation sequencing in the mycology lab Curr. Fungal Infect. Rep. 1–6 2016\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1087-1845",
"issue": "113()",
"journal": "Fungal genetics and biology : FG & B",
"keywords": "Aspergillus fumigatus; Azole-resistance; Fungal growth; In-host microevolution; Whole genome sequencing",
"medline_ta": "Fungal Genet Biol",
"mesh_terms": "D000222:Adaptation, Physiological; D000935:Antifungal Agents; D001228:Aspergillosis; D001232:Aspergillus fumigatus; D001393:Azoles; D003577:Cytochrome P-450 Enzyme System; D025141:Drug Resistance, Fungal; D019143:Evolution, Molecular; D005656:Fungal Proteins; D005838:Genotype; D006105:Granulomatous Disease, Chronic; D054884:Host-Pathogen Interactions; D006801:Humans; D008826:Microbial Sensitivity Tests; D018895:Microsatellite Repeats; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D014774:Virulence; D000073336:Whole Genome Sequencing",
"nlm_unique_id": "9607601",
"other_id": null,
"pages": "1-13",
"pmc": null,
"pmid": "29477713",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "15215142;15855491;16151147;24530175;9174200;29228287;15563516;24577012;16033548;18828858;24245710;21646428;19624922;23226235;20385860;12546680;11514221;7494862;26198097;29072765;26798851;10515900;27638360;25135079;20404915;22498624;20055745;24695404;26428292;18404212;16780512;22914218;14742211;16761185;21502625;26416854;27365388;23369025;23580559;16169926;25430752;15953931;20729241;17379808;28489963;23208831;20038606;11283054;20950221;22445902;24316576;780000;12604551;23308062;26037120;21653522;24571581;25232160;27438017;12135575;15855543;19101840;26115917;21876055;12543662;16081958;15142553;17371828;18998768;26711232;22517427;15034147",
"title": "In-host microevolution of Aspergillus fumigatus: A phenotypic and genotypic analysis.",
"title_normalized": "in host microevolution of aspergillus fumigatus a phenotypic and genotypic analysis"
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"abstract": "With the widespread use of tigecycline, especially in elderly people infected with multidrug-resistant bacteria, the associated coagulation disorders are attracting the attention of clinicians. The risk factors of tigecycline-associated hypofibrinogenemia are still controversial.\nThe aims of our study were to explore the related factors of hypofibrinogenemia caused by tigecycline, and to establish the risk assessment criteria for tigecycline-associated hypofibrinogenemia.\nThis was an observational retrospective cohort study of patients treated for at least 3 days with tigecycline. Hypofibrinogenemia was defined as plasma fibrinogen <2.0 g/L. Risk factors were determined using logistic regression analysis, and the risk assessment criteria were identified by using receiver operating characteristic curves.\nIn total, 148 patients were included in the analysis, mean age was 77.09±15.11 years old. Ninety patients who developed hypofibrinogenemia during tigecycline treatment with mean plasma fibrinogen of 1.42 g/L were included in the hypofibrinogenemia group, the other 58 patients with mean plasma fibrinogen of 2.68 g/L were included in the normal group. In the multivariate analysis, age (p = 0.035), tigecycline treatment duration (p = 0.044), and baseline fibrinogen level (p = 0.002) were independently associated with hypofibrinogenemia. An age of ≥82 years, ≥9 days of medication, and a baseline fibrinogen level of ≤3.5 g/L were selected for predicting hypofibrinogenemia. Hypofibrinogenemia was independently associated with bleeding (OR 8.96, 95% CI [1.132-70.946], p = 0.038).\nHypofibrinogenemia is a common adverse effect of tigecycline in our study. Elderly patients are more prone to developing hypofibrinogenemia after the administration of tigecycline. It is independently associated with bleeding but not death. The risk assessment criteria can help in the identification of patients with high risk of hypofibrinogenemia.",
"affiliations": "Department of Geriatrics, Peking University Third Hospital, Beijing, People's Republic of China.;Department of Pharmacy, Peking University Third Hospital, Beijing, People's Republic of China.;Department of Geriatrics, Peking University Third Hospital, Beijing, People's Republic of China.",
"authors": "Liu|Jia|J|;Yan|Yingying|Y|;Zhang|Fan|F|0000-0003-1781-0571",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/TCRM.S302850",
"fulltext": "\n==== Front\nTher Clin Risk Manag\nTher Clin Risk Manag\ntcrm\ntcriskman\nTherapeutics and Clinical Risk Management\n1176-6336\n1178-203X\nDove\n\n302850\n10.2147/TCRM.S302850\nOriginal Research\nRisk Factors for Tigecycline-Associated Hypofibrinogenemia\nLiu et al\nLiu et al\nLiu Jia 1\nYan Yingying 2\nhttp://orcid.org/0000-0003-1781-0571\nZhang Fan 1\n1 Department of Geriatrics, Peking University Third Hospital, Beijing, People’s Republic of China\n2 Department of Pharmacy, Peking University Third Hospital, Beijing, People’s Republic of China\nCorrespondence: Fan Zhang Department of Geriatrics, Peking University Third Hospital, 49 North Garden Road, Beijing, 100191, People’s Republic of ChinaTel +86-010-82265685 Email zhangfan_puh3@yeah.net\n16 4 2021\n2021\n17 325332\n20 1 2021\n23 3 2021\n© 2021 Liu et al.\n2021\nLiu 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\nWith the widespread use of tigecycline, especially in elderly people infected with multidrug-resistant bacteria, the associated coagulation disorders are attracting the attention of clinicians. The risk factors of tigecycline-associated hypofibrinogenemia are still controversial.\n\nPurpose\n\nThe aims of our study were to explore the related factors of hypofibrinogenemia caused by tigecycline, and to establish the risk assessment criteria for tigecycline-associated hypofibrinogenemia.\n\nPatients and Methods\n\nThis was an observational retrospective cohort study of patients treated for at least 3 days with tigecycline. Hypofibrinogenemia was defined as plasma fibrinogen <2.0 g/L. Risk factors were determined using logistic regression analysis, and the risk assessment criteria were identified by using receiver operating characteristic curves.\n\nResults\n\nIn total, 148 patients were included in the analysis, mean age was 77.09±15.11 years old. Ninety patients who developed hypofibrinogenemia during tigecycline treatment with mean plasma fibrinogen of 1.42 g/L were included in the hypofibrinogenemia group, the other 58 patients with mean plasma fibrinogen of 2.68 g/L were included in the normal group. In the multivariate analysis, age (p = 0.035), tigecycline treatment duration (p = 0.044), and baseline fibrinogen level (p = 0.002) were independently associated with hypofibrinogenemia. An age of ≥82 years, ≥9 days of medication, and a baseline fibrinogen level of ≤3.5 g/L were selected for predicting hypofibrinogenemia. Hypofibrinogenemia was independently associated with bleeding (OR 8.96, 95% CI [1.132–70.946], p = 0.038).\n\nConclusion\n\nHypofibrinogenemia is a common adverse effect of tigecycline in our study. Elderly patients are more prone to developing hypofibrinogenemia after the administration of tigecycline. It is independently associated with bleeding but not death. The risk assessment criteria can help in the identification of patients with high risk of hypofibrinogenemia.\n\nKeywords\n\ntigecycline\nhypofibrinogenemia\ncoagulation disorders\nrisk factors\nnot funded The study was not funded.\n==== Body\nIntroduction\n\nTigecycline is the first antibiotic in the glycylcycline class and has broad-spectrum activity, especially against multidrug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE) strains, and multidrug-resistant Acinetobacter baumanii (MDRAB).1,2 Because it has high levels of antibacterial activity and tolerability, it is widely used for the treatment of community-acquired pneumonia, complicated skin infections, and intra-abdominal infections.3,4 Advanced age and chronic diseases are risk factors related to multidrug-resistant bacteria infections.5 Because of the efficacy and safety, tigecycline is often used in elderly people infected with multidrug–resistant bacteria in clinical practice.6\n\nThe most common adverse drug reactions of tigecycline include nausea, vomiting and diarrhea.7 However, clinicians often overlook a very rare adverse effect, coagulopathy, which occurs in only less than 2% of all patients in premarketing clinical trials.8 With the widespread use of tigecycline, the associated coagulation disorders are attracting the attention of clinicians. In addition to the prolongation of the prothrombin time (PT) and activated partial thromboplastin time (aPTT), hypofibrinogenemia has also been reported.9–11 We should pay more attention to adverse effects in the elderly patients in clinical practice. Risk factors for tigecycline-associated hypofibrinogenemia were unclear. According to few clinical studies, the relevant factors may include renal insufficiency, the treatment dose and course, patient sex and plasma fibrinogen level before administration, but the conclusions are controversial.12–15 Moreover, previous studies have only described the relevant risk factors without effective risk assessment criteria, which can aid the selection of antibiotic drugs and reduce the occurrence of adverse reactions.\n\nIn this article, we conducted a retrospective observational study to explore the related factors of hypofibrinogenemia caused by tigecycline and to establish the risk assessment criteria for tigecycline-associated hypofibrinogenemia.\n\nMaterials and Methods\n\nStudy Population\n\nA retrospective, single-center, observational cohort study was performed at Peking University Third Hospital. Patient data were retrieved from the Pharmacy Department database. The Medical Science Research Ethics Committee of the Peking University Third Hospital approved this study. We identified 203 patients who were treated with tigecycline in 2019. Then, we excluded 55 patients because they met one of the following four criteria: (1) patients who were treated with tigecycline for fewer than 3 days; (2) patients who were treated with tigecycline without coagulation status monitoring; (3) patients with a fibrinogen level less than 2.0 g/L before the administration of tigecycline, and (4) patients who were diagnosed with disseminated intravascular coagulation (DIC). Finally, 148 patients were included in the analysis.\n\nStudy Setting\n\nAccording to the case report form, we collected clinical information from the electronic medical records system. The data we collected included demographic and medical history information (eg, age, sex, height, weight, and chronic diseases), the results of laboratory tests performed before, during and 1 week after the treatment of tigecycline (eg, leukocyte count, hemoglobin level, platelet count, transaminase level, albumin level, creatinine level, urea nitrogen level, prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen level, procalcitonin level), the site of infection, the tigecycline dosage, the duration of tigecycline treatment, concomitant drugs (anticoagulants, antiplatelet drugs, cefoperazone/sulbactam), and clinical outcomes (eg, bleeding, death). All laboratory tests were conducted in the same laboratory. Serum fibrinogen level was measured with HemosIL Fibrinogen–C reagents (Instrumentation Laboratory) using von Clauss assay. The laboratory reference range for fibrinogen was 2.0–4.4 g/L. Hypofibrinogenemia was defined as plasma fibrinogen <2.0 g/L. The primary outcome was the occurrence of hypofibrinogenemia after tigecycline treatment, and the secondary outcome was the incidence of adverse events (eg, bleeding, death).\n\nStatistical Analysis\n\nStatistical analysis was performed with SPSS statistics 19.0. The continuous variables are presented as means ± standard deviations (SDs) (normally distributed) or medians and interquartile ranges (non-normally distributed). We evaluated these variables by the t test or Mann–Whitney U-test. The categorical variables are presented as percentages, and Fisher’s exact test or the Chi-square test was used to evaluate these variables. Multivariable logistic regression models were used in association analyses. P < 0.05 was regarded as statistically significant. The goodness of fit was assessed with the Hosmer–Lemeshow test, and the discrimination threshold was determined by receiver operating characteristic (ROC) curve analysis. The area under the curves (AUCs) and the corresponding 95% confidence intervals (CI 95%) were shown.\n\nResults\n\nThe mean age of the 148 patients was 77.09±15.11 years old. 88.5% of the patients were over 60 years old. We included 108 males and 40 females. Among these patients, 141 were diagnosed with pneumonia, 17 were diagnosed with bloodstream infection, 9 were diagnosed with intra-abdominal infection, and 2 were diagnosed with intracranial infection. Tigecycline was mainly used for the treatment of multidrug-resistant bacterial infections, such as Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, and MRSA. Among these patients, 133 received normal-dose treatment (loading dose 100 mg, maintenance dose 50 mg Q12H), and 15 patients received high-dose treatment (loading dose 100 mg or 200 mg, maintenance dose 100 mg Q12h). The average duration of tigecycline treatment was 12.01±5.73 days. The effect of tigecycline on blood coagulation manifested as a significant decrease in the plasma fibrinogen level, and a significant increase in aPTT, PT and thrombin time (TT). The fibrinogen level decreased from 3.76±1.12 g/L to 1.91±0.78 g/L and recovered to 2.66±0.54 g/L after drug withdrawal (p < 0.001). The activated partial thromboplastin time increased from 33.5±5.6 s to 41.6±10.7 s and recovered to 38.1±8.0 s after drug withdrawal (p < 0.001). The prothrombin time increased from 13.1±2.3 s to 15.3±4.9 s and returned to 13.1±1.88 s after drug withdrawal (p < 0.001). The thrombin time increased from 15.37±3.91 s to 19.47±6.28 s and returned to 16.56±2.18 s after drug withdrawal (p < 0.001). After treatment with tigecycline, the fibrinogen level decreased by an average of 49.2%, PT, aPTT and TT increased by an average of 16.8%, 19.5% and 26.7%, respectively. We found no significant changes in the D-dimer levels in response to the treatment.\n\nA total of 142 patients (95.9%) in the study experienced a decrease in the fibrinogen level during tigecycline treatment, and 90 patients (60.8%) developed hypofibrinogenemia. The patients who developed hypofibrinogenemia were included in the hypofibrinogenemia group. Moreover, the other 58 patients who had fibrinogen >2.0 g/L during tigecycline treatment were included in the normal group. The clinical characteristics of the two groups are shown in Table 1. In the univariate analysis, the ages of the hypofibrinogenemia group and the normal group were 79.06±14.41 and 72.97±18.08 years old (p = 0.025), and the tigecycline treatment duration were 12.86±6.04 and 10.69±4.97 days (p = 0.024). There were no significant differences between the two groups in sex, body mass index or medication dosage. There were no differences between the two groups in the site of infection or the presence of underlying diseases (hepatobiliary system diseases, chronic renal insufficiency, and malignant tumors). In the hypofibrinogenemia group, 22 (24.4%) patients were treated with cefoperazone/sulbactam, 13 (14.4%) patients were treated with anticoagulant drugs, and 16 (17.8%) patients were treated with antiplatelet drugs. There were no differences between the two groups in the combination therapy with anticoagulant, antiplatelet drugs or cefoperazone/sulbactam. There were differences between the two groups in the baseline hemoglobin, total protein, urea nitrogen and fibrinogen levels before medication. In the hypofibrinogenemia group and the normal group, the baseline fibrinogen levels were 3.46±1.01 g/L and 4.21±1.12 g/L, and decreased to 1.42±0.38 g/L and 2.68±0.57 g/L during treatment, respectively. In the hypofibrinogenemia group, the fibrinogen level of 12 patients (13.3%) decreased to less than 1 g/L. The hypofibrinogenemia group had a 56.2% fibrinogen decrease and the normal group had a 33.8% fibrinogen decrease (p < 0.001).Table 1 Univariate Analysis of Risk Factors for Tigecycline-Associated Hypofibrinogenemia\n\n\tNormal Group\tHypofibrinogenemia Group\tP-value\t\nN\t58\t90\t\t\nAge (years)\t72.97±18.08\t79.06±14.41\t0.025*\t\nSex (male, n(%))\t46 (79.3)\t62 (68.9)\t0.163\t\nBody mass index (kg/m2)\t22.74±4.51\t22.41±4.44\t0.706\t\nDose (200mg/d, n(%))\t4 (6.9)\t11 (12.4)\t0.429\t\nTreatment duration (days)\t10.69±4.97\t12.86±6.04\t0.024*\t\nSite of infection\t\t\t\t\n Pneumonia (%)\t56 (98.2)\t85 (96.6)\t0.940\t\n Urinary tract infection (%)\t9 (15.8)\t16 (18.2)\t0.710\t\n Bloodstream infection (%)\t8 (14)\t9 (10.2)\t0.486\t\n Intra-abdominal infection (%)\t4 (7.0)\t5 (5.7)\t0.745\t\n Intracranial infection (%)\t1 (1.8)\t1 (1.1)\t0.755\t\nUnderlying diseases\t\t\t\t\n Chronic renal insufficiency (%)\t8 (14)\t18 (20.5)\t0.325\t\n Hepatobiliary system diseases (%)\t2 (3.4)\t9 (10)\t0.245\t\n Malignant tumors (%)\t10 (17.9)\t21 (23.9)\t0.393\t\nLaboratory tests before tigecycline treatment\t\t\t\t\n WBC (×109/L)\t10.08±3.83\t11.34±7.90\t0.198\t\n HGB (g/L)\t104.05±21.45\t95.78±20.70\t0.021*\t\n PLT (×109/L)\t195.93±99.52\t182.29±95.43\t0.405\t\n ALT (U/L)\t30.41±22.16\t31.06±30.51\t0.890\t\n AST (U/L)\t34.38±22.32\t31.84±22.06\t0.478\t\n TBil (μmol/L)\t14.97±9.76\t20.53±39.14\t0.291\t\n ALP (U/L)\t112.53±86.47\t93.22±46.35\t0.126\t\n TP (g/L)\t65.14±7.82\t61.60±8.86\t0.024*\t\n ALB (g/L)\t31.07±3.27\t30.50±4.78\t0.407\t\n GGT (U/L)\t83.46±151.95\t54.75±63.19\t0.184\t\n BUN (mmol/L)\t10.74±6.68\t14.11±10.94\t0.022*\t\n Cr (μmol/L)\t109.38±99.15\t129.06±118.89\t0.298\t\n eGFR (mL/min/1.73m2)\t67.76±33.78\t65.94±32.63\t0.782\t\n PT (s)\t12.73±1.82\t13.37±2.55\t0.097\t\n Fib (g/L)\t4.21±1.12\t3.46±1.01\t0.000*\t\n aPTT (s)\t33.24±5.01\t33.61±6.02\t0.695\t\n D-dimer (μg/dl)\t1.27±1.47\t1.61±2.12\t0.324\t\n PCT (ng/mL)\t1.34±5.25\t3.95±17.33\t0.335\t\nConcomitant drugs associated with, n (%)\t\t\t\t\n Anticoagulant drugs (%)\t12 (20.7)\t13 (14.4)\t0.322\t\n Antiplatelet drugs (%)\t5 (8.6)\t16 (17.8)\t0.119\t\n CPZ/SAM (%)\t12 (20.7)\t22 (24.4)\t0.596\t\nClinical outcomes\t\t\t\t\n Bleeding (%)\t1 (1.7)\t12 (13.3)\t0.014*\t\n Death (%)\t15 (25.9)\t37 (41.1)\t0.054\t\nNote: *Indicate statistical significance.\n\nAbbreviations: WBC, white blood cells; HGB, hemoglobin; PLT, platelet; ALT, alanine transaminase; AST, aspartate transaminase; TBil, total bilirubin; ALP, alkaline phosphatase; TP, total protein; ALB, albumin; GGT, γ-glutamyl transpeptidase; BUN, blood urea nitrogen; Cr, creatinine; eGFR, estimated glomerular filtration rate; PT, prothrombin time; Fib, fibrinogen; aPTT, activated partial thromboplastin time; PCT, procalcitonin; CPZ/SAM, cefoperazone/sulbactam.\n\nThe following variables that were significant at p < 0.05 in the univariate analyses and risk factors in previous studies were included in the multivariate analysis: age, sex, treatment duration, hemoglobin level, creatinine level, urea nitrogen level, basal fibrinogen, total protein. In the multivariate analysis (stepwise approach), age (p = 0.035), tigecycline treatment duration (p = 0.044), and baseline fibrinogen level (p = 0.002) were independently associated with hypofibrinogenemia (Table 2).Table 2 Multivariate Analysis of Risk Factors for Tigecycline-Associated Hypofibrinogenemia\n\nVariable\tOdds Ratio\t95% CI\tP-value\t\nAge\t1.037\t1.002–1.072\t0.035\t\nTreatment duration\t1.095\t1.003–1.196\t0.044\t\nBasal fibrinogen\t0.489\t0.308–0.777\t0.002\t\nAbbreviation: CI, confidence interval.\n\nThe ROC curve was used to evaluate the predictive ability of age, tigecycline treatment duration and the baseline fibrinogen level for tigecycline-related hypofibrinogenemia. Area under curve (AUC) of age was 0.621 (95% CI: 0.530–0.712, p = 0.013), tigecycline treatment duration was 0.596 (95% CI: 0.501–0.691, p = 0.049), and baseline fibrinogen level was 0.713 (95% CI: 0.630–0.796, p < 0.001). We selected the cutoff point with the largest Youden index. An age of ≥82 years, ≥9 days of medication, and a fibrinogen level of ≤3.5 g/L were selected as the cutoff points for predicting hypofibrinogenemia during tigecycline treatment (Table 3).Table 3 The Sensitivity and Specificity of the Best Cutoff Point of Age, Treatment Duration and the Baseline Fibrinogen Level as a Discriminator of the Probability of Hypofibrinogenemia\n\nVariable\tSensitivity (%)\tSpecificity (%)\t\nAge ≥ 82 years\t0.578\t0.638\t\nMediation ≥ 9 days\t0.789\t0.414\t\nBasal fibrinogen ≤ 3.5 g/L\t0.759\t0.578\t\n\nAmong the 148 patients who received tigecycline, 13 (8.8%) developed bleeding. The main bleeding sites were the digestive tract (84.6%), skin and mucosa (15.4%). There were differences between the two groups in the complication of bleeding (p = 0.014). In the hypofibrinogenemia group, 12 developed bleeding. Five patients received only fresh frozen plasma infusion, two patients discontinued tigecycline without any other treatment for hypofibrinogenemia, two patients discontinued tigecycline and received plasma infusion, one patient received prothrombin complex, fibrinogen, and transfusion of plasma, one patient received vitamin K and transfusion of plasma. Their fibrinogen levels were increased after the above treatment. Disease progressed rapidly in one patient, and died without treatment for hypofibrinogenemia. The hospital mortality rate of the hypofibrinogenemia group and the normal group were 41.1% and 25.9% (p = 0.054) (Table 1). According to the logistic regression analysis, hypofibrinogenemia was independently associated with bleeding (OR 8.96, 95% CI [1.132–70.946], p = 0.038), but not death (OR 2.009, 95% CI [0.952–4.24], p = 0.067).\n\nDiscussion\n\nThe increase in multidrug-resistant bacteria infections has become a major problem that threatens human health, especially among elderly people. Tigecycline has wide-spectrum antibacterial activity, especially against multidrug-resistant bacteria. It is often used for treating severe infections caused by multidrug-resistant bacteria, sometimes with high doses and extended treatments. But data addressing its safety are limited. In premarketing clinical trials, the most common side effect is digestive-system problems. Adverse reactions of the coagulation system are not common (<2%).8 However, according to postmarketing studies, tigecycline is associated with hypofibrinogenemia. To date, most of the published articles about tigecycline-associated hypofibrinogenemia are case reports,8,11,12,16–20 and few of them are retrospective observation studies.10,13,14,21 Our study was a retrospective study that included 148 patients. We found that patients who were administered tigecycline experienced a prolonged PT, a prolonged APTT, a prolonged TT, and a decreased fibrinogen level. According to our research, hypofibrinogenemia was common in clinical practice, which occurred in 60.8% of the patients. This is in agreement with prior reports: in Hu’s research,14 there were 56% developed hypofibrinogenemia, and in Zhang’s research,15 there were 50.5% developed hypofibrinogenemia, respectively. Fibrinogen decreased by an average of 49.2%, PT, aPTT and TT increased by an average of 16.8%, 19.5% and 26.7%, respectively. All of these differences were statistically significant. There was a general decline in fibrinogen. The fibrinogen level decreased from baseline during treatment in 95.9% of patients, and 60.8% of patients had hypofibrinogenemia during treatment, which is consistent with the results of previous studies. Cui et al summarized 13 case reports and 4 retrospective observational studies and found that tigecycline can cause coagulation abnormalities, including a prolonged PT, a prolonged APTT and a decreased fibrinogen level after treatment, which recovered after discontinuation.9 Leng and Hu also reached the same conclusion.10,14\n\nHypofibrinogenemia may be acquired or inherited.22 In this study, the patients’ levels of fibrinogen were within the normal range before the administration of tigecycline. The common causes of acquired hypofibrinogenemia include a) liver disease, as severe liver disease can impair the synthesis function of liver cells, leading to a decrease in fibrinogen.23 In this study, liver function did not differ significantly before and after the administration of tigecycline. b) DIC is a well-defined condition of consumptive coagulopathy that can lead to hypofibrinogenemia.24 In this study, we exclude the patients who were diagnosed with DIC. Meanwhile, D-dimer is an important factor in the diagnosis of DIC, and there was no significant difference in D-dimer before and after the treatment. c) Other factors, including tumors and drugs, have also been reported to be associated with hypofibrinogenemia.25 However, there was no significant difference in tumor incidence between the normal group and the hypofibrinogenemia group in this study. Hypofibrinogenemia appeared after tigecycline was administered and improved when tigecycline was discontinued. Therefore, hypofibrinogenemia was related to tigecycline administration.\n\nAccording to our study, independent risk factors for tigecycline-associated hypofibrinogenemia included patient age, tigecycline treatment duration, and the baseline fibrinogen level. Consistent with the results of previous studies, the duration of medication and the baseline fibrinogen level were associated with hypofibrinogenemia.14 However, the correlation between age and hypofibrinogenemia is controversial. In clinical practice, tigecycline is often used to treat life-threatening infections with multidrug-resistant bacteria, which is often occurred in patients with advanced age. As this study showed, the patients treated with tigecycline were mainly the elderly over 60 years old, most of them had serious infections and with high mortality. Different from previous studies, advanced age was a risk factor for tigecycline-associated hypofibrinogenemia. Zhang et al found that the incidence of hypofibrinogenemia was not related to age.13 However, their study had a small sample size of 20 patients, and the mean patient age was 62.5±22.1 years old, which was 77.09±15.11 years old in our study. Similarly, Hu’s study also showed there is no correlation between hypofibrinogenemia and age.14 But in their study, the age of the hypofibrinogenemia group was 63.72±15.68 years old, and that of the normal group was 55.82±18.59 years old, which were much smaller than the age of the patients in our study. Our study can better reflect the effect of tigecycline on coagulation in elderly patients. And according to our study, elderly patients are more prone to developing hypofibrinogenemia after the administration of tigecycline.\n\nNo correlations were found between the medication dose and infection site. Inconsistent with our findings, Hu et al found that the dosage of medication and intra-abdominal infection were related to the incidence of hypofibrinogenemia.14 This inconsistency may be due to differences in the patient characteristics. The study population in Hu’s research included mainly patients in the intensive care unit. Although the main infection site was the lung, the proportion of intra-abdominal infections and bloodstream infections was relatively high. The population in our study included both critically ill patients and patients in the general wards. The main infection site was also the lung, but the proportion of patients with intra-abdominal infections and bloodstream infections was relatively low. Similarly, in our study, only a small number of patients (15 of 138) were treated with high-dose tigecycline. We further grouped the patients according to the medication dose of tigecycline, compared PT, aPTT, fibrinogen, and TT before and after the application of normal-dose and high-dose tigecycline, and found that there was no statistical difference. However, in the high-dose group, after the application of tigecycline, the degree of fibrinogen reduction was greater than the normal-dose group (2.6 g/L vs 1.8 g/L, p = 0.009), which reached statistical significance. Therefore, according to our research, the application of high-dose tigecycline will also lead to a significant reduction in the concentration of serum fibrinogen. However, due to the limitation of the number of high-dose cases, the incidence of hypofibrinogenemia in the two groups did not reach statistical significance.\n\nWe developed risk assessment criteria for tigecycline-associated hypofibrinogenemia, which can better determine the risk of hypofibrinogenemia after tigecycline administration. Moreover, in our study, hypofibrinogenemia was associated with bleeding. By identifying high-risk patients with hypofibrinogenemia, adjusting treatment programs or closely monitoring patients, we can reduce the occurrence of adverse clinical outcomes. Furthermore, it may be impractical to recommend the routine monitoring of coagulation in all patients using tigecycline, as routine monitoring increases the cost of treatment. Therefore, with these risk assessment criteria, only monitoring coagulation in high-risk patients can reduce the corresponding expenditures. The criteria included an age of ≥82 years, ≥9 days of medication, and a baseline fibrinogen level of ≤3.5 g/L. Patients who meet the criteria are at high risk of hypofibrinogenemia and require close monitoring of coagulation. Plasma infusion and fibrinogen infusion raised the plasma fibrinogen levels in our study. Fibrinogen replacement therapy is effective in the treatment of acute bleeding or the prevention of bleeding complications.26 Advanced age is the risk factor for thrombosis and cardiovascular disease. So thrombotic and bleeding events were needed to be carefully considered in elderly patients.\n\nThe mechanism of tigecycline-induced hypofibrinogenemia remains controversial. The common mechanism by which antibiotics affect coagulation is that the antibiotics destroy the intestinal flora and inhibit the synthesis of vitamin K, leading to vitamin K-dependent coagulation disorders. However, previous studies have shown that vitamin K supplementation is not effective for treating hypofibrinogenemia after the administration of tigecycline.9 The physiological concentration of fibrinogen in plasma is 1.80–4.20 g/L.27 And the reference ranges of plasma fibrinogen varies from region to region and among different laboratories. It is the highest concentration of proteins among the plasma coagulation factors. Fibrinogen is involved in the coagulation, which plays a central role in the hemostatic and thrombosis process.27 The half-life of fibrinogen is 3–4 days, and it is an acute-phase reaction protein. Fibrinogen production is regulated by cytokines. IL-6 promotes fibrinogen biosynthesis, while IL-1, IL-4, IL-10, IL-13, and tumor necrosis factor-α (TNF-α) inhibit fibrinogen synthesis.28 Tigecycline can reduce the levels of IL-6 and TNF–α, which may interfere with fibrinogen production.29–31 At the same time, Brandtner’s in vitro studies showed that after adding a supratherapeutic dose of tigecycline to the blood of healthy adults, the changes in fibrinogen levels and coagulation parameters were not clinically significant. However, the addition of supra-therapeutic tigecycline to the cell culture fluid in vitro significantly reduced the viability of hepatocytes.32 It is speculated that tigecycline may inhibit the liver’s synthetic function.\n\nThis study has certain limitations. A) This study is a retrospective study. Selection bias may be present and may have affected the results. B) The risk assessment criteria have not been verified externally or included in intervention studies. Therefore, the clinical value of the risk assessment criteria needs to be evaluated in future studies. In the future, it is necessary to verify the clinical value of the risk assessment criteria in large-scale cohort studies. Further randomized controlled trials and animal experiments need to be done to explore the mechanisms of tigecycline-associated hypofibrinogenemia.\n\nConclusion\n\nHypofibrinogenemia is a common adverse effect of tigecycline in our study. It is independently associated with bleeding but not death. Tigecycline-associated hypofibrinogenemia is associated with age, tigecycline treatment duration and baseline fibrinogen level. An age of ≥82 years, ≥9 days of medication, and a fibrinogen level of ≤3.5 g/L are risk factors. Elderly patients are more prone to developing hypofibrinogenemia after the administration of tigecycline. With this risk assessment criteria, clinicians can selectively monitor coagulation to reduce the corresponding expenditures.\n\nEthics Approval and Informed Consent\n\nThe Peking University Third Hospital Medical Science Research Ethics Committee approved the study. The procedures used in this study adhere to the tenets of the Declaration of Helsinki. Considering the characteristics of the study (observational retrospective cohort study), the ethical committee allowed us the exemption of obtaining informed consent.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n\n1. Hylands J. Tigecycline: a new antibiotic. Intensive Crit Care Nurs. 2008;24 (4 ):260–263. doi:10.1016/j.iccn.2008.03.006 18554910\n2. Rose WE, Rybak MJ. Tigecycline: first of a new class of antimicrobial agents. Pharmacotherapy. 2006;26 (8 ):1099–1110. doi:10.1592/phco.26.8.1099 16863487\n3. Brink AJ, Bizos D, Boffard KD, et al. Guideline: appropriate use of tigecycline. S Afr Med J. 2010;100 (6 Pt 2 ):388–394. doi:10.7196/SAMJ.4109 20529440\n4. Rubinstein E, Vaughan D. Tigecycline: a novel glycylcycline. Drugs. 2005;65 (10 ):1317–1336. doi:10.2165/00003495-200565100-00002 15977966\n5. Kurihara MNL, Sales ROD, Silva KED, Maciel WG, Simionatto S. Multidrug-resistant Acinetobacter baumannii outbreaks: a global problem in. Rev Soc Bras Med Tro. 2020;53 :e20200248. doi:10.1590/0037-8682-0248-2020\n6. Xia G, Jiang R. Clinical study on the safety and efficacy of high-dose tigecycline in the elderly. Medicine. 2020;99 (10 ):e19466. doi:10.1097/MD.0000000000019466 32150105\n7. Tasina E, Haidich AB, Kokkali S, Arvanitidou M. Efficacy and safety of tigecycline for the treatment of infectious diseases: a meta-analysis. Lancet Infect Dis. 2011;11 (11 ):834–844. doi:10.1016/S1473-3099(11)70177-3 21784708\n8. McMahan J, Moenster RP. Tigecycline-induced coagulopathy. Am J Health Syst Pharm. 2017;74 (3 ):130–134. doi:10.2146/ajhp150894 28122754\n9. Cui N, Cai H, Li Z, Lu Y, Wang G, Lu A. Tigecycline-induced coagulopathy: a literature review. Int J Clin Pharm. 2019;41 (6 ):1408–1413. doi:10.1007/s11096-019-00912-5 31713108\n10. Leng B, Xue YC, Zhang W, Gao TT, Yan GQ, Tang H. A retrospective analysis of the effect of tigecycline on coagulation function. Chem Pharm Bull (Tokyo). 2019;67 (3 ):258–264. doi:10.1248/cpb.c18-00844 30828002\n11. Giryes S, Azzam ZS, Ismael-Badarneh R, Krivoy N, Berger G. Severe coagulation disorder and thrombocytopenia associated with tigecycline - case report and review of literature. Curr Drug Saf. 2017;12 (1 ):7–9. doi:10.2174/1574886311666160920090714 27659942\n12. Wu X, Zhao P, Dong L, Zhang X. A case report of patient with severe acute cholangitis with tigecycline treatment causing coagulopathy and hypofibrinogenemia. Medicine (Baltimore). 2017;96 (49 ):e9124. doi:10.1097/MD.0000000000009124 29245350\n13. Zhang Q, Zhou S, Zhou J. Tigecycline treatment causes a decrease in fibrinogen levels. Antimicrob Agents Ch. 2015;59 (3 ):1650–1655. doi:10.1128/AAC.04305-14\n14. Hu J, Xiao Y, Zheng Y, Lai Y, Fang X, Fang Q. Clinical characteristics and risk factors of tigecycline-associated hypofibrinogenaemia in critically ill patients. Eur J Clin Pharmacol. 2020;76 (7 ):913–922. doi:10.1007/s00228-020-02860-w 32355990\n15. Zhang Q, Wang J, Liu H, Ma W, Zhou S, Zhou J. Risk factors for tigecycline-induced hypofibrinogenaemia. J Clin Pharm Ther. 2020;45 (6 ):1434–1441. doi:10.1111/jcpt.13250 32860258\n16. Wu PC, Wu CC. Tigecycline-associated hypofibrinogenemia: a case report and review of the literature. IDCases. 2018;11 :56–57. doi:10.1016/j.idcr.2018.01.003 29560313\n17. Yilmaz DF, Yildirim H, Sen EM. A lesser known side effect of tigecycline: hypofibrinogenemia. Turk J Haematol. 2018;35 (1 ):83–84. doi:10.4274/tjh.2017.0310 29212626\n18. Rossitto G, Piano S, Rosi S, Simioni P, Angeli P. Life-threatening coagulopathy and hypofibrinogenaemia induced by tigecycline in a patient with advanced liver cirrhosis. Eur J Gastroenterol Hepatol. 2014;26 (6 ):681–684. doi:10.1097/MEG.0000000000000087 24667348\n19. Pieringer H, Schmekal B, Biesenbach G, Pohanka E. Severe coagulation disorder with hypofibrinogenemia associated with the use of tigecycline. Ann Hematol. 2010;89 (10 ):1063–1064. doi:10.1007/s00277-010-0911-7 20174923\n20. Sabanis N, Paschou E, Gavriilaki E, Kalaitzoglou A, Vasileiou S. Hypofibrinogenemia induced by tigecycline: a potentially life-threatening coagulation disorder. Infect Dis (Lond). 2015;47 (10 ):743–746. doi:10.3109/23744235.2015.1043942 25951751\n21. Campany-Herrero D, Larrosa-Garcia M, Lalueza-Broto P, et al. Tigecycline-associated hypofibrinogenemia in a real-world setting. Int J Clin Pharm-Net. 2020;42 (4 ):1184–1189. doi:10.1007/s11096-020-01072-7\n22. Simurda T, Zolkova J, Snahnicanova Z, et al. Identification of two novel fibrinogen Bbeta chain mutations in two Slovak families with quantitative fibrinogen disorders. Int J Mol Sci. 2017;19 (1 ):100. doi:10.3390/ijms19010100\n23. Casini A, Undas A, Palla R, Thachil J, de Moerloose P. Diagnosis and classification of congenital fibrinogen disorders: communication from the SSC of the ISTH. J Thromb Haemost. 2018;16 (9 ):1887–1890. doi:10.1111/jth.14216 30076675\n24. Toh CH, Alhamdi Y, Abrams ST. Current pathological and laboratory considerations in the diagnosis of disseminated intravascular coagulation. Ann Lab Med. 2016;36 (6 ):505–512. doi:10.3343/alm.2016.36.6.505 27578502\n25. Nair RR, Chauhan R, Harankhedkar S, Mahapatra M, Saxena R. Imatinib-induced platelet dysfunction and hypofibrinogenemia in chronic myeloid leukemia. Blood Coagulation Fibrinolysis. 2019;30 (5 ):246–248. doi:10.1097/MBC.0000000000000817 31310595\n26. Simurda T, Vilar R, Zolkova J, et al. A novel nonsense mutation in FGB (c.1421G>A; p.Trp474Ter) in the beta chain of fibrinogen causing hypofibrinogenemia with bleeding phenotype. Biomedicines. 2020;8 (12 ):605. doi:10.3390/biomedicines8120605\n27. Simurda T, Brunclikova M, Asselta R, et al. Genetic variants in the FGB and FGG genes mapping in the beta and gamma nodules of the fibrinogen molecule in congenital quantitative fibrinogen disorders associated with a thrombotic phenotype. Int J Mol Sci. 2020;21 (13 ):4616. doi:10.3390/ijms21134616\n28. Green F, Humphries S. Control of plasma fibrinogen levels. Baillieres Clin Haematol. 1989;2 (4 ):945–959. doi:10.1016/S0950-3536(89)80053-8 2688760\n29. Saliba R, Paasch L, El SA. Tigecycline attenuates staphylococcal superantigen-induced T-cell proliferation and production of cytokines and chemokines. Immunopharmacol Immunotoxicol. 2009;31 (4 ):583–588. doi:10.3109/08923970902838672 19874226\n30. Pichereau S, Moran JJ, Hayney MS, Shukla SK, Sakoulas G, Rose WE. Concentration-dependent effects of antimicrobials on Staphylococcus aureus toxin-mediated cytokine production from peripheral blood mononuclear cells. J Antimicrob Chemother. 2012;67 (1 ):123–129. doi:10.1093/jac/dkr417 21980070\n31. Salvatore CM, Techasaensiri C, Tagliabue C, et al. Tigecycline therapy significantly reduces the concentrations of inflammatory pulmonary cytokines and chemokines in a murine model of Mycoplasma pneumoniae pneumonia. Antimicrob Agents Chemother. 2009;53 (4 ):1546–1551. doi:10.1128/AAC.00979-08 19139287\n32. Brandtner A, Bachler M, Fries D, et al. Tigecycline interferes with fibrinogen polymerization independent of peripheral interactions with the coagulation system. Antibiotics (Basel). 2020;9 (2 ):84. doi:10.3390/antibiotics9020084\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1176-6336",
"issue": "17()",
"journal": "Therapeutics and clinical risk management",
"keywords": "coagulation disorders; hypofibrinogenemia; risk factors; tigecycline",
"medline_ta": "Ther Clin Risk Manag",
"mesh_terms": null,
"nlm_unique_id": "101253281",
"other_id": null,
"pages": "325-332",
"pmc": null,
"pmid": "33888987",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "29286337;32074981;29560313;18554910;24667348;29212626;19139287;19874226;28122754;31310595;32860258;29245350;32504166;33322159;21784708;15977966;32610551;20174923;31713108;2688760;33174956;30076675;21980070;25951751;30828002;32150105;27659942;32355990;20529440;16863487;27578502;25547356",
"title": "Risk Factors for Tigecycline-Associated Hypofibrinogenemia.",
"title_normalized": "risk factors for tigecycline associated hypofibrinogenemia"
} | [
{
"companynumb": "CN-ACCORD-225080",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TIGECYCLINE"
},
"drugadditional": null,
"dru... |
{
"abstract": "OBJECTIVE\nDolutegravir is recommended worldwide as a first-line antiretroviral therapy (ART) for individuals living with HIV. A recent study reported increased rates of neural tube defects in infants of dolutegravir-treated women. This study examined rates of congenital anomalies in infants born to women living with HIV (WLWH) in Canada.\n\n\nMETHODS\nThe Canadian Perinatal HIV Surveillance Programme captures surveillance data on pregnant WLWH and their babies and was analysed to examine the incidence of congenital anomalies.\n\n\nMETHODS\nPaediatric HIV clinics.\n\n\nMETHODS\nLive-born infants born in Canada to WLWH between 2007 and 2017.\n\n\nMETHODS\nData on mother-infant pairs, including maternal ART use at conception and during pregnancy, are collected by participating sites.\n\n\nMETHODS\nCongenital anomalies.\n\n\nRESULTS\nOf the 2423 WLWH, 85 (3.5%, 95% CI 2.85-4.36%) had non-chromosomal congenital anomalies. There was no evidence of a significant difference in rates of congenital anomalies between women who were on ART in their first trimester (3.9%, CI 1.7-7.6%) or later in the pregnancy (3.9%, 95% CI 2.6-5.6%). Four of the 80 (5.0%, 95% CI 1.4-12.3%) neonates born to WLWH on dolutegravir during the first trimester had congenital anomalies, none were neural tube defects (95% CI 0.00-3.10%).\n\n\nCONCLUSIONS\nDespite recent evidence raising a safety concern, this analysis found no signal for increased congenital anomalies.\nFive percent of the infants of Canadian women living with HIV on dolutegravir at conception had congenital anomalies; none had neural tube defects.",
"affiliations": "Women's Hospital and Health Centre of British Columbia, University of British Columbia, Vancouver, BC, Canada.;CIHR Canadian HIV Trials Network, Vancouver, BC, Canada.;BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada.;Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada.;Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.;CHU Ste-Justine, Université de Montréal, Montréal, QC, Canada.;Stollery Children's Hospital, University of Alberta, Edmonton, AB, Canada.;Women's Hospital and Health Centre of British Columbia, University of British Columbia, Vancouver, BC, Canada.;Stollery Children's Hospital, University of Alberta, Edmonton, AB, Canada.;CIHR Canadian HIV Trials Network, Vancouver, BC, Canada.;Women's Hospital and Health Centre of British Columbia, University of British Columbia, Vancouver, BC, Canada.",
"authors": "Money|D|D|;Lee|T|T|;O'Brien|C|C|;Brophy|J|J|;Bitnun|A|A|;Kakkar|F|F|;Boucoiran|I|I|;Alimenti|A|A|;Vaudry|W|W|;Singer|J|J|;Sauve|L J|LJ|https://orcid.org/0000-0003-2341-9018;|||",
"chemical_list": "D019380:Anti-HIV Agents; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; C562325:dolutegravir",
"country": "England",
"delete": false,
"doi": "10.1111/1471-0528.15838",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-0328",
"issue": "126(11)",
"journal": "BJOG : an international journal of obstetrics and gynaecology",
"keywords": "\nHIV\n; Antiretroviral therapy; congenital anomalies; dolutegravir",
"medline_ta": "BJOG",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D002170:Canada; D000013:Congenital Abnormalities; D005260:Female; D015658:HIV Infections; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D010078:Oxazines; D010879:Piperazines; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011297:Prenatal Exposure Delayed Effects; D011728:Pyridones; D018571:Sentinel Surveillance",
"nlm_unique_id": "100935741",
"other_id": null,
"pages": "1338-1345",
"pmc": null,
"pmid": "31188522",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Congenital anomalies following antenatal exposure to dolutegravir: a Canadian surveillance study.",
"title_normalized": "congenital anomalies following antenatal exposure to dolutegravir a canadian surveillance study"
} | [
{
"companynumb": "CA-STRIDES ARCOLAB LIMITED-2019SP009981",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ABACAVIR"
},
"drugadditional":... |
{
"abstract": "Pregnant women with opioid use disorder (OUD) are at risk of overdose, infectious diseases, and inadequate prenatal care. Additional risks include adverse pregnancy and infant outcomes, such as preterm birth and neonatal abstinence syndrome. Management and treatment of OUD during pregnancy are associated with improved maternal and infant outcomes. Professional organizations, including the American College of Obstetricians and Gynecologists, recommend offering opioid agonist pharmacotherapy (i.e., methadone or buprenorphine) combined with behavioral therapy as standard treatment for pregnant women with OUD. Other medications and herbal supplements have also been used by pregnant women for OUD. Determining which OUD treatments optimize maternal and infant outcomes is challenging given the host of potential factors that affect these outcomes. The Centers for Disease Control and Prevention initiated the MATernaL and Infant NetworK to Understand Outcomes Associated with Treatment of Opioid Use Disorder during Pregnancy (MAT-LINK) to monitor more than 2000 mothers and their infants, using data collected from geographically diverse clinical sites. Information learned from MAT-LINK will inform the future management and treatment of pregnant women with OUD.",
"affiliations": "Eagle Global Scientific LLC, San Antonio, Texas, USA.;Division of Birth Defects and Infant Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.;Division of Birth Defects and Infant Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.;Division of Birth Defects and Infant Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.;Division of Birth Defects and Infant Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.;Division of Birth Defects and Infant Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.;Division of Birth Defects and Infant Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.;Division of Birth Defects and Infant Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.;Division of Birth Defects and Infant Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.;Division of Birth Defects and Infant Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.;Division of Birth Defects and Infant Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.",
"authors": "Tran|Emmy L|EL|;Kim|Shin Y|SY|;England|Lucinda J|LJ|;Green|Caitlin|C|;Dang|Elizabeth P|EP|;Broussard|Cheryl S|CS|;Fehrenbach|Nicole|N|;Hudson|Amy|A|;Yowe-Conley|Tineka|T|;Gilboa|Suzanne M|SM|;Meaney-Delman|Dana|D|",
"chemical_list": "D000701:Analgesics, Opioid; D002047:Buprenorphine",
"country": "United States",
"delete": false,
"doi": "10.1089/jwh.2020.8848",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1540-9996",
"issue": "29(12)",
"journal": "Journal of women's health (2002)",
"keywords": "opioid use disorder; outcomes; pregnancy; substance use disorder; surveillance",
"medline_ta": "J Womens Health (Larchmt)",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D002047:Buprenorphine; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders; D011159:Population Surveillance; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D047928:Premature Birth; D016896:Treatment Outcome",
"nlm_unique_id": "101159262",
"other_id": null,
"pages": "1491-1499",
"pmc": null,
"pmid": "33227221",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "31376396;30928567;28742676;31809398;29404599;29614184;9851480;30969219;29706175;9794682;26511390;29449242;26914546;30091969;25622120;31034790;30575679;30114393;30205307;30404789;31836339;28408072;30204703;32185570;26471942;26996987;30204686;23244553;28699096;29630016;28219965;30204704;31298606;31358302;28079573;30855311;30848807;29263121;28594753;30377951;27223595;28086944",
"title": "The MATernaL and Infant NetworK to Understand Outcomes Associated with Treatment of Opioid Use Disorder During Pregnancy (MAT-LINK): Surveillance Opportunity.",
"title_normalized": "the maternal and infant network to understand outcomes associated with treatment of opioid use disorder during pregnancy mat link surveillance opportunity"
} | [
{
"companynumb": "US-SPECGX-T202100201",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "NALTREXONE"
},
"drugadditional": null,
"... |
{
"abstract": "Disruptive mood dysregulation disorder (DMDD) is characterized by nonepisodic irritability and has a high rate of comorbidity with attention-deficit/hyperactivity disorder (ADHD). This is the first study to explore the effects of aripiprazole combined with methylphenidate on clinical symptoms and cognitive functions in patients with DMDD and ADHD.\n\n\n\nPatients with DMDD and ADHD (the DMDD-ADHD Group, n = 24; aged 7-17 years) completed a 6-week, open-label trial of aripiprazole and methylphenidate. The pre- and posttreatment outcome measures included the parent-rated Swanson, Nolan, and Pelham Scale-version IV, Child Behavior Checklist, and self-reported Beck Youth Inventories-II, as well as a neuropsychological battery composed of the Children's Color Trail Test and Conner's Continuous Performance Test. The comparison group consisting of patients with ADHD (the ADHD Group, n = 27) was recruited to investigate the differences in clinical and neuropsychological profiles between the two groups at baseline.\n\n\n\nThe DMDD-ADHD Group showed worse irritability, disruptive behaviors, anxious/depressed symptoms, and social problems relative to the ADHD Group at baseline assessments. The combination treatment significantly improved irritability, externalizing symptoms, depression, anxiety, attention, social problems, and reaction time variability. The effect sizes of reductions in parent-rated irritability, oppositional defiant symptoms, and inattention were comparable (Cohen's d = 1.26, 1.11, and 1.40, respectively).\n\n\n\nThis pilot study showed the tolerability of the aripiprazole/methylphenidate combination by patients with DMDD and ADHD and its efficaciousness for treating clinical symptoms and for improving cognitive function. Further randomized, controlled, cross-over studies are needed.",
"affiliations": "Department of Psychiatry, National Defense Medical Center , Tri-Service General Hospital, Taipei, Taiwan .;Department of Psychiatry, National Defense Medical Center , Tri-Service General Hospital, Taipei, Taiwan .;Department of Psychiatry, National Defense Medical Center , Tri-Service General Hospital, Taipei, Taiwan .",
"authors": "Pan|Pei-Yin|PY|;Fu|An-Ting|AT|;Yeh|Chin-Bin|CB|",
"chemical_list": "D000928:Antidepressive Agents; D000697:Central Nervous System Stimulants; D008774:Methylphenidate; D000068180:Aripiprazole",
"country": "United States",
"delete": false,
"doi": "10.1089/cap.2018.0068",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1044-5463",
"issue": "28(10)",
"journal": "Journal of child and adolescent psychopharmacology",
"keywords": "aripiprazole; attention-deficit/hyperactivity disorder; disruptive mood dysregulation disorder; irritability; methylphenidate",
"medline_ta": "J Child Adolesc Psychopharmacol",
"mesh_terms": "D000293:Adolescent; D000928:Antidepressive Agents; D000068180:Aripiprazole; D001289:Attention Deficit Disorder with Hyperactivity; D019958:Attention Deficit and Disruptive Behavior Disorders; D000697:Central Nervous System Stimulants; D002648:Child; D015897:Comorbidity; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008774:Methylphenidate; D009483:Neuropsychological Tests",
"nlm_unique_id": "9105358",
"other_id": null,
"pages": "682-689",
"pmc": null,
"pmid": "30148656",
"pubdate": "2018-12",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Aripiprazole/Methylphenidate Combination in Children and Adolescents with Disruptive Mood Dysregulation Disorder and Attention-Deficit/Hyperactivity Disorder: An Open-Label Study.",
"title_normalized": "aripiprazole methylphenidate combination in children and adolescents with disruptive mood dysregulation disorder and attention deficit hyperactivity disorder an open label study"
} | [
{
"companynumb": "TW-OTSUKA-2019_000006",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE"
},
"drugadditional": null,
... |
{
"abstract": "We report on a 20-year-old woman who developed a pelvic small round cell tumor with lung metastases 8 years after diagnosis and successful treatment for Ki-1-positive anaplastic large cell lymphoma (Ki-1+ ALCL) with histiocytic differentiation. Molecular genetic detection of EWS/FLI-1 fusion gene expression in the second tumor by RT-PCR unambiguously confirmed the histopathologic diagnosis of Ewing tumor (ET), whereas no evidence for the presence of this specific gene rearrangement was obtained in a retrospective analysis of the lymphoma tissue. In contrast, expression of a NPM/ALK chimeric gene was observed which was absent in the ET. Moreover, the lymphoma contained a monoallelic D delta 2-D delta 3 T-cell receptor gene rearrangement which was also absent in the ET. Thus, our histopathologic, immunohistochemical, and, in particular, molecular genetic studies support the notion that these tumors were most probably pathogenetically unrelated. Since this is the first report describing such an association between a non-Hodgkin's lymphoma and ET and, since the latter has only rarely been observed as a second malignant neoplasm, it remains a matter of speculation whether in this patient ET developed as a therapy-related secondary neoplasm or independently from the lymphoma as a consequence of either genetic tumor predisposition or mere accidental coincidence.",
"affiliations": "Children's Cancer Research Institute, St. Anna Children's Hospital, Vienna, Austria.",
"authors": "Zoubek|A|A|;Simonitsch|I|I|;Panzer-Grümayer|E R|ER|;Ghali|D|D|;Pfleiderer|C|C|;Haas|O A|OA|;Mann|G|G|;Lang|S|S|;Radaszkiewicz|T|T|;Gadner|H|H|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/s0165-4608(95)00014-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-4608",
"issue": "83(1)",
"journal": "Cancer genetics and cytogenetics",
"keywords": null,
"medline_ta": "Cancer Genet Cytogenet",
"mesh_terms": "D001483:Base Sequence; D001859:Bone Neoplasms; D002648:Child; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms; D017728:Lymphoma, Large-Cell, Anaplastic; D008969:Molecular Sequence Data; D016609:Neoplasms, Second Primary; D016133:Polymerase Chain Reaction; D012512:Sarcoma, Ewing",
"nlm_unique_id": "7909240",
"other_id": null,
"pages": "5-11",
"pmc": null,
"pmid": "7656205",
"pubdate": "1995-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Ewing tumor after treatment of Ki-1+ anaplastic large cell lymphoma. Therapy-associated secondary neoplasm or unrelated coincidence?",
"title_normalized": "ewing tumor after treatment of ki 1 anaplastic large cell lymphoma therapy associated secondary neoplasm or unrelated coincidence"
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"abstract": "Transcranial magnetic stimulation is an increasingly popular FDA-approved treatment for resistant depression, migraines, and OCD. Research is also underway for its use in various other psychiatric and medical disorders. Although rare, seizures are a potential adverse event of TMS treatment. In this article, we discuss TMS-related seizures with the various coils used to deliver TMS, the risk factors associated with seizures, the differential diagnosis of its presentations, the effects of sleep deprivation and alcohol use on seizures, as well as seizure risks with protocols for traditional TMS, theta-burst stimulation, and accelerated TMS. A discussion is presented comparing the potential risk of seizures with various psychotropic medications versus TMS. Included are case reports of TMS seizures in the child/adolescent patient, bipolar disorder patients, patients with a history of a traumatic brain injury, and those with epilepsy. Reports are also shared on TMS use without seizures in patients with a history of head injuries and TMS's continued use if patients have a seizure during their TMS treatment. Findings generated in this review suggest the following. Seizures, if present, are usually self-limiting. Most treatment recommendations for TMS-related seizures are supportive in nature. The risk of TMS-related seizures is <1% overall. TMS has successfully been used in patients with epilepsy, traumatic brain injuries, and those with a prior TMS-related seizure. The rate of TMS-related seizures is comparable to that of most psychotropic medications. While having a seizure is a rare but serious adverse effect of TMS, the benefits of treating refractory depression with TMS may outweigh the risk of suicidal ideation and other significant complications of depression.",
"affiliations": "Stultz Sleep & Behavioral Health, Barboursville, WV 25504, USA.;Stultz Sleep & Behavioral Health, Barboursville, WV 25504, USA.;Stultz Sleep & Behavioral Health, Barboursville, WV 25504, USA.;Stultz Sleep & Behavioral Health, Barboursville, WV 25504, USA.;Stultz Sleep & Behavioral Health, Barboursville, WV 25504, USA.",
"authors": "Stultz|Debra J|DJ|0000-0001-5461-9341;Osburn|Savanna|S|0000-0002-2965-0133;Burns|Tyler|T|;Pawlowska-Wajswol|Sylvia|S|;Walton|Robin|R|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/NDT.S276635",
"fulltext": "\n==== Front\nNeuropsychiatr Dis Treat\nNeuropsychiatr Dis Treat\nndt\nneurodist\nNeuropsychiatric Disease and Treatment\n1176-6328 1178-2021 Dove \n\n276635\n10.2147/NDT.S276635\nReview\nTranscranial Magnetic Stimulation (TMS) Safety with Respect to Seizures: A Literature Review\nStultz et alStultz et alhttp://orcid.org/0000-0001-5461-9341Stultz Debra J 1 http://orcid.org/0000-0002-2965-0133Osburn Savanna 1 Burns Tyler 1 Pawlowska-Wajswol Sylvia 1 Walton Robin 1 1 Stultz Sleep & Behavioral Health, Barboursville, WV\n25504, USA\nCorrespondence: Debra J Stultz Stultz Sleep & Behavioral Health, 6171 Childers Road, Barboursville, WV25504, USATel +1 304-733-5380Fax +1 304-733-5796 Email wvsleepdoc@stultzsleep.com\n07 12 2020 \n2020 \n16 2989 3000\n15 8 2020 17 11 2020 © 2020 Stultz et al.2020Stultz et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Abstract\nTranscranial magnetic stimulation is an increasingly popular FDA-approved treatment for resistant depression, migraines, and OCD. Research is also underway for its use in various other psychiatric and medical disorders. Although rare, seizures are a potential adverse event of TMS treatment. In this article, we discuss TMS-related seizures with the various coils used to deliver TMS, the risk factors associated with seizures, the differential diagnosis of its presentations, the effects of sleep deprivation and alcohol use on seizures, as well as seizure risks with protocols for traditional TMS, theta-burst stimulation, and accelerated TMS. A discussion is presented comparing the potential risk of seizures with various psychotropic medications versus TMS. Included are case reports of TMS seizures in the child/adolescent patient, bipolar disorder patients, patients with a history of a traumatic brain injury, and those with epilepsy. Reports are also shared on TMS use without seizures in patients with a history of head injuries and TMS’s continued use if patients have a seizure during their TMS treatment. Findings generated in this review suggest the following. Seizures, if present, are usually self-limiting. Most treatment recommendations for TMS-related seizures are supportive in nature. The risk of TMS-related seizures is <1% overall. TMS has successfully been used in patients with epilepsy, traumatic brain injuries, and those with a prior TMS-related seizure. The rate of TMS-related seizures is comparable to that of most psychotropic medications. While having a seizure is a rare but serious adverse effect of TMS, the benefits of treating refractory depression with TMS may outweigh the risk of suicidal ideation and other significant complications of depression.\n\nKeywords\ntranscranial magnetic stimulationtranscranial magnetic stimulation-related seizurestranscranial magnetic stimulation safetytranscranial magnetic stimulation in epilepsy patientshead injuries and transcranial magnetic stimulationtranscranial magnetic stimulation in children and adolescents\n==== Body\nIntroduction\nTranscranial Magnetic Stimulation (TMS) is FDA approved for depression, migraines, and OCD, with other symptoms and disorders being aggressively studied for benefit. Lefaucheur et al 20201 have an extensive review of the evidence-based use of rTMS in other disorders such as stroke, multiple sclerosis, tinnitus, anxiety, schizophrenia, substance abuse, Alzheimer’s, ALS, epilepsy, panic, PTSD, and others. TMS uses an electromagnetic coil placed on varying areas of the scalp. This coil generates magnetic pulses and stimulates different brain areas to create the desired pathophysiologic and clinical outcome. TMS was first approved for depression in 2008;2 since that time, various coils have been created, altering the area and depth stimulated. It has been suggested that the different coils may have variations in side effects and the possible frequency of the adverse event of a seizure. There are also different protocols of stimulation used with TMS, with the most recent advances called theta-burst stimulation and accelerated treatment. Theta-burst stimulation uses three magnetic pulses 20 ms apart and repeated every 200 ms of 50 Hz stimulation.3 Accelerated TMS uses multiple TMS stimulation treatments per day.4\n\nMethodology\nThis paper will focus on the adverse event of a seizure during TMS, which is an abnormal electrical activity and may be due to systemic or local causes. We will also review TMS use in patients with known epilepsy, which is usually due to a structural abnormality of the brain and is that of repeated seizures.\n\nAfter having a patient who had a seizure during her TMS treatment in 2018, we began looking for all suggestions and references we could find on TMS-related seizures. We had difficulty finding specific information on whether to continue the TMS and what steps to take immediately after the patient had been stabilized from the seizure. From that time forward, we have reviewed articles/books found on PubMed, MEDLINE, Medscape, Cochrane Libray, Scopus, and Google Scholar while collecting information with Mendeley. In this article, we have presented data from 1998 to 2020 (See Table 1). We will discuss the general risk factors associated with seizures, the risks associated with the different TMS coils, reports of seizures with differing TMS protocols, the risk of psychotropic medication alteration on having a seizure, TMS seizures in the child/adolescent population, TMS seizures in bipolar disorder, as well as the possible effects of alcohol use and sleep deprivation on seizures. We will review TMS use with epilepsy and traumatic head injury patients. We will report on continued TMS after a seizure. We will also describe specific steps to take should the patient have a seizure.Table 1 Stultz et al TMS Seizure Review Articles\n\n\tReference\tCoil Type\tDescription\t\nIntroduction\tLefaucheur et al 20201\tMultiple\tReview on the use of TMS for multiple disorders using various coil types such as Figure 8, Circular, Double Cone, Hesed\t\n\tMcClintock et al 20182\tH1, Figure 8\tTMS approved for depression in 2008\t\n\tChung et al 20153\tMultiple\tReview of the application of theta burst TMS using multiple coil types such as Double Cone, Figure 8, H-coil\t\n\tSonmez et al 20194\tNot Specified\tReview on the use of accelerated TMS protocol\t\nTMS and Coils\tRossi et al 20095\tN/A\tGeneral seizure risk with TMS <0.003%\t\n\tOberman et al 20116\tN/A\tSeizure risk with theta burst rTMS is around 0.02%\t\n\tCarpenter et al 20127\tFigure 8\tSeizure risk <1% with TMS\t\n\tJanicak et al 20208\tFigure 8\tNeurostar seizure rates lower than initially reported\t\n\tTendler et al 20189\tH1\tReviewed 31 seizure cases, rate of 0.087%.\t\n\tCavinato et al 201210\tFigure 8\t31 y/o male, Hx of severe TBI, had a partial and secondarily generalized tonic-clonic seizure on 4th of 10 daily sessions\t\n\tKoudijis et al 201011\tRound, Fig. 8\t34 children aged 5 mo. to 19 y/o with intractable epilepsy underwent TMS, temporary increase in seizures in 4 children\t\n\tLerner et al 201912\tMultiple\tRisk of seizures with TMS is 0.08/1000 for Figure 8, 0.12/1000 for Double Cone, 0.43 for H-coil.\t\nTMS Seizure Risk Factors\tRossi et al 20095\tN/A\tHigher frequencies and short intervals between trains can increase risk; See description under TMS & Coils\t\n\tWasserman 199813\tN/A\t<20 second intervals between series leads to increased seizure risk\t\n\tMcClintock et al 20182\tH1, Figure 8\tTonic-clonic seizure during TMS due to direct stimulation of motor cortex or adjacent brain areas; Also cited in Intro\t\n\tGeorge & Belmaker 200714\tN/A\tSeveral factors related to increased seizure risk\t\nDifferential Diagnosis\tSheldon et al 200215\tN/A\tDistinctions between syncope and seizures\t\n\tKinback 201816\tH1\t42 y/o female, Tx 21 had partial tonic seizure\t\nTheta Burst TMS\tOberman & Pascual-Leone 200917\tFigure 8\t33 y/o male, possibly sleep deprived, seizure during final train of session\t\n\tPurushotham et al 201818\tFigure 8\t15 y/o female, Hx of schizophrenia, Tx 1 had seizure\t\n\tLenoir et al 201819\tDouble Cone\t2 cases of seizures (One generalized, one partial complex)\t\n\tAllen et al 201720\tN/A\tReviewed 3 TBS studies involving healthy children and pediatric patients with CNS Disorders, no reported seizures.\t\nAccelerated TMS\tKallel & Brunelin 202021\tFigure 8\t18 y/o female, had seizure that was first localized then generalized during 3rd session of 2nd day\t\nTMS and Psychotropics\tRossi et al 20095\tN/A\tSome meds/substances can potentially increase seizure risk; See description under TMS & Coils and Risk Factors\t\n\tLoo et al 200822\tN/A\tIf medications are adjusted during TMS, re-check motor threshold\t\n\tDobek et al 201523\tN/A\tTMS-induced seizures and antidepressant use; Bupropion is not a contraindication\t\n\tLertxurdi et al 201324\tN/A\t2nd gen antipsychotics may have a higher risk of seizures, especially clozapine\t\n\tKhoury & Ghossoub 201925\tN/A\t0.5–1.2% risk of seizures with antipsychotics, clozapine increases risk the most\t\n\tThanki et al 202026\tFigure 8\t60 y/o male, Hx of hyponatremic seizures, completed TMS safely twice (once on sertraline, another time on venlafaxine)\t\nTMS in Children/Adolescents\tAllen et al 201720\tN/A\tReviewed 23 rTMS studies involving children w/CNS disorders & epilepsy, 3 seizures in CNS. See Theta Burst TMS\t\n\tHu et al 201127\tFigure 8\t15 y/o female, on sertraline, generalized tonic-clonic seizure during Tx 1, became hypomanic from TMS\t\n\tChiramberro et al 201328\tFigure 8\t16 y/o female, Tx 12 had seizure, later found high level of blood alcohol concentration\t\n\tCullen et al 201629\tH1\t17 y/o female, Tx 8 had generalized tonic-clonic seizure\t\n\tPurushotham et al 201818\tFigure 8\tSee description under Theta Burst TMS\t\n\tWang et al 201830\tFigure 8\t16 y/o female, Hx of migraines w/auras, Tx 1 had generalized tonic-clonic seizure\t\n\tMuir et al 201931\tH1\tReviewed 6 pts., 1 case of seizure in pt. w/Hx of autism, multiple head injuries, and D/C of oxcarbazepine prior to TMS\t\n\tZewdie et al 201932\tFig. 8, D.Cone\tReviewed 384 children who underwent TMS, no seizures occurred\t\nTMS and Bipolar Disorder\tTharayil et al 200533\tNot Specified\t35 y/o pt. with family Hx of seizures had generalized seizure while on lithium and chlorpromazine.\t\n\tSakkas et al 200734\tFigure 8\t30 y/o female, Type I Bipolar Disorder, manic, stopped diazepam on her own prior to Tx 9, had Jacksonian seizure\t\n\tHarel et all 201135\tH1\t1 patient out of 19 had a generalized seizure\t\n\tIliceto et al 201836\tFigure 8\t37 y/o male, Type I Bipolar Disorder, Hx of TBI, completed TMS safely\t\nTMS and TBI\tDhaliwal et al 201537\tFig. 8, Focal\tSevere TBI increases seizure risk\t\n\tReti et al 201538\tN/A\tTBI increases seizure risk, low frequency rTMS may be better option for those with a Hx\t\n\tBernabeu et al 200439\tCircular\t28 y/o female with Hx of TBI on fluoxetine, had secondarily generalized tonic-clonic seizure using fast rTMS protocol\t\n\tCavinato et al 201210\tFigure 8\tSee description under TMS & Coils\t\n\tPape et al 201440\tNot Specified\t2 pts. w/Hx of TBI underwent TMS. Pt. #1 completed safely, Pt. #2 had an EEG seizure w/no clinical S/S at Tx 21\t\n\tBoes et al 201641\tH1\t27 y/o male had generalized tonic-clonic seizure at Tx 12, Hx of alcohol use and 4 head injuries\t\n\tMuir et al 201931\tH1\tSee description under TMS in Children/Adolescents\t\nTMS and Head Injuries w/o Seizures\tFitzgerald et al 201142\tFigure 8\t41 y/o female with Hx of mild TBI, completed 20 Txs\t\n\tKreuzer et al 201343\tFigure 8\t53 y/o male had severe tinnitus after TBI, completed 5 Tx series over 3 years\t\n\tNeville et al 201544\tFigure 8\tDouble-blind study involving 36 pts. aged 18–60 y/o with Hx of TBI\t\n\tNielson et al 201545\tFigure 8\t48 y/o male with Hx of severe TBI, finished 30 Txs; 90% lower risk of seizure if none w/in 2 years of injury\t\n\tEnglander et al 200347\tN/A\tCT scan results and neurosurgical procedures useful in determining risk for late posttraumatic seizures\t\n\tKoski et al 201548\tFigure 8\tTreated 12 pts. aged 20–60 y/o, 60% male, 60% had ≥3 concussions\t\n\tRutherford et al 201749\tNot Specified\t13 pts. with mild TBI, 7 real TMS + 6 sham; rTMS may be effective for some symptoms of post-concussion syndrome\t\n\tPaxman et al 201850\tNot Specified\t61 y/o male had chronic dizziness after a mild TBI, completed 10 Txs\t\n\tLee & Kim 201851\tFigure 8\t13 pts. aged 19–60 y/o with Hx of TBI, received 10 sessions of real or sham TMS\t\n\tIliceto et al 201836\tFigure 8\tSee description under TMS and Bipolar Disorder\t\n\tSaunders & Bermudes 201853\tFigure 8\t55 y/o female had TBI unrelated to TMS after 10 sessions, resumed TMS 11 days later, 4 different protocols used\t\n\tSiddiqi et al 201854\tNot Specified\tStudied effects of resting-state fMRI-targeted rTMS in a retired NFL player, Hx of repetitive head trauma.\t\n\tStultz et al 201955\tH1\t23 y/o male with Hx of 4 concussions\t\nTMS and Alcohol Use\tTendler et al 20189\tH1\t6/31 pts. reviewed who had a seizure involved increased alcohol intake\t\n\tBoes et al 201641\tH1\tSee description under TMS and TBI\t\n\tChiramberro et al 201328\tFigure 8\tSee description under TMS in Children/Adolescents\t\nTMS and Sleep Deprivation\tNakken et al 200556\tN/A\tReported on 1677 pts. with epilepsy, those with generalized seizures report to be more sensitive to sleep deprivation\t\n\tFerlisi & Shorvon 201457\tN/A\tPts. with idiopathic generalized epilepsy more sensitive to seizures while sleep deprived\t\n\tPrikryl & Kucerova 200558\tNot Specified\t45 y/o male who was sleep deprived for 2 nights had a grand mal seizure during Tx 6\t\n\tTendler et al 20189\tH1\t3/31 pts. reviewed who had a seizure c/o sleep deprivation\t\n\tOberman & Pascual-Leone 200917\tFigure 8\tSee description under Theta Burst TMS\t\nTMS and Epilepsy\tBae et al 200759\tN/A\tRisk of seizures in pts. with epilepsy <2%\t\n\tPereira et al 201660\tN/A\tReviewed 410 epilepsy pts. receiving TMS, 12 of which had a seizure, suggesting a seizure risk of 2.9%\t\n\tVernet et al 201261\tNot Specified\t22 y/o male, drug-resistant symptomatic focal epilepsy, had seizure clinically similar to typical spontaneous seizures\t\n\tAllen et al 201720\tN/A\tReviewed 23 rTMS studies involving children with CNS disorders & epilepsy, no seizures reported in epileptic pts.\t\n\tKoudijis et al 201011\tRound, Fig. 8\tSee description under TMS and Coils\t\n\tStultz et al 201962\tH1\t69 y/o female, Hx of complex partial seizures, completed TMS without having a seizure\t\n\tFitzgerald 201463\tNot Specified\t57 y/o male, tried ECT in the past, had not experienced seizures for 11 years, completed TMS safely at low-frequency\t\nContinued TMS After a Seizure\tBagati et al 201264\tNot Specified\t44 y/o male, had seizure during Tx 4, continued TMS after being prescribed valproate\t\n\tStultz et al 201965\tH1\t48 y/o female, developed tonic clonic seizure during Tx 11, continued TMS after evaluation with no reported seizures\t\n\tKallel & Brunelin 202021\tFigure 8\tSee description under Accelerated TMS. Continued with TMS after decreasing to 1 session per day.\t\nTreatment Plan\tFitzgerald & Daskalakis 201266\tN/A\trTMS-related seizures likely to terminate quickly and not require additional treatment\t\n\n\n\nTMS and Coils\nThe general risks of a seizure with TMS have been reported to be <1/30,000 (<0.003%) by Rossi et al 2009.5 The risk of seizure with theta burst is estimated at 0.02% by Oberman et al 2011.6 With the Figure-8 coil, the risk of seizure has been estimated by Carpenter et al 20127 to be 3/1000 or <1% overall. Janicak et al 20208 reported postmarketing seizure rates with the Neurostar coil are even lower than previously reported. Tendler et al 20189 reviewed available data for the Brainsway H1-Coil and reported a seizure rate of 0.087%. They reviewed 31 reported cases of seizures with the H1-Coil and felt most were due to the motor threshold (MT) not being rechecked weekly, as recommended by the company. Six seizures were due to stimulation with intensity >120% of the Motor Threshold. No seizures were reported with the first TMS treatment. Nine seizures were associated with medication issues, increased alcohol intake was reported with six patients, and three seizures were associated with sleep issues. While most seizures occur during or around the time of treatment, Cavinato et al 201210 reported on a patient with a traumatic brain injury who had a seizure 3 hours after his TMS treatment. Also, Koudijs et al 201011 reported an increased frequency of seizures for up to 3 days in four children with known epilepsy who had TMS treatment.\n\nLerner et al 201912 reviewed surveys from 174 providers from 2012 to 2016, revealing 24 seizures out of 318,560 TMS sessions. They reported the risk of seizures with TMS was 0.08/1000 and that “TMS delivered within published guidelines to individuals without risk factors appears to cause fewer than one seizure per 60,000 sessions.” In their review, 62% of seizures occurred on the first exposure to TMS and 75% within the first three treatments. Of the 24 seizures, seven occurred in patients with congenital epilepsy, all of whom were on anti-epileptic medication at the time. Two patients were described as having refractory epilepsy. Lerner et al described the seizure risk for the different coil types as follows: 0.08/1000 for conventional figure-8 coils, double cone coils of 0.12/1000 and 0.43/1000 for H-coils. Only three seizures were reported with the H-coil, but only 7577 (2%) of the 318,560 TMS sessions were completed using the H-coil. The smaller sample size may have made the H-coil numbers appear higher.\n\nTMS Seizure Risk Factors\nRossi et al 20095 conveyed\nSeizures are caused by hyper synchronized discharges of groups of neurons in the gray matter, mainly due to an imbalance between inhibitory and excitatory synaptic activity in favor of the latter. Seizures can be induced by rTMS when pulses are applied with relatively high-frequencies and short interval periods between trains of stimulation.\n\n\n\nWasserman 199813 stated that “Intervals between series less than 20 seconds were associated with increased seizures”. (This may have been the cause of the increased seizures reported earlier in the literature using TMS.) McClintock et al 20182 stated\nthe risk of tonic-clonic seizure, a rare event during rTMS, is related to the direct stimulation of motor cortex or stimulation of the adjacent brain areas with spread of neuronal excitation to the motor cortex. Inspection of the contralateral hand for signs of twitching or movement during stimulation may ensure that stimulation does not spread from prefrontal to primary motor cortex, which can lead to generalized seizure induction with tonic-clonic movement pattern.\n\n\n\nMcClintock also stated, “seizures can occur within safety guidelines, even in patients who present with no known risk factors.”\n\nThe risk factors associated with TMS-related seizures were discussed in the book entitled “Transcranial Magnetic Stimulation in Neuropsychiatry” (George and Belmaker 200714). They reported on the increased risk of seizures with focal or generalized encephalopathy, severe head trauma, non-treated epilepsy, family history of epilepsy in first-degree relatives, heavy alcohol use, severe cardiac disease, increased intracranial pressure, medications that lower seizure threshold, cocaine usage, and other epileptogenic drugs. Other risk factors associated with seizures described throughout the years include a personal history of seizure, stroke, epilepsy, concussions, family history of brain tumors, eating disorders, neurologic disease with altered seizure threshold, sleep deprivation, excessive caffeine/stimulant/cocaine use, MDMA (Ecstasy) use, theophylline use, alcohol withdrawal, benzodiazepine withdrawal, electrolyte disturbance (decreased sodium, change in glucose), other medications that lower seizure threshold, depression, demyelinating disorders (such as Multiple Sclerosis), and fever.\n\nDifferential Diagnosis of TMS Seizures\nConcerning the differential diagnosis, a distinction must be made between vasovagal syncope and seizure during an episode. Vasovagal syncope symptoms include a transient rapid onset, self-limited loss of consciousness associated with lightheadedness, pale skin, yawning, blurred vision, and a feeling of being warm, cold, clammy, or sweaty (Sheldon et al 200215). Jerky myoclonic movements have also been reported with both vasovagal syncope and seizures.\n\nTMS seizures can be generalized or partial. Kinback in 201816 described a partial tonic seizure in a 42-year-old white female using the H1 coil during treatment 21, where she developed tense jaw and arm muscles, fixed gaze, unresponsiveness, and bilateral upper extremity flexion with clinched wrists. She had slight spine arching but no lower extremity involvement. She stayed fully aware without incontinence or LOC.\n\nTheta-Burst TMS and Seizures\nAs previously stated, theta-burst TMS has been associated with an estimated seizure risk of 0.02%.6 Oberman and Pascual-Leone 200917 recounted a seizure in a 33-year-old man with no risk factors (except possible sleep deprivation) using theta burst. Purushotham et al 201818 reported on a 15-year-old female with schizophrenia who developed a seizure with theta burst within the first 30 seconds of the first session. Lenoir et al 201819 described two cases of seizures with theta burst. One had a generalized seizure, and one a partial complex seizure. Allen et al 201720 identified no seizures after reviewing three theta-burst studies in 90 healthy children and 40 pediatric patients with CNS disorders.\n\nAccelerated TMS and Seizures\nKallel and Brunelin 202021 described an 18-year-old female with major depression receiving a protocol of 5 sessions per day during four consecutive working days over the left dorsolateral prefrontal cortex using the MagPro X30 figure-eight coil. The patient developed a seizure on the third session of the second day. The seizure underwent secondary generalization and was associated with urinary incontinence and postictal confusion. Twelve days later, the patient agreed to additional TMS given at 1-Hz right DLPFC treatment with one session per day for 30 additional sessions. She also had maintenance TMS scheduled every 2 weeks afterwards and had no seizure activity during her continued or maintenance treatments.\n\nTMS, Psychotropic Medications, and Seizures\nOver the years, various medications have been used during which a TMS-related seizure has occurred, but we have found no absolute contraindication with any specific medication to date. Rossi et al5 in their safety article of 2009 listed several medications described as having either a strong potential for hazard or a relative hazard for interactions with TMS. They also included medications that if withdrawn could create a strong relative hazard. (Please see their article for a complete list of medications listed.) Since their 2009 article, many of these substances have been used during TMS without incident.\n\nThere has been discussion about changing medications during the TMS treatment, and Loo et al 200822 stated,\nIf medications are altered during the TMS course, the motor threshold should be re-measured and the stimulus intensity adjusted accordingly. This is based on the premise that medications which alter seizure threshold could also alter motor cortical threshold.\n\n\n\nDobek et al 201523 while studying bupropion treatment with TMS and after an extensive literature review reported the following seizure incidence rates in percent for psychotropic medications independent of TMS use: Bupropion SR 0.1%, Bupropion IR 0.4%, Citalopram 0.25%, Duloxetine 0.2%, Fluoxetine 0.2%, Fluvoxamine 0.2%, Mirtazapine 0.04%, Paroxetine 0.1%, Sertraline up to 0.2%, Venlafaxine 0.3%, Tricyclics 0.1–0.4%, Olanzapine 0.9%, Quetiapine 0.8%, Aripiprazole 0.4%, Ziprasidone 0.4%, and Risperidone 0.3%. Lertxurdi et al 201324 reported that second-generation antipsychotics might have a higher risk of seizures, especially clozapine and possibly olanzapine and quetiapine. Khoury and Ghossoub 201925 revealed studies with antipsychotics are associated with 0.5% to 1.2% risk of seizures, and also reported clozapine appears to increase the risk the most. The above information reveals that the rates of seizures for psychotropic medications are similar or higher than the general TMS rates of <0.003% to 0.087% mentioned previously. Dobek et al23 also stated that TMS-induced seizure data are not associated with any particular antidepressant, and bupropion is not a contraindication to TMS. Thanki et al 202026 even reported on using rTMS in a 60-year-old male with a history of hyponatremic seizures with antidepressants on two different occasions while on sertraline 50 mg and then later on venlafaxine 75 mg, who was later successfully treated with 1 Hz TMS to the right dorsolateral prefrontal cortex at 90% of the resting motor threshold without having a seizure.\n\nTMS Seizures in Child/Adolescent Patients\nThe overall risk of TMS-related seizures in the child/adolescent population appears to be similar to that of the adult. Allen et al 201720 reported on a review in the pediatric population of 23 repetitive TMS (rTMS) studies (including 230 CNS and 24 epileptic children) identifying three seizures in the CNS patients, with a risk of 0.14% per session. They reviewed three theta-burst studies in 90 healthy children and 40 pediatric patients with CNS disorders and identified no seizures.\n\nCase reports of seizures in the child/adolescent patient have been reported. Hu et al 201127 described an adolescent female on Zoloft who had a seizure and became hypomanic with TMS. She subsequently stopped TMS. Chiramberro et al 201328 reported on a 16-year-old girl who had a seizure during the 12th treatment session with TMS. Of interest, the patient was on sertraline, olanzapine, and hydroxyzine, and she was also found to have used alcohol around the time of treatment. Cullen et al 201629 recounted a 17-year-old female in a sham-controlled study who developed a generalized tonic-clonic seizure during the 8th treatment session of TMS (which was the first day at 120% MT). Purushotham et al 201818 reported a 15-year-old girl with schizophrenia who had a seizure while using theta-burst TMS. Wang et al 201830 told of a 16-year-old girl previously diagnosed as having migraine with aura who had a seizure 10 seconds after the onset of the third rTMS train.\n\nIn the transition years to adulthood ages (18–20), Muir et al 201931 reviewed six patients and presented a case of one seizure using the H 1 coil at 120% MT with the risk factors of autism, multiple head injuries, and the discontinuation of oxcarbazepine during the week before TMS initiation. They felt the spontaneous discontinuation of oxcarbazepine was the most likely cause. Most recently, Zewdie et al 201932 reviewed the results of 384 children over ten years that underwent TMS or direct current stimulation (tDCS). Neuromodulation TMS occurred in 119 of the patients with a median age of 14. “Despite 221 (58%) of the patients having some sort of brain injury/or epilepsy, no seizures occurred with single, paired, or rTMS or with tCDS.”\n\nTMS Seizures in Bipolar Patients\nTMS seizures have been described in diagnoses other than depression and in the bipolar patient have been reported in 2005 by Tharayil et al, by Sakkas et al, and described again by Harel et al in 2011. Tharayil et al 200533 reported a generalized seizure in a bipolar patient while on chlorpromazine and lithium who also had a positive family history of seizures. Sakkas et al 200734 described a Jacksonian seizure in a manic patient treated with rTMS. Harel et al 201135 studied TMS in 19 Bipolar patients and had only one generalized seizure patient. In 2018, Iliceto et al36 treated a patient with bipolar disorder, generalized anxiety, a TBI, and a history of a suicide gesture without the patient having a seizure. The specific seizure rate with TMS in bipolar disorder is not clear at this time.\n\nTMS in Traumatic Brain Injury Patients\nHead injuries are another situation associated with an increased risk of seizures. Dhaliwal et al 201537 stated, “patients with severe TBI do show an increased risk of unprovoked seizures,” and\nthere is a strong connection between the severity of a brain injury and the subsequent risk of seizures; individuals with mild to moderate TBI have a substantially lower seizure risk than those with severe TBI.\n\n\n\nReti et al 201538 indicated,\nTBI is associated with an increased risk of both early and late spontaneous seizures, a significant consideration in evaluating rTMS as a potential treatment for TBI depression. Whilst the risk from rTMS is low; underlying neuropathology may somewhat increase that risk.\n\n\n\nThey suggested that low-frequency rTMS might be less likely to trigger a seizure.\n\nVarious reports of patients with a history of a head injury having a TMS-related seizure have been described. Bernabeu et al 200439 reported a seizure in a TBI patient on fluoxetine but was using a brief interstimulus interval. Cavinato et al 201210 described a 31-year-old male with a history of a severe TBI 8 months before TMS initiation. He had a secondary generalized seizure on the 4th of 10 daily sessions. TMS was delivered at 90% MT, 20 Hz, 1s train duration, and 1-minute inter-train interval to the dorsolateral prefrontal cortex (DLPFC). The seizure developed 3 hours after treatment. Pape et al 201440 reported on a 32-year-old male who had a TBI 9 years before TMS initiation who had an EEG identified seizure during the treatment with no clinical expression. Boes et al 201641 reported on a 27-year-old male with MDE, GAD, alcohol use, and a history of 4 prior head injuries. He was also sleep deprived. He developed a seizure during the 12th treatment session. As described previously, Muir et al 201929 presented a patient with a history of oxcarbazepine withdrawal the week before, autism, and multiple head injuries who had a seizure.\n\nTMS Treatment Without Seizures in Patients with Head Injuries\nTranscranial Magnetic Stimulation has also been used successfully without seizures in patients with a history of brain injury. Fitzgerald et al 201142 presented one of the original studies about using TMS without adverse events in a depressed patient with a history of a mild TBI 14 years before the TMS. Kreuzer et al 201343 treated a TBI patient with TMS for severe tinnitus after a head injury with five treatment series of 1 Hz to the left primary auditory cortex at 110% MT and no reported seizure. Neville et al 201544 completed a randomized controlled trial of 36 patients with TBI divided into two groups and administered ten sessions of 10 Hz TMS over the left DLPFC, which demonstrated improvement in depression and cognitive functioning. Nielson et al 201545 reported on a 48-year-old man with a severe TBI history 5 years before TMS was administered with low-frequency right dorsolateral prefrontal cortex stimulation daily for 6 weeks. The patient demonstrated a 49% improvement in his Hamilton Depression Rating Scale46 with treatment. In their article, they set forth that those who have not had a seizure within 2 years of injury have a 90% lower risk of seizure based on work by Englander et al 2003.47\n\nKoski et al 201548 treated 12 patients with post-concussive symptoms (headaches, depression, and cognitive deficits) following mild TBI using rTMS to the left DLPFC at 5-sec trains, 10 Hz, and 110% Motor Threshold. Their patients demonstrated a decrease of 14.6 points (p= 0.009) of post-concussive symptoms. Rutherford et al 201749 studied 13 patients with mild TBI delivering 13 treatment sessions of rTMS to the left DLPFC at 20 Hz in 1.5-second trains of 30 pulses and an inter-stimulation separation of 28.5 seconds. Paxman et al 201850 safely used TMS in a mild TBI patient when treating for chronic dizziness with ten sessions of rTMS to the left DLPFC at 70% motor threshold and a frequency of 10 HZ. Lee and Kim 201851 studied 13 patients divided into an experimental group and sham group. The patients were given rTMS to the right DLPFC for ten sessions and demonstrated improvements in mood based on the Montgomery-Asberg Depression Rating Scale.52 Iliceto et al 201836 treated a 37-year-old man with a severe TBI secondary to a suicide attempt who had a history of anxiety and bipolar disorder. The patient received 30 treatments of 6 Hz TMS to the left DLPFC at 120% MT and a 26-second inter-stimulation interval. Using the PHQ-9 he had a 70.8% improvement in mood.\n\nSaunders and Bermudes 201853 described a 55-year female with a TBI with loss of consciousness during her series of TMS treatments. The event was unrelated to the TMS, and the patient was hospitalized for 4 days. TMS was restarted 11 days after the injury without incident. In 2018 Siddiqi et al54 used 20 sessions of bilateral TMS in a retired NFL defensive lineman. The patient reported at least 12 previous concussions. Using the Montgomery – Asberg Depression Rating Scale, the patient documented improved scores from 32 to 9. Stultz et al 201955 presented a case of a 23-year-old male with a history of four concussions (two of which required hospitalization) having significant depression, generalized anxiety, panic, and OCD symptoms who received 34 TMS treatments and nine booster sessions without a seizure and with improvement in mood and anxiety. He was treated with the H1 coil at 120% MT to the left DLPFC.\n\nTMS Seizures and Alcohol\nExcessive alcohol use and withdrawal can precipitate seizures and has been found to possibly increase the risk of TMS-related seizures. Tendler et al 20189 indicated 6 of the 31 patients reviewed with TMS-related seizures using the H1 coil had a history of increased alcohol intake. Alcohol use was also reported in TMS seizure patients’ history by Boes et al 201641 and Chiramberro et al 2013.28 These cases are described elsewhere in this report.\n\nTMS Seizures and Sleep Deprivation\nSleep deprivation has long been identified as a precipitant to having a seizure in epilepsy patients and may increase the risk of a TMS-related seizure. Nakken et al 200556 reported on 1677 patients with epilepsy revealing 53% reported at least one seizure precipitant, with 30% reporting two or more factors had contributed at times to having a seizure. The three most common seizure-precipitating factors were emotional stress, sleep deprivation, and tiredness. Patients having generalized seizures were reported to be more sensitive to sleep deprivation. Ferlisi and Shorvon 201457 studied 104 patients at a tertiary-care adult epilepsy clinic to identify triggering factors to their epilepsy. Ninety-seven percent cited at least one precipitant, with stress, sleep deprivation, and fatigue being the most commonly reported. Those with idiopathic generalized epilepsy were more sensitive to seizures during wake periods and sleep deprivation, with those having extratemporal epilepsy reporting more seizures during sleep.\n\nThere are reports of patients having a seizure during TMS in which sleep deprivation may have played a role. Prikryl and Kucerova 200558 described a seizure in a sleep-deprived depressed patient at 110% MT, 15 Hz, and train duration of 10 seconds. Tendler et al 20189 reported that of the 31 patients they reviewed having had a seizure with the H1 coil; three had sleep issues. Oberman and Pascual-Leon 200917 reported on a 33-year-old male who had flown from London to Boston and may have been sleep-deprived before the TMS in which he had a seizure.\n\nTMS in Patients with Epilepsy\nTMS has been used in patients with known epilepsy. Bae et al 200759 reported the seizure risk with TMS in patients with epilepsy is less than 2% (4 of 280 patients). Pereira et al 201660 recounted 12/410 patients who had a history of epilepsy developed a seizure during TMS, suggesting a crude rate of seizures per subject of 2.9% in epilepsy patients treated with TMS. Vernet et al 201261 usually indicated TMS-associated seizures in epilepsy patients have been clinically similar to the patients’ typical spontaneous seizures, and the risk of a seizure in temporal association with TMS is less than 2% in epilepsy patients. Allen et al 2017,20 in their previously mentioned review of 23 rTMS studies using TMS in children, included 24 pediatric patients with epilepsy. Koudijs et al 201011 reported an increased frequency of seizures for up to 3 days after TMS in 4 children with known epilepsy based upon follow-up phone conversations. Stultz et al 201962 reported on a 69-year-old white female with a history of complex partial seizures, resistant depression, generalized anxiety disorder, and panic disorder who had three generalized seizures in her lifetime. She received 31 TMS treatments with the H1 coil at 120% MT over the left DLPFC without having a seizure. She has returned for booster TMS sessions without having a seizure. Fitzgerald 201463 described a 57-year-old man diagnosed with epilepsy when he was 26 years old who had been stabilized on sodium valproate and lamotrigine. He was later treated with rTMS of 1 Hz stimulation to the right dorsolateral prefrontal cortex for 20 consecutive weekdays with documented improvement in both mood and anxiety without a seizure.\n\nContinued TMS After a Seizure\nIf the patient does have a seizure, then the question is that of whether to continue treatment. Bagati et al 201264 described a patient who developed a seizure during treatment session #4, and while using valproate to cover for seizures, he finished TMS. Stultz 201965 reported previously on a patient who had a seizure during treatment session #11 but was then able to continue TMS without additional seizures or additional medications. The patient received 39 treatment sessions in total. In the accelerated TMS article referenced previously by Kalle and Brunelin21, the patient continued treatment and later maintenance treatment after having a seizure.\n\nThe Treatment Plan Should a Patient Have a Seizure\nFitzgerald and Daskalakis66 report,\nSeizures are likely to terminate fairly rapidly and not require medication treatment: emergency response medical units should potentially be summoned if the seizure does not terminate in several minutes.\n\n\n\nMost treatment recommendations for TMS seizures are supportive, with ensuring patient safety, avoiding aspiration, and monitoring blood pressure if possible. Currently, there are no specific recommendations for oxygen or suctioning during the seizure.\n\nAs seizures are usually a rare occurrence in the outpatient psychiatric office, one must also debrief the staff and may use the episode as a teachable moment to review seizure protocols with the staff and emphasize the need to be discussing sleep hygiene continually, alcohol use, medication change, etc., with patients daily before their TMS treatment. Concerning documentation, always include the date of occurrence, TMS treatment number, train, placement, motor threshold, and device used. A detailed description of the seizure, how it first presented and then progressed should be described. Documentation should include any identifiable risk factors and the absence of others. List all medications the patient was taking at the time of the seizure, including non-psychotropic meds. Review with the patient any changes they may have had before the seizure concerning sleep, medications, or alcohol/caffeine use. The risk of not treating severe depression versus the risk of another seizure must be discussed with the patient and the family if TMS is to be continued. While not always necessary, some practitioners have added anti-epileptic medications to the treatment regimen before continuing TMS treatment. The seizure should be reported to the FDA and the manufacturer of the TMS unit. Also, one should consider a letter to the editor of a journal to help keep others informed of potential risks and outcomes.\n\nConclusion\nIn summary, while TMS has a risk of seizure that is generally <1% overall, some situations may increase that risk, such as alcohol use, brain injury, sleep deprivation, family history, etc. Various case studies have been described in this article in which these situations may have been contributing factors. Traditional TMS, theta burst, accelerated TMS, and child/adolescent TMS use have been reviewed with similar risks for seizures. Comparable seizure rates are reported with both TMS and various psychotropic medications we prescribe daily. (TMS has a lower risk than some of the medications.) We have described successful continued TMS use in patients having had a seizure during TMS and in those with a history of head injury/concussion. TMS use in patients with known epilepsy has also been reviewed. While seizure is a potentially serious adverse event of TMS and must be discussed with the patient, the benefit of treating refractory depression and possibly suicidal ideation may outweigh the risk.\n\nDisclosure\nThe authors have no conflict of interests to report.\n==== Refs\nReferences\n1. Lefaucheur \nJP , Aleman \nA , Baeken \nC , et al. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014–2018)\n. Clin Neurophysiol . 2020 ;131 (2 ):474 –528\n. doi:10.1016/j.clinph.2019.11.002 31901449 \n2. McClintock \nSM , Reti \nIM , Carpenter \nLL , et al. Consensus recommendations for the clinical application of repetitive transcranial magnetic stimulation (rTMS) in the treatment of depression\n. J Clin Psychiatry . 2018 ;79 (1 ):35 –48\n. doi:10.4088/JCP.16cs10905 \n3. Chung \nSW , Hoy \nKE , Fitzgerald \nPB . Theta-burst stimulation: a new form of TMS treatment for depression?\n\nDepress Anxiety . 2015 ;32 (3 ):182 –192\n. doi:10.1002/da.22335 25450537 \n4. Sonmez \nAI , Camsari \nDD , Nandakumar \nAL , et al. Accelerated TMS for depression: a systematic review and meta-analysis\n. Psychiatry Res . 2019 ;273 :770 –781\n. doi:10.1016/j.psychres.2018.12.041 31207865 \n5. Rossi \nS , Hallett \nM , Rossini \nPM , et al. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research\n. Clin Neurophysiol . 2009 ;120 (12 ):2008 –2039\n. doi:10.1016/j.clinph.2009.08.016 19833552 \n6. Oberman \nL , Edwards \nD , Eldaief \nM , Pascual-Leone \nA . Safety of theta burst transcranial magnetic stimulation: a systematic review of the literature\n. J Clin Neurophysiol . 2011 ;28 (1 ):67 –74\n. doi:10.1097/WNP.0b013e318205135f 21221011 \n7. Carpenter \nLL , Janicak \nPG , Aaronson \nST , et al. Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice\n. Depress Anxiety . 2012 ;29 (7 ):587 –596\n. doi:10.1002/da.21969 22689344 \n8. Janicak \nP , Heart \nK , McGugan \nB . 166 Post market rate of seizures during TMS treatment with NeuroStar® system appears to be lower than previously estimated\n. CNS Spectr . 2020 ;25 (2 ):306 . doi:10.1017/S1092852920000826 \n9. Tendler \nA , Roth \nY , Zangen \nA . Rate of inadvertently induced seizures with deep repetitive transcranial magnetic stimulation\n. Brain Stimul . 2018 ;11 (6 ):1410 –1414\n. doi:10.1016/j.brs.2018.09.001 30245161 \n10. Cavinato \nM , Iaia \nV , Piccione \nF . Repeated sessions of sub-threshold 20-Hz rTMS. Potential cumulative effects in a brain-injured patient\n. Clin Neurophysiol . 2012 ;123 (9 ):1893 –1895\n. doi:10.1016/j.clinph.2012.02.066 22405994 \n11. Koudijs \nSM , Leijten \nFSS , Ramsey \nNF , van Nieuwenhuizen \nO , Braun \nKPJ . Lateralization of motor innervation in children with intractable focal epilepsy—a TMS and fMRI study\n. Epilepsy Res . 2010 ;90 (1–2 ):140 –150\n. doi:10.1016/j.eplepsyres.2010.04.004 20466521 \n12. Lerner \nAJ , Wassermann \nEM , Tamir \nDI . Seizures from transcranial magnetic stimulation 2012–2016: results of a survey of active laboratories and clinics\n. Clin Neurophysiol . 2019 ;130 (8 ):1409 –1416\n. doi:10.1016/j.clinph.2019.03.016 31104898 \n13. Wassermann \nEM . Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the international workshop on the safety of repetitive transcranial magnetic stimulation, June 5–7, 1996\n. Electroencephalogr Clin Neurophysiol . 1998 ;108 (1 ):1 –16\n. doi:10.1016/S0168-5597(97)00096-8 9474057 \n14. George \nMS , Belmaker \nRH , eds. Transcranial Magnetic Stimulation in Clinical Psychiatry . Washington, D.C : American Psychiatric Publishing ; 2007 .\n15. Sheldon \nR , Rose \nS , Ritchie \nD , et al. Historical criteria that distinguish syncope from seizures\n. J Am Coll Cardiol . 2002 ;40 (1 ):142 –148\n. doi:10.1016/S0735-1097(02)01940-X 12103268 \n16. Kinback \nKM . Unusual or possibly dangerous TMS side effects, a case series\n. Brain Stimul . 2018 ;11 (3 ):e4 . doi:10.1016/j.brs.2018.01.017 \n17. Oberman \nLM , Pascual-Leone \nA . Report of seizure induced by continuous theta burst stimulation\n. Brain Stimul . 2009 ;2 (4 ):246 –247\n. doi:10.1016/j.brs.2009.03.003 20160904 \n18. Purushotham \nA , Sinha \nVK , Goyal \nN , Tikka \nSK . Intermittent theta burst stimulation induced seizure in a child with schizophrenia: a case report\n. Brain Stimul . 2018 ;11 (6 ):1415 –1416\n. doi:10.1016/j.brs.2018.09.008 30245162 \n19. Lenoir \nC , Algoet \nM , Vanderclausen \nC , Peeters \nA , Santos \nSF , Mouraux \nA . Report of one confirmed generalized seizure and one suspected partial seizure induced by deep continuous theta burst stimulation of the right operculo-insular cortex\n. Brain Stimul . 2018 ;11 (5 ):1187 –1188\n. doi:10.1016/j.brs.2018.05.004 29805097 \n20. Allen \nCH , Kluger \nBM , Buard \nI . Safety of transcranial magnetic stimulation in children: a systematic review of the literature\n. Pediatr Neurol . 2017 ;68 :3 –17\n. doi:10.1016/j.pediatrneurol.2016.12.009 28216033 \n21. Kallel \nL , Brunelin \nJ . A case report of transcranial magnetic stimulation–related seizure in a young patient with major depressive disorder receiving accelerated transcranial magnetic stimulation\n. J ECT . 2020 ;36 (3 ):e31 –e32\n. doi:10.1097/YCT.0000000000000666 32040022 \n22. Loo \nCK , McFarquhar \nTF , Mitchell \nPB . A review of the safety of repetitive transcranial magnetic stimulation as a clinical treatment for depression\n. Int J Neuropsychopharmacol . 2008 ;11 (1 ):131 –147\n. doi:10.1017/S1461145707007717 17880752 \n23. Dobek \nCE , Blumberger \nDM , Downar \nJ , Daskalakis \nZJ , Vila-Rodriguez \nF . Risk of seizures in transcranial magnetic stimulation: a clinical review to inform consent process focused on bupropion\n. Neuropsychiatr Dis Treat . 2015 ;11 :2975 . doi:10.2147/NDT.S91126 26664122 \n24. Lertxundi \nU , Hernandez \nR , Medrano \nJ , Domingo-Echaburu \nS , García \nM , Aguirre \nC . Antipsychotics and seizures: higher risk with atypicals?\n\nSeizure . 2013 ;22 (2 ):141 –143\n. doi:10.1016/j.seizure.2012.10.009 23146619 \n25. Khoury \nR , Ghossoub \nE . Antipsychotics and seizures: what are the risks?\n\nCurr Psychiatr . 2019 ;18 (3 ):21 –22\n.:.\n26. Thanki \nMV , Baliga \nSP , Parameshwaran \nS , Rao \nNP , Mehta \nUM , Thirthalli \nJ . Safe administration of low frequency rTMS in a patient with depression with recurrent antidepressant-associated hyponatremic seizures\n. Brain Stimul . 2020 ;13 (5 ):1168 –1169\n. doi:10.1016/j.brs.2020.06.001 32502719 \n27. Hu \nS-H , Wang \n-S-S , Zhang \n-M-M , et al. Repetitive transcranial magnetic stimulation-induced seizure of a patient with adolescent-onset depression: a case report and literature review\n. J Int Med Res . 2011 ;39 (5 ):2039 –2044\n. doi:10.1177/147323001103900552 22118010 \n28. Chiramberro \nM , Lindberg \nN , Isometsä \nE , Kähkönen \nS , Appelberg \nB . Repetitive transcranial magnetic stimulation induced seizures in an adolescent patient with major depression: a case report\n. Brain Stimul . 2013 ;6 (5 ):830 –831\n. doi:10.1016/j.brs.2013.02.003 \n29. Cullen \nKR , Jasberg \nS , Nelson \nB , Klimes-Dougan \nB , Lim \nKO , Croarkin \nPE . Seizure induced by deep transcranial magnetic stimulation in an adolescent with depression\n. J Child Adolesc Psychopharmacol . 2016 ;26 (7 ):637 –641\n. doi:10.1089/cap.2016.0070 27447245 \n30. Wang \nT , Huang \nL , Xu \nH , et al. Seizure induced by repetitive transcranial magnetic stimulation in an adolescent with migraine with aura\n. Brain Stimul . 2018 ;11 (6 ):1380 –1381\n. doi:10.1016/j.brs.2018.07.052 30078543 \n31. Muir \nO , MacMillan \nC , Khan \nM , Sang \nL , Aron \nT . Safety and tolerability of dTMS treatment in 18–20 year old patients: case series\n. Brain Stimul . 2019 ;12 (4 ):e137 –e138\n. doi:10.1016/j.brs.2019.03.049 \n32. Zewdie \nE , Ciechanski \nP , Kuo \nHC , et al. Safety and tolerability of transcranial magnetic and direct current stimulation in children: prospective single center evidence from 3.5 million stimulations\n. Brain Stimul . 2020 ;13 (3 ):565 –575\n. doi:10.1016/j.brs.2019.12.025 32289678 \n33. Tharayil \nBS , Gangadhar \nBN , Thirthalli \nJ , Anand \nL . Seizure with single-pulse transcranial magnetic stimulation in a 35-year-old otherwise-healthy patient with bipolar disorder\n. J ECT . 2005 ;21 (3 ):188 –189\n. doi:10.1097/01.yct.0000177516.38421.9c 16127313 \n34. Sakkas \nP , Theleritis \nCG , Psarros \nC , Papadimitriou \nGN , Soldatos \nCR . Jacksonian seizure in a manic patient treated with rTMS\n. World J Biol Psychiatry . 2008 ;9 (2 ):159 –160\n. doi:10.1080/15622970701624595 18428081 \n35. Harel \nEV , Zangen \nA , Roth \nY , Reti \nI , Braw \nY , Levkovitz \nY . H-coil repetitive transcranial magnetic stimulation for the treatment of bipolar depression: an add-on, safety and feasibility study\n. World J Biol Psychiatry . 2011 ;12 (2 ):119 –126\n. doi:10.3109/15622975.2010.510893 20854181 \n36. Iliceto \nA , Seiler \nRL , Sarkar \nK . Repetitive transcranial magnetic stimulation for treatment of depression in a patient with severe traumatic brain injury\n. Ochsner J . 2018 ;18 (3 ):264 –267\n. doi:10.31486/toj.17.0075 30275792 \n37. Dhaliwal \nSK , Meek \nBP , Modirrousta \nMM . Non-invasive brain stimulation for the treatment of symptoms following traumatic brain injury\n. Front Psychiatry . 2015 ;6 . doi:10.3389/fpsyt.2015.00119 .\n38. Reti \nIM , Schwarz \nN , Bower \nA , Tibbs \nM , Rao \nV . Transcranial magnetic stimulation: a potential new treatment for depression associated with traumatic brain injury\n. Brain Inj . 2015 ;29 (7–8 ):789 –797\n. doi:10.3109/02699052.2015.1009168 25950260 \n39. Bernabeu \nM , Orient \nF , Tormos \nJM , Pascual-Leone \nA . Seizure induced by fast repetitive transcranial magnetic stimulation\n. Clin Neurophysiol . 2004 ;115 (7 ):1714 –1715\n. doi:10.1016/j.clinph.2004.02.021 15203073 \n40. Pape \nTL-B , Rosenow \nJM , Patil \nV , et al. rTMS safety for two subjects with disordered consciousness after traumatic brain injury\n. Brain Stimul . 2014 ;7 (4 ):620 –622\n. doi:10.1016/j.brs.2014.03.007 24836500 \n41. Boes \nAD , Stern \nAP , Bernstein \nM , et al. H-coil repetitive transcranial magnetic stimulation induced seizure in an adult with major depression: a case report\n. Brain Stimul . 2016 ;9 (4 ):632 –633\n. doi:10.1016/j.brs.2016.04.013 27160470 \n42. Fitzgerald \nPB , Hoy \nKE , Maller \nJJ , et al. Transcranial magnetic stimulation for depression after a traumatic brain injury\n. J ECT . 2011 ;27 (1 ):38 –40\n. doi:10.1097/YCT.0b013e3181eb30c6 20938348 \n43. Kreuzer \nPM , Landgrebe \nM , Frank \nE , Langguth \nB . Repetitive transcranial magnetic stimulation for the treatment of chronic tinnitus after traumatic brain injury\n. J Head Trauma Rehabil . 2013 ;28 (5 ):386 –389\n. doi:10.1097/HTR.0b013e318254736e 22688213 \n44. Neville \nIS , Hayashi \nCY , El Hajj \nSA , et al. Repetitive transcranial magnetic stimulation (rTMS) for the cognitive rehabilitation of traumatic brain injury (TBI) victims: study protocol for a randomized controlled trial\n. Trials . 2015 ;16 (1 ):440 . doi:10.1186/s13063-015-0944-2 26438108 \n45. Nielson \nDM , McKnight \nCA , Patel \nRN , Kalnin \nAJ , Mysiw \nWJ . Preliminary guidelines for safe and effective use of repetitive transcranial magnetic stimulation in moderate to severe traumatic brain injury\n. Arch Phys Med Rehabil . 2015 ;96 (4 ):S138 –S144\n. doi:10.1016/j.apmr.2014.09.010 25281871 \n46. Hamilton \nM . A rating scale for depression\n. J Neurol Neurosurg Psychiatry . 1960 ;23 (1 ):56 –62\n. doi:10.1136/jnnp.23.1.56 14399272 \n47. Englander \nJ , Bushnik \nT , Duong \nTT , et al. Analyzing risk factors for late posttraumatic seizures: a prospective, multicenter investigation\n. Arch Phys Med Rehabil . 2003 ;84 (3 ):365 –373\n. doi:10.1053/apmr.2003.50022 12638104 \n48. Koski \nL , Kolivakis \nT , Yu \nC , Chen \nJ-K , Delaney \nS , Ptito \nA . Noninvasive brain stimulation for persistent postconcussion symptoms in mild traumatic brain injury\n. J Neurotrauma . 2015 ;32 (1 ):38 –44\n. doi:10.1089/neu.2014.3449 24955920 \n49. Rutherford \nG , Mansouri \nB , Zhang \nW , et al. rTMS as a treatment for mild traumatic brain injury\n. Brain Stimul . 2017 ;10 (2 ):481 . doi:10.1016/j.brs.2017.01.409 \n50. Paxman \nE , Stilling \nJ , Mercier \nL , Debert \nCT . Repetitive transcranial magnetic stimulation (rTMS) as a treatment for chronic dizziness following mild traumatic brain injury\n. BMJ Case Rep . 2018 ;bcr-2018–226698. doi:10.1136/bcr-2018-226698 \n51. Lee \nSA , Kim \nM-K . Effect of low frequency repetitive transcranial magnetic stimulation on depression and cognition of patients with traumatic brain injury: a randomized controlled trial\n. Med Sci Monit . 2018 ;24 :8789 –8794\n. doi:10.12659/MSM.911385 30513530 \n52. Montgomery \nSA , Asberg \nM . A new depression scale designed to be sensitive to change\n. Br J Psychiatry . 1979 ;134 (4 ):82 –89\n. doi:10.1192/bjp.134.4.382 \n53. Saunders \nR , Bermudes \nR . TBI during a course of TMS - a case report\n. Brain Stimul . 2018 ;11 (3 ):e6 . doi:10.1016/j.brs.2018.01.021 \n54. Siddiqi \nSH , Trapp \nNT , Laumann \nTO , et al. Efficacy and neural network changes with fMRI-targeted rTMS for neuropsychiatric sequelae of repetitive head trauma in a retired NFL player\n. Brain Stimul . 2018 ;11 (3 ):e7 . doi:10.1016/j.brs.2018.01.023 \n55. Stultz \nDJ , Voltin \nR , Thistlethwaite \nD , et al. Transcranial magnetic stimulation in the treatment of post-concussion depression\n. Brain Stimul . 2019 ;12 (4 ):e140 . doi:10.1016/j.brs.2019.03.057 \n56. Nakken \nKO , Solaas \nMH , Kjeldsen \nMJ , Friis \nML , Pellock \nJM , Corey \nLA . Which seizure-precipitating factors do patients with epilepsy most frequently report?\n\nEpilepsy Behav . 2005 ;6 (1 ):85 –89\n. doi:10.1016/j.yebeh.2004.11.003 15652738 \n57. Ferlisi \nM , Shorvon \nS . Seizure precipitants (triggering factors) in patients with epilepsy\n. Epilepsy Behav . 2014 ;33 :101 –105\n. doi:10.1016/j.yebeh.2014.02.019 24632482 \n58. Prikryl \nR , Kucerova \nH . Occurrence of epileptic paroxysm during repetitive transcranial magnetic stimulation treatment\n. J Psychopharmacol . 2005 ;19 (3 ). doi:10.1177/0269881105051545 \n59. Bae \nEH , Riviello \nJJ \nJr., Rotenberg \nA , et al. Safety and tolerability of repetitive transcranial magnetic stimulation in patients with epilepsy: a review of the literature\n. Epilepsy Behav . 2007 ;10 (4 ):521 –528\n. doi:10.1016/j.yebeh.2007.03.004 17493877 \n60. Pereira \nLS , Müller \nVT , da Mota Gomes \nM , Rotenberg \nA , Fregni \nF . Safety of repetitive transcranial magnetic stimulation in patients with epilepsy: a systematic review\n. Epilepsy Behav . 2016 ;57 :167 –176\n. doi:10.1016/j.yebeh.2016.01.015 26970993 \n61. Vernet \nM , Walker \nL , Yoo \nW-K , Pascual-Leone \nA , Chang \nBS . EEG onset of a seizure during TMS from a focus independent of the stimulation site\n. Clin Neurophysiol . 2012 ;123 (10 ):2106 –2108\n. doi:10.1016/j.clinph.2012.03.015 22580176 \n62. Stultz \nDJ , Osburn \nS , Burns \nT , Walton \nR , Wajswol \nSP . TMS treatment in a patient with seizures and refractory depression\n. Brain Stimul . 2019 ;12 (3 ):791 . doi:10.1016/j.brs.2019.08.009 30733145 \n63. Fitzgerald \nPB . Treatment of depression in a patient with epilepsy\n. Brain Stimul . 2014 ;7 (4 ):619 –620\n. doi:10.1016/j.brs.2014.03.003 24680788 \n64. Bagati \nD , Mittal \nS , Praharaj \nSK , Sarcar \nM , Kakra \nM , Kumar \nP . Repetitive transcranial magnetic stimulation safely administered after seizure\n. J ECT . 2012 ;28 (1 ):60 –61\n. doi:10.1097/YCT.0b013e318221f9b1 22343584 \n65. Stultz \nDJ . Successful continued TMS treatment after a seizure: a letter to the editor\n. Brain Stimul . 2019 ;12 (3 ):791 . doi:10.1016/j.brs.2019.01.009 30733145 \n66. Fitzgerald \nPB , Daskalakis \nZJ . A practical guide to the use of repetitive transcranial magnetic stimulation in the treatment of depression\n. Brain Stimul . 2012 ;5 (3 ):287 –296\n. doi:10.1016/j.brs.2011.03.006 22037123\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1176-6328",
"issue": "16()",
"journal": "Neuropsychiatric disease and treatment",
"keywords": "head injuries and transcranial magnetic stimulation; transcranial magnetic stimulation; transcranial magnetic stimulation in children and adolescents; transcranial magnetic stimulation in epilepsy patients; transcranial magnetic stimulation safety; transcranial magnetic stimulation-related seizures",
"medline_ta": "Neuropsychiatr Dis Treat",
"mesh_terms": null,
"nlm_unique_id": "101240304",
"other_id": null,
"pages": "2989-3000",
"pmc": null,
"pmid": "33324060",
"pubdate": "2020",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "30396889;12103268;31207865;31447375;26438108;31901449;19833552;22580176;22343584;24680788;26664122;25281871;24955920;20854181;28216033;15888504;27447245;22118010;17880752;30513530;12638104;26379560;22689344;29805097;30733145;20160904;23146619;25950260;444788;22688213;32040022;20466521;14399272;25450537;30078543;21221011;28541649;17493877;23518261;30245162;32502719;22037123;24836500;15652738;26970993;20938348;16127313;32289678;9474057;24632482;18428081;31104898;30245161;27160470;15203073;30275792;22405994",
"title": "Transcranial Magnetic Stimulation (TMS) Safety with Respect to Seizures: A Literature Review.",
"title_normalized": "transcranial magnetic stimulation tms safety with respect to seizures a literature review"
} | [
{
"companynumb": "US-OTSUKA-2021_011214",
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"patient": {
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"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
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{
"abstract": "BACKGROUND\nThe vein of Galen aneurysm (VGAM) is the most common type of arteriovenous malformation in the neonate. These neonates commonly present with high output cardiac failure that may be associated with pulmonary hypertension. The medical management and stabilization of these neonates can be challenging before staged transarterial embolization of the aneurysm is undertaken.\n\n\nMETHODS\nA 2.34 kilogram neonate, antenatally diagnosed to have VGAM, was born at 36 weeks of gestation for fetal distress. The neonate failed to respond to medical management including inotropes, high frequency mechanical ventilation and inhaled nitric oxide. The patient's high-output heart failure and persistent pulmonary hypertension were stabilized with veno-arterial extra-corporeal membrane oxygenation (VA-ECMO) using central cannulation. Further transarterial staged embolization of the VGAM was undertaken on VA-ECMO support.\n\n\nCONCLUSIONS\nThere may be a role of VA-ECMO using central cannulation to optimize management of high output cardiac failure and persistent pulmonary hypertension in neonatal VGAM patients who fail medical management to facilitate staged transarterial embolization of the VGAM.",
"affiliations": "Department of Pediatric Critical Care, Cleveland Clinic, Cleveland, OH, USA.;Department of Neonatology, Cleveland Clinic, Cleveland, OH, USA.;Department of Pediatric Critical Care, Cleveland Clinic, Cleveland, OH, USA.;Department of Cerebrovascular Surgery, Cleveland Clinic, Cleveland, OH, USA.;Department of Cardio-thoracic Surgery, Cleveland Clinic, Cleveland, OH, USA.;Department of Pediatric Critical Care, Cleveland Clinic, Cleveland, OH, USA.;Department of Pediatric Critical Care, Cleveland Clinic, Cleveland, OH, USA.",
"authors": "Abrahan|D|D|;Yeaney|N K|NK|;Hamzah|M A|MA|;Bain|M D|MD|;Najm|H K|HK|;Latifi|S Q|SQ|;Agarwal|H S|HS|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.3233/NPM-200435",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-4429",
"issue": "14(3)",
"journal": "Journal of neonatal-perinatal medicine",
"keywords": "Extracorporeal membrane oxygenation; heart failure; neonate; pulmonary\nhypertension; vein of Galen aneurysm",
"medline_ta": "J Neonatal Perinatal Med",
"mesh_terms": null,
"nlm_unique_id": "101468335",
"other_id": null,
"pages": "433-436",
"pmc": null,
"pmid": "34486991",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Extra corporeal membrane oxygenation support for neonatal vein of Galen aneurysmal malformation: Case report.",
"title_normalized": "extra corporeal membrane oxygenation support for neonatal vein of galen aneurysmal malformation case report"
} | [
{
"companynumb": "US-MALLINCKRODT-T202104286",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "NITRIC OXIDE"
},
"drugadditional": null,
... |
{
"abstract": "The prognosis of relapsed or refractory lymphoma with central nervous system (CNS) involvement remains poor because of the lack of anticancer drugs with sufficient CNS penetration. [Case 1] A 65-year-old man was diagnosed with Stage IV mantle cell lymphoma. After two courses of chemotherapy and autologous hematopoietic stem cell (HSC) collection, urinary retention with fever developed. Cerebrospinal fluid analysis revealed leptomeningeal involvement, which was refractory to high-dose methotrexate therapy. Autologous peripheral blood stem cell transplantation (ASCT) was performed, followed by intravenous busulfan (ivBU), cyclophosphamide, and etoposide ; thereafter, no relapse has been detected for over six years. [Case 2] A 40-year-old woman with right lower hemiplegia was diagnosed with primary CNS lymphoma. Although four courses of high-dose methotrexate therapy were administered, the cerebral tumor increased in size. HSCs were collected after methotrexate therapy, and ASCT was performed in addition to conditioning using ivBU, cyclophosphamide, and etoposide, followed by whole-brain and local boost irradiation. She achieved complete remission, but relapsed two years after ASCT. High-dose ivBU-containing conditioning regimens with ASCT may be useful for refractory B-cell lymphoma with CNS involvement. J. Med. Invest. 68 : 196-201, February, 2021.",
"affiliations": "Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;Division of Transfusion Medicine and Cell Therapy, Tokushima University Hospital, Tokushima, Japan.;Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.;Department of Community Medicine and Medical Science, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan.",
"authors": "Takahashi|Mamiko|M|;Sumitani|Ryohei|R|;Hori|Taiki|T|;Murai|Jumpei|J|;Kawata|Shiyori|S|;Oura|Masahiro|M|;Sogabe|Kimiko|K|;Harada|Takeshi|T|;Fujii|Shiro|S|;Miki|Hirokazu|H|;Kagawa|Kumiko|K|;Abe|Masahiro|M|;Nakamura|Shingen|S|",
"chemical_list": "D013852:Thiotepa; D002066:Busulfan",
"country": "Japan",
"delete": false,
"doi": "10.2152/jmi.68.196",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1343-1420",
"issue": "68(1.2)",
"journal": "The journal of medical investigation : JMI",
"keywords": "autologous peripheral blood stem cell transplantation; busulfan; central nervous system; malignant lymphoma",
"medline_ta": "J Med Invest",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002066:Busulfan; D002490:Central Nervous System; D003131:Combined Modality Therapy; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016393:Lymphoma, B-Cell; D008297:Male; D009364:Neoplasm Recurrence, Local; D013852:Thiotepa; D014182:Transplantation, Autologous",
"nlm_unique_id": "9716841",
"other_id": null,
"pages": "196-201",
"pmc": null,
"pmid": "33994471",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intravenous busulfan-based conditioning with autologous stem cell transplantation for refractory B-cell lymphoma with central nervous system involvement.",
"title_normalized": "intravenous busulfan based conditioning with autologous stem cell transplantation for refractory b cell lymphoma with central nervous system involvement"
} | [
{
"companynumb": "JP-PFIZER INC-202101661063",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": "3... |
{
"abstract": "Some of the side and beneficial effects of antiepileptic drugs (AEDs) are mediated via the influence on mitochondria. This is of particular importance in patients requiring AED treatment for mitochondrial epilepsy. AED treatment in patients with mitochondrial disorders should rely on the known influences of AEDs on these organelles. AEDs may influence various mitochondrial functions or structures in a beneficial or detrimental way. There are AEDs in which the toxic effect outweighs the beneficial effect, such as valproic acid (VPA), carbamazepine (CBZ), phenytoin (PHT), or phenobarbital (PB). There are, however, also AEDs in which the beneficial effect on mitochondria outweighs the mitochondrion-toxic effect, such as gabapentin (GBT), lamotrigine (LTG), levetiracetam (LEV), or zonisamide (ZNS). In the majority of the AEDs, however, information about their influence of mitochondria is lacking. In clinical practice mitochondrial epilepsy should be initially treated with AEDs with low mitochondrion-toxic potential. Only in cases of ineffectivity or severe mitochondrial epilepsy, mitochondrion-toxic AEDs should be given. This applies for AEDs given orally or intravenously.",
"affiliations": "Krankenanstalt Rudolfstiftung, Postfach 20, 1180, Vienna, Austria. fifigs1@yahoo.de.",
"authors": "Finsterer|Josef|J|",
"chemical_list": "D000927:Anticonvulsants",
"country": "Germany",
"delete": false,
"doi": "10.1007/164_2016_2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0171-2004",
"issue": "240()",
"journal": "Handbook of experimental pharmacology",
"keywords": "Antiepileptic drugs; Apoptosis; Epilepsy; Membrane potential; Mitochondrion; Oxidative stress; Reactive oxygen species; Respiratory chain; Side effects; Toxicity",
"medline_ta": "Handb Exp Pharmacol",
"mesh_terms": "D000818:Animals; D000927:Anticonvulsants; D006801:Humans; D008928:Mitochondria",
"nlm_unique_id": "7902231",
"other_id": null,
"pages": "473-488",
"pmc": null,
"pmid": "27590225",
"pubdate": "2017",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Toxicity of Antiepileptic Drugs to Mitochondria.",
"title_normalized": "toxicity of antiepileptic drugs to mitochondria"
} | [
{
"companynumb": "US-CIPLA LTD.-2016US18559",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"drugadditional": "3",
... |
{
"abstract": "The opioid epidemic in America is real and is estimated to be the number one cause of death in adults under 50 years of age. Finding alternative analgesic medications is part of the effort to decrease the prescription of narcotics, with gabapentin being at the top of the list.\nIn the present case, we discuss the side-effects of gabapentin, used as part of the multimodal treatment approach of painful spinal degenerative disease. The patient stated that he had noticed personality changes after gabapentin was initiated, and that he had become more depressed, frustrated, and aggressive. His uncontrolled pain and acute mood changes led him to attempt suicide by hanging himself. Gabapentin was discontinued and the patient's suicidal ideation completely subsided.\nIt is imperative to screen, identify, and appropriately manage patients with underlying psychiatric disorders prior to initiating pain management with gabapentin. Therefore, it is crucial to raise awareness of gabapentin as a potential cause of depression, aggressive behavior, and suicidal ideation.",
"affiliations": "Department of Anesthesiology, Advocate Illinois Masonic Medical Center, Chicago, Illinois, USA.;Department of Anesthesiology, Advocate Illinois Masonic Medical Center, Chicago, Illinois, USA.;Department of Anesthesiology, Advocate Illinois Masonic Medical Center, Chicago, Illinois, USA.;Department of Anesthesiology, Advocate Illinois Masonic Medical Center, Chicago, Illinois, USA.;Department of Anesthesiology, Advocate Illinois Masonic Medical Center, Chicago, Illinois, USA.",
"authors": "Ghaly|Ramsis F|RF|;Plesca|Ana|A|;Rana|Shalini|S|;Candido|Kenneth D|KD|;Knezevic|Nebojsa Nick|NN|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4103/sni.sni_420_17",
"fulltext": "\n==== Front\nSurg Neurol IntSurg Neurol IntSNISurgical Neurology International2229-50972152-7806Medknow Publications & Media Pvt Ltd India SNI-9-21010.4103/sni.sni_420_17Pain: Case ReportGabapentin-related suicide: Myth or fact? Ghaly Ramsis F. 123*rfghaly@aol.comPlesca Ana 1plesca.ana@gmail.comRana Shalini 1shaldoc@yahoo.comCandido Kenneth D. 13kdcandido1@gmail.comKnezevic Nebojsa Nick 13nick.knezevic@gmail.com1 Department of Anesthesiology, Advocate Illinois Masonic Medical Center, Chicago, Illinois, USA2 Ghaly Neurosurgical Associates, Aurora, Chicago, Illinois, USA3 Department of Anesthesiology, University of Illinois, Chicago, Illinois, USA* Corresponding author\n2018 23 10 2018 9 21015 11 2017 01 12 2017 Copyright: © 2018 Surgical Neurology International2018This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Background:\nThe opioid epidemic in America is real and is estimated to be the number one cause of death in adults under 50 years of age. Finding alternative analgesic medications is part of the effort to decrease the prescription of narcotics, with gabapentin being at the top of the list.\n\nCase Description:\nIn the present case, we discuss the side-effects of gabapentin, used as part of the multimodal treatment approach of painful spinal degenerative disease. The patient stated that he had noticed personality changes after gabapentin was initiated, and that he had become more depressed, frustrated, and aggressive. His uncontrolled pain and acute mood changes led him to attempt suicide by hanging himself. Gabapentin was discontinued and the patient's suicidal ideation completely subsided.\n\nConclusion:\nIt is imperative to screen, identify, and appropriately manage patients with underlying psychiatric disorders prior to initiating pain management with gabapentin. Therefore, it is crucial to raise awareness of gabapentin as a potential cause of depression, aggressive behavior, and suicidal ideation.\n\nChronic low back paingabapentinsuicide\n==== Body\nINTRODUCTION\nSince the beginning of the new millennium, opioid-related deaths have increased five times in women and almost four times in men. More than half a million people died from drug overdoses between 2000 and 2015. It is estimated that 91 Americans die every day from an opioid overdose.[3] Studies conducted among postsurgical patients by Gugelmann et al. indicated that prescribing opioids within 7 days of surgery increased the likelihood of long-term opioid use at 1 year by about 44%.[10] Taking this into account and considering the side-effect profile of opioids, there has been an increasing interest in the potential use of gabapentin and other nonopioid medications for postoperative pain relief.[4]\n\nGabapentin is an antiepileptic medication, and is also frequently used for off-label purposes such as acute and chronic pain management in various neurological and neurosurgical disorders. Reported off-label uses are migraines, trigeminal neuralgia, complex regional pain syndrome, drug and alcohol withdrawal seizures, and bipolar disorder.[4] Recent articles have also shown that the anti-hyperalgesic properties of gabapentin are seen for postoperative pain management in surgeries including breast surgery, hysterectomy, cholecystectomy, and spinal and knee surgery.[1] Some clinical studies have demonstrated a reduction in postoperative opioid consumption when gabapentin was administered preoperatively and pre-emptively for pain control.[18]\n\nHowever, despite its popularity, gabapentin is not free of side effects. The psychiatric side-effects of gabapentin have been infrequently discussed. In this article, we will report a case of a patient who demonstrated aggressive and suicidal behavior after initiation of gabapentin.\n\nCASE DESCRIPTION\nA 28-year-old male with a history of chronic low back pain described his pain as constantly present, 4–8/10 in intensity, shooting down both legs with any movement, and with associated tingling and numbness. His exercise tolerance had decreased to walking a quarter of a mile/day over a period of 6 months, and he ended up quitting his job due to his debilitating pain.\n\nBesides the low back pain, for which the patient frequently visited the emergency room, he also had left testicular pain. He was diagnosed with orchitis, and was started on oral antibiotics. Despite the treatment, his testicular pain worsened, and he was prescribed additional antibiotics. The infection resulted in left groin pain that extended to his mid-back, buttock, and radiated down the hamstring and lateral aspect of leg, correlating with L5-S1 dermatomes.\n\nHis electromyography (EMG) showed decreased sural nerve signals. Magnetic resonance imaging (MRI) of his lumbar spine demonstrated central canal stenosis at the L3-4-5 levels and disc herniations at L3-4 and L4-5 levels. His hip X-ray, computed tomography (CT) of the abdomen, ultrasound of the testicles, and urinalysis were within normal limits.\n\nHe was first started on nonsteroidal anti-inflammatory drugs (NSAIDs), and then acetaminophen/hydrocodone and muscle relaxants were added to his treatment regimen without any relief. The next step was physical therapy and two lumbar epidural steroid injections, which provided no relief. He refused to get a third lumbar epidural steroid injection, and was referred to a neurologist for further evaluation. He was then started on gabapentin 300 mg three times per day, a dose that was gradually increased over 4 weeks to 1600 mg/day by his orthopedic surgeon in conjunction with muscle relaxants and NSAIDs.\n\nThe patient and his fiancé stated that they noticed personality changes in him; he became more depressed and aggressive. They attributed the changes in his behavior to gabapentin. His pain and mood had progressively deteriorated to the point where he attempted to commit suicide by hanging himself by the neck using his belt and a door jam. He was immediately found by his fiancé who emergently took him to the hospital. While he was hospitalized, all his medications were stopped, including gabapentin, and he was started on mood stabilizers. He noticed that his personality had changed back to normal and his suicidal ideation had subsided, after which he was discharged home.\n\nAt this point, after being on a multimodal pain medication regimen including lumbar epidural steroid injections without significant relief, the patient visited our clinic for a second opinion about his back pain. On examination, his vital signs were normal. However, he had an antalgic gait with a forward leaning posture of 15–20 degree, and was unable to stand on his toes or heels without support. Palpation also elicited mild tenderness over the lower lumbar region. His motor strength was 5/5 in both upper extremities and 4/5 in both lower extremities. Extension of the lower extremities was limited to 0 degrees, whereas range of flexion was 70 degrees with improvement in pain. Patellar reflexes were absent bilaterally, ankle reflexes were 1(+) bilaterally, Babinski's sign was negative, and the straight leg raise test was positive, left > right, 1(+) at 60 degrees. The remainder of the examination, including cranial nerve examination, respiratory, cardiovascular and abdominal was normal. Based on the clinical picture, he was recommended conservative treatment in a tertiary center.\n\nDISCUSSION\nSince its introduction in the market in 1993, gabapentin has consistently gained in popularity. A significant proportion of this use has been for non-FDA approved pain conditions. Besides its use in treating refractory partial seizures, the FDA also approved it in 2002 for the treatment of postherpetic neuralgia. Gabapentin is a structural analogue of the neurotransmitter γ-aminobutyric acid (GABA), but it does not bind to GABA receptors nor does it block uptake or metabolism of GABA. Although the mechanism of action of gabapentin is unclear, it does block voltage-gated Ca++ channels by binding to the α2-delta subunit in the dorsal horn, producing a reduced calcium influx, thereby reducing release of glutamate and substancePfrom primary nociceptive afferents and diminishing propagation of pain signals.[713] Other mechanisms contributing to the analgesic effects of gabapentin include a reduction in the release of dopamine, serotonin, and norepinephrine from the brain, as well as limitation of firing of Na+ dependant action potentials in the spinal cord and neocortical neurons.[2428]\n\nThe recommended starting dose for neuropathic pain is 300 mg on day 1, followed by 300 mg twice daily on day 2, and then 300 mg three times a day thereafter. This dose can be gradually increased to 1800 mg/day as 300 mg oftentimes is not sufficient. The most common side effects of gabapentin in therapeutic doses are drowsiness, somnolence, dizziness, movement disorders, diarrhea, and weight gain.[27]\n\nIn addition, cases have been reported of gabapentin-related suicidal acts and aggressive behavior [Table 1].\n\nTable 1 Gabapentin - related suicide and near suicidal cases\n\nThe mechanism of suicide linked to antiepileptic drugs (AEDs) is not very well understood, however, there is a possibility that AEDs lower the threshold for manifesting psychiatric symptoms in individuals who are susceptible because of genetic or historical predisposition to psychiatric disorders.[12] A combination of neurobiological and psychological factors could contribute to changes in people's behavior. It is thought that antiepileptic drugs lead to disinhibition and impulsiveness, which can subsequently influence and promote suicidal acts instead of having a direct effect on behavior.\n\nOne of the factors that could impact patient's suicide intent is their chronic pain. Suicide rate among chronic pain patients was found to be significantly greater than the general population. Literature review concludes that suicidal ideation, suicide attempts, and suicide completions appeared to be common in chronic pain patients. As a result of research conducted in 2003, the American Psychiatric Association included chronic pain as a risk factor for suicidal ideation in their guidelines for the assessment and treatment of patients with suicidal behavior. Two approaches have been recommended – routinely measuring depression and suicidality in any chronic pain patient with tools such as the Beck Depression Inventory or monitoring pain and depression with the Brief Pain Inventory at every visit. High scores on pain or depression rating scales should stimulate the physician to inquire about suicidality.[8]\n\nBased on the most recent systematic review, gabapentin was tested in nine different chronic pain conditions considered to be neuropathic in origin. Numbers needed to treat for an additional beneficial outcome were between 5 and 7 in postherpetic neuralgia and peripheral diabetic neuropathy. Evidence for other types of neuropathic pain was very limited. More than half of the patients treated with gabapentin will not have a justifiable pain relief.[29]\n\nAs part of the program for decreasing opioid prescriptions, the U.S. Centers for Disease Control and Prevention lists gabapentin as an appropriate nonopioid treatment for chronic pain, recommending the drug as a first-line agent for neuropathic pain. More recently, the American Pain Society recommended that gabapentin be included in the Clinical Practice Guideline in the management of postoperative pain.[5]\n\nWe noticed a 23% decrease in opioid dispensed prescriptions in the last 7 years while concomitantly witnessing a total of 153% increase in gabapentin prescriptions over the same period of time [Figure 1]. As an alternative to narcotic medications, gabapentin could be considered to have a reasonable impact on decreasing the dispensed opioid prescriptions. However, the expense in this scenario would indicate that gabapentin would become another drug of abuse, with potential serious side effects, which were not investigated enough. It is crucial to raise awareness of the dangers that gabapentin use entails, and suggest it be added to the controlled substances list.\n\nFigure 1 IMS Health data, Gabapentin dispensed prescriptions, in millions[33]\n\nWhile it may be legal for medical practitioners to prescribe medications for off-label uses, in the United States it is illegal for manufacturers to market medications for off-label uses, which is one reason why Pfizer was fined $420 million after it was acquired from Warner-Lambert.[19]\n\nAfter a recent survey in the USA, gabapentin had the highest proportion of off-label prescriptions (83%) among 160 commonly prescribed drugs; and only 20% of its off-label use had strong scientific evidence of clinical efficacy. This accounted for more than 90% of its sales.[1421]\n\nNumerous cases have been reported supporting the evidence of the abuse potential of gabapentin, in which individuals with a history of opioid abuse were the most susceptible. Prescribers should be aware of high-risk populations and monitor for signs of abuse because gabapentin is often co-prescribed with opioids and pain patients often receive prescription for benzodiazepines due to concomitant anxiety and/or difficulty sleeping.[61516222325]\n\nIn a recent study performed in Central Appalachian region, a near 3,000% increase was found in the use of gabapentin “to get high” from 2008 to 2014 in a cohort of 503 prescription drug users. When compared to the previous year reports, a 165% increase was observed. The major sources of gabapentin were physicians (52%) and drug dealers (36%).[26]\n\nFrom the data presented in Figures 2 and 3, it is noticeable that the number of patients exposed to gabapentin dramatically increased in 2012; however, it was not mentioned in the American Association of Poison Control Centers (AAPCC) annual reports prior to 2011. In addition, the number of those taking gabapentin intentionally with the purpose of overdosing has been exceeding the unintentional poisonings.\n\nFigure 2 Clinical Toxicology report for Gabapentin exposure. American Association of Poison Control Centers Annual reports[30]\n\nFigure 3 The reason for Gabapentin poisoning. American Association of Poison Control Centres AAPCC[30]\n\nAntiepileptic drugs and suicidality\nNumerous studies have been published to confirm or deny the role that antiepileptic drugs play in increasing the risk of suicidal behavior; however, so far they lack concordance and are limited by various methodological limitations.\n\nThe FDA issued a warning regarding the increased risk of suicide in patients taking AEDs based on a study performed among 28,000 people taking AEDs and 16,000 people taking placebo. Four completed suicides were registered in the group that was taking AED and none in the placebo group. The odds ratio for the association between AEDs and suicidal behavior or ideation was 1.8 (95% CI, 1.24–2.66) and 1.45 (95% CI, 0.93–2.3) for ideation alone, which did not reach statistical significance.[31]\n\nThe validity of this meta-analysis was questioned after careful review of the data based on several methodological problems, including the source of outcome data on suicidality, statistical methodologies used, heterogeneity of the trials, and the difference in mechanism of action of the 11 AEDs evaluated.[11]\n\nThe suicide attempt rates before and after gabapentin was prescribed were investigated in a cohort of 131,178 patients. The investigators found no significant differences in suicide attempt rates before (3.45/1000 patient years) versus after gabapentin prescription (3.45/1000 patient years).\n\nWhile no differences were identified before and after gabapentin in the nonpsychiatric population, up to a 5 times post-prescription reduction in suicide-attempts rate were seen for bipolar disorder, major depressive disorder, and other psychiatric conditions. The pre-prescription suicide-attempts rate for patients with bipolar disorder was 48 per 1000 person years (PY); following prescription, the SAs rate decreased to 32 per 1000 PY (a 33% decrease). In patients with pain disorders, the SAs rate was 3 per 1000 PY before gabapentin prescription, and remained unchanged after gabapentin prescription. These findings suggest that gabapentin may have a protective effect among patients at an increased risk of SAs. The absence of a significant association between gabapentin and SAs in patients receiving a prescription for a pain disorder suggests that having comorbid psychiatric and pain disorders may significantly increase SA risk, which greatly decreases if the pain disorder is successfully treated with gabapentin. Their investigation also showed that patients who are on gabapentin monotherapy for pain only are at a lower risk of suicide in comparison to patients who are on multiple medications. The rationale behind this is that patients who are on multiple medications have multiple comorbidities that are difficult to treat and are already at an increased risk for suicide at baseline.[9]\n\nCONCLUSION\nWith the increase in opioid misuse and overdose-related deaths nationwide, health care providers are encouraged to find a nonopioid analgesic. Application of gabapentin for treatment is not without side-effects, especially in patients with an undiagnosed psychiatric disorder or who are at risk of suicidality. It is imperative to screen, identify, and appropriately manage patients with underlying psychiatric disorders prior to initiating pain management with gabapentin. The recommended strategy is to perform more studies to identify the group at high risk of suicide between patients taking gabapentin and those who are not. Therefore, it is crucial to raise awareness of gabapentin as a potential cause of depression, aggressive behavior, and suicidal ideation.\n\n\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nhttp://surgicalneurologyint.com/Gabapentin-related-suicide:-Myth-or-fact?/\n==== Refs\nREFERENCES\n1 Ajori L Nazari L Mazloomfard MM Amiri Z Effects of gabapentin on postoperative pain, nausea and vomiting after abdominal hysterectomy: A double blind randomized clinical trial Arch Gynecol Obstet 2012 285 677 82 21818576 \n2 Cantrell FL Mena O Gary RD McIntyre IM An acute gabapentin fatality: A case report with postmortem concentrations Int J Legal Med 2015 129 771 5 25904080 \n3 CDC. Wide-ranging online data for epidemiologic research (WONDER) 2016 Atlanta, GA CDC, National Center for Health Statistics \n4 Chang CY Challa CK Shah J Eloy JD Gabapentin in acute postoperative pain management Biomed Res Int 2014 2014 631756 24829909 \n5 Chou R Gordon DB Leon-Casasola OA Rosenberg JM Bickler S Brennan T Management of Postoperative Pain: A Clinical Practice Guideline From the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ Committee on Regional Anesthesia, Executive Committee, and Administrative Council J Pain 2016 17 131 57 26827847 \n6 Evoy KE Morrison MD Saklad SR Abuse and Misuse of Pregabalin and Gabapentin Drugs 2017 77 403 26 28144823 \n7 Fink K Meder W Dooley DJ Gothert M Inhibition of neuronal Ca(2+) influx by gabapentin and subsequent reduction of neurotransmitter release from rat neocortical slices Br J Pharmacol 2000 130 900 6 10864898 \n8 Fishbain DA Lewis JE Gao J The pain suicidality association: A narrative review Pain Med 2014 15 1835 49 24995953 \n9 Gibbons RD Hur K Brown CH Mann JJ Gabapentin and suicide attempts Pharmacoepidemiol Drug Saf 2010 19 1241 7 20922708 \n10 Gugelmann H Shofer FS Meisel ZF Perrone J Multidisciplinary intervention decreases the use of opioid medication discharge packs from 2 urban EDs Am J Emerg Med 2013 31 1343 8 23906621 \n11 Hesdorffer DC Berg AT Kanner AM An update on antiepileptic drugs and suicide: Are there definitive answers yet? Epilepsy Curr 2010 10 137 45 21157540 \n12 Kanner AM Are antiepileptic drugs used in the treatment of migraine associated with an increased risk of suicidality? Curr Pain Headache Rep 2011 15 164 9 21479999 \n13 Mao J Chen LL Gabapentin in pain management Anesth Analg 2000 91 680 7 10960399 \n14 Mack A Examination of the evidence for off-label use of gabapentin J Manag Care Pharm 2003 9 559 68 14664664 \n15 Markowitz JS Finkenbine R Myrick H King L Carson WH Gabapentin abuse in a cocaine user: Implications for treatment? J Clin Psychopharmacol 1997 17 423 4 9315994 \n16 Mersfelder TL Nichols WH Gabapentin: Abuse, Dependence, and Withdrawal Ann Pharmacother 2016 50 229 33 26721643 \n17 Middleton O Suicide by gabapentin overdose J Forensic Sci 2011 56 1373 5 21554310 \n18 Misra S Parthasarathi G Vilanilam GC The effect of gabapentin premedication on postoperative nausea, vomiting, and pain in patients on preoperative dexamethasone undergoing craniotomy for intracranial tumors J Neurosurg Anesthesiol 2013 25 386 91 23603887 \n19 Newman M Bitter pills for drug companies BMJ 2010 341 5095 \n20 Pinninti NR Mahajan DS Gabapentin-associated aggression J Neuropsychiatry Clin Neurosci 2001 13 424 \n21 Radley DC Finkelstein SN Stafford RS Off-label prescribing among office-based physicians Arch Intern Med 2006 166 1021 6 16682577 \n22 Reccoppa L Malcolm R Ware M Gabapentin abuse in inmates with prior history of cocaine dependence Am J Addict 2004 13 321 3 15370954 \n23 Reeves RR Burke RS Abuse of combinations of gabapentin and quetiapine Prim Care Companion CNS Disord 2014 16 \n24 Reimann W Inhibition by GABA, baclofen and gabapentin of dopamine release from rabbit caudate nucleus: Are there common or different sites of action? Eur J Pharmacol 1983 94 341 4 6653664 \n25 Smith RV Havens JR Walsh SL Gabapentin misuse, abuse and diversion: A systematic review Addiction 2016 111 1160 74 27265421 \n26 Smith RV Lofwall MR Havens JR Abuse and diversion of gabapentin among nonmedical prescription opioid users in Appalachian Kentucky Am J Psychiatry 2015 172 487 8 \n27 Vollmer KO von Hodenberg A Kolle EU Pharmacokinetics and metabolism of gabapentin in rat, dog and man Arzneimittelforschung 1986 36 830 9 3730018 \n28 Wamil AW McLean MJ Limitation by gabapentin of high frequency action potential firing by mouse central neurons in cell culture Epilepsy Res 1994 17 1 11 8174520 \n29 Wiffen PJ Derry S Bell RF Rice AS Tolle TR Phillips T Gabapentin for chronic neuropathic pain in adults Cochrane Database Syst Rev 2017 6 CD007938 28597471 \n30 Last accessed on 2017 Nov 15 http://www.aapcc.org/annual-reports \n31 Last accessed on 2017 Nov 15 https://www.fda.gov/Drugs/DrugSafety/PostmarketDrug Safety InformationforPatientsandProviders/ucm100197.htm \n32 Last accessed on 2017 Nov 15 http://www.huffingtonpost.com/martha-rosenberg/pfizer-neurontin-suicide_b_875603.html \n33 Last accessed on 2017 Nov 15 http://www.imshealth.com/files/web/IMSH%20Institute/Reports/Medicines-Use-and-Spending-in-the-US-2015-to-2020/IMS_Institute_Medicines_Use_and_Spending_in_2015.pdf\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2152-7806",
"issue": "9()",
"journal": "Surgical neurology international",
"keywords": "Chronic low back pain; gabapentin; suicide",
"medline_ta": "Surg Neurol Int",
"mesh_terms": null,
"nlm_unique_id": "101535836",
"other_id": null,
"pages": "210",
"pmc": null,
"pmid": "30488008",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "25904080;9315994;21157540;24829909;25930135;21818576;10960399;6653664;24995953;21554310;28144823;27265421;20851842;23603887;15370954;10864898;8174520;21479999;23906621;11514656;28597471;3730018;25667805;20922708;26721643;16682577;14664664;26827847",
"title": "Gabapentin-related suicide: Myth or fact?",
"title_normalized": "gabapentin related suicide myth or fact"
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"abstract": "The Food and Drug Administration has approved the use of sodium-glucose co-transporter 2 (SGLT-2) inhibitors for use in Type II diabetics. These are a relatively new addition to the armamentaria of diabetes management. Postmarketing surveillance is a witness to several side effects, a morbid one being ketoacidosis. Herein is discussed a scenario of a Type II diabetic who presented with substantial ketoacidosis without significant hyperglycemia. The absence of the customary precipitating factors and the presence of a recent introduction of canagliflozin, a SGLT-2 inhibitor to the diabetes prescription, hinted at the causal relationship. Of note, she had never experienced diabetic ketoacidosis in the past prior to commencement of SGLT-2 inhibitor therapy. As clinicians, we need to be aware of the treatment-emergent adverse effect of this relatively new class of diabetic treatment.",
"affiliations": "Department of Critical Care Medicine, Gleneagles Global Hospitals, Mumbai, Maharashtra, India.;Department of Internal Medicine, Gleneagles Global Hospitals, Mumbai, Maharashtra, India.",
"authors": "Vadi|Sonali|S|;Agarwal|Manjusha|M|",
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"doi": "10.4103/ijccm.IJCCM_328_17",
"fulltext": "\n==== Front\nIndian J Crit Care MedIndian J Crit Care MedIJCCMIndian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine0972-52291998-359XMedknow Publications & Media Pvt Ltd India IJCCM-21-79310.4103/ijccm.IJCCM_328_17Case ReportCanagliflozin-associated Diabetic Ketoacidosis with Lower-than-anticipated Glucose Levels Vadi Sonali Agarwal Manjusha 1Department of Critical Care Medicine, Gleneagles Global Hospitals, Mumbai, Maharashtra, India1 Department of Internal Medicine, Gleneagles Global Hospitals, Mumbai, Maharashtra, IndiaAddress for correspondence: Dr. Sonali Vadi, Gleneagles Global Hospital, 35 E. Borges Road, Parel, Mumbai - 400 012, Maharashtra, India. E-mail: sonalivadi@hotmail.com11 2017 21 11 793 795 Copyright: © 2017 Indian Journal of Critical Care Medicine2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.The Food and Drug Administration has approved the use of sodium-glucose co-transporter 2 (SGLT-2) inhibitors for use in Type II diabetics. These are a relatively new addition to the armamentaria of diabetes management. Postmarketing surveillance is a witness to several side effects, a morbid one being ketoacidosis. Herein is discussed a scenario of a Type II diabetic who presented with substantial ketoacidosis without significant hyperglycemia. The absence of the customary precipitating factors and the presence of a recent introduction of canagliflozin, a SGLT-2 inhibitor to the diabetes prescription, hinted at the causal relationship. Of note, she had never experienced diabetic ketoacidosis in the past prior to commencement of SGLT-2 inhibitor therapy. As clinicians, we need to be aware of the treatment-emergent adverse effect of this relatively new class of diabetic treatment.\n\nKeywords\nCanagliflozindiabetic ketoacidosis with lower-than-anticipated glucose levelseuglycemic diabetic ketoacidosissodium-glucose co-transporter 2 inhibitors\n==== Body\nINTRODUCTION\nAs clinicians, we need to be aware that medications used for disease management can paradoxically induce effects, causing an already sick patient to become worse. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors, a fairly recent addition to the pool of diabetes medications, are associated with a variety of side effects, the fatal one being ketoacidosis. This adverse effect reported in the postmarketing surveillance significantly adds to the morbidity of illness. Herein is discussed this treatment-emergent adverse effect that clinicians need to be aware of.\n\nCASE REPORT\nA middle aged lady presented to the emergency room with nausea and emesis for 4 days, fever for 2 days, and malaise. Her medical comorbidities included Type II diabetes, hypertension, and hypothyroidism. Her body mass index was 22.3 kg/m2. Hospitalized a month ago for community-acquired pneumonia, she was discharged on a combination of glimepiride-metformin, teneligliptin, human actrapid insulin, and canagliflozin as an add-on. Her serum glycosylated hemoglobin levels were at 11.1% then. At a follow-up 15 days later following an improvement in her glucose control, insulin was discontinued. Initially admitted to the floors with the said complaints, she was later transferred to the Intensive Care Unit following severe metabolic acidosis with serum bicarbonate levels at 3.3 mmol/L and pH at 6.89 on her arterial blood gas. She complained of dryness of mouth and was very thirsty. Clinically dehydrated, she was administered intravenous fluids. Other medications included intravenous sodium bicarbonate, human actrapid insulin infusion titrated as per the glucose levels, and symptomatic treatment for her gastrointestinal symptoms. Severe metabolic acidosis without very high serum glucose levels and the contemporaneous existence of canagliflozin raised the suspicion of diabetic ketoacidosis (DKA) with lower-than-anticipated glucose levels. Table 1 shows the acid–base results while Table 2 depicts the fingerstick glucose levels on the day of presentation. Meanwhile, other laboratory results returned as normal complete blood count, blood urea nitrogen at 12 mg/dl (normal: 9.8–20.1 mg/dl), serum creatinine at 1.4 mg/dl (normal: 0.57–1.11 mg/dl), serum D3-Hydroxybutyrate at 11.79 mmol/L (normal: 0.02–0.27 mmol/L), serum potassium at 6.0 mEq/L (without simultaneous electrocardiogram changes), anion gap: 24, measured serum osmolality: 330 mOsm/kg (normal: 275–300 mOsm/kg), and serum glycosylated hemoglobin levels at 11.1%. Calculated serum osmolality was 306 with osmolar gap of 24 mOsm/kg. Ultrasound of her abdomen was nonrevelatory.\n\nTable 1 Arterial blood gas results on the day of presentation\n\nTable 2 Fingerstick glucose trends\n\nClinical recovery was evident within the following 24 h with an improvement of acidosis and stabilization of serum glucose levels. Seventy-two hours later, she was transferred back to the floors and later discharged on oral hypoglycemic agents without canagliflozin. At 6-month follow-up, her serum glucose levels have remained well under control without any further episodes of euglycemic DKA.\n\nDISCUSSION\nApproved by the Food and Drug Administration (FDA) and released for use in 2013, SGLT-2 inhibitor canagliflozin acts by blocking glucose reabsorption in the proximal renal tubules with a resultant glycosuria.[1] Pancreas decreases its insulin secretion following a reduction in blood glucose. Ensuing increased glucagon-to-insulin ratio[2] leads to gluconeogenesis, ketogenesis,[3] and a consequent ketoacidosis.[45] In the same vein, these effects are pronounced following a reduction in insulin intake.[6] On the other hand, given the inhibition of glucose reabsorption at the renal tubular level, an advantage of this group of medication is that the occurrence of hyperglycemia is moderated without consequent hypoglycemia.[7] This combination of ketoacidosis without significantly elevated serum glucose levels is euglycemic DKA with lower-than-anticipated glucose levels.[8] Postmarketing surveillance has seen the occurrence of DKA following the use of canagliflozin. The FDA issued a warning in May 2015 about SGLT-2 inhibitors leading to ketoacidosis[9] that was updated in December 2015. Reported triggers for occurrence of ketoacidosis in patients on SGLT-2 inhibitors include acute illness, sepsis, recent surgery, starvation, decrease in carbohydrate intake, decrease in insulin intake, and significant changes in the level of physical activity, or pregnancy.[610]\n\nGiven her symptomatic presentation with nausea, emesis, and feeling thirsty with a background of uncontrolled blood glucose levels, a diagnosis of DKA was entertained. However, severe acidosis with high serum D3-Hydroxybutyrate levels and modestly elevated serum glucose levels in the presence of a SGLT-2 inhibitor prescription led to the diagnosis of DKA with lower-than-anticipated glucose levels. Given a satisfactory glycemic control about 2 weeks later and to prevent the occurrence of hypoglycemia, insulin was discontinued. This stoppage of insulin was the likely trigger factor for DKA with lower-than-anticipated glucose levels in the scenario. She was managed on the lines of a standard DKA protocol.[8] Of note, she had never been hospitalized in the past for DKA prior to commencing SGLT-2 inhibitor.\n\nThus, ketoacidosis in the absence of marked hyperglycemia should alert an astute physician about DKA with lower-than-anticipated glucose levels in a diabetic on a SGLT-2 inhibitor prescription. Additionally, it would be prudent to add SGLT-2 inhibitors to the existent list of etiologies for DKA with lower-than-anticipated glucose levels.\n\nCONCLUSION\nOn the spectrum of DKA lies DKA with lower-than-anticipated glucose levels that is characterized by ketoacidosis without significant hyperglycemia. The discussed scenario highlights the significance of the existence of an ominous off-shoot of SGLT-2 inhibitors, DKA with lower-than-anticipated glucose levels, the occurrence of which can be possibly predicted by urine or serum ketone testing in symptomatic individuals despite the absence of significant hyperglycemia. As clinicians, we need to be aware about this life-threatening treatment-emergent adverse effect of SGLT-2 inhibitors which have recently been added to the armamentarium of diabetes management.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Tahrani AA Barnett AH Bailey CJ SGLT inhibitors in management of diabetes Lancet Diabetes Endocrinol 2013 1 140 51 24622320 \n2 Ferrannini E Muscelli E Frascerra S Baldi S Mari A Heise T Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients J Clin Invest 2014 124 499 508 24463454 \n3 Keller U Schnell H Sonnenberg GE Gerber PP Stauffacher W Role of glucagon in enhancing ketone body production in ketotic diabetic man Diabetes 1983 32 387 91 6132846 \n4 Ogawa W Sakaguchi K Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: Possible mechanism and contributing factors J Diabetes Investig 2016 7 135 8 \n5 Taylor SI Blau JE Rother KI SGLT2 inhibitors may predispose to ketoacidosis J Clin Endocrinol Metab 2015 100 2849 52 26086329 \n6 Rosenstock J Ferrannini E Euglycemic diabetic ketoacidosis: A predictable, detectable, and preventable safety concern with SGLT2 inhibitors Diabetes Care 2015 38 1638 42 26294774 \n7 Chao EC SGLT-2 inhibitors: A new mechanism for Glycemic control Clin Diabetes 2014 32 4 11 26246672 \n8 Handelsman Y Henry RR Bloomgarden ZT Dagogo-Jack S DeFronzo RA Einhorn D American association of clinical endocrinologists and American college of endocrinology position statement on the association of sglt-2 inhibitors and diabetic ketoacidosis Endocr Pract 2016 22 753 62 27082665 \n9 US Food and Drug Administration. FDA Drug Safety Communication: FDA Warns that SGLT2 Inhibitors for Diabetes May Result in a Serious Condition of too Much Acid in the Blood Last accessed on 2015 May 15 Available from: http://www.fda.gov/drugs/drugsafety/ucm446845.htm \n10 Peters AL Buschur EO Buse JB Cohan P Diner JC Hirsch IB Euglycemic diabetic ketoacidosis: A potential complication of treatment with sodium-glucose cotransporter 2 inhibition Diabetes Care 2015 38 1687 93 26078479\n\n",
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"issue": "21(11)",
"journal": "Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine",
"keywords": "Canagliflozin; diabetic ketoacidosis with lower-than-anticipated glucose levels; euglycemic diabetic ketoacidosis; sodium-glucose co-transporter 2 inhibitors",
"medline_ta": "Indian J Crit Care Med",
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"pages": "793-795",
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"title": "Canagliflozin-associated Diabetic Ketoacidosis with Lower-than-anticipated Glucose Levels.",
"title_normalized": "canagliflozin associated diabetic ketoacidosis with lower than anticipated glucose levels"
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"abstract": "Given the wide range of manifestations of parkinsonism and its mimics, the diagnosis may remain elusive or be misattributed in some patients. Dopamine transporter (DAT) single photon emission computed tomography (SPECT) (DaTscan), an imaging technique that probes the integrity of the presynaptic nigrostriatal system, can be useful in the evaluation of clinically complex parkinsonian disorders in the appropriate context and when adequately interpreted. Pearls and pitfalls in the use of DaTscan for the differential diagnosis of parkinsonisms are reviewed using a case-based format. While the DaTscan is no replacement for a careful neurological examination in ascertaining the likelihood of Parkinson disease or other parkinsonisms in most clinical scenarios, it can be useful in the assessment of disorders where an abducting resting tremor, a prominent postural tremor, or incongruent features are not sufficiently clear on exam to distinguish neurodegenerative parkinsonism from dystonia, drug-induced parkinsonism and functional (psychogenic) parkinsonism, respectively.",
"affiliations": "a Department of Neurology, UC Neuroscience Institute , University of Cincinnati , Cincinnati , Ohio , USA.;a Department of Neurology, UC Neuroscience Institute , University of Cincinnati , Cincinnati , Ohio , USA.;a Department of Neurology, UC Neuroscience Institute , University of Cincinnati , Cincinnati , Ohio , USA.;a Department of Neurology, UC Neuroscience Institute , University of Cincinnati , Cincinnati , Ohio , USA.",
"authors": "Rodriguez-Porcel|Federico|F|;Jamali|Sheheryar|S|;Duker|Andrew P|AP|;Espay|Alberto J|AJ|",
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"issue": "16(1)",
"journal": "Expert review of neurotherapeutics",
"keywords": "DaTscan; Parkinson disease; SWEDD; drug-induced parkinsonism; parkinsonism; tremor",
"medline_ta": "Expert Rev Neurother",
"mesh_terms": "D006801:Humans; D010300:Parkinson Disease; D015899:Tomography, Emission-Computed, Single-Photon",
"nlm_unique_id": "101129944",
"other_id": null,
"pages": "23-9",
"pmc": null,
"pmid": "26564057",
"pubdate": "2016",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Dopamine transporter scanning in the evaluation of patients with suspected Parkinsonism: a case-based user's guide.",
"title_normalized": "dopamine transporter scanning in the evaluation of patients with suspected parkinsonism a case based user s guide"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/16/0076615",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": "1",
... |
{
"abstract": "Tumor lysis syndrome, a complication of anticancer chemotherapy, results from rapid lysis of malignant cells. We report tumor lysis syndrome in a patient treated with trastuzumab for metastatic breast carcinoma. A 69-year-old woman was diagnosed with multiple liver metastases 1 month after mastectomy. As her liver functions had deteriorated, chemotherapeutic agents were contraindicated and she was treated with trastuzumab alone. On day 6 of the first course of trastuzumab, she developed tumor lysis syndrome. As her liver functions showed deterioration due to multiple hepatic metastases, hemodialysis was contraindicated. Acute renal failure worsened and she died 11 days after the administration of trastuzumab.",
"affiliations": "Department of Breast Oncology, Juntendo University Hospital, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. fmuraka@juntendo.ac.jp.;Department of Breast Oncology, Juntendo University Hospital, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.;Department of Breast Oncology, Juntendo University Hospital, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.",
"authors": "Taira|Fumi|F|;Horimoto|Yoshiya|Y|;Saito|Mitsue|M|",
"chemical_list": "D000970:Antineoplastic Agents; D000068878:Trastuzumab",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12282-013-0448-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1340-6868",
"issue": "22(6)",
"journal": "Breast cancer (Tokyo, Japan)",
"keywords": "Breast cancer; Molecular targeting drug; Solid tumor; Trastuzumab; Tumor lysis syndrome",
"medline_ta": "Breast Cancer",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D008113:Liver Neoplasms; D000068878:Trastuzumab; D015275:Tumor Lysis Syndrome",
"nlm_unique_id": "100888201",
"other_id": null,
"pages": "664-8",
"pmc": null,
"pmid": "23420376",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Tumor lysis syndrome following trastuzumab for breast cancer: a case report and review of the literature.",
"title_normalized": "tumor lysis syndrome following trastuzumab for breast cancer a case report and review of the literature"
} | [
{
"companynumb": "JP-ROCHE-1203085",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": null,
"d... |
{
"abstract": "Hypokalaemia is a common clinical problem. It can lead to severe disturbances in cardiac, neurological and muscle function. We present the case of a 45-year-old woman who was transported to our hospital with cardiac arrest following ventricular fibrillation. Blood sampling revealed severe acidosis (pH 7.02) and extreme hypokalaemia (0.9 mmol/l). The low serum potassium level was most likely caused by the combination of a very deficient diet and use of a thiazide diuretic. She never reported any symptoms. An acute intracellular shift of potassium due to epinephrine and perhaps also the cathecholamines in Red Bull may have further decreased the serum potassium concentration. To our knowledge, this is the lowest potassium level reported in literature. Longer-lasting hypokalaemia might be asymptomatic but when combined with even minor triggers of acute hypokalaemia, serious morbidity or mortality can suddenly occur. Patients on diuretic treatment with suspected malnutrition or chronic gastrointestinal losses require regular monitoring of electrolytes.",
"affiliations": "Department of Obstetrics and Gynaecology, Rijnstate Hospital, Arnhem, the Netherlands.",
"authors": "Ten Bos|L M|LM|;Veenstra|T C|TC|;Westerhof|B D|BD|;Bosch|F H|FH|",
"chemical_list": "D017419:Potassium, Dietary; D049993:Sodium Chloride Symporter Inhibitors; D011188:Potassium",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-2977",
"issue": "74(9)",
"journal": "The Netherlands journal of medicine",
"keywords": null,
"medline_ta": "Neth J Med",
"mesh_terms": "D000138:Acidosis; D005260:Female; D006323:Heart Arrest; D006801:Humans; D007008:Hypokalemia; D008875:Middle Aged; D011188:Potassium; D017419:Potassium, Dietary; D012720:Severity of Illness Index; D049993:Sodium Chloride Symporter Inhibitors; D014693:Ventricular Fibrillation",
"nlm_unique_id": "0356133",
"other_id": null,
"pages": "406-409",
"pmc": null,
"pmid": "27905308",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of extreme hypokalaemia.",
"title_normalized": "a case of extreme hypokalaemia"
} | [
{
"companynumb": "NL-MYLANLABS-2016M1056824",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VALSARTAN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo describe the phenotype of the uveitis that accompanies juvenile psoriatic arthritis or psoriasis.\n\n\nMETHODS\nObservational case series.\n\n\nMETHODS\nSetting: Two university-based referral clinics: 1 in England, 1 in the United States.\n\n\nMETHODS\nFive children with uveitis and psoriatic arthritis and 1 with uveitis and psoriasis Observational Procedure: Retrospective chart review.\n\n\nMETHODS\nDemographics of subjects such as age and sex; description of ocular and joint disease; surgical and other complications; medical treatment.\n\n\nRESULTS\nFive of the 6 children in this series had the onset of disease at or before age 6 (P = .0008 compared to expected age of onset for psoriatic arthritis in childhood). All children in this series had an inadequate response to topical corticosteroids. Most of the children were treated with systemic corticosteroids for many months, yet all of them went on to require methotrexate. Therapy with systemic methotrexate did not suffice, as all the patients also required some form of biologic therapy. Five of 6 had surgeries such as vitrectomy, cataract extraction, or a procedure for glaucoma control.\n\n\nCONCLUSIONS\nThe observations suggest that the uveitis that accompanies juvenile psoriatic arthritis might be a distinct disease that is particularly severe when its onset affects children aged 6 years or younger.",
"affiliations": "Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, Oregon.;University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom.;University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom.;University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom; School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.;Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, Oregon; Department of Medicine, Oregon Health & Science University, Portland, Oregon; Legacy Devers Eye Institute, Portland, Oregon. Electronic address: rosenbaj@ohsu.edu.",
"authors": "Salek|Sherveen S|SS|;Pradeep|Archana|A|;Guly|Catherine|C|;Ramanan|Athimalaipet V|AV|;Rosenbaum|James T|JT|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajo.2017.10.018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9394",
"issue": "185()",
"journal": "American journal of ophthalmology",
"keywords": null,
"medline_ta": "Am J Ophthalmol",
"mesh_terms": "D017668:Age of Onset; D001171:Arthritis, Juvenile; D002648:Child; D002675:Child, Preschool; D004739:England; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D010641:Phenotype; D011565:Psoriasis; D012307:Risk Factors; D014481:United States; D014605:Uveitis",
"nlm_unique_id": "0370500",
"other_id": null,
"pages": "68-74",
"pmc": null,
"pmid": "29101009",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": "10627431;970993;16957887;7699645;26928555;25725620;22898222;19208605;17075862;28148698;11836659",
"title": "Uveitis and Juvenile Psoriatic Arthritis or Psoriasis.",
"title_normalized": "uveitis and juvenile psoriatic arthritis or psoriasis"
} | [
{
"companynumb": "US-CELLTRION INC.-2021US003525",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Long-term data regarding switching from originator infliximab to biosimilar CT-P13 are sparse. Concerns about increased immunogenicity after switching have been raised. We aimed to study the effectiveness, safety and immunogenicity after switching from originator infliximab to CT-P13 in a real-world IBD population with 18 months prospective follow-up.\n\n\n\nAll adult IBD patients treated with originator infliximab at the Department of Gastroenterology, Oslo University Hospital, were switched to CT-P13 and followed prospectively for 18 months. The primary endpoints were (i) the proportion of patients remaining on CT-P13 18 months after switching and (ii) immunogenicity during 18 months after switching. The secondary endpoints included (i) adverse events, (ii) changes in disease activity, C-reactive protein, anaemia, faecal calprotectin, infliximab dose and interval and p-infliximab.\n\n\n\nIn total, 143 IBD patients were switched, 99 with Crohn's disease and 44 with ulcerative colitis. Altogether, 130 (91%) remained on CT-P13 throughout 18 months. Two patients developed ADAs at moderate level and discontinued CT-P13. Another 10 patients discontinued CT-P13 (two due to loss of response without ADAs, four due to adverse events, and four in remission and a personal wish to stop). There was no overall change in disease activity scores or in the other studied variables except for p-infliximab, which increased significantly.\n\n\n\nThe present study provides valuable evidence for the safety and effectiveness of switching from originator to biosimilar infliximab over a prolonged period of 18 months and demonstrates that switching was well tolerated and did not affect the long term clinical outcome.",
"affiliations": "a Department of Gastroenterology , Oslo University Hospital.;a Department of Gastroenterology , Oslo University Hospital.;a Department of Gastroenterology , Oslo University Hospital.;d Department of Medical Biochemistry , Oslo University Hospital.;b Faculty of Medicine , University of Oslo.;a Department of Gastroenterology , Oslo University Hospital.;a Department of Gastroenterology , Oslo University Hospital.",
"authors": "Høivik|Marte L|ML|0000-0002-0104-465X;Buer|Lydia C T|LCT|;Cvancarova|Milada|M|;Warren|David J|DJ|;Bolstad|Nils|N|;Moum|Bjørn A|BA|;Medhus|Asle W|AW|",
"chemical_list": "D000911:Antibodies, Monoclonal; D059451:Biosimilar Pharmaceuticals; C000591237:CT-P13; D039841:Leukocyte L1 Antigen Complex; D002097:C-Reactive Protein; D000069285:Infliximab",
"country": "England",
"delete": false,
"doi": "10.1080/00365521.2018.1463391",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0036-5521",
"issue": "53(6)",
"journal": "Scandinavian journal of gastroenterology",
"keywords": "Crohn’s disease; Inflammatory bowel disease; biosimilar; infliximab; switching; ulcerative colitis",
"medline_ta": "Scand J Gastroenterol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D059451:Biosimilar Pharmaceuticals; D002097:C-Reactive Protein; D057915:Drug Substitution; D005243:Feces; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015212:Inflammatory Bowel Diseases; D000069285:Infliximab; D039841:Leukocyte L1 Antigen Complex; D008297:Male; D008875:Middle Aged; D009664:Norway; D011446:Prospective Studies; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0060105",
"other_id": null,
"pages": "692-699",
"pmc": null,
"pmid": "29852793",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Switching from originator to biosimilar infliximab - real world data of a prospective 18 months follow-up of a single-centre IBD population.",
"title_normalized": "switching from originator to biosimilar infliximab real world data of a prospective 18 months follow up of a single centre ibd population"
} | [
{
"companynumb": "NO-CELLTRION INC.-2019NO018341",
"fulfillexpeditecriteria": "1",
"occurcountry": "NO",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nAnthracyclines are a mainstay of the treatment of several childhood malignancies, but their utility is limited by dose-related cardiotoxicity. This study is aimed to explore the link between exposure of paediatric cancer patients to doxorubicin and its metabolite doxorubicinol, and cardiac troponin I (cTnI).\n\n\nMETHODS\nIn a prospective pilot study plasma doxorubicin, doxorubicinol, and cTnI concentrations were measured in samples from children undergoing cancer chemotherapy. A mixed-effects population pharmacokinetic model for doxorubicin and doxorubicinol and in combination with a turn-over model for cTnI were developed.\n\n\nRESULTS\nSeventeen patients, aged 3.4-14.7 year, treated for a variety of cancers had 99 doxorubicin and 119 doxorubicinol concentrations analysed from samples drawn between 0.5 and 336 h after the start of the infusion. Eleven patients had received previous doses of anthracyclines, with a median cumulative prior dose of 90 mg/m2 (range 0-225 mg/m2). The median administered doxorubicin dose was 30 mg/m2 (range 25-75 mg/m2). Doxorubicin disposition was described by a three-compartment model with first-order elimination and metabolism to doxorubicinol. Body surface area was related to all clearance and distribution parameters and age further influenced clearance (CL, 58.7 L/h/1.8 m2 for an average 8.4-year-old patient). Combined doxorubicin and metabolite exposure stimulated a temporary increase in cTnI in plasma, with a concentration of 11.8 µg/L required to achieve half-maximal effect. Prior cumulative anthracycline dosage received by patients was predictive of an increased cTnI baseline prior to a new doxorubicin dose.\n\n\nCONCLUSIONS\nPrior anthracycline exposure increased baseline cTnI in a dose-dependent manner, consistent with the known cumulative risk of anthracycline exposure-induced cardiotoxicity.",
"affiliations": "The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia.;School of Pharmacy, Pharmacy Australia Centre of Excellence (PACE), The University of Queensland, Brisbane, Australia.;School of Pharmacy, Pharmacy Australia Centre of Excellence (PACE), The University of Queensland, Brisbane, Australia.;Mater Medical Research Institute, The University of Queensland, Brisbane, Australia.;School of Pharmacy, Pharmacy Australia Centre of Excellence (PACE), The University of Queensland, Brisbane, Australia.;Oncology Services Group, Children's Health Queensland Hospital and Health Service, Brisbane, Australia.;The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia. andrew.moore@uq.edu.au.",
"authors": "Kunarajah|Kuhan|K|;Hennig|Stefanie|S|http://orcid.org/0000-0001-5972-3711;Norris|Ross L G|RLG|;Lobb|Michael|M|;Charles|Bruce G|BG|;Pinkerton|Ross|R|;Moore|Andrew S|AS|http://orcid.org/0000-0001-8062-1779",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D019210:Troponin I; D004317:Doxorubicin; C010013:adriamycinol",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-017-3309-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-5704",
"issue": "80(1)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "Anthracycline; Cardiotoxicity; Children; Doxorubicin; Pharmacokinetics; Troponin",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000293:Adolescent; D000903:Antibiotics, Antineoplastic; D066126:Cardiotoxicity; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin; D005260:Female; D006801:Humans; D008297:Male; D008954:Models, Biological; D009369:Neoplasms; D010865:Pilot Projects; D011446:Prospective Studies; D019210:Troponin I",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "15-25",
"pmc": null,
"pmid": "28444427",
"pubdate": "2017-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Population pharmacokinetic modelling of doxorubicin and doxorubicinol in children with cancer: is there a relationship with cardiac troponin profiles?",
"title_normalized": "population pharmacokinetic modelling of doxorubicin and doxorubicinol in children with cancer is there a relationship with cardiac troponin profiles"
} | [
{
"companynumb": "AU-JNJFOC-20170708157",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": "... |
{
"abstract": "A 61-year-old woman with a medical history of intracerebral haemorrhage, hypertension, hyperlipidaemia and carotid stenosis presented to the emergency department with altered mental status 3 weeks after undergoing a vertical sleeve gastrectomy for severe obesity. She presented with a hypertensive emergency and a National Institutes of Health Stroke Scale of 4. CT of the head was unrevealing. MRI showed an abnormal signal within the bilateral posterior border-zone areas, with several foci in the parietal and occipital lobes, and thalami, suggestive of posterior reversible encephalopathy syndrome (PRES). The patient was initially placed on a labetalol drip and her preoperative antihypertensive medications--amlodipine, captopril, triamterene and hydrochlorothiazide--were gradually reintroduced. She returned to her baseline and was stable on discharge. Rapid withdrawal of antihypertensive medications in the early postoperative period of bariatric surgery was the aetiology of PRES in this patient. This case report discusses postoperative care of bariatric surgery patients having hypertension.",
"affiliations": "Department of Medicine- Gastroenterology and Department of Pediatrics, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA.;Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA.;Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA.;Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA.",
"authors": "Stanford|Fatima Cody|FC|http://orcid.org/0000-0003-4616-533X;Pratt|Janey S|JS|http://orcid.org/0000-0002-6850-3427;Meireles|Ozanan R|OR|;Bredella|Miriam A|MA|",
"chemical_list": "D000959:Antihypertensive Agents",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000959:Antihypertensive Agents; D050110:Bariatric Surgery; D002543:Cerebral Hemorrhage; D005260:Female; D005743:Gastrectomy; D006801:Humans; D006973:Hypertension; D001523:Mental Disorders; D008875:Middle Aged; D009767:Obesity, Morbid; D054038:Posterior Leukoencephalopathy Syndrome; D011184:Postoperative Period",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26698202",
"pubdate": "2015-12-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24365441;20013140;23239292;21348922;24613735;24662112;22054155;26184985;25429323;21546321;24517247;17036577;19490286;21569975;22350987;20440579;24189773;23075509;23077152",
"title": "Posterior reversible encephalopathy syndrome (PRES) after bariatric surgery--a potential consequence associated with rapid withdrawal of antihypertensive medications.",
"title_normalized": "posterior reversible encephalopathy syndrome pres after bariatric surgery a potential consequence associated with rapid withdrawal of antihypertensive medications"
} | [
{
"companynumb": "US-ACCORD-036973",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TRIAMTERENE"
},
"drugadditional": null,
"dru... |
{
"abstract": "KRAS mutation is a negative predictive biomarker of anti-EGFR agents in patients with metastatic colorectal cancer (mCRC), and remains an elusive target. Pelareorep, a double-stranded RNA virus selectively replicates in KRAS-mutated cells, and is synergistic with irinotecan. A dose escalation trial of FOLFIRI/bevacizumab [irinotecan (150-180 mg/m2) and pelareorep (1 × 1010 TCID50-3 × 1010 TCID50)] was implemented in adult patients with oxaliplatin refractory/intolerant, KRAS-mutant mCRC. Pelareorep was administered intravenously over 1 hour on days 1-5 every 4 weeks. Additional studies included pharmacokinetics, tumor morphology, and immune responses. Among FOLFIRI-naïve patients, the highest dose of FOLFIRI/bevacizumab (180 mg/m2 irinotecan) and pelareorep (3 × 1010 TCID50) was well tolerated, without a dose-limiting toxicity. At the recommended phase II dose, 3 of 6 patients (50%) had a partial response; the median progression-free and overall survival (PFS, OS) were 65.6 weeks and 25.1 months, respectively. Toxicities included myelosuppression, fatigue, and diarrhea. Transmission electron microscopy revealed viral factories (viral collections forming vesicular structures), at various stages of development. Immunogold staining against viral capsid σ-1 protein demonstrated viral \"homing\" in the tumor cells. The nucleus displayed sufficient euchromatin regions suggestive of active transcription. Flow cytometry revealed rapid dendritic cell maturation (48 hours) with subsequent activation of cytotoxic T cells (7 days). The combination of pelareorep with FOLFIRI/bevacizumab is safe. The PFS and OS data are encouraging and deserve further exploration. Pelareorep leads to a clear recurrent immune stimulatory response with cytotoxic T-cell activation, and homes and replicates in the tumor.",
"affiliations": "Department of Medical Oncology, Montefiore Medical Center, Bronx, New York. sgoel@montefiore.org.;Department of Medical Oncology, New York-Presbyterian/Weill Cornell Medical Center, New York, New York.;Department of Medical Oncology, Montefiore Medical Center, Bronx, New York.;Department of Medical Oncology, Montefiore Medical Center, Bronx, New York.;Department of Medical Oncology, Montefiore Medical Center, Bronx, New York.;Department of Medical Oncology, Montefiore Medical Center, Bronx, New York.;Department of Medical Oncology, Montefiore Medical Center, Bronx, New York.;Department of Medical Oncology, Montefiore Medical Center, Bronx, New York.;Oncolytics Inc., Calgary, Alberta, Canada.;Department of Medical Oncology, Montefiore Medical Center, Bronx, New York.",
"authors": "Goel|Sanjay|S|0000-0002-2798-7568;Ocean|Allyson J|AJ|;Parakrama|Ruwan Y|RY|;Ghalib|Mohammad H|MH|;Chaudhary|Imran|I|0000-0003-0234-1602;Shah|Umang|U|;Viswanathan|Sengottuvel|S|;Kharkwal|Himanshu|H|;Coffey|Matthew|M|;Maitra|Radhashree|R|0000-0002-5365-5890",
"chemical_list": "D014408:Biomarkers, Tumor; C117307:KRAS protein, human; C000632500:reolysin; D000068258:Bevacizumab; D000077146:Irinotecan; D016283:Proto-Oncogene Proteins p21(ras)",
"country": "United States",
"delete": false,
"doi": "10.1158/1535-7163.MCT-19-1117",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1535-7163",
"issue": "19(5)",
"journal": "Molecular cancer therapeutics",
"keywords": null,
"medline_ta": "Mol Cancer Ther",
"mesh_terms": "D000328:Adult; D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis; D000068258:Bevacizumab; D014408:Biomarkers, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D050504:Oncolytic Viruses; D011379:Prognosis; D016283:Proto-Oncogene Proteins p21(ras); D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays",
"nlm_unique_id": "101132535",
"other_id": null,
"pages": "1148-1156",
"pmc": null,
"pmid": "32156785",
"pubdate": "2020-05",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article",
"references": "24798549;29534749;18981012;21645351;26310630;23177514;21106728;23038811;9812900;8523580;22949147;29298869;22810696;23168366;8683231;19097774;23114986;29942799;19572105;29653857;18172278;21944740;9628872;23097702;17227899;4192382;25877855;27019795;29487723;19188670;17195945;31694832;24024839;25970050",
"title": "Elucidation of Pelareorep Pharmacodynamics in A Phase I Trial in Patients with KRAS-Mutated Colorectal Cancer.",
"title_normalized": "elucidation of pelareorep pharmacodynamics in a phase i trial in patients with kras mutated colorectal cancer"
} | [
{
"companynumb": "US-PFIZER INC-2020125465",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEUCOVORIN"
},
"drugadditional": "3",
... |
{
"abstract": "Short bowel syndrome after extensive surgical resection of the intestine is characterised by inadequate digestion and absorption of nutrients. Additional clinical problems include impaired absorption and metabolism of diverse drugs requiring individualised medical therapy or alternative treatments. We report a case of individualised dual antiplatelet therapy in a patient who underwent an extensive intestinal resection complicated by acute myocardial infarction requiring percutaneous coronary intervention and stent implantation. Genetic testing of CYP2C19 gene polymorphisms and platelet aggregation testing were used to assess responses to aspirin, clopidogrel, prasugrel and ticagrelor. Given its unique pharmacokinetics with good absorption and without need of metabolism to an active substance, ticagrelor appears to be the best for patients with short bowel syndrome who require dual antiplatelet therapy after coronary stent implantation.",
"affiliations": "Department of Cardiology and Cardiovascular Medicine, University Hospital of Tübingen, Tübingen, Germany.;Department of Cardiology and Cardiovascular Medicine, University Hospital of Tübingen, Tübingen, Germany.;Department of Cardiology and Cardiovascular Medicine, University Hospital of Tübingen, Tübingen, Germany.;Department of Cardiology and Cardiovascular Medicine, University Hospital of Tübingen, Tübingen, Germany.",
"authors": "Droppa|Michal|M|;Karathanos|Athanasios|A|;Gawaz|Meinrad|M|;Geisler|Tobias|T|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine; D001241:Aspirin",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D015746:Abdominal Pain; D056988:Anterior Wall Myocardial Infarction; D001241:Aspirin; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D008875:Middle Aged; D062645:Percutaneous Coronary Intervention; D010975:Platelet Aggregation Inhibitors; D057285:Precision Medicine; D012778:Short Bowel Syndrome; D015607:Stents; D013988:Ticlopidine",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26150610",
"pubdate": "2015-07-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21895761;23698643;17139373;19943882;24076493;22520250;22922416;23121439;16772608;21406646;18024618;20828644;23238773;25154388;22489610;18217143;16810174",
"title": "Individualised dual antiplatelet therapy in a patient with short bowel syndrome after acute myocardial infarction with coronary artery stenting.",
"title_normalized": "individualised dual antiplatelet therapy in a patient with short bowel syndrome after acute myocardial infarction with coronary artery stenting"
} | [
{
"companynumb": "DE-MYLANLABS-2017M1082842",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": n... |
{
"abstract": "Neutropenia in the setting of acute hematological malignancies may impact disease prognosis, thus affecting therapy dose intensity. This is often due to chemotherapy-induced aplasia as well as to the disease itself. However, chronic neutropenia deserves further investigation, as the management of reversible concomitant causes may avoid treatment delay. The present study describes a case of an acute promyelocytic leukemia patient with chronic severe neutropenia of multifactorial origin, including acute leukemia itself, chemotherapy, autoimmune activation with anti-platelets and anti-neutrophil antibodies positivity, and the rare association of large granular lymphocyte (LGL) expansion. As neutropenia may challenge the diagnosis and treatment of acute malignancies, clinicians and hematopathologists must discuss the differential diagnosis in order to avoid misdiagnosing and undertreating concomitant diseases. In particular, LGL chronic expansion and autoimmunity should be considered.",
"affiliations": "Onco-Hematology Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, I-20100 Milan, Italy.;Onco-Hematology Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, I-20100 Milan, Italy.;Onco-Hematology Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, I-20100 Milan, Italy.;Onco-Hematology Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, I-20100 Milan, Italy.;Onco-Hematology Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, I-20100 Milan, Italy.;Hemopathology Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico and University of Milan, I-20100 Milan, Italy.;Onco-Hematology Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, I-20100 Milan, Italy.;Onco-Hematology Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico and University of Milan, I-20100 Milan, Italy.",
"authors": "Reda|Gianluigi|G|;Fattizzo|Bruno|B|;Cassin|Ramona|R|;Flospergher|Elena|E|;Orofino|Nicola|N|;Gianelli|Umberto|U|;Barcellini|Wilma|W|;Cortelezzi|Agostino|A|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/ol.2016.5549",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1792-1074",
"issue": "13(3)",
"journal": "Oncology letters",
"keywords": "acute myeloid leukemia; autoimmunity; chemotherapy-induced neutropenia; chronic neutropenia; natural killer chronic expansion",
"medline_ta": "Oncol Lett",
"mesh_terms": null,
"nlm_unique_id": "101531236",
"other_id": null,
"pages": "1307-1310",
"pmc": null,
"pmid": "28454252",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article",
"references": "21190991;3876179;25037886;19794080;9462546;20008237;26066399;24706230;8068951;23233648;26009282",
"title": "Multifactorial neutropenia in a patient with acute promyelocytic leukemia and associated large granular lymphocyte expansion: A case report.",
"title_normalized": "multifactorial neutropenia in a patient with acute promyelocytic leukemia and associated large granular lymphocyte expansion a case report"
} | [
{
"companynumb": "IT-FRESENIUS KABI-FK201702779",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IDARUBICIN HYDROCHLORIDE"
},
"drugadditio... |
{
"abstract": "To compare the incidence of postoperative complications and opioid pain medication usage in gynecologic oncology patients who did and did not receive an epidural prior to undergoing exploratory laparotomy.\n\n\n\nRetrospective cohort study of all patients undergoing exploratory laparotomy with the gynecologic oncology division at Washington University in St Louis between January 2012 and October 2015. Data on demographics, pathology, postoperative pain and opioid use, and incidence of postoperative complications were collected.\n\n\n\nFive hundred and sixty-one patients underwent laparotomy, 305 with an epidural and 256 without. Patients with an epidural used significantly less hydromorphone in the post-anesthesia care unit (PACU) (p = 0.003) and on postoperative day (POD)#1 (p = 0.05), less total opioids on POD#0 (p < 0.01), and more non-opioid pain medication on POD#1-3 (p < 0.01). Patients with an epidural had lower pain scores in the PACU (p = 0.01), on POD#0 (p < 0.01), POD#1 (p < 0.01), and POD#3 (p = 0.03). Patients with epidurals had shorter hospital length of stay (p < 0.01), no difference in hospital readmission or incidence of venous thromboembolism up to 90 days postoperatively, longer duration of Foley catheter (20.4 vs 10.3 h, p = 0.02) with no difference in postoperative urinary tract infection, higher incidence of postoperative hypotension (63% vs 36.3%, p < 0.01), and lower incidence of wound complications (5% vs 14.1%, p < 0.01).\n\n\n\nPerioperative epidurals used in patients undergoing major abdominal surgery correlate with decreased postoperative opioid use, increased use of non-opioid pain medications, and improved pain relief postoperatively with acceptable postoperative risks and should be standard of care for these patients.",
"affiliations": "Department of Obstetrics and Gynecology, Washington University, St. Louis, MO, United States of America.;Department of Obstetrics and Gynecology, Washington University, St. Louis, MO, United States of America.;Division of Gynecologic Oncology, Washington University, St. Louis, MO, United States of America.;Washington University School of Medicine, St. Louis, MO, United States of America.;Washington University School of Medicine, St. Louis, MO, United States of America.;Department of Obstetrics and Gynecology, Washington University, St. Louis, MO, United States of America.;Department of Obstetrics and Gynecology, Washington University, St. Louis, MO, United States of America.;Department of Obstetrics and Gynecology, Washington University, St. Louis, MO, United States of America.;Department of Anesthesiology, Washington University, St. Louis, MO, United States of America.;Department of Anesthesiology, Washington University, St. Louis, MO, United States of America.;Division of Gynecologic Oncology, Washington University, St. Louis, MO, United States of America.;Division of Gynecologic Oncology, Washington University, St. Louis, MO, United States of America.;Division of Gynecologic Oncology, Washington University, St. Louis, MO, United States of America.;Division of Gynecologic Oncology, Washington University, St. Louis, MO, United States of America. Electronic address: thakerp@wustl.edu.",
"authors": "Huepenbecker|Sarah P|SP|;Cusworth|Sarah E|SE|;Kuroki|Lindsay M|LM|;Lu|Patricia|P|;Samen|Christelle D K|CDK|;Woolfolk|Candice|C|;Deterding|Rosa|R|;Wan|Leping|L|;Helsten|Daniel L|DL|;Bottros|Michael|M|;Mutch|David G|DG|;Powell|Matthew A|MA|;Massad|Leslie S|LS|;Thaker|Premal H|PH|",
"chemical_list": "D000701:Analgesics, Opioid",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ygyno.2019.02.017",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-8258",
"issue": "153(2)",
"journal": "Gynecologic oncology",
"keywords": null,
"medline_ta": "Gynecol Oncol",
"mesh_terms": "D015360:Analgesia, Epidural; D000701:Analgesics, Opioid; D015331:Cohort Studies; D005260:Female; D005833:Genital Neoplasms, Female; D013509:Gynecologic Surgical Procedures; D006801:Humans; D007813:Laparotomy; D008875:Middle Aged; D009367:Neoplasm Staging; D010149:Pain, Postoperative; D011183:Postoperative Complications; D012189:Retrospective Studies; D054556:Venous Thromboembolism",
"nlm_unique_id": "0365304",
"other_id": null,
"pages": "356-361",
"pmc": null,
"pmid": "30798950",
"pubdate": "2019-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Continuous epidural infusion in gynecologic oncology patients undergoing exploratory laparotomy: The new standard for decreased postoperative pain and opioid use.",
"title_normalized": "continuous epidural infusion in gynecologic oncology patients undergoing exploratory laparotomy the new standard for decreased postoperative pain and opioid use"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201905829",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUPIVACAINE"
},
"drugadditional": null,
... |
{
"abstract": "Immature teratoma is quite uncommon older women, particular in postmenopausal period. Only a few cases of postmenopausal immature teratoma of the genital tract have been reported. This report describes a postmenopausal aggressive pelvic immature teratoma case with a grave course despite treatment. A 67-year-old woman being in menopause for the past 16 years was diagnosed with immature teratoma in the pelvic cavity. The mass was removed completely and hysterectomy plus bilateral salpingo-oophorectomy was done. Histopathological diagnosis was grade 2 immature teratoma. The patient had a grave course with recurrences despite therapy and died within one year after initial diagnosis. In teratomas diagnosed over 45 years of age, the possibility of malignant teratoma should also be borne in mind.",
"affiliations": "Department of Obstetrics and Gynecology, GATA Haydarpasa Training Hospital Istanbul, Turkey.;Department of Obstetrics and Gynecology, Ankara Mevki Military Hospital Ankara, Turkey.;Department of Obstetrics and Gynecology, Beytepe Military Hospital Ankara, Turkey.;Department of Obstetrics and Gynecology, GATA Haydarpasa Training Hospital Istanbul, Turkey.;Department of Obstetrics and Gynecology, GATA Haydarpasa Training Hospital Istanbul, Turkey.;Department of Obstetrics and Gynecology, GATA Haydarpasa Training Hospital Istanbul, Turkey.",
"authors": "Babacan|Ali|A|;Akpak|Yasar Kemal|YK|;Kizilaslan|Cem|C|;Gun|Ismet|I|;Mungen|Ercument|E|;Atay|Vedat|V|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1940-5901",
"issue": "7(4)",
"journal": "International journal of clinical and experimental medicine",
"keywords": "Immature teratoma; menopause; recurrence",
"medline_ta": "Int J Clin Exp Med",
"mesh_terms": null,
"nlm_unique_id": "101471010",
"other_id": null,
"pages": "1172-4",
"pmc": null,
"pmid": "24955203",
"pubdate": "2014",
"publication_types": "D002363:Case Reports",
"references": "21764111;10366474;15863154;7814189;18378402;17466047;3425249;16122185;18575713;7959287;19258947;16894300;11181664;1260722;15581997",
"title": "A rare case of postmenopausal immature teratoma with a recurrent grave course.",
"title_normalized": "a rare case of postmenopausal immature teratoma with a recurrent grave course"
} | [
{
"companynumb": "TR-TEVA-571914ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
"drug... |
{
"abstract": "Diquat is an herbicide that can lead to rapid multiorgan system failure upon toxic ingestion. Although Diquat shares a similar chemical structure with paraquat, diquat is still readily available to the general population, and in contrast to paraquat, it is not regulated. We present a case of an intentional diquat poisoning which emphasizes the necessity of the early recognition due to atypical symptoms within the first 24 hours and certainly enhanced regulatory restrictions on this very toxic compound.\nA 60-year-old male with a history of severe depression presented to the emergency department after intentional ingestion of a commercial herbicide containing diquat dibromide 2.30%. The earliest manifestations of this acute diquat intoxication comprised a glomerulonephritis and proximal tubular dysfunction. Progressive multiorgan system failure then developed with a significant delay (24-38 hours) including acute renal, liver failure, and then respiratory failure with refractory hypoxemia. Despite maximal supportive care, the end organ failure was lethal. Discussion. Diquat intoxication should be suspected in patient presenting an acute glomerulonephritis with coma. Diquat should undergo the same regulatory restrictions as paraquat-containing compounds.",
"affiliations": "Division of Pulmonary and Critical Care Medicine, Department of Medicine, Pennsylvania State University, College of Medicine, Hershey, PA, USA.;Department of Emergency Medicine, Pennsylvania State University, College of Medicine, Hershey, PA, USA.;Department of Emergency Medicine, Pennsylvania State University, College of Medicine, Hershey, PA, USA.;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Pennsylvania State University, College of Medicine, Hershey, PA, USA.;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Pennsylvania State University, College of Medicine, Hershey, PA, USA.",
"authors": "Guck|Daniel|D|https://orcid.org/0000-0003-2688-445X;Hernandez|Reynaldo|R|;Moore|Steven|S|;Van de Louw|Andry|A|;Haouzi|Philippe|P|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/4723092",
"fulltext": "\n==== Front\nCase Rep Nephrol\nCase Rep Nephrol\nCRIN\nCase Reports in Nephrology\n2090-6641\n2090-665X\nHindawi\n\n10.1155/2021/4723092\nCase Report\nRapid Glomerulotubular Nephritis as an Initial Presentation of a Lethal Diquat Ingestion\nhttps://orcid.org/0000-0003-2688-445X\nGuck Daniel dguck@pennstatehealth.psu.edu\n1\nHernandez Reynaldo 2\nMoore Steven 2\nVan de Louw Andry 1\nHaouzi Philippe 1\n1Division of Pulmonary and Critical Care Medicine, Department of Medicine, Pennsylvania State University, College of Medicine, Hershey, PA, USA\n2Department of Emergency Medicine, Pennsylvania State University, College of Medicine, Hershey, PA, USA\nAcademic Editor: Yoshihide Fujigaki\n\n2021\n11 9 2021\n2021 472309215 4 2021\n1 9 2021\nCopyright © 2021 Daniel Guck 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.\nIntroduction\n\nDiquat is an herbicide that can lead to rapid multiorgan system failure upon toxic ingestion. Although Diquat shares a similar chemical structure with paraquat, diquat is still readily available to the general population, and in contrast to paraquat, it is not regulated. We present a case of an intentional diquat poisoning which emphasizes the necessity of the early recognition due to atypical symptoms within the first 24 hours and certainly enhanced regulatory restrictions on this very toxic compound.\n\nCase\n\nA 60-year-old male with a history of severe depression presented to the emergency department after intentional ingestion of a commercial herbicide containing diquat dibromide 2.30%. The earliest manifestations of this acute diquat intoxication comprised a glomerulonephritis and proximal tubular dysfunction. Progressive multiorgan system failure then developed with a significant delay (24–38 hours) including acute renal, liver failure, and then respiratory failure with refractory hypoxemia. Despite maximal supportive care, the end organ failure was lethal. Discussion. Diquat intoxication should be suspected in patient presenting an acute glomerulonephritis with coma. Diquat should undergo the same regulatory restrictions as paraquat-containing compounds.\n==== Body\npmc1. Introduction\n\nDiquat (1, 1′-ethylene-2, 2′-bipyridylium) is an herbicide used commercially to treat terrestrial and aquatic vegetation [1]. The toxidrome of diquat intoxication is usually considered to be very similar to that of paraquat, since both agents share a similar chemical structure. However, their mechanisms of toxicity remain poorly understood but seem to involve a rapid oxidative stress and superoxide radical production [2]. The resultant clinical toxic manifestations range from mild local irritative effects to multiorgan system failure and death, in keeping with the dose ingested [2]. We present a case of an intentional diquat ingestion leading to early neurological and renal toxicity which developed into a delayed fatal multiorgan failure. This emphasizes important recognizing the timeline of the symptoms of an acute diquat intoxication and the necessity to apply early aggressive interventions to reduce gastrointestinal absorption. Last, the regulatory restrictions currently in place for paraquat should be applied to diquat.\n\n2. Case Presentation\n\nA 60-year-old male with a history of severe depression presented to the emergency department two hours after an intentional ingestion of ∼500 milliliters of a commercial herbicide containing diquat dibromide 2.30%. On initial examination, the patient did not show any hypoxemia, circulatory, or renal failure, but had depressed mental status. Within thirty minutes, a rapid decline in mental status prompted intubation for airway protection. Direct laryngoscopy during the intubation revealed mucus membrane erosion in the posterior pharynx. The orogastric tube was placed after intubation, and 400 ml of green liquid was suctioned from the patient's stomach. Activated charcoal was not administered per recommendation of our poison control center due to the delayed arrival of the patient to the emergency department after ingestion. Blood diquat levels determined within 4 hours following the ingestion reached 9.9 µg/ml (a concentration typically associated with a lethal outcome [3]). After transfer to the medical intensive care unit, the patient was started on a combination of N-acetylcysteine, ascorbic acid, vitamin E, and dexamethasone. Within twenty-four hours following the ingestion, the patient presented a nephrotic range proteinuria (urine protein: creatinine >32 g/day) along with marker of proximal tubular dysfunction including glycosuria, phosphaturia, and increased bicarbonaturia. An acute kidney injury later developed (GFR 17 mL/min/1.73 m2) with worsening anion gap metabolic acidosis requiring continuous renal replacement therapy as illustrated in Figure 1. At the same time, a rapid elevation in transaminases and signs of hepatic failure developed (INR 1.4). The respiratory status deteriorated 36 hours only after ingestion with a refractory hypoxemia and imaging of the chest compatible with ARDS. While transthoracic echocardiogram performed and the circulatory status remain within the normal range at 24 hours, an irreversible shock with hyperlactacidemia requiring vasopressor support developed around 36 hours. Despite maximal medical therapy, multiorgan system failure was fatal.\n\n3. Discussion\n\nThere is limited understanding of the mechanisms of diquat toxicity and no clear rationale for an effective strategy of treatment. Diquat ingestion, in contrast to paraquat, appears to produce very early adverse neurological syndromes (depressed mental status) due to either direct or secondary neurologic injury after ingestion [4]. As diquat is renally excreted, tubular damage results in glomerulonephritis with proximal tubular necrosis developing within 24 hours and resulting in glucosuria and proteinuria, often without diuresis [5]. This is often accompanied by liver injury [6]. Only much later, acute hypoxic respiratory failure and refractory shock can develop. This sequence differs from that produced by paraquat which produces an early pulmonary toxicity and delayed neurological symptoms. Agents counteracting the oxidative stress have been proposed for treating paraquat intoxication [7], but we have currently no standard of care for diquat poisoning. The primary treatment goal is to prevent gastrointestinal absorption either by gastric suctioning and administration of activated charcoal or Fullers earth [8]. More research on the mechanisms of toxicity and treatments of poisoning by this family on compounds is certainly warranted. Finally, it is unclear why diquat is still a readily available herbicide, while paraquat usage is tightly regulated, as both chemicals, despite some differences, are extremely toxic.\n\nData Availability\n\nThe data used to support the findings of this study are from the electronic medical record, which is unavailable for public viewing.\n\nConflicts of Interest\n\nThe authors declare that there are no conflicts of interest.\n\nFigure 1 Schematic presentation of the clinical course presented by the patient from admission to the fatal outcome. Trends of the most relevant blood tests, the inspired fraction of O2 required to maintained SaO2 > 90%, and the level of vasopressor (norepinephrine) support after diquat ingestion are displayed. ALT, alanine aminotransferase; HCO3−, bicarbonate; MV, mechanical ventilation.\n==== Refs\n1 Magalhães N. Carvalho F. Dinis-Oliveira R. J. Human and experimental toxicology of diquat poisoning: toxicokinetics, mechanisms of toxicity, clinical features, and treatment Human and Experimental Toxicology 2018 37 1131 1160 10.1177/0960327118765330 2-s2.0-85044614469 29569487\n2 Jones G. M. Vale J. A. Mechanisms of toxicity, clinical features, and management of diquat poisoning: a review Journal of Toxicology—Clinical Toxicology 2000 38 2 123 128 10.1081/clt-100100926 2-s2.0-0034001572 10778908\n3 Ameno K. Fuke C. Shirakawa Y. Different distribution of paraquat and diquat in human poisoning cases after ingestion of a combined herbicide Archives of Toxicology 1994 68 2 134 137 10.1007/s002040050046 2-s2.0-0028044975 8179483\n4 Xing J. Chu Z. Han D. Lethal diquat poisoning manifesting as central pontine myelinolysis and acute kidney injury: a case report and literature review Journal of International Medical Research 2020 48 7 10.1177/0300060520943824\n5 Lock E. A. Ishmael J. The acute toxic effects of paraquat and diquat on the rat kidney Toxicology and Applied Pharmacology 1979 50 1 67 76 10.1016/0041-008x(79)90493-9 2-s2.0-0018648833 158856\n6 Hantson P. Wallemacq P. Mahieu P. A case of fatal diquat poisoning: toxicokinetic data and autopsy findings Journal of Toxicology—Clinical Toxicology 2000 38 2 149 152 10.1081/clt-100100930 2-s2.0-0033996552 10778912\n7 Suntres Z. E. Role of antioxidants in paraquat toxicity Toxicology 2002 180 1 65 77 10.1016/s0300-483x(02)00382-7 2-s2.0-0037201949 12324200\n8 Reigart J. Roberts J. Reigart J. Robert J. Recognition and Management of Pesticide Poisonings 2013 6th Washington, DC, USA US Environmental Protection Agency\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-665X",
"issue": "2021()",
"journal": "Case reports in nephrology",
"keywords": null,
"medline_ta": "Case Rep Nephrol",
"mesh_terms": null,
"nlm_unique_id": "101598418",
"other_id": null,
"pages": "4723092",
"pmc": null,
"pmid": "34552801",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "8179483;32734801;10778912;12324200;29569487;10778908;158856",
"title": "Rapid Glomerulotubular Nephritis as an Initial Presentation of a Lethal Diquat Ingestion.",
"title_normalized": "rapid glomerulotubular nephritis as an initial presentation of a lethal diquat ingestion"
} | [
{
"companynumb": "US-PFIZER INC-202101539967",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETYLCYSTEINE"
},
"drugadditional": "3",
... |
{
"abstract": "Accelerated idioventricular rhythm is defined as a ventricular rhythm of 60-100 beats per minute or a ventricular tachycardia that does nor exceed 120 beats per minutes. Although, it rarely converts to a fatal arrhythmia like ventricular fibrillation, it needs to be differentiated from AIVR, which is from another origin. AIVR may occur due to ischemic heart disease (ST elevated myocardial infarction), cardiomyopathy, rheumatic fever and digitalis intoxication. We report here on a case of AIVR that was related to desflurane administration.",
"affiliations": "Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. hsyang@amc.seoul.kr.;Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. hsyang@amc.seoul.kr.;Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. hsyang@amc.seoul.kr.;Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. hsyang@amc.seoul.kr.",
"authors": "Bang|Jiyoun|J|;Song|Jun Gol|JG|;Park|Young Soo|YS|;Yang|Hong Seuk|HS|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.4097/kjae.2009.56.5.571",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2005-6419",
"issue": "56(5)",
"journal": "Korean journal of anesthesiology",
"keywords": "Accelerated idioventricular rhythm; Arrhythmia; Desflurane; Sevoflurane",
"medline_ta": "Korean J Anesthesiol",
"mesh_terms": null,
"nlm_unique_id": "101502451",
"other_id": null,
"pages": "571-573",
"pmc": null,
"pmid": "30625790",
"pubdate": "2009-05",
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"abstract": "The hypercoagulability state induced by COVID-19 has been well established and various forms of subsequent thromboembolic events have been reported throughout literature including multiple cases of intracardiac thrombi, four of which in our center alone, this case being the fifth.\nWe report the case of a 38-year-old male with no prior cardiovascular history who -subsequently to a COVID-19 infection-developped a right atrial thrombosis associated to a pulmonary embolism, and in whom cardiography revealed an interatrial communication. Management relied upon curative doses of low molecular weight heparin (LMWH) with favourable outcome.\nIn our discussion, we lay out the various physiopathological mechanisms incriminated throughout literature in the genesis of a hypercoagulability state distinctive of COVID-19, before highlighting the incidence of an interatrial communication (whether a Potent Foramen Ovale or Atrial Septal Defect) discovered in patients with COVID-19, and the potential paradoxical embolization risks they imply as well as reported cases. A mention of hemostatic parameters monitored was also warranted. Finally we discuss the guidelines in terms of prophylactic and therapeutic anticoagulation in hospitalized patients before discussing cardiac thrombosis's therapeutic options.\nOur case highlights various key points which could change the prognosis of COVID-19 patients, whether related to the underdiagnosis of interatrial abnormalities or with regards to the diagnosis to thromboembolic events, but also the indisputable place of anticoagulation in COVID-19 management.",
"affiliations": "Anesthesia and Resuscitation Department, MOHAMMED VI University Hospital Center, Oujda, Morocco.;Anesthesia and Resuscitation Department, MOHAMMED VI University Hospital Center, Oujda, Morocco.;Cardiology Department, Mohammed VI University Hospital, Oujda, Morocco.;Cardiology Department, Mohammed VI University Hospital, Oujda, Morocco.;Anesthesia and Resuscitation Department, MOHAMMED VI University Hospital Center, Oujda, Morocco.;Cardiology Department, Mohammed VI University Hospital, Oujda, Morocco.;Cardiology Department, Mohammed VI University Hospital, Oujda, Morocco.;Anesthesia and Resuscitation Department, MOHAMMED VI University Hospital Center, Oujda, Morocco.",
"authors": "Berrichi|Samia|S|;Bouayed|Zakaria|Z|;Benbouchta|Karima|K|;Kossir|Amine|A|;Bkiyar|Houssam|H|;Ismaili|Nabila|N|;Ouafi|Noha El|NE|;Housni|Brahim|B|",
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"doi": "10.1016/j.amsu.2021.102967",
"fulltext": "\n==== Front\nAnn Med Surg (Lond)\nAnn Med Surg (Lond)\nAnnals of Medicine and Surgery\n2049-0801\nElsevier\n\nS2049-0801(21)00917-1\n10.1016/j.amsu.2021.102967\n102967\nCase Report\nIncidental diagnosis of a large cardiac thrombus swinging through an interatrial communication in a COVID-19 patient: Case report and literature review\nBerrichi Samia Sammia9@gmail.com\na∗\nBouayed Zakaria medzakaria.95@gmail.com\na∗∗\nBenbouchta Karima karimabenbouchta397@gmail.com\nb\nKossir Amine aminekossir@gmail.com\nb\nBkiyar Houssam 7b.houssam@gmail.com\na\nIsmaili Nabila nibilette@yahoo.fr\nbd\nOuafi Noha El n.elouafi@ump.ac.ma\nbd\nHousni Brahim brahim.housni@ump.ac.ma\nac\na Anesthesia and Resuscitation Department, MOHAMMED VI University Hospital Center, Oujda, Morocco\nb Cardiology Department, Mohammed VI University Hospital, Oujda, Morocco\nc Simulation Center, Faculty of Medicine and Pharmacy, Oujda, Morocco\nd Laboratory of Epidemiology, Clinical Research, and Public Health, Faculty of Medicine and Pharmacy, Oujda, Morocco\n∗ Corresponding author. Sammia9@gmail.com\n∗∗ Corresponding author. medzakaria.95@gmail.com\n19 10 2021\n11 2021\n19 10 2021\n71 1029677 9 2021\n14 10 2021\n15 10 2021\n© 2021 Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.\n2021\n\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nIntroduction\n\nThe hypercoagulability state induced by COVID-19 has been well established and various forms of subsequent thromboembolic events have been reported throughout literature including multiple cases of intracardiac thrombi, four of which in our center alone, this case being the fifth.\n\nCase report\n\nWe report the case of a 38-year-old male with no prior cardiovascular history who -subsequently to a COVID-19 infection-developped a right atrial thrombosis associated to a pulmonary embolism, and in whom cardiography revealed an interatrial communication. Management relied upon curative doses of low molecular weight heparin (LMWH) with favourable outcome.\n\nDiscussion\n\nIn our discussion, we lay out the various physiopathological mechanisms incriminated throughout literature in the genesis of a hypercoagulability state distinctive of COVID-19, before highlighting the incidence of an interatrial communication (whether a Potent Foramen Ovale or Atrial Septal Defect) discovered in patients with COVID-19, and the potential paradoxical embolization risks they imply as well as reported cases. A mention of hemostatic parameters monitored was also warranted. Finally we discuss the guidelines in terms of prophylactic and therapeutic anticoagulation in hospitalized patients before discussing cardiac thrombosis's therapeutic options.\n\nConclusion\n\nOur case highlights various key points which could change the prognosis of COVID-19 patients, whether related to the underdiagnosis of interatrial abnormalities or with regards to the diagnosis to thromboembolic events, but also the indisputable place of anticoagulation in COVID-19 management.\n\nHighlights\n\n• Thromboembolic events complicating COVID-19 have been well described and are attributed to a hypercoagulability state distinctive of COVID-19.\n\n• A pre-existing Potent Foramen Ovale (PFO) or Atrial septal Defect (ASD) in COVID-19 patients is unknown as only a handful of studies covered the subject.\n\n• The association of a cardiac thrombosis with a pulmonary embolism and interatrial communication exposes patients to risks of paradoxical embolization and subsequent arterial thrombotic events.\n\n• Prophylactic and curatrive anticoagulation is unrefutably a key pillar in the management of COVID-19.\n\nKeywords\n\nCOVID-19\nCardiac thrombosis\nInteratrial shunt\n==== Body\npmc1 Introduction\n\nAfter a year and half since the first cluster of COVID-19 cases have been reported in Wuhan, and now with more than 177 million cases worldwide confirmed to this day [1] and hundreds of cases published, it has become clear that COVID-19 is a complex multisystemic disease involving many organs and body systems [2].\n\nThe thromboembolism events induced by COVID-19 and their consequences in terms of morbidiy and mortality have been well documented [3], and are even greater when occurring in patients with an interatrial communication on account of the paradoxical embolization risks they entail.\n\nProphylactic anticoagulation has been recommended in all hospitalized patients admitted for management of COVID-19 specifically to lower the chances of thromboenbolic events and reduce their mortality [4].\n\nWe report the case of a 38-year-old male with a COVID-19 infection and recent rapid worsening of an acute respiratory distress diagnosed with a pulmionay embolism and in whom cardiography revealed an interatrial communication, managed with curative doses of low molecular weight heparin (LMWH) with favourable outcome.\n\nThis paper has been reported in line with the SCARE 2020 criteria [5].\n\n2 Case report\n\nA 38-year-old man with a history of schizophrenia under Haloperidol, Trihexyphenidyl, and Levomepromazine was admitted to the ER for the management of an acute respiratory distress, history of the present illness revealed that the patient first developed 2 weeks prior to his admission a flu-like syndrome made of fever, shivering, dry cough, myalgia, and shortness of breath on exertion for which the patient self-medicated without any improvement.\n\nFollowing the rapid worsening of his dyspnea a day before, the patient sought the ER. On initial clinical assessment he was conscious and well oriented in time and space with a Glasgow Scale of 15/15, afebrile (36.8 °C), tachycardic at a 140 beat per minute, normotensive at 125/75 mmHg, with an O2 saturation of 84% on ambient air and 91% under nasal oxygen therapy (3L/min), pulmonary auscultation revealed right basal crackles.\n\nAn electrocardiogram (EKG) revealed a sinus rhythm with a high frequency of 140 beat per minute with an incomplete Right Bundle Branch Block (RBBB) and T wave inversion in V1 to V3 (Fig. 1).Fig. 1 EKG showing a sinus rhythm with HB of 140bpm, an incomplete RBBB, and T wave inversion in V1 to V3.\n\nFig. 1\n\nLaboratory tests revealed a slightly elevated WBC (White Blood Count) of 11150/μL, a CRP (C Reactive Protein) level of 193,29 mg/L, with a hemoglobin at 11,1 g/dl, serum ferritin level of 1017,64 ng/mL, and LDH levels of 641 IU/L, HS Troponin levels at 115,2 ng/L, and an IL-6 level of 61 pg/mL, a platelet count of 239,000, D-dimers levels at 3293 ng/mL, normal electrolyte, liver and kidney function tests. A SARS-Cov-2 RT-PCR of a nasal swap sample came back positive.\n\nInitial arterial blood gas revealed: 7,54 pH, 116 mmHg PaO2, 23 mmHg PaCO2, 20mEq/l HCO3-, 2,29mmol/l lactatemia. A CXR showed ground-glass opacities (GGO) in the right lung (Fig. 2), Chest CT showed bilateral multifocal subpleural and peribronchial GGO (Glass Ground Opacities) with septal thickening and consolidation mainly in the periphery (Fig. 3), contrast-enhanced sequences revealed a filling defect in the left lobar pulmonary artery suggestive for pulmonary embolism (Fig. 4).Fig. 2 CXR showing ground glass opacities in the mid and lower zones of the right lung.\n\nFig. 2\n\nFig. 3 Axial (a) and Coronal (b) lung windows showing bilateral multifocal subpleural and peribronchial GGO with septal thickening and consolidation mainly in the periphery.\n\nFig. 3\n\nFig. 4 Axial sequence of a contrast-enhanced CT in mediastinal window showing a filling defect (arrow) in the left lobar pulmonary artery suggestive of pulmonary embolism.\n\nFig. 4\n\nConsidering the rapid worsening of the dyspnea, the EKG abnormalities and the pulmonary embolism we performed a transthoracic echocardiography (TTE) unveiling a large serpiginous floating thrombus (90 × 15mm) in the right and left atrium, straddling across an interatrial communication, and extending across the tricuspid and mitral valves, into the respective ventricles, the right heart cavities were dilated with paradoxical motion of the ventricular septum as well as a severe right ventricular systolic dysfunction with classic McConnell's sign and moderate pulmonary hypertension (pulmonary artery systolic pressure was estimated as 50 mmHg) (Figs. 5 and 6). Transesophageal echocardiography (TEE) was not performed given the patient's respiratory distress.Fig. 5 TTE para-sternal short axis view (a) and apical four-chamber view (b) showing a large thrombus inside the right cavities protruding into the left atrium.\n\nFig. 5\n\nFor the COVID-19 pneumonia the patient was treated with ceftriaxone 2g/day and levofloxacin 500mg/12h during ten days, dexamethasone 6mg/d, vitamins C 2g/12h and D 25000IU/week, zinc 45mg/day, and aspirin 160mg/day for the entire duration of hospitalization. As for the intra-cardiac thrombus and pulmonary embolism he received an 8000 IU subcutaneous injection of sodic enoxaparin every 12h also for the duration of his hospitalization.\n\nA follow-up TTE was performed after 6 days revealing the total disappearance of the thrombus. Even though the patient exhibited no acute symptoms suggestive of a thromboembolic event a whole-body contrast-enhanced CT was performed as a precautionary measure and came back normal except for the pre-existing pulmonary embolism.\n\nFollow-up laboratory tests showed a decrease of the inflammatory markers as well as D-dimers (from 3293 to 748 ng/mL).\n\nTher patient was gradually weaned off oxygen and discharged 14 days after admission, upon discharge we prescribed Apixaban 5mg/12h in concertation with our center's cardiology department which scheduled follow-up appointment for treatment adjustment and management of the interatrial communication.\n\nThe patient was seen 6 weeks later, a TTE was performed revealing a complete resolution of the pulmonary hypertension with normalization of the right heart cavities, completed by a TEE which showed no septal aneurysm, ASD, nor a PFO completed by a bubble test that was negative (Fig. 6).Fig. 6 Six weeks Follow-up TTE apical four-chamber view (a) showing a normalization of the right heart cavities completed by a TEE (b) showing no septal aneurysm, ASD, nor a PFO. No right-to-left shunt on doppler flow (c) as well as a negative bubble test (d).\n\nFig. 6\n\nIn retrospect, we retained the diagnosis of a PFO re-opened by the right-heart high pressure secondary to the pulmonary embolism which progressed towards a functional closure of the PFO after normalization of the right atrial pressure.\n\n3 Discussion\n\nMultiple cases of thromboembolic events related to COVID-19 have been reported, varying in terms of localisation (pulmonary, cardiac, peripheral arterial and/or venous), extension, gravity, and clinical features.\n\nThe high frequency of reported COVID-19 related thromboembolic events [6,7] raises the question of a unique physiopathology [8,9]. Various intrigued pathological phenomena were incriminated [10]: from the cytokin storm [11], passing by the complement cascade activation [12], the macrophage activation [13] and antiphospholipid antibody [14] syndromes, to the Renin angiotensin system overactivation [15]. All contributing to the genesis of a hypercoaguability state.\n\nWe report the case of a 38-year-old male with no cardiovacular risk factors other than his gender and no cardiovascular history who developped a COVID-19 pneumonia complicated shortly after with a large right intraatrial thrombus associated to a left lobar pulmonary artery, subsequently the patient's dyspnea worsened rapidly. The contrast-enhanced CT revealed a pulmonary embolism while the TTE not only unveiled a large thrombus inside the right atrium but also an interatrial communication which exposed the patient to the risk of a paradoxical embolization, subsequently we anticoagulated with curative doses of low-molecular-weight heparin (LMWH). The non-visualisation of the thrombus on the follow-up TTE raised concerns of a paradoxical embolic event despite the absence of any clinical expression prompting us to perform a whole-body contrast-enhanced CT which came back normal.\n\nThe incidental discovery of an atrial septal abnormality should've pushed for a more comprehensive assessement [16] through multiple imaging technics such as a cardiography with agitated saline microbubbles test [17] or an electrocardiography-gated CT using the saline-chaser contrast injection technique [18] allowing to identify an interatrial shunt and to differentiate a patent foramen ovale (PFO) from an atrial septal defect (ASD).\n\nIn an Italian multi-center observational nationwide survey, Sabatino et al. [19] reported a 9% incidence of ASD in patients with a confirmed or suspected COVID-19 infection. Simultaneously, cases of PFO revealed by COVID-19 were reported [[20], [21], [22]]. It is important to keep in mind the high prevalence of PFO in the general population [23] and the plausibility of an under-diagnosis in patients with COVID-19 [24]. As for paradoxial embolisms in patients with COVID-19, to our knowledge only 3 cases were reported in the litterature [[25], [26], [27]].\n\nIn a narrative review, Mondal et al. [28] reported that venous thromboembolism and pulmonary embolism are respectively the most frequent forms of thromboembolic events related to COVID-19. As for intracardiac thrombosis, our case is the fifth reported within our center [29], among a total of 630 COVID-19 patients admitted and managed since the beginning of the pandemic, joining only few cases reported in the litterature [[30], [31], [32], [33], [34], [35], [36], [37]], alternatively Rastogi et al. [38] reported a total of 17 cardiac thrombi among a 1010 COVID-19 patients hospitalized within a one year timeline.\n\nVarious parameters were monitored in order to predict the severity of COVID-19 [39,40], impairement of hemostatic markers (especially elevated D‐dimer and FDP) was widely observed in COVID-19 patients [41], and even linked to a higher incidence of thromboembolic events [42] as well as an unfavourable prognosis [43]. In our case, a gradual decline of D-dimers levels (which were monitored daily since admission) was observed.\n\nThe International Society on Thrombosis and Hemostasis (ISTH) recommends the use of prophylactic doses of low molecular weight heparin (LMWH) in all patients (including non-critically ill) hospitalized for COVID-19 in the absence of any contraindications [4] which has been implimented in our center since the very beginning of the pandemic. Alongside its antucoagulant properties, Poterucha et al. [44] layed out the various effects of hearin on inflammation pathaways, thus providing evidence of its anti-inflammatory properties.\n\nThe benefice of a curative anticoagulation in patients meeting certain criteria such as the sepsis-induced coagulopathy (SIC) score [45] has been proven, thus making the decision to initiate it much easier. Alternatively The American Society of Hematology (ASH) suggests using curative anticoagulation in patients who develop sudden clinical and laboratory findings consistent with pulmonary embolism, patients with physical findings consistent with thrombosis, and patients with respiratory failure, especially when D-dimer and/or fibrinogen levels are very high [46,47].\n\nAs for cardiac thrombosis, treatment options include anticoagulation, thrombolysis, and thrombectomy (surgical or percutaneous). Barrios et al. [48] concluded that in patients with right heart thrombosis associated with pulmonary embolism, there is no significant difference between reperfusion therapy and anticoagulant therapy in terms of mortality and bleeding, in fact, a higher risk of recurrence for reperfusion therapy was reported in comparison with anticoagulation. In our case, the patient upon discussing treatment options opted for curative anticoagulation which led to the lysis of the thrombus.\n\nRegarding limitations, as indicated above, a more comprehensive assessement using targeted imaging technics prevented a more precise diagnosis early-on.\n\nNonetheless, Follow-up led to a retrospective diagnosis of a functional closure of a PFO due to the resolution of the pulmonary embolism and subsequent normalization of right atrial pressure confirmed by cardiography.\n\n4 Conclusion\n\nCOVID-19-related thromboembolic events are associated with a higher risk of mortality [3], and are attributed to specific coagulopathy distinctive of COVID-19 [9].\n\nOur case's uniqueness resides in the unfortunate association of a right atrial embolism and an interatrial communication in a young patient with no cardiovadcular risk factors or history which underlines the likelihood of a significant underdiagnosis of atrial septal abonamalities especially given the high prevalence of PFO in the general population, and might account for a higher mortality in COVID-19 patients.\n\nIt also highlights the importance of contrast-enhanced imaging and cardiac evaluation in COVID-19 patients which may results in diagnosing more thromboembolic events and subsequent adequate management.\n\nThis paper has been reported in line with the SCARE 2020 criteria [5].\n\nEthical approval\n\nThis is a case report, therefore Ethics committee/IRB approval is not required.\n\nSources of funding\n\nThis work hasn't received any funding.\n\nAuthor contributions\n\nSAMIA BERRICHI: Study conception, Data collection; data analysis; writing & editing.\n\nZAKARIA BOUAYED: Data collection; data analysis; writing & editing.\n\nKARIMA BENBOUCHTA: Cardiac imaging and analysis.\n\nAMINE KOSSIR: Cardiac imaging and analysis.\n\nNABILA ISMAILI: Supervision and review data validation.\n\nNOHA EL OUAFI: Supervision and review data validation.\n\nHOUSSAM BKIYAR: Supervision and review data validation.\n\nHOUSNI BRAHIM: Supervision and review data validation.\n\nRegistration of research studies\n\n1. Name of the registry:\n\n2. Unique Identifying number or registration ID:\n\n3. Hyperlink to your specific registration (must be publicly accessible and will be checked):\n\nGuarantor\n\nSAMIA BERRICHI.\n\nZAKARIA BOUAYED.\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 Editorin-Chief of this journal on request.\n\nConflicts of interest\n\nWe have no conflicts of interest.\n\nAppendix A Supplementary data\n\nThe following is the Supplementary data to this article:Multimedia component 1\n\nFig. 6: TTE apical four-chamber view video showing the large thrombus inside the right cavities protruding into the left atrium.\n\nMultimedia component 1\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.amsu.2021.102967.\n==== Refs\nReferences\n\n1 WHO coronavirus (COVID-19) dashboard https://covid19.who.int/\n2 Roberts C.M. Levi M. McKee M. Schilling R. Lim W.S. Grocott M.P.W. COVID-19: a complex multisystem disorder Br. J. Anaesth. 125 3 2020 238 242 10.1016/j.bja.2020.06.013 32731958\n3 Malas M.B. Naazie I.N. Elsayed N. Mathlouthi A. Marmor R. Clary B. Thromboembolism risk of COVID-19 is high and associated with a higher risk of mortality: a systematic review and meta-analysis EClinicalMedicine 29–30 2020 100639 10.1016/j.eclinm.2020.100639\n4 Thachil J. Tang N. Gando S. ISTH interim guidance on recognition and management of coagulopathy in COVID-19 J. Thromb. Haemostasis 18 5 2020 1023 1026 10.1111/jth.14810 32338827\n5 Agha R.A. Franchi T. Sohrabi C. Mathew G. Kerwan A. The SCARE 2020 guideline: updating consensus surgical CAse REport (SCARE) guidelines Int. J. Surg. 84 2020 226 230 10.1016/j.ijsu.2020.10.034 33181358\n6 Klok F.A. Kruip M.J.H.A. van der Meer N.J.M. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis Thromb. Res. 191 2020 148 150 10.1016/j.thromres.2020.04.041 32381264\n7 Wichmann D. Sperhake J.-P. Lütgehetmann M. Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort Study Ann. Intern. Med. 173 4 2020 268 277 10.7326/M20-2003 32374815\n8 Connors J.M. Levy J.H. COVID-19 and its implications for thrombosis and anticoagulation Blood 135 23 2020 2033 2040 10.1182/blood.2020006000 32339221\n9 Marchandot B. Sattler L. Jesel L. COVID-19 related coagulopathy: a distinct entity? J. Clin. Med. 9 6 2020 1651 10.3390/jcm9061651\n10 Hanff T.C. Mohareb A.M. Giri J. Cohen J.B. Chirinos J.A. Thrombosis in COVID-19 Am. J. Hematol. 95 12 2020 1578 1589 10.1002/ajh.25982 32857878\n11 Kaur S. Bansal R. Kollimuttathuillam S. The looming storm: blood and cytokines in COVID-19 Blood Rev. 46 2021 100743 10.1016/j.blre.2020.100743 32829962\n12 Lupu F. Keshari R.S. Lambris J.D. Coggeshall K.M. Crosstalk between the coagulation and complement systems in sepsis Thromb. Res. 133 2014 S28 S31 10.1016/j.thromres.2014.03.014 Suppl(0 1 24759136\n13 Ombrello M.J. Schulert G.S. COVID-19 and cytokine storm syndrome: are there lessons from macrophage activation syndrome? Transl. Res. 232 2021 1 12 10.1016/j.trsl.2021.03.002 33684592\n14 Tung M.L. Tan B. Cherian R. Chandra B. Anti-phospholipid syndrome and COVID-19 thrombosis: connecting the dots Rheumatol Adv Pract 5 1 2021 10.1093/rap/rkaa081\n15 Wiese O.J. Allwood B.W. Zemlin A.E. COVID-19 and the renin-angiotensin system (RAS): a spark that sets the forest alight? Med. Hypotheses 144 2020 110231 10.1016/j.mehy.2020.110231 33254538\n16 Silvestry F.E. Cohen M.S. Armsby L.B. Guidelines for the echocardiographic assessment of atrial septal defect and patent foramen ovale: from the American society of echocardiography and society for cardiac angiography and interventions J. Am. Soc. Echocardiogr. 28 8 2015 910 958 10.1016/j.echo.2015.05.015 26239900\n17 Attaran R.R. Ata I. Kudithipudi V. Foster L. Sorrell V.L. Protocol for optimal detection and exclusion of a patent foramen ovale using transthoracic echocardiography with agitated saline microbubbles Echocardiography 23 7 2006 616 622 10.1111/j.1540-8175.2006.00272.x 16911341\n18 Kosehan D. Akin K. Koktener A. Cakir B. Aktas A. Teksam M. Interatrial shunt: diagnosis of patent foramen ovale and atrial septal defect with 64-row coronary computed tomography angiography Jpn. J. Radiol. 29 8 2011 576 10.1007/s11604-011-0602-x 21928000\n19 Sabatino J. Ferrero P. Chessa M. COVID-19 and congenital heart disease: results from a nationwide survey J. Clin. Med. 9 6 2020 1774 10.3390/jcm9061774\n20 Vanhomwegen C. Taton O. Selvais N. Vanhove O. Leduc D. Patent foramen ovale revealed by COVID-19 pneumonia BMC Pulm. Med. 21 1 2021 126 10.1186/s12890-021-01494-7 33874930\n21 Ashraf M. Sajed S. Acute stroke in a young patient with coronavirus disease 2019 in the presence of patent foramen ovale Cureus 12 9 2020 e10233 10.7759/cureus.10233\n22 Fujikura K. Fontes J.D. Taub C.C. Saddle pulmonary embolism and thrombus-in-transit straddling the patent foramen ovale 28 days after COVID symptom onset Echocardiography 37 8 2020 1296 1299 10.1111/echo.14796 32735050\n23 Koutroulou I. Tsivgoulis G. Tsalikakis D. Karacostas D. Grigoriadis N. Karapanayiotides T. Epidemiology of patent foramen ovale in general population and in stroke patients: a narrative review Front. Neurol. 11 2020 281 10.3389/fneur.2020.00281 32411074\n24 Rajendram R. Kharal G.A. Mahmood N. Kharal M. Systemic thromboemboli in patients with Covid-19 may result from paradoxical embolization Thromb. Res. 196 2020 206 208 10.1016/j.thromres.2020.08.045 32906012\n25 Pons-Pellicé L. Camio-Visauta E. Chocron-Da Prat I. Rodríguez-Palomares J.F. Rosés Noguer F. de Nadal M. Middle cerebral artery stroke due to paradoxical embolism in a patient with COVID-19 pneumonia Rev. Esp. Cardiol. 74 6 2021 558 559 10.1016/j.rec.2020.12.011\n26 Ballvé-Martín A. Boned S. Rubiera M. [Thrombotic complication of severe COVID-19 pneumonia: stroke due to atypical paradoxical embolism] Rev. Neurol. 71 5 2020 186 190 10.33588/rn.7105.2020317 32729110\n27 Yu M.D. Desai N. Sanagala T. Darki A. Paradoxical embolism causing myocardial infarction in a COVID-19 patient presenting with pulmonary embolism Cureus 13 3 2021 e13975 10.7759/cureus.13975\n28 Mondal S. Quintili A.L. Karamchandani K. Bose S. Thromboembolic disease in COVID-19 patients: a brief narrative review J Intensive Care 8 1 2020 70 10.1186/s40560-020-00483-y 32939266\n29 El Aidouni G. Merbouh M. Aabdi M. Intra cardiac thrombus in critically ill patient with coronavirus disease 2019: case report Ann Med Surg 66 2021 102434 10.1016/j.amsu.2021.102434\n30 Torres R. Gul F. Azmaiparashvili Z. Patarroyo-Aponte G. Bi-atrial thrombosis in a patient with SARS-CoV-2 infection: a case report Eur Hear journal Case reports 4 6 2020 1 5 10.1093/ehjcr/ytaa367 33442622\n31 Kaki A. Singh H. Cohen G. Schreiber T. A case report of a large intracardiac thrombus in a COVID-19 patient managed with percutaneous thrombectomy and right ventricular mechanical circulatory support Eur Hear J - Case Reports. 4 6 2020 1 5 10.1093/ehjcr/ytaa308\n32 Hu D. Liu K. Li B. Hu Z. Large intracardiac thrombus in a COVID-19 patient treated with prolonged extracorporeal membrane oxygenation implantation Eur. Heart J. 41 32 2020 3104 3105 10.1093/eurheartj/ehaa524 32607534\n33 Ferguson K. Quail N. Kewin P. Blyth K.G. COVID-19 associated with extensive pulmonary arterial, intracardiac and peripheral arterial thrombosis BMJ Case Rep. 13 8 2020 e237460 10.1136/bcr-2020-237460\n34 Aghaei Moghadam E. Mahmoudi S. Safari Sharari A. Giant intracardiac thrombosis in an infant with leukaemia and prolonged COVID-19 viral RNA shedding: a case report Thromb. J. 19 1 2021 31 10.1186/s12959-021-00285-8 33980250\n35 Valle F.H. Mazzuti G. Santiago Santos A.B. Multiple intracardiac thrombi complicated by pulmonary embolism Rev Española Cardiol (English Ed. 68 4 2015 338 10.1016/j.rec.2014.04.022\n36 Calvi E. Bernardi N. Cimino G. Unusual intracardiac thrombosis in two patients with coronavirus disease 2019 (COVID-19): case series Eur Hear J - Case Reports 5 2 2021 10.1093/ehjcr/ytaa518\n37 Bigdelian H. Sedighi M. Sabri M.R. Right atrial thrombus in a COVID-19 child treated through cardiac surgery Front Cardiovasc Med 7 2020 579522 10.3389/fcvm.2020.579522 33263006\n38 Rastogi S. Azari B. Henry S. Predictors OF COVID-19 related intra-cardiac thrombus from admission laboratory values J. Am. Coll. Cardiol. 77 18 2021 3182 10.1016/S0735-1097(21)04537-X\n39 Shang W. Dong J. Ren Y. The value of clinical parameters in predicting the severity of COVID-19 J. Med. Virol. 92 10 2020 2188 2192 10.1002/jmv.26031 32436996\n40 Moutchia J. Pokharel P. Kerri A. Clinical laboratory parameters associated with severe or critical novel coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis PLoS One 15 10 2020 10.1371/journal.pone.0239802 e0239802-e0239802\n41 Han H. Yang L. Liu R. Prominent changes in blood coagulation of patients with SARS-CoV-2 infection Clin. Chem. Lab. Med. 58 7 2020 1116 1120 10.1515/cclm-2020-0188 32172226\n42 Eljilany I. Elzouki A.-N. D-dimer, fibrinogen, and IL-6 in COVID-19 patients with suspected venous thromboembolism: a narrative review Vasc. Health Risk Manag. 16 2020 455 462 10.2147/VHRM.S280962 33223833\n43 Tang N. Li D. Wang X. Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia J. Thromb. Haemostasis 18 4 2020 844 847 10.1111/jth.14768 32073213\n44 Poterucha T.J. Libby P. Goldhaber S.Z. More than an anticoagulant: do heparins have direct anti-inflammatory effects? Thromb. Haemostasis 117 3 2017 437 444 10.1160/TH16-08-0620 27975101\n45 Iba T. Nisio M Di Levy J.H. Kitamura N. Thachil J. New criteria for sepsis-induced coagulopathy (SIC) following the revised sepsis definition: a retrospective analysis of a nationwide survey BMJ Open 7 9 2017 10.1136/bmjopen-2017-017046 e017046-e017046\n46 Abou-Ismail M.Y. Diamond A. Kapoor S. Arafah Y. Nayak L. The hypercoagulable state in COVID-19: incidence, pathophysiology, and management Thromb. Res. 194 2020 101 115 10.1016/j.thromres.2020.06.029 32788101\n47 Cuker A. Tseng E.K. Nieuwlaat R. American Society of Hematology 2021 guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19 Blood Adv 5 3 2021 872 888 10.1182/bloodadvances.2020003763 33560401\n48 Barrios D. Chavant J. Jiménez D. Treatment of right heart thrombi associated with acute pulmonary embolism Am. J. Med. 130 5 2017 588 595 10.1016/j.amjmed.2016.11.027 28011316\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2049-0801",
"issue": "71()",
"journal": "Annals of medicine and surgery (2012)",
"keywords": "COVID-19; Cardiac thrombosis; Interatrial shunt",
"medline_ta": "Ann Med Surg (Lond)",
"mesh_terms": null,
"nlm_unique_id": "101616869",
"other_id": null,
"pages": "102967",
"pmc": null,
"pmid": "34691408",
"pubdate": "2021-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Incidental diagnosis of a large cardiac thrombus swinging through an interatrial communication in a COVID-19 patient: Case report and literature review.",
"title_normalized": "incidental diagnosis of a large cardiac thrombus swinging through an interatrial communication in a covid 19 patient case report and literature review"
} | [
{
"companynumb": "MA-LUPIN PHARMACEUTICALS INC.-2022-00112",
"fulfillexpeditecriteria": "2",
"occurcountry": "MA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
},
"drugadditiona... |
{
"abstract": "BACKGROUND\nFirst generation cephalosporins are commonly used as antibiotic prophylaxis prior to surgery. Patients labeled as penicillin-allergic are often precluded from receiving cephalosporins because of an allergic cross-reactivity. The aims of this study were to evaluate the clinical practice for surgical prophylaxis at Nationwide Children's Hospital and to determine the incidence of adverse effects and allergic reactions when using cephalosporins in patients labeled as penicillin-allergic.\n\n\nMETHODS\nA retrospective chart review was performed to identify patients who were allergic to penicillin, penicillin antibiotic family, who required surgical treatment for an existing medical condition, and received an antibiotic to prevent surgical site infection.\n\n\nRESULTS\nFive hundred thirteen penicillin-allergic patients were identified, encompassing 624 surgical cases. Cephalosporins were administered in 153 cases (24.5%) with cefazolin used 83% of the time. Only one documented case of nonanaphylactic reaction was reported. Clindamycin was the most common cephalosporin substitute (n=387), and the reported adverse reaction rate was 1.5%. No cases of anaphylaxis were documented.\n\n\nCONCLUSIONS\nOur data suggest that the administration of cephalosporins for surgical prophylaxis following induction of anesthesia in a patient with a known or reported penicillin-allergy appears appropriate and results in a lower adverse event rate that when clindamycin is administered.",
"affiliations": "Department of Anesthesiology and Pain Medicine, Nationwide Children's Hospital, Columbus, Columbus, OH, USA; Department of Anesthesiology, The Ohio State University, Columbus, OH, USA. Electronic address: ralph.beltran@nationwidechildrens.org.;Department of Anesthesiology and Pain Medicine, Nationwide Children's Hospital, Columbus, Columbus, OH, USA; Department of Anesthesiology, The Ohio State University, Columbus, OH, USA. Electronic address: hiromi.kako@nationwidechildrens.org.;Enterprise Data Warehouse, Nationwide Children's Hospital, Columbus, OH, USA. Electronic address: thomas.chovanec@nationwidechildrens.org.;Department of Anesthesiology and Pain Medicine, Nationwide Children's Hospital, Columbus, Columbus, OH, USA; Department of Anesthesiology, The Ohio State University, Columbus, OH, USA. Electronic address: archana.ramesh@nationwidechildrens.org.;Department of Anesthesiology and Pain Medicine, Nationwide Children's Hospital, Columbus, Columbus, OH, USA; Department of Anesthesia, University of Toronto, Toronto, Canada. Electronic address: bruno@brainstorm-anesthesia.com.;Department of Anesthesiology and Pain Medicine, Nationwide Children's Hospital, Columbus, Columbus, OH, USA; Department of Anesthesiology, The Ohio State University, Columbus, OH, USA. Electronic address: joseph.tobias@nationwidechildrens.org.",
"authors": "Beltran|Ralph J|RJ|;Kako|Hiromi|H|;Chovanec|Thomas|T|;Ramesh|Archana|A|;Bissonnette|Bruno|B|;Tobias|Joseph D|JD|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D010406:Penicillins",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3468",
"issue": "50(5)",
"journal": "Journal of pediatric surgery",
"keywords": "Cephalosporin; Cross-reactivity; Pediatrics; Penicillin allergy; Surgical prophylaxis",
"medline_ta": "J Pediatr Surg",
"mesh_terms": "D000293:Adolescent; D000900:Anti-Bacterial Agents; D019072:Antibiotic Prophylaxis; D002511:Cephalosporins; D002648:Child; D002675:Child, Preschool; D004342:Drug Hypersensitivity; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006776:Hospitals, Pediatric; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D010406:Penicillins; D011300:Preoperative Care; D012189:Retrospective Studies; D062606:Tertiary Care Centers; D014481:United States",
"nlm_unique_id": "0052631",
"other_id": null,
"pages": "856-9",
"pmc": null,
"pmid": "25783308",
"pubdate": "2015-05",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Penicillin allergy and surgical prophylaxis: Cephalosporin cross-reactivity risk in a pediatric tertiary care center.",
"title_normalized": "penicillin allergy and surgical prophylaxis cephalosporin cross reactivity risk in a pediatric tertiary care center"
} | [
{
"companynumb": "US-APOTEX-2015AP015183",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "Studies in the renal transplant population have suggested calcium-channel blockers (CCBs) may protect against calcineurin inhibitor (CNI)-induced nephrotoxicity. However, this has not been evaluated in the hematopoietic stem cell transplant (HSCT) population. This retrospective study reviews data from 350 consecutive patients who underwent allogeneic HSCT to determine whether amlodipine improved renal outcomes. Subject data included up to one year from CNI initiation. Patients in the amlodipine group (n = 130) received an average of 143 days treatment with amlodipine and experienced a smaller decrease in creatinine clearance (CrCl) through day 180. At day 30, change in CrCl was -17.4 mL/min in the amlodipine cohort and -33.8 mL/min in the control (P < 0.001). At day 180, change in CrCl was -40.9 and -50.6 mL/min, respectively (P = 0.005). Incidence of hospitalization with acute kidney injury (AKI) was significantly lower in patients receiving amlodipine, 7.7% (10/132) vs 16.4% (36/220) (hazard ratio [HR] 0.44; 95% confidence interval [CI] 0.22-0.89). Median blood pressure in the amlodipine group remained <132/78 through day 360. Our data support the use of amlodipine for hypertension in the allogeneic HSCT population and provide evidence suggesting that CCBs protect against CNI-induced nephrotoxicity.",
"affiliations": "Intermountain Healthcare Acute Leukemia, Blood and Marrow Transplant Program, LDS Hospital, Salt Lake City, Utah.;Intermountain Healthcare Acute Leukemia, Blood and Marrow Transplant Program, LDS Hospital, Salt Lake City, Utah.;Intermountain Healthcare Acute Leukemia, Blood and Marrow Transplant Program, LDS Hospital, Salt Lake City, Utah.;Intermountain Healthcare Acute Leukemia, Blood and Marrow Transplant Program, LDS Hospital, Salt Lake City, Utah.;Intermountain Healthcare Acute Leukemia, Blood and Marrow Transplant Program, LDS Hospital, Salt Lake City, Utah.;Intermountain Healthcare Acute Leukemia, Blood and Marrow Transplant Program, LDS Hospital, Salt Lake City, Utah.;Royal College of Surgeons in Ireland, Dublin, Ireland.;Intermountain Healthcare Acute Leukemia, Blood and Marrow Transplant Program, LDS Hospital, Salt Lake City, Utah.",
"authors": "Jensen|Ryan R|RR|0000-0001-6425-1018;Healy|Regan M|RM|;Ford|Clyde D|CD|;Child|Berrie|B|;Majers|Jacob|J|;Draper|Brent|B|;Hasan|Yousef|Y|;Hoda|Daanish|D|",
"chemical_list": "D000959:Antihypertensive Agents; D065095:Calcineurin Inhibitors; D017311:Amlodipine",
"country": "Denmark",
"delete": false,
"doi": "10.1111/ctr.13633",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-0063",
"issue": "33(7)",
"journal": "Clinical transplantation",
"keywords": "allogeneic hematopoietic stem cell transplantation (HSCT); calcineurin inhibitors (CNI); calcium-channel blockers (CCBs); hypertension; nephrotoxicity; renal protection",
"medline_ta": "Clin Transplant",
"mesh_terms": "D058186:Acute Kidney Injury; D000293:Adolescent; D000328:Adult; D000368:Aged; D017311:Amlodipine; D000959:Antihypertensive Agents; D065095:Calcineurin Inhibitors; D016022:Case-Control Studies; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D055815:Young Adult",
"nlm_unique_id": "8710240",
"other_id": null,
"pages": "e13633",
"pmc": null,
"pmid": "31177566",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Amlodipine and calcineurin inhibitor-induced nephrotoxicity following allogeneic hematopoietic stem cell transplant.",
"title_normalized": "amlodipine and calcineurin inhibitor induced nephrotoxicity following allogeneic hematopoietic stem cell transplant"
} | [
{
"companynumb": "US-APOTEX-2019AP019973",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "3",
... |
{
"abstract": "We present the case of a 29-year-old woman with focal segmental glomerulosclerosis (FSGS) who was treated with rituximab administration under different conditions for refractory nephrotic syndrome and posttransplant FSGS recurrence. At the age of 13 years, she developed FSGS, which followed a refractory clinical course, and eventually necessitated her to undergo plasmapheresis and receive rituximab at the age of 25 years. However, both therapies were ineffective, and she subsequently had progressive renal failure, for which dialysis was initiated at the age of 26 years. At the age of 28 years, she received a renal transplant from a living donor. However, nearly 1 year after the transplantation, nephrotic-range proteinuria was observed and FSGS recurrence was confirmed via biopsy of the transplanted kidney. Plasmapheresis resulted in complete remission, which was maintained by rituximab administration, and the patient followed a favorable course. To date, there have been no reports on the effect of rituximab on both the native kidney and post-transplant FSGS recurrence in the same patient. Interestingly, this case showed different responses to rituximab administration.",
"affiliations": "Department of Medicine, Kidney Center, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan. ino.ayami@twmu.ac.jp.;Department of Medicine, Kidney Center, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.;Department of Medicine, Kidney Center, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.;Department of Medicine, Kidney Center, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.",
"authors": "Ino|Ayami|A|;Kaori|Segawa|S|;Takei|Takashi|T|;Nitta|Kosaku|K|",
"chemical_list": "D007155:Immunologic Factors; D000069283:Rituximab",
"country": "Japan",
"delete": false,
"doi": "10.1007/s13730-020-00451-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-4449",
"issue": "9(3)",
"journal": "CEN case reports",
"keywords": "Kidney transplantation; Plasmapheresis; Recurrent focal segmental glomerulosclerosis; Rituximab",
"medline_ta": "CEN Case Rep",
"mesh_terms": "D000328:Adult; D064591:Allografts; D001706:Biopsy; D003131:Combined Modality Therapy; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental; D006801:Humans; D007155:Immunologic Factors; D007668:Kidney; D016030:Kidney Transplantation; D009404:Nephrotic Syndrome; D010956:Plasmapheresis; D011507:Proteinuria; D012008:Recurrence; D012074:Remission Induction; D000069283:Rituximab",
"nlm_unique_id": "101636244",
"other_id": null,
"pages": "195-199",
"pmc": null,
"pmid": "31997159",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18465150;19011266;20798255;4114718;19667947;24965823;20590697;22174985;19875378;22581994;21632983;19578004;16364987;16133051;21632984",
"title": "Different effects of rituximab on a native kidney and a post-transplant kidney with recurrence of focal segmental glomerulosclerosis.",
"title_normalized": "different effects of rituximab on a native kidney and a post transplant kidney with recurrence of focal segmental glomerulosclerosis"
} | [
{
"companynumb": "JP-MYLANLABS-2021M1068074",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nProton pump inhibitors (PPIs) are potent inhibitors of gastric acid secretion and give hypergastrinemia secondary to gastric hypoacidity. PPI treatment therefore induces enterochromaffin-like (ECL) cell hyperplasia. Long-term hypergastrinemia in rodents and man also leads to ECL cell neoplasia. Whether long-term PPI treatment will induce ECL cell neoplasia in man has been disputed.\n\n\nOBJECTIVE\nTo describe gastric carcinoids in two patients with a history of long-term PPI use.\n\n\nRESULTS\nTwo patients had been taking PPI for 12-13 years due to gastro-oesophageal reflux disease. At routine upper gastrointestinal endoscopy a solitary tumour was found in the oxyntic mucosa of both patients. Histology from the tumours showed in both cases a well-differentiated neuroendocrine tumour. Biopsies from flat oxyntic mucosa showed no signs of atrophic gastritis and a normal presence of parietal cells in both cases, but hyperplasia of ECL cells. The tumour in patient 1 was resected endoscopically. After cessation of PPI treatment the tumour regressed in patient 2 and the ECL cell hyperplasia regressed in both patients. In patient 2 serum gastrin and chromogranin A were elevated during PPI treatment, and normalised after cessation of treatment. In patient 1, unfortunately, we had serum only after treatment, and at that time both parameters were normal.\n\n\nCONCLUSIONS\nThese cases show that hypergastrinemia secondary to proton pump inhibitors treatment, like other causes of hypergastrinemia, may induce enterochromaffin-like cell carcinoids in man.",
"affiliations": "Departments of Gastroenterology and Hepatology, St. Olavs Hospital, Trondheim, Norway. constantin.jianu@ntnu.no",
"authors": "Jianu|C S|CS|;Fossmark|R|R|;Viset|T|T|;Qvigstad|G|G|;Sørdal|O|O|;Mårvik|R|R|;Waldum|H L|HL|",
"chemical_list": "D054328:Proton Pump Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1111/apt.12012",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-2813",
"issue": "36(7)",
"journal": "Alimentary pharmacology & therapeutics",
"keywords": null,
"medline_ta": "Aliment Pharmacol Ther",
"mesh_terms": "D000368:Aged; D001706:Biopsy; D002276:Carcinoid Tumor; D019861:Enterochromaffin-like Cells; D005260:Female; D005753:Gastric Mucosa; D005764:Gastroesophageal Reflux; D006801:Humans; D008297:Male; D008875:Middle Aged; D054328:Proton Pump Inhibitors; D013274:Stomach Neoplasms; D013997:Time Factors",
"nlm_unique_id": "8707234",
"other_id": null,
"pages": "644-9",
"pmc": null,
"pmid": "22861200",
"pubdate": "2012-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Gastric carcinoids after long-term use of a proton pump inhibitor.",
"title_normalized": "gastric carcinoids after long term use of a proton pump inhibitor"
} | [
{
"companynumb": "NO-SUN PHARMACEUTICAL INDUSTRIES LTD-12SUNPA24P",
"fulfillexpeditecriteria": "1",
"occurcountry": "NO",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIAZEPAM"
},
"drugaddit... |
{
"abstract": "Therapy-related thrombocytopenia (TRT), due to chemotherapy and/or radiation therapy, is common with pediatric cancer treatments, and it can result in dose reductions and therapy delays. Romiplostim, a thrombopoietin mimetic, is efficacious as a second-line treatment for immune thrombocytopenia in children and for TRT in adult cancer patients. However, there are no data for its use for TRT in children. We report a case series of five children treated for solid tumors where romiplostim was used without adverse effects to successfully resolve and prevent therapy-limiting refractory TRT. Prospective studies on this use of romiplostim are warranted.",
"affiliations": "Division of Pediatric Hematology/Oncology/BMT, Nationwide Children's Hospital, Columbus, Ohio.;Division of Pediatric Hematology/Oncology/BMT, Nationwide Children's Hospital, Columbus, Ohio.;Division of Pediatric Hematology/Oncology/BMT, Nationwide Children's Hospital, Columbus, Ohio.",
"authors": "Jacobson|Amanda E|AE|;Shah|Nilay|N|;Setty|Bhuvana A|BA|",
"chemical_list": "D000970:Antineoplastic Agents; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D013926:Thrombopoietin; C488777:romiplostim",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.26473",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "64(8)",
"journal": "Pediatric blood & cancer",
"keywords": "Romiplostim; chemotherapy adverse effects; children; pediatric hematology/oncology; radiation adverse effects; thrombocytopenia",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000970:Antineoplastic Agents; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D009369:Neoplasms; D011878:Radiotherapy; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D013921:Thrombocytopenia; D013926:Thrombopoietin",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28150377",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Romiplostim for therapy-related thrombocytopenia in pediatric malignancies.",
"title_normalized": "romiplostim for therapy related thrombocytopenia in pediatric malignancies"
} | [
{
"companynumb": "US-CIPLA LTD.-2017US19824",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DACTINOMYCIN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nGanciclovir (GCV) and foscarnet (FOS) are the most commonly used antivirals for preemptive treatment of cytomegalovirus (CMV) viremia in recipients of allogeneic hematopoietic cell transplantation (alloHCT). The current literature indicates similar efficacy between these agents. Thus, the primary consideration for choice of initial anti-CMV treatment is the safety profile, time period after alloHCT, and concern of myelosuppression or renal dysfunction.\n\n\nMETHODS\nHerein, we retrospectively reviewed medical records of 124 alloHCT recipients who received GCV or FOS between April 27, 2014, and December 31, 2015, during the first year post-transplant. Healthcare resource use included drug, hospitalization, home health, dialysis, and growth factor costs.\n\n\nRESULTS\nTotal duration of therapy was longer in the GCV group (37 days vs 28 days, P = .21) but hospitalization days were similar (9 days) in both groups. The total treatment cost was significantly lower in the GCV group ($38 100 vs $59 400, P < .05).\n\n\nCONCLUSIONS\nPreemptive anti-CMV therapy is associated with major healthcare resource costs, which were greater in patients who required FOS than those who were treated with GCV.",
"affiliations": "Department of Pharmacy, City of Hope, Duarte, California.;Department of Pharmacy, City of Hope, Duarte, California.;Department of Quality, Risk and Regulatory Management, City of Hope, Duarte, California.;Department of Information Sciences, City of Hope, Duarte, California.;Department of Medicine, Division of Infectious Disease, City of Hope, Duarte, California.;Center for Gene Therapy, City of Hope, Duarte, California.;Department of Medicine, Division of Infectious Disease, City of Hope, Duarte, California.;Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.;Department of Clinical Translational Program Development, City of Hope, Duarte, California.;Department of Pharmacy, Grady Health, Atlanta, Georgia.;Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.;Department of Medicine, Division of Infectious Disease, City of Hope, Duarte, California.",
"authors": "Chen|Jason|J|https://orcid.org/0000-0001-6523-7621;Abella Ross|Justine|J|;Tegtmeier|Bernard|B|;Yang|Dongyun|D|;Ito|James I|JI|;Zaia|John A|JA|;Dickter|Jana K|JK|;Nakamura|Ryotaro|R|;Mokhtari|Sally|S|;Kriengkauykiat|Jane|J|;Al Malki|Monzr M|MM|;Dadwal|Sanjeet S|SS|",
"chemical_list": "D000998:Antiviral Agents; D017245:Foscarnet; D015774:Ganciclovir",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13233",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "22(2)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "cytomegalovirus; drug costs; foscarnet; ganciclovir; hematopoietic cell transplant",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D018890:Chemoprevention; D002648:Child; D003365:Costs and Cost Analysis; D003586:Cytomegalovirus Infections; D005260:Female; D017245:Foscarnet; D015774:Ganciclovir; D017048:Health Care Costs; D018380:Hematopoietic Stem Cell Transplantation; D006760:Hospitalization; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D066027:Transplant Recipients; D014766:Viremia; D055815:Young Adult",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13233",
"pmc": null,
"pmid": "31840347",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article",
"references": "24831837;25778751;3005424;31353971;6296961;24850801;17392502;31448830;29211658;11830461;29207952;26884374;9707026",
"title": "Cost analysis of ganciclovir and foscarnet in recipients of allogeneic hematopoietic cell transplant with cytomegalovirus viremia.",
"title_normalized": "cost analysis of ganciclovir and foscarnet in recipients of allogeneic hematopoietic cell transplant with cytomegalovirus viremia"
} | [
{
"companynumb": "US-AMGEN-USASP2020073871",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
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"activesubstance": {
"activesubstancename": "FOSCARNET"
},
"drugadditional": null,
... |
{
"abstract": "Hemophagocytic lymphohistiocytosis (HLH) is a rare but severe and often overwhelming systemic hyper-inflammatory syndrome generally presenting with unexplained fevers, hepatosplenomegaly, and progressive multi-organ dysfunction. Treatment of HLH has two major goals: Halting the triggering event and controlling the overactive immune system. However, patients with primary or recurrent secondary HLH should subsequently undergo allogeneic HCT for long lasting disease remission. Hereby we present the case of a 69 years old man with recurrent HLH who underwent a reduced intensity conditioning of fludarabine, cyclophosphamide and low dose total body irradiation followed by a haploidentical marrow graft and post-transplantation cyclophosphamide (PTCy), tacrolimus and mycophenolate mofetil as GVHD prophylaxis. He achieved a durable remission of HLH symptoms despite persistent myeloid mixed chimerism. The use of haploidentical donors and PTCy as tolerance inducing regimen is feasible in HLH. The achievement of mixed donor chimerism may be enough to control the clinical manifestations and to cure HLH.",
"affiliations": "Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center, Tampa, FL, USA; Department of Oncologic Sciences, University of South Florida Morsani College of Medicine, Tampa, FL, USA. Electronic address: Ernesto.Ayala@Moffitt.org.;Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center, Tampa, FL, USA.;Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center, Tampa, FL, USA; Department of Oncologic Sciences, University of South Florida Morsani College of Medicine, Tampa, FL, USA.;Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center, Tampa, FL, USA; Department of Oncologic Sciences, University of South Florida Morsani College of Medicine, Tampa, FL, USA.",
"authors": "Ayala|Ernesto|E|;LaFave|Denise|D|;Nishihori|Taiga|T|;Kharfan-Dabaja|Mohamed A|MA|",
"chemical_list": "D003520:Cyclophosphamide; D014740:Vidarabine; D009173:Mycophenolic Acid; C024352:fludarabine; D016559:Tacrolimus",
"country": "England",
"delete": false,
"doi": "10.1016/j.hemonc.2016.05.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "11(2)",
"journal": "Hematology/oncology and stem cell therapy",
"keywords": "Haploidentical; Hemophagocytic lymphohistiocytosis; Transplantation",
"medline_ta": "Hematol Oncol Stem Cell Ther",
"mesh_terms": "D000368:Aged; D064591:Allografts; D003520:Cyclophosphamide; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D009173:Mycophenolic Acid; D016559:Tacrolimus; D019172:Transplantation Conditioning; D014740:Vidarabine",
"nlm_unique_id": "101468532",
"other_id": null,
"pages": "96-98",
"pmc": null,
"pmid": "27352259",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Haploidentical transplantation as a promising therapy for relapsed hemophagocytic lymphohistiocytosis in an older adult patient.",
"title_normalized": "haploidentical transplantation as a promising therapy for relapsed hemophagocytic lymphohistiocytosis in an older adult patient"
} | [
{
"companynumb": "US-APOTEX-2018AP005948",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "3",
"... |
{
"abstract": "Primary effusion lymphoma (PEL) is a rare mature B-cell non-Hodgkin's lymphoma arising in body cavities and presenting with effusions. It has been described predominantly in patients with impaired immunity from the acquired immunodeficiency syndrome and is associated with the Human Herpesvirus-8 (HHV-8). Seldom has PEL been diagnosed in persons negative for the human immunodeficiency virus (HIV), and in such cases it has occurred primarily in the setting of posttransplant immunosuppression. We report an instructive case of a Caribbean-American HIV-negative orthotopic heart transplant recipient with a history of HHV-8-associated Kaposi's sarcoma who developed HHV-8 viremia and PEL of the pleural space early in the posttransplant course. This case highlights the importance of considering PEL in the differential diagnosis of a new pleural effusion in a transplant recipient at risk for HHV-8-associated disease.",
"affiliations": "Division of Pulmonary, Critical Care, and Sleep Medicine, Westchester Medical Center, Valhalla, New York.;Department of Internal Medicine, Westchester Medical Center, Valhalla, New York.;Department of Internal Medicine, Westchester Medical Center, Valhalla, New York.;Department of Pathology, Westchester Medical Center, Valhalla, New York.;Department of Pathology, Westchester Medical Center, Valhalla, New York.;Division of Pulmonary, Critical Care, and Sleep Medicine, Westchester Medical Center, Valhalla, New York.",
"authors": "Kugasia|Irfan Ali R|IAR|http://orcid.org/0000-0002-4884-0960;Kumar|Arun|A|;Khatri|Akshay|A|;Saeed|Faisal|F|;Islam|Humayun|H|;Epelbaum|Oleg|O|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "21(1)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "heart transplant; human herpesvirus-8; pleural effusion; primary effusion lymphoma",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D003937:Diagnosis, Differential; D016027:Heart Transplantation; D019288:Herpesvirus 8, Human; D006801:Humans; D007165:Immunosuppression Therapy; D054685:Lymphoma, Primary Effusion; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D035422:Pleural Cavity; D011183:Postoperative Complications; D012514:Sarcoma, Kaposi; D012878:Skin Neoplasms; D014766:Viremia",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13005",
"pmc": null,
"pmid": "30276937",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Primary effusion lymphoma of the pleural space: Report of a rare complication of cardiac transplant with review of the literature.",
"title_normalized": "primary effusion lymphoma of the pleural space report of a rare complication of cardiac transplant with review of the literature"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-307287",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drug... |
{
"abstract": "Accidental administration of non-epidural drugs into the epidural or subarachnoid spaces may be associated with unexpected pain, morbidity, adverse effects, increased level of care, prolonged hospital stay, and mortality. We describe a 12-month-old admitted for secondary-stage hypospadias reconstruction. General anesthesia was induced with sevofiurane and a peripheral catheter was placed. Instead of ropivacaine, rocuronium (80 mg; 6.3 mg/kg) was injected into the epidural space by the caudal route. Surgery was uneventful and was completed 160 minutes after rocuronium was given. The patient exhibited paralysis with 1 of 4 twitches to the train-of-four with some posttetanic potentiation at the end of surgery. He was transferred to the pediatric intensive care unit for supportive ventilation and recovery. He did not experience oxygen desaturation or hypoventilation between the time of rocuronium administration and intubation. He was hemodynamically stable, without respiratory insufficiency, and his neurologic exam was normal, without motor or sensorial block. The patient was discharged home on the morning of the first postoperative day. Clinical examination 1 week after surgery revealed no lasting sequelae from the error.",
"affiliations": "Pharmacy Department, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota.;Pharmacy Department, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota.",
"authors": "Wu|Ting-Ting|TT|;Hoff|David S|DS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.5863/1551-6776-21.5.436",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1551-6776",
"issue": "21(5)",
"journal": "The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG",
"keywords": "epidural; intrathecal; intraventricular; medication error; neuromuscular blocker; rocuronium",
"medline_ta": "J Pediatr Pharmacol Ther",
"mesh_terms": null,
"nlm_unique_id": "101089851",
"other_id": null,
"pages": "436-443",
"pmc": null,
"pmid": "27877098",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "8777115;18078103;9262335;10979380;22137529;19272535;15473627;10716884;1416176;21750999;11094016;15845738;14566499;15169739;11193520;24574586;2782653;16052131;18227309;21804808",
"title": "Accidental Epidural Injection of Rocuronium in a Pediatric Patient: A Case Report and Literature Review.",
"title_normalized": "accidental epidural injection of rocuronium in a pediatric patient a case report and literature review"
} | [
{
"companynumb": "US-PFIZER INC-2016570110",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CEFAZOLIN"
},
"drugadditional": null,
... |
{
"abstract": "Pomalidomide is an analog of thalidomide with immunomodulatory, anti-angiogenic, and anti-neoplastic activity indicated for the treatment of multiple myeloma refractory to at least two prior therapies. The incidence for renal failure was <5% in a single phase II study of pomalidomide and dexamethasone in patients with multiple myeloma that failed both lenalidomide and bortezomib therapy. We report a case suggesting crystal nephropathy as the mechanism for acute kidney injury in pomalidomide and fluoroquinolone use.",
"affiliations": "Department of Internal Medicine, Hofstra North Shore - LIJ School of Medicine, Great Neck, NY, USA.;Department of Internal Medicine, Hofstra North Shore - LIJ School of Medicine, Great Neck, NY, USA Division of Kidney Diseases and Hypertension, Hofstra North Shore - LIJ School of Medicine, Great Neck, NY, USA.;Department of Internal Medicine, Hofstra North Shore - LIJ School of Medicine, Great Neck, NY, USA.;Department of Internal Medicine, Hofstra North Shore - LIJ School of Medicine, Great Neck, NY, USA.;Department of Internal Medicine, Hofstra North Shore - LIJ School of Medicine, Great Neck, NY, USA North Shore LIJ Cancer Institute and the Division of Hematology/Oncology, Hofstra North Shore - LIJ School of Medicine, Great Neck, NY, USA.;Department of Internal Medicine, Hofstra North Shore - LIJ School of Medicine, Great Neck, NY, USA Division of Kidney Diseases and Hypertension, Hofstra North Shore - LIJ School of Medicine, Great Neck, NY, USA.;Department of Internal Medicine, Hofstra North Shore - LIJ School of Medicine, Great Neck, NY, USA Division of Kidney Diseases and Hypertension, Hofstra North Shore - LIJ School of Medicine, Great Neck, NY, USA kdj200@gmail.com.",
"authors": "Baird|Phylicia|P|;Leung|Sam|S|;Hoang|Huy|H|;Babalola|Olawumi|O|;Devoe|Craig E|CE|;Wanchoo|Rimda|R|;Jhaveri|Kenar D|KD|",
"chemical_list": "D013792:Thalidomide; D064704:Levofloxacin; C467566:pomalidomide",
"country": "England",
"delete": false,
"doi": "10.1177/1078155214568581",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "22(2)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Onconephrology; crystal nephropathy; myeloma; pomalidomide; renal failure",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D006801:Humans; D064704:Levofloxacin; D009101:Multiple Myeloma; D013792:Thalidomide",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "357-60",
"pmc": null,
"pmid": "25591868",
"pubdate": "2016-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of acute kidney injury from crystal nephropathy secondary to pomalidomide and levofloxacin use.",
"title_normalized": "a case of acute kidney injury from crystal nephropathy secondary to pomalidomide and levofloxacin use"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201602364",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nSevere venlafaxine intoxication may cause arrhythmias, cardiac failure, and even cardiac arrest.\n\n\nMETHODS\nA 48-year-old caucasian male with an extensive psychiatric history ingested a high dose of venlafaxine causing a serum venlafaxine concentration of 12.6 mg/L 24 hours after ingestion. Seven hours post-ingestion, he experienced tonic-clonic seizures, and 8 hours later, takotsubo cardiomyopathy was recognized followed by cardiac arrest. The patient was resuscitated with prolonged cardiopulmonary resuscitation including ongoing automatic external compressions during helicopter transportation to a tertiary hospital for extracorporeal membrane oxygenation treatment. Despite a cardiopulmonary resuscitation duration of 2 hours, 36 hours of extracorporeal membrane oxygenation, and a total of 30 days of intensive care, the patient made a full recovery.\n\n\nCONCLUSIONS\nIn cases of intoxication-induced cardiac arrests among otherwise young and healthy patients, prolonged cardiopulmonary resuscitation and extracorporeal circulation can be a life-saving bridge to recovery.",
"affiliations": "Department of Anaesthesiology and Intensive Care, Norrtälje Hospital, Norrtälje, Sweden. sune.forsberg@ki.se.;Department of Anaesthesiology and Intensive Care, Norrtälje Hospital, Norrtälje, Sweden.;ECMO Centre Karolinska, Karolinska University Hospital, Stockholm, Sweden.",
"authors": "Forsberg|Sune|S|http://orcid.org/0000-0003-2684-5194;Abazi|Lis|L|;Forsman|Pär|P|",
"chemical_list": "D000069470:Venlafaxine Hydrochloride",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-021-03031-w",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n3031\n10.1186/s13256-021-03031-w\nCase Report\nSuccessful use of extended cardiopulmonary resuscitation followed by extracorporeal oxygenation after venlafaxine-induced takotsubo cardiomyopathy and cardiac arrest: a case report\nhttp://orcid.org/0000-0003-2684-5194\nForsberg Sune sune.forsberg@ki.se\n\n123\nAbazi Lis lis.abazi@tiohundra.se\n\n12\nForsman Pär par.forsman@sll.se\n\n4\n1 Department of Anaesthesiology and Intensive Care, Norrtälje Hospital, Norrtälje, Sweden\n2 grid.4714.6 0000 0004 1937 0626 Centre for Resuscitation Science, Department of Medicine, Karolinska Institutet, Stockholm, Sweden\n3 Swedish Poisons Information Centre, Stockholm, Sweden\n4 grid.24381.3c 0000 0000 9241 5705 ECMO Centre Karolinska, Karolinska University Hospital, Stockholm, Sweden\n27 9 2021\n27 9 2021\n2021\n15 48516 10 2019\n27 7 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nSevere venlafaxine intoxication may cause arrhythmias, cardiac failure, and even cardiac arrest.\n\nCase presentation\n\nA 48-year-old caucasian male with an extensive psychiatric history ingested a high dose of venlafaxine causing a serum venlafaxine concentration of 12.6 mg/L 24 hours after ingestion. Seven hours post-ingestion, he experienced tonic–clonic seizures, and 8 hours later, takotsubo cardiomyopathy was recognized followed by cardiac arrest. The patient was resuscitated with prolonged cardiopulmonary resuscitation including ongoing automatic external compressions during helicopter transportation to a tertiary hospital for extracorporeal membrane oxygenation treatment. Despite a cardiopulmonary resuscitation duration of 2 hours, 36 hours of extracorporeal membrane oxygenation, and a total of 30 days of intensive care, the patient made a full recovery.\n\nConclusion\n\nIn cases of intoxication-induced cardiac arrests among otherwise young and healthy patients, prolonged cardiopulmonary resuscitation and extracorporeal circulation can be a life-saving bridge to recovery.\n\nKeywords\n\nCardiac arrest\nIntoxication\nECMO\nCPR\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nThe antidepressant venlafaxine is a serotonin, a norepinephrine, and to some extent a dopamine reuptake inhibitor. In severe cases, the most severe complications of overdoses are seizures, cardiac dysfunction, and death [1]. Takotsubo cardiomyopathy (TTC) is reported after the ongoing intake of prescribed doses of venlafaxine as well as after acute overdoses [2, 3].\n\nCase presentation\n\nA 48-year-old caucasian male with an extensive psychiatric history of depression was admitted to the intensive care unit at a local hospital following intoxication of approximately 20 g venlafaxine, 450 mg zolpidem, and 250 mg propiomazine. His past history included intensive care hospitalization due to two suicidal attempts through pharmacological intoxication and self-harm with a knife. On admission, he was awake but drowsy and had a Glasgow Coma Scale (GCS) 13 of 15 (E3 + V4 + M6) but stable respiratory and circulatory status. His electrocardiography (ECG) was normal with a sinus rhythm of 57 beats per minute. Laboratory findings were within normal range (Table 1). Admission occurred approximately 2 hours after intake of the pills. Activated charcoal suspension was administered via a nasogastric tube upon arrival at the intensive care unit.Table 1 Clinical data of the case day 1–3\n\nTime intervals differ during the described period.\n\nThe patient was stable during the first 5 hours at the intensive care unit (ICU), but then 7 hours post-intoxication he experienced tonic–clonic seizures. This was successfully treated with diazepam 10 mg intravenously, and he was subsequently intubated and sedated with propofol and remifentanil. Vasopressor support with low-dose norepinephrine was also initiated.\n\nNine hours after ingestion, his circulation began to slowly fail. Increased doses of norepinephrine were required, and the patient developed metabolic acidosis with lactate elevation. Fifteen hours after ingestion, the patient’s blood pressure fell rapidly despite high doses of norepinephrine. Prompt echocardiography revealed prominent hypokinesia with akinesia from the mid-left ventricle to the apex, as in TTC, with a left ventricle ejection fraction (EF) of 20%. The right ventricle was also affected with a tricuspid annular plane systolic excursion (TAPSE) measuring 10 mm. At this point, dobutamine was added to norepinephrine, but only a few micrograms were infused prior to cardiac arrest.\n\nShortly after the addition of dobutamine, his circulatory status deteriorated further, and the patient suffered a cardiac arrest with an initial rhythm of asystole. Advanced cardiac life support was initiated according to national guidelines including manual CPR and intravenous epinephrine. The patient was given three doses of epinephrine 1 mg intravenously, and after 5 minutes without return of spontaneous circulation, the ECMO center at a tertiary hospital was contacted. Fifteen minutes post cardiac arrest, the patient regained circulation temporarily for approximately 10 minutes before relapsing into cardiac arrest. The patient’s circulatory status and blood pressure were, however, inadequate during these 10 minutes. High-dose epinephrine infusion (1.0 µg/kg/minute) was initiated and manual CPR continued for another 30 minutes. The patient was then transported by helicopter to a tertiary hospital using mechanical CPR (AutoPulse Resuscitation System) and ongoing epinephrine infusion. Transportation time was approximately 30 minutes. One hour 15 minutes after the cardiac arrest, the patient was delivered to the tertiary hospital for ECMO initiation.\n\nUpon arrival at the tertiary hospital and prior to initiation of ECMO, the patient had a sinus rhythm but very low cardiac output. Blood pressure was 55/45 mmHg without cardiac arrest, and external compression was continued whilst ECMO system treatment was established. Short pauses were taken during specifically vulnerable periods of the cannulation procedure. Lactate peaked at 4.6 mmol/L. Two hours after the cardiac arrest, the patient was on ECMO.\n\nAfter ECMO initiation treatment with sedation and circulatory drugs continued, continuous renal replacement therapy (CRRT) was initiated. CRRT was initiated due to anuria and creatinine level of 265 µmol/L. Sedation was reinitiated using midazolam and morphine instead of propofol and remifentanil. The amount of epinephrine was significantly decreased during the initial hours of ECMO treatment, and norepinephrine and milrinone were used instead. Multiple plasma and red cell concentrate (RCC) transfusion were also required due to significant bleeding from the femoral artery catheter. The patient was successfully weaned after 32 hours of ECMO. Epinephrine infusion was terminated the same day, while milrinone continued until the following day.\n\nThe patient was transported back to the primary hospital with decreasing doses of norepinephrine the day after ECMO termination. Three days after the cardiac arrest, his cardiac function was echodynamically restored with an EF of above 55%. Values of the cardiac biomarker NT-proBNP decreased from 8360 ng/L the day after the cardiac arrest to 1190 ng/L 36 days after the intoxication. He was ventilated for 8 days and received CRRT for 3 weeks. Two days after extubation, the patient gradually regained consciousness. Thirty days after the intoxication, he had regained normal cardiac and cognitive function and left the hospital for further psychiatric treatment. The patient’s renal function was fully restored with normal creatinine level (82 µmol/L) 7 weeks after the intoxication. He was finally discharged in good health without his former prescribed psychiatric medications. Two years later, his cardiac and renal function were normal, although his psychiatric medication was reinstated.\n\nThe serum venlafaxine concentration 24 hours after ingestion was 12.6 mg/L, but this laboratory result was not received until 1 week after ingestion.\n\nDiscussion\n\nThis is a case report where a lethal dose of venlafaxine [1, 4] led to a sustained cardiac arrest that was successfully treated with ECMO. As venlafaxine has a half-life of approximately 15 hours in overdose cases, the patient’s venlafaxine concentration of 12.6 mg/L 24 hours after ingestion indicates a significantly higher peak concentration would have been reached [5]. In line with previous reported cases, this concentration level is comfortably within the concentration range that can cause severe failure of ventricular dysfunction as well as conduction abnormalities [1, 4, 6, 7].\n\nConduction abnormalities due to overdose of venlafaxine are believed to be caused by sodium channel dysfunction. However, ECG examination in this case did not show any significant arrhythmias prior to the cardiac arrest, and effects on sodium channel function could not be observed due to the high concentration of venlafaxine [8, 9].\n\nSevere left ventricular dysfunction was, however, observed. There has been speculation that the cause of TTC is an increase in catecholamines from venlafaxine [10]. While the exact causes of TTC are unknown, multiple studies show that levels of catecholamines are increased both systemically and locally in the myocardium [8]. Such increase in catecholamines causes myocardial and microvascular dysfunction with coronary spasm, which is considered a potential cause of TTC. This is believed to be mediated by sympathetic innervation in the myocardium, resulting in toxic overload that leads to myocardial dysfunction, and by systemically increased catecholamines through the adrenal medulla.\n\nIn this case, we did not suspect the patient’s condition to progress to circulatory failure and TTC. Echocardiography was not performed until 1 hour prior to the cardiac arrest when the patients’ blood pressure began to fail and lactate levels increased despite increased treatment with norepinephrine. With better knowledge of the clinical course of high-dose intoxication of venlafaxine, cardiac complications could have been suspected earlier. Subsequently, a more informed choice of treatment, inotropy versus vasopressor, could have been made at an earlier stage. Despite this, even when TTC has been found at an early stage, the treatment of choice is far from clear. Hypotension needs to be treated in order to preserve coronary perfusion and mitigate left ventricular failure. If vasopressors are chosen, then an increase in afterload may aggravate the ventricular failure. If inotropes are chosen, both inotropy and tachyarrhythmias may worsen the left ventricular outflow tract obstruction that can often be found in TTC [11]. Treatment choice must, therefore, be individualized, and catecholamines should be used with caution. In cases when pharmacological treatment is insufficient, treatment should be complemented with mechanical support such as ECMO.\n\nOur case illustrates that successful outcome can be achieved even in situations where the patient’s condition deteriorates to cardiac arrest and pharmacological treatment is insufficient. Through good cardiac resuscitation and the use of automatic external compressions, which are known to be as effective as manual compressions, it is possible to maintain sufficient circulation [12]. Given the prolonged half-life of venlafaxine, the heart’s recovery from severe failure takes additional time, and therefore, a temporary rescue circulation with ECMO was preferable despite the 2 hours separating the primary hospital from the ECMO center. It is therefore important to consider cardiac support (such as ECMO) as a bridge to recovery, especially for young and otherwise healthy patients even in cases of prolonged CPR. This bridge may be a life-saving measure even when a patient has a seemingly unfavorable prognosis.\n\nConclusions\n\nIn cases of overdose-induced cardiac arrests, with prolonged periods of CPR, it is important to consider extracorporeal circulation as a bridge to spontaneous recovery.\n\nAbbreviations\n\nCPR Cardiopulmonary resuscitation\n\nECG Electrocardiography\n\nECMO Extracorporeal membrane oxygenation\n\nGCS Glasgow Coma Scale\n\nNT-proNP N-terminal pro-B-type natriuretic peptide\n\nRCC Red cell concentrate\n\nTTC Takotsubo cardiomyopathy\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\nAll three authors have substantially contributed to the manuscript. All authors read and approved the final manuscript.\n\nFunding\n\nNo external support.\n\nAvailability of data and materials\n\nAll relevant data generated during this work are included in this published article, and further data can be requested from the corresponding author.\n\nDeclarations\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declares that they have no competing interests.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Batista M Dugernier T Simon M Haufroid V Capron A Fonseca S The spectrum of acute heart failure after venlafaxine overdose Clin Toxicol 2013 51 92 95 10.3109/15563650.2012.763133\n2. Neil CJ Chong CR Nguyen TH Horowitz JD Occurrence of Tako-Tsubo cardiomyopathy in association with ingestion of serotonin/noradrenaline reuptake inhibitors Heart Lung Circ 2012 21 203 205 10.1016/j.hlc.2011.12.004 22285074\n3. Schroeder I Zoller M Angstwurm M Kur F Frey L Venlafaxine intoxication with development of takotsubo cardiomyopathy: successful use of extracorporeal life support, intravenous lipid emulsion and CytoSorb(R) Int J Artif Organs 2017 40 358 360 10.5301/ijao.5000595 28574114\n4. Hojer J Hulting J Salmonson H Fatal cardiotoxicity induced by venlafaxine overdosage Clin Toxicol 2008 46 336 337 10.1080/15563650701358755\n5. Langford NJ Martin U Ruprah M Ferner RE Alternative venlafaxine kinetics in overdose J Clin Pharm Ther 2002 27 465 467 10.1046/j.1365-2710.2002.00438.x 12472987\n6. Bosse GM Spiller HA Collins AM A fatal case of venlafaxine overdose J Med Toxicol 2008 4 18 20 10.1007/BF03160945 18338306\n7. Howell C Wilson AD Waring WS Cardiovascular toxicity due to venlafaxine poisoning in adults: a review of 235 consecutive cases Br J Clin Pharmacol 2007 64 2 192 10.1111/j.1365-2125.2007.02849.x 17298480\n8. Pelliccia F Kaski JK Crea F Camici PG Pathophysiology of takotsubo syndrome Circulation 2017 135 2426 2441 10.1161/CIRCULATIONAHA.116.027121 28606950\n9. Khalifa M Daleau P Turgeon J Mechanism of sodium channel block by venlafaxine in guinea pig ventricular myocytes J Pharmacol Exp Ther 1999 291 280 284 10490914\n10. Nef HM Möllmann H Akashi YJ Hamm CW Mechanisms of stress (takotsubo) cardiomyopathy Nat Rev Cardiol 2010 7 4 187 193 10.1038/nrcardio.2010.16 20195267\n11. De Backer O Debonnaire P Gevaert S Missault L Gheeraert P Muyldermans L Prevalence, associated factors and management implications of left ventricular outflow tract obstruction in takotsubo cardiomyopathy: a two-year, two-center experience BMC Cardiovasc Disord 2014 14 147 10.1186/1471-2261-14-147 25339604\n12. Rubertsson S Lindgren E Smekal D Östlund O Silfverstolpe J Lichtveld RA Mechanical chest compressions and simultaneous defibrillation vs conventional cardiopulmonary resuscitation in out-of-hospital cardiac arrest: the LINC randomized trial JAMA 2014 311 53 61 10.1001/jama.2013.282538 24240611\n\n",
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"title": "Successful use of extended cardiopulmonary resuscitation followed by extracorporeal oxygenation after venlafaxine-induced takotsubo cardiomyopathy and cardiac arrest: a case report.",
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"abstract": "A targeted reversed-phase gradient UPLC-MS/MS assay has been developed for the quantification /monitoring of 66 amino acids and amino-containing compounds in human plasma and serum using precolumn derivatization with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AccQTag Ultra). Derivatization of the target amines required minimal sample preparation and resulted in analytes with excellent chromatographic and mass spectrometric detection properties. The resulting method, which requires only 10 μL of sample, provides the reproducible and robust separation of 66 analytes in 7.5 min, including baseline resolution of isomers such as leucine and isoleucine. The assay has been validated for the quantification of 33 amino compounds (predominantly amino acids) over a concentration range from 2 to 20 and 800 μM. Intra- and interday accuracy of between 0.05 and 15.6 and 0.78-13.7% and precision between 0.91 and 16.9% and 2.12-15.9% were obtained. A further 33 biogenic amines can be monitored in samples for relative changes in concentration rather than quantification. Application of the assay to samples derived from healthy controls and patients suffering from acetaminophen (APAP, paracetamol)-induced acute liver failure (ALF) showed significant differences in the amounts of aromatic and branched chain amino acids between the groups as well as a number of other analytes, including the novel observation of increased concentrations of sarcosine in ALF patients. The properties of the developed assay, including short analysis time, make it suitable for high-throughput targeted UPLC-ESI-MS/MS metabonomic analysis in clinical and epidemiological environments.",
"affiliations": "Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London , South Kensington, London SW7 2AZ, United Kingdom.;Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London , South Kensington, London SW7 2AZ, United Kingdom.;Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London , South Kensington, London SW7 2AZ, United Kingdom.;Institute of Liver Studies and Transplantation, Kings College Hospital , Denmark Hill, London SE5 9RS, United Kingdom.;Institute of Liver Studies and Transplantation, Kings College Hospital , Denmark Hill, London SE5 9RS, United Kingdom.;Institute of Liver Studies and Transplantation, Kings College Hospital , Denmark Hill, London SE5 9RS, United Kingdom.;Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London , South Kensington, London SW7 2AZ, United Kingdom.;Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London , South Kensington, London SW7 2AZ, United Kingdom.;Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London , South Kensington, London SW7 2AZ, United Kingdom.;Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London , South Kensington, London SW7 2AZ, United Kingdom.",
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"title": "High-Speed Quantitative UPLC-MS Analysis of Multiple Amines in Human Plasma and Serum via Precolumn Derivatization with 6-Aminoquinolyl-N-hydroxysuccinimidyl Carbamate: Application to Acetaminophen-Induced Liver Failure.",
"title_normalized": "high speed quantitative uplc ms analysis of multiple amines in human plasma and serum via precolumn derivatization with 6 aminoquinolyl n hydroxysuccinimidyl carbamate application to acetaminophen induced liver failure"
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"abstract": "Aseptic osteonecrosis of the hip is a clinical entity in which the necrotic process of the bone leads to pain and progressive disability.\nPamidronate seems to reduce drastically the activation of the osteoclasts so that it can be useful only in the early stage of the disease, delaying the time of bone collapsing.\nA 27-years-old male was treated with pamidronate for three consecutive days every four weeks.\nAfter three months the patient came back at control showing a marked improvement in clinical condition, referred full recover from pain and dysmotility with improvement of the quality of life, which was confirmed by the result of MRI he had for control.\nWe reported a case of aseptic osteonecrosis of the hip which was successfully treated pamidronate at dosage of 45 mg.",
"affiliations": "Department of Clinical and Experimental Medicine, University of Messina, 98124 Messina, Italy.;Department of Clinical and Experimental Medicine, University of Messina, 98124 Messina, Italy.;Department of Clinical and Experimental Medicine, University of Messina, 98124 Messina, Italy.",
"authors": "Lo Gullo|A|A|;Talotta|R|R|;Atteritano|M|M|",
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"fulltext": "\n==== Front\nOpen Rheumatol JOpen Rheumatol JTORJThe Open Rheumatology Journal1874-3129Bentham Open TORJ-12-12510.2174/1874312901812010125RheumatologyPamidronate Treatment of Osteonecrosis of the Hip in Young Male Lo Gullo A. Talotta R. Atteritano M. Department of Clinical and Experimental Medicine, University of Messina, 98124 Messina, Italy* Address for correspondence to this auther at the Department of Clinical and Experimental Medicine, University of Messina, Pad. C, 4th floor, A.O.U. Policlinico “G. Martino” Via C. Valeria, 98124 Messina, Italy; Tel: +39 090 2212388; Fax: +39 090 2935162; E-mail: matteritano@unime.it29 8 2018 2018 12 125 128 17 5 2018 28 6 2018 4 7 2018 © 2018 Lo Gullo et al.2018Lo Gullo.This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background:\nAseptic osteonecrosis of the hip is a clinical entity in which the necrotic process of the bone leads to pain and progressive disability.\n\nObjective:\nPamidronate seems to reduce drastically the activation of the osteoclasts so that it can be useful only in the early stage of the disease, delaying the time of bone collapsing.\n\nMethod:\nA 27-years-old male was treated with pamidronate for three consecutive days every four weeks.\n\nResults:\nAfter three months the patient came back at control showing a marked improvement in clinical condition, referred full recover from pain and dysmotility with improvement of the quality of life, which was confirmed by the result of MRI he had for control.\n\nConclusion:\nWe reported a case of aseptic osteonecrosis of the hip which was successfully treated pamidronate at dosage of 45 mg.\n\nKeywords\nAseptic osteonecrosisCRPMRIPamidronateHipDysmotility\n==== Body\n1 INTRODUCTION\nA 27-years-old male attended our clinic with pain and dysmotility at the right hip from 4 months. Six months earlier, he underwent a cardiosurgery intervention due to mitral valvulopathy. He had a history of corticosteroid intake (prednisolone 5 mg/d for 1 month, for cumulative doses of 150 mg) for cutaneous allergic rash assumed in association with vancomycin administration 1-year earlier. He did not refer any alcohol abuse neither previous trauma of the hip. At admission, routine blood exams showed normal values, only C-Reactive Protein (CRP) was mildly increased (1.80 mg/dl; range of normality 0.00-0.50 mg/dl). Magnetic Resonance Imaging (MRI) of the hips performed showed a wide area of hypointensity in T1 sequences, with a diameter of 4x2 cm, at the anterior- superior edge of the right femoral head. A marked bone marrow oedema of the neck of the femur and concomitant joint effusion were detected. In the contralateral femur two small foci of necrosis were also appreciated. We had planned intravenous disodic pamidronate, at dosage of 45 mg for\nthree consecutive days every four weeks, but he received only two of the previewed three infusions because of the development of thromboflebitis of the basilic vein and part of the cefalic and cubital veins of the left forearm, so he was treated with heparin and antibiotics. During the infusion the patient experimented fever (body temperature within 38°C) that was controlled by the administration of paracetamol. The patient was discharged after a further short period of monitoring. After three months, the patient regained control showing a marked improvement in clinical condition referred full recovery from pain and dysmotility with improvement in the quality of life which was confirmed by the result of MRI. (Fig. 1 and Table 1).\n\n2 DISCUSSION\nThe natural history of aseptic osteonecrosis of the hip, in general, is thought to be one of progressive diseases if no intervention is undertaken. Untreated osteonecrosis of the femoral head is believed to carry a poor prognosis [1-7]. An emphasis has been placed on earlier intervention as it has been associated with an improved outcome [8]. During the first stage of the process, when the activity of the osteoclasts is higher, the use of pamidronate shows some benefits in stopping the course of the disease and in ameliorating the symptoms and the quality of life of the patients [9]. Our case suggests new evidences of the successful use of intravenous pamidronate for the treatment of aseptic osteonecrosis in a young male patient. We still don’t know the future course of the disease, as we assessed the therapeutic vantages after three months of therapy. Besides, MRI showed an improvement of perilesional oedema and the diameter of the two smallest areas of resorption and there was no increase in the dimension of the largest focus on the controlateral hip after three months since the end of the treatment with pamidronate. The use of pamidronate in this case is supported by its role in preventing the activation of the osteoclasts and the death of the osteoblasts, but recently other important functions have been attributed to this drug. Pamidronate can stop the cascade of cytokine activation by inhibiting the secretion of IL-1, IL-6 or TNF-beta from the macrophages, which are induced on the contrary by apoptosis. It therefore can antagonize the development of chronic inflammation and fibrosis [10].\n\nCONCLUSION\nIn conclusion, we reported a case of aseptic osteonecrosis of the hip which was successfully treated with two infusion of pamidronate at dosage of 45 mg. Our case could contribute to the therapeutic decisional algorithm acting in favour of the use of bisphosponates.\n\nACKNOWLEDGEMENTS\nDeclared none.\n\nETHICS APPROVAL AND CONSENT TO PARTICIPATE\nThe study protocol was approved by the local Ethical committee at University of Messina.\n\nHUMAN AND ANIMAL RIGHTS\nNo Animals were used in this research. All human research procedures followed were in accordance with the ethical standards of the committee responsible for human experimentation (institutional and national), and with the Helsinki Declaration of 1975, as revised in 2013.\n\nCONSENT FOR PUBLICATION\nAll participants provided written informed consent before any study procedure or examination was performed.\n\nCONFLICT OF INTEREST\n The authors declare no conflict of interest, financial or otherwise.\n\nFig. (1) \na – c= MRI images performed at the onset of the disease.\nb – d= MRI images performed after three month since start of the treatment with intravenous\npamidronate.\nReduction of the perifocal oedema and of the dimensions of the two foci of the head of the left\nfemur (blue arrows). The necrotic area present in the head of the right femur was unchanged\n(orange arrow). \n\nTable 1 Causes of aseptic osteonecrosis.\n\nS.No\tCauses\t\n1\tTrauma\t\n2\tIatrogenis (Use of glucocorticoids, Alcohol, chemotherapy)\t\n3\tHematological (Thalassemia, Thrombophilia, hemophilia, myeloproliferative disorders)\t\n4\tMetabolic (Gaucher disease, hypercholesterolemia, pregnancy, chronic renal failure, Hyperparathyroidism, Cushing’s disease, gout/hyperuricemia, diabetes mellitus)\t\n5\tAutoimmune disease (systemic lupus erythematosus, rheumatoid arthritis)\t\n6\tGastrointestinal (Chronic pancreatitis, inflammatiry bowel disease)\t\n7\tOrthopaedic (congenital hip dislocation)\t\n8\tReduction of the perifocal oedema and of the dimensions of the two foci of the head of the left femur (blue arrows). The necrotic area present in the head of the right femur was unchanged (orange arrow).\n==== Refs\nREFERENCES\n1 Yildiz N. Ardic F. Deniz S. Very early onset steroid-induced avascular necrosis of the hip and knee in a patient with idiopathic thrombocytopenic purpura. Intern. Med. 2008 47 22 1989 1992 10.2169/internalmedicine.47.1038 19015614 \n2 Wong G.K. Poon W.S. Chiu K.H. Steroid-induced avascular necrosis of the hip in neurosurgical patients: Epidemiological study. ANZ J. Surg. 2005 75 6 409 410 10.1111/j.1445-2197.2005.03389.x 15943727 \n3 Abbas A.A. Yoon T.R. Lee J.H. Hur C.I. Posttraumatic avascular necrosis of the femoral head in teenagers treated by a modified transtrochanteric rotational osteotomy: A report of three cases. J. Orthop. Trauma 2008 22 1 63 69 10.1097/BOT.0b013e31815aba30 18176169 \n4 Lee M.S. Hsieh P.H. Shih C.H. Wang C.J. Non-traumatic osteonecrosis of the femoral head - from clinical to bench. Chang Gung Med. J. 2010 33 4 351 360 20804664 \n5 NIshii T Sugano N, Miki H, hashimoto J, Yoshikawa H. Does alendronate prevent collapse in osteonecrosis of the femoral head? Clin. Orthop. Relat. Res. 2006 443 273 279 \n6 Hong Y.C. Luo R.B. Lin T. Zhong H.M. Shi J.B. Efficacy of alendronate for preventing collapse of femoral head in adult patients with nontraumatic osteonecrosis. BioMed Res. Int. 2014 2014 716538 10.1155/2014/716538 25535614 \n7 Ficat R.P. Idiopathic bone necrosis of the femoral head. Early diagnosis and treatment. J. Bone Joint Surg. Br. 1985 67 1 3 9 10.1302/0301-620X.67B1.3155745 3155745 \n8 Lavernia C.J. Sierra R.J. Grieco F.R. Osteonecrosis of the femoral head. J. Am. Acad. Orthop. Surg. 1999 7 4 250 261 10.5435/00124635-199907000-00005 10434079 \n9 Nguyen T. Zacharin M.R. Pamidronate treatment of steroid associated osteonecrosis in young patients treated for acute lymphoblastic leukaemia-two-year outcomes. J. Pediatr. Endocrinol. Metab. 2006 19 2 161 167 10.1515/JPEM.2006.19.2.161 16562590 \n10 Van Offel J.F. Schuerwegh A.J. Bridts C.H. Bracke P.G. Stevens W.J. De Clerck L.S. Influence of cyclic intravenous pamidronate on proinflammatory monocytic cytokine profiles and bone density in rheumatoid arthritis treated with low dose prednisolone and methotrexate. Clin. Exp. Rheumatol. 2001 19 1 13 20 11247319\n\n",
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"keywords": "Aseptic osteonecrosis; CRP; Dysmotility; Hip; MRI; Pamidronate",
"medline_ta": "Open Rheumatol J",
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"title": "Pamidronate Treatment of Osteonecrosis of the Hip in Young Male.",
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"abstract": "BACKGROUND\nOn 30 January 2012, the US FDA approved vismodegib (Erivedge®, Genentech, CA, USA) for the management of both metastatic and locally advanced basal cell carcinoma.\n\n\nOBJECTIVE\nOur objective was to identify evidence of hepatotoxicity with vismodegib in the FDA Adverse Event Reporting System (FAERS) in treated patients in two National Cancer Institute Comprehensive Cancer Centers.\n\n\nMETHODS\nFAERS was searched for reports dated 1 January 2009 through 31 December 2015 using terms including hedgehog pathway and vismodegib and hepatic-related terms such as liver, jaundice, and hepatitis, among others. Disproportionality analyses with estimates of proportional reporting ratio and empirical Bayesian geometric mean were conducted. A comprehensive literature review was conducted, and the clinical databases at the University of Texas MD Anderson Cancer Center and Robert H. Lurie Comprehensive Cancer Center of Northwestern University were searched.\n\n\nRESULTS\nTwo cases of severe liver dysfunction were published (Common Terminology Criteria for Adverse Events [CTCAE] class III), and 94 reports of adverse events (AEs) were detected in FAERS, 35 of which were serious AEs. Safety notifications related to hepatotoxicity have not been issued by the manufacturer or the FDA, although vismodegib is listed in LiverTox and the European Medicines Agency website.\n\n\nCONCLUSIONS\nWe identified a detectable safety signal for hepatotoxicity for vismodegib within 4 years of FDA approval. Vismodegib should be used in patients with severe liver disease only after careful consideration, and concomitant hepatotoxic medications should be avoided. Rapid dissemination of such safety concerns is expected to result in fewer serious hepatotoxic AEs and more optimal outcomes for patients with cancer receiving vismodegib.",
"affiliations": "Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, 1400 Pressler Dr., Unit # 1465, Houston, TX, 77030, USA. BEdwards@mdanderson.org.;College of Pharmacy, University of New Mexico, Albuquerque, NM, USA.;Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, 1400 Pressler Dr., Unit # 1465, Houston, TX, 77030, USA.;Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, 1400 Pressler Dr., Unit # 1465, Houston, TX, 77030, USA.;Department of Dermatology, Northwestern University, Chicago, IL, USA.;Thoracic, Head and Neck Medical Oncology Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, 1400 Pressler Dr., Unit # 1465, Houston, TX, 77030, USA.;College of Pharmacy, University of New Mexico, Albuquerque, NM, USA.;Department of Dermatology, Northwestern University, Chicago, IL, USA.",
"authors": "Edwards|Beatrice J|BJ|;Raisch|Dennis W|DW|;Saraykar|Smita S|SS|;Sun|Ming|M|;Hammel|Josh A|JA|;Tran|Hai T|HT|;Wehr|Nathaniel|N|;Arabyat|Rasha|R|;West|Dennis P|DP|",
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"fulltext": "\n==== Front\nDrugs R DDrugs R DDrugs in R&D1174-58861179-6901Springer International Publishing Cham 16810.1007/s40268-016-0168-2Original Research ArticleHepatotoxicity with Vismodegib: An MD Anderson Cancer Center and Research on Adverse Drug Events and Reports Project Edwards Beatrice J. 713-563-4455BEdwards@mdanderson.org 1Raisch Dennis W. 2Saraykar Smita S. 1Sun Ming 1Hammel Josh A. 3Tran Hai T. 4Wehr Nathaniel 1Arabyat Rasha 2West Dennis P. 351 0000 0001 2291 4776grid.240145.6Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, 1400 Pressler Dr., Unit # 1465, Houston, TX 77030 USA 2 0000 0001 2188 8502grid.266832.bCollege of Pharmacy, University of New Mexico, Albuquerque, NM USA 3 0000 0001 2299 3507grid.16753.36Department of Dermatology, Northwestern University, Chicago, IL USA 4 0000 0001 2291 4776grid.240145.6Thoracic, Head and Neck Medical Oncology Research, University of Texas MD Anderson Cancer Center, Houston, TX USA 5 0000 0001 2299 3507grid.16753.36Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL USA 6 1 2017 6 1 2017 3 2017 17 1 211 218 © The Author(s) 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Background\nOn 30 January 2012, the US FDA approved vismodegib (Erivedge®, Genentech, CA, USA) for the management of both metastatic and locally advanced basal cell carcinoma.\n\nObjective\nOur objective was to identify evidence of hepatotoxicity with vismodegib in the FDA Adverse Event Reporting System (FAERS) in treated patients in two National Cancer Institute Comprehensive Cancer Centers.\n\nMethods\nFAERS was searched for reports dated 1 January 2009 through 31 December 2015 using terms including hedgehog pathway and vismodegib and hepatic-related terms such as liver, jaundice, and hepatitis, among others. Disproportionality analyses with estimates of proportional reporting ratio and empirical Bayesian geometric mean were conducted. A comprehensive literature review was conducted, and the clinical databases at the University of Texas MD Anderson Cancer Center and Robert H. Lurie Comprehensive Cancer Center of Northwestern University were searched.\n\nResults\nTwo cases of severe liver dysfunction were published (Common Terminology Criteria for Adverse Events [CTCAE] class III), and 94 reports of adverse events (AEs) were detected in FAERS, 35 of which were serious AEs. Safety notifications related to hepatotoxicity have not been issued by the manufacturer or the FDA, although vismodegib is listed in LiverTox and the European Medicines Agency website.\n\nConclusion\nWe identified a detectable safety signal for hepatotoxicity for vismodegib within 4 years of FDA approval. Vismodegib should be used in patients with severe liver disease only after careful consideration, and concomitant hepatotoxic medications should be avoided. Rapid dissemination of such safety concerns is expected to result in fewer serious hepatotoxic AEs and more optimal outcomes for patients with cancer receiving vismodegib.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1007/s40268-016-0168-2) contains supplementary material, which is available to authorized users.\n\nUniversity of Texas MD Anderson Cancer Center (US)issue-copyright-statement© Springer International Publishing Switzerland 2017\n==== Body\nKey Points\n\nHepatotoxicity has been reported as an aderse event with Vismodegib.\t\nVismodegib is listed as a hepatotoxic medication in the LiverTox site. The European Medicine Agency reports the elevation of liver enzymes, and the Australian Therapeutic Goods Administration reported 3 cases of hepatotoxicty resulting in hospitalizatons with vismodegib.\t\nThe assessmen of liver profile prior to vismodegib use, and its avoidance in patients with moderate to severe liver disease is recommended. Consider avoidance of concomitant medications with hepatic metabolism. Recommend that safety recommendations be incorporated into the FDA website, and product package insert.\t\n\n\n\nIntroduction\nAbout eight in ten skin cancers are basal cell carcinomas (BCCs) [1], making it the most common type of skin cancer, arising from the lower layer of the skin. In 2014, more than 2 million estimated new cases and 1000 deaths occurred in the USA [2]. Surgery followed by radiation offers the most effective and efficient means for cure. Therapies such as 5-flurouracil, imiquimod, photodynamic therapy, or vigorous cryotherapy can be considered as alternative treatments for individuals with low-risk superficial BCC [3].\n\nOn 30 January 2012, the US FDA approved vismodegib for the treatment of recurrent, locally advanced, or metastatic BCC, based primarily on the results observed in a single-arm parallel-cohort international trial [4]. An overall response rate of 43 and 30% was seen in patients with localized and metastatic BCC [5].\n\nThe most common adverse events (AEs) associated with vismodegib reported in randomized controlled trials (RCTs) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, loss of appetite, and upper respiratory tract infections [4, 6]. One case of severe hepatotoxicity with vismodegib was reported in an 83-year-old female subject [7]. This individual’s medical history included hypertension, atrial fibrillation, and chronic obstructive pulmonary disease but no evidence of prior liver abnormalities. After 1 week of treatment, she developed nausea and emesis and was hospitalized. Liver function tests revealed a cholestatic pattern of hepatotoxicity, and liver biopsy exhibited nonspecific cholestasis with portal fibrosis. Other RCTs in advanced BCC [8] and ovarian cancer [9] have listed, less commonly, elevation of hepatic enzymes and abdominal pain.\n\nThe FDA Adverse Event Reporting System (FAERS) is a self-reported and voluntary database of AEs and medication errors reported to the FDA. It is designed to support the FDA’s post-marketing safety surveillance program for drugs and therapeutic biological products. FAERS data can be used to identify post-marketing safety signals. A safety signal is defined by the Working Group VIII of the Council for International Organizations of Medical Sciences (CIOMS VIII) as “Information that arises from one or multiple sources (including observations and experiments), which suggests a new potentially causal association, or a new aspect of a known association, between an intervention and an event or set of related events, that is judged to be of sufficient likelihood to justify further verification” [10]. Limitations include no proven causal relationship between events and a certain product and potential reporting bias [11].\n\nThe Research on Adverse Drug events And Reports (RADAR) project has received National Cancer Institute (NCI) and National Science Foundation (NSF) funding for pharmacovigilance activities. Based at Northwestern University, RADAR was first initiated in 1998 by a multidisciplinary investigator team that systematically investigated and disseminated information describing serious and previously unrecognized adverse drug and device reactions (ADRs) [12]. The purpose of this study was to determine whether a safety signal for vismodegib-related hepatotoxic AEs is detectable in FAERS and to search the clinical databases of two NCI-designated Comprehensive Cancer Centers in two large urban settings (Houston and Chicago, USA), The University of Texas MD Anderson Cancer Center and R.H. Lurie Comprehensive Cancer Center (RHLCCC) of Northwestern University, respectively.\n\nMethods\nThis retrospective study was approved by the Institutional Review Boards of MD Anderson Cancer Center and Northwestern University. RADAR methodology has been previously described in detail [12]. We searched FAERS for vismodegib and adverse liver event as combined terms from 1 January 2009 through 31 December 2015. All hepatic cases were identified through a search including ascites, hepatobiliary disease, liver toxicity, hepatitis, and cholestasis, among others. Complete search terms are listed in Appendix I in the Electronic Supplementary Material.\n\nWithin FAERS, we calculated disproportionate reporting of hepatic dysfunction using proportional reporting ratios (PRRs) with 95% confidence intervals (CIs). PRRs determined whether the proportion of FAERS cases with hepatic dysfunction was higher in patients receiving vismodegib than in those receiving other drugs. The PRR is a statistical aid that generates signals based on a proportionate approach, which also acknowledges the stability of a large database. PRRs involve calculation of the proportions of specified reactions for drugs of interest, with the comparator being the proportions of the specified reactions reported among all other drugs in the database. Judgment about the existence of a signal and its strength is made based on three pieces of information: the PRR, the chi-squared value of the data, and the number of cases. A signal is defined as a PRR of ≥2, a chi-squared value ≥4, and three or more cases reported to FAERS [12, 13].\n\nThe clinical databases at MD Anderson Cancer Center and RHLCCC were queried to detect individuals exposed to vismodegib. Medical records of these cases were reviewed, and data on demographics (age, sex, race/ethnicity, type of cancer) and liver function tests were collected. In addition, three major electronic databases were searched (MEDLINE, PubMed, and Embase) for peer-reviewed articles published between 1970 and 31 March 2014 using terms such as vismodegib, GDC-0449, sonic hedgehog, neoplasm, and clinical trials. The literature review obtained information on the results of clinical trials of vismodegib reporting on efficacy and adverse effects. We also searched websites and safety databases maintained by the FDA and other major international regulatory agencies.\n\nCommon Terminology Criteria for Adverse Events (CTCAE) version 4.0 was used as toxicity grading criteria for AE reporting. A grading (severity) scale is provided for each AE term (grade 1: mild AE; grade 2: moderate AE; grade 3: severe AE; grade 4: life-threatening or disabling AE; grade 5: death related to AE) [14]. For hepatotoxicity cases detected within FAERS, concomitant drugs were reviewed; those with significant hepatic metabolism were identified based on information contained within multiple databases [15].\n\nResults\nFDA Adverse Event Reporting System (FAERS) Results\nIn total, 94 FAERS cases were reported as having at least one AE of liver dysfunction, with 35 reports including terms demonstrating severe hepatotoxicity (Table 1), all of which were reported to FAERS by the sponsor. Of 35 reports, 20 were serious AEs (SAEs) resulting in hospitalization or death. Other AEs with these cases included dysphagia, abdominal discomfort, and cognitive disorders. The mean age of all 35 individuals was 60 years (range 0–98); 16 were female and 16 were male (of the 32 FAERS cases in which sex was reported). Comorbidities were infrequently reported and included hypertension (3/35), diabetes mellitus (2/35), hypothyroidism (1/35), and acute respiratory distress syndrome (1/35). Signal-detection analyses resulted in PRRs of 2.71 (95% CI 2.3–3.2) among all hepatic dysfunction cases and 2.24 (95% CI 1.7–2.9) among serious hepatotoxicity cases, and reflect a significant safety signal.Table 1 Cases of hepatotoxicity attributed to vismodegib in the FDA Adverse Event Reporting System\n\nReport date\tAgea (sex)\tCancer type\tConcomitant drugs with hepatic metabolism\tCo-morbidities\tAdverse events\tCTCAE\tOutcomes\tVismodegib administration time course (days)\t\n2012\t83 (F)\tBCC\tLanoxin, Lasix, Theophylline\tNA\tHepatocellular injury\t4\tHospitalization, life threatening\tNA\t\n2012\t84 (M)\tBCC\tNA\tNA\tHepatitis\t4\tLife threatening\t47\t\n2012\t63 (F)\tBCC\tCymbalta, Levothyroxine\tNA\tHepatotoxicity\t3\tHospitalization\t55\t\n2012\t58 (NA)\tPancreatic carcinoma metastatic\tOxycontin\tNA\tAscites\t5\tDeath, hospitalization\t218\t\n2012\t59 (M)\tAdenocarcinoma pancreas\tNA\tNA\tAscites\t3\tHospitalization\t5\t\n2012\t41 (F)\tBCC\tNA\tNA\tHepatitis\t3\tHospitalization\t60\t\n2013\tNA (F)\tBCC\tNA\tNA\tDILI\tNA\tOther\tNA\t\n2013\t50 (M)\tBCC\tNA\tNA\tHepatitis\t4\tHospitalization, life threatening\tNA\t\n2013\t76 (M)\tBCC\tUroxatral, Zocor, Zyloprim\tNA\tHepatotoxicity\t4\tHospitalization\tNA\t\n2013\t59 (F)\tBCC\tAdvair, Premarin\tAsthma\tHepatitis\t3\tHospitalization\tNA\t\n2013\t68 (F)\tNA\tDiovan, Vibramycin\tNA\tDILI\tNA\tOther\tNA\t\n2013\tNA\tNA\tNA\tNA\tLiver disorder\tNA\tOther\tNA\t\n2014\t75 (M)\tBCC\tNA\tNA\tHepatocellular injury\t4\tDisability other\t52\t\n2014\t79 (F)\tAML\tAugmentin, Diovan, Dulcolax, Hydrea, Hydrochlorothiazid, Lipitor, Nystatin, Tenormin, Zyloprim\tAutoimmune thyroiditis, hyperlipidemia, hypertension\tHepatic infection\t3\tHospitalization\tNA\t\n2014\t98 (F)\tBCC\tNA\tNA\tDILI\tNA\tOther\t48\t\n2014\t90 (M)\tBCC\tAmoxicillin, Aspirin, Kerlone, Lotensin, Lozol, Norvasc, Rutinoscorbin, Tricor, Ultracet, Vinpocetine, Zocor\tHypercholesterolemia, hyperlipidemia, hypertension\tDILI\t3\tHospitalization\t66\t\n2014\t72 (M)\tBCC\tCialis, Diovan, Norvasc\t\tCholestatic liver injury\t3\tHospitalization\tNA\t\n2014\t68 (M)\tBCC\tAmaryl, Bactrim, Capoten, Cardizem, Coumadin, Glucophage, Jentadueto, Lantus, Pravachol, Ranexa, Xarelto\tHyperlipidemia, hypertension, T2DM\tAcute hepatic failure\t5\tHospitalization, disability, death\t217\t\n2014\t88 (M)\tBCC\tNA\tNA\tHepatitis cholestatic\t3\tHospitalization\tNA\t\n2015\t70 (M)\tNA\tNA\tNA\tHepatotoxicity\tNA\tOther\tNA\t\n2015\t72 (M)\tBCC\tNA\tNA\tLiver injury\tNA\tOther\tNA\t\n2015\t48 (F)\tNA\tNA\tNA\tHepatic failure\tNA\tOther\tNA\t\n2015\t0 (F)\tNA\tNA\tNA\tLiver disorder\tNA\tOther\tNA\t\n2015\t56 (M)\tNA\tNA\tNA\tHepatobiliary disease\t5\tHospitalization, death\t18\t\n2015\t70 (F)\tBCC\tDiosmectite, Elavil, Hexaquine, Miralax, Nexium, Tylenol, Ultracet, Ultram, Vitabact\tDM\tAscites\t3\tHospitalization\t853\t\n2015\t68 (M)\tNA\tCapoten, Cardizem, Colace, Diabeta, Eliquis, Glucophage, Jentadueto, Lantus, Lasix, Lopressor, Nitroglycerin, Plavix, Pravachol, Protonix, Ranexa, Sulfamethoxazole\tNA\tAcute hepatic failure\t5\tHospitalization, life threatening, death\t240\t\n2015\t83 (F)\tBCC\tNA\tNA\tHepatocellular injury\tNA\tOther\t81\t\n2015\t0 (F)\tNA\tNA\tNA\tHepatotoxicity\tNA\tOther\tNA\t\n2015\t0 (M)\tNA\tDiovan, Fusidic Acid, Glucophage, Januvia, Lipitor, Robaxacet, Sectral, Symbicort, Ventolin, Veramyst, Voltaren\tNA\tHepatitis\t3\tHospitalization\tNA\t\n2015\t76 (F)\tNA\tEnbrel, Hyzaar\tNA\tHepatitis toxic\t3\tHospitalization\t21\t\n2015\t89 (F)\tNA\tNA\tNA\tHepatitis\tNA\tOther\tNA\t\n2015\t0 (NA)\tNA\tNA\tNA\tLiver disorder\t3\tHospitalization\tNA\t\n2015\t71 (F)\tBCC\tNA\tNA\tHepatitis acute\tNA\tOther\tNA\t\n2015\t57 (M)\tBCC\tNA\tNA\tHepatic failure\t5\tDeath\tNA\t\n2015\t0 (M)\tBCC\tNA\tNA\tHepatitis cholestatic\tNA\tOther\tNA\t\nAssessment based on FAERS summary data. Since FAERS case data are often incomplete, missing data are shown as ‘NA’\n\n\nAML acute myeloid leukemia, BCC basal cell carcinoma, CTCAE Common Terminology Criteria for Adverse Events, Version 4.0, DILI drug-induced liver injury, DM diabetes mellitus, F female, M male, NA not available, T2DM type 2 diabetes mellitus\n\n\naAge is presented in years\n\n\n\n\nUniversity of Texas MD Anderson Cancer Center and Robert H. Lurie Cancer Center Results\nIn total, 15 patients received vismodegib in two cancer centers: for BCC (n = 13) and for medulloblastoma (n = 2). Two cases experienced elevated alkaline phosphatase (twofold elevation).\n\nDiscussion\nWe ascertained that hepatic events associated with vismodegib in FAERS produced a safety signal. This association was previously described in the study by Ventarola and Silverstein [16]. We identified an increasing incidence over the extended study period. The first case was reported prior to FDA approval in 2011, and there has been an upward trend in cases reported to FAERs over the last 4 years (Fig. 1). It has been reported that a median of 7 years post-marketing elapses before newly detected SAEs are announced by pharmaceutical suppliers and/or the FDA [17], but this report of vismodegib-associated hepatotoxicity is being disseminated within 4 years of approval. The importance of systematic interrogation and analyses with large databases such as FAERS is made evident in that, in two NCI-designated comprehensive cancer centers, initial interrogation showed no detectable reports of hepatotoxicity. Such a finding is not unexpected, given the small number of treated patients (n = 15) in two of the NCI-designated 41 comprehensive cancer centers. Since hepatotoxicity may progress to be severe and/or life threatening, further exploration of this important association is essential. According to the NCI, only about 15% of US cancer patients are diagnosed and treated at the nation’s major academic-based cancer centers, and the large remainder may not be easily tracked for outcomes [18]. Moreover, since FAERS case reports are de-identified, it is not practical to ascertain, and/or contact the initial reporter for, further clinical information and outcomes. Moreover, FAERS reports of vismodegib-associated hepatotoxicity typically do not provide detail on related comorbidities such as prior liver abnormalities or alcohol abuse.Fig. 1 Severe cases reported in the US FDA Adverse Event Reporting System by year\n\n\n\n\nSome possible mechanisms of drug-related hepatotoxicity include disruption of the cell membrane and drug binding to cell protein, leading to cell death; cell apoptosis; inhibition of cell mitochondria function; cellular pathway inhibition; and abnormal bile flow leading to cholestasis and jaundice. Moreover, obesity and malnutrition, pregnancy, history of drug reactions, and pre-existing liver disease are factors that lead to susceptibility to hepatotoxicity [19]. Liver abnormalities may also include etiological factors such as nonalcoholic steatohepatitis (NASH), medication use, alcohol use, and chronic liver disease, among others [20].\n\nIn published RCTs, vismodegib resulted in elevated alanine aminotransferase levels compared with the placebo arm [21]. SAEs (CTCAE grade 3–4) were seen in two participants in an ovarian cancer RCT [9]. Hedgehog signaling has generally been considered inactive in healthy adult hepatocytes. Paracrine connections with hepatic epithelial cells are important for embryonic development, cell proliferation, and recovery from chronic liver damage [22–24]. Vismodegib functions as a small-molecule inhibitor of the hedgehog pathway by binding to smoothened (SMO) receptors in cells. Therefore, it may be reasonable to hypothesize that the damage caused by NASH creates an idiosyncratic trait within patients, placing them at a higher risk for experiencing a liver-based AE if they are treated with vismodegib as the drug attempts to regulate a highly damaged system.\n\nConcomitant medication use, summarized in FAERS for 14 of the serious cases, may prove to be quite important, as four of the reports in FAERS indicated concomitant use of acetaminophen, a common over-the-counter medication (Table 1). Acetaminophen may lead to acute hepatotoxicity or necrosis, especially with overdose; acetaminophen poisoning accounts for nearly 50% of all cases of acute liver failure in the USA [25]. Ash and Jolly [26] reported a case of acute liver injury related to a possible drug–drug interaction between vismodegib, aspirin, and naproxen. Thus, concomitant drug use with vismodegib may contribute to drug–drug interactions that may play a major role in the development of liver toxicity.\n\nThe press announcement at the time of the original FDA approval on 30 January 2012 and the DailyMed website, on which full prescribing information documents are posted by the US National Library of Medicine, both specified that safety and effectiveness were not established for patients with hepatic impairment who receive vismodegib [27–29]. LiverTox currently lists vismodegib as a potentially hepatotoxic medication [30]. Health Canada has a statement similar to that of the FDA in relation to liver impairment but with an arrangement whereby the sponsor agrees to submit additional safety studies, specifically to include results from a renal/hepatic impairment study by March 2015 [31]. The European Medicines Agency (EMA) reported that data on moderate and severe liver impairment were too limited to enable conclusions about liver impairment, but nevertheless posted a table including abnormal liver enzymes as a common side effect in 1–10% of patients [32]. The Australian Government’s Therapeutic Goods Administration released a statement citing study SHH4489g, which attributed three cases of hepatotoxicity to vismodegib, cases resulted in hospitalizations, but no deaths were reported [33]. The agency recommended vismodegib be avoided in patients with severe hepatic impairment [33]. As such, although the FDA labeling (full prescribing information) mentions that medications that are liver metabolized should be avoided, it provides no information on drug interaction risks for vismodegib [27, 28]. Especially in light of healthcare system reform, busy health practitioners must access and utilize ever-increasing amounts of information in the prescribing of medications and patient management, with a continuous need for new and updated post-marketing risk information and newly identified clinically significant drug interactions [34].\n\nIn contrast with other drug regulatory agencies, the FDA has not yet advanced newly evolving risk information regarding vismodegib and hepatotoxicity, although it has issued recommendations for studies of vismodegib use in individuals with renal and liver dysfunction [29]. Patients with mild liver impairment should be carefully monitored if vismodegib is considered for therapy. We also recommend that potentially hepatotoxic agents such as acetaminophen and alcohol be avoided during vismodegib therapy.\n\nLimits of this study may include under-reporting and potential reporting bias because of the voluntary nature of the FAERS database and the impracticability of contacting AE reporters. As such, the ability to establish causality of hepatotoxicity associated with vismodegib based on FAERS data is limited, albeit significant signal detection values were found.\n\nConclusion\nGiven a detectable safety signal for hepatotoxicity within FAERS for vismodegib, its use in patients with severe liver disease should include careful consideration of risk versus benefit. We recommend close monitoring of liver function and cautious use with concomitant hepatotoxic medications. As such, the FDA decision to waive Risk Evaluation and Mitigation Strategies (REMS) as part of its vismodegib labeling may require re-evaluation and carefully conducted prospective pharmacovigilance studies to achieve safe use. Rapid dissemination of such safety concerns is expected to result in fewer serious hepatotoxic adverse events and more optimal outcomes for patients with cancer receiving vismodegib.\n\nElectronic supplementary material\nBelow is the link to the electronic supplementary material.\nSupplementary material 1 (DOCX 13 kb)\n\n \n\n\nAcknowledgements\nThis research was supported by the University of Texas MD Anderson Cancer Center. The authors thank Dr. Franklin H. Herlong who provided insight and expertise that greatly assisted the research.\n\nAuthor contributions\nEach author participated and contributed sufficiently to take public responsibility for appropriate portions of the content. Dr. Beatrice J. Edwards, Dr. HT Tran, and Dr. DP West made substantial contributions to study conception and design as well as the acquisition, analysis, and interpretation of the data. Dr. DW Raisch, Dr. SS Saraykar, Ms. M Sun, Dr. JA Hammel, N Wehr, and Dr. R Arabyat made substantial contributions to the acquisition, analysis, and interpretation of the data. All authors participated in drafting the article or critical revision for important intellectual content, provided final approval of the version to be published, and 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 article are appropriately investigated and resolved.\n\nCompliance with Ethical Standards\nFunding\nUniversity of Texas MD Anderson Cancer Center.\n\nConflict of interest\nBJE, DWR, SSS, MS, JAH, HTT, NW, RA, and DPW have no conflicts of interest.\n==== Refs\nReferences\n1. Rubin AI Chen EH Ratner D Basal-cell carcinoma N Engl J Med 2005 353 21 2262 2269 10.1056/NEJMra044151 16306523 \n2. National Cancer Institute at the National Institutes of Health. Skin cancer. 2014. http://www.cancer.gov/cancertopics/types/skin. Accessed 20 Dec 2016.\n3. Miller SJ Alam M Andersen J Berg D Bichakjian CK Bowen G Basal cell and squamous cell skin cancers J Natl Compr Cancer Netw 2010 8 8 836 864 \n4. Axelson M Liu K Jiang X He K Wang J Zhao H US Food and Drug Administration approval: vismodegib for recurrent, locally advanced, or metastatic basal cell carcinoma Clin Cancer Res 2013 19 9 2289 2293 10.1158/1078-0432.CCR-12-1956 23515405 \n5. Sekulic A Migden MR Oro AE Dirix L Lewis KD Hainsworth JD Efficacy and safety of vismodegib in advanced basal-cell carcinoma N Engl J Med 2012 366 23 2171 2179 10.1056/NEJMoa1113713 22670903 \n6. Sekulic A Mangold AR Northfelt DW LoRusso PM Advanced basal cell carcinoma of the skin: targeting the hedgehog pathway Curr Opin Oncol 2013 25 3 218 223 23493193 \n7. Sanchez BE Hajjafar L Severe hepatotoxicity in a patient treated with hedgehog inhibitor: first case report Gastroenterology 2011 1 S974 S975 \n8. Caro I Von Hoff DD Mackey H Reddy JC Yauch RL Clinical development of GDC-0449, a hedgehog pathway inhibitor, for the treatment of advanced basal cell carcinoma J Am Acad Dermatol 2010 1 AB104 \n9. Kaye SB Fehrenbacher L Holloway R Amit A Karlan B Slomovitz B A phase II, randomized, placebo-controlled study of vismodegib as maintenance therapy in patients with ovarian cancer in second or third complete remission Clin Cancer Res 2012 18 23 6509 6518 10.1158/1078-0432.CCR-12-1796 23032746 \n10. Council for International Organizations of Medical Sciences Working Group VIII. Practical aspects of signal detection in pharmacovigilance. Geneva: CIOMS; 2010.\n11. Centers for Disease Control and Prevention (CDC) Cancer survivors: United States, 2007 MMWR Morb Mortal Wkly Rep 2011 60 9 269 272 21389929 \n12. Bennett CL Nebeker JR Lyons EA Samore MH Feldman MD McKoy JM The research on adverse drug events and reports (RADAR) project JAMA 2005 293 17 2131 2140 10.1001/jama.293.17.2131 15870417 \n13. Hauben M Zhou X Quantitative methods in pharmacovigilance: focus on signal detection Drug Saf 2003 26 3 159 186 10.2165/00002018-200326030-00003 12580646 \n14. US Department of Health and Human Services; National Institutes of Health; National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 28 May 2010. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed 30 Dec 2016.\n15. Lammert C Bjornsson E Niklasson A Chalasani N Oral medications with significant hepatic metabolism at higher risk for hepatic adverse events Hepatology 2010 51 2 615 620 10.1002/hep.23317 19839004 \n16. Ventarola DJ Silverstein DI Vismodegib-associated hepatotoxicity: a potential side effect detected in postmarketing surveillance J Am Acad Dermatol 2014 71 2 397 398 10.1016/j.jaad.2014.04.023 25037792 \n17. Lasser KE Allen PD Woolhandler SJ Himmelstein DU Wolfe SM Bor DH Timing of new black box warnings and withdrawals for prescription medications JAMA 2002 287 17 2215 2220 10.1001/jama.287.17.2215 11980521 \n18. Loewenberg S The US comprehensive cancer centers in perspective Mol Oncol 2010 4 1 9 11 10.1016/j.molonc.2009.10.001 \n19. Navarro VJ Senior JR Drug-related hepatotoxicity N Engl J Med 2006 354 7 731 739 10.1056/NEJMra052270 16481640 \n20. Clark JM The epidemiology of nonalcoholic fatty liver disease in adults J Clin Gastroenterol 2006 40 Suppl 1 S5 S10 16540768 \n21. Catenacci DV Junttila MR Karrison T Bahary N Horiba MN Nattam SR Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic. Cancer J Clin 2015 33 36 4284 92 \n22. Ochoa B Syn WK Delgado I Karaca GF Jung Y Wang J Hedgehog signaling is critical for normal liver regeneration after partial hepatectomy in mice Hepatology 2010 51 5 1712 1723 10.1002/hep.23525 20432255 \n23. Cirrone F Harris CS Vismodegib and the hedgehog pathway: a new treatment for basal cell carcinoma Clin Ther 2012 34 10 2039 2050 10.1016/j.clinthera.2012.08.011 23036338 \n24. Davey MG McTeir L Barrie AM Freem LJ Stephen LA Loss of cilia causes embryonic lung hypoplasia, liver fibrosis, and cholestasis in the talpid ciliopathy mutant Organogenesis 2014 10 2 177 85 10.4161/org.28819 24743779 \n25. Lee WM Acetaminophen and the U.S. Acute Liver Failure Study Group: lowering the risks of hepatic failure Hepatology 2004 40 1 6 9 10.1002/hep.20293 15239078 \n26. Ash MM Jolly PS Cholestatic hepatic injury associated with vismodegib, aspirin, and naproxen use: a case study and review of vismodegib safety Int J Dermatol 2015 54 3 370 374 10.1111/ijd.12543 25039741 \n27. ERIVEDGE (vismodegib) capsule for oral use [package insert]. San Francisco, CA: Genentech USA, Inc.; Jan 2012. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203388lbl.pdf. Accessed 26 June 2014.\n28. US National Library of Medicine. Erivedge—vismodegib capsule [drug label information]. Genentech, Inc.; 2012. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=eb368bb6-80e3-4df9-8a85-91df0a2ada6a#section-8.7. Accessed 30 Dec 2016.\n29. US FDA; Center for Drug Evaluation and Research. Application number: 203388Orig1s000. Cross discipline team leader review. 2012. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203388Orig1s000CrossR.pdf. Accessed 10 Jan 2015.\n30. US National Library of Medicine, National Institute of Diabetes and Digestive and Kidney Diseases. LiverTox: Clinical and research information on drug-induced liver injury. 28 Jun 2016. https://livertox.nlm.nih.gov. Accessed 14 July 2016.\n31. Health Canada. Erivedge: summary basis of decision. 22 Aug 2013. http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_smd_2013_erivedge_154608-eng.php. Accessed 26 June 2014.\n32. European Medicines Agency. Erivedge 150 mg hard capsules [summary of product characteristics]. 30 July 2013. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002602/WC500146817.pdf. Accessed 26 June 2014.\n33. Australian Government Department of Health, Therapeutic Goods Administration. Australian Public Assesment Report: vismodegib. 21 Oct 2013. https://www.tga.gov.au/auspar/auspar-vismodegib. Accessed 26 June 2014.\n34. de Leon J Highlights of drug package inserts and the website DailyMed: the need for further improvement in package inserts to help busy prescribers J Clin Psychopharmacol 2011 31 3 263 265 10.1097/JCP.0b013e318218f3e4 21508855\n\n",
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"mesh_terms": "D016907:Adverse Drug Reaction Reporting Systems; D000813:Anilides; D000970:Antineoplastic Agents; D056486:Chemical and Drug Induced Liver Injury; D006801:Humans; D008099:Liver; D008113:Liver Neoplasms; D011725:Pyridines; D012189:Retrospective Studies",
"nlm_unique_id": "100883647",
"other_id": null,
"pages": "211-218",
"pmc": null,
"pmid": "28063021",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article",
"references": "21389929;12580646;23032746;11980521;16306523;23515405;24743779;21508855;23493193;26527777;20870631;23036338;16481640;19839004;15239078;22670903;20432255;25037792;16540768;25039741;15870417",
"title": "Hepatotoxicity with Vismodegib: An MD Anderson Cancer Center and Research on Adverse Drug Events and Reports Project.",
"title_normalized": "hepatotoxicity with vismodegib an md anderson cancer center and research on adverse drug events and reports project"
} | [
{
"companynumb": "PHHY2017US074360",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BENAZEPRIL HYDROCHLORIDE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nThe risk of gastrointestinal (GI) bleeding with dabigatran when compared to warfarin has been controversial in the literature. The aim of our study was to assess this risk with the use of dabigatran.\n\n\nMETHODS\nWe examined the medical records of patients who were started on dabigatran or warfarin from October 2010 to October 2012. The study was conducted in two hospitals.\n\n\nRESULTS\nA total of 417 patients were included (208 dabigatran vs. 209 warfarin). GI bleeding occurred in 10 patients (4.8%) in the dabigatran group compared to 21 patients (10.1%) in the warfarin group (p=0.0375). Multivariate analysis showed that patients who were on dabigatran for ≤ 100 days had a higher incidence of GI bleeding than those who were on it for >100 days (p=0.0007). The odds of GI bleeding in patients who were on dabigatran for ≤ 100 days was 8.2 times higher compared to those who were on the drug for >100 days. The incidence of GI bleeding in patients >65 years old was higher than in those <65 years old (p=0.0453, OR=3). History of previous GI bleeding was another risk factor for GI bleeding in the dabigatran group (p=0.036, OR=6.3). The lower GI tract was the most common site for GI bleeding in the dabigatran group (80.0% vs. 38.1%, p=0.014).\n\n\nCONCLUSIONS\nThe risk of GI bleeding was lower with dabigatran. The risk factors for GI bleeding with dabigatran were the first 100 days, age >65 years, and a history of previous GI bleeding.",
"affiliations": null,
"authors": "Sherid|Muhammed|M|;Sifuentes|Humberto|H|;Sulaiman|Samian|S|;Samo|Salih|S|;Husein|Husein|H|;Tupper|Ruth|R|;Spurr|Charles|C|;Sridhar|Subbaramiah|S|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin; D000069604:Dabigatran",
"country": "Korea (South)",
"delete": false,
"doi": "10.4166/kjg.2015.65.4.205",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1598-9992",
"issue": "65(4)",
"journal": "The Korean journal of gastroenterology = Taehan Sohwagi Hakhoe chi",
"keywords": "Antithrombins; Dabigatran; Gastrointestinal hemorrhage; Platelet aggregation inhibitors; Warfarin",
"medline_ta": "Korean J Gastroenterol",
"mesh_terms": "D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D001281:Atrial Fibrillation; D000069604:Dabigatran; D005260:Female; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D012189:Retrospective Studies; D012307:Risk Factors; D014859:Warfarin",
"nlm_unique_id": "101189416",
"other_id": null,
"pages": "205-14",
"pmc": null,
"pmid": "25896154",
"pubdate": "2015-04",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Gastrointestinal bleeding with dabigatran, a comparative study with warfarin: a multicenter experience.",
"title_normalized": "gastrointestinal bleeding with dabigatran a comparative study with warfarin a multicenter experience"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2014-BI-49549GD",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "OBJECTIVE\nOne of the most common malignancies in kidney transplant recipients is Kaposi sarcoma. The incidence of Kaposi sarcoma, which develops after renal transplantation, is 400-500 times higher than that in the general population. The aims of this study were to review the experience with Kaposi sarcoma in the highest-volume transplantation Unit in Greece and to analyze clinical characteristics and response to treatment, with respect to both the patients' survival and the renal graft function.\n\n\nMETHODS\nThe records of 2008 renal graft recipients between March 1983 and December 2012 were retrospectively reviewed. Kaposi sarcoma was diagnosed based on clinical, laboratory, radiological, endoscopic, and histopathologic examinations. The disease was staged according to the classification of Al-Khader et al.\n\n\nRESULTS\nThe prevalence of Kaposi sarcoma was 1.2% in our renal transplant population. Of these, 1006 recipients underwent living-donor renal transplantation, whereas 1002 received their graft from deceased donors. Post-transplantation malignancy developed in 153 patients, among which, Kaposi sarcoma has been found in 24 cases. Of the 24 cases of Kaposi sarcoma, lesions were mainly cutaneous in 14 cases, visceral and cutaneous in 8, and concomitant visceral and lymph node involvement was observed in 2 patients. With regard to the final outcome, 20 patients (83.3%) showed remission of the disease, whereas 4 patients with visceral involvement (16.6%) did not respond to chemotherapy and discontinuation of immunosuppression and died. Moreover, 8 deaths occurred due to apparently unrelated causes.\n\n\nCONCLUSIONS\nKaposi sarcoma is an important part (15.7%) of all post-transplantation neoplasias in our series. Furthermore, our findings confirmed the previously described close association between human herpesvirus-8 and post-transplantation Kaposi sarcoma. Reduction of immunosuppression or discontinuation of calcineurin inhibitors results in remission of the disease in most of the cases. Prognosis in patients with Kaposi sarcoma limited to the skin is favorable, whereas visceral involvement is associated with high mortality.",
"affiliations": "Transplantation Unit, \"Laikon\" General Hospital, Athens, Greece.;Transplantation Unit, \"Laikon\" General Hospital, Athens, Greece. Electronic address: dimmoris@yahoo.com.;Transplantation Unit, \"Laikon\" General Hospital, Athens, Greece.;Transplantation Unit, \"Laikon\" General Hospital, Athens, Greece.;Transplantation Unit, \"Laikon\" General Hospital, Athens, Greece.;Transplantation Unit, \"Laikon\" General Hospital, Athens, Greece.;Transplantation Unit, \"Laikon\" General Hospital, Athens, Greece.;Transplantation Unit, \"Laikon\" General Hospital, Athens, Greece.;Transplantation Unit, \"Laikon\" General Hospital, Athens, Greece.",
"authors": "Zavos|G|G|;Moris|D|D|;Vernadakis|S|S|;Bokos|J|J|;Lionaki|S|S|;Mamarelis|G|G|;Panagiotellis|K|K|;Zavvos|V|V|;Boletis|I|I|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "46(9)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D006115:Greece; D006801:Humans; D007165:Immunosuppression Therapy; D015994:Incidence; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D012189:Retrospective Studies; D012514:Sarcoma, Kaposi; D012878:Skin Neoplasms; D066027:Transplant Recipients; D055815:Young Adult",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "3199-202",
"pmc": null,
"pmid": "25420858",
"pubdate": "2014-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Incidence and management of Kaposi sarcoma in renal transplant recipients: the Greek experience.",
"title_normalized": "incidence and management of kaposi sarcoma in renal transplant recipients the greek experience"
} | [
{
"companynumb": "PHHY2014GR159309",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": null,
... |
{
"abstract": "Antiepileptic drugs (AEDs) are fairly commonly associated with drug induced rash that can be mild to life threatening. Aromatic AEDs are often linked to these skin reactions unlike newer non-aromatic ones such as levetiracetam (LEV), lacosamide and zonisamide. Drug rash including drug-induced hypersensitivity syndrome is a rare complication of LEV use. We report a case of maculopapular skin rash due to LEV with cross-sensitivity with CBZ which has not been reported till date.",
"affiliations": "Associate Professor, Department of Neurology, All India Institute of Medical Sciences, Jodhpur, Rajasthan.",
"authors": "Panda|Samhita|S|",
"chemical_list": "D000927:Anticonvulsants; D002220:Carbamazepine; D000077287:Levetiracetam",
"country": "India",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-5772",
"issue": "67(4)",
"journal": "The Journal of the Association of Physicians of India",
"keywords": null,
"medline_ta": "J Assoc Physicians India",
"mesh_terms": "D000927:Anticonvulsants; D002220:Carbamazepine; D063926:Drug Hypersensitivity Syndrome; D005076:Exanthema; D006801:Humans; D000077287:Levetiracetam",
"nlm_unique_id": "7505585",
"other_id": null,
"pages": "89-90",
"pmc": null,
"pmid": "31299852",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cross-sensitivity of Levetiracetam and Carbamazepine Induced Skin Rash.",
"title_normalized": "cross sensitivity of levetiracetam and carbamazepine induced skin rash"
} | [
{
"companynumb": "IN-LUPIN PHARMACEUTICALS INC.-2019-05156",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditio... |
{
"abstract": "Outcomes of acute lymphoblastic leukemia (ALL) in older adults treated with chemotherapy are poor. The CD19/CD3 bispecific T-cell engager (BiTE) antibody blinatumomab is approved for refractory, relapsed or minimal/measurable residual disease (MRD)-positive B-cell ALL, but there is little experience in the upfront setting, including in older patients. We retrospectively analyzed outcomes of blinatumomab monotherapy in five newly diagnosed Philadelphia chromosome-negative B-cell ALL patients over 70 years. Three had cytokine release syndrome, treated with dexamethasone and/or tocilizumab, and four patients had neurotoxicity, treated with dexamethasone, without blinatumomab interruption. All five achieved complete remission (CR) after cycle one, three with undetectable MRD. All five were alive at 8 to 15 months. Three remained in MRD-negative CR. Two relapsed after cycle 3, one with extramedullary disease. In our small cohort of patients over 70 years, blinatumomab was safe initial therapy and produced a high response rate.",
"affiliations": "Departments of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.;Departments of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.;Departments of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.;Departments of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.;Departments of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.;Departments of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.",
"authors": "Niyongere|Sandrine|S|;Sanchez-Petitto|Gabriela|G|;Masur|Jack|J|;Baer|Maria R|MR|;Duong|Vu H|VH|;Emadi|Ashkan|A|0000-0003-3769-3210",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/ph13060124",
"fulltext": "\n==== Front\nPharmaceuticals (Basel)\nPharmaceuticals (Basel)\npharmaceuticals\nPharmaceuticals\n1424-8247 MDPI \n\n10.3390/ph13060124\npharmaceuticals-13-00124\nCommunication\nFrontline Blinatumomab in Older Adults with Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia\nNiyongere Sandrine 12 Sanchez-Petitto Gabriela 1 Masur Jack 1 Baer Maria R. 12 Duong Vu H. 12 https://orcid.org/0000-0003-3769-3210Emadi Ashkan 123* 1 Departments of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Sandrine.Niyongere@umm.edu (S.N.); Gabriela.Sanchez@umm.edu (G.S.-P.); jmasur@som.umaryland.edu (J.M.); mbaer@umm.edu (M.R.B.); vduong@umm.edu (V.H.D.)\n2 Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA\n3 Departments of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA\n* Correspondence: aemadi@umm.edu\n16 6 2020 \n6 2020 \n13 6 12412 5 2020 11 6 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Outcomes of acute lymphoblastic leukemia (ALL) in older adults treated with chemotherapy are poor. The CD19/CD3 bispecific T-cell engager (BiTE) antibody blinatumomab is approved for refractory, relapsed or minimal/measurable residual disease (MRD)-positive B-cell ALL, but there is little experience in the upfront setting, including in older patients. We retrospectively analyzed outcomes of blinatumomab monotherapy in five newly diagnosed Philadelphia chromosome-negative B-cell ALL patients over 70 years. Three had cytokine release syndrome, treated with dexamethasone and/or tocilizumab, and four patients had neurotoxicity, treated with dexamethasone, without blinatumomab interruption. All five achieved complete remission (CR) after cycle one, three with undetectable MRD. All five were alive at 8 to 15 months. Three remained in MRD-negative CR. Two relapsed after cycle 3, one with extramedullary disease. In our small cohort of patients over 70 years, blinatumomab was safe initial therapy and produced a high response rate.\n\nblinatumomabacute lymphoblastic leukemia (ALL)elderly\n==== Body\n1. Introduction\nDespite recent advances, outcomes in older adults with newly diagnosed acute lymphoblastic leukemia (ALL) remain poor, with higher early mortality, lower complete remission (CR) rates, higher relapse rates and shorter survival than younger patients [1]. Reasons include both the poor tolerance of intensive chemotherapy and the higher incidence of leukemia-related poor-risk features, such as adverse karyotype, with increasing age, so that intensive therapies, even if tolerated, are less likely to be effective [1]. Older patients with Philadelphia chromosome (Ph)-positive ALL may tolerate and respond to tyrosine kinase inhibitor-based therapy [2], but older patients with Ph-negative ALL lack tolerable and effective treatment options. Additionally, older adults with ALL are often excluded from clinical trials, with enrollment often limited to patients less than age of 60 or 65 years of age [3,4]. There is therefore a lack not only of effective therapeutic options, but also of evidence-based guidelines for treatment of ALL in patients 70 years of age and older. \n\nGiven that older ALL patients tolerate chemotherapy poorly and also frequently have chemoresistant disease, non-chemotherapy-based treatment approaches are attractive. Blinatumomab is a CD19/CD3 bispecific T-cell engager (BiTE) antibody that is currently approved by the United States Food and Drug Administration (FDA) and the European Medical Agency (EMA) for use in adults and children with refractory or relapsed B-cell ALL or with B-ALL in first or second CR with minimal/measurable residual disease (MRD) detected as 0.1% or greater [5,6,7]. However, there is little experience with blinatumomab in the upfront setting, including in older patients. A phase II Southwest Oncology Group (SWOG) clinical trial of blinatumomab in 29 B-ALL patients 65 years and older published in abstract form [8] demonstrated good tolerability and a favorable response rate. Here, we report five patients over age 70 years receiving single-agent blinatumomab as initial therapy for Ph-negative B-ALL. \n\n2. Results\nFive patients over age 70 years with newly diagnosed Ph-negative B-lineage ALL received blinatumomab monotherapy (Table 1). Ages ranged from 71 to 86 years. Comorbidities included but were not limited to congestive heart failure (CHF), coronary artery disease and atrial fibrillation. ALL was therapy-related in two patients, following treatment for multiple myeloma and for prostate cancer. Median white blood cell (WBC) count was 11,800 per microliter (/mcL), absolute neutrophil count (ANC) 1330/mcL, hemoglobin 9.0 g/dL, and platelet 73,200/mcL. Percentage of marrow lymphoblasts ranged from 31 to 84. CD19 was expressed on over 70% lymphoblasts by flow cytometry in all. All five patients had CD22 expression with three of five patients having over 90% CD22 expression on lymphoblasts while two patients had between 50 and 70% CD22 expression. Cytogenetic analysis demonstrated normal karyotypes in two patients, hyperdiploidy in two, and a complex karyotype in one (Table 1). One patient had lymphoblasts in the cerebrospinal fluid (CSF) at diagnosis.\n\nAll patients received continuous infusions of blinatumomab for 4 weeks, per the approved dose and schedule [9]. Three patients had symptoms of cytokine release syndrome (CRS), two grades 3 and one grade 2, all received dexamethasone and one received tocilizumab. Four patients had symptoms of neurotoxicity, successfully treated with dexamethasone. Blinatumomab infusions were not interrupted in any patient. Other adverse events (AEs) included fatigue (four patients), neutropenia (three patients), anemia (three patients), fever (two patients) and headache (two patients). \n\nAll patients received prophylactic intrathecal (IT) chemotherapy, including cytarabine, methotrexate and hydrocortisone. The patient with lymphoblasts in the CSF at diagnosis received three additional doses of IT chemotherapy, until clearance of blasts. All patients received pre-treatment dexamethasone before each cycle of blinatumomab. \n\nAll patients underwent bone marrow aspirate and biopsy on Day 28 ± 3 of Cycle 1, the last day of blinatumomab infusion. All five patients achieved complete hematologic remission at the end of Cycle 1, with no morphologic evidence of ALL. MRD was not detected in 3 patients at the end of Cycle 1. Gökbuget and colleagues demonstrated the importance of achieving undetectable MRD as a prognostic factor in patients treated with blinatumomab. In a phase II clinical trial NCT01466179 evaluating MRD response with blinatumomab in relapsed/refractory B-cell ALL, the study observed improved longer duration of response and relapsed free survival in the patients who achieved undetectable MRD with blinatumomab [10]. \n\nOne patient received 6 cycles of blinatumomab, one patient received 4 cycles and three patients received 3 cycles with prophylactic IT chemotherapy. All five patients are alive with follow-up ranging from 8 to 15 months. Three are in ongoing MRD-negative CR. Two patients relapsed after cycle 3 of blinatumomab, one with new extramedullary disease (cervical and mediastinal lymphadenopathy). Both patients who relapsed did not maintain CD19 expression on lymphoblasts. Of note, the patient with CSF lymphoblasts at time of diagnosis has not had a CSF recurrence. The two patients who relapsed have started the anti-CD22 immunoconjugate inotuzumab as second-line therapy. \n\n3. Discussion\nIn our small cohort of patients over 70 years of age, we observed that single-agent blinatumomab could be administered safely and produced a high response rate. \n\nChemotherapy outcomes for older adults with ALL remain poor, leading to increased interest and research focusing on chemotherapy-free strategies. The SWOG conducted a phase II trial of blinatumomab followed by prednisone, vincristine, methotrexate, and 6-mercaptopurine (POMP) maintenance chemotherapy in older patients with newly diagnosed Ph-negative B-cell ALL, reported in abstract form [8]. Twenty-nine patients 65 years and older received 1–2 cycles of blinatumomab as induction therapy, then 3 cycles of blinatumomab as post-remission therapy, followed by POMP maintenance chemotherapy for 18 months. Median age was 75 years (range, 66–84 years). The response rate was 66%, with only one patient requiring two cycles for response, and 12 of 17 patients tested were MRD-negative. Treatment was generally well tolerated, with a single induction death. Estimated one-year disease-free survival was 55%. Our series augments this experience, also demonstrating safety and efficacy. CRS and neurotoxicity remain important complications of blinatumomab treatment. In our small cohort they could be managed and did not require treatment interruption.\n\nAdvani and colleagues presented very compelling data from a SWOG 1318 study, which was a phase II trial of blinatumomab followed by POMP maintenance in elderly patients with newly diagnosed Ph-negative B-cell ALL [8]. The primary objective of the study was to estimate the three-year overall survival (OS) and there were several similarities between our study. Both our study and the SWOG study administered IT chemotherapy for central nervous system (CNS) prophylaxis and we both evaluated MRD status at the end of induction cycle one [8]. Both our study and the SWOG study assessed response at the completion of 1–2 cycles of blinatumomab and graded toxicities according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). The difference between our study and the SWOG study is that the eligibility age for the SWOG study was 65 years of age and older while all of our patients were age 70 years or older. The SWOG study excluded patients with evidence of CNS disease and our study included patients with CNS involvement (one of our patients had positive CNS involvement by CSF analysis which cleared with treatment with IT chemotherapy). The SWOG study had longer follow up compared to our study that focused on safety and tolerability during the initial cycles of blinatumomab therapy. We both observed that blinatumomab is not only well-tolerated but also effective in the treatment of newly diagnosed Ph-negative B-cell ALL in elderly patients, however, additional research is required to identify the durability of the response observed.\n\nMulti-agent regimens including blinatumomab are also being tested in older ALL patients. Mini-hyper-CVD (hyperfractionated cyclophosphamide, vincristine, dexamethasone) low-intensity chemotherapy with inotuzumab ozogamicin, with or without blinatumomab, improved 3-year event-free and OS rates, compared to standard hyper-CVAD alone, in newly diagnosed Ph-negative B-ALL patients older than 60 years based on a propensity score analysis [11]. Sequential therapy with inotuzumab ozogamicin followed by blinatumomab is also being studied in a current cooperative group clinical trial.\n\nBlinatumomab in the frontline setting appears to be well tolerated, safe and effective in older adults with B-lineage ALL. Durability of responses may be augmented by combination regimens.\n\n4. Methods\nWe conducted a retrospective analysis of outcome of blinatumomab monotherapy for newly diagnosed Ph-negative B-cell ALL based on 2016 World Health Organization (WHO) criteria [12] in five patients older than 70 years at the University of Maryland Greenebaum Comprehensive Cancer Center, outside of a clinical trial. A waiver of Health Insurance Portability and Accountability Act (HIPAA) authorization for release of the Protected Health Information (PHI) identified in the research application was reviewed and approved for this study by University of Maryland Baltimore (UMB) Institutional Review Board (IRB). The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the University of Maryland School of Medicine IRB (Project identification code: GCCC19138).\n\nBlinatumomab was administered per the approved dose and schedule [9].\n\nCR was defined by red blood cell transfusion independence, ANC >1000/mcL and platelet count >100,000/mcL and less than 5% bone marrow blasts. CR with absence of MRD was defined as CR with absence of abnormal lymphoblasts by flow cytometric analysis performed by Hematologics, Inc. (Seattle, WA, USA) (estimated lower level of detection, 0.02%) [13]. Relapse was defined by presence of >5% lymphoblasts in the bone marrow or peripheral blood or pathologic evidence of extramedullary ALL. Duration of response (DOR) was defined as interval from CR to relapse or death from any cause, and OS as interval from ALL diagnosis to death from any cause. Date of last follow-up was 1 May 2020.\n\nAEs, including neurotoxicity and CRS, were documented and graded per NCI CTCAE Version 5.0.\n\nAuthor Contributions\nConceptualization, S.N. and A.E.; methodology, S.N. and G.S.-P.; validation, M.R.B., V.H.D. and A.E.; formal analysis, S.N.; investigation, S.N., G.S.-P. and J.M.; writing—original draft preparation, S.N.; writing—review and editing, M.R.B. and A.E.; supervision, M.R.B., V.H.D. and A.E.; funding acquisition, A.E. All authors have read and agreed to the published version of the manuscript. \n\nFunding\nThis work was partially supported by the University of Maryland Greenebaum Comprehensive Cancer Center Support grant (P30CA134274) and the State of Maryland’s Cigarette Restitution Funds.\n\nConflicts of Interest\nA.E. is a global oncology advisory board member for Amgen. All other authors have no relevant competing interests.\n\npharmaceuticals-13-00124-t001_Table 1Table 1 Patient and Disease Characteristics.\n\nPatient\t1\t2\t3\t4\t5\t\n\nAge (years)\n\t86\t76\t85\t71\t76\t\n\nGender\n\tF\tF\tM\tM\tM\t\n\nComorbidities\n\tAtrial fibrillation s/p ablation, MI, CHF\tMultiple myeloma\tAtrial fibrillation\tGlaucoma\tProstate cancer, atrial fibrillation, MI × 3 with 5 stents\t\n\nWBC (× 109/L)\n\t38\t2.1\t2.1\t1.4\t15.6\t\n\nBlood blasts (%)\n\t77\t0\t0\t2\t64\t\n\nHemoglobin (g/dL)\n\t8.2\t12.3\t7.4\t10.3\t8.2\t\n\nPlatelets (× 109/L)\n\t22\t104\t186\t63\t14\t\n\nBM blasts (%)\n\t-*\t83\t35\t31\t84\t\n\nCD19 expression (%)\n\t99\t88\t71\t79\t93\t\n\nKaryotype\n\t46,XX,add(6)(q27),del(12)(p12)[3]/55,XX,+3,+5,+8,\n +11,del(12),+del(12),+17,\n+18,+21,+22 [17][cp20]\t46,XX [cp23]\t59-60, Hyperdiploid [2]/46,XY [18][cp20]\t46,XY [cp20]\t46,XY,add(1)(q43),+5,t(5;10)(q11.2;p11.2),der(7)t(7;18)(q10;q10),del(9)(p13),t(15;20)(q11.2;q11.2),-18 [9]/46,XY [11][cp20]\t\n\nCSF involvement\n\tYes\tNo\tNo\tNo\tNo\t\n\nCR post-induction\n\tYes\tYes\tYes\tYes\tYes\t\n\nMRD post-induction (%)\n\t0.06%\tnegative\tnegative\t0.3%\tnegative\t\n\nCR duration (months)\n\t3\t3\t10.5+\t6+\t3.5+\t\n\nCRS\n\tNo\tGrade 2\tGrade 3\tGrade 3\tNo\t\n\nTocilizumab use\n\tNo\tNo\tNo\tYes\tNo\t\n\nNeurotoxicity\n\tYes\tYes\tYes\tYes\tNo\t\n\nSteroid use\n\tYes\tYes\tYes\tYes\tNo\t\n\nBlinatumomab cycles\n\t3\t3\t4\t6\t3\t\n\nRelapse\n\tYes (extramedullary)\tYes\tNo\tNo\tNo\t\n\nSurvival (months)\n\t10+\t10+\t15+\t11+\t8+\t\nF = female; M = male; s/p = status post; MI = myocardial infarction; CHF = congestive heart failure; WBC = white blood cell count; BM = bone marrow; cp is the composite karyotype, which contains all clonally recurring abnormalities in setting of karyotypic heterogeneity; CSF = cerebrospinal fluid; CR = complete remission; MRD = minimal residual disease; CRS = cytokine release syndrome; L = liter. * Bone marrow biopsy was not performed at the time of diagnosis, ALL was diagnosed with peripheral blood flow cytometry. The numbers in square brackets are not references; these numbers in cytogenetic reports are the total number of cells in which the clonal changes were observed.\n==== Refs\nReferences\n1. Sawalha Y. Advani A.S. Management of older adults with acute lymphoblastic leukemia: Challenges & current approaches Int. J. Hematol. Oncol. 2018 7 IJH02 30302234 \n2. Rousselot P. Coude M.M. Gokbuget N. Gambacorti Passerini C. Hayette S. Cayuela J.M. Huguet F. Leguay T. Chevallier P. Salanoubat C. Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome-positive ALL Blood 2016 128 774 782 10.1182/blood-2016-02-700153 27121472 \n3. Chessells J.M. Hall E. Prentice H.G. Durrant J. Bailey C.C. Richards S.M. The impact of age on outcome in lymphoblastic leukaemia; MRC UKALL X and XA compared: A report from the MRC paediatric and adult working parties Leukemia 1998 12 463 473 10.1038/sj.leu.2400959 9557602 \n4. Gokbuget N. How I treat older patients with ALL Blood 2013 122 1366 1375 10.1182/blood-2012-07-379016 23673859 \n5. Topp M.S. Gokbuget N. Stein A.S. Zugmaier G. O’Brien S. Bargou R.C. Dombret H. Fielding A.K. Heffner L. Larson R.A. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: A multicentre, single-arm, phase 2 study Lancet Oncol. 2015 16 57 66 10.1016/S1470-2045(14)71170-2 25524800 \n6. Kantarjian H. Stein A. Gokbuget N. Fielding A.K. Schuh A.C. Ribera J.M. Wei A. Dombret H. Foa R. Bassan R. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia N. Engl. J. Med. 2017 376 836 847 10.1056/NEJMoa1609783 28249141 \n7. Gokbuget N. Dombret H. Bonifacio M. Reichle A. Graux C. Faul C. Diedrich H. Topp M.S. Bruggemann M. Horst H.A. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia Blood 2018 131 1522 1531 10.1182/blood-2017-08-798322 29358182 \n8. Advani A.S. Moseley A. O’Dwyer K.M. Wood B. Fang M. Wieduwilt M.J. Aldoss I. Park J.H. Klisovic R. Baer M.R. Results of SWOG 1318: A phase 2 trial of blinatumomab followed by POMP (prednisone, vincristine, methotrexate, 6-mercaptopurine) maintenance in elderly patients with newly diagnosed Philadelphia chromosome negative B-cell acute lymphoblastic leukemia Blood 2018 132 33 10.1182/blood-2018-99-111992 \n9. FDA Blinatumomab (Blincyto) Food and Drug Administration Silver Spring, MD, USA Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125557s125017lbl.pdf (accessed on 10 May 2020) \n10. Gokbuget N. Kantarjian H.M. Bruggemann M. Stein A.S. Bargou R.C. Dombret H. Fielding A.K. Heffner L. Rigal-Huguet F. Litzow M. Molecular response with blinatumomab in relapsed/refractory B-cell precursor acute lymphoblastic leukemia Blood Adv. 2019 3 3033 3037 10.1182/bloodadvances.2019000457 31648325 \n11. Jabbour E.J. Sasaki K. Ravandi F. Short N.J. Garcia-Manero G. Daver N. Kadia T. Konopleva M. Jain N. Cortes J. Inotuzumab ozogamicin in combination with low-intensity chemotherapy (mini-HCVD) with or without blinatumomab versus standard intensive chemotherapy (hcvad) as frontline therapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukemia: A propensity score analysis Cancer 2019 125 2579 2586 30985931 \n12. Arber D.A. Orazi A. Hasserjian R. Thiele J. Borowitz M.J. Le Beau M.M. Bloomfield C.D. Cazzola M. Vardiman J.W. The 2016 revision to the world health organization classification of myeloid neoplasms and acute leukemia Blood 2016 127 2391 2405 10.1182/blood-2016-03-643544 27069254 \n13. Loken M.R. Alonzo T.A. Pardo L. Gerbing R.B. Raimondi S.C. Hirsch B.A. Ho P.A. Franklin J. Cooper T.M. Gamis A.S. Residual disease detected by multidimensional flow cytometry signifies high relapse risk in patients with de novo acute myeloid leukemia: A report from children’s oncology group Blood 2012 120 1581 1588 10.1182/blood-2012-02-408336 22649108\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1424-8247",
"issue": "13(6)",
"journal": "Pharmaceuticals (Basel, Switzerland)",
"keywords": "acute lymphoblastic leukemia (ALL); blinatumomab; elderly",
"medline_ta": "Pharmaceuticals (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101238453",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32560218",
"pubdate": "2020-06-16",
"publication_types": "D016428:Journal Article",
"references": "27121472;28249141;22649108;27069254;9557602;30985931;23673859;29358182;25524800;30302234;31648325",
"title": "Frontline Blinatumomab in Older Adults with Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia.",
"title_normalized": "frontline blinatumomab in older adults with philadelphia chromosome negative b cell acute lymphoblastic leukemia"
} | [
{
"companynumb": "US-AMGEN-USASP2020113021",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
... |
{
"abstract": "Arginine depletion interferes with pyrimidine metabolism as well as DNA damage repair pathways. Preclinical data indicates that pairing pegylated arginine deiminase (ADI-PEG 20) with fluoropyrimidines or platinum enhances cytotoxicity in vitro and in vivo in arginine auxotrophs.\n\n\n\nThis is a single-center, open-label, phase 1 trial of ADI-PEG 20 and modified FOLFOX6 (mFOLFOX6) in treatment-refractory hepatocellular carcinoma (HCC) and other advanced gastrointestinal tumors. A 3 + 3 dose escalation design was employed to assess safety, tolerability, and determine the recommended phase 2 dose (RP2D) of ADI-PEG 20. A RP2D expansion cohort for patients with HCC was employed to define the objective response rate (ORR). Secondary objectives were to estimate progression-free survival (PFS), overall survival (OS), and to explore pharmacodynamics and immunogenicity. Eligible patients were treated with mFOLFOX6 intravenously biweekly at standard doses and ADI-PEG-20 intramuscularly weekly at 18 (Cohort 1) or 36 mg/m2 (Cohort 2 and RP2D expansion).\n\n\n\nTwenty-seven patients enrolled-23 with advanced HCC and 4 with other gastrointestinal tumors. No dose-limiting toxicities were observed in cohort 1 or 2. The RP2D for ADI-PEG 20 was 36 mg/m2 weekly with mFOLFOX6. The most common any grade adverse events (AEs) were thrombocytopenia, neutropenia, leukopenia, anemia, and fatigue. Among the 23 HCC patients, the most frequent treatment-related Grade ≥ 3 AEs were neutropenia (47.8%), thrombocytopenia (34.7%), leukopenia (21.7%), anemia (21.7%), and lymphopenia (17.4%). The ORR for this group was 21% (95% CI 7.5-43.7). Median PFS and OS were 7.3 and 14.5 months, respectively. Arginine levels were depleted with therapy despite the emergence of low levels of anti-ADI-PEG 20 antibodies. Arginine depletion at 4 and 8 weeks and archival tumoral argininosuccinate synthetase-1 levels did not correlate with response.\n\n\n\nConcurrent mFOLFOX6 plus ADI-PEG-20 intramuscularly at 36 mg/m2 weekly shows an acceptable safety profile and favorable efficacy compared to historic controls. Further evaluation of this combination is warranted in advanced HCC patients.",
"affiliations": "Memorial Sloan Kettering Cancer Center, New York, NY, USA. Hardinj1@mskcc.org.;Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Polaris Pharmaceuticals, Inc., San Diego, CA, USA.;Polaris Pharmaceuticals, Inc., San Diego, CA, USA.;Polaris Pharmaceuticals, Inc., San Diego, CA, USA.;Chi Mei Medical Center, Tainan, Taiwan, Republic of China.;Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Memorial Sloan Kettering Cancer Center, New York, NY, USA.",
"authors": "Harding|James J|JJ|;Do|Richard K|RK|;Dika|Imane El|IE|;Hollywood|Ellen|E|;Uhlitskykh|Khrystyna|K|;Valentino|Emily|E|;Wan|Peter|P|;Hamilton|Casey|C|;Feng|Xiaoxing|X|;Johnston|Amanda|A|;Bomalaski|John|J|;Li|Chien-Feng|CF|;O'Reilly|Eileen M|EM|;Abou-Alfa|Ghassan K|GK|",
"chemical_list": "D014408:Biomarkers, Tumor; D009944:Organoplatinum Compounds; D011092:Polyethylene Glycols; D006867:Hydrolases; C512527:ADI PEG20; D002955:Leucovorin; D005472:Fluorouracil",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-018-3635-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-5704",
"issue": "82(3)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "ADI-PEG 20; Arginine; Arginine deiminase; Argininosuccinate synthetase-1; FOLFOX; Hepatocellular carcinoma",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor; D006528:Carcinoma, Hepatocellular; D005260:Female; D005472:Fluorouracil; D005770:Gastrointestinal Neoplasms; D006801:Humans; D006867:Hydrolases; D002955:Leucovorin; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D011092:Polyethylene Glycols; D000077982:Progression-Free Survival",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "429-440",
"pmc": null,
"pmid": "29971467",
"pubdate": "2018-09",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "29659672;18650514;19097774;19533750;23980077;27584578;24898783;28434648;25122679;20808309;27141887;26560030;25896651;27109103;27932229;20351325;26784254;16943526;12359751;25749046;25164070;28587170;28832976;28388291;15143074;28122247",
"title": "A phase 1 study of ADI-PEG 20 and modified FOLFOX6 in patients with advanced hepatocellular carcinoma and other gastrointestinal malignancies.",
"title_normalized": "a phase 1 study of adi peg 20 and modified folfox6 in patients with advanced hepatocellular carcinoma and other gastrointestinal malignancies"
} | [
{
"companynumb": "US-PFIZER INC-2018371847",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEUCOVORIN CALCIUM"
},
"drugadditional": "1",
... |
{
"abstract": "Relapsed myeloid disease after allogeneic stem cell transplantation (HSCT) remains largely incurable. We previously demonstrated the potent activity of immune checkpoint blockade in this clinical setting with ipilimumab or nivolumab. To define the molecular and cellular pathways by which CTLA-4 blockade with ipilimumab can reinvigorate an effective graft-versus-leukemia (GVL) response, we integrated transcriptomic analysis of leukemic biopsies with immunophenotypic profiling of matched peripheral blood samples collected from patients treated with ipilimumab following HSCT on the Experimental Therapeutics Clinical Trials Network 9204 trial. Response to ipilimumab was associated with transcriptomic evidence of increased local CD8+ T-cell infiltration and activation. Systemically, ipilimumab decreased naïve and increased memory T-cell populations and increased expression of markers of T-cell activation and costimulation such as PD-1, HLA-DR, and ICOS, irrespective of response. However, responding patients were characterized by higher turnover of T-cell receptor sequences in peripheral blood and showed increased expression of proinflammatory chemokines in plasma that was further amplified by ipilimumab. Altogether, these data highlight the compositional T-cell shifts and inflammatory pathways induced by ipilimumab both locally and systemically that associate with successful GVL outcomes. This trial was registered at www.clinicaltrials.gov as #NCT01822509.",
"affiliations": "Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.;Department of Data Science, Dana-Farber Cancer Institute, Boston, MA.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.;Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA.;Human Immune Monitoring Center at the Icahn School of Medicine at Mount Sinai, New York, NY.;Department of Data Science, Dana-Farber Cancer Institute, Boston, MA.;Department of Data Science, Dana-Farber Cancer Institute, Boston, MA.;Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.;Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA.;Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA.;Department of Data Science, Dana-Farber Cancer Institute, Boston, MA.;Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD; and.;Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD; and.;Department of Pathology and.;Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA.;Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA.;Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.;Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD; and.;Department of Data Science, Dana-Farber Cancer Institute, Boston, MA.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.;Human Immune Monitoring Center at the Icahn School of Medicine at Mount Sinai, New York, NY.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.;Department of Data Science, Dana-Farber Cancer Institute, Boston, MA.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.",
"authors": "Penter|Livius|L|0000-0002-9060-0207;Zhang|Yi|Y|0000-0002-7453-6188;Savell|Alexandra|A|;Huang|Teddy|T|;Cieri|Nicoletta|N|0000-0003-1340-6272;Thrash|Emily M|EM|0000-0002-3423-0336;Kim-Schulze|Seunghee|S|;Jhaveri|Aashna|A|;Fu|Jingxin|J|0000-0002-4028-3661;Ranasinghe|Srinika|S|;Li|Shuqiang|S|;Zhang|Wandi|W|;Hathaway|Emma S|ES|;Nazzaro|Matthew|M|;Kim|Haesook T|HT|;Chen|Helen|H|;Thurin|Magdalena|M|;Rodig|Scott J|SJ|;Severgnini|Mariano|M|;Cibulskis|Carrie|C|;Gabriel|Stacey|S|;Livak|Kenneth J|KJ|0000-0001-9105-5856;Cutler|Corey|C|0000-0001-8728-4314;Antin|Joseph H|JH|;Nikiforow|Sarah|S|;Koreth|John|J|;Ho|Vincent T|VT|;Armand|Philippe|P|;Ritz|Jerome|J|0000-0001-5526-4669;Streicher|Howard|H|;Neuberg|Donna|D|;Hodi|F Stephen|FS|;Gnjatic|Sacha|S|0000-0001-5643-9520;Soiffer|Robert J|RJ|;Liu|X Shirley|XS|;Davids|Matthew S|MS|;Bachireddy|Pavan|P|0000-0002-8698-4957;Wu|Catherine J|CJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1182/blood.2021010867",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "137(23)",
"journal": "Blood",
"keywords": "CHEMOKINES/chemokines; FFPE RNA-seq; IMMUNOBIOLOGY/tumor immunology; MARROW AND STEM CELL TRANSPLANTATION/basic biology; NEOPLASIA/myeloid leukemias and dysplasias: immunotherapeutic approaches; allogeneic stem cell transplantation; graft-versus-leukemia; ipilimumab; myeloid disease",
"medline_ta": "Blood",
"mesh_terms": null,
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "3212-3217",
"pmc": null,
"pmid": "33720354",
"pubdate": "2021-06-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D052061:Research Support, N.I.H., Extramural",
"references": "28679300;30578254;31341290;30904967;33277626;31985488;24755770;27622012;30626126;24583799;27912061;22130166;31481761;32478814;33111099;31633216;31069154;29637711;24357730;27410923",
"title": "Molecular and cellular features of CTLA-4 blockade for relapsed myeloid malignancies after transplantation.",
"title_normalized": "molecular and cellular features of ctla 4 blockade for relapsed myeloid malignancies after transplantation"
} | [
{
"companynumb": "DE-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-044028",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IPILIMUMAB"
},
"drugadd... |
{
"abstract": "Everolimus, an immunosuppressant, is approved for the treatment of advanced renal cell carcinoma, metastatic hormone receptor-positive breast cancer, and pancreatic neuroendocrine tumors (P-NETs) but has been reported to be related to hepatitis B reactivation. Here, we present the first case of fatal fulminant hepatitis B reactivation in a man with P-NET accompanied by multiple liver metastases who received everolimus and octreotide long-acting repeatable (LAR).\n\n\n\nA 45-year-old male had a history of chronic hepatitis B infection. He was found to have a complicated liver cyst incidentally, and then he underwent biopsy, which disclosed a grade 2 neuroendocrine tumor (NET). Subsequent MRI of the abdomen and PET revealed a solid mass at the pancreatic tail with numerous liver tumors favoring metastases and peripancreatic lymph node metastases. Transarterial chemoembolization (TACE) of the right lobe of the liver was performed, and he started to take 5 mg everolimus twice a day and 20 mg octreotide LAR every month 8 days after the 1st TACE. No hepatitis B virus (HBV) prophylaxis treatment was administered. He then underwent laparoscopic distal pancreatectomy and splenectomy three and half months after the initial treatment of everolimus. He continued everolimus 5 mg twice a day and octreotide 20 mg every month after the operation. Three months later, hepatic failure occurred due to acute hepatitis B flare-up-related fulminant hepatic failure since other possible causes of hepatic failure were excluded. Five days after hepatic failure presented, hepatic failure was apparent, and pulseless ventricular tachycardia occurred. The patient expired after failed resuscitation.\n\n\n\nA literature review of everolimus-related hepatitis B reactivation was conducted. In P-NET patients with chronic hepatitis B who will undergo everolimus treatment, HBV prophylaxis should be considered since fatal hepatitis B reactivation might occur under rare conditions.",
"affiliations": "Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan.;Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan.;Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan.;Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan.;Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan.;Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan.;Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan.",
"authors": "Chang|Shih-Chun|SC|;Tsai|Chun-Yi|CY|;Liu|Keng-Hao|KH|;Wang|Shang-Yu|SY|;Hsu|Jun-Te|JT|;Yeh|Ta-Sen|TS|;Yeh|Chun-Nan|CN|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fendo.2021.639967",
"fulltext": "\n==== Front\nFront Endocrinol (Lausanne)\nFront Endocrinol (Lausanne)\nFront. Endocrinol.\nFrontiers in Endocrinology\n1664-2392\nFrontiers Media S.A.\n\n10.3389/fendo.2021.639967\nEndocrinology\nCase Report\nEverolimus Related Fulminant Hepatitis in Pancreatic Neuroendocrine Tumor With Liver Metastases: A Case Report and Literature Review\nChang Shih-Chun\n\nTsai Chun-Yi\nLiu Keng-Hao\nWang Shang-yu\nHsu Jun-Te\nYeh Ta-Sen\nYeh Chun-Nan *\n\nDepartment of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan\nEdited by: Annamaria Anita Livia Colao, University of Naples Federico II, Italy\n\nReviewed by: Christian Albert Koch, Fox Chase Cancer Center, United States; Elisa Giannetta, Sapienza University of Rome, Italy\n\n*Correspondence: Chun-Nan Yeh, yehchunnan@gmail.com\nThis article was submitted to Cancer Endocrinology, a section of the journal Frontiers in Endocrinology\n\n01 4 2021\n2021\n12 63996724 12 2020\n03 3 2021\nCopyright © 2021 Chang, Tsai, Liu, Wang, Hsu, Yeh and Yeh\n2021\nChang, Tsai, Liu, Wang, Hsu, Yeh and Yeh\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nBackground\n\nEverolimus, an immunosuppressant, is approved for the treatment of advanced renal cell carcinoma, metastatic hormone receptor-positive breast cancer, and pancreatic neuroendocrine tumors (P-NETs) but has been reported to be related to hepatitis B reactivation. Here, we present the first case of fatal fulminant hepatitis B reactivation in a man with P-NET accompanied by multiple liver metastases who received everolimus and octreotide long-acting repeatable (LAR).\n\nCase Presentation\n\nA 45-year-old male had a history of chronic hepatitis B infection. He was found to have a complicated liver cyst incidentally, and then he underwent biopsy, which disclosed a grade 2 neuroendocrine tumor (NET). Subsequent MRI of the abdomen and PET revealed a solid mass at the pancreatic tail with numerous liver tumors favoring metastases and peripancreatic lymph node metastases. Transarterial chemoembolization (TACE) of the right lobe of the liver was performed, and he started to take 5 mg everolimus twice a day and 20 mg octreotide LAR every month 8 days after the 1st TACE. No hepatitis B virus (HBV) prophylaxis treatment was administered. He then underwent laparoscopic distal pancreatectomy and splenectomy three and half months after the initial treatment of everolimus. He continued everolimus 5 mg twice a day and octreotide 20 mg every month after the operation. Three months later, hepatic failure occurred due to acute hepatitis B flare-up–related fulminant hepatic failure since other possible causes of hepatic failure were excluded. Five days after hepatic failure presented, hepatic failure was apparent, and pulseless ventricular tachycardia occurred. The patient expired after failed resuscitation.\n\nConclusion\n\nA literature review of everolimus-related hepatitis B reactivation was conducted. In P-NET patients with chronic hepatitis B who will undergo everolimus treatment, HBV prophylaxis should be considered since fatal hepatitis B reactivation might occur under rare conditions.\n\nacute hepatitis B flare-up\neverolimus\nfulminant hepatitis B\nneuroendocrine tumor (NE tumor)\npancreatic neuroendocrine tumor (pNET)\n==== Body\nBackground\n\nEverolimus, at type of mammalian target of rapamycin (mTOR) inhibitor, is approved for the treatment of advanced renal cell carcinoma, metastatic hormone receptor-positive breast cancer, and pancreatic neuroendocrine tumors (P-NETs). However, as an immunosuppressant, everolimus has been reported to be related to hepatitis B reactivation. Previous publications have proposed fatal hepatitis B reactivation in patients receiving everolimus for metastatic breast cancer and advanced renal cell carcinoma. Here, we present the first case of fatal fulminant hepatitis B reactivation in a man with P-NET accompanied by multiple liver metastases who received everolimus and octreotide long-acting repeatable (LAR).\n\nCase Report\n\nA 45-year-old male had a history of chronic hepatitis B infection and hypertension and a mild increase in glucose levels. He had been regularly followed up in a gastrointestinal outpatient clinic for chronic hepatitis B infection. Half a year before admission, a complicated liver cyst was incidentally found on liver sonography in another hospital, where computed tomography (CT)-guided biopsy of the complicated liver cyst was performed. The pathology report revealed grade 2 neuroendocrine tumors (NETs) with a mitotic figure of 7 in 10 high-power fields. Immunohistochemical staining confirmed the diagnosis of NETs with positive chromogranin A, synaptophysin, and CD 56 staining. The lesion was negative for CK-7 and hepatocellular carcinoma markers, including Hepar-1, arginase-1, and glypican-3. Metastatic NET was considered. During this period, there was no abdominal pain, flushing, or diarrhea but mild cold sweating.\n\nHe was then hospitalized in our hospital. The hemogram and biochemistry investigations were normal, including serum carbohydrate antigen 19-9 (CA 19-9) levels (<0.6 IU/L, normal: <37 IU/L), carcinoembryonic antigen (CEA) levels (1.36 ng/mL, normal: <5 ng/mL), and alpha-fetoprotein levels (3.8 ng/mL, normal: <9 ng/mL). Serum chromogranin A levels were elevated (119.80 ng/mL, normal: <101.9 ng/mL), but adrenal function (cortisol 12.87 µg/dL, normal: 7-9AM 4.2-22.4 µg/dL, 3-5PM 3.1-16.7 µg/dL; adrenocorticotropic hormone (ACTH) 35.10 pg/mL, normal: 7.2-63.3 pg/mL), gastrin levels (44.2 pg/mL, normal: 28-185 pg/mL), and C-peptide levels (4.5 ng/mL, 1.1-4.4 ng/mL) were all within the normal range, as were urinary vanillylmandelic acid (VMA) (8.1 mg/day, normal: 1.9-9.8 mg/day) and 5-hydroxyindoleacetic acid (5-HIAA) (4.8 mg/day, normal: 2-6 mg/day) levels. Hepatitis B surface antigen (HBsAg) (7069.00, nonreactive: <0.9, equivocal: 0.9-10, reactive: >10), anti-HBs antibody (528.50 IU/L, nonreactive: <10), and anti-HBc antibody (0.005, non-reactive: >1.0) were all reactive but nonreactive to anti-hepatitis C virus (HCV) antibody. Subsequent abdominal CT showed a pancreatic body cystic tumor approximately 1.5 cm in size ( Figure 1A ) and a suspected pancreatic tail tumor associated with liver tumors in the right and left lobes ( Figure 1B ). Magnetic resonance imaging (MRI) of the abdomen revealed a solid mass at the pancreatic tail with numerous liver tumors favoring metastases. The pancreatic body tumor was a cyst ( Figure 2A ). Positron emission tomography (FDG-PET) with MRI also showed peripancreatic lymph node metastases ( Figure 2B ). Transarterial chemoembolization (TACE) of the right lobe of the liver was performed during this admission. He was discharged 3 days after TACE.\n\nFigure 1 (A) Abdominal computed tomography showed a pancreatic body tumor approximately 1.5 cm in size associated with liver tumors in the right and left lobes. Adrenal glands were normal without enlargement. (B) A suspected tumor at the pancreatic tail was disclosed on enhanced abdominal computed tomography (white arrow).\n\nFigure 2 (A) MRI of the abdomen revealed a solid mass at the pancreatic tail with numerous liver tumors favoring metastases. The pancreatic body tumor was a cyst. (B) PET with MRI also showed peripancreatic lymph node metastases.\n\nHe started to take 5 mg everolimus twice a day and 20 mg octreotide LAR every 28 days, starting from 8 days after the 1st TACE. No hepatitis B virus (HBV) prophylaxis treatment was administered. After he took everolimus for three months and octreotide 3 times, and subsequent abdominal CT showed stationary pancreatic NETs but decreased liver metastasis nodule numbers, suggesting partial response to concurrent everolimus ( Figures 3A, B ). Therefore, he underwent laparoscopic distal pancreatectomy and splenectomy three and half months after the initial treatment of everolimus. The pathology report revealed grade 2 NETs of the pancreas with direct invasion of the spleen. Immunohistochemical analysis revealed that tumor cells were positive for CD56, chromogranin A, synaptophysin and beta-catenin on the membrane and negative for insulin. Ki-67 index was 15% ( Figures 4A, B ). The postoperative course was uneventful, and he was discharged 7 days after the surgery.\n\nFigure 3 Abdominal computed tomography after 3 months of treatment with everolimus showed stationary pancreatic neuroendocrine tumors (A, white arrow) but decreasing liver metastasis nodule numbers (B), suggesting a partial response to everolimus.\n\nFigure 4 Pathology from distal pancreatectomy showed a neuroendocrine tumor with numerous mitotic figures (A). Immunohistochemical analysis revealed that tumor cells were all positive for CD56, chromogranin A, synaptophysin, and beta-catenin on the membrane but negative for insulin. Ki-67 index was 15%. Therefore, it was a grade 2 neuroendocrine tumor (B).\n\nHe continued everolimus 5 mg twice a day and octreotide 20 mg every 28 days after the operation. No HBV prophylaxis treatment was administered as before. Two and half months after the surgery, he underwent abdominal CT for follow-up, which disclosed no evidence of local recurrence at the pancreas and regression of the liver tumor where previous TACE was performed; the other liver metastases appeared as stable disease.\n\nApproximately 2 weeks after the last abdominal CT, he had general weakness with an icteric look and then coma. He visited another hospital abroad, and was initially hospitalized there; hepatic failure progressed there. Four days later, he was transferred back to our hospital and admitted to the intensive care unit (ICU). The hemogram and biochemistry study showed coagulopathy but no thrombocytopenia (international normalized ratio (INR) 2.9, platelet count 22,6000/µL), jaundice (total bilirubin 11.1 mg/dL, direct bilirubin 6.9 mg/dL), abnormal liver function test (aspartate aminotransferase (AST) 824 U/L, alanine aminotransferase (ALT) 636 U/L), azotemia (blood urea nitrogen (BUN) 21.2 mg/dL, creatinine 5.87 mg/dL) or elevation in ammonia level (408 µg/dL). The HBV DNA level was 1.832509 million cps/ml, and the anti-hepatitis B e antibody was reactive, so entecavir was prescribed. Anti-hepatitis C antibody, CMV-IgM, HIV antigen, EB-VCA IgM, and RPR were all nonreactive. Acute hepatitis B flare-up–related fulminant hepatic failure was diagnosed since other possible causes of hepatic failure were excluded. However, general tonic clonic seizures occurred in the ICU, but brain CT showed no obvious lesions. Five days after hepatic failure was apparent, pulseless ventricular tachycardia occurred. The patient expired after failed resuscitation.\n\nDiscussion\n\nEverolimus is approved as a single agent for the treatment of advanced renal cell carcinoma and P-NETs and as combination treatment with exemestane for the treatment of hormone receptor-positive breast cancer (1–3). Pavel et al. published the randomized, double-blind, placebo-controlled, phase 3 RADIANT-2 study in which median progression-free survival (PFS) improved for 5.1 months with everolimus plus octreotide LAR compared with placebo plus octreotide LAR in patients with low- or intermediate-grade advanced NETs and a history of carcinoid symptoms (4). Despite no significant improvement in PFS, the latest result of the final overall survival from the RADIANT-2 study was positive with a hazard ratio of 1.08 (5), and everolimus plus octreotide LAR was still considered an effective approach for these patients. This finding was supported by our patient having stable disease of the original P-NET tumor but significant improvement in liver metastases, in which the tumor burden seemed decreased under the control of everolimus plus LAR. However, acute flare-up of hepatitis B leading to fulminant hepatic failure occurred when everolimus plus LAR was used for 5.5 months. One out of 204 patients in the RADIANT-2 trial developed fatal HBV reactivation (4). A similar event has been reported in a patient with metastatic breast cancer who received treatment with everolimus plus exemestane for a 15-day period (6). Everolimus-related acute hepatitis reactivation has also been reported in renal cell carcinoma, in which one event occurred after a 3-month period of everolimus use and another after a 5-month period (7, 8). The latter patient died of fulminant hepatitis. Table 1 summarizes the case reports on everolimus-related HBV reactivation. According to the literature review, this rare but fatal event seems to occur from 0.5 to 6 months after the start of use of everolimus. In breast cancer, fatal events seem to occur earlier (0.5 months and 3 months), and in renal cell carcinoma, they seem to occur later (both 5 months). The fatal event in our case tended to occur later (5.5 months), which is similar to that in renal cell carcinoma. However, since the number of case reports is still limited, the risk factors and the duration of HBV reactivation after everolimus use still need further investigation.\n\nTable 1 Case reports about everolimus related HBV reactivation.\n\nYear\tDisease\tMedicine used\tDuration of treatment till HBV reactivation\tTreatment of HBV reactivation\tOutcome\t\n2013 Sezgin et al. (7)\tRCC with lung and axillary metastases\tEverolimus 10mg daily then tapering to 5mg daily\t5 months\tTenofovir\tResolved\t\n2013, Shinta et al. (8)\tRCC with lung metastases\tEverolimus\t5 months\tEntecavir and steroid pulse therapy (methylprednisolone, 1000 mg/day for 3 days with gradual tapering)\tDied\t\n2013, Eleonora et al. (6)\tBreast cancer with lung, bone, pancreas, intramuscular metastases\tEverolimus 10mg daily+ exemestane 25mg daily\t24 days\tTenofovir\tDied\t\n2016, Olivier et al. (3)\tBreast cancer with bone metastases\tEverolimus 10mg daily+ exemestane 25mg daily\t3 months\tEntecavir\tResolved\t\n2021\nChang et al.\tP-NET accompanied by multiple liver metastases\tEverolimus 5mg twice a day + long acting octreotide 20mg every month\t5.5 months\tEntecavir\tDied\t\nRCC, Renal cell carcinoma.\n\nBased on recent estimates, approximately 350 million people worldwide suffer from chronic hepatitis B infection (9). HBV reactivation is defined as a sudden and rapid increase in the HBV DNA level by at least 100-fold in patients with previously detectable HBV DNA or the reappearance of HBV DNA viremia in individuals who did not have viremia before the initiation of immunosuppressive or biological modifier therapy or cancer chemotherapy. Five stages have been proposed regarding HBV reactivation related to immunosuppressive or biological modifier therapy or cancer chemotherapy (9). HBV reactivation should particularly be paid attention to when people are exposed to cancer chemotherapy, immunosuppressive therapy, or biologic therapies for the management of malignancies or benign conditions, such as rheumatologic conditions, inflammatory bowel disease, dermatologic conditions, or solid-organ or bone marrow transplantation (9, 10). Table 2 summarizes cytotoxic and immunosuppressive agents that have been reported to be related to HBV reactivation.\n\nTable 2 Cytotoxic or immunosuppressive agents associated with HBV reactivation (6, 11).\n\nAlkylating agents\tCyclophosphamide, Chlorambucil, Cisplatin, Temozolomide, Procarbazine\t\nAlkaloids\tVincristine, Vinblastine\t\nAntimetabolites\tCytarabine, Fluorouracil, Gemcitabine, Mercaptopurine, Methotrexate, Thioguanine\t\nMonoclonal antibodies\tRituximab (anti-CD20)\nAlemtuzumab (anti-CD52)\nMogamulizumab (anti CC-chemokine receptor 4)\nAnti-TNF-alpha (infliximab, adalimumab, golimumab, and certolizumab)\t\nOther cytotoxic agents\tDocetaxel, Etoposide, Fludarabine, Mitomycin,\nBleomycin\t\nTyrosine kinase inhibitor (TKI)\tImatinib, Nilotinib, Dasatinib, Erlotinib, Ibrutinib\t\nOther\tInterferon\t\n\nEverolimus is an mTOR inhibitor, and other similar medicines include rapamycin. The immunosuppressive properties of everolimus may predispose patients to opportunistic infections and/or the reactivation of previous infections. As expected, infective pneumonia and other bacterial and invasive fungal infections have been reported in patients treated with everolimus, as well as the reactivation of viral infections (7, 12), including hepatitis E virus (13–16). Another mTOR inhibitor, sirolimus, has also been reported to be associated with the reactivation of hepatitis B with octreiotide previously (17). The possible mechanism was that octreotide has been proposed to significantly reduced hepatic blood flow that decreased the liver metabolic activity in patients with hepatitis B surface antigen positive cirrhotic patients, which might be relevant to the reactivation of hepatitis B (18). In addition, somatostatin has been be hypothesized to be related to autocrine and paracrine regulatory role, and via neuro-endocrine modulation of the immune response, it might represent a direct regulatory relation between the nervous and immune system (19). Consequently, as an analogue of somatostatin, octreotide might play similar role. In contrast, several mechanisms have been proposed regarding the relationship between HBV inactivation, instead of activation, from mTOR inhibitors (20–22). Consequently, the mechanism by which fulminant hepatitis B originates from everolimus remains unclear.\n\nDue to the increased risk of the reactivation of hepatitis B in patients who will receive immunosuppressive or cytotoxic therapies, many institutes have suggested screening before treatment is initiated, with at least HBsAg, anti-HBc, and anti-HBs (9, 10, 23–28); all those who are negative for HBsAg, anti-HBc, and anti-HBS should be vaccinated against HBV. Although no guidelines are available concerning the feasibility of antiviral prophylaxis combined with everolimus in treating P-NET or breast cancer, lamivudine, entecavir or tenofovir were suggested for anti-HBV prophylaxis in advanced renal cell carcinoma patients receiving everolimus (29). The duration of prophylaxis remains inconclusive. However, according to the European Association for the Study of the Liver (EASL) 2017 clinical practice guidelines, HBV prophylaxis should continue for at least 12 months and 18 months for rituximab-based regimens after the cessation of immunosuppressive treatment and discontinued only if the underlying disease is under remission. Close follow-up is also suggested, including liver function tests and HBV DNA during prophylaxis lasting for at least 12 months after antiviral agent withdrawal, since HBV reactivation might develop after antiviral agent discontinuation (26).\n\nIn conclusion, in P-NET patients who will receive everolimus plus octreotide LAR, HBV reactivation might occur, though the incidence is low. The duration of everolimus use for HBV reactivation is still inconclusive. The mechanism between everolimus and hepatitis B reactivation remains unclear. The protocol for HBV prophylaxis in everolimus is not well established. However, since fatal reactivation events have been reported in advanced renal cell carcinoma and metastatic breast cancer, clinicians should consider routine HBV screening and antiviral prophylaxis before everolimus therapy is initiated for P-NET patients receiving everolimus plus octreotide LAR.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.\n\nEthics Statement\n\nWritten informed consent was obtained from the patient’s family for the publication of this case report and any accompanying images.\n\nAuthor Contributions\n\nC-YT, K-HL and S-YW: discussion and review about the organization of this article, and also deal with the pathology and image of this article. J-TH and T-SY: assist with the revised of article. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThis work was supported by the Chang Gung Medical Research Program, Taiwan.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n\n1 Steelman LS Martelli AM Cocco L Libra M Nicoletti F Abrams SL . The therapeutic potential of mTOR inhibitors in breast cancer. Br J Clin Pharmacol (2016) 82 (5 ):1189–212. 10.1111/bcp.12958\n2 Baselga J Campone M Piccart M Burris HA3 Rugo HS Sahmoud T . Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med (2012) 366 (6 ):520–9. 10.1056/NEJMoa1109653\n3 Mir O Toulmonde M Coriat R Ropert S Loulergue P . Hepatitis B reactivation during everolimus treatment. Acta Oncol (2016) 55 (12 ):1505–6. 10.1080/0284186X.2016.1230275\n4 Pavel ME Hainsworth JD Baudin E Peeters M Hörsch D Winkler RE . Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet (2011) 378 (9808 ):2005–12. 10.1016/S0140-6736(11)61742-X\n5 Pavel ME Baudin E Öberg KE Hainsworth JD Voi M Rouyrre N . Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study. Ann Oncol (2017) 28 (7 ):1569–75. 10.1093/annonc/mdx193\n6 Teplinsky E Cheung D Weisberg I Jacobs REA Wolff M Park J . Fatal hepatitis B reactivation due to everolim0us in metastatic breast cancer: case report and review of literature. Breast Cancer Res Treat (2013) 141 (2 ):167–72. 10.1007/s10549-013-2681-0\n7 Göksu SS Bilal S Coşkun HŞ . Hepatitis B reactivation related to everolimus. World J Hepatol (2013) 5 (1 ):43–5. 10.4254/wjh.v5.i1.43\n8 Mizuno S Yoshiyuki Y Ebinuma H Nakamoto N Katahira M Sasaki A . Progressive liver failure induced by everolimus for renal cell carcinoma in a 58-year-old male hepatitis B virus carrier. Clin J Gastroenterol (2013) 6 (2 ):188–92. 10.1007/s12328-013-0371-4\n9 Loomba R Liang TJ . Hepatitis B Reactivation Associated With Immune Suppressive and Biological Modifier Therapies: Current Concepts, Management Strategies, and Future Directions. Gastroenterology (2017) 152 (6 ):1297–309. 10.1053/j.gastro.2017.02.009\n10 Doo EC Hoofnagle JH Rodgers GP . NIH consensus development conference: management of hepatitis B. Introduction. Hepatology (2009) 49 (5 Suppl ):S1–3. 10.1002/hep.22993\n11 Chang CS Tsai C-Y Yan SL . Hepatitis B reactivation in patients receiving targeted therapies. Hematology (2017) 22 (10 ):592–8. 10.1080/10245332.2017.1321882\n12 Carmine D’Aniello ,MM Umberto B . Prevention of Hepatitis B Virus Reactivation With Lamivudine in a Patient With Advanced Renal Cell Carcinoma Treated With Everolimus. Am J Ther (2016) 23 (1 ):e300–3. 10.1097/MJT.0000000000000005\n13 Zhou X Wang Y Metselaar HJ Janssen HL Peppelenbosch MP Pan Q . Rapamycin and everolimus facilitate hepatitis E virus replication: revealing a basal defense mechanism of PI3K-PKB-mTOR pathway. J Hepatol (2014) 61 (4 ):746–54. 10.1016/j.jhep.2014.05.026\n14 Gingras AC Raught B Sonenberg N . eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu Rev Biochem (1999) 68 :913–63. 10.1146/annurev.biochem.68.1.913\n15 Kaur S Lal L Sassano A Majchrzak-Kita B Srikanth M Baker DP . Regulatory effects of mammalian target of rapamycin-activated pathways in type I and II interferon signaling. J Biol Chem (2007) 282 (3 ):1757–68. 10.1074/jbc.M607365200\n16 Colina R Costa-Mattioli M Dowling RJ Jaramillo M Tai LH Breitbach CJ . Translational control of the innate immune response through IRF-7. Nature (2008) 452 (7185 ):323–8. 10.1038/nature06730\n17 Defilippis EM Ludwig E . Fatal Hepatitis B Reactivation in a Patient with Islet Cell Tumor on Octreotide and Sirolimus. J Gastrointest Oncol (2015) 6 (5 ):E66–9. 10.3978/j.issn.2078-6891.2015.042\n18 Lin HC Tsai YT Lee SD Hsia HC Meng HC Wang SS . Octreotide Decreased Liver Metabolic Activity in Patients with Hepatitis B Surface Antigen-Positive Cirrhosis. Clin Pharmacol Ther (1992) 52 (2 ):134–9. 10.1038/clpt.1992.122\n19 Hagen PV Krenning EP Kwekkeboom DJ Reubi JC Anker-Lugtenburg PJ Löwenberg B . Somatostatin and the Immune and Haematopoetic System; a Review. Eur J Clin Invest (1993) 24 (2 ):91–9. 10.1111/j.1365-2362.1994.tb00972.x\n20 HY K Jhun JY Cho ML Choi JY Byun JK Kim EK . Interleukin-6 upregulates Th17 response via mTOR/STAT3 pathway in acute-on-chronic hepatitis B liver failure. J Gastroenterol (2014) 49 (8 ):1264–73. 10.1007/s00535-013-0891-1\n21 H G Zhou T Jiang D Cuconati A Xiao GH Block TM . Regulation of hepatitis B virus replication by the phosphatidylinositol 3-kinase-akt signal transduction pathway. J Virol (2007) 81 (18 ):10072–80. 10.1128/JVI.00541-07\n22 Wang Z Jin W Jin H Wang X . mTOR in viral hepatitis and hepatocellular carcinoma: function and treatment. BioMed Res Int (2014) 2014 :735672. 10.1155/2014/735672 24804240\n23 Reddy KR Beavers KL Hammond SP Lim JK Falck-Ytter YT American Gastroenterological Association Institute. American Gastroenterological Association Institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology (2015) 148 (1 ):215–9. 10.1053/j.gastro.2014.10.039\n24 AS L McMahon BJ . Chronic hepatitis B: update 2009. Hepatology (2009) 50 (3 ):661–2. 10.1002/hep.23190\n25 Khokhar OS Farhadi A McGrail L Lewis JH . Oncologists and hepatitis B: a survey to determine current level of awareness and practice of antiviral prophylaxis to prevent reactivation. Chemotherapy (2009) 55 (2 ):69–75. 10.1159/000183731 19077421\n26 European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol (2017) 67 (2 ):370–98. 10.1016/j.jhep.2017.03.021\n27 Hwang JP Somerfield MR Alston-Johnson DE Cryer DR Feld JJ Kramer BS . Hepatitis B Virus Screening for Patients With Cancer Before Therapy: American Society of Clinical Oncology Provisional Clinical Opinion Update. J Clin Oncol (2015) 33 (19 ):2212–20. 10.1200/JCO.2015.61.3745\n28 Sarin SK Kumar M Lau GK Abbas Z Chan HL Chen CJ . Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int (2016) 10 (1 ):1–98. 10.1007/s12072-015-9675-4\n29 Porta C Osanto S Ravaud A Climent MA Vaishampayan U White DA . Management of adverse events associated with the use of everolimus in patients with advanced renal cell carcinoma. Eur J Cancer (2011) 47 (9 ):1287–98. 10.1016/j.ejca.2011.02.014\n\n",
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"journal": "Frontiers in endocrinology",
"keywords": "acute hepatitis B flare-up; everolimus; fulminant hepatitis B; neuroendocrine tumor (NE tumor); pancreatic neuroendocrine tumor (pNET)",
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"title": "Everolimus Related Fulminant Hepatitis in Pancreatic Neuroendocrine Tumor With Liver Metastases: A Case Report and Literature Review.",
"title_normalized": "everolimus related fulminant hepatitis in pancreatic neuroendocrine tumor with liver metastases a case report and literature review"
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"abstract": "Some elderly patients on chronic lithium therapy for bipolar disorder and their doctors may be faced with a therapeutic dilemma over whether or not to continue prescribing/taking lithium given their increased risk of reduced renal function. We present the case of a 78-year-old woman with bipolar disorder who discontinued lithium therapy due to increased risk factors for renal injury. After discontinuation, she experienced markedly decreased appetite secondary to a depressive episode, and developed acute renal failure, which subsequently progressed to a more advanced stage of chronic kidney disease. This case suggests that extreme care must be taken to prevent the recurrence of depression in elderly patients with bipolar disorder who discontinue lithium therapy, even when they had been emotionally stable for a long time while receiving lithium. Medications other than lithium for bipolar disorder may be needed at the time lithium therapy is discontinued.",
"affiliations": "Department of Neuropsychiatry, Nara Hospital, Kinki University Faculty of Medicine, Ikoma, Nara, Japan.",
"authors": "Okada|Akira|A|",
"chemical_list": "D014150:Antipsychotic Agents; D008094:Lithium",
"country": "England",
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"issue": "2014()",
"journal": "BMJ case reports",
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"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D014150:Antipsychotic Agents; D001066:Appetite; D001714:Bipolar Disorder; D003863:Depression; D003866:Depressive Disorder; D001068:Feeding and Eating Disorders; D005260:Female; D006801:Humans; D008094:Lithium; D012008:Recurrence; D051436:Renal Insufficiency, Chronic; D012307:Risk Factors",
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"title": "Acute renal failure induced by markedly decreased appetite secondary to a depressive episode after discontinuation of long-term lithium therapy in an elderly patient with bipolar disorder.",
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"abstract": "BACKGROUND\nCefuroxime very rarely causes drug-induced liver injury. We present a case of a patient with paradoxical worsening of jaundice caused by cefuroxime-induced cholestasis following therapeutic endoscopic retrograde cholangiopancreatography for a distal common bile duct stone.\n\n\nMETHODS\nA 51-year-old, previously healthy Sri Lankan man presented to our hospital with obstructive jaundice caused by a distal common bile duct stone. Endoscopic retrograde cholangiopancreatography with stone extraction, common bile duct clearance, and stenting failed to improve the cholestasis, with paradoxical worsening of his jaundice. A liver biopsy revealed features of drug-induced intrahepatic cholestasis. Although his case was complicated by an episode of cholangitis, the patient made a complete recovery in 4 months with supportive treatment and withdrawal of the offending drug.\n\n\nCONCLUSIONS\nThis case highlights a very rare drug-induced liver injury caused by cefuroxime as well as our approach to treating a patient with paradoxical worsening of jaundice after therapeutic endoscopic retrograde cholangiopancreatography.",
"affiliations": "Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka. maduniln@yahoo.co.uk.;Colombo North Teaching Hospital, Ragama, Sri Lanka.;Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.;Faculty of Medical Sciences, University of Sri Jayawardenapura, Colombo, Sri Lanka.;Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.;Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.",
"authors": "Niriella|Madunil Anuk|MA|;Kumarasena|Ravindu Sujeewa|RS|;Dassanayake|Anuradha Supun|AS|;Pathirana|Aloka|A|;de Silva Hewavisenthi|Janaki|J|;de Silva|Hithanadura Janaka|HJ|",
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"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 112310.1186/s13256-016-1123-0Case ReportWorsening cholestasis and possible cefuroxime-induced liver injury following “successful” therapeutic endoscopic retrograde cholangiopancreatography for a distal common bile duct stone: a case report Niriella Madunil Anuk +94 11 2953409maduniln@yahoo.co.uk 1Kumarasena Ravindu Sujeewa ravindukumarasena@gmail.com 2Dassanayake Anuradha Supun anuradhadassa@gmail.com 1Pathirana Aloka alokapathi@gmail.com 3de Silva Hewavisenthi Janaki jhewavisenthi@yahoo.co.uk 1de Silva Hithanadura Janaka hjanakadesilva@gmail.com 11 Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka 2 Colombo North Teaching Hospital, Ragama, Sri Lanka 3 Faculty of Medical Sciences, University of Sri Jayawardenapura, Colombo, Sri Lanka 21 12 2016 21 12 2016 2016 10 37130 4 2016 1 11 2016 © The Author(s). 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nCefuroxime very rarely causes drug-induced liver injury. We present a case of a patient with paradoxical worsening of jaundice caused by cefuroxime-induced cholestasis following therapeutic endoscopic retrograde cholangiopancreatography for a distal common bile duct stone.\n\nCase presentation\nA 51-year-old, previously healthy Sri Lankan man presented to our hospital with obstructive jaundice caused by a distal common bile duct stone. Endoscopic retrograde cholangiopancreatography with stone extraction, common bile duct clearance, and stenting failed to improve the cholestasis, with paradoxical worsening of his jaundice. A liver biopsy revealed features of drug-induced intrahepatic cholestasis. Although his case was complicated by an episode of cholangitis, the patient made a complete recovery in 4 months with supportive treatment and withdrawal of the offending drug.\n\nConclusions\nThis case highlights a very rare drug-induced liver injury caused by cefuroxime as well as our approach to treating a patient with paradoxical worsening of jaundice after therapeutic endoscopic retrograde cholangiopancreatography.\n\nKeywords\nCefuroximeDrug-induced liver injuryCholestasisERCPissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nCefuroxime is a second-generation cephalosporin known to very rarely cause drug-induced liver injury (DILI). There have been fewer than five previously reported cases of cefuroxime causing DILI and cholestasis. In a follow-up of a previous report of liver injury caused by ampicillin, Köklü et al. [1] described a case of a 23-year-old man who redeveloped liver injury 17 days after starting a 10-day course of oral cefuroxime (bilirubin 0.7 mg/dl, alanine transaminase [ALT] 427 U/L, alkaline phosphatase [ALP] 646 U/L), which resolved within 2 months, suggesting cross-reactivity with ampicillin. In a report by Chalasani et al. for the Drug-Induced Liver Injury Network [2], among 300 cases of DILI in the United States collected between 2004 and 2008, 5 cases were attributed to cephalosporin, with single cases linked to cefuroxime. In another report, Ekiz et al. described a 60-year-old woman who developed jaundice 4 days after a 10-day course of oral cefuroxime (bilirubin 17.9 mg/dl rising to 30 mg/dl, ALT 1527 U/L, ALP 1006 U/L), with progressive worsening of international normalized ratio (INR) [1.9] and referral for transplant but with a subsequent full recovery [3]. Given the paucity of case reports of cefuroxime-induced DILI, this drug belongs to category D (one to four reported cases) according to a recently suggested categorization of drugs implicated in hepatotoxicity and DILI [4]. In this report, we present a case of a patient with paradoxical worsening of jaundice due to possible drug-induced cholestasis caused by cefuroxime following therapeutic endoscopic retrograde cholangiopancreatography (ERCP) for distal common bile duct (CBD) obstruction by a stone.\n\nCase presentation\nA previously healthy, 51-year-old Sri Lankan man presented with right upper quadrant colicky abdominal pain of 3 days’ duration. The pain was associated with yellow discoloration of the eyes, passage of dark urine, and generalized itching. He had no significant past medical, environmental, or social history. His clinical examination revealed that he was afebrile but had deep icterus, excoriations, and mild right upper quadrant abdominal tenderness. He had no stigmata of chronic liver disease.\n\nThe results of laboratory investigations included a normal full blood count and inflammatory markers, deranged liver biochemistry (total bilirubin 6.4 mg/dl, ALP 325 IU/L, aspartate transaminase [AST] 113 U/L, ALT 318 U/L), normal liver function (serum albumin 3.8 g/dl, serum globulin 2.6 g/dl, INR 1.00, activated partial thromboplastin time [APTT] 29 seconds), and normal renal profile. An ultrasound scan (USS) of the abdomen showed the presence of cholelithiasis with features of chronic cholecystitis and a dilated CBD and intrahepatic ducts due to a distal CBD obstruction. Contrast-enhanced computed tomography of the abdomen confirmed the presence of a distal CBD stone causing proximal CBD and intrahepatic duct dilation and cholelithiasis.\n\nThe patient underwent ERCP with sphincterotomy and balloon extraction of a CBD stone 2 weeks from the onset of symptoms. After surgery, the patient was given intravenous cefuroxime 750 mg three times daily for 1 day, followed by oral cefuroxime 500 mg twice daily for 5 days. The patient’s symptoms and biochemistry failed to improve, with worsening of cholestasis (total bilirubin 20.3 mg/dl, ALP 537 IU/L) following the “successful” therapeutic ERCP. Repeat ERCP 1 week later showed a normal CBD with no residual CBD stones. A 10-French, 10-cm CBD stent was inserted at this stage.\n\nThe patient was then referred to a hepatologist for evaluation of worsening jaundice post-ERCP. By this time, the patient’s obstructive jaundice symptoms were severe and disabling, and biochemical analysis revealed worsening cholestasis (total bilirubin 39 mg/dl, ALP 651 IU/L), relatively normal liver enzymes (AST 61 U/L, ALT 62 U/L, gamma-glutamyltransferase [GGT] 25 U/L] with normal liver function (serum albumin 3.7 g/dl, serum globulin 1.9 g/dl, INR 1.00, APTT 29 seconds), normal full blood count, normal inflammatory markers, and normal renal profile. Repeat USS of the abdomen revealed multiple cholelithiasis, chronic cholecystitis, stent in the CBD, and no intrahepatic biliary radical dilation. Test results for the patient’s hepatitis A immunoglobulin M (IgM), hepatitis E antibodies, hepatitis B surface antigen, anti-hepatitis C antibodies, and Leptospira IgM antibodies were negative.\n\nOn the basis of all the above-mentioned information, an ultrasound-guided liver biopsy was performed. The patient was commenced on prednisolone 40 mg daily, ursodeoxycholic acid 300 mg three times daily, and cholestyramine 5 g three times daily for symptomatic relief. A liver biopsy showed no evidence of portal tract edema or inflammation, lesions or paucity of bile ducts, bile infarcts or leaks, or inflammation or interphase hepatitis. However, there was marked bilirubinostasis in zone 3 canaliculi, with surrounding hepatocytes revealing feathery degeneration and surrounding inflammation (Fig. 1). These features were compatible with intrahepatic cholestasis related to either drugs or sepsis.Fig. 1 Hepatic parenchyma around the central vein (lower left) showing cholestasis, feathery degeneration, inflammation, and lobular disarray (hematoxylin and stain, original magnification ×400)\n\n\n\n\nOne week later, the patient developed fever with chills and rigors, worsening cholestasis clinically and biochemically (total bilirubin 48 mg/dl, ALP 901 IU/L) with relatively normal liver enzymes (AST 55 U/L, ALT 91 U/L, GGT 43 U/L), raised inflammatory markers (C-reactive protein 36 mg/dl), and neutrophil leukocytosis (white blood cell count 14,400/mm3 with 80% neutrophils). A clinical diagnosis of cholangitis was made, and the patient was commenced on intravenous meropenem 1 g three times daily, after blood cultures, for 14 days. The CBD stent was removed endoscopically to exclude the possibility of a blocked stent as the precipitant of cholangitis. Oral prednisolone was tapered rapidly in view of the infection. The cholangitis episode settled with the antibiotics, with resolution of fever and normalizing of full blood count and inflammatory markers.\n\nThe patient’s cholestasis improved gradually over the next 2 months with ursodeoxycholic acid therapy. He had complete resolution of both clinical and biochemical features (total bilirubin 1.1 mg/dl, ALP 135 IU/L) of cholestasis 4 months into his illness. He was referred back to a hepatobiliary surgeon for elective laparoscopic cholecystectomy for residual cholelithiasis to prevent recurrence of complications and was advised to avoid cephalosporin use in the future. The timeline of the patient’s clinical course is presented in Table 1.Table 1 Timeline of the patient’s clinical course\n\nTime\tTotal bilirubin (mg/dl)\tALP (IU/L)\tAST (IU/L)\tALT (IU/L)\tGGT (IU/L)\tAlbumin (g/dl)\tGlobulin (g/dl)\tFBC\tCRP (mg/dl)\t\nInitial presentation with right upper quadrant pain, jaundice, dark urine, and pruritus\t\nDay 3\t6.4\t325\t113\t318\t\t3.8\t2.6\tNormal\t<6\t\nThe patient underwent ERCP on day 14, followed by cefuroxime for 5 days.\t\nDay 17\t20.3\t537\t29\t47\t\t4.1\t\tNormal\t<6\t\nThe patient underwent repeat ERCP on day 21 (1 week after the therapeutic ERCP), and a CBD stent was inserted. He was then referred to a hepatologist for worsening obstructive jaundice.\t\nDay 23\t32.8\t364\t42\t40\t\t3.6\t\tNormal\t<6\t\nThe patient was commenced on prednisolone 40 mg daily, ursodeoxycholic acid 300 mg, and cholestyramine 5 g three times daily. The patient was readmitted with fever with rigors and worsening of jaundice on day 32.\t\nDay 32\t39\t651\t62\t61\t25\t3.7\t1.9\t\t\t\nStent removed endoscopically on day 33. The patient was treated for cholangitis with intravenous meropenem for the next 14 days; prednisolone was tapered; ursodeoxycholic acid 300 mg and cholestyramine 5 g three times daily were continued.\t\nDay 34\t35\t595\t57\t52\t18\t3.23\t1.57\tNeutrophil leukocytosis (white blood cell count 14,400/mm3 with 80% neutrophils)\t42\t\nDay 36\t48\t901\t55\t91\t\t\t\t\t36\t\nDay 40\t38\t752\t\t\t\t\t\t\t\t\n4 months after onset of illness\t1.1\t135\t30\t40\t\t\t\t\t\t\n\nAbbreviations: ALP Alkaline phosphatase, ALT Alanine transaminase, AST Aspartate transaminase, CBD Common bile duct; ERCP Endoscopic retrograde cholangiopancreatography GGT Gamma-glutamyltransaminase, FBC Full blood count, CRP C-reactive protein\n\n\n\n\nDiscussion\nThis case is unique and complicated, involving a very rare DILI secondary to cefuroxime in the setting of therapeutic ERCP for distal CBD obstruction. Previously reported cases of DILI caused by cefuroxime were not complicated by preexisting obstructive jaundice.\n\nThe cholestasis in our patent, which was due to distal CBD obstruction by a stone, was expected to improve following therapeutic ERCP. However, despite successful stone extraction, CBD clearance, and stenting, our patient’s cholestasis paradoxically continued to worsen.\n\nWorsening cholestasis post-ERCP may be due to a retained CBD stone, ascending cholangitis, a blocked or migrated stent, or drug-induced cholestasis. In our patient, the most likely reason was drug-induced cholestasis. This was suggested by the absence of features of sepsis following initial ERCP, the absence of ductal dilation seen on an USS with stent in situ in the CBD, and the features present on liver histology favoring intrahepatic cholestasis of drug-induced etiology. The agents that may be responsible for this may be the drugs used during or after ERCP. Our patient was given propofol, pethidine during ERCP, and cefuroxime post-ERCP. All of these agents are known to cause cholestasis, but cefuroxime seems the likely causative agent.\n\nCefuroxime is a second-generation cephalosporin very rarely known to cause DILI. Prior to the present report, fewer than five cases of cefuroxime causing DILI and cholestasis had been reported [1–3]. Although the exact mechanism of cholestatic DILI of cefuroxime is not known, it is likely idiosyncratic in nature and due to hypersensitivity. Conversely, a closely related third-generation cephalosporin, ceftriaxone, is known to cause biliary sludge formation because of the propensity of ceftriaxone to bind calcium and form insoluble crystals in bile in the gallbladder, resulting in biliary sludge or frank stones [5].\n\nOur patient’s cholestasis worsened further following an episode of cholangitis, which was successfully treated with meropenem, thereby avoiding further exposure to cephalosporin. Following successful treatment of his cholangitis, the patient was managed with only ursodeoxycholic acid and cholestyramine. This resulted in gradual resolution of his cholestasis, with complete resolution in 4 months.\n\nThe place of steroids in drug-induced cholestasis is equivocal [6]. Corticosteroids can be effective for DILI associated with autoimmune or systemic hypersensitivity features. In our patient, there was no marked improvement of cholestasis on commencing steroids. Furthermore, the episode of cholangitis was worsened by steroids. Therefore, steroids were tapered rapidly at the onset of cholangitis with antibiotic cover.\n\nConclusions\nOur patient’s case illustrates a rare DILI due to cefuroxime, presenting as prolonged cholestatic jaundice following “successful” therapeutic ERCP for an obstructing distal CBD stone. Clinicians must be aware of the causes of worsening cholestasis post-ERCP to manage as well as to prevent the recurrence of similar complications in such patients.\n\nAbbreviations\nALPAlkaline phosphatase\n\nALTAlanine transaminase\n\nAPTTActivated partial thromboplastin time\n\nASTAspartate transaminase\n\nCBDCommon bile duct\n\nCRPC-reactive protein\n\nDILIDrug-induced liver injury\n\nERCPEndoscopic retrograde cholangiopancreatography\n\nFBCFull blood count\n\nGGTGamma-glutamyltransferase\n\nIgMImmunoglobulin M\n\nINRInternational normalized ratio\n\nUSSUltrasound scan\n\nAcknowledgements\nNot applicable.\n\nFunding\nNot applicable. No external source of funding was obtained in reporting this case.\n\nAvailability of data and materials\nData supporting this case report will be made available on request by the corresponding author.\n\nAuthors’ contributions\nMAN drafted the initial manuscript. RSK, ASD, AP, JdSH, and HJdS completed a review of the literature and revised it critically for important intellectual content. All authors are accountable for all aspects of the work. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nEthics approval and consent to participate\nNot applicable.\n==== Refs\nReferences\n1. Köklü S Yüksel O Yolcu OF Arhan M Altiparmak E Cholestatic attack due to ampicillin and cross-reactivity to cefuroxime Ann Pharmacother 2004 38 1539 40 10.1345/aph.1E025 15266040 \n2. Chalasani N Fontana RJ Bonkovsky HL Watkins PB Davern T Serrano J Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States Gastroenterology 2008 135 1924 34 10.1053/j.gastro.2008.09.011 18955056 \n3. Ekiz F Usküdar O Simsek Z Yüksel I Basar O Altinbas A Cefuroxime axetil-induced liver failure Ann Hepatol 2010 9 306 20720277 \n4. Björnsson ES Hoofnagle JH Categorization of drugs implicated in causing liver injury: critical assessment based upon published case reports Hepatology 2016 63 590 603 10.1002/hep.28323 26517184 \n5. Zinberg J Chernaik R Coman E Rosenblatt R Brandt LJ Reversible symptomatic biliary obstruction associated with ceftriaxone pseudolithiasis Am J Gastroenterol 1991 86 1251 4 1882806 \n6. Stine JG Lewis JH Current and future directions in the treatment and prevention of drug-induced liver injury: a systematic review Expert Rev Gastroenterol Hepatol 2016 10 517 36 10.1586/17474124.2016.1127756 26633044\n\n",
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"title": "Worsening cholestasis and possible cefuroxime-induced liver injury following \"successful\" therapeutic endoscopic retrograde cholangiopancreatography for a distal common bile duct stone: a case report.",
"title_normalized": "worsening cholestasis and possible cefuroxime induced liver injury following successful therapeutic endoscopic retrograde cholangiopancreatography for a distal common bile duct stone a case report"
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"abstract": "After being exposed to a kindergarten teacher with infectious pulmonary tuberculosis, a7-year-old girl with a positive tuberculin skin test was treated with isoniazid. 3 days after initiation of the tuberculostatic therapy, the girl was referred to our hospital with an acute onset of blurred vision. Visual acuity (VA) was 20/200 in both eyes. Examination revealed mild anterior chamber inflammation, optic disc swelling, cystoid macular edema and periphlebitis in both eyes. However, although active tuberculosis was ruled out, the interferon-gamma release assay was positive. The anti-tuberculosis therapy was intensified with pyrazinamide, isoniazid, rifampicin and methylprednisolone. Within 10 days we saw a resolution of the macular edema and VA was 20/25. The paradoxical worsening of the patient’s condition after initiation of tuberculostatic therapy with isoniazid and the prompt response to systemic steroids are typical for Jarisch-Herxheimer reaction (JHR). Our patient presented no symptoms before the isoniazid therapy was started and the reaction was ocular without any generalized symptoms. This is unique among all other reported cases of ocular JHR.",
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"title": "Isolated ocular Jarisch-Herxheimer reaction after initiating tuberculostatic therapy in a child.",
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"abstract": "Clonidine poisoning's clinical feature is well documented in the medical literature, but the minimal toxic dose has not yet been established. The effectiveness of naloxone is also controversial. The authors describe a clonidine overdose in a 9-year-old boy (25 kg) during a growth hormone test: he received tenfold the prescribed clonidine dose (0.23 mg instead of 0.023 mg) with 6.2 mg betaxolol. About 40 min later, he became drowsy and then complained of low blood pressure, bradycardia, and myosis. By maintaining the Trendelenburg position, administering fluids as well as salbutamol and naloxone (three doses of 0.2 mg were required), he recovered and was discharged from the hospital on day 2. The minimal clonidine toxic dose, the clinical picture, and the effectiveness of naloxone administration are discussed in this paper.",
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"abstract": "This report describes an unusual reaction to injected subconjunctival corticosteroid. The authors examined a patient with large areas of conjunctival necrosis at the site of a previous subconjunctival corticosteroid injection. A Gram's strain and culture of the affected conjunctival area and the bottled corticosteroid suspension were negative. Necrosis of the conjunctiva is a heretofore unreported adverse reaction to a subconjunctival corticosteroid injection. These lesions probably represent a localized toxic reaction rather than a sequela of infection.",
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"keywords": null,
"medline_ta": "Ophthalmic Surg Lasers",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents; D003228:Conjunctiva; D003229:Conjunctival Diseases; D005260:Female; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D005654:Fundus Oculi; D006801:Humans; D007267:Injections; D008269:Macular Edema; D008775:Methylprednisolone; D000077555:Methylprednisolone Acetate; D009336:Necrosis",
"nlm_unique_id": "9517132",
"other_id": null,
"pages": "79-80",
"pmc": null,
"pmid": "9474603",
"pubdate": "1998-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Conjunctival necrosis following the administration of subconjunctival corticosteroid.",
"title_normalized": "conjunctival necrosis following the administration of subconjunctival corticosteroid"
} | [
{
"companynumb": "US-PFIZER INC-2018517633",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE ACETATE"
},
"drugadditional... |
{
"abstract": "BACKGROUND\nPatients with Parkinson disease (PD) frequently experience visual hallucinations (VH). Visual hallucinations are most often viewed as an adverse effect of antiparkinsonian treatment. Possible treatments for this disturbance include a reduction of antiparkinsonian medications, adding atypical antipsychotics, or cholinesterase inhibitors. Some studies demonstrated that selective serotonin reuptake inhibitors may be an optional treatment for patients experiencing psychosis or agitation in dementia. Currently, there is no standard recommended treatment for VH in patients with PD. We present here our clinical experience with escitalopram (selective serotonin reuptake inhibitor) for treating this disturbance.\n\n\nMETHODS\nThirteen patients with PD (8 men and 5 women; age range 67-83 years) experiencing VH were openly treated with escitalopram 10 or 15 mg/d as add-on. Efficacy was assessed at baseline, then after 4 and 8 weeks of treatment using Clinical Global Impression-Severity and Clinical Global Impression-Improvement.\n\n\nRESULTS\nAt the end of the 4th week of treatment, of 13 patients, 11 subjects demonstrated improvement, and in only 2 patients were there no changes in their condition. After an additional 4 weeks, 2 of the responders showed very significant improvement, 6 demonstrated much improvement, and 3 patients demonstrated minimal improvement. Only 1 patient showed no change in his condition. One additional patient stopped taking escitalopram after 5 weeks because of an absence of improvement in his state.\n\n\nCONCLUSIONS\nEscitalopram was well tolerated as treatment of VH in PD patients. This medication could be a promising optional therapy for this disturbance; however, further randomized controlled and bigger studies are necessary.",
"affiliations": "*Mental Health Center, Ma'ale Carmel, The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa; †Geha Mental Health Center, Petakh Tikva; ‡Israel Defense Force, Tel Aviv; and §Be'er-Sheva Mental Health Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel.",
"authors": "Bergman|Joseph|J|;Lerner|Paul P|PP|;Sokolik|Shmuel|S|;Lerner|Vladimir|V|;Kreinin|Anatoly|A|;Miodownik|Chanoch|C|",
"chemical_list": "D000978:Antiparkinson Agents; D017367:Serotonin Uptake Inhibitors; D015283:Citalopram",
"country": "United States",
"delete": false,
"doi": "10.1097/WNF.0000000000000254",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0362-5664",
"issue": "40(6)",
"journal": "Clinical neuropharmacology",
"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000978:Antiparkinson Agents; D015283:Citalopram; D005260:Female; D005500:Follow-Up Studies; D006212:Hallucinations; D006801:Humans; D008297:Male; D010300:Parkinson Disease; D012189:Retrospective Studies; D017367:Serotonin Uptake Inhibitors; D016896:Treatment Outcome",
"nlm_unique_id": "7607910",
"other_id": null,
"pages": "246-250",
"pmc": null,
"pmid": "29059136",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Successful Use of Escitalopram for the Treatment of Visual Hallucinations in Patients With Parkinson Disease.",
"title_normalized": "successful use of escitalopram for the treatment of visual hallucinations in patients with parkinson disease"
} | [
{
"companynumb": "IL-TEVA-2018-IL-849850",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBIDOPA"
},
"drugadditional": "3",
"... |
{
"abstract": "BACKGROUND\nData from animal studies suggest that glucagon-like peptide-1 analogues should not be used in pregnancy, but there have been no reports to date of their effects in human pregnancy. The aim of the present report was to describe a case of exposure to liraglutide during the first trimester of pregnancy in a patient with Type 2 diabetes mellitus.\n\n\nMETHODS\nA 37-year-old woman with Type 2 diabetes mellitus who had been taking liraglutide for 2 years was admitted in the 13(th) week of gestation. Liraglutide was immediately discontinued and intensive insulin therapy instituted. The woman gave birth to a healthy child after completing an uneventful gestation period.\n\n\nCONCLUSIONS\nAlthough the present normal pregnancy outcome does not mean that glucagon-like peptide-1 analogues are safe to use in pregnancy, this report contributes to the limited knowledge regarding human exposure to these drugs during pregnancy in women with diabetes.",
"affiliations": "Unit of Diabetology, 'Paolo Borsellino' Hospital, Marsala, Italy.",
"authors": "Greco|D|D|",
"chemical_list": "D007328:Insulin; D000069450:Liraglutide",
"country": "England",
"delete": false,
"doi": "10.1111/dme.12726",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0742-3071",
"issue": "32(10)",
"journal": "Diabetic medicine : a journal of the British Diabetic Association",
"keywords": null,
"medline_ta": "Diabet Med",
"mesh_terms": "D000328:Adult; D003924:Diabetes Mellitus, Type 2; D057915:Drug Substitution; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007328:Insulin; D000069450:Liraglutide; D011247:Pregnancy; D011256:Pregnancy Outcome; D011261:Pregnancy Trimester, First; D011254:Pregnancy in Diabetics",
"nlm_unique_id": "8500858",
"other_id": null,
"pages": "e29-30",
"pmc": null,
"pmid": "25683470",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Normal pregnancy outcome after first-trimester exposure to liraglutide in a woman with Type 2 diabetes.",
"title_normalized": "normal pregnancy outcome after first trimester exposure to liraglutide in a woman with type 2 diabetes"
} | [
{
"companynumb": "IT-BRISTOL-MYERS SQUIBB COMPANY-BMS-2016-068666",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LIRAGLUTIDE"
},
"druga... |
{
"abstract": "OBJECTIVE\nPerioperative use of serotonergic agents increases the risk of serotonin syndrome. We describe the occurrence of serotonin syndrome after fentanyl use in two patients taking multiple serotonergic agents.\n\n\nMETHODS\nTwo patients who had been taking multiple serotonergic medications or herbal supplements (one patient taking fluoxetine, turmeric supplement, and acyclovir; the other taking fluoxetine and trazodone) developed serotonin syndrome perioperatively when undergoing outpatient procedures. Both experienced acute loss of consciousness and generalized myoclonus after receiving fentanyl. In one patient, the serotonin syndrome promptly resolved after naloxone administration. In the other patient, the onset of serotonin syndrome was delayed and manifested after discharge, most likely attributed to the intraoperative use of midazolam for sedation.\n\n\nCONCLUSIONS\nEven small doses of fentanyl administered to patients taking multiple serotonergic medications and herbal supplements may trigger serotonin syndrome. Prompt reversal of serotonin toxicity in one patient by naloxone illustrates the likely opioid-mediated pathogenesis of serotonin syndrome in this case. It also highlights that taking serotonergic agents concomitantly can produce the compounding effect that causes serotonin syndrome. The delayed presentation of serotonin syndrome in the patient who received a large dose of midazolam suggests that outpatients taking multiple serotonergic drugs who receive benzodiazepines may require longer postprocedural monitoring.",
"affiliations": "Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. sprung.juraj@mayo.edu.",
"authors": "Warner|Mary E|ME|;Naranjo|Julian|J|;Pollard|Emily M|EM|;Weingarten|Toby N|TN|;Warner|Mark A|MA|;Sprung|Juraj|J|",
"chemical_list": "D018490:Serotonin Agents; D005473:Fluoxetine; D009270:Naloxone; D008874:Midazolam; D005283:Fentanyl; D014196:Trazodone",
"country": "United States",
"delete": false,
"doi": "10.1007/s12630-017-0918-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0832-610X",
"issue": "64(9)",
"journal": "Canadian journal of anaesthesia = Journal canadien d'anesthesie",
"keywords": null,
"medline_ta": "Can J Anaesth",
"mesh_terms": "D000368:Aged; D030024:Curcuma; D019587:Dietary Supplements; D004347:Drug Interactions; D005283:Fentanyl; D005473:Fluoxetine; D006801:Humans; D008297:Male; D008874:Midazolam; D009270:Naloxone; D059035:Perioperative Period; D018490:Serotonin Agents; D020230:Serotonin Syndrome; D013997:Time Factors; D014196:Trazodone; D055815:Young Adult",
"nlm_unique_id": "8701709",
"other_id": null,
"pages": "940-946",
"pmc": null,
"pmid": "28667541",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Serotonergic medications, herbal supplements, and perioperative serotonin syndrome.",
"title_normalized": "serotonergic medications herbal supplements and perioperative serotonin syndrome"
} | [
{
"companynumb": "US-HETERO CORPORATE-HET2017US00198",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nThe prognosis of Ewing tumor (ET) patients has significantly improved to cure rates approximating 70%. The prognosis in relapse, however, is poor. Promising response rates have recently been reported for the combination of topotecan (TOPO) and cyclophosphamide (CYC) encouraging wider application of this combination in patients with relapsed ETs. This report summarizes the experience of patients treated with TOPO/CYC for recurrent or refractory disease within the German ET trials.\n\n\nMETHODS\nFifty-four patients aged 3.2-49.5 (median: 17.4) years received TOPO (0.75 mg/m2/day, days 1-5) and CYC (250 mg/m2/day, days 1-5) following first (40) or second (6) relapse or progression under first-line therapy (8).\n\n\nRESULTS\nA median of 3 (range: 1-11) TOPO/CYC courses were given. Sixteen patients (32.6%) showed partial response (PR), 13/49 (26.5%) had stable disease (SD), 14/49 (28.6%) progressed, 2/49 (4.1%) showed a mixed response (MR). In 4 patients response was not documented, 5/54 patients with complete initial resection at the diagnosis of relapse were excluded from the response analysis. At completion of relapse therapy, 24/54 patients had entered complete (19) or partial (5) remission, 2 had SD, 26 showed progression, information was unavailable in 2 patients. Of the 19 relapse patients achieving complete response (CR), 10 maintained remission (52.6%). At the time of evaluation, after a median follow-up for survivors of 23.1 (range: 7.8-59.8) months from the event prompting TOPO/CYC treatment, 14/54 patients (25.9%) were in continuous complete (13) or partial (1) remission. Overall survival (OAS) after 1 year was 0.61 (95%-CI 0.47-0.74).\n\n\nCONCLUSIONS\nTOPO/CYC is active in relapsed ETs and warrants further evaluation.",
"affiliations": "Department of Pediatric Hematology and Oncology, University Children's Hospital, Muenster, Germany.",
"authors": "Hunold|Andrea|A|;Weddeling|Nicole|N|;Paulussen|Michael|M|;Ranft|Andreas|A|;Liebscher|Caren|C|;Jürgens|Herbert|H|",
"chemical_list": "D019772:Topotecan; D003520:Cyclophosphamide",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.20719",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "47(6)",
"journal": "Pediatric blood & cancer",
"keywords": null,
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001859:Bone Neoplasms; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D012008:Recurrence; D012074:Remission Induction; D016879:Salvage Therapy; D012512:Sarcoma, Ewing; D015996:Survival Rate; D019772:Topotecan; D016896:Treatment Outcome",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "795-800",
"pmc": null,
"pmid": "16411206",
"pubdate": "2006-11",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Topotecan and cyclophosphamide in patients with refractory or relapsed Ewing tumors.",
"title_normalized": "topotecan and cyclophosphamide in patients with refractory or relapsed ewing tumors"
} | [
{
"companynumb": "NL-CIPLA LTD.-2015NL00429",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Background: Metformin-associated lactic acidosis (MALA) and metformin-induced lactic acidosis (MILA) remain controversial entities. Metformin toxic effect depends on accumulation to lead to lactic acidosis (LA), particularly during an episode of acute kidney injury (AKI). In MILA, no other condition contributing to LA is found. The aims of this study were to describe the characteristics and prognosis of AKI associated with LA in metformin users and to clarify the role of this drug in the different types of LA.Methods: We performed a French multicenter retrospective study in diabetic patients treated by metformin presenting with LA in a context of AKI in 2015. 126 nephrology units (NU) and 23 intensive care units (ICU) were contacted. We individualized MILA and MALA patients in order to illustrate the role of metformin.Results: We included 173 patients (109 MILA, 64 MALA). 103 patients presented without hemodynamic instability (82 MILA and 21 MALA) whereas 70 patients were shocked including 27 MILA. The shock was associated with death with an odds ratio (OR) of 12.92 (p < .001). Digestive disorders (DD) were strongly associated with MILA (p = .0001). MALA was significantly associated with shock (p < .0001). The mortality rate was higher in MALA (26%) when compared with MILA (7%). Dialysis performed in 133 patients was significantly associated with shock, kalemia, lactate and serum creatinine levels. In multivariate analysis, metformin level was independently associated with pH or lactate level only in MILA patients.Conclusions: MILA is associated with DD and death is due to severe refractory acidosis leading to cardiovascular collapse attributed to metformin accumulation mainly via AKI. MALA patients are more frequently shocked and death is related to their underlying condition, metformin accumulation increasing LA.",
"affiliations": "Department of Nephrology, CHU Reims, Reims, France.;Department of Nephrology, CHU Reims, Reims, France.;Department of Nephrology, William Morey Hospital, Chalon-sur-Saône, France.;Department of Nephrology, APHM Hôpital de la Conception, CHU Marseille, Marseille, France.;Department of Nephrology, Belfort Montbéliard Hospital, Montbéliard, France.;Intensive Care Unit, CHU Gabriel-Montpied, Clermont-Ferrand, France.;Intensive Care Unit, Hôpital Saint Louis, Paris, France.;Department of Pharmacology, CHU Amiens, Reims, France.;Department of Nephrology, CHU Nîmes, Nîmes, France.;Department of Internal Medicine & Nephrology, Valenciennes Hospital, Valenciennes, France.;Department of Pharmacology, CHU Reims, Reims, France.;Department of Nephrology, CHU Reims, Reims, France.",
"authors": "Corchia|Anthony|A|;Wynckel|Alain|A|;Journet|Julien|J|;Moussi Frances|Julie|J|;Skandrani|Nihel|N|;Lautrette|Alexandre|A|;Zafrani|Lara|L|;Lewandowski|Elisabeth|E|;Reboul|Pascal|P|;Vrigneaud|Laurence|L|;Djerada|Zoubir|Z|;Rieu|Philippe|P|",
"chemical_list": "D007004:Hypoglycemic Agents; D008687:Metformin",
"country": "England",
"delete": false,
"doi": "10.1080/15563650.2019.1648816",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "58(5)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "Metformin; acute kidney injury; diabetes; lactic acidosis; renal replacement therapy",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000140:Acidosis, Lactic; D058186:Acute Kidney Injury; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007004:Hypoglycemic Agents; D008297:Male; D008687:Metformin; D008875:Middle Aged; D017582:Renal Replacement Therapy; D012189:Retrospective Studies",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "375-382",
"pmc": null,
"pmid": "31387415",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "Metformin-related lactic acidosis with acute kidney injury: results of a French observational multicenter study.",
"title_normalized": "metformin related lactic acidosis with acute kidney injury results of a french observational multicenter study"
} | [
{
"companynumb": "FR-CADILA HEALTHCARE LIMITED-FR-ZYDUS-050452",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
... |
{
"abstract": "Hypercalcemia can be hazardous during pregnancy, most cases being due to primary hyperparathyroidism. We report a case of hypercalcemia with suppressed PTH levels necessitating treatment with bisphosphonates during pregnancy. A 38-year-old woman at the 26th week gestation was admitted because of symptomatic hypercalcemia. She did not take any medication that could influence her calcium levels. Physical examination was unremarkable. Laboratory tests on admission were: calcium 12.7 mg/dL (8.5-10.5 mg/dL), phosphorus 1.8 mg/dL (2.5-4.5 mg/dL) and PTH on 3 consecutive tests 1.2, 1.3 and 1.2 pg/mL (15-65 pg/mL). Her 24h urine calcium was 900 mg, 25-OH-D 40 ng/mL (30-58 ng/mL) and 1,25-OH-D 99 pg/mL (80-146 for women in the third trimester). Abdominal ultrasound revealed multiple hypervascular liver lesions consistent with hemangiomas by MRI. Breast and neck ultrasound were normal, and chest CT revealed few non-significant 0.3-0.7 cm pulmonary nodules with no change after an interval of 3 months. She was treated with isotonic saline, loop diuretics and calcitonin. Despite this treatment, calcium levels remained high (14.1 mg/dL), and pamidronate was initiated. On 35th week gestation, she underwent a cesarean section complicated by hypocalcemia of the newborn. Eight weeks after delivery, her calcium levels are 9.4 mg/dL and PTH 18 mg/dL. According to the extensive workup and the post-partum normalization of PTH and calcium levels, we conclude that excessive secretion of placental PTHrP was the cause of hypercalcemia in this patient. No significant adverse effect of bisphosphonate on the mother or baby were seen at the short term follow up.",
"affiliations": "Department of Internal Medicine A, Assaf Harofeh Medical Center, Zerifin, Israel.;Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin, Israel.;Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.;Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.",
"authors": "Koren|Ronit|R|;Neeman|Ortal|O|;Koren|Shlomit|S|;Benbassat|Carlos A|CA|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D010281:Parathyroid Hormone",
"country": "Brazil",
"delete": false,
"doi": "10.20945/2359-3997000000016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2359-3997",
"issue": "62(1)",
"journal": "Archives of endocrinology and metabolism",
"keywords": null,
"medline_ta": "Arch Endocrinol Metab",
"mesh_terms": "D000328:Adult; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005260:Female; D006801:Humans; D006934:Hypercalcemia; D010281:Parathyroid Hormone; D011247:Pregnancy; D011248:Pregnancy Complications",
"nlm_unique_id": "101652058",
"other_id": null,
"pages": "125-128",
"pmc": null,
"pmid": "29694631",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Humoral hypercalcemia of pregnancy treated with bisphosphonates.",
"title_normalized": "humoral hypercalcemia of pregnancy treated with bisphosphonates"
} | [
{
"companynumb": "IL-SUN PHARMACEUTICAL INDUSTRIES LTD-2018R1-177005",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PAMIDRONATE DISODIUM"
},
... |
{
"abstract": "OBJECTIVE\nIntracranial atherosclerotic disease is the cause of up to 10% of ischemic strokes and transient ischemic attacks. Intracranial stenting with off-label balloon mounted coronary stents (BMCS) may be a viable alternative for patients with symptomatic intracranial stenosis who fail best medical therapy.\n\n\nMETHODS\nBetween December 2005 and June 2012, 42 symptomatic intracranial stenoses were treated with a BMCS after failing medical management. Procedural records, clinical outcomes, and imaging follow-up were reviewed. Outcome measurements included technical success rate, morbidity and mortality, long term stent patency, and clinical outcomes, as measured by the modified Rankin Scale.\n\n\nRESULTS\nThe technical success rate was 98% (41 of 42 lesions). Morbidity within the first 30 days was 7.1% (three of 42 lesions). Overall morbidity, including both periprocedural and long term evaluation, was 9.5% (four of 42 lesions). There were no deaths. Follow-up imaging was available for 30 stents (71%) with an average follow-up time of 35.1 months. Restenosis (>50%) and retreatment were observed in 20% and 10% of cases, respectively. Clinical evaluation by a neurologist ≥ 30 days postprocedure was available in 40 of 42 cases (95%) with an average of 32.1 months. At presentation, 55% of patients had a modified Rankin Scale (mRS) score of ≤ 2. At follow-up, 74% of patients were found to have an mRS score of ≤ 2.\n\n\nCONCLUSIONS\nThis study suggests that BMCS may benefit patients with symptomatic intracranial stenosis who experience stroke or transient ischemic attack in spite of best medical therapy.",
"affiliations": "Department of Radiology and Medical Imaging, University of Virginia Health System, Charlottesville, Virginia, USA.;Advocate Neurovascular Center, Chicagoland, Illinois, USA.;Department of Neurology, University of Virginia Health System, Charlottesville, Virginia, USA.;Department of Neurosurgery, University of Virginia Health System, Charlottesville, Virginia, USA.;Department of Neurology, Tufts Medical Center, Boston, Massachusetts, USA.;Department of Neurology, Henry Ford Health System, Detroit, Michigan, USA.;Department of Radiology and Medical Imaging, University of Virginia Health System, Charlottesville, Virginia, USA.;Department of Neurosurgery, University of Virginia Health System, Charlottesville, Virginia, USA.;Department of Neurosurgery, University of Virginia Health System, Charlottesville, Virginia, USA.;Department of Radiology and Medical Imaging, University of Virginia Health System, Charlottesville, Virginia, USA.;Department of Radiology and Medical Imaging, University of Virginia Health System, Charlottesville, Virginia, USA.;Department of Radiology and Medical Imaging, University of Virginia Health System, Charlottesville, Virginia, USA.",
"authors": "Durst|Christopher R|CR|;Geraghty|Scott R|SR|;Southerland|Andrew M|AM|;Starke|Robert M|RM|;Rembold|Karen|K|;Malik|Shaneela|S|;Wintermark|Max|M|;Liu|Kenneth C|KC|;Crowley|R Webster|RW|;Gaughen|John|J|;Jensen|Mary E|ME|;Evans|Avery J|AJ|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/neurintsurg-2014-011185",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1759-8478",
"issue": "7(4)",
"journal": "Journal of neurointerventional surgery",
"keywords": "Atherosclerosis; Intervention; Stenosis; Stent; Stroke",
"medline_ta": "J Neurointerv Surg",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000800:Angioplasty, Balloon; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D002537:Intracranial Arteriosclerosis; D008297:Male; D008875:Middle Aged; D011859:Radiography; D012189:Retrospective Studies; D015607:Stents; D016896:Treatment Outcome",
"nlm_unique_id": "101517079",
"other_id": null,
"pages": "245-9",
"pmc": null,
"pmid": "24646693",
"pubdate": "2015-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Stenting of symptomatic intracranial stenosis using balloon mounted coronary stents: a single center experience.",
"title_normalized": "stenting of symptomatic intracranial stenosis using balloon mounted coronary stents a single center experience"
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"abstract": "Nivolumab-induced immune thrombocytopenia (ITP) is a rare process with few reported cases. We present a 67-year-old man with advanced non-small cell lung cancer who was hospitalized with severe thrombocytopenia. Physical exam was notable for petechiae across his chest and extremities as well as bullae in his oral cavity. The patient initially received high-dose glucocorticoids and intravenous immuno - globulin, but did not respond to treatment. He was then started on weekly rituximab and after three doses, there was complete resolution of his thrombocytopenia. Altogether, his presentation was an extreme case and rare side effect of immune checkpoint therapy, known as nivolumab-induced ITP. Diagnosis of nivolumab-induced ITP is challenging given the lack of specific testing and a wide differential diagnosis. There are few cases reporting severe ITP following nivolumab treatment. We highlight the importance of recognizing and treating this rare complication of immunotherapy.",
"affiliations": "Department of Medicine, Stony Brook University Hospital, NY, USA.;Department of Medicine, Stony Brook University Hospital, NY, USA.",
"authors": "Khorasanchi|Adam|A|;Keresztes|Roger|R|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.4081/cp.2020.1249",
"fulltext": "\n==== Front\nClin Pract\nCP\nClinics and Practice\n2039-7275 2039-7283 PAGEPress Publications, Pavia, Italy \n\n10.4081/cp.2020.1249\nCase Report\nSevere immune thrombocytopenia induced by a single dose of nivolumab in a patient with advanced non-small cell lung cancer\nKhorasanchi Adam Keresztes Roger Department of Medicine, Stony Brook University Hospital, NY, USA\nDepartment of Internal Medicine, Health Science Center T16, Room 020, Stony Brook, NY 11790-8160, USA. +1.(631).444.7411 - +1.(631).444.2493. adam.khorasanchi@stonybrookmedicine. eduContributions: the authors contributed equally.\n\nConflict of interest: the authors declare no potential conflict of interest.\n\nEthics approval: No approval is required.\n\nInformed consent: Informed consent was unable to be obtained, however no identifiable information about the patient was included in the publication of this manuscript\n\n\n17 6 2020 \n19 5 2020 \n10 2 124924 3 2020 15 6 2020 ©Copyright: the Author(s)2020Licensee PAGEPress, ItalyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Nivolumab-induced immune thrombocytopenia (ITP) is a rare process with few reported cases. We present a 67-year-old man with advanced non-small cell lung cancer who was hospitalized with severe thrombocytopenia. Physical exam was notable for petechiae across his chest and extremities as well as bullae in his oral cavity. The patient initially received high-dose glucocorticoids and intravenous immuno - globulin, but did not respond to treatment. He was then started on weekly rituximab and after three doses, there was complete resolution of his thrombocytopenia. Altogether, his presentation was an extreme case and rare side effect of immune checkpoint therapy, known as nivolumab-induced ITP. Diagnosis of nivolumab-induced ITP is challenging given the lack of specific testing and a wide differential diagnosis. There are few cases reporting severe ITP following nivolumab treatment. We highlight the importance of recognizing and treating this rare complication of immunotherapy.\n\nKey words\nNivolumabimmune checkpoint inhibitornon-small cell lung cancerimmunerelated thrombocytopenia\n==== Body\nIntroduction\nLung cancer is the leading cause of cancer death worldwide. Nivolumab, an anti- PD1 immune checkpoint inhibitor (ICI) has been approved for use in a wide variety of malignancies including advanced non-small cell lung cancer (NSCLC). ICIs can provide substantial therapeutic benefit, however many immune-related adverse events (ir- AEs) have also emerged. Mechanistically, ir-AEs are thought to be caused by a reinvigoration of exhausted T-cells, which evoke inflammation and ultimately lead to their toxicity. Other immune cells may also play a role, including B cells that produce antibodies and mediate the toxicity.1,2\n\nWhile virtually any organ system can be affected by ICIs, the dermatologic, gastrointestinal tract, and endocrine systems are most commonly involved.1 Involvement of the hematopoietic system is rare, but important to recognize as it can be associated with life-threatening outcomes. In a 2019 study, grade 2 or worse hematologic ir-AEs were noted in thirty-five patients or 3.7% of the study population.3,4 In this paper, we present a rare case of severe ITP induced by a single dose of nivolumab in a patient with advanced NSCLC and review the current literature.\n\nCase Report\nA 67-year-old man who was a former tobacco smoker (100 pack-year history) presented to our oncology clinic following a diagnosis of Stage IIIa NSCLC. He had a past medical history significant for ulcerative colitis, which was well-controlled on balsalazide with no recent flares. He was initially noted to have a lung nodule on a surveillance computed tomography (CT) scan for abdominal aortic aneurysm. A positron emission tomography (PET) scan was done, which demonstrated a metabolically active right lower lobe lesion measuring 9.1 x 3.9 centimeter with an extension to the hilum. Enlarged right paratracheal lymph nodes were also noted be metabolically active. He underwent endobronchial ultrasound guided fine needle aspiration of the mass and mediastinal lymph nodes. Results were consistent with squamous cell carcinoma with metastases in the lymph nodes. The pathological diagnosis was T3N2M0 stage IIIa squamous cell lung carcinoma. PET scan at the time did not demonstrate any evidence of extra thoracic metastatic disease and therefore he was advised to undergo neoadjuvant chemotherapy followed by restaging of mediastinum for consideration of curative surgical resection. The patient was deemed to be of good functional status and started on paclitaxel, carboplatin. After a single course of chemotherapy, he was hospitalized with near fatal sepsis. He was treated with intravenous (IV) vancomycin and Zosyn, followed by levofloxacin to complete a fourteen- day course. Following his recovery, his case was discussed at our institutional tumor board and given the severe toxicity and low likelihood chemotherapy would make him operable, the patient was started on a course of concurrent chemoradiation. He tolerated this treatment well until the end of his six-week course when he developed febrile neutropenia and was found to have C. difficile colitis. He was treated with IV cefepime, followed by Augmentin to complete a ten-day course as well as fourteen days of oral vancomycin. CT scan during this hospitalization showed a new liver lesion, which was proven by biopsy to be metastatic squamous cell carcinoma.\n\nHe was subsequently started on immunotherapy nivolumab 3 mg/kg every two weeks. Two weeks following his first nivolumab administration, the patient was noted to have a platelet count of 1000/μL (previously 188,000/μL) as well as petechiae on his arms and legs. His platelet count was repeated in a citrate tube and confirmed on peripheral smear. His hemoglobin and white blood cell count remained unchanged compared to prior laboratory results. Based on his severe thrombocytopenia, he was admitted to the hospital urgently that same day. On arrival, he was hemodynamically stable. Physical exam was notable for petechiae across his chest and extremities as well as bullae in his oral cavity. Given the acute drop in his platelet count and recent immunotherapy exposure, he was diagnosed with a rare ir-AE, known as nivolumab- induced ITP. Platelet-associated immunoglobulin G antibody levels (PAIgG) were not measured. He was initially started on IV steroids and received three doses of IV immunoglobulin (IVIG). His platelet count had increased to 37,000/μL. At this point, the patient was switched to oral prednisone. However, his platelet count decreased to 18,000/μL. He was then started on weekly rituximab and after three doses, his platelet count recovered to 150,000/μL.\n\nFollowing platelet count recovery, the patient was enrolled in our clinical trial and started on an antibody-drug conjugate as treatment for his advanced NSCLC. One week after receiving his first dose, he was readmitted to the hospital for neutropenic fever and respiratory distress. He was treated for pneumonia as well as suspected radiation pneumonitis. Despite treatment, his respiratory status worsened and after a goals of care discussion with his family, the decision was made to pursue comfort measures. Unfortunately, the patient died fourteen days following hospital admission.\n\nDiscussion\nNivolumab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits programmed cell death-1 (PD-1) activity by binding to the PD-1 receptor and blocking its interaction with both PD-L1 and PD-L2. PD-1 receptor blockade removes inhibitory signals of T-cell activation, thus enabling tumor-reactive T cells to overcome regulatory mechanisms and mount an effective anti-tumor response. This anti-tumor response is manifested through reinvigoration of CD8 T-cells, leading to both increased functional activity and frequency.5-8 Unrestrained T-cell activation provoked by ICIs can manifest as toxicity in the form of ir-AEs, including ITP as seen in our patient.\n\nIn this report, we highlight a case of severe ITP following a single cycle of nivolumab therapy. Previous case reports have noted the development of ITP following 2-8 cycles of treatment.5,6 ITP is an autoimmune hematologic disorder characterized by isolated thrombocytopenia (platelet count <100,000/μL) in the absence of an identifiable cause. The underlying pathophysiology of ITP entails autoantibody production by B cells resulting in platelet destruction via macrophages in the spleen and liver. T-cell changes include reduction of regulatory T cell activity and an increase in cytotoxic T-cells.3 A majority of patients are asymptomatic, however a minority may present with mild or lifethreatening bleeding. A clinical history is important to rule out other causes of thrombocytopenia as ITP is a diagnosis of exclusion. Examination of the peripheral-blood smear typically shows reduced numbers of platelets.3 Increased levels of platelet specific IgG autoantibodies have been reported in previous cases which can provide further support for the diagnosis, but these were not checked in our patient.\n\nTreatment options for ITP include platelet transfusions, which can help to limit bleeding, but its effects are transient. Use of glucocorticoids is the standard initial therapy for patients with ITP. Concomitant use of glucocorticoids with IVIG can be associated with a more sustained response. Rituximab, a monoclonal antibody which targets the CD20 antigen expressed on the surface of B-lymphocytes, can be considered in those who do not respond to the above therapies. The main advantage of rituximab is sustained platelet responses that last more than two years in 50% of patients who have a response.3 Our patient experienced complete resolution of ITP following rituximab reaffirming the major role of B cells in the pathogenesis of ITP.\n\nOf note, our patient had a history of ulcerative colitis prior to nivolumab therapy. While patients with pre-existing autoimmune disease were previously excluded from most ICI clinical trials due to concerns for increased toxicity, a 2019 review by Kennedy et al suggests ICIs may be considered in patients with good control of their underlying autoimmune disorder. This is defined as patients who are either on no immunosuppression or relatively low levels of immunosuppressive therapy.7 Unfortunately, despite our patient’s ulcerative colitis being well-controlled with no recent flares, he still developed toxicity from immunotherapy.\n\nConclusions\nIn conclusion, the diagnosis of nivolumab-induced ITP is challenging given the lack of specific testing and a wide differential diagnosis. In our patient, the clinical course and laboratory results suggested nivolumab-induced ITP given the acute drop in platelets, and recent exposure to immunotherapy. Platelet specific IgG autoantibodies were not checked but previous reports have noted increased levels which can provide further support for the diagnosis. There are few cases reporting severe ITP following nivolumab treatment. We highlight the importance of recognizing and treating this rare complication of immunotherapy.\n\nFigure 1. Clinical course of the present case. The patient was hospitalized with severe thrombocytopenia two weeks after first nivolumab administration. His platelet count initially increased following IV steroids and IVIG treatment. However, it decreased when he was tapered to oral steroids. Pulse IV steroids and one dose of rituximab were given which stabilized his platelet count prior to hospital discharge. Resolution of thrombocytopenia (not shown) was ultimately achieved following two additional doses of rituximab as an outpatient. Shown are the changes in platelet count during his hospitalization.\n==== Refs\nReferences\n1. Bagley S Kosteva J Evans T \nImmune thrombocytopenia exacerbated by nivolumab in a patient with nonsmall cell lung cancer\n. Cancer Treat Commun \n2016 ;6 :20 -3\n.\n2. Calvo R \nHematological side effects of immune checkpoint inhibitors: the example of immune-related thrombocytopenia\n. Front Pharmacol \n2019 ;10 :454 .31105573 \n3. Cooper N Ghanima W. \nImmune thrombocytopenia\n. N Engl J Med \n2019 ;381 : 945 -55\n.31483965 \n4. Delanoy N Michot JM Comont T \nHaematological immune-related adverse events induced by anti-PD-1 or anti-PD-L1 immunotherapy: a descriptive observational study\n. Lancet Haematol \n2019 ;6 :e48 -57\n.30528137 \n5. Hasegawa T Ozaki Y Inoue T \nNivolumab-related severe thrombocytopenia in a patient with relapsed lung adenocarcinoma: a case report and review of the literature\n. J Med Case Rep \n2019 ;13 :316 .31647029 \n6. Karakas Y Yuce D Kilickap S. \nImmune thrombocytopenia induced by nivolumab in a metastatic non-small cell lung cancer patient\n. Oncol Res Treat \n2017 ;40 :621 -2\n.28950270 \n7. Kennedy L Bhatia S Thompson J \nPreexisting autoimmune disease: implications for immune checkpoint inhibitor therapy in solid tumors\n. J Natl Compr Canc Netw \n2019 ;17 :750 -7\n.31200356 \n8. Wei S Duffy C Allison J. \nFundamental mechanisms of immune checkpoint blockade therapy\n. Cancer Discov \n2018 ;8 :1069 -86\n.30115704\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2039-7275",
"issue": "10(2)",
"journal": "Clinics and practice",
"keywords": "Nivolumab; immune checkpoint inhibitor; immunerelated thrombocytopenia; non-small cell lung cancer",
"medline_ta": "Clin Pract",
"mesh_terms": null,
"nlm_unique_id": "101563282",
"other_id": null,
"pages": "1249",
"pmc": null,
"pmid": "32582418",
"pubdate": "2020-05-19",
"publication_types": "D016428:Journal Article",
"references": "31200356;31483965;31647029;30115704;30528137;28950270;31105573",
"title": "Severe immune thrombocytopenia induced by a single dose of nivolumab in a patient with advanced non-small cell lung cancer.",
"title_normalized": "severe immune thrombocytopenia induced by a single dose of nivolumab in a patient with advanced non small cell lung cancer"
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"companynumb": "US-ROCHE-2661719",
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"activesubstancename": "RITUXIMAB"
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"abstract": "BACKGROUND\nProphylaxis for venous thromboembolism is routinely performed for all patients undergoing bariatric surgery. However, there is disagreement regarding the optimal dosing and duration of anticoagulant therapy. Furthermore, there is little data regarding the incidence of asymptomatic deep venous thrombosis (DVT) in this population. Our objective was to conduct a pilot randomized double blind study to evaluate the pharmacodynamic parameters of 2 different anticoagulation medications (enoxaparin and fondaparinux) administered to patients undergoing bariatric surgery.\n\n\nMETHODS\nFrom July 2010 to August 2013, 198 consecutive bariatric surgery patients from an academic institution were randomized in a double blinded manner to receive either 40 mg enoxaparin twice daily or 5mg fondaparinux sodium once daily. Antifactor Xa activity was measured on all patients in both study arms, 3 hours after the first dose (on the day of the operation), immediately before the second dose (postoperative day one), and 3 hours after the second dose. At the routine 2 week postoperative visit, patients underwent magnetic resonance venography (MRV) to detect DVT. The primary outcome was attainment of therapeutic antifactor Xa levels. The secondary outcome was DVT, as detected by MRV. Safety outcomes were perioperative bleeding, perioperative complications, and death.\n\n\nRESULTS\nOf 198 patients randomized, 177 underwent MRV and 137 had interpretable antifactor Xa levels. Nearly half of the patients (47.4%) did not attain target prophylactic antifactor Xa levels. Adequate antifactor Xa levels were more common with fondaparinux (74.2%) than with enoxaparin (32.4%). Antifactor Xa levels were also associated with preoperative D-dimer level. 4 of the 175 patients who underwent MRV developed DVT, 2 in each arm of the study. No major adverse events occurred in either arm.\n\n\nCONCLUSIONS\nFondaparinux was much more likely to produce target prophylactic antifactor Xa levels than enoxaparin. Both regimens appear to be equally effective at reducing the risk of DVT. Further prospective studies are needed to determine the optimal DVT prophylaxis regimen in the bariatric surgical population.",
"affiliations": "Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: ksteele3@jhmi.edu.;Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.;Research Pharmacy, The Johns Hopkins Bayview Medical Center, Baltimore, Maryland.;Department of International Health, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.;Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Hematology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.",
"authors": "Steele|Kimberley E|KE|;Canner|Joseph|J|;Prokopowicz|Gregory|G|;Verde|Franco|F|;Beselman|Aleksandra|A|;Wyse|Ransom|R|;Chen|Junnan|J|;Streiff|Michael|M|;Magnuson|Thomas|T|;Lidor|Anne|A|;Schweitzer|Michael|M|",
"chemical_list": "D000925:Anticoagulants; D017984:Enoxaparin; D011134:Polysaccharides; D000077425:Fondaparinux",
"country": "United States",
"delete": false,
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"issn_linking": "1550-7289",
"issue": "11(3)",
"journal": "Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery",
"keywords": "Anticoagulation; Bariatric surgery; Clinical trial; Prophylaxis; Venous thromboembolism",
"medline_ta": "Surg Obes Relat Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000925:Anticoagulants; D050110:Bariatric Surgery; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D017984:Enoxaparin; D005260:Female; D005500:Follow-Up Studies; D000077425:Fondaparinux; D006801:Humans; D008297:Male; D008875:Middle Aged; D009767:Obesity, Morbid; D010865:Pilot Projects; D011134:Polysaccharides; D011182:Postoperative Care; D011183:Postoperative Complications; D011300:Preoperative Care; D011446:Prospective Studies; D016896:Treatment Outcome; D054556:Venous Thromboembolism; D055815:Young Adult",
"nlm_unique_id": "101233161",
"other_id": null,
"pages": "672-83",
"pmc": null,
"pmid": "25620436",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "The EFFORT trial: Preoperative enoxaparin versus postoperative fondaparinux for thromboprophylaxis in bariatric surgical patients: a randomized double-blind pilot trial.",
"title_normalized": "the effort trial preoperative enoxaparin versus postoperative fondaparinux for thromboprophylaxis in bariatric surgical patients a randomized double blind pilot trial"
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"abstract": "Acquired angioedema due to deficiency of C1 esterase inhibitor is also called acquired angioedema and is abbreviated as C1INH-AAE. It is a rare syndrome of recurrent episodes of angioedema, without urticaria, and in some patients, it is associated with B-cell lymphoproliferative disorders. Kidney involvement is rare in this condition. The monoclonal immunoglobulin secreted by a nonmalignant or premalignant B-cell or plasma cell clone, causing renal damage that represents a group of disorders which are termed as monoclonal gammopathy of renal significance (MGRS). In this article, we report a rare case of acquired C1 esterase deficiency angioedema and acute kidney injury with renal biopsy-proven MGRS. We present a 64-year-old Caucasian woman who presented with 2 weeks of recurring urticaria and new onset of acute kidney injury. She was diagnosed with monoclonal gammopathy-associated proliferative glomerulopathy through kidney biopsy, and serological workup came back positive for C1 esterase deficiency, implying acquired angioedema. Acquired angioedema is a rare disease with systemic involvement. Recurrent allergic manifestations and acute kidney injury should prompt MGRS as a differential.",
"affiliations": "Lynchburg Nephrology Physicians, Lynchburg, VA, USA.;Ashland Bellefonte Cancer Center, Ashland, KY, USA.;Lynchburg Nephrology Physicians, Lynchburg, VA, USA.;Miami Valley Hospital, Dayton, OH, USA.;Adventist Medical Center, Hanford, CA, USA.;Interfaith Medical Center, Brooklyn, NY, USA.;The Nephrology Group, Fresno, CA, USA.;Lynchburg Nephrology Physicians, Lynchburg, VA, USA.",
"authors": "Roy|Sasmit|S|0000-0002-2509-3915;Konala|Venu Madhav|VM|0000-0003-1953-8815;Kyaw|Thurein|T|;Chakraborty|Sandipan|S|;Naramala|Srikanth|S|;Gayam|Vijay|V|0000-0001-5194-9134;Adapa|Sreedhar|S|0000-0001-5608-5654;Bose|Subhasish|S|",
"chemical_list": "D050718:Complement C1 Inhibitor Protein",
"country": "United States",
"delete": false,
"doi": "10.1177/2324709620912096",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096 SAGE Publications Sage CA: Los Angeles, CA \n\n10.1177/2324709620912096\n10.1177_2324709620912096\nCase Report\nAn Unusual Case of Acquired Angioedema and Monoclonal Gammopathy of Renal Significance in a Middle-Aged Caucasian Female\nhttps://orcid.org/0000-0002-2509-3915Roy Sasmit MD1 https://orcid.org/0000-0003-1953-8815Konala Venu Madhav MD2 Kyaw Thurein MD1 Chakraborty Sandipan MD3 Naramala Srikanth MD4 https://orcid.org/0000-0001-5194-9134Gayam Vijay MD5 https://orcid.org/0000-0001-5608-5654Adapa Sreedhar MD6 Bose Subhasish MD1 1 Lynchburg Nephrology Physicians, Lynchburg, VA, USA\n2 Ashland Bellefonte Cancer Center, Ashland, KY, USA\n3 Miami Valley Hospital, Dayton, OH, USA\n4 Adventist Medical Center, Hanford, CA, USA\n5 Interfaith Medical Center, Brooklyn, NY, USA\n6 The Nephrology Group, Fresno, CA, USA\nSasmit Roy, Consultant Nephrologist, Lynchburg Nephrology Physicians, Lynchburg, VA, USA. Email: docsasmit@gmail.com\n13 3 2020 \nJan-Dec 2020 \n8 232470962091209631 1 2020 9 2 2020 13 2 2020 © 2020 American Federation for Medical Research2020American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution 4.0 License (https://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).Acquired angioedema due to deficiency of C1 esterase inhibitor is also called acquired angioedema and is abbreviated as C1INH-AAE. It is a rare syndrome of recurrent episodes of angioedema, without urticaria, and in some patients, it is associated with B-cell lymphoproliferative disorders. Kidney involvement is rare in this condition. The monoclonal immunoglobulin secreted by a nonmalignant or premalignant B-cell or plasma cell clone, causing renal damage that represents a group of disorders which are termed as monoclonal gammopathy of renal significance (MGRS). In this article, we report a rare case of acquired C1 esterase deficiency angioedema and acute kidney injury with renal biopsy-proven MGRS. We present a 64-year-old Caucasian woman who presented with 2 weeks of recurring urticaria and new onset of acute kidney injury. She was diagnosed with monoclonal gammopathy–associated proliferative glomerulopathy through kidney biopsy, and serological workup came back positive for C1 esterase deficiency, implying acquired angioedema. Acquired angioedema is a rare disease with systemic involvement. Recurrent allergic manifestations and acute kidney injury should prompt MGRS as a differential.\n\nacquired C1 esterase inhibitor deficiencyacquired angioedemaacute kidney injurymonoclonal gammopathy of renal significanceproliferative glomerulonephritis with monoclonal immunoglobulin depositioncover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nThe monoclonal immunoglobulin (MIg) secreted by a nonmalignant or premalignant B-cell or plasma cell clone causes renal damage that represents a group of disorders that are termed as monoclonal gammopathy of renal significance (MGRS). The renal injury is caused by direct deposition or indirect functional interference of MIg.1-3 The hematological abnormality in patients with MGRS is generally consistent with monoclonal gammopathy of undetermined significance (MGUS) and does not meet the criteria for symptomatic multiple myeloma or lymphoma. The renal prognosis of MGRS is not benign. MGRS can cause multiple renal manifestations of which cast nephropathy, MIg deposition disease, and renal amyloidosis are more predominant. Proliferative glomerulonephritis with MIg deposition (PGNMID) is a monoclonal gammopathy–associated kidney disease that mimics immune-complex glomerulonephritis.4,5 Patients can present with renal insufficiency, hematuria, and nephrotic syndrome.4\n\nAcquired C1 esterase inhibitor deficiency is an infrequent condition that is often related to underlying lymphoproliferative disorders and autoimmune diseases. It usually presents after the second decade of life. This contrasts with hereditary C1 esterase inhibitor deficiency, which is inherited as an autosomal dominant trait and presents earlier in life.6 The most common clinical presentation is painless swellings subsiding over a few days, which is similar in both forms.\n\nA similar clinical presentation with low C1 esterase inhibitor concentration in elderly patients should raise suspicion for B-cell neoplasm. Multiple myeloma can sometimes present in this manner.7 In this article, we present a patient whose paraprotein was discovered on renal biopsy, and subsequently, further investigations showed spurious low C1q, C3, and C4 complement level.\n\nCase Presentation\nA 64-year-old Caucasian female presented to the emergency department with complaints of waxing and waning maculopapular rashes in both upper and lower extremities along with chills accompanied by lower extremity swelling.\n\nOn examination, she was alert, awake, and could breathe normally and swallow but had hoarseness of voice. She also had 2+ pedal edema in both lower extremities. She had bilateral nonblanching papular rashes in both lower extremities. Her blood pressure and heart rate were essentially normal, and she was saturating 98% on room air. The patient denied any family history of angioedema. She had a past medical history of essential hypertension, on and off urticaria with lip swelling, and paroxysmal tachycardia. She was not taking an angiotensin-converting enzyme inhibitor. She was getting short courses of 3 to 5 days of oral prednisone at urgent care. Her rash subsided with steroids but recurred on completion of steroids.\n\nRoutine blood samples taken on admission showed an increase in urea and creatinine at 44 mg/dL (reference range = 5-23) and 2.4 mg/dL (reference range = 0.5-1.3), respectively. The serum calcium level was normal. Erythrocyte sedimentation rate was increased at 63 mm/h (reference range <20). All other routine biochemistry was unremarkable. A full blood count showed mild leukocytosis (white blood cells count = 11500/µL, reference range <10 000/µL). She had no anemia. Urine analysis showed 1+ proteinuria and 1+ hematuria. The urine protein creatinine ratio was 0.19. There were no casts visible on the urinary microscope examination.\n\nComplement levels, hepatitis panel, vasculitis workup, and immunoglobulin studies were requested as part of a standard protocol to investigate glomerulonephritis and angioedema. Hepatitis B and C, antinuclear antibody, double-stranded deoxyribonucleic acid, anti-Sjogren’s syndrome A and B, anti-neutrophil cytoplasmic antibody, and cryoglobulins were all negative.\n\nThe C4 concentration was extremely low at <2 mg/dL (reference range = 14-44), C3 was very low at 23 mg/dL (reference range = 92-190), and C1 q level was low at 1.3 mg/dL (reference range = 11.8-24.4). C1 esterase inhibitor level came high at 48 mg/dL (reference range = 21-39).\n\nShe was initially treated with intravenous hydration, but her creatinine continued to escalate. Her hospital course was complicated with swelling of lips and face along with episodes of supraventricular tachycardia. She subsequently underwent a kidney biopsy because of her unusual presentation and hematuria. Kidney biopsy came positive for diffuse proliferate glomerulonephritis with monoclonal immunoglobulin G1 lambda immune deposits (Figures 1-5). An immunofluorescent study suggested a lambda light chain disease (Figure 6). Given the patient had a clinical presentation of acute angioedema along with low C1q concentration, immunoglobulin studies were checked to investigate the possibility of acquired angioedema secondary to a B-cell neoplasm. Capillary electrophoresis showed the only hypoalbuminemia with no abnormal M spike. No abnormal bands were detected on serum or urine electrophoresis. Free kappa light chain was high at 45.9 mg/dL (reference range = 3.3-19.4), free lambda light chain was high at 28.9 mg/dL (reference range = 5.7- 26.3), but the kappa-lambda light ratio was normal at 1.59. A total 24-hour urine protein was normal at 173 mg/24 h, but there was no Bence Jones proteinuria present.\n\nFigure 1. Glomeruli with global endocapillary hypercellularity with leukocytes (mainly monocytes/macrophages) obliterating most capillary lumens (top) compared with normal (bottom).\n\nFigure 2. Glomeruli with global endocapillary hypercellularity with leukocytes (mainly monocytes/macrophages) obliterating most capillary lumens.\n\nFigure 3. Glomeruli with global endocapillary hypercellularity with leukocytes (mainly monocytes/macrophages) obliterating most capillary lumens with different stains.\n\nFigure 4. Electron microscopy showing macrophage in the capillary lumen and subendothelial dense deposits.\n\nFigure 5. Electron microscopy showing macrophage and subendothelial dense deposits.\n\nFigure 6. Immunofluorescence showing monoclonal immunoglobulin G1 lambda immune deposits.\n\nShe was referred to the hematologist for investigation of a possible B-cell malignancy. Hematologist did not recommend bone marrow biopsy because of unremarkable urinary electrophoresis and normal free light chain ratio. There was no clinical evidence of organomegaly or lymphadenopathy. Computed tomography scan of the abdomen did not reveal any splenomegaly or lymphadenopathy. They did not suspect she had any underlying lymphoproliferative disorder.\n\nShe was started on pulse methylprednisolone 500 mg intravenous daily and then switched to oral prednisone 60 mg daily. She had supraventricular tachycardia on day 4 of pulse steroids and hence was switched to oral prednisone. Her renal parameters improved dramatically, and her swelling and rashes subsided. She developed cellulitis of her face, and thus her steroids were discontinued after 1 week only. She was referred to a tertiary center allergy clinic who did not recommend any further specialized treatment as hereditary angioedema was not implied.\n\nShe was followed-up subsequently in the renal clinic. She had normal kidney function, but her hematuria is persistent. She is in clinical remission now with no rashes or further leg swelling. She had another episode of similar flare after 4 months and was treated with pulse steroids again. She is being followed by an allergy clinic and is carrying epinephrine pen as prophylaxis.\n\nDiscussion\nParaproteinemias are characterized by clonal proliferation of B-cells and or plasma cells resulting in overproduction of monoclonal proteins and can cause significant renal dysfunction. Paraprotein-induced renal disease can occur without malignancy, now termed as monoclonal gammopathy of renal significance. The various mechanisms of renal injury are through paraprotein deposition or precipitation or crystallization with complement and cytokine activation.8 MGRS has objective evidence of renal involvement indicating end-organ damage, which differentiates from commonly known disease state MGUS. MGRS includes a wide spectrum of disorders like light and heavy chain deposition disease, C3 glomerulopathy, immunotactoid glomerulopathy, PGNMID, and primary amyloidosis.2\n\nOur patient had an initial clinical presentation with urticaria, acute kidney injury, and a low complement level, raising the suspicion of acquired angioedema, possibly secondary to a monoclonal gammopathy. In a patient of this age, with the absence of family history, we abated the possibility of hereditary angioedema as a cause of her initial features. Our suspicion was validated by low C1q, which is low in acquired angioedema and normal in the hereditary form. Acquired angioedema generally presents with head and neck symptoms, mainly swollen upper airways, cheeks, and tongue.6 Localized, nonpruritic, subcutaneous rash, along with recurrent swellings that appear rapidly and resolve within 24 to 48 hours, is classic of this disease. Systemic manifestations are more common with the acquired angioedema and are mostly absent in hereditary angioedema. In a middle-aged or elderly patient presenting with a clinical history of angioedema, the lymphoproliferative disorder should be ruled out. In a series by Markovic et al, there was a considerable delay in the diagnosis of acquired angioedema by 2.3 years.6 This diagnosis has implications for multiple specialties, including head and neck surgeon, the dermatologist, the hematologist, the anesthetist, and the general practitioner. The anesthetist should be vigilant about the possibility of upper airway obstruction caused by laryngeal angioedema in this condition.9 Similarly, primary care physicians should be aware of this condition, given angiotensin-converting enzyme inhibitors are contraindicated.\n\nNasr et al in 2004 described PGNMID, a novel category of monoclonal IgG deposition disease characterized by membranoproliferative glomerulonephritis or endocapillary glomerulonephritis on light microscopy, staining for a single light chain isotype and a single gamma heavy chain subclass on immunofluorescence, and granular electron-dense deposits on electron microscopy.10\n\nOur patient was diagnosed with PGNMID, which is always confirmed by kidney biopsy. Our patient also had negative serum protein electrophoresis, normal ratio of serum-free light chains, and negative urine protein electrophoresis that typically occurs in PGNMID as reported in 75% of the published cases.11\n\nNo treatment is indicated in MGUS as it is a benign condition, and close monitoring is warranted. The finding of MGRS on kidney biopsy necessitates more strict monitoring and necessary interventions to prevent ongoing deposition and end-organ damage.11 In the most extensive case series by Nasr et al with PGNMID involving 37 patients, only 38% experienced complete or partial recovery of renal function.4\n\nOnly one extensive review of literature by Castelli et al has shown in 35% of cases an association of MGUS and acquired angioedema.12 However, no recent literature has shown an association of MGRS, especially the more active PGNMID variant of the disease with acquired angioedema and low complement levels.\n\nConclusion\nIn this report, we try to highlight this unique presentation of acquired angioedema and MGRS. Both are relatively rare but active disorders and need careful monitoring and frequent follow-ups. Further case report series needs to be done to find any large-scale association of MGRS with acquired angioedema.\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 ethical approval for reporting individual cases.\n\nInformed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.\n\nORCID iDs: Sasmit Roy \nhttps://orcid.org/0000-0002-2509-3915\n\nVenu Madhav Konala \nhttps://orcid.org/0000-0003-1953-8815\n\nVijay Gayam \nhttps://orcid.org/0000-0001-5194-9134\n\nSreedhar Adapa \nhttps://orcid.org/0000-0001-5608-5654\n==== Refs\nReferences\n1. \nLeung N Bridoux F Hutchison CA , et al\nMonoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant\n. Blood . 2012 ;120 :4292 -4295\n.23047823 \n2. \nBridoux F Leung N Hutchison CA , et al\nDiagnosis of monoclonal gammopathy of renal significance\n. Kidney Int . 2015 ;87 :698 -711\n.25607108 \n3. \nLeung N Bridoux F Batuman V , et al\nThe evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group\n. Nat Rev Nephrol . 2019 ;15 :45 -59\n.30510265 \n4. \nNasr SH Satoskar A Markowitz GS , et al\nProliferative glomerulonephritis with monoclonal IgG deposits\n. J Am Soc Nephrol . 2009 ;20 :2055 -2064\n.19470674 \n5. \nBhutani G Nasr SH Said SM , et al\nHematologic characteristics of proliferative glomerulonephritides with nonorganized monoclonal immunoglobulin deposits\n. Mayo Clin Proc . 2015 ;90 :587 -596\n.25939936 \n6. \nMarkovic SN Inwards DJ Phyliky RP. \nAcquired C1 esterase inhibitor deficiency\n. Ann Intern Med . 2000 ;133 :839 .\n7. \nBatsakis JG Medeiros JL Luna MA El-Naggar AK. \nPlasma cell dyscrasias and the head and neck\n. Ann Diagn Pathol . 2002 ;6 :129 -140\n.12004363 \n8. \nMerlini G Pozzi C. \nMechanisms of renal damage in plasma cell dyscrasias: an overview\n. Contrib Nephrol . 2007 ;153 :66 -86\n.17075224 \n9. \nDobson G Edgar D Trinder J. \nAngioedema of the tongue due to acquired C1 esterase inhibitor deficiency\n. Anaesth Intensive Care . 2003 ;31 :99 -102\n.12635405 \n10. \nNasr SH Markowitz GS Stokes MB , et al\nProliferative glomerulonephritis with monoclonal IgG deposits: a distinct entity mimicking immune-complex glomerulonephritis\n. Kidney Int . 2004 ;65 :85 -96\n.14675039 \n11. \nHogan JJ Weiss BM. \nBridging the divide: an onco-nephrology approach to monoclonal gammopathies of renal significance\n. Clin J Am Soc Nephrol . 2016 ;11 :1681 -1691\n.27416775 \n12. \nCastelli R Deliliers DL Zingale LC Pogliani EM Cicardi M. \nLymphoproliferative disease and acquired C1 inhibitor deficiency\n. Haematologica . 2007 ;92 :716 -718\n.17488706\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2324-7096",
"issue": "8()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "acquired C1 esterase inhibitor deficiency; acquired angioedema; acute kidney injury; monoclonal gammopathy of renal significance; proliferative glomerulonephritis with monoclonal immunoglobulin deposition",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D000799:Angioedema; D001402:B-Lymphocytes; D001706:Biopsy; D050718:Complement C1 Inhibitor Protein; D005260:Female; D006801:Humans; D007668:Kidney; D008875:Middle Aged; D008998:Monoclonal Gammopathy of Undetermined Significance",
"nlm_unique_id": "101624758",
"other_id": null,
"pages": "2324709620912096",
"pmc": null,
"pmid": "32167383",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12004363;12635405;17488706;27416775;17075224;23047823;25939936;14675039;30510265;19470674;25607108;11085856",
"title": "An Unusual Case of Acquired Angioedema and Monoclonal Gammopathy of Renal Significance in a Middle-Aged Caucasian Female.",
"title_normalized": "an unusual case of acquired angioedema and monoclonal gammopathy of renal significance in a middle aged caucasian female"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-20-02177",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"dr... |
{
"abstract": "OBJECTIVE\nFor the first time to present a systematic review of observational studies on the efficiency of lithium monotherapy in comparison with other maintenance mood stabilizers in monotherapy and in combination.\n\n\nMETHODS\nAs part of the International Society for Bipolar Disorders (ISBD) Task Force on Lithium Treatment, we undertook a systematic literature search of non-randomized controlled observational studies on (i) lithium monotherapy vs treatment with another maintenance mood stabilizer in monotherapy and (ii) lithium in combination with other mood stabilizers vs monotherapy.\n\n\nRESULTS\nIn eight out of nine identified studies including a total of < 14 000 patients, maintenance lithium monotherapy was associated with improved outcome compared with another mood stabilizer in monotherapy, including valproate, lamotrigine, olanzapine, quetiapine, unspecified anticonvulsants, carbamazepine/lamotrigine, unspecified atypical antipsychotics and unspecified antipsychotics. Among the four identified studies including a total of > 4000 patients comparing maintenance combination therapy with maintenance monotherapy, a few combination therapies were found to be superior to monotherapy in some analyses, but many were not.\n\n\nCONCLUSIONS\nThe results show the superiority in real life of lithium monotherapy compared with monotherapy with other maintenance mood stabilizers. The four largest register-based studies largely addressed confounding, but, as ever, residual confounding cannot be excluded. Nevertheless, the observational findings substantially add to the findings from randomized controlled trials, whose designs often limit the validity of comparison between medicines.",
"affiliations": "Department O, Psychiatric Center Copenhagen, Copenhagen, Denmark.;Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.;Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.;Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.;University Department of Psychiatry and Oxford Health NHS Foundation Trust, University of Oxford, Warneford Hospital, Oxford, UK.;University Department of Psychiatry and Oxford Health NHS Foundation Trust, University of Oxford, Warneford Hospital, Oxford, UK.",
"authors": "Kessing|Lars Vedel|LV|http://orcid.org/0000-0001-9377-9436;Bauer|Michael|M|;Nolen|Willem A|WA|;Severus|Emanuel|E|;Goodwin|Guy M|GM|;Geddes|John|J|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/bdi.12623",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-5647",
"issue": null,
"journal": "Bipolar disorders",
"keywords": "bipolar disorder; lithium; mania; mood stabilizer; non-randomized trial; observational",
"medline_ta": "Bipolar Disord",
"mesh_terms": null,
"nlm_unique_id": "100883596",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29441712",
"pubdate": "2018-02-14",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Effectiveness of maintenance therapy of lithium vs other mood stabilizers in monotherapy and in combinations: a systematic review of evidence from observational studies.",
"title_normalized": "effectiveness of maintenance therapy of lithium vs other mood stabilizers in monotherapy and in combinations a systematic review of evidence from observational studies"
} | [
{
"companynumb": "DE-LEADING PHARMA, LLC-2067703",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HYDROCHLOROTHIAZIDE"
},
"drugadditional"... |
{
"abstract": "We aim to calculate 2 metrics of relative lethal toxicity; the fatal toxicity index (FTI; number of deaths per year of a daily dose) and the case fatality (CF; number of deaths per overdose) with a focus on opioids, antidepressants, antipsychotics, benzodiazepines and illicit drugs.\n\n\n\nThis descriptive cohort study used the Australian National Coronial Information System (NCIS) to identify a population of individuals with drug-associated deaths in the Greater Newcastle Hunter Area between January 2002 and December 2016. This was combined with Australian medicine dispensing data and corresponding data from the Hunter Area Toxicology Service to calculate FTI and CF.\n\n\n\nThere were 444 drug-related deaths and 21,296 overdoses during the study period. FTI and CF were well correlated (Spearman's rho 0.64, P < .001). Of the classes of interest, opioids had the highest FTI (40.3 95% confidence interval [CI] 35.2-45.4 deaths per 100 years of use at the defined daily dose or deaths/DDD/100 years) and CF (12.4% 95%CI 11.0-13.9). Fentanyl, methadone and morphine had the highest relative fatal toxicity within this class. Tricyclic antidepressants had the highest relative fatal toxicity of all antidepressants (FTI 14.5 95%CI 9.7-19.3 deaths/DDD/100 years and CF 7.1% [95%CI 4.8-9.3]) and benzodiazepines appeared to be more associated with multiple agent deaths than single. Of the illicit drugs, heroin had the highest CF (26.4%, 95%CI 19.1-33.7).\n\n\n\nKnowledge of relative lethal toxicity is useful to prescribers and medicines and public health policy makers in restricting access to more toxic drugs and may also assist coroners in determining cause of death.",
"affiliations": "St. Vincent's Hospital, Sydney & New South Wales Poison Information Centre, Sydney, Australia.;Translational Australian Clinical Toxicology Program, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Australia.;School of Medicine and Public Health, University of Newcastle, Australia.;School of Medicine and Public Health, University of Newcastle, Australia.;Translational Australian Clinical Toxicology Program, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Australia.",
"authors": "Brett|Jonathan|J|0000-0003-3065-7495;Wylie|Claire E|CE|0000-0001-8076-4235;Raubenheimer|Jacques|J|;Isbister|Geoff K|GK|0000-0003-1519-7419;Buckley|Nick A|NA|",
"chemical_list": "D013287:Illicit Drugs; D055553:Prescription Drugs",
"country": "England",
"delete": false,
"doi": "10.1111/bcp.14019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0306-5251",
"issue": "85(9)",
"journal": "British journal of clinical pharmacology",
"keywords": "death; epidemiology; fatal toxicity; poisoning; toxicology",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001315:Australia; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D066264:Datasets as Topic; D004305:Dose-Response Relationship, Drug; D062787:Drug Overdose; D005260:Female; D006801:Humans; D013287:Illicit Drugs; D007223:Infant; D008297:Male; D008875:Middle Aged; D055553:Prescription Drugs; D055815:Young Adult",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "2098-2107",
"pmc": null,
"pmid": "31173392",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "6480013;26945707;26526064;23419969;12144195;31173392;19778188;25929508;24450521;7877541;30193662;29442611;26987318;24397714;9589848;29280224;28689375;15979670;3690249;7866122;14705844;21215785;9485562;29482434;21048990;9828983;20104506;20298551;23442164;28758432;15739105;10612268;24962372;26001916;27286742;16272190",
"title": "The relative lethal toxicity of pharmaceutical and illicit substances: A 16-year study of the Greater Newcastle Hunter Area, Australia.",
"title_normalized": "the relative lethal toxicity of pharmaceutical and illicit substances a 16 year study of the greater newcastle hunter area australia"
} | [
{
"companynumb": "NVSC2019AU003150",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARVEDILOL"
},
"drugadditional": null,
"drug... |
{
"abstract": "OBJECTIVE\nMirabegron is a new selective β3-adrenoreceptor agonist licensed for the treatment of overactive bladder (OAB). In clinical trials, mirabegron is well-tolerated with a low side-effect profile. There is little data available on the risks in a non-selected population. The presence of β-adrenoreceptors in cardiac and vascular tissue leads to the possibility of the development of adverse cardiovascular events. We conducted a consecutive cohort study to assess the risk of developing palpitations, the severity of the condition and to investigate any underlying risk factors that predispose patients with OAB to develop palpitations whilst taking mirabegron.\n\n\nMETHODS\nA consecutive cohort of patients with OAB was studied between February 2013 and June 2014. Patients were prescribed mirabegron 50mg daily and outcomes assessed at 6 weeks. Patients with known cardiac arrhythmias were excluded. In patients who developed palpitations, a detailed account of their symptoms and medical history were documented and a 12-lead electrocardiogram (ECG) was performed to assess heart rate, QT interval and the presence of any persisting arrhythmia was conducted.\n\n\nRESULTS\nA total of 279 patients were started on mirabegron. Eight patients (2.9%) reported palpitations whilst taking the drug. Two patients with a history of palpitations with no history of prolonged QT interval or arrhythmia on ECG developed worsening palpitations. The QTc was prolonged in two patients at 0.458 and 0.441s (QTc <420). Three patients developed chest pain or tightness. The palpitations resolved once therapy was stopped and did not result in serious adverse events such as hospitalisation.\n\n\nCONCLUSIONS\nPalpitations in an unselected population have a similar incidence to that demonstrated in previous drug trials. Palpitations may be associated with a worsening of cardiovascular dysfunction.",
"affiliations": "Department of Obstetrics and Gynaecology, Medway Maritime Hospital, Windmill Road, Gillingham Kent ME7 5NY, UK. Electronic address: aswini@doctors.net.uk.;Department of Obstetrics and Gynaecology, Medway Maritime Hospital, Windmill Road, Gillingham Kent ME7 5NY, UK.",
"authors": "Balachandran|Aswini A|AA|;Duckett|Jonathan R A|JR|",
"chemical_list": "D000083:Acetanilides; D058667:Adrenergic beta-3 Receptor Agonists; D013844:Thiazoles; C520025:mirabegron",
"country": "Ireland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-2115",
"issue": "187()",
"journal": "European journal of obstetrics, gynecology, and reproductive biology",
"keywords": "Chest pain; Mirabegron; Palpitations; Side-effects; Tachyarrhythmia; Tachycardia",
"medline_ta": "Eur J Obstet Gynecol Reprod Biol",
"mesh_terms": "D000083:Acetanilides; D058667:Adrenergic beta-3 Receptor Agonists; D000368:Aged; D000369:Aged, 80 and over; D001145:Arrhythmias, Cardiac; D015331:Cohort Studies; D004562:Electrocardiography; D005260:Female; D006339:Heart Rate; D006801:Humans; D008875:Middle Aged; D012307:Risk Factors; D013844:Thiazoles; D053201:Urinary Bladder, Overactive",
"nlm_unique_id": "0375672",
"other_id": null,
"pages": "60-3",
"pmc": null,
"pmid": "25756594",
"pubdate": "2015-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The risk and severity of developing symptomatic palpitations when prescribed mirabegron for overactive bladder.",
"title_normalized": "the risk and severity of developing symptomatic palpitations when prescribed mirabegron for overactive bladder"
} | [
{
"companynumb": "GB-ASTELLAS-2014EU004287",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MIRABEGRON"
},
"drugadditional": null,
... |
{
"abstract": "Increasing data support the importance of preexisting host immune response and neoantigen burden for determining response to immune checkpoint inhibitors (ICIs). In lung cancer and melanoma, tumor mutational burden (TMB) has emerged as an independent biomarker for ICI response. However, the significance of TMB in breast cancer, particularly in the context of PD-L1 negativity, remains unclear. This report describes a patient with HER2-negative breast cancer with high TMB and an apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) trinucleotide signature; her disease was refractory to multiple lines of treatments but achieved durable complete response using ICIs and capecitabine. Additional analysis of the tumor revealed a low amount of stromal tumor-infiltrating lymphocytes (sTILs) and PD-L1 negativity, reflecting a poor preexisting host immune response. In collaboration with Foundation Medicine, comprehensive genomic profiling from 14,867 patients with breast cancer with the FoundationOne test was evaluated. Using the cutoff of ≥10 mutations/megabase (mut/Mb) for high TMB, PD-L1 positivity and TMB-high populations were not significantly overlapping (odds ratio, 1.02; P=.87). Up to 79% of TMB-high tumors with >20 mut/Mb were PD-L1-negative. Our study highlights that despite having low TILs and PD-L1 negativity, some patients may still experience response to ICIs.",
"affiliations": "Robert and Monica Jacoby Center for Breast Health, Mayo Clinic, Jacksonville, Florida.;Foundation Medicine, Cambridge, Massachusetts; and.;Robert and Monica Jacoby Center for Breast Health, Mayo Clinic, Jacksonville, Florida.;Robert and Monica Jacoby Center for Breast Health, Mayo Clinic, Jacksonville, Florida.;Robert and Monica Jacoby Center for Breast Health, Mayo Clinic, Jacksonville, Florida.;Pathology Department, and.;Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida.",
"authors": "Chumsri|Saranya|S|;Sokol|Ethan S|ES|;Soyano-Muller|Aixa E|AE|;Parrondo|Ricardo D|RD|;Reynolds|Gina A|GA|;Nassar|Aziza|A|;Thompson|E Aubrey|EA|",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1540-1405",
"issue": "18(5)",
"journal": "Journal of the National Comprehensive Cancer Network : JNCCN",
"keywords": null,
"medline_ta": "J Natl Compr Canc Netw",
"mesh_terms": "D000368:Aged; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D009154:Mutation",
"nlm_unique_id": "101162515",
"other_id": null,
"pages": "517-521",
"pmc": null,
"pmid": "32380464",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Durable Complete Response With Immune Checkpoint Inhibitor in Breast Cancer With High Tumor Mutational Burden and APOBEC Signature.",
"title_normalized": "durable complete response with immune checkpoint inhibitor in breast cancer with high tumor mutational burden and apobec signature"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-264606",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LETROZOLE"
},
"druga... |
{
"abstract": "Disseminated Mycobacterium simiae is a rare opportunistic infection reported most commonly in advanced human immunodeficiency virus (HIV) infection. Treatment can be further complicated by the occurrence of severe immune reconstitution inflammatory syndrome (IRIS). We present the first case of disseminated multi-drug-resistant M. simiae in the setting of advanced HIV, complicated by IRIS in the form of granulomatous interstitial nephritis causing acute renal failure. This case highlights the importance of recognizing rare complications of IRIS, as delays in therapy can be life threatening.",
"affiliations": "Department of Internal Medicine, Division of Infectious Disease, University of New Mexico Hospital Health Science Center, Albuquerque, NM, USA.;Department of Internal Medicine, Division of Infectious Disease, University of New Mexico Hospital Health Science Center, Albuquerque, NM, USA.",
"authors": "Salas|Natalie Mariam|NM|0000-0002-8795-3431;Byrd|Thomas F|TF|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/0956462420926881",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0956-4624",
"issue": "31(9)",
"journal": "International journal of STD & AIDS",
"keywords": "Granulomatous interstitial nephritis; Mycobacterium simiae; immune reconstitution inflammatory syndrome; non-tuberculous mycobacteria",
"medline_ta": "Int J STD AIDS",
"mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D015658:HIV Infections; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D008297:Male; D009161:Mycobacterium; D009164:Mycobacterium Infections; D009395:Nephritis, Interstitial; D016896:Treatment Outcome",
"nlm_unique_id": "9007917",
"other_id": null,
"pages": "911-913",
"pmc": null,
"pmid": "32605502",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Granulomatous interstitial nephritis in the setting of disseminated Mycobacterium simiae: a rare presentation of immune reconstitution inflammatory syndrome.",
"title_normalized": "granulomatous interstitial nephritis in the setting of disseminated mycobacterium simiae a rare presentation of immune reconstitution inflammatory syndrome"
} | [
{
"companynumb": "US-009507513-2009USA009953",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TEDIZOLID PHOSPHATE"
},
"drugadditional": nu... |
{
"abstract": "Massive upper gastrointestinal bleeding is an uncommon presentation of Burkitt's lymphoma in a patient with HIV/AIDS, and is seldom reported in the literature. A 39-year-old man who has sex with men presented with abdominal pain and massive haematemesis and a rapid drop in haemoglobin level to 4.8 g/dL. Upper gastrointestinal endoscopy showed a large blood clot in the stomach, and an emergency laparotomy was performed because of unstable haemodynamics. This showed active bleeding from multiple tumours in the fundus and body of the stomach. The patient underwent gastrectomy and gastric biopsy confirmed Burkitt's lymphoma. Further tests showed lymphoma involvement in bone marrow and central nervous system. The patient tested positive for HIV, and had a CD4 count of 212 cells/mm(3) and viral load of 18,000 copies/mL at diagnosis. He was commenced on a chemotherapy regimen of CODOX-M/IVAC, and highly active antiretroviral therapy consisting of indinavir, stavudine and lamivudine. The major side effect was peripheral neuropathy. Infective complications during chemotherapy were controlled by broad-spectrum antibiotics and anti-fungal agents. Complete remission of the lymphoma was achieved after the chemotherapy and remission was maintained for more than 14 years.",
"affiliations": "Department of Medicine, Tuen Mun Hospital, Hong Kong Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong mflaw99@yahoo.com.hk.;Department of Medicine, Tuen Mun Hospital, Hong Kong.;Department of Pathology, North District Hospital, Hong Kong.;Department of Medicine, Tuen Mun Hospital, Hong Kong.;Department of Medicine, Tuen Mun Hospital, Hong Kong.;Department of Medicine, Tuen Mun Hospital, Hong Kong.;Department of Medicine, North District Hospital, Hong Kong.;Department of Radiology, Tuen Mun Hospital, Hong Kong.;Department of Medicine, Tuen Mun Hospital, Hong Kong.;Department of Medicine, Tuen Mun Hospital, Hong Kong.",
"authors": "Law|Man F|MF|;Chan|Hay N|HN|;Pang|Chun Y|CY|;Lai|Ho K|HK|;Ha|Chung Y|CY|;Ng|Celia|C|;Ho|Rita|R|;Wong|Cheuk K|CK|;Yeung|Yiu M|YM|;Yip|Sze F|SF|",
"chemical_list": "D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1177/0956462415596301",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0956-4624",
"issue": "27(8)",
"journal": "International journal of STD & AIDS",
"keywords": "AIDS; Burkitt’s lymphoma; HIV; haematemesis; massive gastrointestinal bleeding",
"medline_ta": "Int J STD AIDS",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D023241:Antiretroviral Therapy, Highly Active; D001706:Biopsy; D002051:Burkitt Lymphoma; D003520:Cyclophosphamide; D004317:Doxorubicin; D016099:Endoscopy, Gastrointestinal; D005743:Gastrectomy; D006471:Gastrointestinal Hemorrhage; D005770:Gastrointestinal Neoplasms; D015658:HIV Infections; D018451:Homosexuality, Male; D006801:Humans; D007813:Laparotomy; D008297:Male; D008727:Methotrexate; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "9007917",
"other_id": null,
"pages": "690-6",
"pmc": null,
"pmid": "26185043",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Durable survival after chemotherapy in a HIV patient with Burkitt's lymphoma presenting with massive upper gastrointestinal bleeding.",
"title_normalized": "durable survival after chemotherapy in a hiv patient with burkitt s lymphoma presenting with massive upper gastrointestinal bleeding"
} | [
{
"companynumb": "PHHY2016HK097395",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Herpes zoster (HZ) is a clinical manifestation of the reactivation of the varicella zoster virus (VZV). HZ of the male genital area is a rarely reported condition. The exact mechanism of latency and reactivation of VZV in these patients is unknown. The incidence of HZ can be associated with various conditions such as malignancies, immune deficiencies, autoimmune diseases, psychological conditions, and human immunodeficiency infection or HIV disease. In this report, we describe a rare case of HZ on male genitalia following the administration of immunosuppressant drugs for bowel cancer. The patient developed classical features of HZ during chemotherapy, 2 years after the initial chemotherapy for his bowel cancer. The ulcers of HZ lesions were treated with chlorhexidine (Curasept) ointment to prevent secondary bacterial infection. All the lesions subsided gradually and in 2 weeks with no later symptoms or pain. Genitalia are an unusual site of eruption in HZ. Patients with malignancy and iatrogenic immunodeficiency have an increased risk of reactivation of VZV and development of HZ.",
"affiliations": "Centre for Medicine and Oral Health, Griffith Health Institute, Griffith University Gold Coast Campus, Gold Coast, QLD 4222, Australia.",
"authors": "Gopalan|Vinod|V|;Nair|Raj G|RG|;Pillai|Suja|S|;Oberholzer|Theunis|T|",
"chemical_list": "D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10156-012-0400-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "18(6)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": null,
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000970:Antineoplastic Agents; D006558:Herpes Genitalis; D006562:Herpes Zoster; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D012004:Rectal Neoplasms",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "955-7",
"pmc": null,
"pmid": "22398883",
"pubdate": "2012-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Genital herpes zoster as a consequence of cancer chemotherapy-induced immunosuppression: report of a case.",
"title_normalized": "genital herpes zoster as a consequence of cancer chemotherapy induced immunosuppression report of a case"
} | [
{
"companynumb": "AU-MYLANLABS-2015M1003480",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CHLOROCRESOL"
},
"drugadditional": null,
... |
{
"abstract": "Cataract may cause visual loss especially in the newborn period if early and urgent intervention is not managed. Approximately 1/3 of cases are congenital, 1/3 are related with systemic diseases and the remaining 1/3 are idiopathic or sporadic. The prevalence of congenital cataract in developed countries is estimated as 1 - 3 per 10,000 live births. There are a number of medicines besides systemic and infectious diseases which may cause cataract. Linezolid is a member of the oxazolidinone antibiotic family which can be used in serious infections caused by vancomycin resistant E. faecium (VRE), methicillin resistant S. aureus (MRSA), methicillin resistant coagulase negative staphylococci and penicillin resistant S. pneumonia in infants and children. Side effects are reported as diarrhea, vomiting, headache, transaminase elevation, rashes and optic neuropathy. Herein, we report a preterm newborn who developed thrombocytopenia and bilateral cataracts during linezolid therapy and relieved one week after the discontinuation of the therapy.",
"affiliations": "Department of Neonatology, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey.;Department of Neonatology, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey.;Department of Ophthalmology, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey.;Department of Neonatology, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey.;Department of Neonatology, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey.;Department of Neonatology, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey.;Department of Neonatology, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey.",
"authors": "Ilarslan|Eda|E|;AydÊn|Banu|B|;Kabatas|Emrah Utku|EU|;Beken|Serdar|S|;Dilli|Dilek|D|;Zenciroglu|Aysegul|A|;Okumus|Nurullah|N|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000069349:Linezolid",
"country": "Pakistan",
"delete": false,
"doi": "11.2014/JCPSP.S281S283",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1022-386X",
"issue": "24 Suppl 3()",
"journal": "Journal of the College of Physicians and Surgeons--Pakistan : JCPSP",
"keywords": null,
"medline_ta": "J Coll Physicians Surg Pak",
"mesh_terms": "D000900:Anti-Bacterial Agents; D002386:Cataract; D024901:Drug Resistance, Multiple, Bacterial; D016983:Enterococcus; D006801:Humans; D007231:Infant, Newborn; D000069349:Linezolid; D008297:Male",
"nlm_unique_id": "9606447",
"other_id": null,
"pages": "S281-3",
"pmc": null,
"pmid": "25518803",
"pubdate": "2014-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cataract in a preterm newborn: a possible side effect of linezolid therapy.",
"title_normalized": "cataract in a preterm newborn a possible side effect of linezolid therapy"
} | [
{
"companynumb": "TR-PFIZER INC-2014357839",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LINEZOLID"
},
"drugadditional": null,
... |
{
"abstract": "Drug-induced acute pancreatitis is a rare condition in childhood, and information about the incidence of valproic acid-induced acute pancreatitis in the pediatric population is scarce. In this clinical case, we report a first documented pediatric case of valproic acid-induced pancreatitis in Estonia. A 15-year-old boy with juvenile myoclonic epilepsy developed acute pancreatitis after 2-month therapy with valproic acid. The symptoms of pancreatitis subsided within 1 week after the discontinuation of treatment with valproic acid. Acute pancreatitis should be suspected in any pediatric patient with gastrointestinal symptoms during valproate treatment.",
"affiliations": "Department of Pediatrics, University of Tartu, Lunini 6, 51014 Tartu, Estonia. kadi.veri@lastehaigla.ee.",
"authors": "Veri|Kadi|K|;Uibo|Oivi|O|;Talvik|Inga|I|;Talvik|Tiina|T|",
"chemical_list": "D000927:Anticonvulsants; D014635:Valproic Acid",
"country": "Switzerland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1010-660X",
"issue": "49(11)",
"journal": "Medicina (Kaunas, Lithuania)",
"keywords": null,
"medline_ta": "Medicina (Kaunas)",
"mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000927:Anticonvulsants; D004957:Estonia; D006801:Humans; D008297:Male; D020190:Myoclonic Epilepsy, Juvenile; D010195:Pancreatitis; D014635:Valproic Acid; D028761:Withholding Treatment",
"nlm_unique_id": "9425208",
"other_id": null,
"pages": "487-9",
"pmc": null,
"pmid": "24823930",
"pubdate": "2013",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Valproic acid-induced pancreatitis in a 15-year-old boy with juvenile myoclonic epilepsy.",
"title_normalized": "valproic acid induced pancreatitis in a 15 year old boy with juvenile myoclonic epilepsy"
} | [
{
"companynumb": "EE-ABBVIE-15P-221-1347925-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "EE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VALPROIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nRestless legs syndrome (RLS) is not a rare condition in patients on long-term dialysis. Pramipexole is a small molecule used in the treatment of idiopathic and uremic RLS. Although some information concerning the efficacy and safety of pramipexole in uremic patients is available, data concerning the pharmacokinetics of pramipexole in hemodialysis (HD) are lacking. Following the occurrence of accidental pramipexole intoxication in a chronic HD patient, we were concerned about the efficacy of HD in removing pramipexole. Our aim was thus to assess plasma pramipexole concentrations and pramipexole clearance in a stable chronic HD patient without any residual kidney function.\n\n\nMETHODS\nOur patient was a 63-year-old man on chronic HD for 5 years who had been treated uneventfully with oral pramipexole for uremic RLS since then. During a routine 4-hour high-flux HD session, blood, ultrafiltrate, and dialysate samples were collected every hour to determine pramipexole concentrations over time.\n\n\nRESULTS\nPramipexole blood concentrations ranged from 12.1 to 23.9 µg/L. Pramipexole reduction ratio was 32.5%. Mean dialytic clearance of pramipexole was 76.8 mL/min. Postdialysis rebound was 5.6%.\n\n\nCONCLUSIONS\nIn the absence of any side effect, pramipexole blood concentrations at steady state were 2- to 4-fold higher than those observed in subjects with normal kidney function. Like other drugs with a high volume of distribution, pramipexole was poorly removed by HD. Therefore, HD is not recommended as a treatment option for pramipexole intoxication in patients with a glomerular filtration rate superior to 30 mL/min/1.73m².",
"affiliations": "Department of Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain Brussels.;Department of Intensive Care, Cliniques Universitaires Saint-Luc.;Department of Pharmacology and Toxicology, CHU Limoges, Limoges, France.;Department of Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain Brussels.;Department of Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain Brussels.;Department of Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain Brussels.",
"authors": "Hanset|Nicolas|N|;Hantson|Philippe|P|;Saint-Marcoux|Franck|F|;Devresse|Arnaud|A|;Jadoul|Michel|M|;Labriola|Laura|L|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.5414/CNCS109641",
"fulltext": "\n==== Front\nClin Nephrol Case StudDustriClinical Nephrology. Case Studies2196-5293Dustri-Verlag Dr. Karl Feistle 10.5414/CNCS109641Case ReportNephrologyInfluence of hemodialysis on pramipexole pharmacokinetics: Lessons from two cases and literature review Hanset Nicolas 1Hantson Philippe 23Saint-Marcoux Franck 4Devresse Arnaud 1Jadoul Michel 1Labriola Laura 11 Department of Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain Brussels, 2 Department of Intensive Care, Cliniques Universitaires Saint-Luc, 3 Louvain Center for Toxicology and Applied Pharmacology, Université Catholique de Louvain, Brussels, Belgium, and 4 Department of Pharmacology and Toxicology, CHU Limoges, Limoges, FranceCorrespondence to: Laura Labriola, MD Department of Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Av. Hippocrate 10, 1200 Bruxelles, Belgium laura.labriola@uclouvain.be2019 22 3 2019 7 11 16 28 8 2018 8 1 2019 © Dustri-Verlag Dr. K. Feistle2019 This is an open-access article distributed under the terms of the Creative\nCommons Attribution License, which permits unrestricted use, distribution, and\nreproduction in any medium, provided the original work is properly cited.Background: Restless legs syndrome (RLS) is not a rare condition in patients on long-term dialysis. Pramipexole is a small molecule used in the treatment of idiopathic and uremic RLS. Although some information concerning the efficacy and safety of pramipexole in uremic patients is available, data concerning the pharmacokinetics of pramipexole in hemodialysis (HD) are lacking. Following the occurrence of accidental pramipexole intoxication in a chronic HD patient, we were concerned about the efficacy of HD in removing pramipexole. Our aim was thus to assess plasma pramipexole concentrations and pramipexole clearance in a stable chronic HD patient without any residual kidney function. Materials and methods: Our patient was a 63-year-old man on chronic HD for 5 years who had been treated uneventfully with oral pramipexole for uremic RLS since then. During a routine 4-hour high-flux HD session, blood, ultrafiltrate, and dialysate samples were collected every hour to determine pramipexole concentrations over time. Results: Pramipexole blood concentrations ranged from 12.1 to 23.9 µg/L. Pramipexole reduction ratio was 32.5%. Mean dialytic clearance of pramipexole was 76.8 mL/min. Postdialysis rebound was 5.6%. Conclusion: In the absence of any side effect, pramipexole blood concentrations at steady state were 2- to 4-fold higher than those observed in subjects with normal kidney function. Like other drugs with a high volume of distribution, pramipexole was poorly removed by HD. Therefore, HD is not recommended as a treatment option for pramipexole intoxication in patients with a glomerular filtration rate superior to 30 mL/min/1.73m². \n\npramipexolehemodialysispharmacokinetics\n==== Body\nIntroduction \nRestless legs syndrome (RLS) is not a rare condition in patients on long-term dialysis. Reported prevalence in hemodialysis (HD) is variable (6.6 – 49%), due to differences in diagnostic methods [1]. Pramipexole, an oral non-ergoline dopamine agonist, has selective activity for the dopamine D3 receptor and is used as an antiparkinsonian agent. It has been approved in 2006 in the EU [2] and the US [3] for the treatment of moderate to severe idiopathic RLS in adults [4, 5]. The metabolism of pramipexole is minimal and the drug is excreted virtually unchanged in the urine by tubular secretion [6]. Although some information concerning the efficacy and safety of pramipexole in uremic patients is available [7], data concerning the removal of pramipexole during HD are lacking, and recommendations concerning its use in HD patients are extrapolated from data obtained in the general population. \n\nWe previously reported the case of a 79-year-old anuric chronic HD patient, who accidentally suffered a pramipexole overdose (the dosage was increased from 0.09 to 1.4 mg/d and administered 2 days in a row) and presented an acute deterioration of the level of consciousness with hypercapnic respiratory failure, necessitating admission to intensive care unit and non-invasive ventilation [8]. Pramipexole intoxication was suspected as a potential etiology. The medication was thus withdrawn, and daily intermittent HD was performed. The patient’s neurological and respiratory status returned to normal very slowly from the third day. Maximal pramipexole blood concentration was 7.8 µg/L (measured 51 hours after the last dose), and clearance by HD was measured at 73.3 mL/min. \n\nThe pharmacokinetics of drugs vary widely in HD, depending on characteristics, such as molecular weight, protein binding capacity, and volume of distribution. Thus, one specific molecule may tend to accumulate or, on the contrary, be excreted by HD, which can result in a major impact on safety and therapeutic efficacy, respectively. Even though one might assume dialyzability and pharmacokinetic profiles on the basis of the key features mentioned above, confirmative data are needed for a safe use of drugs in HD patients. In this setting, we were concerned about the efficacy of HD in clearing pramipexole. Given its small molecular weight and a low protein binding [6], significant HD removal could be expected. However, the efficacy of HD in pramipexole clearance is likely to be mitigated by the huge volume of distribution of pramipexole (7 L/kg) [9]. Our purpose was thus to assess plasma pramipexole concentrations and pramipexole clearance and removal in a chronic HD patient without residual kidney function. \n\nMaterials and methods \nPatient and hemodialysis \nOur patient was a 63-year-old Caucasian man on in-center chronic HD for 5 years for end-stage renal disease secondary to autosomal dominant polycystic kidney disease. Relevant medical history included combined kidney and liver transplantation 5 years earlier, hypertension, post-transplant lymphoproliferative disease, and uremic RLS diagnosed 5 years earlier according to international RLS diagnostic criteria [10]. He weighed 80.3 kg at a height of 178 cm. He had been treated with oral pramipexole 0.18 mg twice daily for the last 5 years, resulting in a complete remission of RLS, without any side effect. He was dialyzed 4 hours 3 times a week. His vascular access was a native upper arm arteriovenous fistula (AVF) created 5 years earlier and cannulated using the buttonhole technique with blunt needles. Access blood flow was measured at 3,065 mL/min using saline dilution (Transonic Systems Inc., Ithaca, NY, USA), without recirculation. \n\nAll the measurements for this pharmacokinetic study were performed during the mid-week HD session using a GENIUS 90 Therapy System (Fresenius Medical Care, Bad Homburg, Germany) with a HDF 600 hollow-fiber high-flux polysulfone dialyser (Fresenius Medical Care) for 4 hours. Dialysate composition was: sodium 138 mMol/L, potassium 4 mMol/L, calcium 1.5 mMol/L, bicarbonate 32 mMol/L, acetate 3.0 mMol/L, magnesium 0.5 mMol/L, and glucose 100 mg/dL. Blood flow and dialysate flow rates were set at 340 mL/min. Dialysate temperature was 36 °C. Anticoagulation was achieved using nadroparin calcium 0.6 mL. The dialyzer was not reused. \n\nSample handling and analysis \nThe patient received the last pramipexole dose 4 hours before starting the HD session. Blood samples for pramipexole measurements were drawn from the blunt needle placed at the arterial puncture site of the AVF 2 (H–2) and 1 (H–1) hour(s), and immediately before (H0), the HD session. During HD, blood samples were collected hourly (H1, H2, H3) from the arterial needle. Blood was also taken from the venous needle at H1 and H3. Post-HD samples were obtained from the arterial needle tubing after disconnection (H4), as well as 30 and 120 minutes after the end of the HD session. Ultrafiltrate was collected every hour from the ultrafiltrate vessel, after stirring its content. Spent dialysate was collected hourly from the efferent dialysate port and sampled immediately after dialysis. All samples described above were collected in heparinized blood collection tubes, then centrifuged and stored in a –20 °C freezer until assayed (Department of Pharmacology and Toxicology, CHU Limoges, Limoges, France). \n\nAnalytical methods \nConcentrations of pramipexole were determined by using a liquid chromatography coupled to tandem mass spectrometry method (LC-MS/MS). The chromatographic system consisted of two Shimadzu LC-30 AD pumps (Nexera X2), a CTO 20AC oven, and a SIL-30 AC-MP autosampler (Shimadzu, Marne-la-Vallée, France). Chromatographic separation was performed using a Pinnacle DB PFPP, 1.9 μm (50 × 2.1 mm I.D.) column (Restek, Lisses, France). A Shimadzu 8050 triple quadrupole mass spectrometer (Marne-la-Vallée, France) was used in the positive electrospray ionization mode, and multiple-reaction monitoring (MRM) transitions were as follows: 212.10-153.05; 212.10-111.00; 212.10-126.05. The laboratory of Pharmacology-Toxicology of the Limoges University Hospital works in accordance with the International Standards Organization (ISO) 15189 standard (accreditation number: 8-2607), and the method was developed according to an accredited validation protocol. Among the usual acceptance criteria, Coefficient of variability (CV) values were less than 15% in the range 2.5 – 500 µg/L for intra-assay and the inter-assay precision and accuracy. Creatinine measurements were performed on a Cobas 8000 analyzer module c702 (Roche Diagnostics, Basel, Switzerland), with the Jaffe generation 2 method, a kinetic colorimetric assay, according to the manufacturer recommendations. \n\nPharmacokinetic analysis \nPlasma pramipexole reduction ratio (PRR) was calculated according to the following formula: \n\n\n\nwhere Cpredialysis and Cpostdialysis are blood concentrations of pramipexole at the start and the end of HD session, respectively. \n\nThe total mass of pramipexole removed by HD (XHp) was estimated by the following equation: \n\n\n\nwhere CU is the pramipexole concentration in ultrafiltrate, VU is the total volume of ultrafiltrate, CD is the pramipexole concentration in the efferent dialysate, VD is the volume of dialysate, and t is the time interval at which measures were made. \n\nOn the basis of the two previous equations, total pramipexole blood mass before HD (XBp) was calculated as: \n\n\n\nDialytic clearance of pramipexole (Cldial) was derived from the Fick principle, using the following equation: \n\n\n\nwhere Qb is blood flow rate, Hct is hematocrit, Ca is the predialyzer blood pramipexole concentration, and Cv is the postdialyzer blood pramipexole concentration. \n\nRebound (Rbd) was calculated using the following equation: \n\n\n\nwhere Cend is the blood pramipexole concentration measured on the predialyzer (arterial) port at the end of dialysis and Cafter is the maximal pramipexole blood concentration measured after dialysis by direct venipuncture. \n\nResults \nCharacteristics of the HD session are depicted in Table 1. Pramipexole and creatinine concentrations over time are reported in Table 2 and Figure 1. \n\nPramipexole blood concentrations ranged from 12.1 to 23.9 µg/L. As shown in Figure 1, the drug concentrations, measured starting 2 hours after oral intake, were not stable prior to the HD session, a finding suggestive of ongoing absorption and distribution of the drug. Pramipexole reduction ratio was 32.5%. Total mass of pramipexole removed by HD was estimated at 469 µg. Total blood mass of pramipexole before HD was estimated at 1,466 µg. Mean dialytic clearance of pramipexole was 76.8 mL/min. Postdialysis rebound was 5.6%. \n\nDiscussion \nPramipexole is a synthetic aminobenzothiole derivative with selective agonist action on D2 – D3 presynaptic dopamine autoreceptors and thus beneficial effects on parkinsonian symptoms [11]. Although its mechanism of action in restless legs syndrome remains unclear [4], pramipexole has been found to be effective as symptomatic treatment of idiopathic and uremic RLS [5, 7]. \n\nPramipexole is rapidly absorbed, has an oral bioavailability > 90%, and undergoes minimal metabolism [6]. It has a linear pharmacokinetic, with maximal plasma concentration achieved in 1 hour [9]. In individuals with normal kidney function, serum half-life is 8 – 14 hours, whereas in end-stage renal disease, half-life extends up to 38 hours [12]. \n\nIn subjects with normal renal function, ~ 90% of a dose of pramipexole is excreted via renal tubular secretion, unchanged into the urine [4, 9]. As renal function decreases, pramipexole clearance correlates with creatinine clearance (411 ± 85.9 mL/min, 297 ± 57.2 mL/min, 192 ± 52.5 mL/min and 131 ± 22.2 mL/min in subjects with normal, mild (creatinine clearance 66.0 ± 8.9 mL/min), moderate (creatinine clearance 42.3 ± 6.8 mL/min) and severe (creatinine clearance 21.9 ± 3.9 mL/min) renal impairment, respectively) [12]. Given its small molecular weight (302.3 Da) and a low protein binding (< 20%) [6], significant HD removal could be expected. However, HD efficacy seems to be very low, probably due to the huge volume of distribution of pramipexole (7 L/kg) [9], which indicates that a significant amount of the drug is distributed in the extravascular space, i.e., not directly accessible for removal by HD. \n\nIn the only report focusing on that subject, including three chronic HD patients treated with pramipexole 0.250 mg twice daily, Wright et al. document that less than 9% of the dose was cleared by a 3-hour dialysis. Pramipexole clearance was not measured [12]. Dexpramipexole, also known as R-(+)-Pramipexole, is an enantiomer of pramipexole recently developed, and used as neuroprotective agent in amyotrophic lateral sclerosis, with pharmacokinetic features similar to those of pramipexole. In a study evaluating the impact of renal failure and HD on dexpramipexole concentration, high-flux HD decreased dexpramipexole plasma concentration by 25% [13]. In the present case, and in our other previously reported patient [8], pramipexole reduction ratios by HD were 32.5 and 44.3%, respectively, and mean dialytic clearances of pramipexole were estimated at 76.8 and 73.3 mL/min, respectively. Postdialysis rebound was low (~ 5%), probably owing to an early start of the redistribution, before the end of dialysis, because of high volume of distribution and continuous high refilling rate. Even though concentrations were measured during the distribution phase of the drug, the simultaneous measurement of pramipexole concentrations in post-dialyzer blood, ultrafiltrate and dialysate provides unquestionable information about the effects of HD on drug removal. In the light of those findings, given the poor efficacy of HD in pramipexole removal, HD is not recommended as a treatment option in intoxicated patients with an estimated glomerular filtration rate superior to 30 mL/min/1.73m². \n\nData on pramipexole blood levels are scanty, especially regarding RLS. In healthy volunteers taking 0.375 – 4.5 mg/d, mean trough plasma concentrations ranging around 1.5 – 5.0 µg/L have been measured, with a peak plasma concentration of ~ 6.0 µg/L [9]. Although uncommon, adverse events such as nausea, dizziness, headache, sleep disorders (insomnia, somnolence, sudden onset of sleep), and psychiatric reactions (mainly hallucinations) might occur, mainly in association with dose escalation [9, 11]. There is limited information on pramipexole overdose [14, 15], but, since tolerance appears rapidly, slow titration is indicated [9]. In HD patients with uremic RLS, treatment with lower doses of pramipexole (0.125 – 0.5 mg/d) was effective, with no major adverse event [7]. In our patient, under long-established daily dose of 0.36 mg, plasma concentrations of pramipexole ranged from 12.1 to 23.9 µg/L, 2- to 4-fold higher than those reported in healthy volunteers in the absence of apparent toxicity. Total blood pramipexole mass before HD was estimated to be equivalent to approximately four daily doses. These findings suggest a propensity of pramipexole to accumulate despite HD, in association with a strong tolerance phenomenon, and question the reliability of serum concentrations measurement to assess intoxication in HD patients. Even if based on low-level evidence, we agree with the experts’ recommendations to use doses ranging from 0.125 to 1.6 mg/d in patients with no significant renal impairment, to initiate treatment at low doses with slow titration until symptoms relief is obtained, and, in dialysis patients, to consider 0.75 mg as a maximal daily dose [16]. \n\nConclusion \nPharmacokinetic features of pramipexole in HD, assessed by blood and dialysate measures, correlate with those expected from a theoretical point of view. Surprisingly though, despite the lack of any apparent side effect, pramipexole blood concentrations at steady state exceeded by far those observed in subjects with normal kidney function. This suggests a propensity to drug accumulation and tolerance along with long-term administration and questions the reliability of plasma pramipexole concentration measurement to diagnose intoxication. We confirm a poor efficacy of HD in pramipexole clearance (close to 80 mL/min), which does not outperform the renal pramipexole clearance observed in patients with moderate chronic kidney disease. Therefore, HD is not recommended as a treatment option for pramipexole intoxication in patients with an estimated glomerular filtration rate superior to 30 mL/min/1.73m². \n\nCompliance with ethical standards \nAll patients cited in this paper gave written informed consent to participate in the study. \n\nFunding \nNone of the authors received any support/funding for this study. \n\nConflict of interest \nProf. L. Labriola reports personal fees (lecture fees) from Fresenius, personal fees (lecture fees) from Amgen, personal fees (travel support) from Shire, personal fees (travel support) from Bellco, personal fees travel support) from Janssen-Cilag, outside the submitted work. Prof. M. Jadoul reports consulting fees from Amgen, consulting fees from Astellas, consulting fees from Fresenius, consulting fees from GSK, consulting fees from MSD, consulting fees from Sanofi, traveling support from Amgen, grants from Alexion, grants from Amgen, grants from Baxter, grants from Otsuka, grants from Janssen-Cilag, grants from Roche, lecture fees from Abbvie, lecture fees from Menarini, lecture fees from MSD, lecture fees from Amgen, outside the submitted work. Dr. N. Hanset, Prof. P. Hantson, Prof. F Saint-Marcoux, Dr. A. Devresse: no conflict of interest to declare. \n\n\nTable 1. Hemodialysis session characteristics. \nActual hemodialysis time (min)\t240\t\nBlood flow rate (mL/min)\t340\t\nDialysate flow rate (mL/min)\t340\t\nUltrafiltration rate (mL/h)\t320\t\nActual total ultrafiltration volume (mL)\t1,170\t\nCreatinine reduction ratio (%)\t64.9%\t\n\n\n\n\nTable 2. Pramipexole and creatinine concentrations over time. \nTime (hours)\tPredialysis\tPeridialysis\tPostdialysis\t\nH–2\n\tH–1\n\tH0\n\tH1\n\tH2\n\tH3\n\tH4\n\tH4.5\n\tH6\n\t\nPramipexole (µg/L)\t\nPredialyzer blood\t33.9\t29.1\t20.0\t22.1\t23.9\t12.1\t13.5\t14.3\t13.1\t\nPostdialyzer blood\t\t\t\t10.6\t\t10.7\t\t\t\t\nDialysate\t\t\t\t10.9\t5.1\t3.6\t5.1\t\t\t\nUltrafiltrate\t\t\t\t11.4\t6.8\t5.2\t4.5\t\t\t\nCreatinine in predialyzer blood (mg/dL)\t\n\t\t\t9.51\t\t\t\t3.34\t\t\t\nH = hour.\n\n\n\n\nFigure 1. Effect of HD on pramipexole concentrations.\n==== Refs\nReferences\n1 \nKavanagh D \nSiddiqui S \nGeddes CC \nRestless legs syndrome in patients on dialysis. \nAm J Kidney Dis .\n2004 ;\n43 :\n763 –771 .\n15112166 \n2 \nBoehringer Ingelheim International GmbH. Mirapexin®: European public assessment report – Scientific Discussion – Variation. \nhttp://www.ema.europa.eu. Accessed 2018 Jun 11.\n\n3 \nBoehringer Ingelheim International GmbH. Mirapex® (pramipexole dihydrochloride): Efficacy – New Indication. \nhttps://www.accessdata.fda.gov. Accessed June 11, 2018.\n\n4 \nMcCormack PL \nSiddiqui MAA \nPramipexole: in restless legs syndrome. \nCNS Drugs .\n2007 ;\n21 :\n429 –437 , discussion 438-440.\n17447832 \n5 \nWinkelman JW \nArmstrong MJ \nAllen RP \nChaudhuri KR \nOndo W \nTrenkwalder C \nZee PC \nGronseth GS \nGloss D \nZesiewicz T \nPractice guideline summary: Treatment of restless legs syndrome in adults: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. \nNeurology .\n2016 ;\n87 :\n2585 –2593 .\n27856776 \n6 \nBoehringer Ingelheim International GmbH. Mirapexin® (pramipexole dihydrochloride monohydrate): summary of product characteristics. \nhttp://www.ema.europa.eu. Accessed 2018 Jun 11.\n\n7 \nMiranda M \nKagi M \nFabres L \nAguilera L \nAlvo M \nElgueta L \nErazo S \nVenegas P \nPramipexole for the treatment of uremic restless legs in patients undergoing hemodialysis. \nNeurology .\n2004 ;\n62 :\n831 –832 .\n15007148 \n8 \nHanset N \nSaint-Marcoux F \nHantson P \nSurdosage accidentel en pramipexole chez un patient insuffisant rénal chronique. \nToxicologie analytique et clinique .\n2018 ; 30 (Suppl) : Abstr. P 66 .\n\n9 \nWright CE \nSisson TL \nIchhpurani AK \nPeters GR \nSteady-state pharmacokinetic properties of pramipexole in healthy volunteers. \nJ Clin Pharmacol .\n1997 ;\n37 :\n520 –525 .\n9208359 \n10 \nInternational Restless Legs Syndrome Study Group. 2012 Revised IRLSSG Diagnostic Criteria for RLS, Rochester MN: IRLSSG, 2012. \nhttp://irlssg.org/diagnostic-criteria. Accessed June 11; 2018.\n\n11 \nDeleu D \nNorthway MG \nHanssens Y \nClinical pharmacokinetic and pharmacodynamic properties of drugs used in the treatment of Parkinson’s disease. \nClin Pharmacokinet .\n2002 ;\n41 :\n261 –309 .\n11978145 \n12 \nWright CE \nLasher Sisson T \nIchhpurani AK \nPeters GR \nInfluence of renal impairment and hemodialysis on pramipexole pharmacokinetics. \n Mov Disord .\n1997 ; 12 (Suppl 1,66) : Abstr. P 249 .\n\n13 \nHe P \nKerr D \nMarbury T \nRies D \nFarwell W \nStecher S \nDong Y \nWei D \nRogge M \nPharmacokinetics of renally excreted drug dexpramipexole in subjects with impaired renal function. \nJ Clin Pharmacol .\n2014 ;\n54 :\n1383 –1390 .\n24965504 \n14 \nCardon-Dunbar A \nRobertson T \nRoberts MS \nIsbister GK \nPramipexole overdose associated with visual hallucinations, agitation and myoclonus. \nJ Med Toxicol .\n2017 ;\n13 :\n343 –346 .\n28547577 \n15 \nHong CT \nSun Y \nLu CJ \nFatal intoxication using amantadine and pramipexole in a uremic patient. \nActa Neurol Taiwan .\n2008 ;\n17 :\n109 –111 .\n18686651 \n16 \nMolnar MZ \nNovak M \nMucsi I \nManagement of restless legs syndrome in patients on dialysis. \nDrugs .\n2006 ;\n66 :\n607 –624 .\n16620140\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2196-5293",
"issue": "7()",
"journal": "Clinical nephrology. Case studies",
"keywords": "hemodialysis; pharmacokinetics ; pramipexole",
"medline_ta": "Clin Nephrol Case Stud",
"mesh_terms": null,
"nlm_unique_id": "101638685",
"other_id": null,
"pages": "11-16",
"pmc": null,
"pmid": "31008016",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "11978145;15007148;15112166;16620140;17447832;18686651;24965504;27856776;28547577;9208359",
"title": "Influence of hemodialysis on pramipexole pharmacokinetics: Lessons from two cases and literature review.",
"title_normalized": "influence of hemodialysis on pramipexole pharmacokinetics lessons from two cases and literature review"
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"activesubstancename": "PRAMIPEXOLE"
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... |
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"abstract": "An analysis of complex examination of 110 patients with venous thromboembolism was made. The patients were separated into 2 groups. The first group included 60 patients, who had the start heparin therapy during 7 days with the following 6-month warfarin therapy. Warfarin was substituted by pradaxa (dabigatran) for 50 patients of the second group. The efficacy of pradaxa could be compared with warfarin. However, pradaxa had a number of advantages such as the predictable anticoagulant effect, standard dosages. This medicine is more predictable and doesn't require a control of homeostasis and an adjustment of drug dosage.",
"affiliations": null,
"authors": "Sukovatykh|B S|BS|;Belikov|L N|LN|;Savchuk|O F|OF|;Sukovatykh|M B|MB|",
"chemical_list": "D000925:Anticoagulants; D001562:Benzimidazoles; D015091:beta-Alanine; D014859:Warfarin; D006493:Heparin; D000069604:Dabigatran",
"country": "Russia (Federation)",
"delete": false,
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"issn_linking": "0042-4625",
"issue": "173(4)",
"journal": "Vestnik khirurgii imeni I. I. Grekova",
"keywords": null,
"medline_ta": "Vestn Khir Im I I Grek",
"mesh_terms": "D000925:Anticoagulants; D001562:Benzimidazoles; D001777:Blood Coagulation; D000069604:Dabigatran; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D057915:Drug Substitution; D005260:Female; D006470:Hemorrhage; D006493:Heparin; D006801:Humans; D035002:Lower Extremity; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D036542:Tomography, Spiral Computed; D016896:Treatment Outcome; D018616:Ultrasonography, Doppler, Duplex; D054556:Venous Thromboembolism; D014859:Warfarin; D015091:beta-Alanine",
"nlm_unique_id": "0411377",
"other_id": null,
"pages": "87-91",
"pmc": null,
"pmid": "25552114",
"pubdate": "2014",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Advantages and disadvantages of warfarin and pradaxa therapy for venous thromboembolism.",
"title_normalized": "advantages and disadvantages of warfarin and pradaxa therapy for venous thromboembolism"
} | [
{
"companynumb": "RU-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-09682GD",
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"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
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"abstract": "A 67-year-old female presented for evaluation of a left inguinal mass. Contrast-enhanced computed tomography revealed a tumor surrounding the urethra. Magnetic resonance imaging showed that the tumor had invaded the bladder neck on the anterior aspect of the urethra. The serum carbohydrate antigen 19-9 level was elevated. The clinical diagnosis was a primary adenocarcinoma of the female urethra (cT4N2M0). The initial treatment consisted of gemcitabine plus cisplatin (GC) and oral fluoropyrimidine (S-1). A total cysto-urethrectomy with anterior vaginal wall resection, pelvic and inguinal lymphadenectomy, and urinary diversion with ileal conduit formation were performed. The final diagnosis was urethral adenocarcinoma (ypT4ypN2, stage IV). Twelve months post-operatively, there was no evidence of recurrence or distant metastases.",
"affiliations": "The Department of Urology, Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine.;The Department of Urology, Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine.;The Department of Urology, Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine.;The Department of Urology, Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine.;The Department of Urology, Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine.;The Department of Urology, Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine.;The Department of Urology, Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine.;The Department of Urology, Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine.;The Department of Urology, Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine.;The Department of Urology, Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine.;The Department of Urology, Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine.;The Department of Urology, Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine.;The Department of Oncologic Pathology, Mie University Graduate School of Medicine.",
"authors": "Nishikawa|Taketomo|T|;Sugino|Yusuke|Y|;Owa|Shunsuke|S|;Kitano|Goshi|G|;Sasaki|Takeshi|T|;Kato|Manabu|M|;Masui|Satoru|S|;Nishikawa|Kohei|K|;Yoshio|Yuko|Y|;Kanda|Hideki|H|;Arima|Kiminobu|K|;Sugimura|Yoshiki|Y|;Uchida|Katsunori|K|",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine; D002945:Cisplatin",
"country": "Japan",
"delete": false,
"doi": "10.14989/ActaUrolJap_66_4_115",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0018-1994",
"issue": "66(4)",
"journal": "Hinyokika kiyo. Acta urologica Japonica",
"keywords": null,
"medline_ta": "Hinyokika Kiyo",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D002945:Cisplatin; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local; D014521:Urethra; D014523:Urethral Neoplasms; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "0421145",
"other_id": null,
"pages": "115-119",
"pmc": null,
"pmid": "32483945",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Neoajuvant Chemotherapy with Gemcitabine and Cisplatin Plus S-1 for Primary Female Urethral Adenocarcinoma.",
"title_normalized": "neoajuvant chemotherapy with gemcitabine and cisplatin plus s 1 for primary female urethral adenocarcinoma"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022RR-327532",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE"
},
"dru... |
{
"abstract": "BACKGROUND\nA fluoropyrimidine plus irinotecan or oxaliplatin, combined with bevacizumab (a monoclonal antibody against vascular endothelial growth factor), is standard first-line treatment for metastatic colorectal cancer. Before the introduction of bevacizumab, chemotherapy with fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) showed superior efficacy as compared with fluorouracil, leucovorin, and irinotecan (FOLFIRI). In a phase 2 study, FOLFOXIRI plus bevacizumab showed promising activity and an acceptable rate of adverse effects.\n\n\nMETHODS\nWe randomly assigned 508 patients with untreated metastatic colorectal cancer to receive either FOLFIRI plus bevacizumab (control group) or FOLFOXIRI plus bevacizumab (experimental group). Up to 12 cycles of treatment were administered, followed by fluorouracil plus bevacizumab until disease progression. The primary end point was progression-free survival.\n\n\nRESULTS\nThe median progression-free survival was 12.1 months in the experimental group, as compared with 9.7 months in the control group (hazard ratio for progression, 0.75; 95% confidence interval [CI], 0.62 to 0.90; P=0.003). The objective response rate was 65% in the experimental group and 53% in the control group (P=0.006). Overall survival was longer, but not significantly so, in the experimental group (31.0 vs. 25.8 months; hazard ratio for death, 0.79; 95% CI, 0.63 to 1.00; P=0.054). The incidences of grade 3 or 4 neurotoxicity, stomatitis, diarrhea, and neutropenia were significantly higher in the experimental group.\n\n\nCONCLUSIONS\nFOLFOXIRI plus bevacizumab, as compared with FOLFIRI plus bevacizumab, improved the outcome in patients with metastatic colorectal cancer and increased the incidence of some adverse events. (Funded by the Gruppo Oncologico Nord Ovest and others; ClinicalTrials.gov number, NCT00719797.).",
"affiliations": "From Azienda Ospedaliero-Universitaria Pisana and Università di Pisa, Pisa (F.L., C. Cremolini, G.M., L.S., A.F.), Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua (S.L., V.Z.), Sapienza Università di Roma (E.C.) and Università Campus Biomedico (G. Tonini), Rome, Azienda Istituti Ospitalieri, Cremona (G. Tomasello), Ospedale San Raffaele, IRCCS, Milan (M.R.), Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, Turin (R.S.), Fondazione Poliambulanza, Brescia (A.Z.), Centro di Riferimento Oncologico, IRCCS, Aviano (A.B.), Ospedale Versilia, Lido di Camaiore (D.A.), Ospedale San Martino, IRCCS, Genoa (S.C.), Azienda Ospedaliera Universitaria Federico II, Naples (C. Carlomagno), Arcispedale Santa Maria Nuova, IRCCS, Reggio Emilia (C.B.), Ospedale Felice Lotti, Pontedera (G.A.), and Azienda Ospedaliero-Universitaria Careggi and Istituto Toscano Tumori, Florence (L.B.) - all in Italy.",
"authors": "Loupakis|Fotios|F|;Cremolini|Chiara|C|;Masi|Gianluca|G|;Lonardi|Sara|S|;Zagonel|Vittorina|V|;Salvatore|Lisa|L|;Cortesi|Enrico|E|;Tomasello|Gianluca|G|;Ronzoni|Monica|M|;Spadi|Rosella|R|;Zaniboni|Alberto|A|;Tonini|Giuseppe|G|;Buonadonna|Angela|A|;Amoroso|Domenico|D|;Chiara|Silvana|S|;Carlomagno|Chiara|C|;Boni|Corrado|C|;Allegrini|Giacomo|G|;Boni|Luca|L|;Falcone|Alfredo|A|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D009944:Organoplatinum Compounds; D000068258:Bevacizumab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "United States",
"delete": false,
"doi": "10.1056/NEJMoa1403108",
"fulltext": null,
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"issn_linking": "0028-4793",
"issue": "371(17)",
"journal": "The New England journal of medicine",
"keywords": null,
"medline_ta": "N Engl J Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D002166:Camptothecin; D015179:Colorectal Neoplasms; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D002955:Leucovorin; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds",
"nlm_unique_id": "0255562",
"other_id": null,
"pages": "1609-18",
"pmc": null,
"pmid": "25337750",
"pubdate": "2014-10-23",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer.",
"title_normalized": "initial therapy with folfoxiri and bevacizumab for metastatic colorectal cancer"
} | [
{
"companynumb": "IT-SA-2014SA156395",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
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"drugadditional": null,
"... |
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"abstract": "The objective of this study was to evaluate effectiveness, retention, and tolerability of brivaracetam (BRV) in genetic generalized epilepsies (GGE) in clinical practice.\n\n\n\nA multicenter, retrospective cohort study recruiting all patients that started BRV in 2016 and 2017.\n\n\n\nA total of 61 patients (mean age = 29.8, range = 9-90 years, 41 female [67%]) were treated with BRV. They were difficult to control, with 2.4 failed antiepileptic drugs (AEDs) in the past, taking 1.9 AEDs on average at baseline. The length of exposure to BRV ranged from 7 days to 24 months, with a mean retention time of 7.9 months, resulting in a total exposure time to BRV of 483 months. The retention rate was 82% at 3 months and 69% at 6 months. Efficacy at 3 months was 36% (50% responder rate), with 25% seizure-free for 3 months. Patients with juvenile myoclonic epilepsy showed a responder rate of 60%, with 40% being free of any seizures. Long-term 50% responder rate was present in 17 patients (28%; 11 seizure-free [18%]) for >6 months and in 14 patients (23%; 10 seizure-free [16%]) for >12 months. Treatment-emergent adverse events were observed in 26% of the patients, with the most common being somnolence, ataxia, and psychobehavioral adverse events. Use of intravenous BRV with bolus injection of 200-300 mg in two females with absence status epilepticus was well tolerated, but did not result in cessation of status epilepticus.\n\n\n\nUse of BRV in GGE is well tolerated, and 50% responder rates are similar to those observed in the regulatory trials for focal epilepsies. An immediate switch from levetiracetam (LEV) to BRV at a ratio of 15:1 is feasible. The occurrence of psychobehavioral adverse events seems less prominent than under LEV, and a switch to BRV can be considered in patients with LEV-induced adverse events.",
"affiliations": "Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Goethe University, Frankfurt am Main, Germany.;Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Goethe University, Frankfurt am Main, Germany.;Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Goethe University, Frankfurt am Main, Germany.;Epilepsy Center Hessen and Department of Neurology, Philipps University, Marburg, Germany.;Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Goethe University, Frankfurt am Main, Germany.;Epilepsy Center Hessen and Department of Neurology, Philipps University, Marburg, Germany.;Department of Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.;Epilepsy Center Greifswald and Department of Neurology, Ernst Moritz Arndt University, Greifswald, Germany.;Department of Neuropediatrics, Westfälische Wilhelms University, Münster, Germany.;Epilepsy Center Münster-Osnabrück, Department of Neurology, Westfälische Wilhelms University, Münster, Germany.;Epilepsy Center Münster-Osnabrück, Department of Neurology, Westfälische Wilhelms University, Münster, Germany.;Epilepsy Center for Children, University Hospital Neuruppin, Brandenburg Medical School, Neuruppin, Germany.;Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Goethe University, Frankfurt am Main, Germany.;Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Goethe University, Frankfurt am Main, Germany.;Kork Epilepsy Center, Kehl-Kork, Germany.;Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Goethe University, Frankfurt am Main, Germany.;Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Goethe University, Frankfurt am Main, Germany.;Epilepsy Center Greifswald and Department of Neurology, Ernst Moritz Arndt University, Greifswald, Germany.;Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Goethe University, Frankfurt am Main, Germany.",
"authors": "Strzelczyk|Adam|A|0000-0001-6288-9915;Kay|Lara|L|;Bauer|Sebastian|S|;Immisch|Ilka|I|;Klein|Karl Martin|KM|;Knake|Susanne|S|;Kowski|Alexander|A|;Kunz|Rhina|R|;Kurlemann|Gerhard|G|;Langenbruch|Lisa|L|;Möddel|Gabriel|G|;Müller-Schlüter|Karen|K|;Reif|Philipp S|PS|;Schubert-Bast|Susanne|S|;Steinhoff|Bernhard J|BJ|;Steinig|Isabel|I|;Willems|Laurent M|LM|;von Podewils|Felix|F|;Rosenow|Felix|F|",
"chemical_list": "D000927:Anticonvulsants; D011760:Pyrrolidinones; C482793:brivaracetam",
"country": "United States",
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"doi": "10.1111/epi.14476",
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"issn_linking": "0013-9580",
"issue": "59(8)",
"journal": "Epilepsia",
"keywords": "levetiracetam; myoclonus; refractory; seizure; synaptic vesicle protein 2A",
"medline_ta": "Epilepsia",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants; D002648:Child; D015331:Cohort Studies; D004829:Epilepsy, Generalized; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D011358:Product Surveillance, Postmarketing; D011760:Pyrrolidinones; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "2983306R",
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"pages": "1549-1556",
"pmc": null,
"pmid": "29943451",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Use of brivaracetam in genetic generalized epilepsies and for acute, intravenous treatment of absence status epilepticus.",
"title_normalized": "use of brivaracetam in genetic generalized epilepsies and for acute intravenous treatment of absence status epilepticus"
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"abstract": "To present the case of a patient on long-term anticoagulants who developed acute spinal epidural hematoma (SEH) after percutaneous kyphoplasty (PKP) without signs of major cement extravasation to the spinal canal.\nA 64-year-old woman with long-term oral antiplatelet drugs underwent the L1 PKP. Immediately after the operation, the back pain improved significantly without neurological deficit. However, 12 hours later, she developed progressive weakness of the bilateral lower limbs. No intraspinal cement leakage was obvious on the postoperative lumbar radiograph and computed tomography.\nAn emergency MRI examination revealed a high signal aggregation in front of the spinal cord from T12 to L1, indicating spinal cord compression. The SEH was verified and removed during the laminectomy from T12-L1. Following the decompression surgery, the neurological deficit of the lower limbs improved. On follow-up after 6 months, the muscle strength of the bilateral lower limbs had returned to normal.\nFor the patient with long-term oral antiplatelet drugs or coagulation malfunction, the transpedicle approach or that via the costovertebral joint with a smaller abduction angle is recommended to reduce the risk of injury to the inner wall of the pedicle. For progressive aggravation of neurological dysfunction after surgery, SEH formation should be suspected despite the absence of intraspinal bone cement leakage. Secondary emergency decompression should be considered to avoid permanent damage to spinal cord nerve function caused by continuous compression.",
"affiliations": "Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.;Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, People's Republic of China.;Department of Spine Surgery, Baoji City Hospital of Traditional Chinese Medicine, Shaanxi, People's Republic of China.;Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu 610041, People's Republic of China.;Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.;Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.;Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.;Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.;Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.",
"authors": "Zou|Peng|P|;Gong|Han-Lin|HL|;Wei|Jian-Min|JM|;Wei|Dong-Mei|DM|;Qian|Li-Xiong|LX|;Liu|Peng|P|0000-0002-2992-9345;Hao|Ding-Jun|DJ|;Yang|Jun-Song|JS|;Zhao|Yuan-Ting|YT|",
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"doi": "10.2147/JPR.S280650",
"fulltext": "\n==== Front\nJ Pain Res\nJ Pain Res\njpr\njpainres\nJournal of Pain Research\n1178-7090 Dove \n\n280650\n10.2147/JPR.S280650\nCase Report\nSpinal Epidural Hematoma After Percutaneous Kyphoplasty: Case Report and Literature Review\nZou et alZou et alZou Peng 1* Gong Han-Lin 2* Wei Jian-Min 3* Wei Dong-Mei 4 Qian Li-Xiong 1 http://orcid.org/0000-0002-2992-9345Liu Peng 1 Hao Ding-Jun 1 Yang Jun-Song 1 Zhao Yuan-Ting 1 1 Department of Spine Surgery, Honghui Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China\n2 Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province\n610041, People’s Republic of China\n3 Department of Spine Surgery, Baoji City Hospital of Traditional Chinese Medicine, Shaanxi, People’s Republic of China\n4 Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu\n610041, People’s Republic of China\nCorrespondence: Yuan-Ting Zhao Tel +86 15229376812 Email zytqy@163.comJun-Song Yang Tel +86 18792883498 Email yangjunsong1988@126.com* These authors contributed equally to this work\n\n\n03 11 2020 \n2020 \n13 2799 2804\n10 9 2020 05 10 2020 © 2020 Zou et al.2020Zou et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Objective\nTo present the case of a patient on long-term anticoagulants who developed acute spinal epidural hematoma (SEH) after percutaneous kyphoplasty (PKP) without signs of major cement extravasation to the spinal canal.\n\nMethods\nA 64-year-old woman with long-term oral antiplatelet drugs underwent the L1 PKP. Immediately after the operation, the back pain improved significantly without neurological deficit. However, 12 hours later, she developed progressive weakness of the bilateral lower limbs. No intraspinal cement leakage was obvious on the postoperative lumbar radiograph and computed tomography.\n\nResults\nAn emergency MRI examination revealed a high signal aggregation in front of the spinal cord from T12 to L1, indicating spinal cord compression. The SEH was verified and removed during the laminectomy from T12–L1. Following the decompression surgery, the neurological deficit of the lower limbs improved. On follow-up after 6 months, the muscle strength of the bilateral lower limbs had returned to normal.\n\nConclusion\nFor the patient with long-term oral antiplatelet drugs or coagulation malfunction, the transpedicle approach or that via the costovertebral joint with a smaller abduction angle is recommended to reduce the risk of injury to the inner wall of the pedicle. For progressive aggravation of neurological dysfunction after surgery, SEH formation should be suspected despite the absence of intraspinal bone cement leakage. Secondary emergency decompression should be considered to avoid permanent damage to spinal cord nerve function caused by continuous compression.\n\nKeywords\nspinal epidural hematomapercutaneous vertebroplastypercutaneous kyphoplastyspinal cord compressioncoagulation malfunction\n==== Body\nIntroduction\nPercutaneous kyphoplasty (PKP), a minimally invasive procedure, is widely used for treatment of pain owing to osteoporotic vertebral compression fractures (OVCF). However, it has many serious clinical complications, including cement intraspinal canal leakage, that causes spinal cord compression,1–4 pulmonary or renal vascular embolism,5–8 infection,9 and adjacent vertebral body fractures.10 As an emergency complication, spinal epidural hematoma (SEH) is clinically rare after PKP or percutaneous vertebroplasty (PVP), and has been reported in seven studies.11–17 In this report, we present the case of a patient on long-term anticoagulants who developed acute SEH after PKP without signs of major cement extravasation to the spinal canal. Further, we comprehensively review the relevant literature on the possible pathogenesis of SEH.\n\nCase Presentation\nA 64-year-old woman with severe back pain was admitted to the primary hospital. Six months ago, she underwent cardiac stent implantation for myocardial infarction and was prescribed oral aspirin (100 mg/daily) and clopidogrel (75 mg/daily). The prothrombin time (PT) and activated partial thromboplastin time (APTT) were within the normal range on preoperative laboratory examination. The lumbar magnetic resonance imaging (MRI) showed a L1 and L2 compression fracture; the high signal of the short time inversion recovery (STIR) sequence was seen in the L1 vertebral body (Figure 1A and B). She had no neurological symptoms, and she underwent the L1 PKP. The puncture, balloon dilatation, and cement injection were performed using intraoperative fluoroscopy (Figure 2A–F). Immediately after the operation, the back pain improved significantly without neurological deficit. However, 12 hours later, she developed progressive weakness of bilateral lower limbs. No intraspinal cement leakage was obvious on the postoperative lumbar radiograph (Figure 3) and computed tomography (CT) (Figure 4). The patient was transferred to our hospital and underwent an emergency MRI examination, which revealed a high signal aggregation in front of the spinal cord from T12 to L1, indicating spinal cord compression (Figure 1C and D). Physical examination revealed grade III strength in the bilateral iliopsoas, quadriceps femoris, and tibialis anterior muscles. We suspected postoperative SEH and performed laminectomy and decompression from T12–L1. Following excision of SEH and decompression of the spinal cord, the neurological deficit of the lower limbs improved. On follow-up after 6 months, the muscle strength of the bilateral lower limbs had returned to normal.Figure 1 Although the L1 and L2 vertebra are wedge shaped at the T2 weighted imaging of magnetic resonance imaging (MRI) (A), the high signal of the short time inversion recovery (STIR) sequence was only seen in the L1 vertebral body (B). Twelve hours after the PKP, a high signal aggregation in front of the spinal cord from T12 to L1 was detected at the sagittal ((C), red arrow) plane of MRI examination, which gathered in the left part of the spinal canal at the axial plane of MRI ((D), red arrow).\n\nFigure 2 At the biplane monitoring, the puncture (A, B), balloon dilatation (C, D), and cement injection (E, F) were performed stepwise. Notably, when the needle arrived at the posterior wall of the vertebral body in the sagittal plane of fluoroscopic view, the intraoperative puncture revealed extension of the puncture needle beyond the inner edge of the projection of the pedicle in the coronal plane, suggesting a large abduction angle of the needle (A, B).\n\nFigure 3 No intraspinal cement leakage was obvious on the anteroposterior (A) and lateral (B) view of the postoperative lumbar radiograph.\n\nFigure 4 While there was no obvious intraspinal cement leakage on the postoperative lumbar computed tomography, there is visible dispersion of the bone cement on the left side of the vertebral body along the puncture trajectory, whose extension line is medial to the inner wall of the pedicle.\n\n\n\nDiscussion\nPVP and PKP are often used to treat OVCF. They have been applied successfully even in burst fractures without neurological deficit.18 We describe the case of a patient on long-term anticoagulants, who developed acute SEH after PKP, despite the absence of major cement extravasation into the spinal canal, and review the possible pathogenesis.\n\nSEH is associated with idiopathic, iatrogenic, traumatic, and coagulation diseases, and is relatively rare in clinical practice. SEH may cause severe acute spinal cord injury (SCI). Domenicucci et al19 reviewed 1,010 SEH cases in 16 years and concluded that 18% of the significant cases were iatrogenic (spinal puncture), while 29% were non-iatrogenic and caused by factors such as clotting, trauma, and pregnancy. However, iatrogenic SEH after PKP or PVP has been reported in seven previous studies11–17 (Table 1). Wang et al11 suspected that SEH after PKP was caused by direct injury from intraoperative puncture. This finding was supported by three other studies.12–14 Mattei et al15 suggested that venous congestion plays a pivotal role in the etiology of SEH. von der Brelie et al16 attributed the development of SEH after PVP in a patient with long-term oral aspirin to coagulation malfunction owing to aspirin.Table 1 Surgical Level, Anticoagulants, Symptoms, Cause Analysis, and Clinical Outcome for the Cases with Iatrogenic SEH after PKP or PVP\n\nAuthor\tSurgical Level\tAnticoagulants\tSymptoms\tCause Analysis\tClinical Outcome\t\nFang 201812\tT8–T12 (6 cases)\tNot described\tLow back pain, spinal cord injury after PKP\tThe piercing damage\tRecovery after surgical decompression\t\nWang 201811\tT12\tNot described\tWeakness of both lower limbs\tThe piercing damage\tRecovery after surgical decompression\t\nMattei 201515\tT8\tNot described\tWeakness of left lower limb\tThe congestion of venae spinales\tRecovery after surgical decompression\t\nTropeano 201717\tL1–L3\tNot described\tWeakness of both lower limbs\tNot described\tRecovery after surgical decompression\t\nvon der Brelie 201916\tT12\tPreoperative medication of Aspirin\tWeakness of both lower limbs\tAnticoagulation\tRecovery after surgical decompression\t\nCosar 200913\tL1; L2–L4 (2 cases)\tNot described\tWeakness of both lower limbs\tThe piercing damage\tRecovery after surgical decompression\t\nLee 201214\tT11–T12\tNot described\tRadiate pain for both lower limps\tThe piercing damage\tRecovery after drug therapy\t\nAbbreviations: SHE, spinal epidural hematoma; PKP, percutaneous kyphoplasty; PVP, percutaneous vertebroplasty.\n\n\n\n\nWhen the needle arrived at the posterior wall of the vertebral body in the sagittal plane of fluoroscopic view, the intraoperative puncture revealed an extension of the puncture needle beyond the inner edge of the projection of the pedicle in the coronal plane, suggesting a large abduction angle of the needle (Figure 2) and increased risk of perforation of the inner wall of the pedicle. Postoperative CT also revealed dispersion of the bone cement on the left side of the vertebral body along the puncture trajectory whose extension line is medial to the inner wall of the pedicle (Figure 4). Owing to the significant buffer space surrounding the spinal cord at the level of L1, the puncture needle did not damage it, despite it's large puncture angle or slightly perforated inner wall of the pedicle. Thus, the patient did not experience nerve dysfunction immediately after the operation. Owing to stent implantation, long-term oral aspirin and clopidogrel were administered, which had inhibitory effects on platelet aggregation. Despite normal preoperative PT and APTT, a lack of effective blood clotting resulted in flow of blood from the sinus of the vertebral body through the hole in the inner wall of the pedicle along the pressure gradient, causing SEH and acute compression of the spinal cord. Therefore, the patient showed a gradual decline in neurological function 12 hours after surgery.\n\nÖzkan20 reported that if a patient receiving anticoagulant therapy has local or reflected pain and loss of strength and sensation, spontaneous SEH should be considered. There is a lack of consensus on the role of long-term oral antiplatelet drugs and coagulation malfunction on the risk of postoperative SEH in patients with OVCF. In this case, anexcessive puncture angle was considered to have damaged the inner wall of the pedicle, causing SEH. The transpedicle approach or that via the costovertebral joint with a smaller abduction angle is recommended to reduce the risk of injury to the inner wall of the pedicle. Thus, a bilateral procedure is theoretically better than a unilateral procedure. For progressive aggravation of neurological dysfunction after surgery, SEH formation should be suspected despite the absence of intraspinal bone cement leakage. Secondary emergency decompression should be considered to avoid permanent damage to spinal cord nerve function caused by continuous compression.\n\nAcknowledgments\nWe thank the National Natural Science Foundation of China (No. 81830077), the Project of China post-doctoral research fund (project no.: 2016M602943XB); Basic scientific research operating expenses (natural science); scientific research project of central university (project no.: XZY012019124); and Shaanxi province post-doctoral research fund enterprise project (project no.: 2017BSHQYXMZZ19) for providing the grant.\n\nDisclosure\nThe authors report no conflicts of interest for this work.\n==== Refs\nReferences\n1. Lee \nBJ , Lee \nSR , Yoo \nTY . Paraplegia as a complication of percutaneous vertebroplasty with polymethylmethacrylate: a case report\n. Spine (Phila Pa 1976) . 2002 ;27 (19 ):E419 –E422\n. doi:10.1097/00007632-200210010-00022 12394938 \n2. Sidhu \nGS , Kepler \nCK , Savage \nKE , et al. Neurological deficit due to cement extravasation following a vertebral augmentation procedure\n. J Neurosurg Spine . 2013 ;19 (1 ):61 –70\n. doi:10.3171/2013.4.SPINE12978 23641675 \n3. Chen \nYJ , Tan \nTS , Chen \nWH , et al. Intradural cement leakage: a devastatingly rare complication of vertebroplasty\n. Spine (Phila Pa 1976) . 2006 ;31 (12 ):E379 –E382\n. doi:10.1097/01.brs.0000219495.57470.67 16721284 \n4. Chen \nJK , Lee \nHM , Shih \nJT , et al. Combined extraforaminal and intradiscal cement leakage following percutaneous vertebroplasty\n. Spine (Phila PA 1976) . 2007 ;32 (12 ):E358 –E362\n. doi:10.1097/BRS.0b013e31805c0b25 17515810 \n5. Zhao \nY , Liu \nT , Zheng \nY , et al. Successful percutaneous retrieval of a large pulmonary cement embolus caused by cement leakage during percutaneous vertebroplasty: case report and literature review\n. Spine (Phila PA 1976) . 2014 ;39 (26 ):E1616 –E1621\n. doi:10.1097/BRS.0000000000000613 25271513 \n6. Chung \nSE , Lee \nSH , Kim \nTH , et al. Renal cement embolism during percutaneous vertebroplasty\n. Eur Spine J . 2006 ;15 (Suppl S5 ):590 –594\n. doi:10.1007/s00586-005-0037-0 16362386 \n7. Choe \nDH , Marom \nEM , Ahrar \nK , et al. Pulmonary embolism of polymethyl methacrylate during percutaneous vertebroplasty and kyphoplasty\n. AJR Am J Roentgenol . 2004 ;183 (4 ):1097 –1102\n. doi:10.2214/ajr.183.4.1831097 15385313 \n8. Iliopoulos \nP , Korovessis \nP , Vitsas \nV . PMMA embolization to the left dorsal foot artery during percutaneous vertebroplasty for spinal metastases\n. Eur Spine J . 2014 ;23 (Suppl S2 ):187 –191\n. doi:10.1007/s00586-013-2919-x 23884552 \n9. Abdelrahman \nH , Siam \nAE , Shawky \nA , et al. Infection after vertebroplasty or kyphoplasty. A series of nine cases and review of literature\n. Spine J . 2013 ;13 (12 ):1809 –1817\n. doi:10.1016/j.spinee.2013.05.053 23880354 \n10. Kamano \nH , Hiwatashi \nA , Kobayashi \nN , et al. New vertebral compression fractures after prophylactic vertebroplasty in osteoporotic patients\n. AJR Am J Roentgenol . 2011 ;197 (2 ):451 –456\n. doi:10.2214/AJR.10.5937 21785093 \n11. Wang \nX , Peng \nY , Qiu \nJ , et al. Spinal subdural and epidural hematomas after vertebroplasty for compression fracture: a case report\n. Spinal Cord Ser Cases . 2018 ;4 (1 ):1 –4\n. doi:10.1038/s41394-018-0120-5 \n12. Fang \nM , Zhou \nJ , Yang \nD , et al. Management and outcomes of spinal epidural hematoma during vertebroplasty: case series\n. Medicine (Baltimore) . 2018 ;97 (21 ):p. e10732. doi:10.1097/MD.0000000000010732 \n13. Cosar \nM , Sasani \nM , Oktenoglu \nT , et al. The major complications of transpedicular vertebroplasty\n. J Neurosurg Spine . 2009 ;11 (5 ):607 –613\n. doi:10.3171/2009.4.SPINE08466 19929366 \n14. Lee \nKD , Sim \nHB , Lyo \nIU , et al. Delayed onset of spinal subdural hematoma after vertebroplasty for compression fracture: a case report\n. Korean J Spine . 2012 ;9 (3 ):285 –288\n. doi:10.14245/kjs.2012.9.3.285 25983834 \n15. Mattei \nTA , Rehman \nAA , Dinh \nDH . Acute spinal subdural hematoma after vertebroplasty: a case report emphasizing the possible etiologic role of venous congestion\n. Global Spine J . 2015 ;5 (5 ):e52 –e58\n. doi:10.1055/s-0035-1544155 26430602 \n16. von der Brelie \nC , Fiss \nI , Rohde \nV . Multilevel spinal combined subdural/subarachnoid hemorrhage resulting in paraplegia: an unusual complication of kyphoplasty\n. J Neurol Surg a Cent Eur Neurosurg . 2019 ;80 (3 ):220 –222\n. doi:10.1055/s-0038-1676594 30708389 \n17. Tropeano \nMP , La Pira \nB , Pescatori \nL , et al. Vertebroplasty and delayed subdural cauda equina hematoma: review of literature and case report\n. World J Clin Cases . 2017 ;5 (8 ):333 –339\n. doi:10.12998/wjcc.v5.i8.333 28868305 \n18. Yin \nP , Li \nZ , Zhu \nS , et al. The treatment of osteoporotic thoraco-lumbar burst fractures by unilateral percutaneous kyphoplasty: a prospective observation study\n. Eur J Pain . 2020 ;24 (3 ):659 –664\n. doi:10.1002/ejp.1516 31782863 \n19. Domenicucci \nM , Mancarella \nC , Santoro \nG , et al. Spinal epidural hematomas: personal experience and literature review of more than 1000 cases\n. J Neurosurg Spine . 2017 ;27 (2 ):1 –11\n. doi:10.3171/2016.12.SPINE15475 28409668 \n20. Özger \nÖ , Kaplan \nN . Spontaneous spinal epidural hematoma following warfarin treatment: case report\n. J Turk Spinal Surg . 2020 ;31 (2 ):108 –110\n. doi:10.4274/jtss.galenos.2020.93\n\n",
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"issue": "13()",
"journal": "Journal of pain research",
"keywords": "coagulation malfunction; percutaneous kyphoplasty; percutaneous vertebroplasty; spinal cord compression; spinal epidural hematoma",
"medline_ta": "J Pain Res",
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"title": "Spinal Epidural Hematoma After Percutaneous Kyphoplasty: Case Report and Literature Review.",
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"abstract": "BACKGROUND\nThe translocation t(1;19)(q23;p13), which results in the TCF3-PBX1 chimeric gene, is one of the most frequent rearrangements observed in B cell acute lymphoblastic leukemia. It appears in both adult and pediatric patients with B cell acute lymphoblastic leukemia at an overall frequency of 3 to 5%. Most cases of pre-B cell acute lymphoblastic leukemia carrying the translocation t(1;19) have a typical immunophenotype with homogeneous expression of CD19, CD10, CD9, complete absence of CD34, and at least diminished CD20. Moreover, the translocation t(1;19) correlates with known clinical high risk factors, such as elevated white blood cell count, high serum lactate dehydrogenase levels, and central nervous system involvement; early reports indicated that patients with translocation t(1;19) had a poor outcome under standard treatment.\n\n\nMETHODS\nWe report the case of a 15-year-old Syrian boy with pre-B cell acute lymphoblastic leukemia with abnormal karyotype with a der(19)t(1;19)(q21.1;p13.3) and two yet unreported chromosomal aberrations: an interstitial deletion 6q12 to 6q26 and a der(13)t(1;13)(q21.1;p13). According to the literature, cases who are translocation t(1;19)-positive have a significantly higher incidence of central nervous system relapse than patients with acute lymphoblastic leukemia without the translocation. Of interest, central nervous system involvement was also seen in our patient.\n\n\nCONCLUSIONS\nTo the best of our knowledge, this is the first case of childhood pre-B cell acute lymphoblastic leukemia with an unbalanced translocation t(1;19) with two additional chromosomal aberrations, del(6)(q12q26) and t(1;13)(q21.3;p13), which seem to be recurrent and could influence clinical outcome. Also the present case confirms the impact of the translocation t(1;19) on central nervous system relapse, which should be studied for underlying mechanisms in future.",
"affiliations": "Molecular Biology and Biotechnology Department, Human Genetics Div., Atomic Energy Commission of Syria, P.O. Box 6091, Damascus, Syria.;Molecular Biology and Biotechnology Department, Human Genetics Div., Atomic Energy Commission of Syria, P.O. Box 6091, Damascus, Syria.;Jena University Hospital, Institute of Human Genetics, Kollegiengasse 10, D-07743, Jena, Germany.;Molecular Biology and Biotechnology Department, Mammalians Biology Div., Flow-cytometry Lab., Atomic Energy Commission of Syria, P.O. Box 6091, Damascus, Syria.;Molecular Biology and Biotechnology Department, Human Genetics Div., Atomic Energy Commission of Syria, P.O. Box 6091, Damascus, Syria. ascientific@aec.org.sy.",
"authors": "Wafa|Abdulsamad|A|;As'sad|Manar|M|;Liehr|Thomas|T|;Aljapawe|Abdulmunim|A|;Al Achkar|Walid|W|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D015514:Oncogene Proteins, Fusion; C543638:TCF3-PBX1 fusion protein, human; D014750:Vincristine; D004317:Doxorubicin; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-017-1251-1",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 125110.1186/s13256-017-1251-1Case ReportChildhood pre-B cell acute lymphoblastic leukemia with translocation t(1;19)(q21.1;p13.3) and two additional chromosomal aberrations involving chromosomes 1, 6, and 13: a case report Wafa Abdulsamad awafa@mail2world.com 1As’sad Manar ascientific@aec.org.sy 1Liehr Thomas i8lith@mti.uni-jena.de 2Aljapawe Abdulmunim abdmaljapawe@gmail.com 3Al Achkar Walid ascientific@aec.org.sy 11 0000 0000 9342 9009grid.459405.9Molecular Biology and Biotechnology Department, Human Genetics Div., Atomic Energy Commission of Syria, P.O. Box 6091, Damascus, Syria 2 0000 0000 8517 6224grid.275559.9Jena University Hospital, Institute of Human Genetics, Kollegiengasse 10, D-07743 Jena, Germany 3 0000 0000 9342 9009grid.459405.9Molecular Biology and Biotechnology Department, Mammalians Biology Div., Flow-cytometry Lab., Atomic Energy Commission of Syria, P.O. Box 6091, Damascus, Syria 7 4 2017 7 4 2017 2017 11 9429 9 2016 26 2 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nThe translocation t(1;19)(q23;p13), which results in the TCF3-PBX1 chimeric gene, is one of the most frequent rearrangements observed in B cell acute lymphoblastic leukemia. It appears in both adult and pediatric patients with B cell acute lymphoblastic leukemia at an overall frequency of 3 to 5%. Most cases of pre-B cell acute lymphoblastic leukemia carrying the translocation t(1;19) have a typical immunophenotype with homogeneous expression of CD19, CD10, CD9, complete absence of CD34, and at least diminished CD20. Moreover, the translocation t(1;19) correlates with known clinical high risk factors, such as elevated white blood cell count, high serum lactate dehydrogenase levels, and central nervous system involvement; early reports indicated that patients with translocation t(1;19) had a poor outcome under standard treatment.\n\nCase presentation\nWe report the case of a 15-year-old Syrian boy with pre-B cell acute lymphoblastic leukemia with abnormal karyotype with a der(19)t(1;19)(q21.1;p13.3) and two yet unreported chromosomal aberrations: an interstitial deletion 6q12 to 6q26 and a der(13)t(1;13)(q21.1;p13). According to the literature, cases who are translocation t(1;19)-positive have a significantly higher incidence of central nervous system relapse than patients with acute lymphoblastic leukemia without the translocation. Of interest, central nervous system involvement was also seen in our patient. \n\nConclusions\nTo the best of our knowledge, this is the first case of childhood pre-B cell acute lymphoblastic leukemia with an unbalanced translocation t(1;19) with two additional chromosomal aberrations, del(6)(q12q26) and t(1;13)(q21.3;p13), which seem to be recurrent and could influence clinical outcome. Also the present case confirms the impact of the translocation t(1;19) on central nervous system relapse, which should be studied for underlying mechanisms in future.\n\nKeywords\nAcute lymphoblastic leukemia (ALL)t(1;19)TCF3-PBX1CytogeneticsFluorescence in situ hybridization (FISH)Prognostic factorsissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nTranslocation t(1;19)(q23;p13) is a repeatedly but overall rarely observed rearrangement in B cell acute lymphoblastic leukemia (B-ALL), and can be found in both adult and pediatric patients at an overall frequency of 3 to 5% [1, 2]. Most cases of pre-B-ALL carrying the translocation t(1;19) express a typical immunophenotype with homogeneous expression of CD19, CD10, CD9, complete absence of CD34, and reduced expression of CD20 [3]. This translocation can occur in two forms: a balanced or an unbalanced one. The unbalanced form of pre-B-ALL leads to a derivative of chromosome 19 [2]. Both the balanced and the unbalanced translocations t(1;19) result in the fusion of transcription factor 3 (TCF3) located in 19p13 with pre-B cell leukemia homeobox 1 (PBX1) in 1q23, to form a chimeric gene whose protein product alters, among other cellular processes, cell differentiation arrest [1]. Specifically, the fusion gene encodes for a transcription factor bearing the transactivation domain of TCF3 and the deoxyribonucleic acid (DNA)-binding domain of PBX1, which facilitates genes constitutive activation [4]. In addition, the fusion protein appears to have a dominant negative effect on the wild-type TCF3 activity. So both increased expression of PBX1 target genes and reduction in TCF3 activity are thought to be important in leukemogenesis [5].\n\nOther partner genes of TCF3 include ZNF384 (12p13; prognosis unknown), NOL1 (12p13; prognosis unknown), an unknown partner gene in 13q14 (prognosis unknown), HLF (17q22; extremely poor prognosis), and FB1/TFPT (19q13.4; prognosis unknown) [6–8]. Moreover, the translocation t(1;19) correlates with known clinical high risk features, such as elevated white blood cell (WBC) count, high serum lactate dehydrogenase (LDH) levels, central nervous system (CNS) involvement, and poor outcome under standard treatment [9].\n\nHere we report the clinical, G-banding, and molecular cytogenetic results obtained in a childhood patient with pre-B-ALL with an unbalanced translocation t(1;19) and two additional chromosomal aberrations.\n\nCase presentation\nOn 22 May 2014, a 15-year-old Syrian boy without significant personal or familial history of malignancies presented to Al-Biruni University Hospital with a 1-month history of bleeding gums, fatigue, and pallor. He had no familial history of malignancies and no social and environmental history or exposure to toxins and animals. A physical examination revealed splenomegaly without lymph node involvement. An initial laboratory evaluation of peripheral blood (PB) revealed elevated WBC count of 56×109/l with 94% of blasts cells, anemia (9.1 g/dL), and a thrombocytopenia (123×109/L). His serum LDH value was 862 U/l (normal value up to 480 U/l). He was diagnosed as having pre-B-ALL according to the World Health Organization (WHO) classification. A biopsy of his bone marrow (BM) revealed hypercellular marrow (WBC count 155.3×109/l with 94% of blasts cells).\n\nHe was referred (on 25 May 2014) to our Chromosomes Laboratory and Flow-cytometry Laboratory, Molecular Biology and Biotechnology Department, Atomic Energy Commission of Syria, for cytogenetics and flow-cytometric analyses. He could be classified in a high risk group. Thus, he was supplied with German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia (GMALL) protocol treatment after the initial diagnosis for 5 months. Unfortunately, due to the political situation in his home country he was given available drugs such as vincristine 1.4 mg/m2, doxorubicin 25 mg/m2, and methotrexate 20 mg/m2. He responded to that treatment without any infiltrations in his BM; he received platelets and blood transfusions many times; his PB showed pancytopenia and neutropenia. The treatment was stopped before consolidation phase because his BM biopsy evaluation showed morphologic remission (8% blasts left); a cerebrospinal fluid test revealed abnormal cells; he also had a pulmonary infection. Approximately 5.5 months after initial diagnosis he died due to unknown causes while under treatment. No autopsy was performed because he died in his house. His parents agreed with the scientific evaluation of the case and a study was approved by the ethical committee of the Atomic Energy Commission, Damascus, Syria.\n\nA chromosome analysis on a BM sample using GTG-banding according to standard procedures [10] was performed before his treatment started; it revealed a karyotype of 46,XY,del(6)(q?),der(13)t(1;13),der(19)t(1;19)[6]/46,XY,del(6)(q?),der(19)t(1;19)[5]/47,XY,+i(1)(q?),del(6)(q?),der(19)t(1;19)[1]/46,XY[6] (Fig. 1). Karyotype was described according to the International System for Human Cytogenetic Nomenclature (ISCN) of 2013 [11].Fig. 1 GTG-banding revealed the following karyotype in 6/18 metaphases: 46,XY,del(6)(q?),der(13)t(1;13),der(19)t(1;19)[6]. All derivative chromosomes are marked and highlighted by arrow heads\n\n\n\n\n\nFurther studies were performed on BM sample using molecular cytogenetics (Fig. 2). We performed dual-color fluorescence in situ hybridization (D-FISH) with specific whole chromosome paint (WCP) probes for chromosomes 1, 6, 13, and 19 (MetaSystems, Altlussheim, Germany) [10], which did not provide any information on the cryptic translocations (data not shown), and array-proven high-resolution multicolor banding (aMCB) [12], using probes for the corresponding chromosomes 1, 6, 13, and 19 involved according to GTG-banding (Fig. 2). Reverse transcriptase-polymerase chain reaction (RT-PCR) for E2A-PBX1 fusion transcripts was performed prior the treatment using specific primers previously described [13], confirmed the presence of the TCF3/PBX1 fusion (E2A/PBX1 transcript; 373-base pair band), most often identified in acute lymphoblastic leukemia (ALL; data not shown). Thus, the following final karyotype prior to treatment was determined using a fluorescence microscope (AxioImager.Z1 mot, Carl Zeiss Ltd, Hertfordshire, UK) equipped with appropriate filter sets to discriminate between a maximum of five fluorochromes plus the counterstain 4',6-diamidino-2-phenylindole (DAPI). Image capture and processing were performed using an ISIS imaging system (MetaSystems): 46,XY,del(6)(q12q26),der(13)t(1;13)(q21.1;p13),der(19)t(1;19)(q21.1;p13.3)[6]/46,XY,del(6)(q12q26),der(19)t(1;19)(q21.1;p13.3)[5]/47,XY,+i(1)(q10),del(6)(q12q26),der(19)t(1;19)(q21.1;p13.3)[1]/46,XY[6].Fig. 2 Array-proven multicolor banding results are shown. The normal chromosomes (#) are depicted on the left side of each image and the derivative of the four chromosomes on the right side of normal chromosomes. The unstained regions when suing chromosome-specific array-proven multicolor banding probe sets on the derivative chromosomes are shown in gray. a Different pseudocolor depictions for array-proven multicolor banding1 probe set revealed the breakpoints in derivative chromosomes 13, 19 and isochromosome 1q. b Array-proven multicolor banding6 uncovered the interstitial deletion in der(6). c Array-proven multicolor banding13 revealed that practically the whole short arm of chromosome 13 remained intact in the der(13). d The breakpoint on der(19) could be determined by multicolor banding19 probe set. # chromosome, der derivative chromosome, MCB multicolor banding\n\n\n\n\nImmunophenotyping was performed on BM sample using a general panel of fluorescent antibodies against the following antigens typical for different cell lineages and cell types: CD1a, CD2, CD3, CD4, CD5, CD8, CD10, CD11b, CD11c, CD13, CD14, CD15, CD16, CD19, CD20, CD22, CD23, CD32, CD33, CD34, CD38, CD41a, CD45, CD56, CD57, CD64, CD103, CD117, CD123, CD138, CD209, CD235a, and CD243; in addition, antibodies to kappa and lambda light chains, IgD, surface-bound IgM (sIgM), and human leukocyte antigen-antigen D related (HLA-Dr) were tested. All antibodies were purchased from BD Biosciences (San Jose CA, USA). Samples were analyzed on a BD FACSCalibur™ flow cytometer. Autofluorescence, viability, and isotype controls were included. Flow cytometric data acquisition and analysis were conducted by BD Cellquest™ Pro software. Flow cytometric analysis of BM specimen characterized this case as pre-B-ALL according to WHO classifications. The abnormal cell population (94% of tested cells) was positive for CD45+dim, CD19+, CD10+, HLA-DR+, and CD79a+. This cell population was negative for CD34, CD2, CD7, CD13, CD14, CD15, CD20, CD33, and CD117.\n\nDiscussion\nAccording to the literature, the translocation t(1;19)(q23;p13) is a translocation that is repeatedly but, overall, rarely seen in B-ALL cases; it generates the TCF3-PBX1 fusion gene [1, 2]. According to Mitelman Database of Chromosome Aberrations in Cancer [14], there are five cases of ALL with translocation t(1;19)(q21;p13), seven such cases with translocation t(1;13) involving short and/or long arms of both chromosomes, five cases of ALL with isochromosome i(1)(q10), and 710 cases of ALLs with del(6)(q) including 21 cases with del(6)(q12) and three cases with del(6)(q26). In addition, the chromosomal bands 1q21, 13p13, and 19p13 are involved in chromosomal rearrangements in 252, 785, and eight cases, respectively [14]. To the best of our knowledge, the present case report is the first one to observe a childhood pre-B-ALL with unbalanced translocation t(1;19)(q21.1;p13.3) associated with two additional chromosomal aberrations del(6)(q12q26) and der(13)t(1;13)(q21.1;p13) [14]. Of interest, one metaphase with an isochromosome 1q was also observed in GTG-banding and found in 1/25 metaphases in fluorescence in situ hybridization (FISH) analyses too (Fig. 2). As aforementioned this was also seen in five earlier cases of ALL [14].\n\nThe translocation t(1;19)(q23;p13) can be observed in two principal forms [2, 15, 16]. Abnormalities of chromosome 1, such as complete or partial trisomies for the long arm, are known to arise during clonal evolution and can be observed as recurrent in hematologic malignancies [16–18].\n\nThe CKS1B gene mapped at 1q21 is a member of the highly conserved cyclin kinase subunit 1 (CKS1) protein family that interacts with cyclin-dependent kinases (Cdks) and plays a critical role in cell cycle progression [19]. CKS1B overexpression is correlated with low p27 expression and adverse survival in several human malignancies including gastric, colorectal, and oral squamous cell carcinomas [20–22] because of its critical role as a cell cycle regulator and its involvement in various human carcinomas.\n\nThis 6q12-22 area contains several genes with a known or suspected tumor-suppressing function including MAP3K7, for which a tumor-suppressive role for prostate epithelial cells has recently been demonstrated [23]. MAP3K7 is ubiquitary expressed and involved in various biological processes such as cell growth, differentiation, and apoptosis. MAP3K7 exerts these effects by interacting with a number of different signaling pathways and activator molecules [24–27].\n\nIn contrast to early reports on patients with translocation t(1;19) reporting a more adverse outcome for patients with balanced translocation compared with patients with an unbalanced translocation t(1;19) [28–30], more recent studies found no difference in event-free survival (EFS) among these two subgroups [30–32]. However, cases who are translocation t(1;19)-positive have a significantly higher incidence of CNS involvement in cases of relapse than patients with ALL without the translocation [30]; the St Jude’s group observed four patients with CNS relapse but no patients with BM relapse among 41 patients with translocation t(1;19) [33]. Also, Moorman et al. [34] reported six relapses in 50 patients with translocation t(1;19) of which three relapses involved the CNS. Moreover, CNS disease was found to be more common in patients with T cell acute lymphoblastic leukemia (T-ALL) compared with those with pre-B-ALL [35], and CNS involvement was associated with poor survival. Fielding et al. [36] showed as well that the outcome of relapsing patients was very poor, and that patients with T cell disease had only a 5% 5-year survival compared with 8% in those with B-ALL.\n\nAdditional cytogenetic abnormalities (ACAs) were observed in 63% (47 out of 2640, which is 1.8%, children diagnosed as having B-ALL), with no significant differences between translocation t(1;19) and/or der(19)t(1;19)-positive cases [37]. The most common ACAs were del(9p), i(9q), del(6q), and del(13q) [16, 20]. None of their 47 patients with translocation t(1;19) demonstrated concomitant aberrations of 13p13 and/or 6q12 to 6q26 regions. Thus, the clinical significance of an unbalanced translocation t(1;19)(q21.1;p13.3) in our patient with a 13p13 translocation and/or del(6)(q12q26) is unclear. According to the literature the presence of ACAs has no significant impact on EFS or overall survival [35]. This observation is in line with findings from other recurrent leukemia-associated translocations, where ACAs seem to have no influence on prognosis [37, 38]. Still, the adverse outcome of the present case may be a hint that there are exceptions to that rule.\n\nPatients with pediatric ALL with WBC counts of more than 50×109/l are considered to be at high risk of relapse and thus receive intensive treatment [39, 40]. In retrospective analysis, patients with hyperleukocytosis (WBC count >50×109/l) were significantly correlated with shorter survival times. The cytogenetic features were closely linked to the WBC and at least partly explain the prognostic value of WBC, although there is evidence that children with similar cytogenetic aberrations may have very different WBCs [41–43].\n\nConclusions\nHere, we described the presence of two uncommon chromosomal aberrations, that is, del(6)(q12q26) and der(13)t(1;13)(q21.1;p13) in a case of childhood pre-B-ALL with unbalanced translocation t(1;19), which might suggest that special ACAs could have an adverse effect on clinical outcome, in contrast to what is widely discussed at present.\n\nAbbreviations\nACAsAdditional cytogenetic abnormalities\n\nALLAcute lymphoblastic leukemia\n\naMCBArray-proven high-resolution multicolor banding\n\nB-ALLB cell acute lymphoblastic leukemia\n\nBMBone marrow\n\nCdksCyclin-dependent kinases\n\nCKS1Cyclin kinase subunit 1\n\nCNSCentral nervous system\n\nDAPI4',6- diamidino-2-phenylindole\n\nD-FISHDual-color fluorescence in situ hybridization\n\nDNADeoxyribonucleic acid\n\nEFSEvent-free survival\n\nFISHFluorescence in situ hybridization\n\nGMALLGerman Multicenter Study Group for Adult Acute Lymphoblastic Leukemia\n\nHLA-DrHuman leukocyte antigen-antigen D related\n\nISCNInternational System for Human Cytogenetic Nomenclature\n\nLDHLactate dehydrogenase\n\nPBPeripheral blood\n\nPBX1Pre-B cell leukemia homeobox 1\n\nRT-PCRReverse transcriptase-polymerase chain reaction\n\nsIgMSurface-bound IgM\n\nT-ALLT cell acute lymphoblastic leukemia\n\nTCF3Transcription factor 3\n\nWBCWhite blood cell\n\nWCPWhole chromosome paint\n\nWHOWorld Health Organization\n\nAcknowledgements\nWe thank Prof. I. Othman, the Director General of Atomic Energy Commission of Syria (AECS) and Dr N. Mirali, Head of Molecular Biology and Biotechnology Department for their support.\n\nFunding\nThis work was supported by the Atomic Energy Commission of Syria (AECS).\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this published article.\n\nAuthors’ contributions\nAW, MA, and WA performed banding cytogenetics and provided the clinical data; AW and TL performed the molecular cytogenetic analyses; AA did the immunophenotyping. AW and TL drafted the paper and all authors worked on the final version of the paper. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nEthics approval and consent to participate\nAs all tests were done during diagnostic testing so in principle no ethical approval or consent to participate was necessary. Still for publication of the case the authors requested an ethical approval, which is available for inspection for the editors. The study was approved by the ethical committee of the Atomic Energy Commission, Damascus, Syria. The committee’s reference number is 4130/2015.\n==== Refs\nReferences\n1. Heim S Mitelman F Cancer Cytogenetics 2009 3 Hoboken Wiley-Blackwell Publishers \n2. Schmiegelow K Forestier E Hellebostad M Heyman M Kristinsson J Söderhäll S Taskinen M Nordic Society of Paediatric Haematology and Oncology. Long-term results of NOPHO ALL-92 and ALL-2000 studies of childhood acute lymphoblastic leukaemia Leukemia 2010 24 345 54 10.1038/leu.2009.251 20010622 \n3. Borowitz MJ Hunger SP Carroll AJ Shuster JJ Pullen J Steuber CP Cleary ML Predictability of the t(1;19)(q23;p13) from surface antigen phenotype: implication for screening cases of childhood acute lymphoblastic leukemia for molecular analysis: a Pediatric Oncology Group Study Blood. 1993 83 1086 91 \n4. Troussard X Rimokh R Valensi F Leboeuf D Fenneteau O Guitard AM Manel AM Schillinger F Leglise C Brizard A Heterogeneity of t(1;19)(q23;p13) acute leukaemias. French Haematological Cytology Group Br J Haematol 1995 89 516 26 10.1111/j.1365-2141.1995.tb08357.x 7734349 \n5. Aspland SE Bendall HH Murre C The role of E2A -PBX1 in leukemogenesis Oncogene. 2001 20 5708 17 10.1038/sj.onc.1204592 11607820 \n6. Barber KE Harrison CJ Broadfield ZJ Stewart AR Wright SL Martineau M Strefford JC Moorman AV Molecular cytogenetic characterization of TCF3 (E2A )/19p13.3 rearrangements in B-cell precursor acute lymphoblastic leukemia Genes Chromosomes Cancer 2007 46 478 86 10.1002/gcc.20431 17311319 \n7. Boomer T Varella-Garcia M McGavran L Meltesen L Olsen AS Hunger SP Detection of E2A translocations in leukemias via fluorescence in situ hybridization Leukemia. 2001 15 95 102 10.1038/sj.leu.2401988 11243406 \n8. Brambillasca F Mosna G Colombo M Rivolta A Caslini C Minuzzo M Giudici G Mizzi L Biondi A Privitera E Identification of a novel molecular partner of the E2A gene in childhood leukemia Leukemia. 1999 13 369 75 10.1038/sj.leu.2401338 10086727 \n9. Crist WM Carrol AJ Shuster JJ Behm FG Whitehead M Vieti TJ Look AT Mahoney D Ragab A Pullen DJ Poor prognosis of children with pre-B acute lymphoblastic leukemia is associated with the 1(1;19)(q23;p13). A pediatric Oncology Group Study Blood. 1990 76 117 22 2364165 \n10. Al-achkar W Wafa A Nweder MS A complex translocation t(5;9;22) in Philadelphia cells involving the short arm of chromosome 5 in a case of chronic myelogenous leukemia J Exp Clin Cancer Res. 2007 26 411 5 17987804 \n11. Shaffer LG McGowan-Joran J Schmid MS ISCN 2013. An International System of Human Cytogenetic Nomenclature 2013 Unionville Karger Publications, Inc \n12. Liehr T Heller A Starke H Rubtsov N Trifonov V Mrasek K Weise A Kuechler A Claussen U Microdissection based high resolution multicolor banding for all 24 human chromosomes Int J Mol Med. 2002 9 335 9 11891523 \n13. van Dongen JJ Macintyre EA Gabert JA Delabesse E Rossi V Saglio G Gottardi E Rambaldi A Dotti G Griesinger F Parreira A Gameiro P Diáz MG Malec M Langerak AW San Miguel JF Biondi A Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease Leukemia. 1999 13 1901 28 10.1038/sj.leu.2401592 10602411 \n14. Mitelman F, Johansson B, Mertens F, editors. Mitelman database of chromosome aberrations and gene fusions in cancer (2015). http://cgap.nci.nih.gov/Chromosomes/Mitelman. Accessed 20 Sep 2015\n15. Heim S Mitelman F Heim S Mitelman F Acute lymphoblastic leukemia Cancer Cytogenetics 1995 2 New York Wiley-Liss 180 \n16. Pui C-H Raimondi SC Hancock ML Rivera GK Ribeiro RC Mahmoud HH Sandlund JT Crist WM Behm FG Immunologic, cytogenetic, and clinical characterization of childhood acute lymphoblastic leukemia with the t(1;19)(q23;p13) or its derivative J Clin Oncol. 1994 12 2601 10.1200/JCO.1994.12.12.2601 7989935 \n17. Rowley JD Abnormalities of chromosome no. 1: Significance in malignant transformation Virchows Arch B Cell Path 1978 29 139 103305 \n18. Mamaeva SE Mamaev NN Jartseva NM Belyaeva LV Scherbakova EG Complete or partial trisomy for the long arm of chromosome 1 in patients with various hematologic malignancies Hum Genet. 1983 63 107 10.1007/BF00291527 6573295 \n19. Hadwiger JA Wittenberg C Mendenhall MD Reed SI The Saccharomyces cerevisiae CKS1 gene, a homolog of the Schizosaccharomyces prombe suc1 + gene, encodes a subunit of the Cdc28 protein kinase complex Mol Cell Biol. 1989 9 2034 41 10.1128/MCB.9.5.2034 2664468 \n20. Masuda TA Inoue H Nishida K Sonoda H Yoshikawa Y Kakeji Y Utsunomiya T Mori M Cyclin-dependent kinase 1 gene expression is associated with poor prognosis in gastric carcinoma Clin Cancer Res. 2003 9 5693 8 14654553 \n21. Kitajima S Kudo Y Ogawa I Bashir T Kitagawa M Miyauchi M Role of Cks1 overexpression in oral squamous cell carcinomas Am J Pathol. 2004 165 2147 55 10.1016/S0002-9440(10)63264-6 15579456 \n22. Shapira M Ben-Izhak O Linn S Futerman B Minkov I Hershko DD The prognostic impact of the ubiquitin ligase subunits Skp2 and Cks1 in colorectal carcinoma Cancer. 2005 103 1336 46 10.1002/cncr.20917 15717322 \n23. Wu M Shi L Cimic A Romero L Sui G Lees CJ Suppression of Tak1 Promotes Prostate Tumorigenesis Cancer Res. 2012 72 2833 43 10.1158/0008-5472.CAN-11-2724 22467172 \n24. Delaney JR Mlodzik M TGF-beta activated kinase-1: new insights into the diverse roles of TAK1 in development and immunity Cell Cycle. 2006 5 2852 5 10.4161/cc.5.24.3558 17218788 \n25. Edlund S Bu S Schuster N Aspenström P Heuchel R Heldin NE Landström M Transforming growth factor-beta1 (TGF-beta)-induced apoptosis of prostate cancer cells involves Smad7-dependent activation of p38 by TGF-beta-activated kinase 1 and mitogenactivated protein kinase kinase 3 Mol Biol Cell. 2003 14 529 44 10.1091/mbc.02-03-0037 12589052 \n26. Verheyen EM Opposing effects of Wnt and MAPK on BMP/Smad signal duration Dev Cell. 2007 13 755 6 10.1016/j.devcel.2007.11.006 18061555 \n27. Yang YM Bost F Charbono W Dean N McKay R Rhim JS Depatie C Mercola D C-Jun NH(2)- terminal kinase mediates proliferation and tumor growth of human prostate carcinoma Clin Cancer Res. 2003 9 391 401 12538493 \n28. Secker-Walker LM Berger R Fenaux P Lai JL Nelken B Garson M Michael PM Hagemeijer A Harrison CJ Kaneko Y Prognostic significance of the balanced t(1;19) and unbalanced der(19)t(1;19) translocations in acute lymphoblastic leukemia Leukemia. 1992 6 363 9 1593901 \n29. Uckun FM Sensel MG Sather HN Gaynon PS Arthur DC Lange BJ Steinherz PG Kraft P Hutchinson R Nachman JB Reaman GH Heerema NA Clinical significance of translocation t(1;19) in childhood acute lymphoblastic leukemia in the context of contemporary therapies: a report from the Children’s Cancer Group J Clin Oncol. 1998 16 527 35 10.1200/JCO.1998.16.2.527 9469337 \n30. Jeha S Pei D Raimondi SC Onciu M Campana D Cheng C Sandlund JT Ribeiro RC Rubnitz JE Howard SC Downing JR Evans WE Relling MV Pui CH Increased risk for CNS relapse in pre-B cell leukaemia with t(1;19)/TCF3 -PBX1 Leukemia. 2009 23 1406 9 10.1038/leu.2009.42 19282835 \n31. Kager L Lion T Attarbaschi A Koenig M Strehl S Haas OA Dworzak MN Schrappe M Gadner H Mann G Austrian BFM Study Group Incidence and outcome of TCF3 -PBX1 -positive acute lymphoblastic leukemia in Austrian children Haematologica 2007 92 1561 4 10.3324/haematol.11239 18024406 \n32. Andersen MK Autio K Barbany G Borgstrom G Cavelier L Golovleva I Heim S Heinonen K Hovland R Johannsson JH Johansson B Kjeldsen E Nordgren A Palmqvist L Forestier E Paediatric B-cell precursor acute lymphoblastic leukaemia with t(1;19)(q23;p13): clinical and cytogenetic characteristics of 47 cases from the Nordic countries treated according to NOPHO protocols Br J Hematol. 2011 155 235 43 10.1111/j.1365-2141.2011.08824.x \n33. Pui CH Pei D Sandlund JT Ribeiro RC Rubnitz JE Raimondi SC Onciu M Campana D Kun LE Jeha S Cheng C Howard SC Metzger ML Bhojwani D Downing JR Evans WE Relling MV Long-term results of St Jude Total Therapy Studies 11, 12, 13A, 13B, and 14 for childhood acute lymphoblastic leukemia Leukemia. 2010 24 371 82 10.1038/leu.2009.252 20010620 \n34. Moorman AV Chilton L Wilkinson J Ensor HM Bown N Proctor SJ A population-based cytogenetic study of adults with acute lymphoblastic leukemia Blood. 2010 115 206 14 10.1182/blood-2009-07-232124 19897583 \n35. Lazarus HM Richards SM Chopra R Litzow MR Burnett AK Wiernik PH Franklin IM Tallman MS Cook L Buck G Durrant IJ Rowe JM Goldstone AH Medical Research Council (MRC)/National Cancer Research Institute (NCRI) Adult Leukaemia Working Party of the United Kingdom and the Eastern Cooperative Oncology Group CNS involvement in adult acute lymphoblastic leukaemia at diagnosis: results from the international ALL trial MRC UKALL XII/ECOG 2993 Blood 2006 108 465 72 10.1182/blood-2005-11-4666 16556888 \n36. Fielding AK Richards SM Chopra R Lazarus HM Litzow MR Buck G Durrant IJ Luger SM Marks DI Franklin IM McMillan AK Tallman MS Rowe JM Goldstone AH Medical Research Council of the United Kingdom Adult ALL Working Party; Eastern Cooperative Oncology Group Outcome of 609 adults after relapse of acute lymphoblastic leukaemia (ALL): an MRC UKALL XII/ ECOG 2993 study Blood 2007 109 944 50 10.1182/blood-2006-05-018192 17032921 \n37. Grimwade D Walker H Oliver F Wheatley K Harrison C Harrison G Rees J Hann I Stevens R Burnett A Goldstone A The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children’s Leukaemia Working Parties Blood. 1998 92 2322 33 9746770 \n38. De Botton S Chevret S Sanz M Dombret H Thomas X Guerci A Fey M Rayon C Huguet F Sotto JJ Gardin C Cony Makhoul P Travade P Solary E Fegueux N Bordessoule D San Miguel J Link H Desablens B Stamatoullas A Deconinck E Geiser K Hess U Maloisel F Castaigne S Preudhomme C Chomienne C Degos L Fenaux P European APL Group Additional chromosomal abnormalities in patients with acute promyelocytic leukaemia (APL) do not confer poor prognosis: results of APL 93 trial Brit J Haematol 2000 111 801 6 11122141 \n39. Robison LL Late effects of acute lymphoblastic leukemia therapy in patients diagnosed at 0-20 years of age ASH Educ Program Book. 2011 2011 238 42 \n40. Pulte D Gondos A Brenner H Improvement in survival in younger patients with acute lymphoblastic leukemia from the 1980s to the early 21st century Blood. 2009 113 1408 11 10.1182/blood-2008-06-164863 18974371 \n41. Wood AJJ Pui CH Evans WE Acute lymphoblastic leukemia New Engl J Med. 1998 339 605 15 10.1056/NEJM199808273390907 9718381 \n42. Ribeiro RC Broniscer A Rivera GK Hancock ML Raimondi SC Sandlund JT Crist W Evans WE Pui CH Philadelphia chromosome-positive acute lymphoblastic leukemia in children: durable responses to chemotherapy associated with low initial white blood cell counts Leukemia. 1997 11 1493 10.1038/sj.leu.2400749 9305603 \n43. Schrappe M Arico M Harbott J Biondi A Zimmermann M Conter V Reiter A Valsecchi MG Gadner H Basso G Bartram CR Lampert F Riehm H Masera G Philadelphia chromosome-positive (Ph+) childhood acute lymphoblastic leukemia: good initial steroid response allows early prediction of a favorable treatment outcome Blood. 1998 92 2730 41 9763557\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "11(1)",
"journal": "Journal of medical case reports",
"keywords": "Acute lymphoblastic leukemia (ALL); Cytogenetics; Fluorescence in situ hybridization (FISH); Prognostic factors; TCF3-PBX1; t(1;19)",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000293:Adolescent; D000964:Antimetabolites, Antineoplastic; D002869:Chromosome Aberrations; D002878:Chromosomes, Human, Pair 1; D002882:Chromosomes, Human, Pair 13; D002885:Chromosomes, Human, Pair 16; D004317:Doxorubicin; D017809:Fatal Outcome; D006297:Health Services Accessibility; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D008727:Methotrexate; D015514:Oncogene Proteins, Fusion; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D013593:Syria; D014178:Translocation, Genetic; D014750:Vincristine",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "94",
"pmc": null,
"pmid": "28385156",
"pubdate": "2017-04-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10602411;2664468;9469337;103305;18061555;7989935;20010620;6573295;17218788;18974371;16556888;22160040;17987804;18024406;17311319;22467172;10086727;20010622;8353275;12589052;9746770;12538493;9763557;15579456;11122141;7734349;15717322;2364165;11891523;17032921;9718381;14654553;19897583;21902680;11607820;1593901;19282835;9305603;11243406",
"title": "Childhood pre-B cell acute lymphoblastic leukemia with translocation t(1;19)(q21.1;p13.3) and two additional chromosomal aberrations involving chromosomes 1, 6, and 13: a case report.",
"title_normalized": "childhood pre b cell acute lymphoblastic leukemia with translocation t 1 19 q21 1 p13 3 and two additional chromosomal aberrations involving chromosomes 1 6 and 13 a case report"
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"abstract": "BACKGROUND\nDabigatran etexilate was the first direct-acting oral anticoagulant approved in the United States. The prevalence of intracranial hemorrhage after blunt head trauma in patients on dabigatran is currently unknown, complicating adequate ability to accurately compare the risks and benefits of dabigatran to alternative anticoagulants. We aimed to determine the prevalence of intracranial hemorrhage for patients on dabigatran presenting to a Level I trauma center.\n\n\nMETHODS\nThis is a retrospective observational study of adult patients on dabigatran who presented to a Level I trauma center and received cranial computed tomography (CT) following blunt head trauma. Patients who met inclusion criteria underwent manual chart abstraction. Our primary outcome was intracranial hemorrhage on initial cranial CT.\n\n\nRESULTS\nWe included a total of 33 eligible patient visits for analysis. Mean age was 74.8 years (SD 11.2, range 55-91). The most common cause of injury was ground-level fall (n = 22, 66.7%). One patient (3.0%, 95% confidence interval [CI] 0.[1-15.8%]) had intracranial hemorrhage on cranial CT. No patients (0%, 95% CI [0-8.7%]) required neurosurgical intervention. One in-hospital death occurred from infection.\n\n\nCONCLUSIONS\nTo our knowledge, this is the first study to evaluate the prevalence of intracranial hemorrhage after blunt head trauma for patients on dabigatran presenting to the emergency department, including those not admitted. The intracranial hemorrhage prevalence in our study is similar to previous reports for patients on warfarin. Further studies are needed to determine if the prevalence of intracranial hemorrhage seen in our patient population is true for a larger patient population in more diverse clinical settings.",
"affiliations": "University of California Davis, School of Medicine, Department of Emergency Medicine, Davis, California.;University of California Davis, School of Medicine, Department of Emergency Medicine, Davis, California.;University of California Davis, School of Medicine, Davis, California.;University of California Davis, School of Medicine, Department of Emergency Medicine, Davis, California.;University of California Davis, School of Medicine, Department of Emergency Medicine, Davis, California.;University of California Davis, School of Medicine, Department of Emergency Medicine, Davis, California.",
"authors": "Chenoweth|James A|JA|;Johnson|M Austin|MA|;Shook|Laura|L|;Sutter|Mark E|ME|;Nishijima|Daniel K|DK|;Holmes|James F|JF|",
"chemical_list": "D000991:Antithrombins; D000069604:Dabigatran",
"country": "United States",
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"doi": "10.5811/westjem.2017.5.33092",
"fulltext": "\n==== Front\nWest J Emerg MedWest J Emerg MedWestJEMWestern Journal of Emergency Medicine1936-900X1936-9018Department of Emergency Medicine, University of California, Irvine School of Medicine 10.5811/westjem.2017.5.33092wjem-18-794NeurologyOriginal ResearchPrevalence of Intracranial Hemorrhage after Blunt Head Trauma in Patients on Pre-injury Dabigatran Chenoweth James A. MD, MAS*†Johnson M. Austin MD, PHD*Shook Laura BA‡Sutter Mark E. MD*†Nishijima Daniel K. MD, MAS*Holmes James F. MD, MPH*\n* University of California Davis, School of Medicine, Department of Emergency Medicine, Davis, California\n† Veterans Affairs Northern California, Mather Medical Center, Mather, California\n‡ University of California Davis, School of Medicine, Davis, CaliforniaAddress for Correspondence: Address for Correspondence: James Chenoweth, MD, MAS, University of California Davis, School of Medicine, Department of Emergency Medicine, 4150 V St., PSSB 2100. Sacramento, CA 95817. Email: jachenoweth@ucdavis.edu.8 2017 14 7 2017 18 5 794 799 16 11 2017 10 5 2017 08 5 2017 Copyright: © 2017 Chenoweth et al2017This 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/Introduction\nDabigatran etexilate was the first direct-acting oral anticoagulant approved in the United States. The prevalence of intracranial hemorrhage after blunt head trauma in patients on dabigatran is currently unknown, complicating adequate ability to accurately compare the risks and benefits of dabigatran to alternative anticoagulants. We aimed to determine the prevalence of intracranial hemorrhage for patients on dabigatran presenting to a Level I trauma center.\n\nMethods\nThis is a retrospective observational study of adult patients on dabigatran who presented to a Level I trauma center and received cranial computed tomography (CT) following blunt head trauma. Patients who met inclusion criteria underwent manual chart abstraction. Our primary outcome was intracranial hemorrhage on initial cranial CT.\n\nResults\nWe included a total of 33 eligible patient visits for analysis. Mean age was 74.8 years (SD 11.2, range 55–91). The most common cause of injury was ground-level fall (n = 22, 66.7%). One patient (3.0%, 95% confidence interval [CI] 0.[1–15.8%]) had intracranial hemorrhage on cranial CT. No patients (0%, 95% CI [0–8.7%]) required neurosurgical intervention. One in-hospital death occurred from infection.\n\nConclusion\nTo our knowledge, this is the first study to evaluate the prevalence of intracranial hemorrhage after blunt head trauma for patients on dabigatran presenting to the emergency department, including those not admitted. The intracranial hemorrhage prevalence in our study is similar to previous reports for patients on warfarin. Further studies are needed to determine if the prevalence of intracranial hemorrhage seen in our patient population is true for a larger patient population in more diverse clinical settings.\n==== Body\nINTRODUCTION\nDabigatran etexilate is a direct thrombin inhibitor first approved in October 2010 for primary prevention of stroke in patients with atrial fibrillation.1 It is the first of several direct-acting oral anticoagulants (DOAC) to market. These agents have gained popularity due to the simplicity of dosing and the fact that they do not require routine laboratory testing.2 In fact, a recent cohort study of patients started on anticoagulation medications for atrial fibrillation indicated that up to 62% were prescribed a DOAC.3\n\nEach year traumatic brain injury results in approximately 1.4 million emergency department (ED) visits at an annual cost of U.S. $60 billion.4 An increasing proportion of these patients are elderly and taking anticoagulant medications.5 Patients on pre-injury warfarin or clopidogrel have significant risk of traumatic intracranial hemorrhage, even in cases with low-impact mechanisms of injury.6\n\nIn addition to the increased risk of intracranial hemorrhage, pre-injury use of warfarin also significantly increases mortality in elderly patients after head trauma. Early data suggest that this may not be the case for patients on DOACs, although the data for dabigatran is mixed.10–12 Additionally, management of trauma patients on dabigatran is especially challenging due to questions regarding coagulation testing and reversal strategies.13\n\nDespite Food and Drug Administration approval six years ago, the true prevalence of intracranial hemorrhage after head trauma for patients on dabigatran is still unknown. Furthermore, there is a paucity of evidence regarding monitoring of the level of anticoagulation in trauma victims on dabigatran. In this study we aimed to determine the prevalence of intracranial hemorrhage for patients on pre-injury dabigatran presenting to a Level I trauma center after blunt head trauma.\n\nMETHODS\nStudy Setting and Design\nThis is a retrospective observational study of all patients presenting to a university-based, urban Level 1 trauma center between November 1, 2010 and February 28, 2015. The study was approved by the site’s institutional review board.\n\nSelection of Participants\nAll patients who received cranial computed tomography (CT) as part of their ED evaluation and were reported to be on dabigatran during the study period were evaluated for study inclusion. Inclusion criteria were as follows: 1) patient reported head trauma or physical examination findings of head trauma were documented in the ED history and physical examination, and 2) patient was over the age of 18 years at the time of ED presentation. We excluded from the final analysis prisoners, patients who were transferred from an outside hospital, and pregnant patients.\n\nData Collection and Processing\nManual chart abstraction from the electronic medical record was performed by a single abstractor for all patients who met inclusion criteria. Standard chart review methodology was followed for all data abstraction.14 Investigators agreed upon all inclusion/exclusion criteria and definitions prior to chart abstraction. All patient baseline data were abstracted prior to abstraction of CT results. A second abstractor reviewed approximately 20% of charts to measure interrater reliability for the presence of trauma (inclusion/exclusion criteria), intracranial hemorrhage on cranial CT, and the initial Glasgow Coma Scale (GCS) score.\n\nBaseline factors including age, sex, and indication for anticoagulation (atrial fibrillation, deep venous thrombosis, pulmonary embolism, other, or unknown) were recorded. Data regarding the mechanism of injury, initial GCS score, international normalized ratio (INR), and activated thromboplastin time were abstracted from the electronic medical record. For all patients admitted to the hospital we calculated an abbreviated injury severity score (ISS).15\n\nPopulation Health Research Capsule\n\nWhat do we already know about this issue?\n\nClinical trial data suggests an improved bleeding profile for dabigatran when compared to warfarin. There are limited data regarding the intracranial hemorrhage risk after head trauma.\n\nWhat was the research question?\n\nWhat is the prevalence of intracranial hemorrhage after blunt head trauma for patients on dabigatran?\n\nWhat was the major finding of the study?\n\nDabigatran appears to have a similar prevalence of intracranial hemorrhage after blunt head trauma as has been reported for warfarin.\n\nHow does this improve population health?\n\nIf validated, these findings suggest that previously established guidelines regarding fall- and trauma-risk assessment and warfarin use could be applied to dabigatran.\n\nOutcome Measures\nThe primary outcome of interest was the presence of intracranial hemorrhage on initial cranial CT as interpreted by a board-certified/eligible radiologist. The presence of intracranial hemorrhage as well as the type and extent of injury were directly abstracted from the final radiology report. Specific treatments including attempted reversal (defined as either administration of prothrombin complex concentrates, plasma, recombinant factor VIIa, or dialysis for the specific purpose of reversing the effects of dabigatran), neurosurgical intervention, and hospital length of stay (in days) were abstracted. Final disposition as reported on hospital discharge summary was also recorded.\n\nPrimary Data Analysis\nWe reported normally distributed continuous data as the mean with standard deviations (SD), and we described ordinal or non-normally distributed continuous data as medians with interquartile (25%–75%) ranges (IQR). Interrater reliability is reported as Cohen’s kappa. We performed all statistical analyses using STATA 14.1 (STATA Corp., College Station, TX).\n\nRESULTS\nCharacteristics of Study Participants\nDuring the study period there were a total of 98 ED visits by 85 patients taking dabigatran during which cranial CT was performed. Of the 98 visits, 33 met inclusion/exclusion criteria and were included in the final study population. We excluded 49 visits because there were no history or physical exam findings of trauma. Eleven patients with traumatic injuries were excluded because they did not sustain head trauma. We excluded an additional five patients were excluded because they were transferred from outside facilities (Figure).\n\nBaseline characteristics for the study population are provided in Table 1. Mean age was 74.8 years (SD 11.2, range 55–91). The most common cause of injury was ground-level fall (n = 22, 66.7%). Initial GCS scores were all either 14 (n=4) or 15 (n=29). A total of 19 patients (57.6%, 95% CI 39.2–74.5%) were admitted to the hospital with a median ISS of 6 (IQR 3–9). Treatment and outcomes are reported in Table 2. Initial INR measurements were available in 24 patients, and activated partial thromboplastin time (aPTT) measurements were available in 23 patients. Median INR was 1.2 (IQR 1.1–1.3) and mean aPTT was 38.8 (SD 12.9, range 14.3–66.1). Thirteen (54%, 95% CI [33–74%]) patients had INR measurements greater than the upper limit of normal (1.18) for the study site, and 13 (57%, 95% CI [34–77%]) had aPTT measurements greater than the upper limit of normal (36.7) for the study site.\n\nOne patient was found to have an intracranial hemorrhage on cranial CT (3.0%, 95% CI [0.1%–15.8%]) following a motorcycle collision. This patient had an intra-ventricular hemorrhage on CT and was also noted to have pelvic, cervical spine, and rib fractures. After a hospital stay of 19 days this patient was discharged to a skilled nursing facility. There were no patients that required neurosurgical intervention (0%, 95% CI [0–8.7%]).\n\nPatients also suffered the following major injuries: spinal fractures (n=3), long bone fractures (n=2), rib fractures (n=2), and pelvic fracture (n=1). The median hospital length of stay was two days (IQR 1–7 days) for those admitted, and one in-hospital death was identified following infectious complications after a hospital stay of 19 days.\n\nReversal of anticoagulation was attempted in two patients. One patient received both 4-factor activated prothrombin complex concentrate (FEIBA©) and dialysis following a cervical spine fracture. The second patient received a combination of fresh frozen plasma, FEIBA©, and dialysis for intracranial hemorrhage, pelvic fractures, rib fractures, and a cervical spine fracture.\n\nInterrater reliability\nTo measure interrater reliability of data abstraction, 20 patients had duplicate abstraction for presence of trauma, intracranial hemorrhage on cranial CT, and initial GCS score. There was perfect agreement for presence of trauma and the presence of intracranial hemorrhage on cranial CT (kappa=1.0, 95% CI [0.63–1]). There was excellent agreement for initial GCS (kappa=0.78, 95% CI [0.30–1.0]).\n\nDISCUSSION\nIn this study we found that the risk of intracranial hemorrhage after blunt head trauma in patients taking dabigatran is similar to the prevalence previously reported for warfarin.16 Furthermore, we have demonstrated that many patients who report taking dabigatran at the time of ED presentation have normal clotting parameters (PT and aPTT), suggesting either non-compliance or a poor correlation between dabigatran effects and currently available anticoagulant tests. There were a significant number of patients who required intensive care unit monitoring. However, a majority of patients were discharged home and the mortality rate was low.\n\nThe relatively low prevalence of intracranial hemorrhage in patients initially presenting to our institution is surprising. Given the large CI, it may be true that a larger sample size would reveal a higher “true” prevalence. It could also partially be explained by the fact that a majority of patients had ground-level falls and low ISS. Previous studies of patients with mild head injury found a prevalence of intracranial hemorrhage of 4.3% if the patient was on pre-injury warfarin.6\n\nDabigatran is the first of several DOACs to receive approval by the FDA. It exerts its action by directly binding to thrombin. When it first entered the market it was touted for its benefits of not requiring routine lab testing and very few drug-drug interactions. Initial experience with hemorrhaging patients on dabigatran raised concerns regarding the lack of ability to accurately determine the degree of anticoagulation and unclear method of reversal.12,17 Fortunately, with the recent approval of idarucizumab, a dabigatran-specific antibody fragment, the ability to treat bleeding patients on dabigatran is likely to improve.18 The impact of this agent on patient outcomes or patient need for dialysis, however, is still unknown.\n\nBleeding risk remains the main concern associated with anticoagulant use. The Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) study upon which initial approval of dabigatran was based demonstrated that patients taking dabigatran have a lower risk of major bleeding than patients taking warfarin.2 In this study of 18,113 patients, 46 cases of traumatic intracranial hemorrhage were identified, 24 in patients on warfarin and 22 in the dabigatran groups.19 However, this study did not report the number of patients with blunt head trauma without resultant intracranial hemorrhage. Additional case reports of intracranial hemorrhage have been reported in the literature with some raising concern that pre-injury dabigatran use could result in significant hemorrhage expansion.17 In an animal model, Schaeffer et al. analyzed the size of hemorrhage produced in a standardized fashion in rats given pre-injury dabigatran or warfarin. This study showed smaller hematoma size in rats given dabigatran; however, no differences in neurologic outcomes at day 21 were identified.20\n\nTo date, only one human study has evaluated the prevalence of intracranial hemorrhage in patients on dabigatran. This study included elderly patients (>65 years) with ground-level falls who were admitted to a trauma service. The authors compared the intracranial hemorrhage prevalence in the dabigatran group to patients on warfarin and found no difference (13.6% (warfarin) vs. 8.2%(dabigatran)).21 However, this study excluded patients discharged from the ED and included patients transferred to the study site. Both of these factors could result in overestimation of the risk of intracranial hemorrhage after trauma.\n\nLIMITATIONS\nThis was a retrospective analysis, which has inherent limitations. We attempted to minimize potential bias from the design by adhering to best practice guidelines for retrospective reviews.14 However, because all abstractors were part of the initial study design, they were not blinded to the study hypothesis. The potential bias that this lack of blinding could introduce is mitigated by the fact that the primary study outcome is an objective finding on cranial CT. We also demonstrate excellent interrater reliability enhancing the reliably of the data.\n\nWe selected only those patients undergoing cranial CT scanning in the ED, resulting in an inability to identify patients with minor trauma treated without cranial imaging. We used this criterion as it gave us the greatest chance of identifying all head trauma patients. It is normal practice in the study site’s ED to image patients with head trauma who are on anticoagulation medications.16 We believe that the bias this decision introduced might have increased the reported prevalence of intracranial hemorrhage due to exclusion of patients at lowest risk. However, there is the possibility that there were patients who did not receive initial imaging and subsequently presented to other centers with traumatic intracranial hemorrhage.\n\nDue to the fact that this was a single-center study, we were unable to evaluate for later presentations for delayed bleeding. Our methods would have discovered any patients that re-presented to the ED during the study period, but could not evaluate for patients who later presented to alternate sites. The single-center nature of this study also resulted in a small sample size, which limits the generalizability of our results.\n\nFinally, because we are a tertiary-care referral center, we excluded patients transferred from outside facilities to allow for determination of a “true” prevalence of intracranial hemorrhage in patients presenting to the ED. Two of the five excluded patients were transferred to the study site because they had intracranial hemorrhages. Neither of these patients died during hospitalization at the study site and only one required neurosurgical intervention. Including these patients would have falsely increased the reported prevalence of intracranial hemorrhage on CT.\n\nCONCLUSION\nIn our study, intracranial hemorrhage after blunt head trauma in patients on pre-injury dabigatran was rare. The incidence in our study is similar to previous reports for patients on warfarin, although the wide confidence interval and different methodology make direct comparison difficult. Further studies are needed to determine if the prevalence of intracranial hemorrhage seen in our patient population is true for a larger patient cohort in more diverse clinical settings.\n\nSection Editor: Mark I. Langdorf\n\nFull text available through open access at http://escholarship.org/uc/uciem_westjem\n\nConflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The project described was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant number UL1 TR000002. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Support for this research was provided by grant number T32HS022236 from the Agency for Healthcare Research and Quality (AHRQ) through the Quality, Safety, and Comparative Effectiveness Research Training (QSCERT) Program. There are no conflicts of interest or sources of funding to declare.\n\nFigure Flow of patients in a study of the prevalence of intracranial hemorrhage after blunt head trauma for patients on dabigatran.\n\nED, emergency department.\n\nTable 1 Demographics and injury characteristics.\n\n\tNo.\t%\t\nSex\t\n Female\t18\t54.5\t\n Male\t15\t45.5\t\nIndication for dabigatran\t\n Atrial fibrillation\t27\t81.8\t\n Deep venous thrombosis\t2\t6.1\t\n Pulmonary embolism\t1\t3.0\t\n Unknown\t1\t3.0\t\n Other\t2\t6.1\t\nMechanism of injury\t\n Assault\t1\t3.0\t\n Auto vs pedestrian\t1\t3.0\t\n Ground-level fall\t22\t66.7\t\n Motorcycle collision\t2\t6.1\t\n Motor vehicle collision\t3\t9.1\t\n Other\t4\t12.1\t\n ICH\t1\t3.0\t\nICH, intracranial hemorrhage.\n\nTable 2 Treatment and outcomes of patients with blunt head trauma who were taking dabigatran at time of arrival to Level I trauma center.\n\n\tNo.\t%\t\nReversal Agent\t\n None\t30\t93.9\t\n aPCC\t2\t6.1\t\n Transfused with Plasma\t1\t3.0\t\nDialysis\t2\t6.1\t\nPRBC Transfusion\t1\t3.0\t\nED disposition\t\n Discharged from the ED\t14\t42.4\t\n Ward\t5\t15.2\t\n Telemetry\t6\t18.2\t\n ICU\t8\t24.2\t\nFinal Hospital/ED disposition\t\n Died\t1\t3.0\t\n Skilled Nursing facility\t5\t15.2\t\n Home\t24\t72.7\t\n Other\t3\t9.1\t\naPCC, activated 4-factor prothrombin complex concentrate; PRBC, packed red blood cells; ED, emergency department\n==== Refs\nREFERENCES\n1 US Food and Drug Administration FDA approves Pradaxa to prevent stroke in people with atrial fibrillation 2010 Available at: https://wayback.archive-it.org/7993/20170111150606/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2010/ucm230241.htm Accessed November 29, 2015 \n2 Connolly SJ Ezekowitz MD Yusuf S Dabigatran versus warfarin in patients with atrial fibrillation N Engl J Med 2009 361 12 1139 51 19717844 \n3 Desai NR Krumme AA Schneeweiss S Patterns of initiation of oral anticoagulants in patients with atrial fibrillation- quality and cost implications Am J Med 2014 127 11 1075 82 e1 24859719 \n4 Pearson WS Sugerman DE McGuire LC Emergency department visits for traumatic brain injury in older adults in the United States: 2006–08 West J Emerg Med 2012 13 3 289 93 22928058 \n5 McMillian WD Rogers FB Management of prehospital antiplatelet and anticoagulant therapy in traumatic head injury: a review J Trauma 2009 66 3 942 50 19276776 \n6 Nishijima DK Offerman SR Ballard DW Risk of traumatic intracranial hemorrhage in patients with head injury and preinjury warfarin or clopidogrel use Acad Emerg Med 2013 20 2 140 5 23406072 \n7 Lavoie A Ratte S Clas D Preinjury warfarin use among elderly patients with closed head injuries in a trauma center J Trauma 2004 56 4 802 7 15187746 \n8 Mina AA Knipfer JF Park DY Intracranial complications of preinjury anticoagulation in trauma patients with head injury J Trauma 2002 53 4 668 72 12394864 \n9 Li J Brown J Levine M Mild head injury, anticoagulants, and risk of intracranial injury Lancet 2001 357 9258 771 2 11253975 \n10 Dezman ZD Comer AC Smith GS Narayan M Hess JR Hirshon JM The severity of bleeding and mortality in trauma patients taking dabigatran J Emerg Med 2016 51 3 238 45 27364823 \n11 Maung AA Bhattacharya B Schuster KM Trauma patients on new oral anticoagulation agents have lower mortality than those on warfarin J Trauma Acute Care Surg 2016 81 4 652 7 27438683 \n12 Parra MW Zucker L Johnson ES Dabigatran bleed risk with closed head injuries: are we prepared? J Neurosurg 2013 119 3 760 5 23634730 \n13 Pakraftar S Atencio D English J Dabigatran etixilate and traumatic brain injury: Evolving anticoagulants require evolving care plans World J Clin Cases 2014 2 8 362 6 25133148 \n14 Kaji AH Schriger D Green S Looking through the retrospectoscope: reducing bias in emergency medicine chart review studies Ann Emerg Med 2014 64 3 292 8 24746846 \n15 Civil ID Schwab CW The Abbreviated Injury Scale, 1985 revision: a condensed chart for clinical use J Trauma 1988 28 1 87 90 3339667 \n16 Nishijima DK Offerman SR Ballard DW Immediate and delayed traumatic intracranial hemorrhage in patients with head trauma and preinjury warfarin or clopidogrel use Ann Emerg Med 2012 59 6 460 8 e1–7 22626015 \n17 Wassef SN Abel TJ Grossbach A Traumatic intracranial hemorrhage in patients taking dabigatran: report of 3 cases and review of the literature Neurosurgery 2013 73 2 E368 73 discussion E373–4 23670031 \n18 US Food and Drug Administration FDA approves Praxbind, the first reversal agent for the anticoagulant Pradaxa 2015 Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm467300.htm Accessed November 30, 2015 \n19 Hart RG Diener HC Yang S Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial Stroke 2012 43 6 1511 7 22492518 \n20 Schaefer JH Leung W Wu L Translational insights into traumatic brain injury occurring during dabigatran or warfarin anticoagulation J Cereb Blood Flow Metab 2014 34 5 870 875 24549187 \n21 Pozzessere A Grotts J Kaminski S Dabigatran Use Does Not Increase Intracranial Hemorrhage in Traumatic Geriatric Falls When Compared with Warfarin Am Surg 2015 81 10 1039 42 26463304\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1936-900X",
"issue": "18(5)",
"journal": "The western journal of emergency medicine",
"keywords": null,
"medline_ta": "West J Emerg Med",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000991:Antithrombins; D001281:Atrial Fibrillation; D000069604:Dabigatran; D005260:Female; D016489:Head Injuries, Closed; D006785:Hospitals, University; D006801:Humans; D020198:Intracranial Hemorrhage, Traumatic; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D011655:Pulmonary Embolism; D012189:Retrospective Studies; D020521:Stroke; D014057:Tomography, X-Ray Computed; D014193:Trauma Centers; D014505:Urban Population; D020246:Venous Thrombosis",
"nlm_unique_id": "101476450",
"other_id": null,
"pages": "794-799",
"pmc": null,
"pmid": "28874930",
"pubdate": "2017-08",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "24746846;26463304;22492518;11253975;15187746;22928058;24549187;27364823;23670031;19276776;12394864;24859719;3339667;19717844;22626015;23406072;23634730;27438683;25133148",
"title": "Prevalence of Intracranial Hemorrhage after Blunt Head Trauma in Patients on Pre-injury Dabigatran.",
"title_normalized": "prevalence of intracranial hemorrhage after blunt head trauma in patients on pre injury dabigatran"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-048450",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "A 38-year-old male suffering from a low backache since 3 months was diagnosed as a case of L4-L5 disc prolapse after magnetic resonance imaging examination. He was treated with tolperisone, aceclofenac, and paracetamol in these drugs deflazacort added later. From the 2nd day of an addition of deflazacort in the therapy, sharply marginated, infiltrative, and erythematous skin eruptions with discrete itching sensations were seen. It was diagnosed as deflazacort-induced acneiform eruption and treated with doxycycline for 2 months which led to the disappearance of acneiform eruptions.",
"affiliations": "Department of Pharmacology, Faculty of Dentistry, Taif University, Taif, Saudi Arabia.;Department of Anatomy, NKP Salve Institute of Medical Sciences and Research Centre, Nagpur, Maharashtra, India.;Department of Skin & VD, Consultant Dermatologist, Nagpur, India.",
"authors": "Bashir|Mohammed Shakeel Mohammed|MSM|;Saleem|Mohammad|M|;Choudhari|Uday|U|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/jpbs.JPBS_67_17",
"fulltext": "\n==== Front\nJ Pharm Bioallied SciJ Pharm Bioallied SciJPBSJournal of Pharmacy & Bioallied Sciences0976-48790975-7406Medknow Publications & Media Pvt Ltd India JPBS-9-28410.4103/jpbs.JPBS_67_17Case ReportDeflazacort-induced Acneiform Eruptions Bashir Mohammed Shakeel Mohammed Saleem Mohammad 1Choudhari Uday 2Department of Pharmacology, Faculty of Dentistry, Taif University, Taif, Saudi Arabia1 Department of Anatomy, NKP Salve Institute of Medical Sciences and Research Centre, Nagpur, Maharashtra, India2 Department of Skin & VD, Consultant Dermatologist, Nagpur, IndiaAddress for correspondence: Dr. Mohammed Shakeel Mohammed Bashir, Department of Pharmacology, Faculty of Dentistry, Taif University, Taif, Saudi Arabia. E-mail: drmsmbashir76@rediffmail.comOct-Dec 2017 9 4 284 286 Copyright: © 2018 Journal of Pharmacy and Bioallied Sciences2018This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.A 38-year-old male suffering from a low backache since 3 months was diagnosed as a case of L4-L5 disc prolapse after magnetic resonance imaging examination. He was treated with tolperisone, aceclofenac, and paracetamol in these drugs deflazacort added later. From the 2nd day of an addition of deflazacort in the therapy, sharply marginated, infiltrative, and erythematous skin eruptions with discrete itching sensations were seen. It was diagnosed as deflazacort-induced acneiform eruption and treated with doxycycline for 2 months which led to the disappearance of acneiform eruptions.\n\nKEYWORDS\nAcneiform eruptionsdeflazacortdoxycycline\n==== Body\nINTRODUCTION\nAcne is a dermatological disease of pilosebaceous follicle. Depending on etiological factors, it may be of hormone dependent acne, drug-induced acne, or mechanical acne. Drug-induced acne is the occurrence of acne like eruptions arising after drug intake. Specific features associated with drug-induced acne include a monomorphic pattern, lesion location away from seborrheic area, and history of recent drug intake. A number of drugs are either directly involved or are associated with drug-induced eruptions including corticosteroids, neurological, and immunomodulating drugs.[1] We present and discuss a case of deflazacort, a derivative of prednisolone, induced acneiform eruptions.\n\nCASE REPORT\nA 38-year-old male of weight 60 kg was suffering from a low backache for 3 months. He used topical diclofenac sodium gel intermittently to get relief from a low backache. However, during the last 15 days, the intensity of pain increased hence he was prescribed tablet aceclofenac 100 mg with paracetamol 325 mg twice daily and pantoprazole 40 mg once daily for 5 days and advised bed rest. When he reported after 1 week, the intensity of pain was further increased as he avoided bed rest and was involved in heavy physical work. Due to the severity of pain, he was not able to move his entire right leg and even slight movement was responsible for severe pain. On examination, right lower limb radiculopathy was observed with loss of power in the right toe. On magnetic resonance imaging (MRI) examination diffuse posterior protrusion with large posterocentral extrusion with an inferior migration of L4-L5 disc was causing severe compression of the thecal sac, bilateral recess was observed. Focal posterocentral protrusion of L5-S1 disc compressing thecal sac, bilateral budding nerve root, and causing mild canal narrowing was observed. After MRI examination, L4-L5 disc prolapse was diagnosed. Relief from pain was not seen.\n\nHe was prescribed tablet deflazacort 36 mg twice daily for 5 days and tablet tolperisone 450 mg once daily for 5 days in addition to tablet aceclofenac (100 mg) and paracetamol (325 mg) twice daily for 5 days, tablet pantoprazole 40 mg once daily for 5 days.\n\nThe patient showed improvement in the painful condition due to the addition of deflazacort but from the 2nd day of the addition of deflazacort in the therapy, sharply marginated, infiltrative, erythematous skin eruptions with discrete itching sensations was seen. Comedones were absent. These eruptions distributed over the neck, chest, upper abdomen, back, and both the arms but not involved face [Figures 1–3].\n\nFigure 1 Eruptions on back\n\nFigure 2 Eruptions on arm\n\nFigure 3 Eruptions on chest and neck\n\nWithin 5 days of deflazacort therapy, the patient showed dramatic improvement with the treatment, intensity of pain reduced, the movement started, and power in the toe increased. The dose of deflazacort was tapered and withdrawn over another 15 days. The 30 days course of drug therapy involving various drugs such as 20 days deflazacort, 10 days tolperisone, and 30 days aceclofenac, paracetamol, and pantoprazole was responsible for recovery of the patient from the painful situation.\n\nDuring the entire 20 days course of deflazacort therapy number and size of acneiform eruption increased. No effect of tolperisone withdrawal was observed in the pattern and intensity of acneiform eruptions. The therapy with aceclofenac, paracetamol, and pantoprazole was not shown any positive or negative effect on pattern and progress of acneiform eruptions. However, when the deflazacort was withdrawn, there was no further increase in number and size of eruption seen. Based on the relation between duration of deflazacort therapy and eruptions, diagnosis of deflazacort-induced acneiform eruption was made.\n\nAfter the withdrawal of deflazacort drug, tablet doxycycline 100 mg twice daily for 1 month was prescribed for the management of acneiform eruptions. Adapalene 0.1% gel and benzoyl peroxide 5% gel to apply over the eruptions in the night for 1 month was also advised. During 1 month of therapy with doxycycline and adapalene and benzoyl peroxide, lesions were partly controlled. The same treatment for acne control was advised for another 1 month which led to the disappearance of acneiform eruptions.\n\nDISCUSSION\nIn this case, eruption was diagnosed as drug-induced (deflazacort induced) acneiform eruptions. Acneiform eruptions were visible from the 2nd day of deflazacort therapy. Progression of acneiform eruptions was stopped after the completion of 20 days deflazacort course indicating the strong role of deflazacort behind the eruptions.\n\nThe role of diclofenac was eliminated as the causative agent for acneiform eruption as it was withdrawn much before the onset of eruptions. Tolperisone was also not suspected as causative agents since its withdrawal did not affect the course and pattern of acneiform eruptions. Aceclofenac and pantoprazole were also ruled out as factors behind acneiform eruptions because these drugs were started 5 days earlier and no eruptions were found, moreover, drug was continued for 10 days more after progression of acneiform eruptions was stopped. Aceclofenac and pantoprazole did not show any change in the behavior of the acneiform eruptions.\n\nThe development of monomorphic follicular inflammatory papulopustules with an absence of comedones often presenting acutely, distributed on the site not commonly affected by acne is typical of acneiform drug eruptions. Acneiform eruptions can be induced by many drugs.[2] Among the several drugs which are associated with acneform eruptions, corticosteroids constitute a major class of the drugs.[3] Exposure to topical or inhaled or systemic corticosteroid therapy may lead to acneiform eruption which sometimes can simulate acne vulgaris.[456] Deflazacort is a relatively newer steroid introduced in 1969. It has D-ring substituted cortisol structure. It is a synthetic oxazoline derivative of prednisolone and have anti-inflammatory and immunosuppressive activity and is as effective as prednisolone or methylprednisolone but with decreased adverse reaction profile. The adverse drug reaction profile is similar to betamethasone but lower than prednisone or methylprednisolone in the same anti-inflammatory doses.[78910]\n\nSteroid-induced acne may be characterized by monomorphic inflammatory papules and pustules.[11] Glucocorticoids increase toll-like receptor 2 expressions in human keratinocytes which are stimulated by Propionibacterium acnes or proinflammatory cytokines and leads to acne.[12]\n\nP. acnes secrete many enzymes such as proteases, hyaluronidases, and neuraminidases which are involved in epithelium permeabilization and inflammatory infiltration. It also produces chemotactic factors and proinflammatory cytokine leading to the appearance of the clinical picture. In the acute inflammatory lesions, polymorphonuclear cells are seen while in chronic cases mononuclear cells, mainly T-cells of the CD4 phenotype are involved.[131415]\n\nTreatment of steroid-induced acne involves withdrawal or decrease in dose of the steroid, sensitive antimicrobial agent and benzoyl peroxide.[12] Doxycycline was used to control the bacteria involved in the deflazacort-induced acneiform eruption because among the antimicrobial agents, tetracyclines mainly doxycycline and minocycline are most commonly used drugs for the management of acne due to their better efficacy and low level of bacterial resistance.[16] Since adapalene and benzoyl peroxide are most effective topical agents for the management of acne, we used both the drugs. Adapalene modulate keratinization and inflammatory process.[17] Benzoyl peroxide markedly reduces P. acnes by a direct toxic effect on the bacteria. It also has anti-inflammatory property.[18]\n\nCONCLUSION\nDeflazacort was considered as safer molecule however it is not free from inducing drug-induced acneiform eruptions. While prescribing deflazacort previous drug history including drug eruptions should be taken.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Du-Thanh A Kluger N Bensalleh H Guillot B Drug-induced acneiform eruption Am J Clin Dermatol 2011 12 233 45 21668032 \n2 Walon L Gilbeau C Lachapelle JM Acneiform eruptions induced by cetuximab Ann Dermatol Venereol 2003 130 443 6 12843857 \n3 Momin SB Peterson A Del Rosso JQ A status report on drug-associated acne and acneiform eruptions J Drugs Dermatol 2010 9 627 36 20645524 \n4 Monk B Cunliffe WJ Layton AM Rhodes DJ Acne induced by inhaled corticosteroids Clin Exp Dermatol 1993 18 148 50 8481992 \n5 Hughes JR Higgins EM du Vivier AW Acne associated with inhaled glucocorticosteroids BMJ 1992 305 1000 \n6 Smith MJ Hodson ME Effects of long term inhaled high dose beclomethasone dipropionate on adrenal function Thorax 1983 38 676 81 6684806 \n7 Markham A Bryson HM Deflazacort. A review of its pharmacological properties and therapeutic efficacy Drugs 1995 50 317 33 8521761 \n8 Coirini H Flores D Vega MC Gonzalez Deniselle MC De Nicola AF Binding of the anti-inflammatory steroid deflazacort to glucocorticoid receptors in brain and peripheral tissues. In vivo and in vitro studies J Steroid Biochem Mol Biol 1994 49 43 9 8003438 \n9 Nayak S Acharjya B Deflazacort versus other glucocorticoids: A comparison Indian J Dermatol 2008 53 167 70 19882026 \n10 Joshi N Rajeshwari K Deflazacort J Postgrad Med 2009 55 296 300 20083885 \n11 Saira Momin DO Aaron Peterson DO Del Rosso D Drug-Induced acneform eruptions: Definitions and causes Cosmet Dermatol 2009 22 28 37 \n12 Kim J Ochoa MT Krutzik SR Takeuchi O Uematsu S Legaspi AJ Activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses J Immunol 2002 169 1535 41 12133981 \n13 Puhvel SM Sakamoto M Chemoattractant properties of Corynebacterium parvum and pyran copolymer for human monocytes and neutrophils J Natl Cancer Inst 1977 58 781 3 839571 \n14 Vowels BR Yang S Leyden JJ Induction of proinflammatory cytokines by a soluble factor of propionibacterium acnes: Implications for chronic inflammatory acne Infect Immun 1995 63 3158 65 7542639 \n15 Norris JF Cunliffe WJ A histological and immunocytochemical study of early acne lesions Br J Dermatol 1988 118 651 9 2969256 \n16 Del Rosso JQ Oral doxycycline in the management of acne vulgaris: Current perspectives on clinical use and recent findings with a new double-scored small tablet formulation J Clin Aesthet Dermatol 2015 8 19 26 \n17 Piskin S Uzunali E A review of the use of adapalene for the treatment of acne vulgaris Ther Clin Risk Manag 2007 3 621 4 18472984 \n18 Del Rosso JQ What is the role of benzoyl peroxide cleansers in acne management? J Clin Aesthet Dermatol 2008 1 48 51 21218192\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0975-7406",
"issue": "9(4)",
"journal": "Journal of pharmacy & bioallied sciences",
"keywords": "Acneiform eruptions; deflazacort; doxycycline",
"medline_ta": "J Pharm Bioallied Sci",
"mesh_terms": null,
"nlm_unique_id": "101537209",
"other_id": null,
"pages": "284-286",
"pmc": null,
"pmid": "29456382",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "839571;26029331;8003438;21668032;19882026;18472984;7542639;20645524;21218192;1458105;12133981;12843857;2969256;8481992;8521761;20083885;6684806",
"title": "Deflazacort-induced Acneiform Eruptions.",
"title_normalized": "deflazacort induced acneiform eruptions"
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{
"companynumb": "SA-GLAXOSMITHKLINE-SA2018033557",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DICLOFENAC SODIUM"
},
"drugadditional":... |
{
"abstract": "A major recent advance in cancer therapy involves the use of immune checkpoint therapy for tumors with mismatch repair deficiency, as they have a high tumor mutation load and neoantigen burden. Approximately 4% of advanced colorectal cancer harbors a mismatch repair deficiency. When mismatch repair deficiency exists in the germline, there is increased susceptibility to a variety of cancers including colorectal cancer, uterine cancer, urothelial carcinoma, and skin cancer. Herein we report the case of a 62-year-old man with mismatch repair deficient metastatic colorectal adenocarcinoma, urothelial carcinoma and a history of sebaceous carcinomas. As the patient in 2016 was ineligible for clinical trials he received immune checkpoint anti-PD-1 therapy with pembrolizumab (200 mg every 3 weeks), on compassionate use basis, after the failure of second-line treatment. The patient's CEA initially responded to pembrolizumab for 4 months and then kept rising for 5 months before mildly declining again. His treatment was then switched to anti-PD-L1 therapy with atezolizumab as it was approved for urothelial carcinoma at that time, and his CEA declined again. This case raises interesting questions about caring for patients with mismatch repair deficient colorectal cancer, including the role of PD-L1 therapy, sequencing of immunotherapy, relying on CEA trends and determining future therapies after progression on pembrolizumab.",
"affiliations": "a Department of Hematology/Oncology , Fox Chase Cancer Center , Philadelphia , USA.;b Department of Pathology , Fox Chase Cancer Center , Philadelphia , USA.;b Department of Pathology , Fox Chase Cancer Center , Philadelphia , USA.;a Department of Hematology/Oncology , Fox Chase Cancer Center , Philadelphia , USA.;a Department of Hematology/Oncology , Fox Chase Cancer Center , Philadelphia , USA.",
"authors": "Ghatalia|Pooja|P|;Nagarathinam|Rajeswari|R|;Cooper|Harry|H|;Geynisman|Daniel M|DM|;El-Deiry|Wafik S|WS|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological",
"country": "United States",
"delete": false,
"doi": "10.1080/15384047.2017.1356506",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1538-4047",
"issue": "18(9)",
"journal": "Cancer biology & therapy",
"keywords": "Atezolizumab; Pembrolizumab; colon cancer; urothelial cancer",
"medline_ta": "Cancer Biol Ther",
"mesh_terms": "D000074322:Antineoplastic Agents, Immunological; D015179:Colorectal Neoplasms; D003131:Combined Modality Therapy; D053843:DNA Mismatch Repair; D006801:Humans; D007150:Immunohistochemistry; D056747:Immunomodulation; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D000072078:Positron Emission Tomography Computed Tomography; D016896:Treatment Outcome; D014571:Urologic Neoplasms",
"nlm_unique_id": "101137842",
"other_id": null,
"pages": "651-654",
"pmc": null,
"pmid": "28726535",
"pubdate": "2017-09-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28424325;25358689;28591715;19165197;20420947;24585723;16136380;26028255",
"title": "Mismatch repair deficient metastatic colon cancer and urothelial cancer: A case report of sequential immune checkpoint therapy.",
"title_normalized": "mismatch repair deficient metastatic colon cancer and urothelial cancer a case report of sequential immune checkpoint therapy"
} | [
{
"companynumb": "US-TEVA-2017-US-832167",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEUCOVORIN"
},
"drugadditional": "2",
... |
{
"abstract": "BACKGROUND\nLaparoscopic resection is the most well described minimally-invasive approach for adrenalectomy. While it allows for improved cosmesis, faster recovery and decreased length of hospital stay compared with the open approach, instrument articulation limitations can hamper surgical dexterity in pediatric patients. Use of robotic assistance can greatly enhance operative field visualization and instrument control, and is in the early stages of adoption in academic centers for pediatric populations.\n\n\nMETHODS\nWe present a single-institution series of pediatric adrenalectomy cases. The da Vinci Xi surgical system was used to perform adrenalectomies on three consecutive patients (ages, 2-13 years) at our center. Final pathology revealed ganglioneuroblastoma (n = 2) and pheochromocytoma (n = 1). Median operating time was 244 min (range, 244-265 min); median blood loss was estimated at 100 ml (range, 15-175 ml). Specimens were delivered intact and all margins were negative. Median post-operative hospital stay was 2 days (range, 1-6 days). All patients remain disease-free at median follow-up of 19 months (range, 12-30 months).\n\n\nCONCLUSIONS\nOur experience continues to evolve, and suggests that robotic surgery is safe, feasible and oncologically effective for resection of adrenal masses in well-selected pediatric patients.",
"affiliations": "Institute of Urology, University of Southern California, Los Angeles, CA, USA. apmitra@gmail.com.;Institute of Urology, University of Southern California, Los Angeles, CA, USA.;Institute of Urology, University of Southern California, Los Angeles, CA, USA.;Institute of Urology, University of Southern California, Los Angeles, CA, USA.",
"authors": "Mitra|Anirban P|AP|http://orcid.org/0000-0002-6549-5943;Vasquez|Evalynn|E|;Kokorowski|Paul|P|;Chang|Andy Y|AY|",
"chemical_list": null,
"country": "England",
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"doi": "10.1186/s12894-020-00727-x",
"fulltext": "\n==== Front\nBMC Urol\nBMC Urol\nBMC Urology\n1471-2490 BioMed Central London \n\n727\n10.1186/s12894-020-00727-x\nCase Report\nRobotic adrenalectomy in the pediatric population: initial experience case series from a tertiary center\nhttp://orcid.org/0000-0002-6549-5943Mitra Anirban P. apmitra@gmail.com 1 Vasquez Evalynn 12 Kokorowski Paul 12 Chang Andy Y. 12 1 grid.42505.360000 0001 2156 6853Institute of Urology, University of Southern California, Los Angeles, CA USA \n2 grid.239546.f0000 0001 2153 6013Division of Urology, Children’s Hospital Los Angeles, Los Angeles, CA USA \n7 10 2020 \n7 10 2020 \n2020 \n20 1553 2 2020 24 9 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nLaparoscopic resection is the most well described minimally-invasive approach for adrenalectomy. While it allows for improved cosmesis, faster recovery and decreased length of hospital stay compared with the open approach, instrument articulation limitations can hamper surgical dexterity in pediatric patients. Use of robotic assistance can greatly enhance operative field visualization and instrument control, and is in the early stages of adoption in academic centers for pediatric populations.\n\nCase presentation\nWe present a single-institution series of pediatric adrenalectomy cases. The da Vinci Xi surgical system was used to perform adrenalectomies on three consecutive patients (ages, 2–13 years) at our center. Final pathology revealed ganglioneuroblastoma (n = 2) and pheochromocytoma (n = 1). Median operating time was 244 min (range, 244–265 min); median blood loss was estimated at 100 ml (range, 15–175 ml). Specimens were delivered intact and all margins were negative. Median post-operative hospital stay was 2 days (range, 1–6 days). All patients remain disease-free at median follow-up of 19 months (range, 12–30 months).\n\nConclusion\nOur experience continues to evolve, and suggests that robotic surgery is safe, feasible and oncologically effective for resection of adrenal masses in well-selected pediatric patients.\n\nKeywords\nMinimally-invasive surgeryRoboticsPediatricsAdrenal massNeuroblastomaPheochromocytomaCase reportissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nWhile no randomized trials have evaluated the efficacy of open versus minimally-invasive surgery for treatment of solid abdominal tumors in pediatric populations, the minimally-invasive approach to adrenalectomy is a feasible alternative in well-selected patients [1, 2]. It offers the advantages of improved exposure, reduced soft tissue dissection, improved cosmesis, decreased morbidity and post-operative pain allowing for early feeding, faster return to activity, and decreased length of stay. In adults, it has been associated with decreased blood loss and need for transfusion [3]. Laparoscopic adrenalectomy is the most extensively described minimally-invasive approach, but can be technically challenging due to the small intra-abdominal spaces of pediatric patients, as well as limited instrument dexterity [4].\n\nUse of robotic assistance allows the added advantages of magnified three-dimensional view and articulating instruments with increased range of motion, tremor control, which facilitate precise dissection and hemostasis. Robotic surgery has also been suggested to further reduce duration of hospital stay and blood loss compared to laparoscopic adrenalectomy [5]. However, the body of literature on robotic adrenalectomy for pediatric patients has been sparse, with only two cases reported thus far [6, 7]. We present our technique and initial institutional experience with pediatric adrenalectomies performed using the da Vinci Xi system (Intuitive Surgical, Sunnyvale, CA).\n\nCase presentation\nCase 1\nA 2-year-old female had previously undergone a robot-assisted adrenal-sparing left upper pole partial nephrectomy at 14 months of age for recurrent febrile urinary tract infections and a poorly functioning renal moiety with ectopic ureter. Postoperative ultrasound showed a new 2.5 cm right adrenal mass, which was confirmed on MRI. Metabolic activity was confirmed by MIBG study (Fig. 1a, b). 24-h urine metanephrines, homovanillate and vanillylmandelate, and corresponding plasma chemistry levels were within normal limits.Fig. 1 a MRI for Case 1 showing a 2.1 cm × 1.7 cm × 2.5 cm T2 hyperintense, heterogeneously enhancing lobulated structure replacing the right adrenal gland without gross evidence of local invasion and local or distant adenopathy. b MIBG study showing activity in the right adrenal gland without any abnormal foci of uptake elsewhere. c Location of ports. After placement of an 8 mm periumbilical robotic camera port (red), additional 8 mm midline robotic ports were placed in the suprapubic and subxiphoid regions, and midway between xiphoid and umbilicus (blue) in a straight line. A 5 mm laparoscopic assistant port with insufflation was placed over the right abdominal wall (green). Representative intraoperative screen captures for Case 1 showing d primary repair of a small cavotomy with figure-of-eight 4–0 polypropylene suture, and e surgical anatomy of the dissected right adrenal gland (a) in relation to the right suprarenal vein (v), inferior vena cava (ivc), right kidney (k) and liver (l). f FISH of the final tumor specimen did not demonstrate MYCN amplification\n\n\n\nUnder general anesthesia, the patient was positioned in left lateral decubitus. An 8 mm robotic camera port was introduced at the umbilicus using the Hasson technique [8]. Following low-pressure insufflation, the camera was introduced and visceral injuries were ruled out. Three additional 8 mm robotic ports and a 5 mm assistant port were then placed (Fig. 1c). After docking the da Vinci Xi robot, the hepatic flexure of the right colon was minimally mobilized to aid in visualization of the right adrenal gland. After identifying the right suprarenal vein and adrenal gland, dissection was carried cephalad under the liver. Combination of monopolar and bipolar cautery was used to obtain hemostasis. A tough dissection plane between the medial aspect of the adrenal gland and the inferior vena cava resulted in creation of a small inadvertent cavotomy that was rapidly repaired primarily with figure-of-eight 4–0 polypropylene suture (Fig. 1d). The right adrenal gland was mobilized (Fig. 1e). The adrenal vein was suture-ligated with 4–0 polypropylene suture before transection. Hemostasis was confirmed and the kidney was well perfused throughout. Specimen was delivered intact through the umbilical port incision using an EndoCatch specimen pouch (Covidien, Minneapolis, MN). Estimated blood loss was 175 ml; 125 ml packed red blood cells, 1000 ml crystalloids and 60 ml colloids were transfused intraoperatively. Operative time was 244 min.\n\nPatient had an uneventful hospital course with good in-house pain control and was discharged on post-operative day two. Final pathological evaluation of the 7.1 gm specimen revealed nodular ganglioneuroblastoma that was negative for c-Myc by immunohistochemistry. FISH did not show MYCN amplification (Fig. 1e). Surgical margins were negative. No lymphovascular invasion was noted. Patient is being followed with serial MRI, MIBG scan, and urine catecholamines. She remains disease-free at 30 months of post-operative follow-up.\n\nCase 2\nA 13-year-old male was noted to be intermittently tachycardic and hypertensive during hospitalization for a pneumonia episode, and found to have a 6 cm right adrenal mass on MRI (Fig. 2). Patient’s father has von Hippel-Lindau disease and had undergone bilateral adrenalectomy for pheochromocytoma and bilateral nephrectomy for renal cell carcinoma. A pathogenic VHL mutation (c.583C > T, p.Q195X) was found in the patient, which was same as the father. 24-h urine norepinephrine level was elevated.Fig. 2 MRI for Case 2 showing a 6.0 cm × 3.6 cm × 3.2 cm solid enhancing structure in the right adrenal gland region suggestive of a pheochromocytoma\n\n\n\nThree weeks after initiating alpha-adrenergic blockade, patient underwent robotic right adrenalectomy. Patient and robotic port positioning were the same as in Case 1. Dissection was performed in the plane between the inferior vena cava and the right adrenal gland, and the latter was also released from the right upper renal pole and liver. After freeing the adrenal gland circumferentially without complication, it was delivered intact by extending the suprapubic port incision using an EndoCatch pouch. Estimated blood loss was 100 ml; 2500 ml crystalloids and 750 ml colloids were transfused intraoperatively. Operative time was 244 min.\n\nPatient’s postoperative stay was prolonged due to a generalized morbilliform eruption attributed to a previously unknown allergy to clindamycin. This gradually resolved after administration of systemic corticosteroids and stopping the offending drug, and he was discharged on post-operative day six. Pathological evaluation of the 48.5 gm specimen was consistent with pheochromocytoma. No capsular or vascular invasion was seen. Surgical margins were negative. Patient is being monitored with serial ultrasound and MRI. He remains disease-free at 19 months of post-operative follow-up.\n\nCase 3\nRenal ultrasound for workup of microscopic hematuria in a 4-year-old male showed an incidental mass in the area of the right kidney. A subsequent CT scan showed a 6.4 cm heterogeneous mass replacing the right adrenal gland, which was MIBG-avid (Fig. 3a–c). CT chest and bone scan were negative for metastatic disease. 24-h urine homovanillate and vanillylmandelate were elevated.Fig. 3 a Renal ultrasound for Case 3 showing a heterogeneous complex mass in the area of the right kidney. b CT scan of abdomen and pelvis showing a 6.4 cm × 4.2 cm × 3.4 cm heterogeneous calcified mass replacing the right adrenal gland concerning for neuroblastoma. No regional or distant lymphadenopathy was noted. c MIBG study showing activity in the right adrenal gland without evidence of avid metastatic disease. d FISH of the final tumor did not demonstrate MYCN amplification\n\n\n\nThe patient underwent robotic right adrenalectomy as described in Case 1. Dissection was carried over the inferior vena cava, and small vessels feeding into the mass were controlled with bipolar electrocautery before transection. A prominent lymph node overlying the vena cava was also excised. Specimen was delivered through a mini Pfannenstiel incision along the suprapubic port. Estimated blood loss was 15 ml; 500 ml crystalloids were transfused intraoperatively. Operative time was 265 min.\n\nPatient had an uneventful hospital course and was discharged on post-operative day one. Pathological diagnosis of the 57 gm specimen was intermixed type, Schwannian stroma-rich ganglioneuroblastoma with negative surgical margins. Immunohistochemistry was negative for c-Myc and n-Myc. FISH did not show MYCN amplification (Fig. 3d). No malignancy was identified in the resected lymph node. Patient is being followed with serial MRI, MIBG scan, and urine catecholamines. He remains disease-free at 12 months of post-operative follow-up.\n\nDiscussion and conclusions\nWe herein report on the initial experience with robotic pediatric adrenalectomy from our institution. All cases followed a standardized surgical approach independent of suspected adrenal pathology, and none required open conversion. All specimens were resected and delivered intact (median weight, 48.5 g; range, 7.1–57 g), and all surgical margins were negative.\n\nWe demonstrate that robotic adrenalectomy is feasible in a wide range of ages and body habitus in the pediatric population. While use of robotic assistance has been described in two pediatric adrenalectomy cases previously [6, 7], this is the first reported series using the da Vinci Xi robot. This provides additional advantages over prior generation robots including improved patient arm clearance, versatility of camera placement into any port, ability to place arms along a single line thereby avoiding clashing, and guided docking and targeting [9].\n\nMedian operative time was 244 min (range, 244–265 min), and reflects our initial learning curve in performing this complex surgery at a tertiary center with more than 50% trainee participation in each case. As with most complex robotic procedures, we do anticipate that operative time will continue to improve as our experience matures. However, one is cautioned by findings from the adult population that indicate significantly longer operating time in patients who underwent robotic adrenalectomy when compared with those undergoing laparoscopic resection [10]. Median estimated blood loss was 100 ml (range, 15–175 ml). Injury to surrounding vasculature is a known complication during adrenalectomy; Case 1 also demonstrates ability of the da Vinci Xi system for rapid control and primary repair of such injuries due to precise articulation of the robotic instruments.\n\nWhile median post-operative hospital stay for this series was 2 days, one patient had a protracted recovery due to an unexpected drug reaction (range, 1–6 days). Typical postoperative recovery, however, appears to be similar or better to prior reports for minimally-invasive adrenalectomies [4, 6, 7]. At a median post-operative follow-up of 19 months (range, 12–30 months), all patients remain disease-free. Our series represents the longest reported follow-up for pediatric patients undergoing robotic adrenalectomy. There were no mortality and local recurrence or metastases, and biochemical and hormonal parameters have remained within normal limits for functional tumors in this series. This further demonstrates the oncologic safety and efficacy of this approach.\n\nIn conclusion, robotic assistance has been successfully and reproducibly used for resecting adrenal masses in adults. We report the first series of pediatric adrenalectomy using the latest generation da Vinci Xi robot. Our experience demonstrates that robot-assisted adrenalectomy is a safe, effective and viable option in well-selected pediatric patients. Surgical excision can be accomplished with rapid recovery time, relatively low surgical morbidity, and comparable oncologic outcomes. While adhering to sound oncologic principles, a robotic approach provides added advantages of improved visualization, precision and dexterity. Maturing operative experience and larger series may be able to address if this approach can potentially improve surgical outcomes.\n\nAbbreviations\nMRIMagnetic resonance imaging\n\nMIBGMetaiodobenzylguanidine\n\nFISHFluorescent in situ hybridization\n\nCTComputed tomography\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors' contributions\nAPM and AYC were responsible for study conception and design. APM, EV, PK and AYC participated in the patients’ treatment. APM collected the data and organized the reports. APM, EV, PK and AYC participated in analysis of the data. APM drafted the initial version of the manuscript, and AYC helped with critical revisions. APM, EV, PK and AYC contributed to manuscript revisions. All authors read and approved the final version of the manuscript.\n\nFunding\nNo funding was obtained for this study.\n\nAvailability of data and materials\nAll data supporting our findings and conclusions are contained within the manuscript, and any missing details will be shared upon request.\n\nEthics approval and consent to participate\nAll patients underwent surgeries after written informed consent, which included discussions about the procedure, and corresponding risks, benefits and alternatives, were obtained from their legal guardians and the patients, if of appropriate age, gave verbal affirmations. While reporting of this case series met criteria for waiver of prior formal ethics approval by the University of Southern California Institutional Review Board, all legal guardians of individual patients herein provided consent for inclusion in the report.\n\nConsent for publication\nAll legal guardians provided a written informed consent for publication of the case report and any accompanying images as per University of Southern California Institutional Review Board guidelines.\n\nCompeting interests\nAPM is an Associate Editor of this journal. All other authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Kelleher CM Smithson L Nguyen LL Casadiego G Nasr A Irwin MS Gerstle JT Clinical outcomes in children with adrenal neuroblastoma undergoing open versus laparoscopic adrenalectomy J Pediatr Surg 2013 48 8 1727 1732 10.1016/j.jpedsurg.2013.03.056 23932613 \n2. Bin X Qing Y Linhui W Li G Yinghao S Adrenal incidentalomas: experience from a retrospective study in a Chinese population Urol Oncol 2011 29 3 270 274 10.1016/j.urolonc.2009.03.027 19481963 \n3. Brunt LM Doherty GM Norton JA Soper NJ Quasebarth MA Moley JF Laparoscopic adrenalectomy compared to open adrenalectomy for benign adrenal neoplasms J Am Coll Surg 1996 183 1 1 10 8673301 \n4. Dokumcu Z Divarci E Ertan Y Celik A Laparoscopic adrenalectomy in children: a 25-case series and review of the literature J Pediatr Surg 2018 53 9 1800 1805 10.1016/j.jpedsurg.2017.11.055 29254846 \n5. Brandao LF Autorino R Laydner H Haber GP Ouzaid I De Sio M Perdona S Stein RJ Porpiglia F Kaouk JH Robotic versus laparoscopic adrenalectomy: a systematic review and meta-analysis Eur Urol 2014 65 6 1154 1161 10.1016/j.eururo.2013.09.021 24079955 \n6. Uwaydah NI Jones A Elkaissi M Yu Z Palmer BW Pediatric robot-assisted laparoscopic radical adrenalectomy and lymph-node dissection for neuroblastoma in a 15-month-old J Robot Surg 2014 8 3 289 293 10.1007/s11701-013-0441-0 27637693 \n7. Rogers CG Blatt AM Miles GE Linehan WM Pinto PA Concurrent robotic partial adrenalectomy and extra-adrenal pheochromocytoma resection in a pediatric patient with von Hippel-Lindau disease J Endourol 2008 22 7 1501 1503 10.1089/end.2007.0314 18690816 \n8. Hasson HM A modified instrument and method for laparoscopy Am J Obstet Gynecol 1971 110 6 886 887 10.1016/0002-9378(71)90593-X 4254516 \n9. Wilson TG Advancement of technology and its impact on urologists: release of the daVinci Xi, a new surgical robot Eur Urol 2014 66 5 793 794 10.1016/j.eururo.2014.05.026 24924552 \n10. Economopoulos KP Mylonas KS Stamou AA Theocharidis V Sergentanis TN Psaltopoulou T Richards ML Laparoscopic versus robotic adrenalectomy: a comprehensive meta-analysis Int J Surg 2017 38 95 104 10.1016/j.ijsu.2016.12.118 28043926\n\n",
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"abstract": "The combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has been suggested to be safe and effective for adult acute promyelocytic leukaemia (APL). As of 2010, the role of cytarabine (Ara-C) in APL was controversial. The aim of this study was to test the efficacy and safety of ATRA and ATO in paediatric APL patients. Also, we assessed whether Ara-C could be omitted in ATO and ATRA- based trials in children.\n\n\n\nWe performed a randomized controlled trial in paediatric APL patients (≤14 years of age) in our hospital from May 2010 to December 2016. All of the patients were assigned to receive ATRA plus ATO for induction followed by one course of idarubicin (IDA) and ATO (28 days). The patients were then randomly assigned to receive two courses of daunorubicin (DNR, no- Ara-C group) or DNR + Ara-C (Ara-C group). All of the patients were followed with maintenance therapy with oral ATRA, 6-mercaptopurine, and methotrexate for 1.5 years.\n\n\n\nAmong the 66 patients, 43 were male and 23 were female. All of the patients achieved complete remission (CR) with the exception of one who gave up the treatment. During induction therapy, all toxicity events were reversed after appropriate management. Thirty patients in the Ara-C group underwent 57 courses of treatment, and 35 patients in the no-Ara-C group underwent 73 courses of treatment. No significant differences in age, genders, white blood cell counts, haemoglobin levels, and platelet counts were found between the Ara-C and no-Ara-c groups. Greater myelosuppression and sepsis were observed in the Ara-C group during the consolidation courses. No patient died at consolidation, and only one patient relapsed. No differences were found in event-free survival, disease-free survival and overall survival between the two groups. Additionally, our analysis of the arsenic levels in the plasma, urine, hair and nails of the patients indicated that no significant accumulation of arsenic occurred after ATO was discontinued for 12 months.\n\n\n\nOverall, ATO and ATRA are safe and effective for paediatric APL patients and Ara-C could be omitted when ATO is used for two courses.\n\n\n\nClinicalTrials.gov ( NCT01191541 , retrospectively registered on 18 August 2010).",
"affiliations": "State Key Laboratory of Experimental Hematology, Department of Paediatrics Haematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People's Republic of China.;State Key Laboratory of Experimental Hematology, Department of Paediatrics Haematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People's Republic of China.;State Key Laboratory of Experimental Hematology, Department of Paediatrics Haematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People's Republic of China.;State Key Laboratory of Experimental Hematology, Department of Paediatrics Haematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People's Republic of China.;State Key Laboratory of Experimental Hematology, Department of Paediatrics Haematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People's Republic of China.;State Key Laboratory of Experimental Hematology, Department of Paediatrics Haematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People's Republic of China.;State Key Laboratory of Experimental Hematology, Department of Paediatrics Haematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People's Republic of China.;State Key Laboratory of Experimental Hematology, Department of Paediatrics Haematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People's Republic of China.;State Key Laboratory of Experimental Hematology, Department of Paediatrics Haematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People's Republic of China.;State Key Laboratory of Experimental Hematology, Department of Paediatrics Haematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People's Republic of China.;State Key Laboratory of Experimental Hematology, Department of Paediatrics Haematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People's Republic of China.;State Key Laboratory of Experimental Hematology, Department of Paediatrics Haematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People's Republic of China.;State Key Laboratory of Experimental Hematology, Department of Paediatrics Haematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People's Republic of China.;State Key Laboratory of Experimental Hematology, Department of Paediatrics Haematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People's Republic of China.;State Key Laboratory of Experimental Hematology, Department of Paediatrics Haematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People's Republic of China.;State Key Laboratory of Experimental Hematology, Department of Paediatrics Haematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People's Republic of China.;State Key Laboratory of Experimental Hematology, Department of Paediatrics Haematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People's Republic of China. xfzhu@ihcams.ac.cn.",
"authors": "Zhang|Li|L|;Zou|Yao|Y|;Chen|Yumei|Y|;Guo|Ye|Y|;Yang|Wenyu|W|;Chen|Xiaojuan|X|;Wang|Shuchun|S|;Liu|Xiaoming|X|;Ruan|Min|M|;Zhang|Jiayuan|J|;Liu|Tianfeng|T|;Liu|Fang|F|;Qi|Benquan|B|;An|Wenbin|W|;Ren|Yuanyuan|Y|;Chang|Lixian|L|;Zhu|Xiaofan|X|",
"chemical_list": "D015415:Biomarkers; D003561:Cytarabine; D014212:Tretinoin; D000077237:Arsenic Trioxide",
"country": "England",
"delete": false,
"doi": "10.1186/s12885-018-4280-2",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 428010.1186/s12885-018-4280-2Research ArticleRole of cytarabine in paediatric acute promyelocytic leukemia treated with the combination of all-trans retinoic acid and arsenic trioxide: a randomized controlled trial Zhang Li Zou Yao Chen Yumei Guo Ye Yang Wenyu Chen Xiaojuan Wang Shuchun Liu Xiaoming Ruan Min Zhang Jiayuan Liu Tianfeng Liu Fang Qi Benquan An Wenbin Ren Yuanyuan Chang Lixian Zhu Xiaofan +86 22 -13752090418xfzhu@ihcams.ac.cnxfzhu1981@126.com grid.461843.cState Key Laboratory of Experimental Hematology, Department of Paediatrics Haematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020 People’s Republic of China 3 4 2018 3 4 2018 2018 18 37419 9 2017 21 3 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nThe combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has been suggested to be safe and effective for adult acute promyelocytic leukaemia (APL). As of 2010, the role of cytarabine (Ara-C) in APL was controversial. The aim of this study was to test the efficacy and safety of ATRA and ATO in paediatric APL patients. Also, we assessed whether Ara-C could be omitted in ATO and ATRA- based trials in children.\n\nMethods\nWe performed a randomized controlled trial in paediatric APL patients (≤14 years of age) in our hospital from May 2010 to December 2016. All of the patients were assigned to receive ATRA plus ATO for induction followed by one course of idarubicin (IDA) and ATO (28 days). The patients were then randomly assigned to receive two courses of daunorubicin (DNR, no- Ara-C group) or DNR + Ara-C (Ara-C group). All of the patients were followed with maintenance therapy with oral ATRA, 6-mercaptopurine, and methotrexate for 1.5 years.\n\nResults\nAmong the 66 patients, 43 were male and 23 were female. All of the patients achieved complete remission (CR) with the exception of one who gave up the treatment. During induction therapy, all toxicity events were reversed after appropriate management. Thirty patients in the Ara-C group underwent 57 courses of treatment, and 35 patients in the no-Ara-C group underwent 73 courses of treatment. No significant differences in age, genders, white blood cell counts, haemoglobin levels, and platelet counts were found between the Ara-C and no-Ara-c groups. Greater myelosuppression and sepsis were observed in the Ara-C group during the consolidation courses. No patient died at consolidation, and only one patient relapsed. No differences were found in event-free survival, disease-free survival and overall survival between the two groups. Additionally, our analysis of the arsenic levels in the plasma, urine, hair and nails of the patients indicated that no significant accumulation of arsenic occurred after ATO was discontinued for 12 months.\n\nConclusions\nOverall, ATO and ATRA are safe and effective for paediatric APL patients and Ara-C could be omitted when ATO is used for two courses.\n\nTrial registration\nClinicalTrials.gov (NCT01191541, retrospectively registered on 18 August 2010).\n\nKeywords\nAcute promyelocytic leukaemiaAll-trans retinoic acidArsenic trioxidePaediatricCytarabinethe Natural Science Fund Foundation Project8142100281200396Zhang Li Zhu Xiaofan issue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nAll-trans retinoic acid (ATRA) and anthracycline-based chemotherapy is highly effective for newly diagnosed cases of acute promyelocytic leukaemia (APL) [1, 2]. Additionally, arsenic trioxide (ATO) is the most potent single agent in APL therapy [3, 4]. Furthermore, the combination of ATRA and ATO has been suggested to be safe and effective as a frontline treatment, at least in adult patients with low- and intermediate- risk disease [5–11]. In paediatric APL, the use of ATO and ATRA as an induction and consolidation chemotherapy regimen has also resulted in excellent outcomes and improved the long-term prognosis [12, 13]. Our retrospective analysis also indicated that using a combination including ATRA and ATO resulted in good therapeutic outcomes in children with APL [14].\n\nIn the pre- ATO era, the role of cytarabine (Ara-C) in APL was controversial [15–17]. More recently, the introduction of ATO and its use in association with ATRA, either with or without chemotherapy, has further improved patient outcomes by allowing the intensity of chemotherapy to be minimized while maintaining a high level of anti-leukaemic efficacy [7, 11, 18]. However, when our trial began, the feasibility of treating patients with APL without chemotherapy was unknown. Furthermore, whether the use of the combination of ATO and ATRA would allow Ara-C to be omitted in consolidation chemotherapy has not been a prospectively studied in children.\n\nHere, we present the results of the protocol-specified analysis of China children with APL study 2010 (CCAPL2010). We assessed whether a combination including ATRA and ATO is safe and effective in paediatric APL. Additionally, we assessed whether a high level of anti-leukaemia efficacy was maintained when Ara-C was omitted from ATO and ATRA combination therapy.\n\nMethods\nEligibility criteria\nEligible patients were those who were less than 14 years old, were newly diagnosed with APL, and had not previously received chemotherapy. A molecular diagnosis was not required for enrollment, but a subsequent molecular confirmation, including the demonstration of PML-RARA transcripts, was required for inclusion in the analysis. A genetic diagnosis was established by detecting the PML-RARA fusion gene using polymerase -chain -reaction (PCR) assays [19, 20] or by demonstrating t (15; 17) translocation using conventional karyotyping or fluorescence in situ hybridization (FISH) [21]. Written informed consent was obtained from all patients before study entry.\n\nStudy design and treatment groups\nThe study was a prospective, randomized, single-centre trial. It was designed to determine whether the combination of ATRA and ATO is safe and effective in paediatric APL and whether Ara-C can be omitted when ATO is added for 2 courses. Patients were assigned to receive ATRA plus ATO for induction followed by 1 consolidation course of idarubicin (IDA) and 1 consolidation course of a 28-day cycle of ATO. The patients were then randomly assigned using a computer-generated random allocation schedule to receive 2 courses of either daunorubicin (DNR) or DNR + Ara-C. Patients who were treated with DNR alone were included as the no-Ara-C group. Patients who were treated with DNR + Ara-C were included as the Ara-C group. The patients were subsequently treated with maintenance therapy consisting of oral ATRA, 6-mercaptopurine, and methotrexate for 1.5 years. When CR was achieved, all patients received a prophylactic intrathecal injection (cytarabine, methotrexate, and dexamethasone) for the first time. The patients with an initial white blood cell count > 10 × 109/L then received intrathecal injection once every course. Patients with an indication of CNS leukaemia received intrathecal injection once every other day until normal results were achieved. The regimen is shown in Fig. 1. This trial was conducted in accordance with the Declaration of Helsinki and was retrospectively registered at Clinical- Trials.gov (identifier: NCT01191541).Fig. 1 The CCAPL 2010 regimen and MRD test results. BM, bone marrow aspiration; IT, intrathecal injection; ATRA, all-trans-retinoic acid; ATO, arsenic trioxide; DNR, daunorubicin; Ara-C, cytosine arabinoside; MTX, methotrexate; 6-MP, 6-mercaptopurine\n\n\n\nAll children were monitored using reverse transcription polymerase chain reaction (RT-PCR) of bone marrow samples [19]. To amplify the PML/RARa fusion gene, a two-step qualitative RT-PCR analysis was performed as previously described [19]. From January 2011, real-time quantitative PCR (RQ-PCR) was used to identify the PML/RARa fusion transcript [20]. In the RQ-PCR method, established in our laboratory based on cDNA, a dilution of the NB4 cell line reached a sensitivity of 1 × 10− 5 for PML-RARa. Bone-marrow morphology, cytogenetics, and RT-PCR/RQ-PCR for PML-RARA were assessed after induction and each consolidation cycle. After consolidation, the patients were assessed every 3 months for 1 year and then every 6 months for 1 year. No pharmaceutical company was involved in the design of the study, data collection or analysis, or the writing of the manuscript.\n\nCriteria for response and end points\nHaematological complete remission (HCR) and haematologic relapse were defined as described in previous publications [1, 9]. Molecular remission was defined as undetectable PML/RARa fusion transcripts. Molecular relapse was defined as the detection of the fusion oncogene PML/RARa in multiple samples within 2 weeks in the same patient. Early death (ED) was considered a death that occurred within two weeks of the beginning of treatment.\n\nThe follow-up of the patients was updated in May 2017. The overall survival (OS) durations were calculated as the date of diagnosis to the date of last follow-up or death. Event-free survival (EFS) was defined as the time from diagnosis to the time at last follow-up or an event (i.e., relapse or death). Disease-free survival (DFS) was calculated as the time from the day HCR was achieved to the date of the last follow-up or an event (i.e., relapse). Death at any time and relapse were considered events for the EFS curve, while death in HCR and relapse were considered for DFS curves. Due to the open label character of the study, survival analysis was performed on an intention-to-treat (ITT) and a per-protocol (PP) basis.\n\nSupportive measures and management of complications\nCoagulopathy was treated using fresh frozen plasma or fibrinogen. Platelet transfusions were administered to maintain a platelet count above 50 × 109/L until any significant sign of coagulopathy was resolved. The patients were administered hydroxyurea (1–1.5 g per day), or homoharringtonine (HHT, 1–2 mg per day for 5–10 days) when their peripheral white blood cell (WBC) counts were greater than 25 × 109/L. At the earliest manifestation of suspected differentiation syndrome, ATRA, arsenic trioxide, or both were temporarily discontinued, and intravenous dexamethasone was administered at a dose of 5–10 mg/m2 until these signs and symptoms disappeared. Antibiotics and antifungal drugs were administered for fever when required.\n\nDetection of arsenic concentration\nForty-one patients and 11 healthy children as controls were included in the study to analyse the arsenic concentrations. All samples were collected on Oct 10, 2016. The arsenic concentration in collected plasma, urine, hair, and nail samples was determined using inductively coupled plasma mass spectrometry (ICP-MS). For each assay, 2 mL of plasma, 5 mL of urine or 0.1–0.5 g of nails or hair was collected. Plasma and urine specimens were stored at 4 °C and analysed within 2 weeks. Other specimens were collected in polypropylene tubes. An Agilent 7700× ICP-MS (Agilent technology, USA) equipped with a pure He octopole reaction system (ORS) was used for the total arsenic analysis. No polyatomic interference or argon chloride interference was observed while using this system. The ICP-MS instrument operating conditions are shown in Table 1. A 1.0 mL volume of blood (or urine) or 0.1 g of hair (or nails) was digested in 2 mL of HNO3 (65%) and 1 mL of H2O2 (30%) in a microwave digestion system and then diluted to a total volume of 8 mL using deionized water. (Nitric acid (UP, China), BV-III grade). A blank digest was performed using the same method. All sample solutions were clear. The following digestion conditions were used for the microwave system: 5 min at 1300 W and 160 °C, 5 min at 1300 W and 200 °C, and 20 min at 1300 W and 200 °C. The digested samples were filled to the final volume using ultrapure water and then analysed using ICP-MS. A standard curve was generated for a linear range of 0 to 20 ng/ml and a detection limit of 0.01 μg/L.Table 1 ICP-MS instrument (Agilent 7700×) operating condition\n\nRF power\t1550 W\t\nRF matching\t1.8 V\t\nSample depth\t10 mm\t\nCarrier gas\t1.0 L/min\t\nNebuliser pump speed\t0.1 mL/min\t\nSpray chamber temp\t2 °C\t\nPeak pattern\t1 point\t\nReaction cell gas flow\tHe (4.5 mL/min)\t\nReplicates\t3\t\n\n\nStatistical analysis\nThe primary objective was to demonstrate the noninferiority of DNR alone compared to DNR + Ara-C in terms of the DFS rate at 2 years. Assuming a 95% rate of DFS in the two groups, a margin of − 14%, 5% type 1 error, and 80% power, 31 evaluable patients per group were required to draw a noninferiority conclusion.\n\nThe characteristics of all of the included patients were summarized using cross-tabulations (for categorical variables) and quantiles (e.g., the median; for continuous variables). Nonparametric tests were used to analyse comparisons between groups (i.e., χ2 and Fisher’s exact tests for categorical variables). EFS, DFS and OS were estimated using the Kaplan -Meier method, and log-rank tests were used for comparisons. All P values were two-sided, and those with values of 0.05 or less were considered to be statistically significant. All statistical analyses were performed using SPSS 16.0 software.\n\nResults\nBetween May 2010 and December 2016, 66 consecutive paediatric (≤14 years of age) patients who were genetically confirmed with a new diagnosis of APL were admitted in our hospital. The follow-up of the patients was updated in May 2017 and included a median of 36 months (range, 5 to 83 months). One patient ended treatment for economic reasons. The main clinical and biologic characteristics of these patients are shown in Table 2.Table 2 Clinical and Biological Characteristics of the Eligible Patients\n\nParameter\tTotal\tno-Ara-c group\tAra-c group\t\nP\n\t\nN\t66\t35\t30\t\t\nAge, years\t\n Median\t8\t8.0\t8\t0.119\t\n Range\t2–14.0\t2–14.0\t2–13.0\t\t\nGender\t\t\t\t0.749\t\n Male\t43\t22\t20\t\t\n Female\t23\t13\t10\t\t\nWBC count, 109/L\t\t\t\t0.220\t\n Median\t4.71\t5.74\t4.23\t\t\n Range\t0.82–202.4\t0.82–202.4\t0.99–130\t\t\nWBC ≤ 10 × 109/L (n, %)\t44 (66.7%)\t22 (62.9%)\t22 (73.3%)\t0.362\t\nWBC > 10 × 109/L (n, %)\t22 (33.3%)\t13 (37.1%)\t8 (26.7%)\t\t\nHaemoglobin count, g/L\t\t\t\t0.075\t\n Median\t79\t81.5\t78\t\t\n Range\t44–127\t49–127\t44–124\t\t\nPlatelet count, 109/L\t\t\t\t0.418\t\n Median\t30.5\t32.0\t24.5\t\t\n Range\t2–130\t6–130\t2–125\t\t\nPML-RARA\t\t\t\t0.846\t\n Long transcript\t26\t13\t12\t\t\n Short transcript\t17\t8\t9\t\t\n Variable\t9\t6\t4\t\t\n Not done\t14\t8\t5\t\t\n\n\nFms-like tyrosine kinase 3 (FLT3) mutations were analysed in all patients in total, 11 patients (16.7%) had a FLT3-internal tandem duplication (ITD) mutation and 10 (15.2%) had a FLT3-tyrosine kinase domain (TKD) D835 mutation. There were no significant difference in FLT3-ITD mutation between the patients with WBC > 10 × 109/L and WBC ≤10 × 109/L (P = 0.310). C-KIT mutations were identified in 2 (3.0%) patients, a K-RAS mutation was identified in 1 (1.5%) patient, and a TET2 mutation was identified in 1 (1.5%) patient.\n\nInduction therapy\nAmong the 66 patients, some had severe symptoms at presentation. These included intracranial bleeding in 4 (6.1%), intraocular bleeding in 6 (9.1%), and mild partial splenic embolization in 2 (3.0%). There were no significant difference in the rate of severe symptoms between the patients with WBC > 10 × 109/L and WBC ≤10 × 109/L (P = 0.225). No early deaths occurred. One patient ended treatment for economic reasons. A total of 65 patients were evaluated to determine their response to induction therapy. Haematologic complete remission was achieved in all of these patients.\n\nDuring induction, hyperleukocytosis (> 10 × 109/L) developed in 59 (90.8%) of the 65 patients with peak WBC counts ranging from 12.8 to 267.8 × 109/L(median, 38.0 × 109/L). In addition, 24 (36.9%) of the 65 patients exhibited an increase in peak WBC counts to more than 50 × 109/L. HHT was used in 28 patients. The dosage of HHT was 1–2 mg/d, and it was administered for 2 to 15 days (median, 7 days). After CR was achieved, 11 (11/28, 39.3%) of the HHT-treated patients tested negative for PML-RARA fusion transcripts, whereas of the patients without HHT, 16 (16/37, 43.2%) tested negative for PML-RARA fusion transcripts. There was no significant difference in the proportion of patients who were negative for PML-RARA fusion transcripts between those who were treated with or without HHT (P = 0.749). There was also no significant difference in initial WBC, Hb, and PLT counts and outcomes between the two groups.\n\nDuring induction therapy, retinoic acid syndrome (RAS) was diagnosed in 9 (13.8%) patients, but it did not contribute to any deaths. Four (6.2%) of the 65 patients suffered Common Terminology Criteria for Adverse Events (CTCAE V.4.0) grade 1–2 hepatotoxicity. Other ATO-associated adverse reactions included extremity oedema in 9 (13.8%) cases, nausea in 2 (3.1%) cases, skin pigmentation in 2 (3.1%) cases, bone ache in 2 (3.1%) cases, cardiac arrhythmia in 1 (1.5%) case and asymptomatic QTc prolongation on electrocardiography in 2 (3.1%) cases. Additional ATRA-associated adverse reactions included headache in 24 (36.9%) cases, skin rash in 3 (4.6%) cases, nausea in 7 (10.8%) cases, abdominal pain in 2 (3.1%) cases, bone ache in 8 (12.3%) cases and skin desquamation in 4 (6.2%) cases. All toxicity events were reversed by appropriate management.\n\nConsolidation therapy\nConsolidation therapy was administered in all patients except for the patient who ended therapy early. No patient died after CR was achieved. Side-effects included sepsis in 6 (9.2%) cases, and hepatotoxicity in 3 (4.6%) cases. No secondary malignancies have so far been reported in our patients.\n\nAccording to the results of our regimens, which were applied to 2 groups using random selection, 31 patients were included in the Ara-C group, and 34 patients were included in the no-Ara-C group. One patient in the Ara-C group voluntarily transferred to the no-Ara-C group before the random treatment was administered. After the first course of random treatment was administered, three patients in the Ara-C group voluntarily transferred to the no-Ara-C group due to haematologic toxicity. Finally, 30 patients were included in the Ara-C group with 57 courses of treatment and 35 patients in the no-Ara-C group with 73 courses of treatment. There were no significant differences in baseline characteristics between the Ara-C and no-Ara-C groups on a PP basis analysis (Table 2). Also, there was no significant difference (P ≥ 0.05) between the two groups on an ITT basis analysis in baseline characteristics (data not shown). In addition, there was no difference in EFS, DFS and OS between the two groups on an ITT and a PP basis analysis. Based on the actual application of the treatment, we compared the hematology toxicity between the two groups. The percentages of courses that included platelet and red blood cell (RBC) transfusions in the Ara-C group were 91.2% (52/57) and 24.6% (14/57), respectively. During consolidation, no blood product was required in the no-Ara-C group. A total of 84.2% (48/57) and 5.5% (4/73) of the patients in the Ara-C and no-Ara-C groups, respectively, had WBC counts <1.0 × 109/L (P = 0.000). In the Ara-C group, the median lowest WBC count was 0.62 × 109/L (range, 0.02 to 1.82 × 109/L). The median days of neutropenia was 0 day (range, 0 to 9 days) in the no-Ara-C group and 6 days (range, 0 to 13 days) in the Ara-C group, respectively (P = 0.000). There were 6 cases of sepsis, including five in the Ara-C group and one in the no-Ara-C group. No deaths occurred during consolidation therapy.\n\nMRD tests\nTwenty-seven (41.5%) of the 65 patients who were tested after induction were negative for PML-RARA fusion transcripts. After the first consolidation cycle, 58 (89.2%) of the 65 patients were negative, and after the second ATO treatment cycle, 64 (98.5%) of the 65 patients tested negative. After the third consolidation cycle (i.e. the first cycle of DNR/DA), a complete remission (molecular) was achieved in all patients (Fig. 1). There were no significant differences in baseline characteristics between the cohorts that were positive or negative after induction and IDA chemotherapy.\n\nPrognostic factors and their impact on relapse and survival\nOf the 65 patients who entered haematologic CR, the median follow-up time was 36 months (range, 5 to 83 months). Only one patient in the no Ara-C group relapsed. After a median follow-up of 36 months, the EFS was 97.3 ± 2.7%, and the OS was 100%. No factor impacted relapse or survival in our study.\n\nArsenic retention on follow-up\nArsenic concentrations were assayed in plasma, urine, hair, and nail samples during and after the cessation of arsenic treatment in forty-one patients. Eleven healthy children were used as the control group. In our patients, 5 ceased ATO treatment after fewer than 3 months, 9 ceased ATO treatment after 3–12 months, 7 ceased ATO treatment after 12–24 months, and 20 ceased ATO treatment after more than 24 months.\n\nFigure 2 shows the arsenic concentrations in the plasma, urine, hair, and nail samples at different time points and compared to the control group. Patients who had been off of the arsenic-containing treatment for less than 3 months had higher arsenic concentrations in the plasma, urine, hair and nail samples than the patients in the control group. The arsenic levels in the nails obtained from patients who had ceased treatment for 3–12 months (median, 264.2 ng/g; range, 117–24,240 ng/g) were higher than the levels in the controls (median, 198.8 ng/g; range, 33.6–588.1 ng/g). But statistical analyses revealed no significant difference between the two groups (P = 0.215). There was no difference in the median arsenic concentrations in plasma, urine, hair, and nail samples between patients in whom arsenic treatment had been ceased for more than 12 months and normal controls.Fig. 2 Arsenic concentrations in the plasma (a), urine (b), hair (c) and nail (d) samples obtained from the different groups. m, months. * indicates a P value less than 0.05 in a comparison with the control group\n\n\n\nDiscussion\nBecause earlier findings showed that ATO, with or without ATRA was highly effective in adult APL patients and allowed the intensity of chemotherapy to be minimized, we performed a clinical trial in 2010 to determine whether ATO plus ATRA was safe and effective in children and whether we could eliminate Ara-C therapy from consolidation when ATO was added for 2 courses.\n\nATRA-ATO was recently shown to have an advantage over ATRA-chemotherapy in large, randomized adult trials. This option has since become the new standard of care for low-risk patients [5, 7, 8, 10, 22]. The APL0406 randomized trial showed that in patients with non-high-risk APL, better outcomes were achieved in those treated with ATRA-ATO than in those treated with standard ATRA-chemotherapy [7, 8]. The long term follow-up results of this trial are especially supportive of the advantages of ATRA-ATO over ATRA-chemotherapy, showing that they increase over time [22]. Studies in children with APL showed minimal toxicities and favourable outcomes when they were treated with the ATO and ATRA combination during induction [12, 14]. Creutzig U et al. [13] also reported results for paediatric APL patients treated with the ATRA-ATO regimen that resembled the Lo-coco regimen for adults [7]. No patient died early after diagnosis or during induction. Treatment with ATRA and ATO was well tolerated in their paediatric standard- risk patients with APL [13]. In our CCAPL2010 study, no patients had an early death, and only one patient relapsed. All toxicity events were tolerable, and all were reversed by appropriate management. All of our patients achieved molecular complete remission after the third consolidation cycle. The results of our study indicated that our protocol, which included ATO, ATRA and cytotoxic chemotherapy, achieved good outcomes with only moderate side-effects in children.\n\nIn the pre-ATO era, the role of Ara-C in APL was controversial [15–17]. However, the role of Ara-C when a combination ATRA and ATO treatment was applied for paediatric APL had not been studied as of 2010. In our study, there was no difference in outcomes between the Ara-C group and the no Ara-C group on an ITT and a PP basis analyses. These results indicated that in paediatric APL, Ara-C can be omitted, at least when regimens similar to ours are applied.\n\nIt has been suggested that higher cumulative doses of anthracyclines yield better results in APL [23]. However, a higher cumulative dose may also lead to cardiac toxicity, especially in children [24]. In our study, the cumulative dose of anthracycline was 420 mg/m2. To date, no severe anthracycline-related cardiac toxicity has occurred. However, cardiac complication from anthracyclines should be monitored every year after completion of therapy. Recent results have shown that the ATRA+ATO combination (without chemotherapy) is at least as effective as the classical ATRA+CT regimens in low –risk APL patients and is also less myelosuppressive [7]. However, when our CCAPL2010 trial began, the feasibility of treatment of APL without chemotherapy was unknown. Thus, our patients with low- risk APL may have been over-treated. With increasing evidence confirming the efficacy of therapy including ATO, a chemotherapy-sparing approach with ATO should be planned for paediatric APL low-risk patients. Additionally, suitable treatment for paediatric patients with high-risk APL should be further studied.\n\nIn the pre-ATO era, the prognostic factors for APL included the presenting WBC and platelet counts, gender, CD56 expression, HLA-B13, and the subtype of fusion product [25]. WBC and platelet counts are especially considered the definitive indexes for relapse risk [26]. However, in the ATO era, the prognostic value of many of these factors has been questioned [27, 28]. Lou et al. [27] examined records from 184 APL patients who were treated with ATRA+ATO and found that there was no association between the 3-year relapse-free survival (RFS) rate and presenting WBC counts, FLT3-ITD status, or PML/RARA isoforms. In line with previous ATO-based upfront studies, we did not identify any prognostic indicators in our study.\n\nATO has been shown to be the most potent single agent in APL therapy [3, 4]. However, an increase in the risk of solid cancers has been reported in patients with long-term exposure to low doses of inorganic arsenic compounds [29]. Fortunately, Zhou J et al. [4] reported that no severe side-effects were documented in patients who continued ATO therapy for more than 3 years, nor were second malignancies encountered after a follow-up of 3 or more years after the completion of therapy. Our patients received ATO for 56 days. The side-effects of ATO were moderate and reversible given appropriate management. An analysis of arsenic levels in the plasma, urine, nails and hair of patients indicated that there was no significant accumulation of arsenic after ATO had been discontinued for 12 months. Further investigations that include long-term follow up times are needed.\n\nNotably, no early deaths occurred in our study. Some patients died of intracranial haemorrhage in transit, which might provide an explanation. Although 4 (6.1%) patients with intracranial haemorrhage were admitted to our hospital, none of the patients died. Early recognition of APL, prompt ATRA/ATO administration and aggressive supportive care might explain this outcome.\n\nConclusion\nThe results of our study indicate that ATO is safe and effective in paediatric APL and that Ara-C can be omitted, at least when using regimens similar to ours. Unfortunately, our patients with low- risk APL may have been over-treated. A decreased intensity of treatment in paediatric APL patients should be further studied based on the ATRA and ATO combination.\n\nAbbreviations\nAPLAcute promyelocytic leukemia\n\nATOArsenic trioxide\n\nATRAAll-trans-retinoic acid\n\nCRComplete remission\n\nDFSDisease-free survival\n\nEDEarly death\n\nEFSEvent-free survival\n\nFISHFluorescence in situ hybridization\n\nFLT3Fms-like tyrosine kinase 3\n\nHCRHaematological complete remission\n\nICP-MSInductively coupled plasma mass spectrometry\n\nITDInternal tandem duplication\n\nORSOctopole reaction system\n\nOSOverall survival\n\nPCRPolymerase-chain-reaction\n\nRASRetinoic acid syndrome\n\nRBCRed blood cell\n\nRFSRelapse-free survival\n\nTKDTyrosine kinase domain\n\nWBCWhite blood cell\n\nAcknowledgements\nWe thank all of the patients who participated in this study and all of the participants and research staff in our hospital. We thank the AIYOU and SHENHUA foundations for their financial support for our study of leukaemia in children. We thank Lynne Hyman (AJE Research Communication Partner) for her professional writing services.\n\nFunding\nThis study was funded by the Natural Science Fund Foundation Project (81200396 and 81421002).\n\nAvailability of data and materials\nThe datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request.\n\nPresentations\nInternational Society of Paediatric Oncology Annual Meeting, October 12–15, 2017; Washington DC, USA (abstract SIOP7–0104).\n\nAuthors’ contributions\nLZ and XZ designed the study. All authors performed the study, participated in the drafting of the manuscript and approved the final version of the manuscript for submission.\n\nEthics approval and consent to participate\nThis study was approved by the Medical Ethics Committee of the Institute of Haematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. Written informed consent was obtained from the parents of the study participants before enrollment in accordance with the Declaration of Helsinki.\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. Sanz MA Montesinos P Vellenga E Rayón C de la Serna J Parody R Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy: long-term outcome of the LPA 99 multicenter study by the PETHEMA group Blood 2008 112 3130 3134 10.1182/blood-2008-05-159632 18664623 \n2. Sanz MA Grimwade D Tallman MS Lowenberg B Fenaux P Estey EH Management of acute promyelocytic leaukemia: recommendations from an expert panel on behalf of the European LeukemiaNet Blood 2009 113 1875 1891 10.1182/blood-2008-04-150250 18812465 \n3. Chen SJ Zhou GB Zhang XW Mao JH de Thé H Chen Z From an old remedy to a magic bullet: molecular mechanisms underlying the therapeutic effects of arsenic in fighting leukemia Blood 2011 117 6425 6437 10.1182/blood-2010-11-283598 21422471 \n4. Zhou J Zhang Y Li J Li X Hou J Zhao Y Single-agent arsenic trioxide in the treatment of children with newly diagnosed acute promyelocytic leukemia Blood 2010 115 1697 1702 10.1182/blood-2009-07-230805 20029047 \n5. Daver N Kantarjian H Marcucci G Pierce S Brandt M Dinardo C Clinical characteristics and outcomes in patients with acute promyelocytic leukaemia and hyperleucocytosis Br J Haematol 2015 168 646 653 10.1111/bjh.13189 25312977 \n6. Cicconi L Lo-Coco F Current management of newly diagnosed acute promyelocytic leukemia Ann Oncol 2016 27 1474 1481 10.1093/annonc/mdw171 27084953 \n7. Lo-Coco F Avvisati G Vignetti M Thiede C Orlando SM Iacobelli S Retinoic acid and arsenic trioxide for acute promyelocytic leukemia N Engl J Med 2013 369 111 121 10.1056/NEJMoa1300874 23841729 \n8. Lo-Coco F Di Donato L GIMEMA Schlenk RF German–Austrian acute myeloid leukemia study group and study alliance leukemia Targeted therapy alone for acute Promyelocytic leukemia N Engl J Med 2016 374 1197 1198 10.1056/NEJMc1513710 27007970 \n9. Shen ZX Shi ZZ Fang J Gu BW Li JM Zhu YM All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia Proc Natl Acad Sci U S A 2004 101 5328 5335 10.1073/pnas.0400053101 15044693 \n10. Burnett AK Russell NH Hills RK Bowen D Kell J Knapper S Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial Lancet Oncol 2015 16 1295 1305 10.1016/S1470-2045(15)00193-X 26384238 \n11. Iland HJ Collins M Bradstock K Supple SG Catalano A Hertzberg M Australasian Leukaemia and lymphoma Group Use of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and lymphoma group (ALLG) APML4 study: a non-randomised phase 2 trial Lancet Haematol 2015 2 e357 e366 10.1016/S2352-3026(15)00115-5 26685769 \n12. Cheng Y Zhang L Wu J Lu A Wang B Liu G Long-term prognosis of childhood acute promyelocytic leukaemia with arsenic trioxide administration in induction and consolidation chemotherapy phases: a single-Centre experience Eur J Haematol 2013 91 483 489 10.1111/ejh.12194 24033687 \n13. Creutzig U, Dworzak MN, Bochennek K, Faber J, Flotho C, Graf N, et al. First experience of the AML-berlin-Frankfurt-Münster group in pediatric patients with standard-risk acute promyelocytic leukemia treated with arsenic trioxide and all-trans retinoid acid. Pediatr Blood Cancer. 2017;64(8) 10.1002/pbc.26461.\n14. Zhang L Zhao H Zhu X Chen Y Zou Y Chen X Retrospective analysis of 65 Chinese children with acute promyelocytic leukemia: a single center experience Pediatr Blood Cancer 2008 51 210 215 10.1002/pbc.21510 18428427 \n15. Lengfelder E Haferlach C Saussele S Haferlach T Schultheis B Schnittger S High dose ara- C in the treatment of newly diagnosed acute promyelocytic leukemia: long-term results of the German AMLCG Leukemia. 2009 23 2248 58 10.1038/leu.2009.183 19741727 \n16. Adès L Chevret S Raffoux E de Botton S Guerci A Pigneux A Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European acute Promyelocytic leukemia group J Clin Oncol 2006 24 5703 5710 10.1200/JCO.2006.08.1596 17116939 \n17. Adès L Chevret S Raffoux E Guerci-Bresler A Pigneux A Vey N Long-term follow-up of European APL 2000 trial, evaluating the role of cytarabine combined with ATRA and Daunorubicin in the treatment of nonelderly APL patients Am J Hematol 2013 88 556 559 10.1002/ajh.23451 23564205 \n18. Gore SD Gojo I Sekeres MA Morris L Devetten M Jamieson K Single cycle of arsenic trioxide-based consolidation chemotherapy spares anthracycline exposure in the primary management of acute promyelocytic leukemia J Clin Oncol 2010 28 1047 1053 10.1200/JCO.2009.25.5158 20085935 \n19. van Dongen JJ Macintyre EA Gabert JA Delabesse E Rossi V Saglio G Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 concerted action: investigation of minimal residual disease in acute leukemia Leukemia 1999 13 1901 1928 10.1038/sj.leu.2401592 10602411 \n20. Gabert J Beillard E van der Velden VH Bi W Grimwade D Pallisgaard N Standardization and quality control studies of 'real-time' quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia - a Europe against Cancer program Leukemia 2003 17 2318 2357 10.1038/sj.leu.2403135 14562125 \n21. Grimwade D Biondi A Mozziconacci MJ Hagemeijer A Berger R Neat M Characterization of acute promyelocytic leukemia cases lacking the classic t(15;17): results of the European working party. Groupe Français de Cytogénétique Hématologique, Groupe de Français d'Hematologie Cellulaire, UK Cancer cytogenetics group and BIOMED 1 European Community-concerted action \"molecular cytogenetic diagnosis in Haematological malignancies\" Blood 2000 96 1297 1308 10942371 \n22. Platzbecker U Avvisati G Cicconi L Thiede C Paoloni F Vignetti M Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non-High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial J Clin Oncol. 2017 35 605 12 10.1200/JCO.2016.67.1982 27400939 \n23. Head D Kopecky KJ Weick J Files JC Ryan D Foucar K Effect of aggressive daunomycin therapy on survival in acute promyelocytic leukemia Blood 1995 86 1717 1728 7655004 \n24. Bally C Fadlallah J Leverger G Bertrand Y Robert A Baruchel A Outcome of acute promyelocytic leukemia (APL) in children and adolescents: an analysis in two consecutive trials of the European APL Group J Clin Oncol 2012 30 1641 1646 10.1200/JCO.2011.38.4560 22473162 \n25. Tallman MS Nabhan C Feusner JH Rowe JM Acute promyelocytic leukemia: evolving therapeutic strategies Blood 2002 99 759 767 10.1182/blood.V99.3.759 11806975 \n26. Sanz MA Lo Coco F Martín G Avvisati G Rayón C Barbui T Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups Blood 2000 96 1247 1253 10942364 \n27. Lou Y Ma Y Suo S Ni W Wang Y Pan H Prognostic factors of patients with newly diagnosed acute promyelocytic leukemia treated with arsenic trioxide-based frontline therapy Leuk Res 2015 39 938 944 10.1016/j.leukres.2015.05.016 26183877 \n28. Hu J Liu YF Wu CF Xu F Shen ZX Zhu YM Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia Proc Natl Acad Sci U S A 2009 106 3342 3347 10.1073/pnas.0813280106 19225113 \n29. Firkin F Carcinogenic risk of retained arsenic after successful treatment of acute promyelocytic leukemia with arsenic trioxide: a cause for concern? Leuk Lymphoma 2014 55 977 978 10.3109/10428194.2013.856429 24144311\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "18(1)",
"journal": "BMC cancer",
"keywords": "Acute promyelocytic leukaemia; All-trans retinoic acid; Arsenic trioxide; Cytarabine; Paediatric",
"medline_ta": "BMC Cancer",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D000077237:Arsenic Trioxide; D015415:Biomarkers; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D060830:Consolidation Chemotherapy; D003561:Cytarabine; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D015473:Leukemia, Promyelocytic, Acute; D008297:Male; D016896:Treatment Outcome; D014212:Tretinoin",
"nlm_unique_id": "100967800",
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"pages": "374",
"pmc": null,
"pmid": "29615003",
"pubdate": "2018-04-03",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "7655004;10602411;21422471;24033687;18812465;25312977;20029047;23564205;11806975;26685769;20085935;27400939;28111878;18428427;15044693;27007970;17116939;27084953;26183877;10942364;18664623;19225113;14562125;22473162;10942371;26384238;23841729;19741727;24144311",
"title": "Role of cytarabine in paediatric acute promyelocytic leukemia treated with the combination of all-trans retinoic acid and arsenic trioxide: a randomized controlled trial.",
"title_normalized": "role of cytarabine in paediatric acute promyelocytic leukemia treated with the combination of all trans retinoic acid and arsenic trioxide a randomized controlled trial"
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"abstract": "Ponatinib is a third-generation tyrosine kinase inhibitor (TKI) reported to show a higher efficacy for adult Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) than other TKIs. However, few studies describe ponatinib for pediatric Ph+ALL; therefore, the efficacy, safety, and optimal dosage have not been determined. Here, we report a 3-year-old girl with Ph+ALL treated by a ponatinib-containing regimen with therapeutic drug monitoring in the plasma and cerebrospinal fluid (CSF). In our case, a ponatinib-containing regimen was able to keep minimal residual disease negative, and the pharmacokinetics (PKs) of plasma ponatinib resembled that previously reported in adults. Penetration to the CSF was extremely limited. Thus, ponatinib was feasible and effective for a child with Ph+ALL, although the plasma concentration of ponatinib varied significantly throughout the treatment. The appropriate dosage should be confirmed in a prospective trial, including a detailed PK study.",
"affiliations": "Department of Pediatric Hematology and Oncology, Children's Medical Center, Osaka City General Hospital, Osaka, Japan.;Department of Pediatric Hematology and Oncology, Children's Medical Center, Osaka City General Hospital, Osaka, Japan.;Department of Pediatric Hematology and Oncology, Children's Medical Center, Osaka City General Hospital, Osaka, Japan.;Department of Pediatric Hematology and Oncology, Children's Medical Center, Osaka City General Hospital, Osaka, Japan.;Department of Pediatric Hematology and Oncology, Children's Medical Center, Osaka City General Hospital, Osaka, Japan.;Department of Pediatric Hematology and Oncology, Children's Medical Center, Osaka City General Hospital, Osaka, Japan.;Department of Pediatric Hematology and Oncology, Children's Medical Center, Osaka City General Hospital, Osaka, Japan.;Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kyoto, Japan.;Department of Pediatric Hematology and Oncology, Children's Medical Center, Osaka City General Hospital, Osaka, Japan.",
"authors": "Tanimura|Kazuki|K|;Yamasaki|Kai|K|;Okuhiro|Yuki|Y|;Hira|Kota|K|;Nitani|Chika|C|;Okada|Keiko|K|;Fujisaki|Hiroyuki|H|;Matsumoto|Kana|K|;Hara|Junichi|J|",
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"doi": "10.1159/000511071",
"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575\nS. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com\n\n10.1159/000511071\ncro-0014-0024\nCase Report\nMonitoring Ponatinib in a Child with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia\nTanimura Kazuki a*\nYamasaki Kai a\nOkuhiro Yuki a\nHira Kota a\nNitani Chika a\nOkada Keiko a\nFujisaki Hiroyuki a\nMatsumoto Kana b\nHara Junichi a\naDepartment of Pediatric Hematology and Oncology, Children's Medical Center, Osaka City General Hospital, Osaka, Japan\nbDepartment of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kyoto, Japan\n*Kazuki Tanimura, Department of Pediatric Hematology and Oncology, Osaka City General Hospital, 2-13-22, Miyakojima-hondouri, Miyakojima-ku, Osaka 534-0021 (Japan), k-tanimura@med.osakacity-hp.or.jp\nJan-Apr 2021\n15 2 2021\n15 2 2021\n14 1 2428\n23 8 2020\n24 8 2020\n2021\nCopyright © 2021 by S. Karger AG, Basel\n2021\nThis article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.\nPonatinib is a third-generation tyrosine kinase inhibitor (TKI) reported to show a higher efficacy for adult Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) than other TKIs. However, few studies describe ponatinib for pediatric Ph+ALL; therefore, the efficacy, safety, and optimal dosage have not been determined. Here, we report a 3-year-old girl with Ph+ALL treated by a ponatinib-containing regimen with therapeutic drug monitoring in the plasma and cerebrospinal fluid (CSF). In our case, a ponatinib-containing regimen was able to keep minimal residual disease negative, and the pharmacokinetics (PKs) of plasma ponatinib resembled that previously reported in adults. Penetration to the CSF was extremely limited. Thus, ponatinib was feasible and effective for a child with Ph+ALL, although the plasma concentration of ponatinib varied significantly throughout the treatment. The appropriate dosage should be confirmed in a prospective trial, including a detailed PK study.\n\nKeywords\n\nPhiladelphia chromosome-positive acute lymphoblastic leukemia\nPonatinib\nPlasma concentration\n==== Body\nIntroduction\n\nThe clinical outcome of pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) has improved dramatically since the introduction of imatinib. Imatinib has enabled most children with Ph+ALL to avoid allogenic hematopoietic stem cell transplantation (allo-HSCT) as the first complete response [1]. However, dasatinib, a second-generation tyrosine kinase inhibitor (TKI), failed to show a higher efficacy than imatinib in the Children's Oncology Group (COG) AALL0622 trial [2]. Ponatinib (ICLUSIG®) is a third-generation TKI reported to show higher efficacy for adult Ph+ALL than other TKIs [3]. In adult Ph+ALL, allo-HSCT for the first complete response is still a standard treatment. However, some clinical studies have suggested the possibility of avoiding allo-HSCT by using ponatinib-containing regimens [3]. However, few studies describe ponatinib for pediatric Ph+ALL; therefore, the efficacy, safety, and optimal dosage have not been determined.\n\nHere, we report a case of pediatric Ph+ALL treated with a ponatinib-containing regimen with therapeutic drug monitoring in the plasma and cerebrospinal fluid (CSF). Ponatinib concentrations in the plasma and CSF were measured using liquid chromatography-tandem mass spectrometry as previously described, with some modifications [4].\n\nCase Report\n\nA 3-year-old girl experienced long-lasting fever and pallor and was admitted to our hospital. She presented with systemic lymphadenopathy and hepatosplenomegaly. Laboratory analysis showed the following: white blood cell count: 595,720/µL (blasts: 49.5%), hemoglobin: 3.6 g/dL, and platelets: 29,000/µL. There were no extramedullary lesions; however, CSF cytology indicated central nervous system (CNS) infiltration. Minor BCR-ABL transcripts were detected by fluorescent in situ hybridization and quantitative reverse transcription-polymerase chain reaction (RT-PCR) (6.7 × 104 copies/µg RNA). She responded poorly to prednisolone. Therefore, we started induction chemotherapy based on the Japan Association of Childhood Leukemia Study (JACLS) HR-02 concurrent with dasatinib 60 mg/m2/day [5]. Her parents provided consent for treatment. After induction chemotherapy, complete cytogenetic remission was achieved; however, minimal residual disease (MRD) measured by RT-PCR of minor BCR-ABL fusion transcripts was detected at a level of 1 × 10−4. Dasatinib was continued based on the COG AALL0622 protocol. After intensification block 1, MRD was still detected. Therefore, after obtaining written informed consent, we switched dasatinib to ponatinib from re-induction block 2.\n\nInitially, we started ponatinib at a dose of 10 mg/day (equivalent to 30 mg/day in adults by Augsberger's method). The daily ponatinib dose was adjusted by assessing the plasma concentration and adverse clinical events. The plasma concentration-time profiles following a single oral dose and during steady-state are shown in Figure 1A and B. In addition, penetration to the CSF was extremely limited with a peak concentration of 0.1 ng/mL. After increasing to 15 mg/day, the patient developed hypertension and required an antihypertensive agent. After high-dose methotrexate therapy, we needed to stop ponatinib because of acute kidney injury owing to delayed methotrexate elimination. After 3 weeks of withdrawal, ponatinib was restarted at a dose of 5 mg/day and gradually increased according to plasma concentration. After the introduction of ponatinib, MRD disappeared after re-induction block 2. Therefore, ponatinib was continued concurrently with the AALL0622 protocol. Finally, ponatinib at a dose of 5 mg was continued throughout maintenance chemotherapy. During the maintenance phase, she presented several mild complications, such as abdominal pain, otalgia, aspartate aminotransferase and alanine aminotransferase elevation, and hyperbilirubinemia; however, these complications were controllable by standard supportive therapy. Growth deceleration in height was observed throughout her treatment. We evaluated the plasma ponatinib concentration non-periodically during her treatment (Fig. 1C). During the maintenance phase, the plasma trough concentrations of ponatinib at a dose of 5 mg/day were lower than those during the re-induction phase. At present, she has completed maintenance chemotherapy and receives careful observation without HSCT.\n\nDiscussion\n\nThis is the first report of the detailed monitoring of ponatinib in a pediatric patient with Ph+ALL. The pharmacokinetics (PKs) during the initiation phase resembled those in a phase I study of adult Ph+ALL [3], but the trough value of ponatinib varied significantly throughout treatment. Following single 45-mg doses of ponatinib in the adult, peak concentrations were observed approximately 4 h after administration, and the terminal elimination half-life was 22 h. In adults, steady-state conditions are typically achieved within 1 week of continuous dosing. Moreover, it has been reported that the trough value of ponatinib is stable throughout each treatment phase in adult Ph+ALL cases [6]. In our case, the trough value of ponatinib varied throughout each treatment phase despite the same daily dose, which implied instability of the ponatinib plasma concentration. One possible reason is the effect of chemotherapeutic agents on metabolism. Ponatinib is metabolized to an inactive carboxylic acid by esterases, amidases, and CYP3A4, CYP2C8, CYP2D6, and CYP3A5 to an N-desmethyl metabolite that is four times less active than ponatinib. The carboxylic acid and N-desmethyl metabolite comprise 58 and 2% of the circulating ponatinib, respectively. The metabolic activity of CYP enzymes is easily affected by many antileukemic agents, such as vincristine, cyclophosphamide, and etoposide. As the pediatric ALL regimen is more complicated than the adult ALL regimen, the instability of the ponatinib plasma concentration in pediatric cases may be different from that in adult cases.\n\nSevere adverse events associated with a high ponatinib concentration have been reported, and even concentrations as low as 40 nM can induce severe adverse events [6]. Therefore, it is important to determine the appropriate dose of ponatinib based on the trough concentration in pediatric cases. The CSF penetration of ponatinib was as low as that reported previously [3]. The efficacy of ponatinib for CNS leukemia has not yet been proven. It has been reported that dasatinib slightly crosses the blood-brain barrier (BBB) and is an efficient therapy for CNS Ph+ALL [7]. However, there are limited data on whether ponatinib crosses the BBB as well. Abid and De Mel [8] presented a case that showed CNS relapse during ponatinib treatment and concluded that ponatinib does not penetrate the CSF. However, Masuda et al. [9] showed successful experiences for Ph+ALL cases with CNS relapse using ponatinib concomitant with ALL chemotherapy. From our result, ponatinib showed a slight CNS penetration. Additionally, our case is now successfully managed without cranial irradiation, though CNS infiltration was positive. Therefore, our case might demonstrate the potential utility of ponatinib for managing CNS leukemias.\n\nConclusion\n\nPonatinib was feasible and effective for a child with Ph+ALL. The plasma concentration of ponatinib varied significantly throughout treatment. The appropriate dosage may need to be determined by considering simultaneously used anti-leukemic agents. Further clinical trials, including a detailed PK study, are required.\n\nStatement of Ethics\n\nThis case report complied with the guidelines for human studies and included evidence that the research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. Written 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 declare no conflict of interest.\n\nFunding Sources\n\nOur work was not funded from any sources.\n\nAuthor Contributions\n\nK.T. wrote the manuscript and K.Y. intensively revised it. K.T. and K.Y. treated the patient and collected and interpreted the data. K.M. measured the plasma and CSF concentration of ponatinib. Y.O., K.H., C.N., K.O., H.F., and J.H. supervised the entire study process. All authors have read and approved the final manuscript.\n\nAcknowledgements\n\nWe thank our colleagues and the medical staff at the Osaka City General Hospital who helped with the treatment of this child.\n\nFig. 1 A Pharmacokinetics (PKs) of ponatinib after initiation (dose: 10 mg/day) during re-induction chemotherapy. B PK of ponatinib during steady phase (solid line: 10 mg/day, dotted line: 15 mg/day). The steady-phase plasma concentration was measured after the patient received the same dose for a week. C Schematic of ponatinib trough plasma concentration during chemotherapy. Intensive chemotherapy included re-induction block 2 and intensification block 2. Daily ponatinib dose was adjusted between 0 and 15 mg based on trough plasma concentration and medical adverse events.\n==== Refs\nReferences\n\n1 Schultz KR Bowman WP Aledo A Slayton WB Sather H Devidas M Improved early event-free survival with imatinib in Philadelphia chromosome - Positive acute lymphoblastic leukemia: A Children's Oncology Group Study J Clin Oncol 2009 Nov 27 (31) 5175 81 19805687\n2 Slayton WB Schultz KR Kairalla JA Devidas M Mi X Pulsipher MA Dasatinib plus intensive chemotherapy in children, adolescents, and young adults with Philadelphia chromosome–positive acute lymphoblastic leukemia: Results of Children's Oncology Group Trial AALL0622 J Clin Oncol 2018 Aug 36 (22) 2306 13 29812996\n3 Tojo A Kyo T Yamamoto K Nakamae H Takahashi N Kobayashi Y Ponatinib in Japanese patients with Philadelphia chromosome-positive leukemia, a phase 1/2 study Int J Hematol 2017 Sep 106 (3) 385 97 28444644\n4 Andriamanana I Gana I Duretz B Hulin A Simultaneous analysis of anticancer agents bortezomib, imatinib, nilotinib, dasatinib, erlotinib, lapatinib, sorafenib, sunitinib and vandetanib in human plasma using LC/MS/MS J Chromatogr B Analyt Technol Biomed Life Sci 2013 May 926 83 91\n5 Hasegawa D Imamura T Yumura-Yagi K Takahashi Y Usami I Suenobu SI Risk-adjusted therapy for pediatric non-T cell ALL improves outcomes for standard risk patients: results of JACLS ALL-02 Blood Cancer J 2020 Feb 10 (2) 23 32107374\n6 Cortes JE Kantarjian H Shah NP Bixby D Mauro MJ Flinn I Ponatinib in refractory Philadelphia chromosome-positive leukemias N Engl J Med 2012 Nov 367 (22) 2075 88 23190221\n7 Marchesi F Salvatorelli E Renzi D Mengarelli A Minotti G Menna P Efficacy and safety of low dose ponatinib in a case of Ph-positive acute lymphoblastic leukaemia Br J Haematol 2019 Aug 187 (1) e15 7 31368155\n8 Abid MB De Mel S Does ponatinib cross the blood-brain barrier? Br J Haematol 2017 Nov 179 (3) 497 8 27352067\n9 Masuda K Nakazato T Nishiyama-Fujita Y Ito C Ogura S Mizuno K Successful treatment with ponatinib for central nervous system relapse of Philadelphia chromosome-positive B-cell acute lymphoblastic leukaemia Intern Med J 2019 Oct 49 (10) 1332 4 31602766\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "14(1)",
"journal": "Case reports in oncology",
"keywords": "Philadelphia chromosome-positive acute lymphoblastic leukemia; Plasma concentration; Ponatinib",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "24-28",
"pmc": null,
"pmid": "33776678",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "23562906;23190221;28444644;29812996;31602766;31368155;27352067;32107374;19805687",
"title": "Monitoring Ponatinib in a Child with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.",
"title_normalized": "monitoring ponatinib in a child with philadelphia chromosome positive acute lymphoblastic leukemia"
} | [
{
"companynumb": "JP-PFIZER INC-2021682887",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
... |
{
"abstract": "An appreciable proportion of patients in need of salvage high-dose chemotherapy (HDC) and autologous peripheral blood stem cell (PBSC) transplantation (PBSCT) fail to mobilize adequate numbers of hematopoietic progenitors, and plerixafor is applied for that purpose. Limited data exist on remobilization of PBSCs in patients who have relapsed after prior HDC + PBSCT. Herein, we report on consecutive patients that had undergone successful prior single or tandem HDC for a variety of malignant neoplasms in our institution, and later required re-mobilization of PBSCs in order to support further HDC cycles.\n\n\n\nPlerixafor was administered in combination with granulocyte-colony stimulating factor alone, or after mobilizing chemotherapy. Five patients, 2 B-cell non-Hodgkin lymphomas, 1 multiple myeloma, 1 germ-cell tumor, and 1 Ewing sarcoma, having relapsed after prior HDC + PBSCT, were deemed candidates for further cycle(s) of PBSC-supported HDC. Plerixafor was applied in a \"just-in-time\" strategy after low CD34+ numbers were measured on the first day of anticipated hematopoietic stem cell collection (non-Hodgkin lymphoma, germ-cell tumor, and Ewing sarcoma), or pre-emptively in multiple myeloma.\n\n\n\nSuccessful collection of adequate PBSCs was achieved in all patients, from 1.8 to 3.8 × 106/kg after a median of 2 (range, 1-3) leukaphereses; 4 of 5 patients underwent subsequent HDC + PBSCT and engrafted after a median of 11 days (range, 9-55 days) and 25 days (range, 17-76 days) for neutrophils and platelets, respectively.\n\n\n\nPlerixafor proved effective to mobilize adequate numbers of PBSCs in individual patients with relapsed malignancies after prior single or tandem HDC + PBSCT. These PBSCs could establish sustained multi-lineage hematopoietic engraftment without any sequelae.",
"affiliations": "Department of Medicine, Division of Medical Oncology-Hematopoietic Cell Transplant Unit, \"Metaxa\" Cancer Hospital, Piraeus, Greece.;Department of Medicine, Division of Medical Oncology-Hematopoietic Cell Transplant Unit, \"Metaxa\" Cancer Hospital, Piraeus, Greece.;Department of Medicine, Division of Medical Oncology-Hematopoietic Cell Transplant Unit, \"Metaxa\" Cancer Hospital, Piraeus, Greece.;Department of Medicine, Division of Medical Oncology-Hematopoietic Cell Transplant Unit, \"Metaxa\" Cancer Hospital, Piraeus, Greece.;Department of Medicine, Division of Medical Oncology-Hematopoietic Cell Transplant Unit, \"Metaxa\" Cancer Hospital, Piraeus, Greece.;Department of Medicine, Division of Medical Oncology-Hematopoietic Cell Transplant Unit, \"Metaxa\" Cancer Hospital, Piraeus, Greece.;Department of Medicine, Division of Medical Oncology-Hematopoietic Cell Transplant Unit, \"Metaxa\" Cancer Hospital, Piraeus, Greece.;Department of Medicine, Division of Medical Oncology-Hematopoietic Cell Transplant Unit, \"Metaxa\" Cancer Hospital, Piraeus, Greece.;Cryopreservation Laboratory, Department of Blood Transfusion, \"Metaxa\" Cancer Hospital, Piraeus, Greece.;Department of Medicine, Division of Medical Oncology-Hematopoietic Cell Transplant Unit, \"Metaxa\" Cancer Hospital, Piraeus, Greece.;Department of Medicine, Division of Medical Oncology-Hematopoietic Cell Transplant Unit, \"Metaxa\" Cancer Hospital, Piraeus, Greece. Electronic address: ckosmas1@hotmail.com.",
"authors": "Fergadis|Evangelos|E|;Assi|Abraam|A|;Kranidioti|Eleftheria|E|;Kosma|Aikaterini|A|;Karakosta|Maria|M|;Miltiadous|Constantinos|C|;Dimitriadis|George K|GK|;Grivas|Anastasios|A|;Athanasopoulos|Aggelos|A|;Lianos|Evangelos|E|;Kosmas|Christos|C|",
"chemical_list": "D001596:Benzylamines; D000080027:Cyclams; C088327:plerixafor",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clml.2019.11.022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "20(2)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "Ewing family of tumors; Germ-cell tumors; Hematopoietic stem cell mobilization; Myeloma; Non-Hodgkin's lymphoma; Plerixafor",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000328:Adult; D000368:Aged; D001596:Benzylamines; D000080027:Cyclams; D005260:Female; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D008297:Male; D008875:Middle Aged; D036102:Peripheral Blood Stem Cell Transplantation; D014182:Transplantation, Autologous",
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "e50-e57",
"pmc": null,
"pmid": "31884151",
"pubdate": "2020-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Plerixafor-aided Mobilization of Peripheral Blood Hematopoietic Stem Cells to Support Subsequent High-dose Chemotherapy After a Prior Autologous Transplant.",
"title_normalized": "plerixafor aided mobilization of peripheral blood hematopoietic stem cells to support subsequent high dose chemotherapy after a prior autologous transplant"
} | [
{
"companynumb": "GR-MYLANLABS-2020M1030235",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "A 66-year-old man was admitted to our department with hypercalcemia, pancreatic and liver tumors, and periportal lymph node enlargement. Contrast-enhanced computed tomography revealed a tumor in the pancreatic tail and the right hepatic lobe along with periportal lymphadenopathy. Laboratory data revealed hypercalcemia and high serum parathyroid hormone-related protein (PTHrP) levels. Using a 22-gauge Franseen needle, we performed endoscopic ultrasonography-guided fine-needle biopsy of the pancreatic mass and an enlarged lymph node. Histopathological examination of the biopsy specimen revealed moderately to well-differentiated pancreatic adenocarcinoma with poorly differentiated squamous cell elements, as well as squamous cell carcinoma of the lymph node. Immunohistochemical examination showed that the pancreatic tissue was weakly immunopositive and the lymph node was strongly immunopositive for anti-PTHrP antibody. We diagnosed the patient with pancreatic adenosquamous carcinoma with liver and lymph node metastasis, associated with hypercalcemia of malignancy secondary to PTHrP secretion. We administered systemic chemotherapy comprising gemcitabine and nab-paclitaxel. Unfortunately, the patient died 8 months after being diagnosed with this malignancy. PTHrP-producing adenosquamous carcinoma of the pancreas is rare;only 14 cases are reported in the literature. Based on immunohistochemical evaluation, this case report suggests that metastatic lymph nodes may lead to the overproduction of PTHrP in such cases.",
"affiliations": "Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki.;Section of Oncopathology and Regenerative Biology, Faculty of Medicine, University of Miyazaki.;Division of Pathology, Department of Diagnosis Pathology, University of Miyazaki Hospital.",
"authors": "Hatada|Hiroshi|H|;Kawakami|Hiroshi|H|;Uchiyama|Naomi|N|;Ogawa|Soichiro|S|;Kubota|Yoshimasa|Y|;Ban|Tessin|T|;Akaki|Mayumi|M|;Sato|Yuichiro|Y|",
"chemical_list": "D044162:Parathyroid Hormone-Related Protein",
"country": "Japan",
"delete": false,
"doi": "10.11405/nisshoshi.118.480",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0446-6586",
"issue": "118(5)",
"journal": "Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology",
"keywords": null,
"medline_ta": "Nihon Shokakibyo Gakkai Zasshi",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D044963:Biopsy, Fine-Needle; D006801:Humans; D008297:Male; D010190:Pancreatic Neoplasms; D044162:Parathyroid Hormone-Related Protein; D018084:Ultrasonography, Interventional",
"nlm_unique_id": "2984683R",
"other_id": null,
"pages": "480-489",
"pmc": null,
"pmid": "33967133",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Endoscopic ultrasound-guided fine-needle biopsy for diagnosis of pancreatic metastases producing parathyroid hormone-related protein.",
"title_normalized": "endoscopic ultrasound guided fine needle biopsy for diagnosis of pancreatic metastases producing parathyroid hormone related protein"
} | [
{
"companynumb": "JP-TEVA-2021-JP-1933448",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "A 34-year-old man was referred to our hospital for leukocytosis and fundal hemorrhage. Peripheral blood and coagulation tests showed increases in cells at all stages of the neutrophilic series and a low level of fibrinogen (Fbg). Chronic myelogenous leukemia (CML) was diagnosed, and nilotinib was administered. During the clinical course of CML treatment, plasma Fbg levels continued to be low, but the patient showed neither hemorrhagic nor thrombotic complications. Fbg analysis showed normal antigen levels and low activity levels, which indicated dysfibrinogenemia. Genetic analysis revealed a heterozygous gene mutation (γ308AAT→AAG), a mutation which was also found in the patient's mother. Asymptomatic patients with dysfibrinogenemia have a low risk of hemorrhage in daily life and do not require treatment. However, in those undergoing major surgery or in serious accidents, replacement therapy may be required. When the cause of low Fbg levels is unknown, dysfibrinogenemia or fibrinogen deficiency should be considered. Even asymptomatic patients may benefit from more detailed immunologic and genetic analyses.",
"affiliations": "Department of Hematology, Nagano Red Cross Hospital.",
"authors": "Kirihara|Takehiko|T|;Fujikawa|Yuko|Y|;Takeda|Wataru|W|;Kurihara|Taro|T|;Sato|Keijiro|K|;Ueki|Toshimitsu|T|;Hiroshima|Yuki|Y|;Sumi|Masahiko|M|;Ueno|Mayumi|M|;Ichikawa|Naoaki|N|;Arai|Shinpei|S|;Soya|Keisuke|K|;Okumura|Nobuo|N|;Kobayashi|Hikaru|H|",
"chemical_list": "D005340:Fibrinogen",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "55(5)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": null,
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000328:Adult; D000347:Afibrinogenemia; D005340:Fibrinogen; D020022:Genetic Predisposition to Disease; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D009154:Mutation",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "541-5",
"pmc": null,
"pmid": "24881919",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Congenital dysfibrinogenemia coincidentally diagnosed at the onset of chronic myelogenous leukemia.",
"title_normalized": "congenital dysfibrinogenemia coincidentally diagnosed at the onset of chronic myelogenous leukemia"
} | [
{
"companynumb": "PHHY2014JP079065",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DASATINIB"
},
"drugadditional": null,
"druga... |
{
"abstract": "We report a case of neurotoxicity as a side effect of a calcineurin inhibitor (tacrolimus), which is used as an immunosuppressive drug after liver transplant. Our patient had chronic hepatic failure due to Budd-Chiari syndrome and underwent a liver transplant after an appropriate deceased donor organ was obtained. After organ transplant surgery, he was kept under the effect of an immunosuppressive drug (tacrolimus) with daily control of the level of drug in his blood to avoid drug toxicity. Despite the level of drug in his blood being within the ideal range, the patient developed neurotoxicity that presented as weakness of his extremities. Appropriate diagnostic tests were done, and all proved that these signs and symptoms were related to the use of tacrolimus. Therefore, the drug was changed to cyclosporine. After a few months, the patient regained normal neurological functions of his extremities. We should take precautions to monitor neurological symptoms and signs while we administer calcineurin inhibitors.",
"affiliations": "From the Department of General Surgery, Bursa Uludag University, Bursa, Turkey.",
"authors": "Aksoy|Fuat|F|;Dundar|Halit Ziya|HZ|;Bican Demir|Aylin|A|;Kiyici|Murat|M|;Kaya|Ekrem|E|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2020.0278",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": null,
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": null,
"nlm_unique_id": "101207333",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34085919",
"pubdate": "2021-06-03",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Myelitis After Liver Transplant: A Case Report.",
"title_normalized": "myelitis after liver transplant a case report"
} | [
{
"companynumb": "TR-ACCORD-228479",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "1",
"druga... |
{
"abstract": "BACKGROUND\nAtypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system (CNS) is a rare embryonal neoplasm of early childhood with dismal outcome and no current uniformly accepted treatment. Given its highly aggressive nature and predilection for dissemination at diagnosis, intensive multimodal therapy is required.\n\n\nMETHODS\nNineteen children with newly diagnosed CNS AT/RT were treated on the head start (HS) III protocol. Treatment consisted of surgical resection, 5 cycles of induction chemotherapy, followed by consolidation with myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue (AuHCR). Irradiation was given following recovery from consolidation based on patient age, disease extent at diagnosis, and treatment response to induction.\n\n\nRESULTS\nNineteen children (median age of 14 months) were treated on HS III between 2003 and 2009. Only four finished induction and three proceeded to consolidation. There are presently four survivors at 40, 42, 46, and 79 months from study enrollment. Eleven patients experienced tumor progression at a median time to progression of 4.1 months of whom 10 died with a median time from progression to death of 2.6 months. Five toxic deaths occurred, three of them while on the study. The 3-year event-free survival (EFS) and overall survival (OS) for the whole group was 21 ± 9% and 26 ± 10%, respectively. Five patients received irradiation at progression with only one long-term survivor.\n\n\nCONCLUSIONS\nA minority of children with CNS AT/RT treated on HS III may be long-term survivors without irradiation. More effective therapies are desperately needed.",
"affiliations": "Division of Pediatric Hematology and Oncology, Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas.",
"authors": "Zaky|Wafik|W|;Dhall|Girish|G|;Ji|Lingyun|L|;Haley|Kelley|K|;Allen|Jeffrey|J|;Atlas|Mark|M|;Bertolone|Salvatore|S|;Cornelius|Albert|A|;Gardner|Sharon|S|;Patel|Ramesh|R|;Pradhan|Kamnesh|K|;Shen|Violet|V|;Thompson|Stephen|S|;Torkildson|Joseph|J|;Sposto|Richard|R|;Finlay|Jonathan L|JL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.24648",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "61(1)",
"journal": "Pediatric blood & cancer",
"keywords": "CNS tumors; chemotherapy; clinical trials; stem cell transplantation; teratoid/rhabdoid; tumors",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D016543:Central Nervous System Neoplasms; D002675:Child, Preschool; D003131:Combined Modality Therapy; D060830:Consolidation Chemotherapy; D018572:Disease-Free Survival; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D060828:Induction Chemotherapy; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D008297:Male; D019635:Neurosurgical Procedures; D011878:Radiotherapy; D018335:Rhabdoid Tumor; D014182:Transplantation, Autologous; D016896:Treatment Outcome",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "95-101",
"pmc": null,
"pmid": "23934933",
"pubdate": "2014-01",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Intensive induction chemotherapy followed by myeloablative chemotherapy with autologous hematopoietic progenitor cell rescue for young children newly-diagnosed with central nervous system atypical teratoid/rhabdoid tumors: the Head Start III experience.",
"title_normalized": "intensive induction chemotherapy followed by myeloablative chemotherapy with autologous hematopoietic progenitor cell rescue for young children newly diagnosed with central nervous system atypical teratoid rhabdoid tumors the head start iii experience"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2015US-103317",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"dr... |
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