article dict | reports listlengths 1 3.97k |
|---|---|
{
"abstract": "Difficult airway management in the gravid patient is a well-described phenomenon. We present a case of emergent cesarean delivery complicated by a \"cannot intubate, cannot ventilate\" scenario that was later determined to be secondary to an allergic, IgE-mediated reaction to epidurally administered local anesthetic.",
"affiliations": "From the *Department of Anesthesiology, University of Cincinnati, Cincinnati, Ohio; Departments of †Anesthesia, Critical Care, and Pain Medicine, and ‡Allergy and Immunology, Massachusetts General Hospital, Boston, Massachusetts.",
"authors": "Maxey-Jones|Courtney L|CL|;Palmerton|Alec|A|;Farmer|Jocelyn R|JR|;Bateman|Brian T|BT|",
"chemical_list": "D000779:Anesthetics, Local; D008012:Lidocaine",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000533",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2325-7237",
"issue": "9(3)",
"journal": "A & A case reports",
"keywords": null,
"medline_ta": "A A Case Rep",
"mesh_terms": "D000328:Adult; D058109:Airway Management; D000707:Anaphylaxis; D000779:Anesthetics, Local; D000799:Angioedema; D002585:Cesarean Section; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D008012:Lidocaine; D011247:Pregnancy",
"nlm_unique_id": "101637720",
"other_id": null,
"pages": "84-86",
"pmc": null,
"pmid": "28448320",
"pubdate": "2017-08-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Difficult Airway Management Caused by Local Anesthetic Allergy During Emergent Cesarean Delivery: A Case Report.",
"title_normalized": "difficult airway management caused by local anesthetic allergy during emergent cesarean delivery a case report"
} | [
{
"companynumb": "US-MYLANLABS-2017M1053780",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LIDOCAINE"
},
"drugadditional": null,
... |
{
"abstract": "Data are limited regarding the effectiveness of omalizumab in patients with eosinophilic granulomatosis with polyangiitis (EGPA). Our aim was to evaluate the clinical and functional effectiveness of omalizumab in patients with EGPA in long-term follow-up.\nThis study was a retrospective chart review of patients with EGPA who were treated with omalizumab injections between May 2012 and April 2018. Once treatment with omalizumab was started, data were collected at various time points: baseline, the 16th week, 1st year, and annually until the last evaluation.\nEighteen patients (16F/2M) with a mean age of 48.61 ± 11.94 years were included. Data were available for all patients for the first year, 12 patients for the second year, 10 patients for the third year, 8 patients for the fourth year and 5 patients for the fifth year. All patients were on mean dosage of 15.77 ± 7.6 mg/day oral corticosteroid (OCS) as daily bases for mean 8.61 ± 4 years besides high-dose inhaler corticosteroid/long-acting beta agonist. Antineutrophil cytoplasmic antibodies (ANCA) were positive in 2 patients, and 8 patients were diagnosed as having vasculitis by skin biopsy, one patient had polyneuropathy, and one patient had cardiac involvement.By considering the individual responses of patients and the level of improvement at the last evalulation, 10 (55.6%) patients responded completely, 1 responded partially, and 7 (38.9%) had no improvement. Omalizumab worked as a steroid-sparing agent in all patients and the daily OCS dose was reduced with a mean dosage of 6.28 mg/day at the end of the first year. The mean OCS reduction time for the whole group was 4 months. A reduction in asthma exacerbations/hospitalizations, improvement in forced expiratory volume in 1 second, and no decrease in the eosinophil count during treatment with omalizumab were also observed.\nOmalizumab improved asthma control in some patients with EGPA with uncontrolled asthma by reducing asthma exacerbations and oral steroid requirement. However, more data are needed before recommending widespread use of omalizumab in patients with EGPA.",
"affiliations": "1Department of Chest Diseases, Division of Immunology and Allergy, School of Medicine, Ankara University, Ankara, Turkey.;1Department of Chest Diseases, Division of Immunology and Allergy, School of Medicine, Ankara University, Ankara, Turkey.;1Department of Chest Diseases, Division of Immunology and Allergy, School of Medicine, Ankara University, Ankara, Turkey.;1Department of Chest Diseases, Division of Immunology and Allergy, School of Medicine, Ankara University, Ankara, Turkey.;1Department of Chest Diseases, Division of Immunology and Allergy, School of Medicine, Ankara University, Ankara, Turkey.;1Department of Chest Diseases, Division of Immunology and Allergy, School of Medicine, Ankara University, Ankara, Turkey.;1Department of Chest Diseases, Division of Immunology and Allergy, School of Medicine, Ankara University, Ankara, Turkey.",
"authors": "Celebi Sozener|Zeynep|Z|;Gorgulu|Begum|B|;Mungan|Dilsad|D|;Sin|Betul Ayse|BA|;Misirligil|Zeynep|Z|;Aydin|Omur|O|;Bavbek|Sevim|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1186/s40413-018-0217-0",
"fulltext": "\n==== Front\nWorld Allergy Organ JWorld Allergy Organ JThe World Allergy Organization Journal1939-4551BioMed Central London 21710.1186/s40413-018-0217-0Original ResearchOmalizumab in the treatment of eosinophilic granulomatosis with polyangiitis (EGPA): single-center experience in 18 cases Celebi Sozener Zeynep zeynepsozener@gmail.com 1Gorgulu Begum drbegumgorgulu@gmail.com 1Mungan Dilsad dilsadmungan@gmail.com 1Sin Betul Ayse betulasin@gmail.com 1Misirligil Zeynep drmisirli@gmail.com 1Aydin Omur mdomuraydin@gmail.com 1Bavbek Sevim +90312595 65 81bavbek@medicine.ankara.edu.tr 121 0000000109409118grid.7256.6Department of Chest Diseases, Division of Immunology and Allergy, School of Medicine, Ankara University, Ankara, Turkey 2 0000000109409118grid.7256.6Division of Allergy and Clinical Immunology Department of Chest Diseases, Ankara University School of Medicine, Ankara, Turkey 3 12 2018 3 12 2018 2018 11 1 3926 7 2018 9 10 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nData are limited regarding the effectiveness of omalizumab in patients with eosinophilic granulomatosis with polyangiitis (EGPA). Our aim was to evaluate the clinical and functional effectiveness of omalizumab in patients with EGPA in long-term follow-up.\n\nMethods\nThis study was a retrospective chart review of patients with EGPA who were treated with omalizumab injections between May 2012 and April 2018. Once treatment with omalizumab was started, data were collected at various time points: baseline, the 16th week, 1st year, and annually until the last evaluation.\n\nResults\nEighteen patients (16F/2M) with a mean age of 48.61 ± 11.94 years were included. Data were available for all patients for the first year, 12 patients for the second year, 10 patients for the third year, 8 patients for the fourth year and 5 patients for the fifth year. All patients were on mean dosage of 15.77 ± 7.6 mg/day oral corticosteroid (OCS) as daily bases for mean 8.61 ± 4 years besides high-dose inhaler corticosteroid/long-acting beta agonist. Antineutrophil cytoplasmic antibodies (ANCA) were positive in 2 patients, and 8 patients were diagnosed as having vasculitis by skin biopsy, one patient had polyneuropathy, and one patient had cardiac involvement.\n\nBy considering the individual responses of patients and the level of improvement at the last evalulation, 10 (55.6%) patients responded completely, 1 responded partially, and 7 (38.9%) had no improvement. Omalizumab worked as a steroid-sparing agent in all patients and the daily OCS dose was reduced with a mean dosage of 6.28 mg/day at the end of the first year. The mean OCS reduction time for the whole group was 4 months. A reduction in asthma exacerbations/hospitalizations, improvement in forced expiratory volume in 1 second, and no decrease in the eosinophil count during treatment with omalizumab were also observed.\n\nConclusions\nOmalizumab improved asthma control in some patients with EGPA with uncontrolled asthma by reducing asthma exacerbations and oral steroid requirement. However, more data are needed before recommending widespread use of omalizumab in patients with EGPA.\n\nKeywords\nEGPAChurg-Strauss syndromeVasculitisAsthmaSevere asthmaOmalizumabAnti-IgEissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nEosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg–Strauss syndrome (CSS), is a rare systemic, small-to-medium vessel vasculitis associated with asthma, sinusitis, blood and tissue eosinophilia [1].\n\nConventional treatment of EGPA consisted of high doses of systemic steroids; however, for patients with severe or refractory diseases, immunosuppressive therapies including cyclophosphamide, azathioprine, intravenous immunglobulin (IVIG) are indicated [2]. Currently, an anti-interleukin (IL)-5 biologic agent, mepolizumab, has produced glucocorticoid reduction and protocol-defined remission in fifty perecent of patients with EGPA and has been approved by the United States Food and Drug Administration (FDA) in relapsing/refractory EGPA [2, 3].\n\nOmalizumab, as an immunoglobulin (Ig)-E targeting biologic agent, has been demonstrated to be clearly effective in the treatment of patients with severe allergic asthma [4]. Omalizumab has also been reported to benefit patients with many different conditions such as allergic bronchopulmonary aspergillosis (ABPA), chronic urticaria, atopic dermatitis, and food allergy [5]. Besides blockage of free IgE, omalizumab reduces the recruitment and activation of eosinophils and other inflammatory cells to the inflammation site through the inhibition of Th2-type immune response [6, 7]. Considering the efficacy of omalizumab in the reduction of circulating and tissue eosinophils, the drug has also been given to patients with EGPA in off-label conditions, but experience is limited and even conflicting [8–10]. In the first reported case, a three-month administration of omalizumab to a patient with EGPA resulted in significant improvement of asthma and a marked decrease in the eosinophil count [8]. A recent multicenter study with seventeen patients with EGPA suggested that omalizumab might have a corticosteroid-sparing effect in patients with EGPA with asthma and/or sinusitis, but reducing the corticosteroid dose might also increase the risk of severe EGPA flares, which raises the question of the safety of omalizumab in patients with EGPA [11]. At an established allergy and clinical immunology referral center located in the capital city of Turkey, we have been using omalizumab since 2008 for patients with severe allergic asthma [12]. We recently reported our experience with omalizumab for patients with severe non-allergic asthma and ABPA [13, 14]. We have also prescribed the drug off-label in patients with EGPA whose asthma was uncontrolled despite receiving optimal treatment including long-term systemic steroids. Therefore, considering the limited experience in such cases, we aimed to evaluate the clinical and functional effectiveness of omalizumab in patients with EGPA in real-life settings.\n\nMethods\nStudy design\nThe study was conducted as a retrospective chart review of patients with EGPA who were treated with omalizumab between May 2012 and April 2018 in Ankara University, School of Medicine, Department of Chest Diseases, Division of Clinical Immunology and Allergy. The charts were reviewed by three physicians. Details of the evaluation, time points at which the assessments were conducted, and the number of patients are given in a flowchart (Fig. 1). The local ethics committee of Ankara University, School of Medicine, approved the study (Approval number: 07–453-18) and written informed consent was obtained from all subjects.Fig. 1 A flowchart of the patients at the time points\n\n\n\nSubjects\nThe diagnosis of asthma was made by using the clinical history and by demonstrating objective measures of reversible airway obstruction. In the diagnosis of EGPA, the criteria defined by the American College of Rheumatology (ACR) were used [15]. Accordingly, the diagnosis of EGPA is based on the presence of four or more of the following six findings at the time of the diagnosis: asthma, > 10% eosinophilia in a differential white blood cell count, mononeuropathy or polyneuropathy due to a systemic vasculitis, paranasal sinus abnormalities, migratory or transient pulmonary opacities, and histologic evidence of extravascular eosinophils in a biopsy specimen.\n\nPatients with EGPA with at least 2 asthma exacerbations despite high-dose inhaled corticosteroid/long-acting beta agonist (ICS/LABA) treatment, and frequent or continuous oral corticosteroid (OCS) requirement with severe adverse effects were considered as candidates for omalizumab treatment. The omalizumab (Xolair, Genentech, Novartis, Sweden) dose was calculated from the chart according to the patients’ total IgE level and weight. Twelve patients received 150 mg omalizumab/month(m), 3 patients recieved 300 mg/m, 1 had 600 mg/m, one received 450 mg every 2 weeks (w), and 1 had 150 mg/2w; no dosing adjustments were made during the treatment period. Fourteen patients were still continuing omalizumab treatment and under regular follow-up in our department; 5 of whom use azathioprine as an add-on treatment. For 4 patients (patient # 2, 3, 14, 17) outside of these 14, omalizumab was discontiuned because of pregnancy (n = 1), gastric metaplasia (n = 2), and myalgia (n = 1), respectively.\n\nMeasurements\nDemographic features and clinical characteristics were recorded from the patients’ files. An asthma control test (ACT) and pulmonary function tests (PFT) (ZAN 100; nSpire, Oberthulba, Germany) (forced expiratory volume in 1 s [FEV1], forced vital capacity [FVC] and FEV1: FVC ratio) were routinely performed in all patients at every omalizumab visit. ICS doses were calculated as beclomethasone dipropionate (BDP), chlorofluorocarbon equivalent according to the Global Initiative for Asthma guidelines [16]. All patients were taking methylprednisolone as an OCS continuously and the doses given at the time points were calculated as a mean daily value.\n\nOutcomes\nAfter treatment with omalizumab was started, data including PFTs, ACT scores, eosinophil count/percentage, and medications (OCS, ICS, LABA, and other controllers) for asthma were collected at baseline, the sixteenth week, first year, and annually thereafter. Outcome measurements are detailed in Fig. 1. The number of asthma exacerbations and hospitalizations for 1 year prior to omalizumab and yearly after starting omalizumab were also recorded.\n\nThe effectiveness of omalizumab treatment was determined according to asthma symptoms, decreases in mean daily OCS dosage and/or doses of ICS, LABA, and improvements in PFTs, decreases in asthma exacerbations, and in emergency visits and hospitalizations, which were assessed by at least 3 physicians who were all authors of this manuscript. Patients were classified as complete responders, partial responders, and refractory disease. Complete response was defined as the absence of asthma and/or ear, nose, and throat (ENT) exacerbations with a prednisone dosage of ≤7.5 mg/day, and partial response was defined as the absence of asthma and/or ENT exacerbations with a prednisone dosage of > 7.5 mg/day. Refractory disease was defined as the absence of improvement with omalizumab, i.e., presence of asthma and/or ENT exacerbations with a prednisone dosage of 7.5 mg/day. Relapsing disease was defined as initial improvement with complete response or partial response followed by disease flare. These definitions were formulated according to the recommendations of the EGPA Task Force and EULAR experts and approved for use in routine clinical practice [11].\n\nStatistical analysis\nThe statistical analysis was performed using SPSS version 20.0 (SPSS Inc., Chicago, IL, USA). Numeric values with normal dispersion are expressed as means±SD, and non-normally distributed variables are given as median values (min–max). Categorical variables are given as n (percentage). Time point comparisons were performed using repeated measures for variables with normal distribution and the Wilcoxon signed-rank test or Friedman’s test for variables with non-normal distribution. All directional p values were two-tailed and significance was assigned to values lower than 0.05.\n\nResults\nDemographics and diseases characteristics\nEighteen patients (16 women and 2 men) with a mean age of 48.61 ± 11.94 years were included. Patients were followed up regularly and had complete healthcare coverage. Data were available for all patients for the first year, 12 patients for the second year, 10 patients for the third year, eight patients for the fourth year, and 5 patients for the fifth year. The mean EGPA duration was 7.4 ± 4.3 years and the mean elapsed time between the diagnosis of asthma and diagnosis of EGPA was 8.5 ± 8.3 years. All patients were on high-dose ICS (min: 1000 μg BDP/day, max: 2000 μg, BDP/day) plus LABA and OCS. The baseline demographic findings and clinical characteristics of each subject in the study group are shown in Table 1. All patients in the study group used OCS as methylprednisolone at a mean dosage of 15.77 ± 7.6 mg/day (min: 4 mg/day, max: 60 mg/day) with a mean period of 8.61 ± 4 years (min: 4 years, max: 18 years). Nearly half of the patients were atopic (44.8%), 83.3% had sinusitis, and 33.3% had nasal polyposis. ANCA was only positive in 2 patients (patients #6, 11), and 8 patients (#3, 5, 9, 10, 12, 13, 14, 18) were diagnosed as having vasculitis via skin biopsy. Patient #15 had polyneuropathy and patient #17 had cardiac involvement.Table 1 Demographic and disease characteristics\n\nPatient/ sex/ Age\tDuration of asthma (yr)\tDuration of EGPA(yr)\tTotal IgE kU/L\tEosinophil cells/mm3, (%)\tRadiologic Findings\tVasculitis\tPolyeuropathy\tCardiac involvement\tANCA\tAzathioprine\tOmalizumab\nDose (mg) / treatment duration (m)\tResponse\t\nParanasal CT\tTorax CT\t\n1.F/63\t27\t8\t46.9\t1700 (21.5)\tPansinusitis\tMigratory ground glass opacities, bronchial wall thickness bronchiectasis\tNo\tNo\tNo\tNeg\tNo\t150/m/48 m\tComplete\t\n2.F/25\t5\t4\t865\t1800 (20.2)\tPansinusitis, nasal polyposis\tGround glass opacities, bronchial wall thickness\tNo\tNo\tNo\tNeg\tNo\t450/2w/15 m\nStopped\tNone\t\n3.F/52\t24\t21\t11.8\t13,480 (60)\tFronthoetmoid sinusitis, nasal polyposis\tGround glass opacities, bronchial wall thickness\tYes\tNo\tNo\tNeg\tNo\t150/m/18 m\nStopped\tNone\t\n4.F/44\t11\t8\t47.9\t3300 (27)\tPansinusitis\tTransient ground glass opacities, bronchial wall thickness, milimetric nodules\tNo\tNo\tNo\tNeg\tNo\t150/m/44 m\tComplete\t\n5.F/47\t12\t4\t134\t1000 (15.9)\tPansinusitis\tGround glass opacities\tYes\tNo\tNo\tNeg\tNo\t300/m/39 m\tComplete\t\n6.F/67\t22\t8\t17.8\t8400 (53)\tPansinusitis\tTransient ground glass opacities, milmetric nodules\tNo\tYes\tNo\tPos\tNo\t150/m/62 m\tComplete\t\n7.F/62\t19\t4\t114\t1200 (20.3)\tPansinusitis\tTransient ground glass opacities, bronchial wall thickness, mucous impactions\tNo\tNo\tNo\tNeg\tNo\t150/m/48 m\tComplete\t\n8.M/36\t7\t7\t108\t2900 (26)\tPansinusitis\tPeribronchial thickness, ground glass opacities dominant at left upper lobe, focal patchy infiltrations\tNo\tNo\tNo\tNeg\tNo\t150/m/48 m\tComplete\t\n9.F/50\t10\t10\t41\t2500 (24.9)\tMaxiller sinusitis, nasal poliposis\tMucous impaction, bronchial wall thickness, bronchiectasis\tYes\tYes\tYes\tNeg\tYes\t150/m/42 m\tNone\t\n10.F/40\t11\t8\t142\t1100 (14)\tPansinusitis\tSubpleural ground glass opacification, pulmonary nodules\tYes\tNo\tNo\tNeg\tYes\t150/m/60 m\tPartial\t\n11.F/52\t19\t3.5\t543\t13,600 (52.4)\tNasal poliposis\tBronchial wall thickness, sublobuler patchy infiltrations\tNo\tNo\tNo\tPos\tNo\t600/m/27 m\tNone\t\n12.M/38\t17\t11\t126\t8900 (47.5)\tPansinusitis\tParanchimal nodules, bronchial wall thickness\tYes\tNo\tNo\tNeg\tNo\t300/m/70 m\tComplete\t\n13.F/61\t36\t7\t186\t2700 (20.7)\tPansinusitis\tMigratory ground glass opasities, nodules and mucus impaction\tYes\tNo\tNo\tNeg\tNo\t300/m/64 m\tNone\t\n14.F/45\t21\t8\t321\t2200 (21.5)\tChronic sinusitis\tBilateral bronchial wall thickness\tYes\tYes\tNo\tNeg\tYes\t300/2w/14 m\nStopped\tNone\t\n15.F/46\t22\t4\t46\t3800 (28.8)\tFrontoetmoid sinusitis, nasal polipozis\tTransient ground glass opacities\tNo\tYes\tNo\tNeg\tNo\t150/m/18 m\tComplete\t\n16.F/37\t9\t5\t87.5\t2700 (36.5)\tPansinusitis, nasal polyposis\tTransient ground glass opacities\tNo\tNo\tNo\tNeg\tYes\t150/m/20 m\tNone\t\n17.F/50\t12\t12\t29\t5070 (35.9)\tPan sinusitis\tBronchial wall thickness\tNo\tNo\tYes\tNeg\tNo\t150/m/17 m\nStopped\tComplete\t\n18.F/28\t5\t2\t71\t1440 (15.1)\tPansinusitis\tPeribronchioler ground glass opasities, micronodules\tYes\tNo\tNo\tNeg\tYes\t150/m/18 m\tComplete\t\n\n\nThe most frequently observed radiologic sign in patients with EGPA consisted of transient and often migratory ground-glass lung opacities [17], and these were seen in 72% (n = 13) of the patients in our group. Other relatively common findings were the presence of airway involvement consisting of bronchial dilatation, bronchial wall thickening, and small peribronchial and centrilobular nodules related to eosinophilic infiltration of the bronchial wall and asthma [17], and these were seen in 11% (n = 2), 55.5% (n = 10), and 33.3% (n = 6) of patients, respectively.\n\nAssessment of treatment response\nIn general, considering the individual responses of the patients and the level of improvement at the last evalulation; 10 patients (55.6%) responded completely, one patient responded partially, and seven patients (38.9%) had no improvement. Approximately one-third of the patients received another immunosuppressive agent in addition to prednisone. The individual and the mean OCS dosage were significantly decreased at all time points and prednisone dosages were able to be tapered from a mean of 15.7 mg/day to 8.05 mg/day after 4 months (p = 0.001), to 6.28 mg/day at the first year (p < 0.0001) (n = 18). The dosages continued at this level for the second year of the study, p = 0.001 (n = 12), and then tapered again to 5.8 mg/day, 4.7 mg/day, and 4.9 mg/day at the end of the third p = 0.002 (n = 10), 4th p < 0.0001 (n = 8), and the fifth years p = 0.03 (n = 5) (Figs. 2 and 3). Only in one patient, OCS was discontinued after omalizumab therapy. The mean OCS reduction time for the entire group was 4 months (min 4, max 36 months).Fig. 2 Decrease in the mean OCS dosage from baseline at the time points\n\nFig. 3 Mean OCS dosage of the patients at the time points\n\n\n\nThe mean ACT score was increased at all timepoints compared with the baseline score (p = 0.03 for sixteenth week, n = 18; p = 0.07 for first year, n = 18; p = 0.05 for second year, n = 12; p = 0.15 for 3rd third year, n = 10; p = 0.01 for fourth year, n = 8; p = 0.06 for fifth year, n = 5).\n\nThe baseline exacerbation rate was 3.56 ± 2.33 times per year (range, 1–10), and the hospitalization rate was 1.61 ± 1.72 times per year (range, 0–6) for 1 year prior to omalizumab, and both were significantly decreased at the first year (n = 18; p < 0.0001, p = 0.005), second year (n = 12; p = 0.01, p = 0.009), third year (n = 10; p = 0.006, p = 0.001), fourth year (n = 8; p = 0.03, p = 0.01), and fifth year (n = 5; p = 0.01, p = 0.04) (Fig. 4a, b).Fig. 4 a The number of exacerbations per year for each patient b The mean exacerbation/hospitalization frequency per year, one year prior to omalizumab and annually thereafter\n\n\n\nAccording to the pulmonary function parameters, a significant increase in FEV1%, mL was observed only at the sixteenth week and first year vs. baseline in the entire group (p = 0.01, p = 0.08, p = 0.004, p = 0.01, respectively).\n\nTotal eosinophil numbers at the diagnosis of EGPA were higher in the non-responder group than in responder patients, although it did not reach statistical significance (5564 ± 5454 cells/mm3 vs. 3747 ± 2897 cells/mm3). Eosinophil numbers decreased among responders when we compared the data between the basal numbers of eosinophil and those of the first, second, and third year of follow-up (584 ± 304 cells/mm3, 508 ± 204 cells/mm3, 458 ± 194 cells/mm3, and 424 ± 93 cells/mm3, respectively). In contrast, there was a slight increase in eosinophil numbers in non-responders during the same follow-up period (395 ± 342 cells/mm3, 497 ± 214 cells/mm3, 412 ± 117 cells/mm3, and 667 ± 266 cells/mm3, respectively). We could not find a statistical significance either in increases or in decreases in the eosinophil counts within the groups because the numbers of patients were small.\n\nConsidering the individual responses of the patients: Patients # 1, 4, 5, 6, 7, 8, 12, 15, 17, and 18 were considered as complete responders in the last year and provided this response with under ≤7.5 mg prednisolone doses. Patient #1 had 2 exacerbations in the first 2 years and then no exacerbation in the following 2 years. Patients #6–7-12 also used ≤7.5 mg/day OCS dosages and had controlled disease without exacerbations or hospitalizations in last year of the omalizumab treatment but all had exacerbations and/or hospitalizations at some of the time points. Other patients had no exacerbations and hospitalizations after omalizumab was started and their ACT scores were increased at all time points. Patient #4’s OCS was stopped at the fourth year but was then started again at 4 mg/day dosage according to the elevation in eosinophil count. Patients #5, 12 and 18 had vasculitis. Patient #18’s OCS was stopped after omalizumab was started, but azathioprine was added becouse of vasculitis exacerbation in the first year of omalizumab treatment.\n\nPatient #10 was considered a partial responder without exacerbation and hospitalization in the last year but they provided this response with under > 7.5 mg/day prednisolone dosage.\n\nPatients #2, 3, 9, 11, 13, 14, and 16 were considered as non-responders. They all had exacerbations and/or hospitalizations (except patient #13) at all time points. In patient #13, disease control was provided nearly 2 years after beginning omalizumab treatment but she had 2 exacerbations in the fifth year of the therapy. Her OCS dose was changed between 7 and 4 mg/day dosages. These patients (except #2, 11, and 16), had vasculitis in the skin biopsies, and patient #11 had ANCA positivity. Patients #9 and 14 were under a high dosage of OCS (10 mg/day, 8 mg/day, respectively) and add-on azathioprine treatment. Patient 16 also took azathioprine as add-on to a 5.7 mg/day OCS dosage. Patient #2 had one exacerbation under a 7 mg/day prednisolone dosage but omalizumab was not continued because of pregnancy at the end of 15 months. Patient #3 had two exacerbations and one hospitalization under 4 mg/day OCS but omalizumab was not continued because of gastric metaplasia.\n\nIn the comparison of responders and non-responders, patients with complete response had shorter asthma and EGPA disease duration but had been taking omalizumab for longer than the non-responder patients (15.4 ± 7.1 vs. 17.71 ± 10.6 years; 6.8 ± 3.2 vs. 8.3 ± 6 years; 42.6 ± 19 vs. 28.57 ± 18.37 months, respectively). They had lower C-reactive protein (CRP) and sedimentation levels and lower eosinophil percentages than the patients with no response (2.2 ± 3.2 vs. 5.1 ± 5.9; 12.3 ± 7 vs. 19.7 ± 10; 29.1 ± 12.7% vs. 33 ± 16% respectively). Moreover, non-responder patients were using OCS for longer than the patients with complete response (10.4 ± 5.4 years vs. 7.3 ± 2.4 years). In non-responders, the number of patients diagnosed as having vasculitis was higher than among complete responders [4/7 (57%), 3/10 (30%), respectively]; all these data were statistically insignificant.\n\nExcept for 3 cases, omalizumab was well tolerated and no serious adverse events were observed. In patient #3 and patient #14, omalizumab was discontinued because of gastric metaplasia at 18 and 15 months after initiation, respectively. Patient #17 developed myalgia; EGPA involvement was excluded after neurologic and electromyographic examination, thus this was accepted as an adverse event and omalizumab was stopped at 17 months after initiation.\n\nDiscussion\nOur case series demonstrated that treatment with omalizumab in some patients with EGPA was effective in improving asthma symptoms and reducing OCS requirement, along with reducing asthma exacerbations and hospitalizations. There was also an improvement in functional parameters measured using FEV1. Therapeutic response appeared to be independent of asthma and EGPA diseases duration, duration of omalizumab OCS use, having vasculitis, CRP levels, sedimentation levels, and eosinophil numbers, but we could not analyze which patient characteristics would predict omalizumab responsiveness due to the small number of patients.\n\nEGPA is presently defined as a syndrome consisting of 3 components; hypereosinophilic syndrome, ANCA-associated vasculitic manifestations, and asthma/ rhinosinusitis. Eosinophils are abundant and sustained both in the blood and in tissue and possibly play a central and/or additional role in the development of EGPA. Asthma and rhinosinusitis are the main features of the disease and almost all patients with EGPA have a history of nasal involvement and late-onset asthma [2, 18, 19]. As it was pointed out in the current study, the 3 components of EGPA may require separate approaches for their management because persistent eosinophilic inflammation in the upper and lower airways has been documented in patients with EGPA, although they were receiving low-dose oral corticosteroids and immunomodulating drugs and were in remission from systemic manifestations of the disease [1, 20].\n\nGiven the antiallergic and anti-inflammatory effectiveness of omalizumab, including the reduction of circulating and tissue eosinophils, it was proposed that omalizumab could be used to decrease eosinophilic activity resulting in asthma control in patients with EGPA [6, 7, 18]. Hovewer, there are limited data in single case reports/case series regarding the efficacy of omalizumab in patients with EGPA [8, 9, 21–23]. In the first case, the same group presented 3 months’ and 1 years’ administration of omalizumab. The patient showed significant improvement of asthma symptoms and a marked improvement in eosinophilia in both time periods [8, 22, 23]. Later, in the first documented pediatric case with EGPA, omalizumab treatment was demonstrated to control asthma as well as gastrointestinal symptoms [9]. There are recent data from a multicenter retrospective study including 17 patients with EGPA who received omalizumab as adjunctive therapy for refractory and/or relapsing asthmatic and/or sinonasal manifestations. After a median follow-up of 22 months, 6 (35%) patients achieved a complete response, 5 patients (30%) achieved a partial response, and 6 patients (35%) had no improvement based on the defined response criteria [11]. The median prednisone dosage decreased from 16 mg/day to 10 mg/day after 3 months of therapy and this reduction continued during the 12 months of follow-up whereas no significant difference was noted for the eosinophil count. Similarly, the number of asthma exacerbations also decreased, and the FEV1 value increased. The authors concluded that in EGPA patients with asthmatic and/or sinonasal manifestations, omalizumab had mild efficacy for the treatment of asthma and/or ENT symptoms [11]. Our data were quite similar to the results reported in that study in terms of responder and non-responder rates, reductions in mean dosage of daily OCS, reductions in asthma exacerbations, improvements in FEV1, and no decrease in eosinophil counts in whole group. However, we observed a tendency for a decrease in blood eosinophil numbers among omalizumab responder patients. In contrast, there was a slight increase in eosinophil numbers in non-responders during the same follow-up period. The responsiveness to omalizumab might be related to the reduction in the numbers of eosinophils, and non-responsiveness may be related with the lack of efficacy of omalizumab in the extensive eosinophilic infiltration derived from the Th2 response and different sources (1). However, we could not found a statistical significance either in increases or in decreases in the eosinophil counts within the groups. The limited number of patients prevents us from speculating on that issue. The immunopathogenesis of EGPA is still poorly understood, and large and long-term studies would be appropriate to determine the mechanistic role of omalizumab in patients with EGPA.\n\nSystemic steroids are the cornerstone of EGPA treatment. They are combined with immune-suppressants such as cyclophosphamide and azathioprine, when necessary, as steroid-sparing agents. Persistent asthma is a major problem for patients with EGPA and exacerbations can occur repeatedly throughout the disease course, especially when the prednisone dosage is lower than 10 mg/day, thus leading to the concern for steroid-associated adverse reactions [1, 2, 19, 24–26]. A glucocorticoid-sparing effect of omalizumab has been reported in patients with severe allergic asthma [4], patients with nonallergic asthma, and ABPA [5, 13, 14]. In our trial, all patients were on mean dosage of 15.77 ± 7.6 mg methylprednisolone as daily bases for a mean 8.61 ± 4 years besides high-dose ICS-LABA and other controller medications for the management of EGPA. They had osteoporosis, obesity, diabetes mellitus, and steroid acnes as common steroid-induced adverse effects. As reported previously [11], omalizumab seemed to work as a steroid-sparing agent in all patients in our group, and the daily OCS dosage was reduced to 6.28 mg/day at the end of the first year. This decrease in the prednisolone dosage is a substantial clinical benefit when the adverse effects of long-term steroid treatment are considered. In 4 out of 8 patients with vasculitis, vasculitis flared when the steroid dosage was reduced. Azathioprine was added to omalizumab in only 5 patients as a glucocorticoid-sparing agent or treatment of cutaneous vasculitis.\n\nThe diagnosis of EGPA can be challenging because there is a lack of agreement on the diagnostic criteria, which usually relies on the characteristics of clinical manifestations and ANCA when present. We used the diagnostic criteria of ACR, the most commonly used criteria because they have been used in previous studies evaluating the effect of omalizumab in EGPA [8, 9, 11, 15]. There may be 2 EGPA phenotypes depending on the presence or absence of ANCA: The vasculitic and ANCA-positive phenotype, characterized by small vessel vasculitic features such as purpura, mono neuritis multiplex, glomerulonephritis, and the eosinophilic, ANCA-negative phenotype, characterized by peripheral eosinophilia and eosinophilic tissue infiltration (e.g., pulmonary infiltrates, cardiomyopathy) [2, 17, 19, 24, 27–29]. Our study group mostly comprised ANCA-negative patients, with only 2 ANCA-positive subjects (#6, 11). One of these ANCA-positive patients also had polyneuropathy in addition to pulmonary involvement. All ANCA-negative patients had pulmonary involvement and half had cutaneusvasculitis in the skin biopsy, 3 had polyneuropathy and two had cardiac involvement. Skin was the second most common organ involved in the EGPA presentation in our group. EGPA which is ANCA positive is predominantly in vasculitic from whereas eosinophilic tissue involvement is predominant in ANCA negative ones. Confirming this with future studies may provide inddividualization of treatment [24, 28, 30]. In our series, none of the patients with vasculitis had ANCA positivity; however, the number of subjects in our study group was limited.\n\nClinically, 3 distinct phases in the development of EGPA have been shown. These include (a) the prodromal period, which may persist for several years, consisting of asthma and allergic rhinitis; (b) a phase of marked peripheral blood eosinophilia and eosinophil tissue infiltrates; (c) and a life-threatening vasculitic phase [2, 31]. The first 2 prevasculitic phases are characterized by marked tissue eosinophilia, which manifests in the lung as eosinophilic pneumonia [32]. In our study, 8 patients had vasculitis shown by skin biopsy.The remaining patients were in the pre-vasculitic phases. Accordingly, migratory infiltration indicating pulmonary eosinophilic involvement was demonstrated using high-resolution computed tomography (HRCT) in all patients, along with increased peripheral eosinophilia, suggesting that most of our patients were in pre vasculitic phase.\n\nThe study had limitations such as the retrospective nature and the small number of subjects without a control group. However, there are only case reports and case series reported and only one multicenter study with 17 patients with EGPA and no controls [11]. To the best of our knowledge, as a single center, we had the largest number of patients with EGPA. Furthermore, off-label use of omalizumab in such patients is a limiting factor for conducting studies with larger numbers of patients. We used the patients’ own data before treatment with omalizumab as a comparison. However, incomplete data may have been obtained regarding doses of OCS due to self-managing dosing by patients and/or concomitant primary care prescribing and further supplies from admissions at other hospitals and/or emergency units. For the pre-omalizumab course, we made assumptions regarding the typical use of steroids for exacerbations in our country, which starts with a 40 mg dose of methyl prednisolone and the dose is then tapered to 8 mg at 3-day intervals for 15 days, when we could not obtain clear information. We believe that we had more accurate data about the doses of OCS because the patients were monitored more closely during the post-omalizumab period.\n\nOn the other hand, the study had some advantages such as the long follow-up period, which had a mean of 39 months. The longest follow up in the literature was a median 22 months in the multicenter study [11]. For the remaining cases series, data were reported for 3–12 months of treatment with omalizumab [8–10, 33]. Therefore, we believe that it is important to see the long-term effects of omalizumab in this disease, which has complex underlying immunopathogenesis.\n\nConclusions\nEGPA is a heterogeneous disease with several endotypes. This study indicates that omalizumab improved asthma control in some patients with EGPA with uncontrolled asthma by reducing asthma exacerbations and doses of oral steroids. However, more data are needed before recommending the use of omalizumab in patients with EGPA.\n\nAbbreviations\nABPAAllergic bronchopulmonary aspergillosis\n\nACRAmerican Collage of Rheumatology\n\nACTAsthma control test\n\nANCAAntineutrophil cytoplasmic antibodies\n\nBDPBeclomethasone dipropionate\n\nCRPC-reactive protein\n\nCSSChurg–Strauss syndrome\n\nEGPAEosinophilic granulomatosis with polyangiitis\n\nENTEar, nose, and throat\n\nFDAFood and Drug Administration EULAR: European League Against Rheumatism\n\nFEV1Forced expiratory volume in 1 s\n\nFVCForced vital capacity\n\nHRCTHigh-resolution computed tomography\n\nICS/LABAInhaled corticosteroid/long-acting beta agonist\n\nIgImmunglobulin\n\nIVIGIntravenous immunglobulin\n\nmMonth\n\nOCSOral corticosteroid\n\nPFTpulmonary function tests\n\nwWeek\n\nAcknowledgements\nNot applicable.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nData are available as printed material and as electronic files in the hospital computer.\n\nPatients’ data protection\nConfidentiality of data. The authors declare that they have followed the protocols of their work center on the publication of patient data and that the patients included in the study have received sufficient information and given their informed consent in writing to participate in the study.\n\nAuthors’ contributions\nAll authors are involved in the collection of the data and the writing of the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThe local ethics committee of Ankara University, School of Medicine, approved the study (Approval number: 07–453-18) and written informed consent was obtained from all subjects.\n\nConsent for publication\nThe authors declare that they have followed the protocols of their work centre on the publication of patient data and that the patients included in the study received sufficient information and gave their informed consent in writing to participate in that study.\n\nCompeting interests\nSB and DM are advisory Board Member of Xolair/Novartis/Turkey. The author 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. Raffray L Guillevin L Treatment with eosinophilic granulomatosis with polyangiitis: a review Drugs 2018 78 809 821 10.1007/s40265-018-0920-8 \n2. Greco A Rizzo MI De Virgilio A Gallo A Fusconi M Ruoppolo G Altissimi G De Vincentiis M Churg-Strauss syndrome Autoimmun Rev 2015 14 4 341 348 10.1016/j.autrev.2014.12.004 25500434 \n3. Wechsler ME Akuthota P Jayne D Khoury P Klion A Langford CA Merkel PA Moosig F Specks U Cid MC Luqmani R Brown J Mallett S Philipson R Yancey SW Steinfeld J Weller PF Gleich GJ EGPA Mepolizumab study team. Mepolizumab or placebo for eosinophilic granulomatosis with Polyangiitis N Engl J Med 2017 376 20 1921 1932 10.1056/NEJMoa1702079 28514601 \n4. Humbert M Beasley R Ayres J Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE Allergy 2005 60 309 316 10.1111/j.1398-9995.2004.00772.x 15679715 \n5. Stokes JR Casal TB The use of anti-IgE therapy beyond allergic asthma J Allergy Clin Immunol Pract 2015 3 162 166 10.1016/j.jaip.2014.10.010 25609342 \n6. Noga O Hanf G Brachmann I Klucken AC Kleine-Tebbe J Rosseau S Effect of omalizumab treatment on peripheral eosinophil and T-lymphocyte function in patients with allergic asthma J Allergy Clin Immunol 2006 117 1493 1499 10.1016/j.jaci.2006.02.028 16751018 \n7. Djukanovic R Wilson SJ Kraft M Jarjour NN Steel M Chung KF Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma Am J Resp Crit Care Med 2004 170 583 593 10.1164/rccm.200312-1651OC 15172898 \n8. Giavina-Bianchi P Giavina-Bianchi M Agondi R Kalil J Three months’ administration of anti-IgE to a patient with Churg-Strauss syndrome J Allergy Clin Immunol 2007 119 5 1279 10.1016/j.jaci.2007.01.041 17349685 \n9. Iglesias E Camacho Lovillo M Delgado Pecellın I Lirola Cruz MJ Falcon Neyra MD Salazar Quero JC Successful management of Churg-Strauss syndrome using omalizumab as adjuvant immunomodulatory therapy: first documented pediatric case Pediatr Pulmonol 2014 49 E78 E81 10.1002/ppul.22884 24136903 \n10. Ruppert AM Averous G Stanciu D Deroide N Riehm S Poindron V Development of Churg-Strauss syndrome with controlled asthma during omalizumab treatment J Allergy Clin Immunol 2008 121 253 254 10.1016/j.jaci.2007.10.040 18206510 \n11. Jachiet M Samson M Cottin V Kahn JE Le Guenno G Bonniaud P Devilliers H Bouillet L Gondouin A Makhlouf F Meaux-Ruault N Gil H Bienvenu B Coste A Groh M Giraud V Dominique S Godeau B Puéchal X Khouatra C Ruivard M Le Jeunne C Mouthon L Guillevin L Terrier B French Vasculitis study group. Anti-IgE monoclonal antibody (Omalizumab) in refractory and relapsing eosinophilic granulomatosis with Polyangiitis (Churg-Strauss): data on seventeen patients Arthritis Rheumatol 2016 68 9 2274 2282 10.1002/art.39663 26946346 \n12. Bavbek S Aydın O Kepil Özdemir S Yılmaz I Celik GE Demirel YS Mungan D Sin B Kurşun N Mısırlıgil Z Therapy with omalizumab in patients with severe persistent allergic asthma: a reallife data in Turkey Tuberk Toraks 2010 58 4 425 434 21341120 \n13. Celebi Sözener Z Aydın Ö Mısırlıgil Z Mungan D Demirel YS Çelik GE Sin BA Bavbek S Omalizumab in non-allergic asthma: a report of 13 cases J Asthma 2017 11 8 1 \n14. Aydın Ö Sözener ZÇ Soyyiğit Ş Kendirlinan R Gençtürk Z Mısırlıgil Z Mungan D Sin BA Demirel YS Çelik GE Bavbek S Omalizumab in the treatment of allergic bronchopulmonary aspergillosis: one center’s experience with 14 cases Allergy Asthma Proc 2015 36 6 500 493 10.2500/aap.2015.36.3909 \n15. Masi AT Hunder GG Lie JT The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis) Arthritis Rheum 1990 33 1094 1100 10.1002/art.1780330806 2202307 \n16. Global Initiative for Asthma (GINA) Global Strategy for Asthma Management and Prevention 2018 \n17. Feragalli B Mantini C Sperandeo M Galluzzo M Belcaro G Tartaro A The lung in systemic vasculitis: radiological patterns and differential diagnosis Br J Radiol 2016 89 1061 20150992 10.1259/bjr.20150992 26876879 \n18. Seo P Eosinophilic granulomatosis with Polyangiitis: challenges and opportunities J Allergy Clin Immunol Pract 2016 4 3 520 521 10.1016/j.jaip.2016.03.019 27157939 \n19. Pagnoux C Updates in ANCA-associated vasculitis Eur J Rheumatol 2016 3 122 133 10.5152/eurjrheum.2015.0043 27733943 \n20. Latorre M Baldini C Seccia V Pepe P Novelli F Celi A Bacci E Cianchetti S Dente FL Bombardieri S Paggiaro P Asthma control and airway inflammation in patients with eosinophilic granulomatosis with Polyangiitis J Allergy Clin Immunol Pract 2016 4 3 512 519 10.1016/j.jaip.2015.12.014 26883543 \n21. Spina MF Miadonna A Role of omalizumab and steroids in Churg-Strauss syndrome J Allergy Clin Immunol 2009 124 600 601 10.1016/j.jaci.2009.05.023 \n22. Giavina-Bianchi P Giavina-Bianchi M Agondi R Kalil J Administration of anti-IgE to a Churg-Strauss syndrome patient Int Arch Allergy Immunol 2007 144 155 158 10.1159/000103228 17536214 \n23. Giavina-Bianchi P Agondi R Kalil J One year administration of anti-IgE to a Churg-Strauss syndrome patient Int Arch Allergy Immunol 2008 146 176 10.1159/000113524 18204287 \n24. Pagnoux C Guilpain P Guillevin L Churg-Strauss syndrome Curr Opin Rheumatol 2007 19 1 25 32 10.1097/BOR.0b013e3280119854 17143092 \n25. Groh M Pagnoux C Guillevin L Eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome): where are we now? Eur Respir J 2015 46 5 1255 1258 10.1183/13993003.00963-2015 26521277 \n26. Groh M Pagnoux C Baldini C Bel E Bottero P Cottin V Dalhoff K Dunogué B Gross W Holle J Humbert M Jayne D Jennette JC Lazor R Mahr A Merkel PA Mouthon L Sinico RA Specks U Vaglio A Wechsler ME Cordier JF Guillevin L Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA) consensus task force recommendations for evaluation and management Eur J Intern Med 2015 26 7 545 553 10.1016/j.ejim.2015.04.022 25971154 \n27. Gioffredi A Maritati F Oliva E Buzio C Eosinophilic granulomatosis with polyangiitis: an overview Front Immunol 2014 5 549 10.3389/fimmu.2014.00549 25404930 \n28. Pagnoux C Guillevin L Churg-Strauss syndrome: evidence for disease subtypes? Curr Opin Rheumatol 2010 22 1 21 28 10.1097/BOR.0b013e328333390b 19851111 \n29. Jennette JC Overview of the 2012 revised international Chapel Hill consensus conference nomenclature of vasculitides Clin Exp Nephrol 2013 17 603 606 10.1007/s10157-013-0869-6 24072416 \n30. Dunogue B Pagnoux C Guillevin L Churg-Strauss syndrome: clinical symptoms, complementary investigations, prognosis and utcome, and treatment Semin Respir Crit Care Med 2011 32 298 309 10.1055/s-0031-1279826 21674415 \n31. Kim YK Lee KS Chung MP Han J Chong S Chung MJ Pulmonary involvement in Churg–Strauss syndrome: an analysis of CT, clinical, and pathologic findings Eur Radiol 2007 17 3157 3165 10.1007/s00330-007-0700-4 17605012 \n32. Silva CI M¨uller NL, Fujimoto K, Johkoh T, Ajzen SA, Churg a. Churg–Strauss syndrome: high resolution CT and pathologic findings J Thorac Imaging 2005 20 80 74 10.1097/01.rti.0000155268.00125.de \n33. Cazzola M Mura M Segreti A Mattei MA Rogliani P Eosinophilic pneumonia in an asthmatic patient treated with omalizumab therapy: forme-fruste of Churg-Strauss syndrome? Allergy 2009 64 1389 1390 10.1111/j.1398-9995.2009.02061.x 19392997\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1939-4551",
"issue": "11(1)",
"journal": "The World Allergy Organization journal",
"keywords": "Anti-IgE; Asthma; Churg-Strauss syndrome; EGPA; Omalizumab; Severe asthma; Vasculitis",
"medline_ta": "World Allergy Organ J",
"mesh_terms": null,
"nlm_unique_id": "101481283",
"other_id": null,
"pages": "39",
"pmc": null,
"pmid": "30524647",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "27157939;17605012;24072416;25609342;26883543;25971154;28514601;19631973;27733943;21341120;25404930;26534756;17536214;18204287;15172898;19851111;24136903;26876879;21674415;26521277;19392997;15679715;17349685;17143092;2202307;16751018;25500434;29766394;26946346;15818205;18206510",
"title": "Omalizumab in the treatment of eosinophilic granulomatosis with polyangiitis (EGPA): single-center experience in 18 cases.",
"title_normalized": "omalizumab in the treatment of eosinophilic granulomatosis with polyangiitis egpa single center experience in 18 cases"
} | [
{
"companynumb": "TR-ROCHE-2259880",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BECLOMETHASONE"
},
"drugadditional": "3",
"d... |
{
"abstract": "The fixed drug eruption is a non-immediate hypersensitivity reaction to drug, characterized by recurrent erythematous or violaceous, rounded, well-defined border plaques, which always appear in the same location every time the culprit drug is administered. The usual practice is to avoid the drug involved and to use a structurally different drug. However, there are situations in which there is no safe and effective therapy. In such situations, desensitization is the only option. We describe the case of a patient who presented fixed eruption due to sulfamethoxazole-trimethoprim, who underwent successful desensitization, but required a repeat procedure twice due to relapse after inadvertent full-dose reintroduction. In non-immediate hypersensitivity reaction to drug, the indication is controversial and there is no technical standardization. Furthermore, the time at which such tolerance is lost after discontinuing the drug involved is unknown. In severe non-immediate reactions of types II and III, desensitization is contraindicated. The patient underwent desensitisation to sulfamethoxazole-trimethoprim three times - the first with recurrence of lesions and the second and third without manifestations, all concluded successfully and with no premedication.",
"affiliations": "Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.;Faculdade Israelita de Ciências da Saúde Albert Einstein, São Paulo, SP, Brazil.;Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.;Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.;Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.;Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.",
"authors": "Pereira|Amanda Rocha Firmino|ARF|0000-0003-1536-5291;Aun|Marcelo Vivolo|MV|0000-0001-9882-5200;Kelmann|Nathália Coelho Portilho|NCP|0000-0003-1912-4049;Motta|Antônio Abílio|AA|0000-0003-0276-3362;Kalil|Jorge|J|0000-0001-8415-4274;Giavina-Bianchi|Pedro|P|0000-0002-1034-7580",
"chemical_list": "D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D014295:Trimethoprim; D013420:Sulfamethoxazole",
"country": "Brazil",
"delete": false,
"doi": "10.31744/einstein_journal/2020RC5002",
"fulltext": "\n==== Front\nEinstein (Sao Paulo)Einstein (Sao Paulo)einsEinstein1679-45082317-6385Instituto Israelita de Ensino e Pesquisa Albert Einstein 317784670050210.31744/einstein_journal/2020RC5002Case ReportLoss of tolerance 5 days after discontinuing sulphonamide introduced via desensitization in delayed reaction https://orcid.org/0000-0003-1536-5291Pereira Amanda Rocha Firmino 1https://orcid.org/0000-0001-9882-5200Aun Marcelo Vivolo 2https://orcid.org/0000-0003-1912-4049Kelmann Nathália Coelho Portilho 3https://orcid.org/0000-0003-0276-3362Motta Antônio Abílio 3https://orcid.org/0000-0001-8415-4274Kalil Jorge 3https://orcid.org/0000-0002-1034-7580Giavina-Bianchi Pedro 3\n1 \nUniversidade de São Paulo\nFaculdade de Medicina\nHospital das Clínicas\nSão PauloSP\nBrazil\nHospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil\n2 \nFaculdade Israelita de Ciências da Saúde Albert Einstein\nSão PauloSP\nBrazil\nFaculdade Israelita de Ciências da Saúde Albert Einstein, São Paulo, SP, Brazil\n3 \nUniversidade de São Paulo\nFaculdade de Medicina\nSão PauloSP\nBrazil\nFaculdade de Medicina, Universidade de São Paulo, São Paulo, SP, BrazilCorresponding author: Amanda Rocha Firmino Pereira, Ambulatório de Imunologia Clínica e Alergia Avenida Dr. Enéas Carvalho Aguiar, nº 155, 5º floor, building 4B – Pinheiros Zip code: 05403-000 – São Paulo, SP, Brazil Phone: (55 11) 2661-9571 E-mail: amandafirpe@yahoo.com.br14 11 2019 2020 18 eRC500214 2 2019 25 6 2019 This content is licensed under a Creative Commons Attribution 4.0 International License.ABSTRACT\nThe fixed drug eruption is a non-immediate hypersensitivity reaction to drug, characterized by recurrent erythematous or violaceous, rounded, well-defined border plaques, which always appear in the same location every time the culprit drug is administered. The usual practice is to avoid the drug involved and to use a structurally different drug. However, there are situations in which there is no safe and effective therapy. In such situations, desensitization is the only option. We describe the case of a patient who presented fixed eruption due to sulfamethoxazole-trimethoprim, who underwent successful desensitization, but required a repeat procedure twice due to relapse after inadvertent full-dose reintroduction. In non-immediate hypersensitivity reaction to drug, the indication is controversial and there is no technical standardization. Furthermore, the time at which such tolerance is lost after discontinuing the drug involved is unknown. In severe non-immediate reactions of types II and III, desensitization is contraindicated. The patient underwent desensitisation to sulfamethoxazole-trimethoprim three times − the first with recurrence of lesions and the second and third without manifestations, all concluded successfully and with no premedication.\n\nKeywords:\nDrug hypersensitivityTrimethoprim, sulfamethoxazole drug combinationDrug eruptionsDesensitization, immunologicDrug tolerance\n==== Body\nINTRODUCTION\nThe fixed drug eruption (FDE) is a drug hypersensitivity reaction (DHR) that is not immediate, characterized by recurrent, rounded, erythematous or violaceous plaques, with well-defined borders, which occur always in the same location, whenever the culprit drug is administered. This reaction may be caused by many different drugs, especially sulfonamides.(1–7)\n\nThe pathogenic mechanisms of FDE are still not well-defined, but TCD8+ cells seem to play an important role at the start of the epidermal lesion, with strong evidence that they permanently reside at the site of the lesions as memory TCD8+ cells.(8)\n\nThe habitual practice is to avoid the drug involved and to use a structurally different medication. Nevertheless, there are situations in which there is no safe and effective treatment, and desensitization is the only option. The literature about non-immediate desensitization in DHR is less extensive and more controversial than that for immediate reactions. There are no controlled studies on the theme.(9)\n\nWe describe the case of a patient who presented with FDE due to sulfamethoxazole-trimethoprim (SMX-TMP) and underwent successful desensitization, but required two repetitions of the process.\n\nCASE REPORT\nA 68-year-old male patient with Young's syndrome and bronchiectasis as sequelae, with several hospital stays due to exacerbations, presenting with Nocardia sp infection in cultures, and for whom the first option of treatment would be SMX-TMP.\n\nRefractory to other antibiotic regimens, and reporting that during hospitalization, in 2002, he presented with erythematous maculae on his body 24 hours after initiating on SMX-TMP. He was referred to the Clinical Immunology and Allergy Division for investigation and diagnostic evaluation. The interval between taking the last tablet of SMX-TMP and the appearance of the lesions was not precise. He was submitted to the oral challenge test in January 2013, with a dose of 400/80mg, which had a negative result for immediate reactions. This was followed by a challenge to assess the likely delayed reaction, which after 7 days of use at home, led to onset of erythematous-violaceous macula on his forearm and lower right limb, which was short-lived and not seen by the medical team.\n\nIn the following month, considering the imprecision of the diagnosis, the two-step open oral challenge test was performed. Initially, placebo was administered, which was negative, then SMX-TMP, at a total dose of 1,600/320mg. After 40 minutes, the patient reported pruritus on his hands, more intense on the right hand, and 2 hours later, he presented with erythematous plaque on the medial aspect of the upper right limb, in the same topography as the previous reaction, in 2002. This led to the diagnosis of FDE, and he was treated with oral steroids, with resolution.\n\nIn May 2014, the patient was hospitalized for desensitization with SMX-TMP, and a 10-day protocol was employed (Table 1).(10) Twenty-four hours after the first administration, the patient presented with a lesion on the medial aspect of the right upper limb, anterior and posterior aspects of the left thigh, and posterior aspect of the right thigh. On the third day, patient evolved with blisters on the palms, right upper limb, and left foot (Figures 1 to 3). The lesions were treated with topical corticoids and desensitization (Figure 4). The procedure was successfully concluded, and the patient maintained the use of 2,400/480 mg a day, with no intercurrent events.\n\nTable 1 Protocol for oral desensitization to sulfamethoxazole-trimethoprim using the pediatric suspension (1mL=8mg/40mg) and 80mg/400 mg tablets\nDay\tDose\tSMX-TMP (mg)\t\n1\t1mL of 1:20 of the pediatric suspension of SMX-TMP\t0.4/2\t\n2\t2mL of 1:20 of the pediatric suspension of SMX-TMP\t0.8/4\t\n3\t4mL of 1:20 of the pediatric suspension of SMX-TMP\t1.6/8\t\n4\t8mL of 1:20 of the pediatric suspension of SMX-TMP\t3.2/16\t\n5\t1mL of the pediatric suspension of SMX-TMP\t8/40\t\n6\t2mL of the pediatric suspension of SMX-TMP\t16/80\t\n7\t4mL of the pediatric suspension of SMX-TMP\t32/160\t\n8\t8mL of the pediatric suspension of SMX-TMP\t64/320mg\t\n9\t1 tablet of SMX-TMP\t80/400mg\t\n10\t2 tablets of SMX-TMP\t160/800mg\t\nSMX-TMP: sulfamethoxazole-trimethoprim.\n\nFigure 1 Erythematous bullous lesion on the palmar region\nFigure 2 Erythematous violaceous bullous lesion on the plantar region\nFigure 3 Erythematous bullous lesion on the upper limb\nFigure 4 Lesion with residual erythema on the posterior aspect of the lower limb after corticoid treatment\nIn February 2015, the patient maintained the use of SMX-TMP, when he presented with diarrhea, and discontinued himself the medication for 5 days. After the episode improved, he tried to reintroduce the medication, but the lesions recurred. In April 2015, he was admitted for his second desensitization, which, on this occasion, occurred with no intercurrent events and no need of steroids, maintaining a daily use of 2,400/480mg a day.\n\nIn June 2015, since he presented with clinical criteria of cure, the patient's treatment for Nocardia was discontinued. Thirty days later, he presented new symptoms, and alternative treatments were prescribed, with no clinical control. The patient, on his own initiative, used one tablet of SMX-TMP 400/80mg every 12 hours, and lesions appeared two hours after ingestion of the second tablet. He was referred again on September 2015, and for the third time, desensitization was performed, without complications, and the patient was released with 2,400/480mg a day, with no interruption. All the procedures were performed upon his signing of the Informed Consent Form, using the same protocol.\n\nDISCUSSION\nDesensitization is an induction of transient tolerance. In non-immediate DHR, there is no technical standardization and it is not known how soon this tolerance is lost after discontinuing the drug involved. The time may depend on the type of reaction, drug, and factors related to the patient. Desensitized patients who discontinue the drug need to undergo a new procedure for a fresh induction of tolerance.(9)\n\nIn severe non-immediate reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, induced hypersensitivity syndrome, and acute generalized exanthematous pustulosis), and in type II and type III non-immediate reactions, desensitization is contraindicated.(9,11) Occasionally, blisters may develop into the FDE lesions, rarely affecting large body surfaces, and this condition has been called generalized bullous fixed drug eruption (GBFDE).(1,12) An Iranian study concluded that many cases of FDE, such as GBFDE, are presented for the first time as FDE with limited lesions, which result in dissemination by repeated exposures to the causative medication. The site most involved in the group treated with antibiotics, especially SMX-TMP, was the upper limb.(6) GBFDE could be considered a contraindication for desensitization, but it is important to emphasize the absence or scarcity of constitutional symptoms, and no involvement of organs.(1,12)\n\nThe literature has reports of successful desensitization in patients with non-immediate reactions to various drugs.(8,13–16) Nevertheless, these are questionable, since in many cases, the diagnosis of hypersensitivity to the drug was not confirmed by tests, including the challenge test.(9)\n\nA study done in a patient with FDE who was desensitized with allopurinol aimed to evaluate the changes produced on the epidermal damage during the procedure. It is believed that, during desensitization, regulatory cells TCD4+ CD25+ migrate to the lesion site, exerting a suppression effect on the effector function of the T CD8+ cells.(8,17)\n\nAt any reintroduction of the drug in a patient who has experienced a DHR, there is the risk that the same reaction might occur, leading to more extensive manifestations; therefore, it is always important that desensitization occurs in a hospital environment, bearing in mind that complications in non-immediate reactions can occur within hours or even days.(11,18)\n\nProtocols found for the non-immediate DHR vary in duration from hours to weeks. There seems to be no advantage of the intravenous route over the oral route. There is no consensus on the value of pre-medication and if there is influence on the efficacy of desensitization.(9) There are reports of patients with HIV who presented with complications during and after desensitization with sulfonamides.(19,20)\n\nAfter literature review of the topic, covering the period from 1987 to 2019, this seems to be the first case report of desensitization with sulfa in a patient with GBFDE, which evolved with relapsed reaction after reintroduction of the drug at a therapeutic dose, showing loss of tolerance after discontinuing the drug for a few days. It would be interesting to observe that our patient presented with no manifestations during the second and third desensitization, unlike the first one, perhaps due to early rescue of the memory CD4+ CD25+.\n\nCONCLUSION\nWe reported a case in which the patient was submitted to desensitization to sulfamethoxazole-trimethoprim three times, and all were successful without the use of pre-medication. This patient, even while maintaining the use of the medication for months, when it was interrupted, presented with no acquired tolerance. Therefore, in cases of chronic diseases, it would be desirable to sustain the tolerance acquired after desensitization.\n\nRelato de CasoPerda da tolerância 5 dias após suspensão de sulfonamida introduzida através de dessensibilização por reação tardia https://orcid.org/0000-0003-1536-5291Pereira Amanda Rocha Firmino 1https://orcid.org/0000-0001-9882-5200Aun Marcelo Vivolo 2https://orcid.org/0000-0003-1912-4049Kelmann Nathália Coelho Portilho 3https://orcid.org/0000-0003-0276-3362Motta Antônio Abílio 3https://orcid.org/0000-0001-8415-4274Kalil Jorge 3https://orcid.org/0000-0002-1034-7580Giavina-Bianchi Pedro 3\n1 \nSão PauloSP\nBrasil\nHospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil\n2 \nSão PauloSP\nBrasil\nFaculdade Israelita de Ciências da Saúde Albert Einstein, São Paulo, SP, Brasil\n3 \nSão PauloSP\nBrasil\nFaculdade de Medicina, Universidade de São Paulo, São Paulo, SP, BrasilAutor correspondente: Amanda Rocha Firmino Pereira Ambulatório de Imunologia Clínica e Alergia Avenida Dr. Enéas Carvalho Aguiar, nº 155, 5º andar, bloco 4B – Pinheiros CEP: 05403-000 – São Paulo, SP, Brasil Tel.: (11) 2661-9571 E-mail: amandafirpe@yahoo.com.brRESUMO\nA erupção fixa por drogas é uma reação de hipersensibilidade a medicamento não imediata, caracterizada por placas eritematosas ou violáceas, arredondadas, recorrentes, de bordas bem definidas e que aparecem sempre na mesma localização cada vez que o medicamento culpado é administrado. A prática habitual é evitar a droga envolvida e utilizar um medicamento estruturalmente diferente. Contudo, há situações em que não há terapêutica segura e eficaz. Em tais situações, a dessensibilização é a única opção. Descrevemos o caso de um paciente que apresentou erupção fixa por drogas por sulfametoxazol-trimetoprim, tendo sido submetido à dessensibilização com sucesso, mas necessitou repetição do procedimento duas vezes, por recidiva da reação após reintrodução inadvertida em dose plena. Em reação de hipersensibilidade a medicamento não imediata, a indicação é controversa e não há padronização técnica. Além disso, não se conhece o tempo durante o qual essa tolerância é perdida após a suspensão da droga envolvida. Nas reações não imediatas graves e dos tipos II e III, a dessensibilização está contraindicada. O paciente foi submetido a dessensibilização ao sulfametoxazol-trimetoprim por três vezes − a primeira com recorrência de lesões, e a segunda e terceira sem manifestações, sendo todas concluídas com sucesso e sem uso de pré-medicação.\n\nDescritores:\nHipersensibilidade a drogasCombinação trimetoprima e sulfametoxazolErupção por drogaDessensibilização imunológicaTolerância a medicamentosINTRODUÇÃO\nA erupção fixa por drogas (EFD) é uma reação de hipersensibilidade a medicamento (RHM) não imediata, caracterizada por placas eritematosas ou violáceas arredondadas, recorrentes, de bordas bem definidas e que aparecem sempre na mesma localização, cada vez que o medicamento culpado é administrado. Essa reação pode ser causada por muitas drogas diferentes, principalmente pelas sulfonamidas.(1–7)\n\nOs mecanismos patogênicos da EFD ainda não estão bem definidos, mas as células TCD8+ parecem desempenhar papel importante no início da lesão epidérmica, com fortes evidências de que residam persistentemente no local das lesões como TCD8+ de memória.(8)\n\nA prática habitual é que se evite a droga envolvida e utilize medicamento estruturalmente diferente. Contudo, há situações em que não há terapêutica segura e eficaz, sendo a dessensibilização a única opção. A literatura sobre as dessensibilizações em RHM não imediatas é menos extensa e mais controversa do que para as reações imediatas. Não existem estudos controlados sobre o tema.(9)\n\nDescrevemos o caso de um paciente que apresentou EFD por sulfametoxazol-trimetoprim (SMX-TMP) e foi submetido à dessensibilização com sucesso, mas necessitou repetição do procedimento por duas vezes.\n\nRELATO DE CASO\nHomem de 68 anos, portador de síndrome de Young e bronquiectasias sequelares, com diversas hospitalizações por exacerbação, apresentando, às culturas, infecção por Nocardia sp, cuja primeira opção terapêutica seria o SMX-TMP.\n\nRefratário a outros esquemas de antibioticoterapia e com relato de que, durante internação em 2002, apresentara máculas eritematosas no corpo após 24 horas do início do tratamento com SMX-TMP, tendo sido encaminhado à Divisão de Imunologia Clínica e Alergia para investigação e avaliação diagnóstica. Havia imprecisão com relação ao intervalo de tomada do último comprimido de SMX-TMP e o aparecimento das lesões. Foi submetido a teste de provocação oral em janeiro de 2013, com dose de 400/80mg, que resultou negativo para reações imediatas. Foi seguido por provocação para avaliar provável reação tardia, que, após 7 dias do uso domiciliar, cursou com aparecimento de mácula eritêmato-violácea em antebraço e membro inferior direito, fugaz, não visualizada pela equipe médica.\n\nNo mês seguinte, diante da imprecisão do diagnóstico, foi realizado novamente o teste de provocação oral aberto em duas etapas. Foi administrado inicialmente o placebo, o qual foi negativo, e SMX-TMP, em dose total de 1.600/320mg. Após 40 minutos, o paciente referiu prurido em mãos, sendo mais intenso em mão direita, e, 2 horas após, apresentava lesão em placa eritematosa na face medial do membro superior direito na mesma topografia da reação de 2002, levando ao diagnóstico de EFD, sendo tratado com corticoide oral com resolução.\n\nEm maio de 2014, foi internado para dessensibilização com SMX-TMP, sendo optado por protocolo de 10 dias (Tabela 1).(10) Após 24 horas da primeira administração, apresentou lesão na face medial do membro superior direito, face anterior e posterior da coxa esquerda, e face posterior da coxa direita. No terceiro dia, evoluiu com bolhas em palmas das mãos, membro superior direito e pé esquerdo (Figuras 1 a 3). As lesões foram tratadas com corticoide tópico, e prosseguiu-se com a dessensibilização (Figura 4). O procedimento foi finalizado com sucesso, e o paciente manteve o uso de 2.400/480mg ao dia, sem intercorrências.\n\nTabela 1 Protocolo de dessensibilização via oral a sulfametoxazol-trimetoprim utilizando suspensão pediátrica (1mL=8mg/40mg) e comprimido 80mg/400mg\nDia\tDose\tSMX-TMP (mg)\t\n1\t1mL de 1:20 da suspensão pediátrica de SMX-TMP\t0,4/2\t\n2\t2mL de 1:20 da suspensão pediátrica de SMX-TMP\t0,8/4\t\n3\t4mL de 1:20 da suspensão pediátrica de SMX-TMP\t1,6/8\t\n4\t8mL de 1:20 da suspensão pediátrica de SMX-TMP\t3,2/16\t\n5\t1mL da suspensão pediátrica de SMX-TMP\t8/40\t\n6\t2mL da suspensão pediátrica de SMX-TMP\t16/80\t\n7\t4mL da suspensão pediátrica de SMX-TMP\t32/160\t\n8\t8mL da suspensão pediátrica de SMX-TMP\t64/320mg\t\n9\t1 comprimido de SMX-TMP\t80/400mg\t\n10\t2 comprimidos de SMX-TMP\t160/800mg\t\nSMX-TMP: sulfametoxazol-trimetoprim.\n\nFigura 1 Lesão eritêmato-bolhosa em região palmar\nFigura 2 Lesão bolhosa eritêmato-violácea em região plantar\nFigura 3 Lesão eritêmato-bolhosa em membro superior\nFigura 4 Lesão com eritema residual em face posterior do membro inferior após tratamento com corticoide\nEm fevereiro de 2015, o paciente mantinha uso do SMX-TMP, quando apresentou quadro de diarreia, e suspendeu o medicamento por conta própria por 5 dias. Após melhora do quadro, tentou reintroduzi-lo, porém, houve recorrência das lesões. Em abril de 2015, foi internado para segunda dessensibilização, que, nessa ocasião ocorreu sem intercorrências e sem necessidade de uso de corticoide, mantendo uso diário de 2.400/480mg ao dia.\n\nEm junho de 2015, por apresentar critérios clínicos de cura, teve o tratamento para Nocardia suspenso. Após 30 dias, novos sintomas surgiram, sendo instituídos tratamentos alternativos sem controle clínico. Por conta própria, o paciente fez uso do SMX-TMP 400/80mg 1 comprimido a cada 12 horas com aparecimento de lesões duas horas após ingestão do segundo comprimido. Foi reencaminhado em setembro de 2015 e, pela terceira vez, foi realizada a dessensibilização, sem intercorrências, obtendo alta com 2.400/480mg ao dia, sem interrupções. Todos os procedimentos foram realizados mediante assinatura de consentimento livre e informado, utilizando o mesmo protocolo.\n\nDISCUSSÃO\nA dessensibilização é uma indução de tolerância transitória. Em RHM não imediatas, não há padronização técnica e não se conhece em que tempo essa tolerância é perdida após a suspensão da droga envolvida. O tempo pode depender do tipo de reação, droga e de fatores relacionados ao paciente. Pacientes dessensibilizados que suspenderam a droga necessitam ser submetidos a novo procedimento para nova indução da tolerância.(9)\n\nNas reações não imediatas graves (síndrome de Stevens-Johnson, necrólise epidérmica tóxica, síndrome de hipersensibilidade induzida e pustulose exantemática generalizada aguda) e nas reações não imediatas dos tipos II e III, a dessensibilização está contraindicada.(9,11) Ocasionalmente, bolhas podem se desenvolver nas lesões de EFD, raramente abrangendo grandes superfícies corpóreas, entidade que vem sendo então denominada como EFD bolhosa disseminada (EFDBD).(1,12) Estudo iraniano concluiu que muitos casos de EFD como de EFDBD são apresentados pela primeira vez como EFD com lesões limitadas, que resultam em disseminação por repetidas exposições ao medicamento causador. O que foi mais observado entre o grupo de antibióticos, especialmente o SMX-TMP, e o local mais envolvido foi o membro superior.(6) A EFDBD poderia ser considerada contraindicação para a dessensibilização, mas é importante frisar a ausência ou escassez de sintomas constitucionais e o não comprometimento de vísceras.(1,12)\n\nNa literatura, existem relatos de dessensibilização com sucesso em pacientes com reações não imediatas para diversos medicamentos.(8,13–16) Porém, estes são questionáveis, já que, em muitos, o diagnóstico de hipersensibilidade ao fármaco não foi confirmado por testes, incluindo o de provocação.(9)\n\nUm estudo em um paciente com EFD que foi dessensibilizado com alopurinol buscou avaliar as mudanças produzidas na epiderme lesional durante o procedimento. Acredita-se que, na dessensibilização, as células reguladoras TCD4+CD25+ migram para o local da lesão, exercendo efeito de supressão na função efetora das células T CD8+.(8,17)\n\nEm qualquer reintrodução de droga em paciente que tenha experimentado uma RHM, há risco de que a mesma reação possa ocorrer e manifestações mais extensas possam ser provocadas, por isto é sempre interessante que a dessensibilização ocorra em ambiente hospitalar, lembrando que as complicações em reações não imediatas podem ocorrer em horas ou mesmo dias.(11,18)\n\nOs protocolos encontrados para as RHM não imediatas variam em duração de horas a semanas. Parece não haver vantagem da via intravenosa sobre a oral, também não há consenso sobre o valor da pré-medicação e se há influência na eficácia da dessensibilização.(9) Há relatos de pacientes com HIV que apresentaram intercorrências durante e após a dessensibilização com sulfonamidas.(19,20)\n\nApós revisão de literatura sobre o assunto, cobrindo o período de 1987 a 2019, este parece ser o primeiro relato de caso de dessensibilização com sulfa em um paciente com EFDBD, que evoluiu com recidiva da reação após reintrodução da droga em dose terapêutica, mostrando a perda da tolerância após suspensão da droga por poucos dias. Seria interessante observar também que nosso paciente não apresentou manifestações durante a segunda e terceira dessensibilização, diferente da primeira, talvez por resgate precoce dos CD4+ CD25+ de memória.\n\nCONCLUSÃO\nRelatamos um caso em que o paciente foi submetido à dessensibilização a sulfametoxazol-trimetoprim por três vezes, sendo todas bem-sucedidas e sem uso de pré-medicação. Este paciente, mesmo mantendo o uso do medicamento por meses, ao interrompê-lo, não apresentou tolerância adquirida. Portanto, nos casos de doenças crônicas, seria desejável sustentar a tolerância alcançada após dessensibilização.\n==== Refs\nREFERENCES\n1 Brockow K Ardern-Jones MR Mockenhaupt M Aberer W Barbaud A Caubet JC EAACI position paper on how to classify cutaneous manifestations of drug hypersensitivity Allergy 2019 74 1 14 27 30028512 1. Brockow K, Ardern-Jones MR, Mockenhaupt M, Aberer W, Barbaud A, Caubet JC, et al. EAACI position paper on how to classify cutaneous manifestations of drug hypersensitivity. Allergy. 2019;74(1):14-27.\n2 Patriarca G Schiavino D Buonomo A Aruanno A Altomonte G Nucera E Desensitization to co-trimoxazole in a patient with fixed drug eruption J Investig Allergol Clin Immunol 2008 18 4 309 311 2. Patriarca G, Schiavino D, Buonomo A, Aruanno A, Altomonte G, Nucera E. Desensitization to co-trimoxazole in a patient with fixed drug eruption. J Investig Allergol Clin Immunol. 2008;18(4):309-11.\n3 Jung JW Cho SH Kim KH Min KU Kang HR Clinical features of fixed drug eruption at a tertiary hospital in Korea Allergy Asthma Immunol Res 2014 6 5 415 420 25228998 3. Jung JW, Cho SH, Kim KH, Min KU, Kang HR. Clinical features of fixed drug eruption at a tertiary hospital in Korea. Allergy Asthma Immunol Res. 2014;6(5):415-20.\n4 Emre S Ahsen H Aktaş A Ornidazole-induced fixed drug reaction on sole: case report and review of the literature Cutan Ocul Toxicol 2017 36 3 294 296 Review 27780370 4. Emre S, Ahsen H, Aktaş A. Ornidazole-induced fixed drug reaction on sole: case report and review of the literature. Cutan Ocul Toxicol. 2017;36(3):294-6. Review.\n5 Can C Akkelle E Bay B Arıcan O Yalçın O Yazicioglu M Generalized fixed drug eruption in a child due to trimethoprim/sulfamethoxazole Pediatr Allergy Immunol 2014 25 4 413 415 24750132 5. Can C, Akkelle E, Bay B, Arıcan O, Yalçın O, Yazicioglu M. Generalized fixed drug eruption in a child due to trimethoprim/sulfamethoxazole. Pediatr Allergy Immunol. 2014;25(4):413-5.\n6 Kavoussi H Rezaei M Derakhshandeh K Moradi A Ebrahimi A Rashidian H Clinical Features and Drug Characteristics of Patients with Generalized Fixed Drug Eruption in the West of Iran (2005-2014) Dermatol Res Pract 2015 2015 236703 236703 26783389 6. Kavoussi H, Rezaei M, Derakhshandeh K, Moradi A, Ebrahimi A, Rashidian H, et al. Clinical Features and Drug Characteristics of Patients with Generalized Fixed Drug Eruption in the West of Iran (2005-2014). Dermatol Res Pract. 2015;2015:236703.\n7 Kouotou EA Nansseu JR Ngono VN Tatah SA Zoung-Kanyi Bissek AC Ndjitoyap Ndam EC Prevalence and Clinical Profile of Drug Eruptions among Antiretroviral Therapy-Exposed HIV Infected People in Yaoundé, Cameroon Dermatol Res Pract 2017 2017 6216193 6216193 28744306 7. Kouotou EA, Nansseu JR, Ngono VN, Tatah SA, Zoung-Kanyi Bissek AC, Ndjitoyap Ndam EC. Prevalence and Clinical Profile of Drug Eruptions among Antiretroviral Therapy-Exposed HIV Infected People in Yaoundé, Cameroon. Dermatol Res Pract. 2017;2017:6216193.\n8 Teraki Y Shiohara T Successful desensitization to fixed drug eruption: the presence of CD25+CD4+ T cells in the epidermis of fixed drug eruption lesions may be involved in the induction of desensitization Dermatology 2004 209 1 29 32 15237264 8. Teraki Y, Shiohara T. Successful desensitization to fixed drug eruption: the presence of CD25+CD4+ T cells in the epidermis of fixed drug eruption lesions may be involved in the induction of desensitization. Dermatology. 2004;209(1):29-32.\n9 Scherer K Brockow K Aberer W Gooi JH Demoly P Romano A Schnyder B Whitaker P Cernadas JS Bircher AJ ENDA, the European Network on Drug Allergy and the EAACI Drug Allergy Interest Group. Desensitization in delayed drug hypersensitivity reactions -- an EAACI position paper of the Drug Allergy Interest Group Allergy 2013 68 7 844 852 Review 23745779 9. Scherer K, Brockow K, Aberer W, Gooi JH, Demoly P, Romano A, Schnyder B, Whitaker P, Cernadas JS, Bircher AJ; ENDA, the European Network on Drug Allergy and the EAACI Drug Allergy Interest Group. Desensitization in delayed drug hypersensitivity reactions -- an EAACI position paper of the Drug Allergy Interest Group. Allergy. 2013;68(7):844-52. Review.\n10 Absar N Daneshvar H Beall G Desensitization to trimethoprim/sulfamethoxazole in HIV-infected patients J Allergy Clin Immunol 1994 93 6 1001 1005 8006304 10. Absar N, Daneshvar H, Beall G. Desensitization to trimethoprim/sulfamethoxazole in HIV-infected patients. J Allergy Clin Immunol. 1994;93(6):1001-5.\n11 Zaouak A Ben Salem F Ben Jannet S Hammami H Fenniche S Bullous fixed drug eruption: A potential diagnostic pitfall: a study of 18 cases Therapie 2019 74 5 527 530 31006486 11. Zaouak A, Ben Salem F, Ben Jannet S, Hammami H, Fenniche S. Bullous fixed drug eruption: A potential diagnostic pitfall: a study of 18 cases. Therapie. 2019;74(5):527-30.\n12 Lipowicz S Sekula P Ingen-Housz-Oro S Liss Y Sassolas B Dunant A Prognosis of generalized bullous fixed drug eruption: comparison with Stevens-Johnson syndrome and toxic epidermal necrolysis Br J Dermatol 2013 168 4 726 732 23413807 12. Lipowicz S, Sekula P, Ingen-Housz-Oro S, Liss Y, Sassolas B, Dunant A, et al. Prognosis of generalized bullous fixed drug eruption: comparison with Stevens-Johnson syndrome and toxic epidermal necrolysis. Br J Dermatol. 2013;168(4):726-32.\n13 Audiacana M Echechipia S Fernandez E Urrutia I Desensitization in a case of fixed drug eruption from allopurinol Clin Exp Allergy 1990 Suppl 1 121 121 13. Audiacana M, Echechipia S, Fernandez E, Urrutia I. Desensitization in a case of fixed drug eruption from allopurinol. Clin Exp Allergy. 1990;(Suppl 1):121.\n14 Garces M Alonso L Perez R Marcos L Juste S Blanco J Successful oral desensitization in a patient with fixed eruption from allopurinol Allergy 1995 50 suppl 26 213 213 14. Garces M, Alonso L, Perez R, Marcos L, Juste S, Blanco J, et al. Successful oral desensitization in a patient with fixed eruption from allopurinol. Allergy. 1995;50 suppl 26:213.\n15 Kelso JM Keating RM Successful desensitization for treatment of a fixed drug eruption to allopurinol J Allergy Clin Immunol 1996 97 5 1171 1172 8626998 15. Kelso JM, Keating RM. Successful desensitization for treatment of a fixed drug eruption to allopurinol. J Allergy Clin Immunol. 1996;97(5):1171-2.\n16 Umpiérrez A Cuesta-Herranz J De Las Heras M Lluch-Bernal M Figueredo E Sastre J Successful desensitization of a fixed drug eruption caused by allopurinol J Allergy Clin Immunol 1998 101 2 Pt 1 286 287 9500766 16. Umpiérrez A, Cuesta-Herranz J, De Las Heras M, Lluch-Bernal M, Figueredo E, Sastre J. Successful desensitization of a fixed drug eruption caused by allopurinol. J Allergy Clin Immunol. 1998;101(2 Pt 1):286-7.\n17 García Rodríguez R Galindo Bonilla PA Feo Brito FJ Gómez Torrijos E Borja Segade J Lara de la Rosa P Chronic desensitization to quinolones in fixed drug eruption J Investig Allergol Clin Immunol 2011 21 1 76 77 17. García Rodríguez R, Galindo Bonilla PA, Feo Brito FJ, Gómez Torrijos E, Borja Segade J, Lara de la Rosa P, et al. Chronic desensitization to quinolones in fixed drug eruption. J Investig Allergol Clin Immunol. 2011;21(1):76-7.\n18 Borish L Tamir R Rosenwasser LJ Intravenous desensitization to beta-lactam antibiotics J Allergy Clin Immunol 1987 80 3 Pt 1 314 319 3040836 18. Borish L, Tamir R, Rosenwasser LJ. Intravenous desensitization to beta-lactam antibiotics. J Allergy Clin Immunol. 1987;80(3 Pt 1):314-9.\n19 Leoung GS Stanford JF Giordano MF Stein A Torres RA Giffen CA Wesley M Sarracco T Cooper EC Dratter V Smith JJ Frost KR American Foundation for AIDS Research (amfAR) Community-Based Clinical Trials Network. Trimethoprim-sulfamethoxazole (TMP-SMZ) dose escalation versus direct rechallenge for Pneumocystis Carinii pneumonia prophylaxis in human immunodeficiency virus-infected patients with previous adverse reaction to TMP-SMZ J Infect Dis 2001 15 184 8 992 997 11574913 19. Leoung GS, Stanford JF, Giordano MF, Stein A, Torres RA, Giffen CA, Wesley M, Sarracco T, Cooper EC, Dratter V, Smith JJ, Frost KR; American Foundation for AIDS Research (amfAR) Community-Based Clinical Trials Network. Trimethoprim-sulfamethoxazole (TMP-SMZ) dose escalation versus direct rechallenge for Pneumocystis Carinii pneumonia prophylaxis in human immunodeficiency virus-infected patients with previous adverse reaction to TMP-SMZ. J Infect Dis. 200115;184(8):992-7.\n20 Fégueux S De Truchis P Balloul H Maslo C Matheron S Coulaud JP Sulphadiazine desensitization in AIDS patients AIDS 1991 5 10 1275 1276 1786163 20. Fégueux S, De Truchis P, Balloul H, Maslo C, Matheron S, Coulaud JP. Sulphadiazine desensitization in AIDS patients. AIDS. 1991;5(10):1275-6.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1679-4508",
"issue": "18()",
"journal": "Einstein (Sao Paulo, Brazil)",
"keywords": null,
"medline_ta": "Einstein (Sao Paulo)",
"mesh_terms": "D000368:Aged; D003888:Desensitization, Immunologic; D003875:Drug Eruptions; D004342:Drug Hypersensitivity; D006801:Humans; D008297:Male; D013420:Sulfamethoxazole; D014295:Trimethoprim; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "101281800",
"other_id": null,
"pages": "eRC5002",
"pmc": null,
"pmid": "31778467",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "27780370;8006304;15237264;23745779;3040836;23413807;8626998;24750132;18714541;21370729;9500766;31006486;30028512;28744306;25228998;26783389;11574913;1786163",
"title": "Loss of tolerance 5 days after discontinuing sulphonamide introduced via desensitization in delayed reaction.",
"title_normalized": "loss of tolerance 5 days after discontinuing sulphonamide introduced via desensitization in delayed reaction"
} | [
{
"companynumb": "BR-VISTA PHARMACEUTICALS INC.-2081368",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
... |
{
"abstract": "Proprotein convertase 1/3 (PC1/3) deficiency is a very rare disease characterized by severe intractable diarrhea in the first years of life, followed by obesity and several hormonal deficiencies later. Diabetes mellitus requiring insulin treatment and diabetic ketoacidosis have not been reported in this disorder. We herein present a girl with PC1/3 deficiency who has been followed from birth to 17 years of age. She developed deficiencies of all pituitary hormones over time as well as diabetes mellitus while receiving growth hormone (GH) therapy. She was complicated with diabetic ketoacidosis during dietary management of diabetes mellitus, thus insulin treatment was initiated. Insulin requirement to regulate hyperglycemia was short-lived. Repeat oral glucose tolerance test five years later was normal. The findings of this patient show that diabetes mellitus can develop at any time during follow-up of cases with proportein convertase 1/3 deficiency especially under GH therapy.",
"affiliations": "Hacettepe University Faculty of Medicine, Department of Pediatric Endocrinology, Ankara, Turkey;Hacettepe University Faculty of Medicine, Department of Pediatric Endocrinology, Ankara, Turkey;Hacettepe University Faculty of Medicine, Department of Pediatric Endocrinology, Ankara, Turkey;Hacettepe University Faculty of Medicine, Department of Pediatric Endocrinology, Ankara, Turkey",
"authors": "Gönç|E. Nazlı|EN|;Özön|Alev|A|;Alikaşifoğlu|Ayfer|A|;Kandemir|Nurgün|N|",
"chemical_list": "D019382:Human Growth Hormone; D045664:Proprotein Convertase 1",
"country": "Turkey",
"delete": false,
"doi": "10.4274/jcrpe.3986",
"fulltext": "\n==== Front\nJ Clin Res Pediatr EndocrinolJ Clin Res Pediatr EndocrinolJCRPEJournal of Clinical Research in Pediatric Endocrinology1308-57271308-5735Galenos Publishing 10.4274/jcrpe.39862062Case ReportLong-Term Follow-up of a Case with Proprotein Convertase 1/3 Deficiency: Transient Diabetes Mellitus with Intervening Diabetic Ketoacidosis During Growth Hormone Therapy Gönç E. Nazlı 1*Özön Alev 1Alikaşifoğlu Ayfer 1Kandemir Nurgün 1\n1 \nHacettepe University Faculty of Medicine, Department of Pediatric Endocrinology, Ankara, Turkey\n* Address for Correspondence: Hacettepe University Faculty of Medicine, Department of Pediatric Endocrinology, Ankara, Turkey Phone: +90 312 305 11 24 E-mail: ngonc@hacettepe.edu.tr9 2017 1 9 2017 9 3 283 287 18 1 2017 28 5 2017 ©Copyright 2017 by Turkish Pediatric Endocrinology and Diabetes Society\n\nThe Journal of Clinical Research in Pediatric Endocrinology published by Galenos Publishing House.2017This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Proprotein convertase 1/3 (PC1/3) deficiency is a very rare disease characterized by severe intractable diarrhea in the first years of life, followed by obesity and several hormonal deficiencies later. Diabetes mellitus requiring insulin treatment and diabetic ketoacidosis have not been reported in this disorder. We herein present a girl with PC1/3 deficiency who has been followed from birth to 17 years of age. She developed deficiencies of all pituitary hormones over time as well as diabetes mellitus while receiving growth hormone (GH) therapy. She was complicated with diabetic ketoacidosis during dietary management of diabetes mellitus, thus insulin treatment was initiated. Insulin requirement to regulate hyperglycemia was short-lived. Repeat oral glucose tolerance test five years later was normal. The findings of this patient show that diabetes mellitus can develop at any time during follow-up of cases with proportein convertase 1/3 deficiency especially under GH therapy.\n\nProprotein convertase 1/3 deficiencydiabetes mellitusdiabetic ketoacidosistreatmentdiabetes insipidus\n==== Body\nWhat is already known on this topic?\nDiabetes mellitus may develop over time during the course of the disease, which may be due to insufficient conversion of proinsulin into insulin.\n\nWhat this study adds?\nProprotein convertase 1/3 is an enzyme that converts prohormones into active hormones. Thus, proprotein convertase 1/3 deficiency has been reported to be characterized by several hormonal deficiencies. Elevation of proinsulin levels is used in the diagnosis; however, diabetes mellitus has not been reported before.\n\nINTRODUCTION\nProprotein convertase 1/3 (PC1/3) is an enzyme that is responsible for conversion of inactive peptides into active form. It is particularly expressed in neuroendocrine tissues. Thus, its deficiency leads to insufficient activation of several hormones including proinsulin, proopiomelanocortin, pro-thyrotropin-releasing hormone, pro-glucagon, and pro-gonadotropin-releasing hormone (1,2). To date, fewer than 20 patients with PC1/3 deficiency have been reported (3,4,5,6,7,8,9). Clinical presentation of these patients is variable. However, intestinal malabsorption in the first years of life and obesity thereafter are relatively constant findings. Other manifestations such as hypocortisolism, hypothyroidism, diabetes insipidus, hypogonadism, growth deficiency, and disorders of glucose metabolism are not seen in every patient. The time of onset for development of these hormone deficiencies is also variable (3,4,5,6,7,8,9).\n\nInsulin deficiency due to inefficient conversion of proinsulin to insulin is one of the hallmarks of the disease. High proinsulin level is a diagnostic marker for PC1/3 deficiency. However, the patients reported so far did not have a significant disorder related to glucose metabolism.\n\nHerein, we report a long-term follow-up of a 19-year-old girl with PC1/3 deficiency who developed multiple pituitary hormone deficiencies. She had a transient period of insulin-dependent diabetes mellitus with an intervening diabetic ketoacidosis during growth hormone (GH) therapy.\n\nCASE REPORT\nA female proband was born by cesarean section with a birth weight of 3.5 kg. She was the only child of second-degree cousins of Turkish origin. Chronic diarrhea started in the first week of life. She was hospitalized several times for severe dehydration and metabolic acidosis. Total parenteral nutrition was started at 9 months of age and she was followed at a medical center for six months. Subsequently, the parents managed to offer parenteral nutrition to the patient in the household setting till she reached age 2 years. Since glucose, galactose, lactose, and long-chain fatty acids in the diet increased the amount and frequency of loose stools, they were eliminated from the oral feedings. The intestinal biopsy showed villous atrophy with nonspecific changes. Her appetite was so good that although the diarrheic attacks continued, the patient gained weight. During infections, attacks of metabolic acidosis reappeared, suggesting renal tubular acidosis, and bicarbonate therapy was started. In the following 2 years, diarrhea has nearly resolved, but the restricted diet was continued. At 4.3 years of age, the patient was referred to pediatric endocrinology for polyuria and polydipsia. The parents have been aware of her increased water intake since infancy, but they did not consider it a problem till the cessation of diarrhea. She used to drink 3-4 liters a day.\n\nWhen the patient was 4.3-year-old, her height was 96 cm (3-10p), weight 22 kg (97p), and body mass index (BMI) was 23.9 kg/m2 (> 95p). Her physical examination was normal, and she did not have any dysmorphic features. The laboratory findings were as follows: hemoglobin (Hb): 12.2, hematocrit: 36, white blood cell: 7600, platelet: 270.000, glucose: 77 mg/dL, Na: 137 mEq/L, K: 4.8 mEq/L, Cl: 116 mEq/L, blood urea nitrogen: 4.1 mg/dL, creatinine 0.53 mg/dL, calcium: 9.9 mg/dL, P: 4.2 mg/dL, alkaline phosphatase: 373 U/L, alanine aminotransferase: 28 U/L, aspartate aminotransferase: 42 U/L. Blood gas analysis revealed: pH: 7.43 and bicarbonate (HCO3): 24.3 mmol/L. Urine density was 1003 and no proteinuria or glucosuria was noted. Water deprivation test yielded an increase in Na level to 151 mEq/L and a urine osmolality to 238 mOsmol/kg, while plasma osmolality was 320 mOsmol/kg. Simultaneous plasma arginine vasopressin (AVP) after water deprivation test was 1.3 pg/mL (0-8). Administration of intranasal DDAVP at a test dose of 5 µg increased the urine osmolality and alleviated the symptoms of polyuria and polydipsia. Diagnosis of central diabetes insipidus was established and intranasal DDAVP at a dose of 1.25 µg per day was started. At that time, morning cortisol, free thyroxine (fT4), and prolactin levels (cortisol: 19.8 µg/dL, fT4: 15. 2 pmol/L, prolactin: 8.2 ng/mL) were normal, insulin-like growth factor 1 (IGF-1) and IGF binding protein-3 (IGFBP-3) levels were low [IGF-1: 15 ng/mL (<-3 standard deviation [SD]) and IGFBP3: 1529 ng/mL (-2 SD–[-3 SD])]. Her weight and height gains are shown in Figures 1a and 1b.\n\nAt age 9 years, when her height was at 10th percentile, fT4 was found to be lower than the normal range (fT4: 11.9 pmol/L, normal: 12-22; thyroid-stimulating hormone: 3.6 mIU/L, normal: 0.27-4.2). Fasting morning cortisol level was 4 µg/dL and adrenocorticotropic hormone (ACTH) was 21 pg/mL. Low-dose ACTH test was performed and cortisol peak was subnormal at 15 µg/dL [N: 19.8 µg/dL] (10). The diagnosis of central hypothyroidism and adrenal insufficiency were established, and Na L-thyroxin (100 µg per day) and hydrocortisone (10 mg/m2 per day in three doses) replacements were started accordingly.\n\nAt the age of 10.5 years, she was 129.7 cm in height [-1.49 standard deviation score (SDS)], and growth velocity decreased to 1.8 cm/year (Figures 1a, 1b). Her bone age was 8 years. The midparental height was 156.25 cm (-0.99 SDS). The levels of IGF-1 and IGFBP3 were 56 ng/mL (<-3 SD) and 1848 ng/mL (-3 SD), respectively. GH stimulation tests with levodopa and clonidine were carried out and peak GH responses were 4.03 and 4.6 ng/mL, respectively (normal GH response: >7 ng/mL). Recombinant human GH (rhGH) was started at a dose of 0.03 mg/kg per day subcutaneously. The repeat magnetic resonance imaging of the pituitary gland was normal with a 6-mm height in the anterior lobe and a normal bright spot on the posterior lobe.\n\nAt the age of 11.5 years, after receiving GH therapy for one year, the patient had gained 7 cm. Her height was 134.5 cm and weight 50.3 kg, with a BMI 27.9 kg/m2 (>97p). The diagnosis of PC1/3 deficiency was established by the mutation analysis of PCSK1 gene. A novel essential splice site mutation (IVS8+1G>T) was identified (7).\n\nFasting blood glucose level was 85 mg/dL, and there were neither signs and symptoms nor any family history for diabetes mellitus. However, a derangement in glucose metabolism was likely in PC1/3 deficiency, so oral glucose tolerance test was performed. The results revealed diabetes mellitus (Figure 2). HbA1c was 5.8% (4.5-6.2). Anti-insulin, anti-GAD, and anti-IA2 antibodies were negative. Weight loss, physical activity, and diabetic diet were recommended. GH therapy was not discontinued.\n\nThree months later, HbA1c increased to 6% and continued to increase to 6.5% in the next 6 months on GH treatment. At the age of 12.5 years, she was brought to emergency clinic by her parents for lethargy. No signs or symptoms of infection were noted. She was dehydrated. Blood glucose was 725 mg/dL (simultaneous insulin level was 15 mIU/L) with ketosis (urine ketones were 4+), and acidosis (blood pH: 7.15 and HCO3: 9.2 mmol/L). HbA1c was 10.5%. Diabetic ketoacidosis was treated with intravenous fluid-electrolyte and insulin therapy. Basal-bolus insulin regimen using rapid-acting insulin three times a day and long-acting insulin, glargine, once a day was started thereafter. Initially, total daily dose of insulin was nearly 1.5 U/kg. However, the daily requirement of insulin progressively decreased to 0.15 U/kg per day within 10 days and eventually it was discontinued within one month. HbA1c levels were between 5.3 and 6.2% and fasting and postprandial glucose levels remained within normal levels thereafter. She received GH treatment till 15.1 years of age under a diabetic diet without any further deterioration in glucose metabolism.\n\nThe patient remained prepubertal during her follow-up and at 13 years of age, gonadotropin and estradiol levels were very low (follicle-stimulating hormone<0.07 mIU/mL, luteinizing hormone<0.07 mIU/mL, E2: 2.65 pg/mL), so estradiol replacement was started at the age of 13 years and switched to cyclic treatment at 15.5 years.\n\nAt 16.5 years, her final height is 153 cm (-1.5 SDS) and weight 69 kg (body mass index: 29.5 kg/m2). She is receiving Na l-thyroxine (2 mcg/kg/day) for hypothyroidism, sublingual lyophilized DDAVP tablet (30 µg two times a day) for central diabetes insipidus, hydrocortisone (10 mg/m2/day) for adrenal insufficiency, combined estrogen-progesterone pills for hypogonadism, and a diabetic diet for diabetes mellitus.\n\nAt the age of 17 years, HbA1c was 5.4% and a repeat oral glucose tolerance test showed normal glucose homeostasis (Figure 2).\n\nDISCUSSION\nMultiple hormonal insufficiencies have been reported in patients with PC1/3 deficiency. However, every patient with PC1/3 deficiency varies in the nature of hormonal insufficiency as well as its severity. The first reported case with PC1/3 deficiency was a 43-year-old woman who had obesity, hypogonadotropic hypogonadism and hypoadrenalism (3,11). Although GH response to insulin-induced hypoglycemia was low, she had a normal height of 161 cm. Oral glucose tolerance test showed an elevated two-hour blood glucose level (206 mg/dL) indicating diabetes mellitus. She also had postprandial hypoglycemia after a standardized meal (3).\n\nThe second patient was a female infant with intractable diarrhea who subsequently developed obesity (4). She had several episodes of hypoglycemia which were attributed to low cortisol response to hypoglycemia. Hydrocortisone replacement was started. She died of uncertain cause at the age of 18 months (4).\n\nThe third case was a boy who was followed till six years of age (5). He developed severe obesity after a period of intractable diarrhea which required 5-week parenteral nutrition in addition to oral feedings with specialized infant formula. At the age of 4 years, he developed polyuria and polydipsia. However, the water deprivation test was not diagnostic for diabetes insipidus. Consequently, following the diagnosis of PC1/3 deficiency, he was further evaluated for hormone insufficiencies; hypocortisolism and hypothyroidism were detected. In the case report, there was no detailed information about glucose metabolism of the boy except a normal fasting glucose and elevated proinsulin levels (5).\n\nThe fourth case was the first report in the literature with PC1/3 deficiency who had a documented central diabetes insipidus (6). He had hypocortisolism, hypothyroidism, and low testosterone level with micropenis suggesting hypogonadism as well. He had a normal GH response at the time of hypoglycemia. No further evaluation of glucose metabolism was mentioned in the report (6).\n\nThen, Martín et al (7) reported the clinical, laboratory, and genetic features of 13 children with PC1/3 deficiency from 11 families. Our patient was in that cohort (represented as family 3). Eleven of thirteen cases reported by Martín et al (7) were alive and 8 were younger than 10 years old. Hypothyroidism, hypocortisolism, and diabetes insipidus were relatively more common than GH deficiency in that cohort. It was reported that the patients who received GH had had a good response. Data about glucose metabolism of the patients was scarce except a note of postprandial hypoglycemia in 8 of the cases. Oral glucose tolerance test or HbA1c levels were not determined.\n\nWe had the opportunity to follow our patient from birth to 17 years of age and to observe nearly all consequences of PC1/3 deficiency reported so far. PC1/3 activity is essential for the activating cleavage of many peptide hormone precursors including hypothalamic hormones (1,2). So, lack of activation of hypothalamic hormones may mimic multiple pituitary hormone deficiency due to a defect in hypothalamus-pituitary axis. Diabetes insipidus was the earliest hormonal deficiency detected in the current patient. It probably started even before, possibly early in infancy but was disregarded till 4 years of age as the parents assigned the symptoms of polyuria and polydipsia to ongoing diarrhea.\n\nThyroid hormones and cortisol level were in normal ranges till 9 years of age in the current patient. Although IGF-1 and IGFBP-3 levels were low at 4 years of age, height was at the 10th percentile and growth velocity was normal. At 10.5 years, growth velocity decreased, GH response was low in GH stimulation tests and rhGH was initiated at a conventional dose. One year after the GH therapy, the diagnosis of PC1/3 deficiency was established definitively by genetic analysis. Oral glucose tolerance test was performed since a potential disorder in glucose metabolism was considered and diabetes mellitus was diagnosed. Insulin response to elevated glucose levels indicated neither absolute insulinopenia nor insulin resistance, however suggested a relative insulin deficiency. There was no symptom suggestive of hyperglycemia at the time of testing. HbA1c increased to 6.5% while the patient was on a diabetic diet, and two years after the onset of rhGH therapy (at age 12.5 years), diabetic ketoacidosis developed without any identifiable precipitating cause. Insulin requirement continued for one month only. Although rhGH therapy was continued, a similar picture of insulin insufficiency did not recur till 15.1 years of age. Two years after cessation of rhGH therapy, a repeat oral glucose tolerance test was completely normal.\n\nDiabetes mellitus was not defined as a part of PC1/3 deficiency although it can be speculated that there must be a relative insulin deficiency due to the defect in conversion of proinsulin to insulin. The patients reported so far did not have history of low birth weight suggesting insulinopenia during intrauterine life. Diabetes mellitus was identified only in the first reported patient with PC1/3 deficiency (3). She developed gestational diabetes mellitus requiring insulin treatment (3). The same patient was tested again at age 43 years and at that time, her 2-hour post-load blood glucose level was 206 mg/dL (3).\n\nOur patient is the first patient with PC1/3 deficiency who developed diabetic ketoacidosis. Diabetic ketoacidosis and one month of insulin requirement coincided with rhGH therapy which may be a contributing factor for relative insulin deficiency due to the anti-insulin effect of GH (12). However, since the insulin requirement was transient even in the course of rhGH therapy in our patient, it is difficult to consider GH as the sole factor responsible for deterioration of glucose metabolism. Diabetic ketoacidosis can complicate cases with excess GH secretion such as gigantism or acromegaly (13,14,15). However, we found only one report of a patient developing diabetic ketoacidosis during GH therapy (16). The case was a 13-year-old boy with Prader-Willi syndrome who presented with diabetic ketoacidosis four weeks after initiation of GH treatment (16). The status of glucose metabolism before GH was unknown in this patient and hyperglycemia resolved just 2 months after cessation of GH treatment. Later, this boy was diagnosed as type 2 diabetes (16). Thus, impaired glucose metabolism can associate with GH treatment, but diabetic ketoacidosis is very unlikely to develop and in such a case, presence of a predisposing condition needs to be investigated. Previous reports of patients with PC1/3 deficiency do not include details of routine investigations of glucose homeostasis, especially glucose tolerance test. The most commonly reported disturbance in glucose metabolism was postprandial hypoglycemia. Therefore, the true prevalence of diabetes mellitus in cases with PC1/3 deficiency is yet unknown.\n\nDisorders of glucose homeostasis should be assessed in patients with PC1/3 deficiency. Diabetes mellitus with asymptomatic hyperglycemia may be one of the disorders of hormone metabolism in PC1/3 deficiency. There may be periods with relative or sometimes even severe deficiency of insulin (i.e. leading to ketoacidosis) requiring insulin treatment especially under GH treatment.\n\nEthics\n\nInformed Consent: Written consent was obtained from the patient’s parents.\n\nPeer-review: Externally peer-reviewed.\n\nAuthorship Contributions\n\nConcept: E. Nazlı Gönç, Design: E. Nazlı Gönç, Alev Özön, Data Collection and Processing: E. Nazlı Gönç, Alev Özön, Ayfer Alikaşifoğlu, Nurgün Kandemir, Analysis and Interpretation: E. Nazlı Gönç, Alev Özön, Ayfer Alikaşifoğlu, Nurgün Kandemir, Literature Research: E. Nazlı Gönç, Writing: E. Nazlı Gönç, Alev Özön, Ayfer Alikaşifoğlu, Nurgün Kandemir.\n\nFinancial Disclosure: The authors declared that this study received no financial support.\n\nFigure 1a Growth chart of the patient before and after growth hormone therapy\n\nGH: growth hormone\nFigure 1b Body mass index chart of the patient\n\nBMI: body mass index\nFigure 2 Oral glucose tolerance test at two different time points (11.5 and 17 years of age)\n\nOGTT: oral glucose tolerance test\n==== Refs\nReferences\n1 Seidah NG The proprotein convertases, 20 years later Methods Mol Biol 2011 768 23 57 21805237 \n2 Schaner P Todd RB Seidah NG Nillni EA Processing of prothyrotropin-releasing hormone by the family of prohormone convertases J Biol Chem 1997 272 19958 19968 9242664 \n3 O’Rahilly S Gray H Humphreys PJ Krook A Polonsky KS White A Gibson S Taylor K Carr C Brief report: impaired processing of prohormones associated with abnormalities of glucose homeostasis and adrenal function N Engl J Med 1995 333 1386 1390 7477119 \n4 Bandsma RH Sokollik C Chami R Cutz E Brubaker PL Hamilton JK Perlman K Zlotkin S Sigalet DL Sherman PM Martin MG Avitzur Y From diarrhea to obesity in prohormone convertase 1/3 deficiency: age-dependent clinical, pathologic, and enteroendocrine characteristics J Clin Gastroenterol 2013 47 834 843 24135795 \n5 Farooqi IS Volders K Stanhope R Heuschkel R White A Lank E Keogh J O’Rahilly S Creemers JW Hyperphagia and early-onset obesity due to a novel homozygous missense mutation in prohormone convertase 1/3 J Clin Endocrinol Metab 2007 92 3369 3373 17595246 \n6 Frank GR Fox J Candela N Jovanovic Z Bochukova E Levine J Papenhausen PR O’Rahilly S Farooqi IS Severe obesity and diabetes insipidus in a patient with PCSK1 deficiency Mol Genet Metab 2013 110 191 194 23800642 \n7 Martín MG Lindberg I Solorzano-Vargas RS Wang J Avitzur Y Bandsma R Sokollik C Lawrence S Pickett LA Chen Z Egritas O Dalgic B Albornoz V Ridder L de Hulst J Gok F Aydoğan A Al-Hussaini A Gok DE Yourshaw M Wu SV Cortina G Stanford S Georgia S Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort Gastroenterology 2013 145 138 148 23562752 \n8 Bandsma RH Sokollik C Chami R Cutz E Brubaker PL Hamilton JK Perlman K Zlotkin S Sigalet DL Sherman PM Martin MG Avitzur Y From diarrhea to obesity in prohormone convertase 1/3 deficiency: age-dependent clinical, pathologic, and enteroendocrine characteristics J Clin Gastroenterol 2013 47 834 843 24135795 \n9 Wilschanski M Abbasi M Blanco E Lindberg I Yourshaw M Zangen D Berger I Shteyer E Pappo O Bar-Oz B Martín MG Elpeleg O A Novel Familial Mutation in the PCSK1 Gene That Alters the Oxyanion Hole Residue of Proprotein Convertase 1/3 and Impairs Its Enzymatic Activity PLoS One 2014 9 e108878 25272002 \n10 Gonc EN Kandemir N Kinik ST Significance of low-dose and standard-dose ACTH tests compared to overnight metyrapone test in the diagnosis of adrenal insufficiency in childhood Horm Res 2003 60 191 197 14530608 \n11 Jackson RS Creemers JW Ohagi S Raffin-Sanson ML Sanders L Montague CT Hutton JC O’Rahilly S Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene Nat Genet 1997 16 303 306 9207799 \n12 Fathallah N Slim R Larif S Hmouda H Ben Salem C Drug-Induced Hyperglycaemia and Diabetes Drug Saf 2015 38 1153 1168 26370106 \n13 Dosi RV Patell RD Shah PJ Joshi HK Diabetic ketoacidosis: an unusual presentation of acromegaly BMJ Case Rep 2013 2013. pii: bcr2013313198 \n14 Palakawong P Arakaki R Diabetic Ketoacidosis in Acromegaly: A Case Report Endocr Pract 2012 1 15 \n15 Erem C Ersöz HO Ukinç K Avunduk AM Hacihasanoglu A Koçak M Acromegaly presenting with diabetic ketoacidosis, associated with retinitis pigmentosa and octreotide-induced bradycardia: a case report and a review of the literature Endocrine 2006 30 145 149 17185803 \n16 Yigit S Estrada E Bucci K Hyams J Rosengren S Diabetic ketoacidosis secondary to growth hormone treatment in a boy with Prader-Willi syndrome and steatohepatitis J Pediatr Endocrinol Metab 2004 17 361 364 15112913\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "9(3)",
"journal": "Journal of clinical research in pediatric endocrinology",
"keywords": "Proprotein convertase 1/3 deficiency; diabetes mellitus; diabetic ketoacidosis; treatment diabetes insipidus.",
"medline_ta": "J Clin Res Pediatr Endocrinol",
"mesh_terms": "D003920:Diabetes Mellitus; D016883:Diabetic Ketoacidosis; D004700:Endocrine System Diseases; D005260:Female; D005500:Follow-Up Studies; D019382:Human Growth Hormone; D006801:Humans; D009765:Obesity; D045664:Proprotein Convertase 1; D055815:Young Adult",
"nlm_unique_id": "101519456",
"other_id": null,
"pages": "283-287",
"pmc": null,
"pmid": "28588004",
"pubdate": "2017-09-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24135795;25272002;21805237;23761570;7477119;23562752;23186966;15112913;9207799;17595246;9242664;26370106;23800642;17185803;14530608",
"title": "Long-Term Follow-up of a Case with Proprotein Convertase 1/3 Deficiency: Transient Diabetes Mellitus with Intervening Diabetic Ketoacidosis During Growth Hormone Therapy.",
"title_normalized": "long term follow up of a case with proprotein convertase 1 3 deficiency transient diabetes mellitus with intervening diabetic ketoacidosis during growth hormone therapy"
} | [
{
"companynumb": "TR-PFIZER INC-2018231764",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": null,
"drugadditional": null,
"drugadministrationroute": null,
"drugautho... |
{
"abstract": "Transplantation-associated thrombotic microangiopathy (TA-TMA) is a known complication of autologous hematopoietic cell transplantation (aHCT), particularly in children with neuroblastoma. We describe a pediatric single-institution experience of TA-TMA after aHCT. Data were abstracted from the medical record of patients who underwent aHCT between January 1, 2008, and July 1, 2018, at Boston Children's Hospital. TA-TMA was diagnosed using either the International Working Group criteria or the \"probable TA-TMA criteria\" of Cho et al. Overall, 318 aHCTs were performed in 243 patients. Nine patients (3.7%) were diagnosed with TA-TMA. TA-TMA occurred most frequently in children with neuroblastoma (n = 7; 78%), all of whom were conditioned with carboplatin, etoposide, and melphalan. The median age at aHCT in children who developed TA-TMA was 3 years, 5 months (range, 18 months to 25 years). TMA was diagnosed at a median of 35 days (range, 8 to 106 days) after stem cell infusion. On a retrospective chart review using the same criteria used by the provider, patients met criteria a median of 5 days before the clinical diagnosis (range, 0 to 58 days). Eight patients had renal involvement at presentation, including nephrotic range proteinuria and severe hypertension, requiring from 2 to 6 antihypertensive medications. Two patients presented with multiorgan failure. Six patients were treated with eculizumab a median of 0 days after TA-TMA diagnosis (range, 0 to 11 days). On retrospective review, patients were treated a median of 18 days (range, 0 to 58 days) after meeting criteria for TA-TMA. Before initiation of therapy, 4 of 6 patients checked for serum complement levels had normal values, 1 had elevated CH50 and 1 had elevated sC59-b and CH50. All patients had CH50 levels within the target range (≤3 CAE) after induction therapy. Two patients (33%) had no response to eculizumab and died of multiorgan failure. The other 4 had both a hematologic response with transfusion independence (median, 6.5 weeks; range, 4 to 9 weeks) and renal response, defined as resolution of nephrotic range proteinuria (median, 21 weeks; range, 13 to 25 weeks). Among the eculizumab-treated survivors, 2 patients remained on prolonged eculizumab therapy, and one had recurrence of TA-TMA after discontinuation of eculizumab. All 4 eculizumab treated survivors have persistent organ dysfunction. Three children were treated with supportive care only; 2 died of relapsed cancer, and the third is alive with stage 2 chronic kidney disease. The median duration of follow-up after TA-TMA diagnosis was 2.5 years (range, 9 months to 4 years). The 1-year overall survival was 78% (SE = 14%). However, regardless of treatment, no survivors had complete normalization of function in all organs. Three children with normal serum CH50 and sc5b-9 levels responded to eculizumab. This report highlights the importance of maintaining a high suspicion for TA-TMA after aHCT. Further study is warranted to identify individual risk factors for TMA after aHCT, predict the response to eculizumab, and capture long-term sequelae in survivors.",
"affiliations": "Dana Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts, United States. Electronic address: michelle_schoettler@dfci.harvard.edu.;Dana Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts, United States.;Boston Children's Hospital, Massachusetts, United States.;Boston Children's Hospital, Massachusetts, United States.;Dana Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts, United States.",
"authors": "Schoettler|Michelle|M|;Lehmann|Leslie|L|;Li|Anran|A|;Ma|Clement|C|;Duncan|Christine|C|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D051056:Complement Inactivating Agents; C481642:eculizumab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2018.12.840",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "25(5)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Autologous hematopoietic cell transplantation; Chronic kidney disease; Eculizumab; Neuroblastoma; Transplant associated thrombotic microangiopathy",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D002648:Child; D002675:Child, Preschool; D051056:Complement Inactivating Agents; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D009102:Multiple Organ Failure; D010372:Pediatrics; D012189:Retrospective Studies; D057049:Thrombotic Microangiopathies; D014182:Transplantation, Autologous; D055815:Young Adult",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "e163-e168",
"pmc": null,
"pmid": "30639820",
"pubdate": "2019-05",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "25037630;26603840;23294015;26456258;20697372;23227092;23814021;20717073;16275594;29674658;28705839;30144562;24370861;25483393;29920784;16969286;24876561;12201469;17229640",
"title": "Thrombotic Microangiopathy Following Pediatric Autologous Hematopoietic Cell Transplantation: A Report of Significant End-Organ Dysfunction in Eculizumab-Treated Survivors.",
"title_normalized": "thrombotic microangiopathy following pediatric autologous hematopoietic cell transplantation a report of significant end organ dysfunction in eculizumab treated survivors"
} | [
{
"companynumb": "US-ACCORD-103990",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "3",
"drug... |
{
"abstract": "BACKGROUND\nIdiopathic myointimal hyperplasia of mesenteric veins (IMHMV) is an uncommon cause of ischemic bowel disease resulting from the proliferation of smooth muscles in the venous intima. Delayed diagnosis could only be made following the surgical resection due to lack of imaging data, which may lead to bowel severe bleeding, perforation, necrosis, infection, or shock. In previous reports, few cases have provided the detailed pre-operative radiological characteristics of IMHMV. Herein, we are the first to provide the complete clinical course and comprehensive pre-operative radiological data of a 21-year-old female diagnosed with IMHMV.\nA 21-year-old female was admitted to our hospital with bloody diarrhea and abdominal pain. Physical examination revealed tenderness localized to the left lower abdomen. The patient had no prior history of similar symptoms. A computed tomography scan was performed and showed diffuse wall thickening from the rectum to sigmoid colon with poor mural enhancement, multiple ulcers, fat stranding, and free fluid. The arterial phase images demonstrated many tortuous pericolic arteries and submucosal pseudoaneurysm.\n\n\nMETHODS\nConservative treatment including empirical antibiotics, Mesalazine, and methylprednisolone sodium succinate were administrated to relief the symptoms. However, the diarrhea and abdominal pain worsened. An emergency surgery was arranged and total proctocolectomy with ileal pouchanal anastomosis with ileostomy was performed.\n\n\nMETHODS\nMacroscopic and histopathological examinations of the excised specimen showed ischemic colitis. Elastica van Gieson staining revealed extensive myointimal hyperplasia and confirmed the diagnosis of IMHMV.\n\n\nRESULTS\nDuring the 2-year follow-up period, no additional medical management was needed. The patient was well and surveillance colonoscopy showed normal colon and anastomosis.\n\n\nCONCLUSIONS\nPre-operative computed tomography with imaging features including pronounced continuous concentric thickening colonic wall with poor enhancement and enlarged tortuous pericolic arteries could specifically facilitate the speedy diagnosis of IMHMV.",
"affiliations": "Department of Radiology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.",
"authors": "Xie|Huanhuan|H|;Xu|Xiaopei|X|0000-0002-0342-383",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000027574",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974\n1536-5964\nLippincott Williams & Wilkins Hagerstown, MD\n\nMD-D-21-05262\n10.1097/MD.0000000000027574\n27574\n6800\nResearch Article\nClinical Case Report\nRadiological and clinical findings of idiopathic myointimal hyperplasia of mesenteric veins\nCase report\nXie Huanhuan MD\nXu Xiaopei PhD ∗\nSaranathan. Maya\nDepartment of Radiology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.\n∗ Correspondence: Xiaopei Xu, Department of Radiology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China 310000 (e-mail: xiaopeix@zju.edu.cn).\n22 10 2021\n22 10 2021\n100 42 e2757430 7 2021\n20 9 2021\n7 10 2021\nCopyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0\n\nAbstract\n\nIntroduction:\n\nIdiopathic myointimal hyperplasia of mesenteric veins (IMHMV) is an uncommon cause of ischemic bowel disease resulting from the proliferation of smooth muscles in the venous intima. Delayed diagnosis could only be made following the surgical resection due to lack of imaging data, which may lead to bowel severe bleeding, perforation, necrosis, infection, or shock. In previous reports, few cases have provided the detailed pre-operative radiological characteristics of IMHMV. Herein, we are the first to provide the complete clinical course and comprehensive pre-operative radiological data of a 21-year-old female diagnosed with IMHMV.\n\nPatient concerns:\n\nA 21-year-old female was admitted to our hospital with bloody diarrhea and abdominal pain. Physical examination revealed tenderness localized to the left lower abdomen. The patient had no prior history of similar symptoms. A computed tomography scan was performed and showed diffuse wall thickening from the rectum to sigmoid colon with poor mural enhancement, multiple ulcers, fat stranding, and free fluid. The arterial phase images demonstrated many tortuous pericolic arteries and submucosal pseudoaneurysm.\n\nIntervention:\n\nConservative treatment including empirical antibiotics, Mesalazine, and methylprednisolone sodium succinate were administrated to relief the symptoms. However, the diarrhea and abdominal pain worsened. An emergency surgery was arranged and total proctocolectomy with ileal pouchanal anastomosis with ileostomy was performed.\n\nDiagnosis:\n\nMacroscopic and histopathological examinations of the excised specimen showed ischemic colitis. Elastica van Gieson staining revealed extensive myointimal hyperplasia and confirmed the diagnosis of IMHMV.\n\nOutcomes:\n\nDuring the 2-year follow-up period, no additional medical management was needed. The patient was well and surveillance colonoscopy showed normal colon and anastomosis.\n\nConclusion:\n\nPre-operative computed tomography with imaging features including pronounced continuous concentric thickening colonic wall with poor enhancement and enlarged tortuous pericolic arteries could specifically facilitate the speedy diagnosis of IMHMV.\n\nKeywords\n\ncolonic wall thickening\nCT features\nidiopathic myointimal hyperplasia of the mesenteric veins\nischemic colitis\npoor mural enhancement\nOPEN-ACCESSTRUE\n==== Body\npmc1 Introduction\n\nIdiopathic myointimal hyperplasia of mesenteric veins (IMHMV) is a rare condition which poses diagnostic challenge to pathologists, radiologists, and clinicians. It has often been misdiagnosed as inflammatory bowel disease (IBD) or ischemic colitis due to their similar clinical manifestations. IMHMV primarily affects the rectosigmoid colon of middle-aged men, while the small intestine[1] is only involved in very few patients. Most patients suffer from persistent abdominal pain and hematochezia,[2] while some patients present with weight loss and small bowel obstruction.[3] The pathogenesis of the myointimal hyperplasia in mesenteric veins is still unknown. The more widely accepted hypothesis is that IMHMV stems from an acquired vascular or hemodynamic etiology, which believed that the traumatic injury of sigmoid mesocolon secondary to torsion or stretching could lead to arteriovenous fistulization and eventually myointimal hyperplasia of the mesenteric veins.[4] IMHMV usually requires complete surgical resection rather than medical treatment like IBD does. Delayed diagnosis may lead to bowel severe bleeding, perforation, necrosis, infection, or shock. In previous reports, few cases have provided the detailed pre-operative radiological characteristics of IMHMV. Here, we describe the detailed computed tomography (CT) imaging features and clinical course of a 21-year-old female. A review of the pertinent literatures is also given.\n\n2 Case presentation\n\n2.1 Clinical history\n\nA 21-year-old female was admitted to our hospital with abdominal pain, tenesmus, and bloody diarrhea for more than 10 days. Physical examination revealed tenderness localized to the left lower abdomen. The patient had no prior history of similar symptoms and no prior history of surgery, trauma, or connective tissue disorders. On admission, initial laboratory examinations revealed an elevated level of white blood cell count (18,700/mm3), C-reactive protein (14.6 mg/L), D-dimer (6820 μg/L), and carbohydrate antigen 125 (CA125, 60.6 U/mL). Colonoscopy at initial workup revealed edematous wall thickening, hyperemia and shallow ulceration with continuous involvement from rectum to sigmoid colon. The friable mucosa was difficult to identify and was easily bleeding (Fig. 1). No obvious abnormalities in transverse colon, ascending colon, and ileocecum was identified.\n\nFigure 1 Colonoscopy revealed diffuse severe edema and circumferential ulceration with exudates in the distal descending colon to the rectum. The mucosa was congested, edematous, and erythematous. The submucosal vessels were invisible and easily bleeding.\n\n2.2 Radiological findings\n\nMultiphase contrast-enhanced abdominopelvic CT were performed on the second day of admission. The CT imaging showed a long segment of marked wall thickening extending from the sigmoid colon to the distal rectum with poor mural enhancement, multiple ulcers, pericolic fat stranding, and free fluid. The colonic wall thickened to 1.6 cm and the marked submucosal edema caused the target sign of colonic wall. Thickening of the omentum was also noted while multiple enlarged lymph nodes could be seen in the retroperitoneum (Fig. 2A–C). The arterial phase images demonstrated the inferior mesentery artery with enlarged tortuous pericolic arteries and submucosal pseudoaneurysm (Fig. 2A, D). The portal phase image showed that the inferior mesenteric vein (IMV) was patent without filling defects or luminal irregularities (Fig. 2E). However, the ovarian veins were tortuous and dilated on the delayed phase images (Fig. 2B).\n\nFigure 2 Abdominopelvic CT findings of the IMHMV. Axial image of arterial phase (A) demonstrated the continuous concentric thick, edematous colonic wall (thick arrows) with poor enhancement and ulceration (arrows) of colonic wall. The prominent pericolic arteries (arrowheads) with pseudoaneurysm are the specific signs of IMHMV. Axial image of portal phases (B) showed the fat stranding, omental cake sign (arrowheads), and dilated ovarian veins (thick arrows). Oblique coronal reformatted image (C) of portal phase demonstrated severe rectum wall thickening with mural stratification, pericolic fat infiltration (arrows) and ascites (thick arrows). Many retroperitoneal enlarged lymph nodes were showed (arrowheads). Pseudoaneurysm (D) in the submucosa might be responsible for the bloody diarrhea. Axial delayed phase image (E) demonstrated the patent inferior mesenteric vein (arrowheads), superior mesenteric artery and superior mesenteric vein (thick arrows). CT = computed tomography, IMHMV = idiopathic myointimal hyperplasia of mesenteric veins.\n\n2.3 Treatment\n\nBased on the clinical symptoms, acute IBD was clinically suspected, and the patient was treated with empirical antibiotics (Sulperazon). However, the diarrhea and abdominal pain worsened overnight and resulted in sleep disturbance of the patient. Mesalazine and methylprednisolone sodium succinate were administrated after 4 days though did not offer symptomatic relief. Ten days after admission, the patient developed fever, massive hematochezia with decreased hemoglobin (from 123–57 g/L), and elevated white blood cell count and C-reactive protein (30,500/mm3 and 63.5 mg/L, respectively). The patient went into shock on her way to the second CT scan and was transferred to the emergency room immediately.\n\n2.4 Intra-operative findings and pathological examination results\n\nThe clinician explained the necessity of surgical resection to the patient. Total proctocolectomy with ileal pouchanal anastomosis with ileostomy was performed on the same day. Intra-operative exploration revealed multiple ulcerative lesions in the colon and rectum, with diffuse bleeding and local necrosis and perforations. Microscopically, mucosal ulcer, sub-mucosal edema with hemorrhage, and chronic serositis with fat necrosis were observed in the involved colon. Importantly, fibrous intimal thickening and luminal occlusion of mesentery and subserosal vascular could be observed, while there were no findings of surrounding venulitis or thrombi within veins. These findings were consistent with IMHMV. Additionally, Elastica van Gieson staining confirmed the presence of elastic fiber at the site of the thickened venous intima and the final diagnosis has been confirmed as IMHMV.\n\n2.5 Postoperative course\n\nThe patient was discharged 10 days after the surgery with no postoperative complications. At 4 months after the operation, the patient had a swift recovery without any additional medication. During the 2-years follow-up period, there was no evidence of disease recurrence. Postoperative contrast-enhanced abdominopelvic CT imaging indicated no abnormality.\n\n3 Discussion and conclusions\n\nIn 1991, Genta and Haggitt[5] were the first to describe 4 patients with segmental ischemic colitis caused by idiopathic myointimal hyperplasia in the small mesenteric veins. IMHMV is a rare and poorly understood cause of non-thrombotic, non-inflammatory mesenteric venous occlusion which affects the rectum and sigmoid colon. It is often misdiagnosed as IBD due to their similar clinical symptoms such as abdominal pain and bloody diarrhea. These patients often suffer from frequently prolonged clinical course and are placed on high doses of immunosuppressant which hindered the proper treatment.[6] IMHMV is rarely recognized in mucosal biopsies. Histologically, the distinctive pathognomonic feature includes non-thrombotic, non-inflammatory occlusion of the involved vessels secondary to extensive myointimal hyperplasia of the mesenteric veins in submucosa, adventitia, and mesocolon.[7] Venous myointimal hyperplasia without surrounding venulitis and arteritis is the key feature in the diagnosis of IMHMV. In addition, IMHMV has severe complications such as enterobrosis or severe internal bleeding which require emergency surgery.[4] Segmental resection is curative and there have not been any reports of the postoperative disease recurrence.[8,9]\n\nThe distinctive pre-operative CT features of IMHMV have yet to be fully described. So far, there have been 7 case reports about the expression of CT in IMHMV (Table 1). Together with our present case, the sigmoid colon was involved in 6 patients and rectum in 5 patients. There were 2 cases involving the descending colon or transverse colon. Only 1 patient had a focal lesion involving the ileum. Thus, the involvement almost confined to the rectosigmoid colon. To the best of our knowledge, IMHMV was only reported in the small bowel of 6 cases.[3,10–14] Two of 7 cases were focal lesion and 1 case had small bowel obstruction.[3,15] The focal lesion suspicious of a malignancy was easily misdiagnosed. Four out of 7 cases showed pericolic vessels with aneurysmal change or vascular congestion. All cases showed the distinct wall thickening and fat stranding.\n\nTable 1 Summary of radiological findings of IMHMV in previously reported cases.\n\nCase\tAuthor\tYear\tAge/gender\tClinical presentation\tLocation\tImaging modalities\tCT findings\t\n1\tSahara et al[20]\t2015\t76/M\tDiarrhea, abdominal pain\tSigmoid colon, rectum\tCECT\tWall thickening, severe edema, and the fat stranding\t\n2\tYang et al[15]\t2016\t44/M\tDiarrhea, abdominal pain\tRecto-sigmoid junction\tCECT\tFocal wall thickening, fat stranding\t\n3\tGarcia-Castellanos et al[17]\t2011\t32/F\tDiarrhea with blood and mucus, abdominal pain\tSigmoid colon, rectum\tCECT/angiography\tWall thickening, fat stranding, hypertrophic and collateral vessels\t\n4\tAnsari et al[18]\t2021\t63/M\tNon-bloody diarrhea, abdominal pain\tDistal transverse colon to sigmoid\tCECT\tWall thickening, serosal irregularity, pericolic inflammation change with mesocolic vascular congestion and hyperemia, free fluid\t\n5\tMartin et al[1]\t2019\t63/M\tFrom watery diarrhea to progressive bloody diarrhea, fecal incontinence, weight loss\tDistal descending colon to the rectum\tCECT/angiography\tContiguous concentric wall thickening, fat stranding, engorgement of the vessels\t\n6\tYun et al[2]\t2016\t64/M\tDiarrhea, left lower abdominal pain,\tDescending colon, sigmoid, rectum\tCECT/angiography\tActive bleeding, wall thickening, mural stratification, poor bowel wall enhancement and pericolic fat infiltration, pericolic veins with aneurysmal change\t\n7\tYamada et al[3]\t2021\t81/F\tAbdominal pain, nausea, and vomiting\tIleum\tCECT/barium X-ray series\tFocal wall thickening, stenosis of the terminal ileum, bowel obstruction\t\n\nIn addition, pronounced non-segmental, concentric, colonic wall thickening, which is consistent with the ischemic changes, is also a prominent radiological appearance of IMHMV. The marked submucosal edema caused the colonic wall a target sign. However, bowel wall thickening is also the least specific CT finding in cases of bowel ischemia, since it may be observed in a variety of non-ischemic conditions affecting the small or large bowel.[16] Another common sign which discriminates IMHVM from IBD is the poor mural enhancement. The intestinal wall edema and poor enhancement usually resulted from the hemodynamic changes and increased blood pressure due to the proliferation of smooth muscles in the venous intima. Histologically, the mesenteric veins in IMHMV closely resemble those seen in failed cardiac saphenous vein bypass grafts, consistent with a secondary ‘arterialization’ effect caused by greatly increased pressure within affected veins.[7] Abu-Alfa et al[7] hypothesized that the venous myointimal hyperplasia in IMHMV is caused by the increased intraluminal pressure due to an acquired segmental arteriovenous fistulization. We recognized that pre-operative contrast-enhanced CT showed many dilating peripheral arteries in the colonic region with edematous wall thickening. These findings may specifically support the diagnosis of IMHMV. Yun et al[2] and García-Castellanos[17] et al have reported a similar case demonstrating prominent pericolic veins with aneurysmal change and occlusion of the distal IMV using CT or angiography. Ansari et al[18] also reported mesocolic vascular congestion and hyperemia signs. Chiang et al[19] reported no demonstrable IMV is observed during venous-phase angiography and no arteriovenous fistula was found. However, our case demonstrated the IMV was patent. Thus, we concluded that IMV may be demonstrable in early stage of the disease. As the disease progresses, IMV may be occluded and arteriovenous fistula occur. All these reports showed no filling defects or luminal irregularities in the inferior mesentery artery and IMV. This was distinct from the mesenteric venous thrombosis cause of ischemic bowel disease. Therefore, we should examine angiography to investigate for venous occlusive diseases.[20] Previous literature reported that severe bloody stool was common. This symptom may lead to shock and even death threatening in patients. We recognize that the presence of multiple aneurysmal arteries in the submucosa is an important cause of bloody stool.\n\nUlceration and inflammatory exudates may be seen later in the disease process.[4] Our case indicated the ulceration of IMHMV was widespread and transmural. Severe bleeding and perforation could occur finally. Meanwhile, we found that the fat stranding was more diffuse, more severe in IMHMV than IBD. Our case showed the omental cake sign and showed a large amount of ascites.\n\nThe differential diagnosis of IMHMV includes IBD especially ulcerative colitis (UC), other ischemic bowel diseases such as mesenteric vasculitis and mesenteric venous thrombosis, and mesenteric inflammatory veno-occlusive disease (MIVOD). The most predilection sites and pronounced non-segmental wall thickening were similar to UC. The distinction between the 2 disease always was difficult. CT findings of UC include hyperenhancement and colorectal narrowing, widening of presacral space which differs from IMHMV. Contiguous thickening of the colon to the rectum was the distinguishing sign with Crohn disease which always manifested as discontinuous and eccentric thickening of the intestinal wall. The site of involvement in IMHMV was distinct from other ischemic bowel diseases such as mesenteric vasculitis. One of the most characteristic features of mesenteric vasculitis is the tendency to involve both the jejunum and the ileum, as well as both the small and large intestine.[21] Mesenteric venous thrombosis can be caused by various reasons. Thrombosis can be confidently detected with CT, even in the peripheral branches in nowadays. The CT features of MIVOD are similar to IMHMV, except the site of involvement. MIVOD has been reported to occur in all colonic segments as well as in the small bowel.[22] The pre-operative diagnosis of focal lesions was challenging. Sherman et al[23] reported that focal myointimal hyperplasia of mesenteric veins were associated with pre-resection trauma to the involved bowel segment. Thus, we need to be differentiated from colon cancer combining the clinical history and serum tumor markers.\n\nIn summary, we described the distinguishing CT features and complete clinical course of a rare case of IMHMV. Despite its rarity, we found that the characteristic radiological features of IMHMV include: typical sites of involvement including descending colon, sigmoid, and rectum; pronounced continuous concentric thick, edematous colonic wall with poor enhancement; no mesenteric venous thrombosis or occlusion in the IMV; many dilating peripheral arteries and pseudoaneurysm; ulceration and fat stranding. Although the diagnosis of IMHMV was difficult in patients with abdominal pain and bloody diarrhea, these radiological features may contribute to the pre-operative diagnosis of IMHMV. Radiologists should alert the clinicians with the possibility of IMHMV when noticing these imaging features, so as to perform the surgery in time and reducing diagnostic delays. Prompt operation can reduce patients’ suffering and improve their quality of life.\n\nAuthor contributions\n\nHh X analyzed and interpreted the patient data and was a major contributor in writing the manuscript. Xp X designed the study and edited the manuscript. All authors read and approved the final manuscript.\n\nInvestigation: Huanhuan Xie.\n\nSupervision: Xiaopei Xu.\n\nWriting – original draft: Huanhuan Xie.\n\nWriting – review & editing: Xiaopei Xu.\n\nAbbreviations: CT = computed tomography, IBD = inflammatory bowel disease, IMHMV = idiopathic myointimal hyperplasia of mesenteric veins, IMV = inferior mesenteric vein, MIVOD = mesenteric inflammatory veno-occlusive disease, UC = ulcerative colitis.\n\nHow to cite this article: Xie H, Xu X. Radiological and clinical findings of idiopathic myointimal hyperplasia of mesenteric veins: case report. Medicine. 2021;100:42(e27574).\n\nThis study was approved by our institutional ethics review board. Informed consent was waived based on ethics review board approval.\n\nInformed broad consent and written informed consent for publication of this case report and accompanying images were obtained from the patient. A copy of the written consent is available on request for review by the Editor-in-Chief of this journal.\n\nThe authors have no funding and conflicts of interest to disclose.\n\nAll data generated or analyzed during this study are included in this published article [and its supplementary information files].\n\nCECT = contrast-enhanced computed tomography, CT = computed tomography, IMHMV = idiopathic myointimal hyperplasia of mesenteric veins.\n==== Refs\nReferences\n\n[1] Martin FC Yang LS Fehily SR D'Souza B Lim A McKelvie PA . Idiopathic myointimal hyperplasia of the mesenteric veins: case report and review of the literature. JGH Open 2020;4 :345–50.32514435\n[2] Yun SJ Nam DH Kim J Ryu JK Lee SH . The radiologic diagnosis of idiopathic myointimal hyperplasia of mesenteric veins with a novel presentation: case report and literature review. Clin Imaging 2016;40 :870–4.27179160\n[3] Yamada K Hiraki M Tanaka T . A case of idiopathic myointimal hyperplasia of the mesenteric veins presenting with small bowel obstruction. Surg Case Rep 2021;7 :17.33438070\n[4] Kao PC Vecchio JA Hyman NH West AB Blaszyk H . Idiopathic myointimal hyperplasia of mesenteric veins: a rare mimic of idiopathic inflammatory bowel disease. J Clin Gastroenterol 2005;39 :704–8.16082281\n[5] Genta RM Haggitt RC . Idiopathic myointimal hyperplasia of mesenteric veins. Gastroenterology 1991;101 :533–9.2065929\n[6] Wangensteen KJ Fogt F Kann BR Osterman MT . Idiopathic myointimal hyperplasia of the mesenteric veins diagnosed preoperatively. J Clin Gastroenterol 2015;49 :491–4.25626629\n[7] Abu-Alfa AK Ayer U West AB . Mucosal biopsy findings and venous abnormalities in idiopathic myointimal hyperplasia of the mesenteric veins. Am J Surg Pathol 1996;20 :1271–8.8827035\n[8] Korenblit J Burkart A Frankel R . Refractory pancolitis: a novel presentation of idiopathic myointimal hyperplasia of mesenteric veins. Gastroenterol Hepatol (N Y) 2012;8 :696–700.24683381\n[9] Anderson B Smyrk TC Graham RP Lightner A Sweetser S . Idiopathic myointimal hyperplasia is a distinct cause of chronic colon ischaemia. Colorectal Dis 2019;21 :1073–8.31074117\n[10] Bryant J . Unexpected sudden death during propranolol therapy in a patient with mild mesenteric venous myointimal hyperplasia. J Forensic Sci 1998;43 :905–7.9670518\n[11] Lanitis S Kontovounisios C Karaliotas C . An extremely rare small bowel lesion associated with refractory ascites. Idiopathic myointimal hyperplasia of mesenteric veins of the small bowel associated with appendiceal mucocoele and pseudomyxoma peritonei. Gastroenterology 2012;142 :e5–7.\n[12] Laskaratos FM Hamilton M Novelli M . A rare cause of abdominal pain, diarrhoea and GI bleeding. Idiopathic myointimal hyperplasia of the mesenteric veins (IMHMV). Gut 2015;64 : 214, 350.\n[13] Guadagno E De Caro MDB Del PE D’Armiento FP Campione S . Coexistence of multiple ileal neuroendocrine tumors and idiopathic myointimal hyperplasia of mesenteric veins: coincidence or consequence? Case report and review of literature. Int J Surg Pathol 2016;24 :627–30.27069024\n[14] Song SJ Shroff SG . Idiopathic myointimal hyperplasia of mesenteric veins of the ileum and colon in a patient with Crohn's disease: a case report and brief review of the literature. Case Rep Pathol 2017;2017 :6793031.28894617\n[15] Yang KH Kwon TH Park KS . Idiopathic myointimal hyperplasia of mesenteric veins. Korean J Gastroenterol 2016;67 :54–7.27213200\n[16] Wiesner W Khurana B Ji H Ros PR . CT of acute bowel ischemia. Radiology 2003;226 :635–50.12601205\n[17] García-Castellanos R López R de Vega VM . Idiopathic myointimal hyperplasia of mesenteric veins and pneumatosis intestinalis: a previously unreported association. J Crohns Colitis 2011;5 :239–44.21575888\n[18] Ansari AA Ahmed S Mansour E Abass MA . Idiopathic myointimal hyperplasia of the mesenteric veins. J Surg Case Rep 2021;2021 : rjaa453.\n[19] Chiang CK Lee CL Huang CS Huang SH Wu CH . A rare cause of ischemic proctosigmoiditis: idiopathic myointimal hyperplasia of mesenteric veins. Endoscopy 2012;44 : (Suppl 2 UCTN) : E54–5.22396277\n[20] Sahara K Yamada R Fujiwara T . Idiopathic myointimal hyperplasia of mesenteric veins: rare case of ischemic colitis mimicking inflammatory bowel disease. Dig Endosc 2015;27 :767–70.25777655\n[21] Rha SE Ha HK Lee SH . CT and MR imaging findings of bowel ischemia from various primary causes. Radiographics 2000;20 :29–42.10682769\n[22] Hu JC Forshaw MJ Thebe P Stewart M . Mesenteric inflammatory veno-occlusive disease as a cause of acute abdomen: report of five cases. Surg Today 2005;35 :961–4.16249852\n[23] Sherman J Kao PC Brian WA Blaszyk H . Focal myointimal hyperplasia of mesenteric veins is associated with previous trauma in surgical specimens. Pathol Res Pract 2006;202 :517–22.16684590\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "100(42)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D017091:Colitis, Ischemic; D005260:Female; D006801:Humans; D006965:Hyperplasia; D008642:Mesenteric Veins; D014652:Vascular Diseases; D055815:Young Adult",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e27574",
"pmc": null,
"pmid": "34678900",
"pubdate": "2021-10-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Radiological and clinical findings of idiopathic myointimal hyperplasia of mesenteric veins: Case report.",
"title_normalized": "radiological and clinical findings of idiopathic myointimal hyperplasia of mesenteric veins case report"
} | [
{
"companynumb": "CN-PRA-000198",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
"... |
{
"abstract": "Statin-induced myopathy is well-known, but the effect of cholesterol-lowering agents on myasthenia gravis (MG) has not been studied in detail. We investigated statin use and its effects on MG among patients with this disease. Statin information was systemically obtained from 170 patients being treated at the Neuromuscular Disease Clinic at the University of Alabama at Birmingham. When a new myalgic syndrome or worsening of MG developed within 4 months after statin treatment, no other likely cause was found, and clinical improvement occurred either with or without discontinuation of the statin, we considered these symptoms to be statin-induced. Fifty-four patients (31%) were on statins. The statin group had proportionally more males, and older patients compared with the non-statin group. A myalgic syndrome was noted in 7 (13%) patients, but it resolved without any sequelae after withdrawal of the statin. MG worsening occurred in 6 (11%) patients without regard to type of MG or brand of statin. MG worsening occurred independently of myalgic syndrome and involved predominantly oculobulbar symptoms within 1-16 weeks of statin treatment. In 4 patients, additional treatment was needed to reverse MG worsening. Statins are safe in the majority of MG patients, but their use must be accompanied by close observation for possible MG worsening.",
"affiliations": "Department of Neurology, University of Alabama at Birmingham, Veterans Affairs Medical Center, Birmingham, Alabama 35294, USA. shinjoh@uab.edu",
"authors": "Oh|Shin J|SJ|;Dhall|Rohit|R|;Young|Angela|A|;Morgan|Marla B|MB|;Lu|Liang|L|;Claussen|Gwendolyn C|GC|",
"chemical_list": "D000906:Antibodies; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011950:Receptors, Cholinergic",
"country": "United States",
"delete": false,
"doi": "10.1002/mus.21074",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0148-639X",
"issue": "38(3)",
"journal": "Muscle & nerve",
"keywords": null,
"medline_ta": "Muscle Nerve",
"mesh_terms": "D000328:Adult; D000368:Aged; D000906:Antibodies; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis; D011950:Receptors, Cholinergic; D012189:Retrospective Studies",
"nlm_unique_id": "7803146",
"other_id": null,
"pages": "1101-7",
"pmc": null,
"pmid": "18720508",
"pubdate": "2008-09",
"publication_types": "D016428:Journal Article",
"references": "1324429;12241896;12186811;10721974;15389654;15596782;2930608;8041396;9668273;9854600;9046891;16609346;16864763;10877038;16688722;12517506;11893380;12804701;16018797;15006590",
"title": "Statins may aggravate myasthenia gravis.",
"title_normalized": "statins may aggravate myasthenia gravis"
} | [
{
"companynumb": "PHHY2012US137951",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SIMVASTATIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "A 75-year-old woman presented with new onset of confusion, intense episodic dizziness and formed visual hallucinations. Herpes simplex encephalitis and non-convulsive temporal lobe seizures were confirmed with cerebrospinal fluid (CSF) and electroencephalography testing. In addition, her hospital course was complicated by syndrome of inappropriate antidiuretic hormone secretion and atonic bladder contributing to an episode of urinary tract infection. After completing 3 weeks of acyclovir treatment, the patient became obtunded with right arm choreiform movements and persistent inflammatory CSF findings not attributable to persistent herpes simplex virus infection or other confounding factors. The patient responded to steroid treatment. Repeated autoimmune and paraneoplastic evaluations were negative. Both clinical (cognitive testing and atonic bladder) and CSF inflammatory finding improved in the follow-up period.",
"affiliations": "Department of Neurological Sciences, University of Vermont Medical Center, Burlington, Vermont, USA.;Department of Neurological Sciences, University of Vermont Medical Center, Burlington, Vermont, USA.;Department of Neurological Sciences, University of Vermont Medical Center, Burlington, Vermont, USA.;Department of Neurological Sciences, University of Vermont Medical Center, Burlington, Vermont, USA.",
"authors": "Mrad|Luay|L|;Moustakas|Argirios|A|;Fuino|Robert|R|;Waheed|Waqar|W|",
"chemical_list": "D000998:Antiviral Agents; D005938:Glucocorticoids; D000212:Acyclovir; D008775:Methylprednisolone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-230005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(7)",
"journal": "BMJ case reports",
"keywords": "clinical neurophysiology; epilepsy and seizures; immunology; neurology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000212:Acyclovir; D000368:Aged; D000998:Antiviral Agents; D002819:Chorea; D004569:Electroencephalography; D004660:Encephalitis; D020803:Encephalitis, Herpes Simplex; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007177:Inappropriate ADH Syndrome; D008775:Methylprednisolone; D012640:Seizures; D000077295:Urinary Bladder, Underactive; D016055:Urinary Retention; D014552:Urinary Tract Infections",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31337628",
"pubdate": "2019-07-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28639214;9153470;11941546;12587075;18983763;17541231;15572000;26205506;10648433;24152761;26443565;26700486;25795644;21704564;18959773;16540518;28536235;12874408;24009096;25192177;30049614;1325041;28450685;28363090;9489547",
"title": "Severe presentation of antibody-negative, postinfectious steroid-responsive encephalitis and atonic bladder after herpes simplex encephalitis.",
"title_normalized": "severe presentation of antibody negative postinfectious steroid responsive encephalitis and atonic bladder after herpes simplex encephalitis"
} | [
{
"companynumb": "US-APOTEX-2019AP020774",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VALACYCLOVIR HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "BACKGROUND\nThe prevalence of childhood onset type 2 diabetes (T2D) is increasing, but prepubertal T2D is still unusual.\n\n\nMETHODS\nWe report four cases of T2D with onset at or below 10 years of age registered at a tertiary diabetes centre in southern India.T2D was diagnosed based on the absence of ketosis, good beta cell reserve as shown by the C peptide assay, absence of GAD antibodies and pancreatic calculi, and response to oral hypoglycemic agents.\n\n\nRESULTS\nAll four patients were female, obese and had acanthosis nigricans. Polycystic ovarian syndrome and fatty liver were found in two cases. All were treated with metformin but two patients needed insulin additionally. Two had hypercholesterolemia and hypertension. One patient developed non-proliferative diabetic retinopathy on follow up.\n\n\nCONCLUSIONS\nT2D is now beginning to be seen in the first decade of life. A proper clinical work up of children with diabetes will prevent misclassification as type 1 diabetes and help avoid unnecessary insulin therapy.",
"affiliations": "Scientist, Madras Diabetes Research Foundation, Chennai, Tamil Nadu.;Vice Chairman, Dr. Mohan's Diabetes Specialities Centre & Madras Diabetes Research Foundation, Chennai, Tamil Nadu.;Vice President and Managing Director, Madras Diabetes Research Foundation & Dr. Mohan's Diabetes Specialities Centre, Chennai, Tamil Nadu.;President, Madras Diabetes Research Foundation & Chairman, Dr. Mohan's Diabetes Specialities Centre, Chennai, Tamil Nadu.",
"authors": "Amutha|Anandakumar|A|;Unnikrishnan|Ranjit|R|;Anjana|Ranjit Mohan|RM|;Mohan|Viswanathan|V|",
"chemical_list": "D002096:C-Peptide; D006442:Glycated Hemoglobin A; D007004:Hypoglycemic Agents; C517652:hemoglobin A1c protein, human",
"country": "India",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-5772",
"issue": "65(2)",
"journal": "The Journal of the Association of Physicians of India",
"keywords": null,
"medline_ta": "J Assoc Physicians India",
"mesh_terms": "D002096:C-Peptide; D002648:Child; D003924:Diabetes Mellitus, Type 2; D005260:Female; D006442:Glycated Hemoglobin A; D006801:Humans; D007004:Hypoglycemic Agents; D010375:Pedigree; D011627:Puberty",
"nlm_unique_id": "7505585",
"other_id": null,
"pages": "43-46",
"pmc": null,
"pmid": "28457031",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Prepubertal Childhood Onset Type 2 Diabetes Mellitus: Four Case Reports.",
"title_normalized": "prepubertal childhood onset type 2 diabetes mellitus four case reports"
} | [
{
"companynumb": "IN-IMPAX LABORATORIES, INC-2018-IPXL-03283",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
... |
{
"abstract": "A 45-year-old woman presented to the Emergency Department complaining of severe headache for 3 hours duration associated with bilateral blurred vision, photophobia, and one attack of vomiting. Her clinical examination revealed normal vital signs and decrease in visual acuity with hazy cornea bilaterally. There were no signs of increased intracranial pressure and no neck rigidity or meningeal signs. The patient was diagnosed with bilateral acute closed angle glaucoma (AACG) with intraocular pressure of 60 mmHg in both eyes. She was using escitalopram for the treatment of depression, which was the only known risk factor for her condition. Standard treatment for AACG was provided. It included topical β-blocker, α agonists, and acetazolamide. This was followed by bilateral peripheral iridotomy. Follow-up intraocular pressure measurement revealed a value of 5 mmHg after 24 hours, indicating complete recovery. To the best of our knowledge, this is the first case to describe AACG after stopping the medication. It is highly important that clinicians be aware of this risk factor for AACG and have high index of suspicion in such patients with vision-threatening condition even after discontinuing the medication, because the risk persists for some time.",
"affiliations": "Department of ENT.;Department of Emergency Medicine, King Fahad Hospital of the University, University of Dammam, Dammam, Saudi Arabia.;Department of Emergency Medicine, King Fahad Hospital of the University, University of Dammam, Dammam, Saudi Arabia.",
"authors": "AlQuorain|Sara|S|;Alfaraj|Sukayna|S|;Alshahrani|Mohammed|M|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/OAEM.S107551",
"fulltext": "\n==== Front\nOpen Access Emerg MedOpen Access Emerg MedOpen Access Emergency MedicineOpen Access Emergency Medicine : OAEM1179-1500Dove Medical Press 10.2147/OAEM.S107551oaem-8-061Case-ReportBilateral acute closed angle glaucoma associated with the discontinuation of escitalopram: a case report AlQuorain Sara 1Alfaraj Sukayna 2Alshahrani Mohammed 21 Department of ENT2 Department of Emergency Medicine, King Fahad Hospital of the University, University of Dammam, Dammam, Saudi ArabiaCorrespondence: Mohammed Alshahrani, Department of Emergency Medicine, College of Medicine, King Fahad Hospital of the University, University of Dammam, PO Box 40236, AlKhobar, Saudi Arabia, Tel +966 5 5696 6663, Email msshahrani@ud.edu.sa2016 08 9 2016 8 61 65 © 2016 AlQuorain et al. This work is published and licensed by Dove Medical Press Limited2016The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.A 45-year-old woman presented to the Emergency Department complaining of severe headache for 3 hours duration associated with bilateral blurred vision, photophobia, and one attack of vomiting. Her clinical examination revealed normal vital signs and decrease in visual acuity with hazy cornea bilaterally. There were no signs of increased intracranial pressure and no neck rigidity or meningeal signs. The patient was diagnosed with bilateral acute closed angle glaucoma (AACG) with intraocular pressure of 60 mmHg in both eyes. She was using escitalopram for the treatment of depression, which was the only known risk factor for her condition. Standard treatment for AACG was provided. It included topical β-blocker, α agonists, and acetazolamide. This was followed by bilateral peripheral iridotomy. Follow-up intraocular pressure measurement revealed a value of 5 mmHg after 24 hours, indicating complete recovery. To the best of our knowledge, this is the first case to describe AACG after stopping the medication. It is highly important that clinicians be aware of this risk factor for AACG and have high index of suspicion in such patients with vision-threatening condition even after discontinuing the medication, because the risk persists for some time.\n\nKeywords\nacute closed angle glaucomaescitalopramintraocular pressure\n==== Body\nBackground\nBy 2020, 79.6 million people will have open and closure angle glaucoma, and this will be the second leading cause of blindness in the world.1 Angle-closure glaucoma is characterized by narrowing or closure of the anterior chamber angle of the eye. Patients present with decreased vision, halos around lights, headache, severe eye pain, and vomiting. Eye examination usually shows conjunctival redness, corneal edema or clouding, shallow anterior chambers, and mid-dilated pupils (4–6 mm) that react poorly to light. Angle-closure glaucoma is divided into two main groups: primary – in which patients are anatomically predisposed to this type of glaucoma with no identifiable risk factor – and secondary – which includes the presence of known cause for narrowing or closure of the anterior chamber angle.2 Drugs were found to be among those secondary causes. The eye is prone to drug-related adverse effects due, in part, to its extensive blood supply and relatively small mass. Examples of these drugs include topical anticholinergic or sympathomimetic dilating drops, some antidepressants such as tricyclic and selective serotonin reuptake inhibitor (SSRI), monoamine oxidase inhibitors, antihistamines, antiparkinsonian drugs, antipsychotic medications, and antispasmolytic agents.3–5 According to one study, 33% of acute closed angle glaucoma is secondary to over-the-counter and prescription medications.6\n\nWe reported a rare case of a 45-year-old woman with typical symptoms and signs of bilateral acute closed angle glaucoma with the risk factor of previous use of SSRI medicine for her depression symptoms (escitalopram), which she stopped recently.\n\nCase presentation\nHistory\nHere, we describe the case of a 45-year-old woman known to have controlled hypertension for 5 years for which she was taking oral beta-blocker medications, and she also had a history of depression for 1 year. The patient presented to the Emergency Department complaining of moderate right-sided headache associated with bilateral blurred vision, photophobia, and one attack of vomiting. Two hours later, the headache shifted to the left side and became much more severe. There was no history of previous similar episodes of headache, head trauma, fever, neck rigidity, rash, loss of consciousness, aphasia, weakness, numbness, and diplopia. In addition, there was also no previous history of eye trauma or surgery or family history of glaucoma.\n\nThe patient gave the history of using escitalopram for the treatment of depression for 1 year, which she stopped suddenly 1 month prior to presentation. The patient’s vital signs were all normal. On physical examination, cranial nerves were intact. Neurological examination showed normal sensory and motor systems, and reflexes and normal cerebellar function. Neck movement was normal, and no meningeal signs were present. Eye examination revealed normal white sclera and middilated pupils, which were nonreactive to light. Visual acuity examination showed results of 0.3 and 0.4 for right and left eyes, respectively. The cornea was slightly hazy in both eyes. Intraocular pressure (IOP) was 60 mmHg in both eyes. Retinal examination showed a cup-to-disc ratio of 0.4 and 0.2 for right and left eyes, respectively, with no other retinal findings on fundoscopy. Pentacam examination of the eyes is shown in Figures 1 and 2. Results of all laboratory investigations, including complete blood count, renal, liver function, and electrolytes, were within the normal range. Nonenhanced transaxial computed tomography scan of the brain was done and showed preserved gray-white matter with no obvious hemorrhage. There were no space-occupying lesions, mass effect, or midline shift, and also no hydrocephalus, and orbit and sinuses were normal.\n\nTreatment\nThe patient was treated for acute closed angle glaucoma secondary to escitalopram with IV acetazolamide (Diamox), mannitol, timolol, Alphagan, pilocarpine eye drops, followed next day by bilateral peripheral iridotomy. Follow-up of the patient after 48 hours showed normal anterior chambers, with an IOP of 5 mmHg for each eye, which indicates a complete recovery. As per the University of Dammam Institutional Review Board, case reports do not need ethical approval or patient consent, as long as there is no intervention encountered and no identifiers for the patients appear in the report. Therefore, neither ethical approval nor patient consent was required for this case report.\n\nDiscussion\nOur case describes a patient who presented to the emergency department with typical symptoms and signs of acute closed angle glaucoma, and the identified risk factors were hypertension and escitalopram use for her depression for 1 year (which she stopped recently). In this case, we are in favor of blaming this antidepressant drug over the systemic hypertension as the risk factor for her presenting condition because her blood pressure was controlled by using a beta blocker, which was found by Langman et al7 in a cohort of 27,080 hypertensive patients to be decreasing the risk of glaucoma in hypertensive patients.\n\nEscitalopram belongs to a group of antidepressant medicines known as SSRIs. Serotonin (5-HT) receptors have been shown to be present in human eyes and present at a higher concentration in mammalian ciliary body and cornea than in nonmammalian species.8,9 Meyer et al10 showed that topical application of SSRI increases IOP in rabbits’ eyes where serotonin raised the IOP in a dose-dependent manner over time, with a maximum reached within 1 hour. Similarly, in a study of 20 consecutive depressed patients, administration of a single dose of 20 mg fluoxetine increased the IOP by 4 mmHg.11\n\nThere are few case reports in the literature that described acute glaucoma after the use of escitalopram. But to the best of our knowledge, this is the first case to describe the condition after stopping the medication. However, it has been reported by Fava et al12 in a large systematic review, including 15 randomized controlled studies, four open trials, four retrospective studies, and 38 case reports, in which the withdrawal effects of SSRIs were found to be multisystem. Eye manifestations were reported as visual changes and blurred vision. This visual effect of SSRIs can be explained by delayed action of this class of drugs. The mechanism by which SSRIs result in angle-closure glaucoma remains uncertain. It has been postulated that serotonin is responsible for increased pupil dilation and aqueous production.13 Another study suggested that the anticholinergic effects of the medications cause pupil dilation.14 Zelefsky et al15 reported a similar case of bilateral angle-closure glaucoma that was resistant to medical and surgical treatment after 4 weeks of use of escitalopram, and complete recovery was achieved only after the discontinuation of the medication. The similarity between our case and the case described by Zelefsky et al15 is that both were resistant to medical treatments initially, but our case responded to laser peripheral iridotomy whereas Zelefsky et al’s15 case only responded after stopping the offending drug, which was stopped already in our case by the patient.\n\nThis report serves to highlight the importance of constant vigilance when diagnosing and treating acute glaucoma, particularly in cases with no clear risk factors and resistant to usual treatment, this case did not respond to the normal range of treatments for the condition.\n\nConclusion\nThe correlation between the usage of SSRIs and the development of acute glaucoma has been described and discussed previously in the literature. Whether there is a correlation between the development of acute glaucoma and SSRIs after discontinuing the medication needs to be elucidated by further studies.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Pentacam of the left eye.\n\nNote: Pentacam of the left eye of the patient indicates that the cornea is normal and all other measurement aspects are normal except the increase in the AC depth, which indicates angle-closure glaucoma in that eye.\n\nAbbreviations: AC, anterior chamber; BFS, Brillouin frequency shifts; OD, optical density.\n\nFigure 2 Pentacam of the right eye.\n\nNote: Pentacam of the right eye of the patient indicates that the cornea is normal and all other measurement aspects are normal except the increase in the AC depth, which indicates angle-closure glaucoma in that eye.\n\nAbbreviations: AC, anterior chamber; BFS, Brillouin frequency shifts; OD, optical density.\n==== Refs\nReferences\n1 Quigley HA Broman AT The number of people with glaucoma worldwide in 2010 and 2020 Br J Ophthalmol 2006 90 3 262 267 16488940 \n2 See JL Chew PT Angle-closure Glaucoma Yanoff M Duker JS Ophthalmology 3rd ed St Louis, MO Mosby 2009 1162 \n3 Razeghinejad MR Myers JS Katz LJ Iatrogenic glaucoma secondary to medications Am J Med 2011 124 20 25 21092926 \n4 Tripathi RC Tripathi BJ Haggerty C Drug induced glaucoma’s: mechanisms and management Drugs Saf 2003 26 11 749 767 \n5 Lachkar Y Bouassida W Drug-induced acute angle closure glaucoma Curr Opin Ophthalmol 2007 18 2 129 133 17301614 \n6 Rudkin AK Gray TL Awadalla M Craig JE Bilateral simultaneous acute angle closure glaucoma precipitated by non-prescription cold and flu medication Emerg Med Australas 2010 22 5 477 479 21040488 \n7 Langman MJ Lancashire RJ Cheng KK Stewart PM Systemic hypertension and glaucoma: mechanisms in common and co-occurrence Br J Ophthalmol 2005 89 960 963 16024843 \n8 Barrett JE Vanover KE 5-HT receptors as targets for the development of novel anxiolytic drugs: models, mechanisms and future directions Psychopharmacology (Berl) 1993 112 1 1 12 7870996 \n9 Osbourne NN Tobin AB Serotonin accumulating cells in the iris-ciliary body and cornea of various species Exp Eye Res 1987 44 731 746 3653269 \n10 Meyer-Bothling U Bron AJ Osborne NN Topical application of serotonin or the 5-HTX-agonist 5-CT intraocular pressure in rabbits Invest Ophthalmol Vis Sci 1993 34 3035 3042 8395485 \n11 Osbourne NN Serotonin and melatonin in the iris/ciliary processes and their involvement in intraocular presence Acta Neurobiol Exp 1994 54 Suppl 57 64 \n12 Fava GA Gatti A Belaise C Guidi J Offidani E Withdrawal symptoms after selective serotonin reuptake inhibitor discontinuation: a systematic review Psychother Psychosom 2015 84 72 81 25721705 \n13 Santaella RM Fraunfelder FW Ocular adverse effects associated with systemic medications Drugs 2007 67 1 75 93 17209665 \n14 Costagliola C Parmeggiani F Sebastiani A SSRIs and intraocular pressure modifications: evidence, therapeutic implications and possible mechanisms CNS Drugs 2004 18 8 475 484 15182218 \n15 Zelefsky JR Fine HF Rubinstein VJ Hsu IS Finger PT Escitalopram-induced uveal effusions and bilateral angle closure glaucoma Am J Ophthalmol 2006 141 6 1144 1147 16765693\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-1500",
"issue": "8()",
"journal": "Open access emergency medicine : OAEM",
"keywords": "acute closed angle glaucoma; escitalopram; intraocular pressure",
"medline_ta": "Open Access Emerg Med",
"mesh_terms": null,
"nlm_unique_id": "101570796",
"other_id": null,
"pages": "61-5",
"pmc": null,
"pmid": "27660499",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "17301614;25721705;7870996;15182218;16765693;16488940;16024843;21040488;21092926;12908846;17209665;7801793;8395485;3653269",
"title": "Bilateral acute closed angle glaucoma associated with the discontinuation of escitalopram: a case report.",
"title_normalized": "bilateral acute closed angle glaucoma associated with the discontinuation of escitalopram a case report"
} | [
{
"companynumb": "SA-LUPIN PHARMACEUTICALS INC.-2016-05098",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ESCITALOPRAM OXALATE"
},
"drug... |
{
"abstract": "For some patients with medically refractory epilepsy (MRE), surgery is a safe and effective treatment for controlling epilepsy. However, the functional consequences of such surgery on brain activity and connectivity in children remain unknown. In the present study, we carried out a longitudinal study using resting-state functional magnetic resonance imaging in 10 children with MRE before and again at a mean of 79 days after surgery, as well as in a group of 28 healthy controls. Compared with the controls, children with epilepsy exhibited abnormalities in intrinsic activity in the thalamus, putamen, pallidum, insula, hippocampus, cerebellum, and cingulate gyrus both before and after surgery. Longitudinal analyses showed that the amplitude of low frequency fluctuations (ALFF) increased in the parietal-frontal cortex and decreased in the deep nuclei from pre- to post-surgery. The percentage changes in ALFF values in the deep nuclei were positively correlated with the age of epilepsy onset. Functional connectivity (FC) analyses demonstrated a reorganization of FC architecture after surgery. These changes in brain activity and FC after surgery might indicate that the previously disrupted functional interactions were reorganized after surgery. All these results provide preliminary evidence that the age of epilepsy onset may have some potential to predict the outcome of brain functional reorganization after surgery in children with MRE.",
"affiliations": "Guangdong Provincial Key Laboratory of Medical Biomechanics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.;Department of Pediatric Neurosurgery, Shenzhen Children's Hospital, Shenzhen, China.;The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.;Guangdong Provincial Key Laboratory of Medical Biomechanics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.;Department of Pediatric Neurosurgery, Shenzhen Children's Hospital, Shenzhen, China.;Department of Pediatric Neurosurgery, Shenzhen Children's Hospital, Shenzhen, China.;Department of Pediatric Neurosurgery, Shenzhen Children's Hospital, Shenzhen, China.;Centre for Biomedical Engineering, School of Electrical and Electronic Engineering, University of Adelaide, Adelaide, SA, Australia.;School of Medicine, Western Sydney University, Campbelltown, NSW, Australia.;Guangdong Provincial Key Laboratory of Medical Biomechanics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.",
"authors": "Li|Yongxin|Y|;Tan|Zhen|Z|;Wang|Jianping|J|;Wang|Ya|Y|;Gan|Yungen|Y|;Wen|Feiqiu|F|;Chen|Qian|Q|;Abbott|Derek|D|;Wong|Kelvin K L|KKL|;Huang|Wenhua|W|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fneur.2017.00374",
"fulltext": "\n==== Front\nFront NeurolFront NeurolFront. Neurol.Frontiers in Neurology1664-2295Frontiers Media S.A. 10.3389/fneur.2017.00374NeuroscienceOriginal ResearchAlterations in Spontaneous Brain Activity and Functional Network Reorganization following Surgery in Children with Medically Refractory Epilepsy: A Resting-State Functional Magnetic Resonance Imaging Study Li Yongxin 1†Tan Zhen 2†Wang Jianping 3Wang Ya 1Gan Yungen 2Wen Feiqiu 2Chen Qian 2*Abbott Derek 4Wong Kelvin K. L. 5Huang Wenhua 1*1Guangdong Provincial Key Laboratory of Medical Biomechanics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China2Department of Pediatric Neurosurgery, Shenzhen Children’s Hospital, Shenzhen, China3The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China4Centre for Biomedical Engineering, School of Electrical and Electronic Engineering, University of Adelaide, Adelaide, SA, Australia5School of Medicine, Western Sydney University, Campbelltown, NSW, AustraliaEdited by: Mark Richardson, King’s College London, United Kingdom\n\nReviewed by: Qianfa Long, Xi’an Jiao Tong University, China; Luiz Eduardo Betting, Universidade Estadual Paulista Júlio Mesquita Filho, Brazil\n\n*Correspondence: Qian Chen, chenqian68@126.com; Wenhua Huang, huangwenhua2009@sina.com†These authors have contributed equally to this work.\n\nSpecialty section: This article was submitted to Epilepsy, a section of the journal Frontiers in Neurology\n\n03 8 2017 2017 8 37411 3 2017 17 7 2017 Copyright © 2017 Li, Tan, Wang, Wang, Gan, Wen, Chen, Abbott, Wong and Huang.2017Li, Tan, Wang, Wang, Gan, Wen, Chen, Abbott, Wong and HuangThis 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) or licensor 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.For some patients with medically refractory epilepsy (MRE), surgery is a safe and effective treatment for controlling epilepsy. However, the functional consequences of such surgery on brain activity and connectivity in children remain unknown. In the present study, we carried out a longitudinal study using resting-state functional magnetic resonance imaging in 10 children with MRE before and again at a mean of 79 days after surgery, as well as in a group of 28 healthy controls. Compared with the controls, children with epilepsy exhibited abnormalities in intrinsic activity in the thalamus, putamen, pallidum, insula, hippocampus, cerebellum, and cingulate gyrus both before and after surgery. Longitudinal analyses showed that the amplitude of low frequency fluctuations (ALFF) increased in the parietal–frontal cortex and decreased in the deep nuclei from pre- to post-surgery. The percentage changes in ALFF values in the deep nuclei were positively correlated with the age of epilepsy onset. Functional connectivity (FC) analyses demonstrated a reorganization of FC architecture after surgery. These changes in brain activity and FC after surgery might indicate that the previously disrupted functional interactions were reorganized after surgery. All these results provide preliminary evidence that the age of epilepsy onset may have some potential to predict the outcome of brain functional reorganization after surgery in children with MRE.\n\nmedically refractory epilepsychildrensurgeryamplitude of low-frequency fluctuationfunctional connectivityNational Natural Science Foundation of China10.13039/501100001809No. 81601483, No. 61427807\n==== Body\nIntroduction\nEpilepsy is the second most common neurological disease worldwide. Currently, the mainstay of epilepsy management is therapy with antiepileptic drugs. However, previous studies have shown that up to one-third of all patients with epilepsy are resistant to medical treatment (1). It is now widely accepted that epilepsy surgery is a safe and effective treatment in children diagnosed with medically refractory epilepsy (MRE) (2, 3). Successful epilepsy surgery not only controls seizures, but also substantially improves patients’ cognition, behavior, and quality of life (4). Despite these behavioral observations, the exact neural mechanisms underlying these phenomena remain obscure.\n\nRecently, the non-invasive technique of functional magnetic resonance imaging (fMRI) has played a prominent role in the investigation of the neural mechanisms underlying epilepsy in the human brain. Prior neuroimaging studies have primarily focused on adults with epilepsy and on the evaluation of patients under consideration for epilepsy surgery (2, 5). Functional neuroimaging studies have found that functional abnormalities in epileptic patients are not limited to the epileptogenic region and that region with neuronal connections to the entire brain can also be impacted (6, 7). With surgical intervention, there is a cortical reorganization of function in the language-specific cortex and the default mode network (8–10). Nevertheless, very little is known about the functional consequences of epilepsy surgery in children. Moreover, few studies have longitudinally assessed brain activity changes after neurosurgery in children with MRE and how these neural changes relate to clinical characteristics. To the best of our knowledge, only three studies have used fMRI to examine brain activity changes after neurosurgery in children with MRE (11–13). All of these longitudinal studies in children have demonstrated restoration of functional connectivity (FC) architecture, especially in the thalamo-cortical circuitry (13). However, these three publications are case studies. Therefore, the restoration of functional plasticity following surgery needs to be validated in a larger cohort to clarify the neural mechanisms underlying these changes.\n\nThe aim of the present study was to identify a pattern of intrinsic brain activity in children diagnosed with MRE. Furthermore, we used resting-state fMRI to assess the location and extent of intrinsic brain activity after surgery and to investigate the causes of these changes. The amplitude of low frequency fluctuations (ALFF) of resting-state fMRI has been widely used to investigate the aberrant intrinsic brain activity of clinical patients (14). Recent studies have validated the high temporal stability of this approach in identifying potential biomarkers for neurological diseases (15–17). Mesial temporal lobe epilepsy patients showed a decrease in ALFF in the default mode network and an increase in ALFF in the mesial temporal, thalamus, and other cortical regions. ALFF analysis may provide a useful tool in fMRI for the study of epilepsy (18). FC is a widely used metric obtained from resting-state fMRI that measures the temporal correlation of neuronal activity-induced signal variations in anatomically different brain regions (19). This technique has also been used to capture functional brain changes in response to epilepsy treatment in adults (9, 10). Before surgery, temporal lobe epilepsy patients showed abnormal neural activity in the frontal gyri and default mode network. Post-surgery data revealed that the epilepsy patients showed a recovery of the activity in these networks. Therefore, it is potentially feasible and valuable to use this technique to investigate the response to surgery in children with MRE.\n\nIn the present study, we applied these techniques to a group of children with MRE in whom resting-state fMRI data were acquired before and after surgery. The ALFF values were calculated to compare the differences in these patients to those in the matched controls. Longitudinal changes in ALFF and FC from pre- to post-surgery were identified to explore the neural mechanism of functional plasticity after surgery. We also investigated the influence of clinical factors on ALFF in children with MRE. Based on previous research in epilepsy, we hypothesized that spontaneous brain activity and the functional network of epilepsy-related areas in children with MRE would change compared with normal children. Abnormal activity and network architecture may reorganize with surgical treatment.\n\nMaterials and Methods\nSubjects\nTen children with MRE [three females, age (mean ± SD): 49.94 ± 48.52 months] participated in this study. The diagnosis and location of the seizure foci were determined by a comprehensive evaluation including a detailed history and video-EEG telemetry. The details of epilepsy type and the clinical information are presented in Table 1. All patients underwent a pre-surgical evaluation and subsequently underwent resection surgery for the treatment of their epilepsy at the Shenzhen Children Hospital in Shenzhen, China. All patients who underwent epilepsy surgery were seizure free at the time of post-surgical testing. Post-surgical structural images for all patients are shown in Figure 1. Resting-state fMRI data were collected for all patients at two-time points: before and after surgery. Same imaging protocol was used for the pre- and post-surgical scans. Twenty-eight sex- and age-matched healthy controls [10 females, age (mean ± SD): 53.21 ± 37.99 months] were also recruited. These control subjects had no history of neurological disorders or psychiatric illnesses. All control subjects were scanned only once, on the day when they were recruited for this study. Written informed consent forms were obtained from all participant’s parents in accordance with the standards of the Declaration of Helsinki. The Ethics Committee of the Shenzhen Children Hospital approved this study.\n\nTable 1 Summary of the clinical characteristics of child epilepsy patients.\n\nPatient no.\tSex\tAge 1 (months)\tAge 2 (months)\tAge 3 (months)\tInterval 1 (months)\tInterval 2 (months)\tPathogency\tType\tAntiepileptic drugs\tSeizure frequency (pre- to postoperative)\t\n1\tF\t7\t13\t3\t4\t6\tR cortex dysplasia\tInfantile spasm\tVPA, OXC, TPM\t5–10/day to seizure free\t\n2\tM\t9\t14\t0.5\t9\t4.5\tR frontal dysplasia\tAsymmetric tonic-closure seizures\tVPA, CBZ, TPM\t1–2/day to seizure free\t\n3\tM\t161\t165\t36\t125\t4\tR parietal occupation lesions\tFrontal epilepsy\tVPA, CBZ, TPM\t2–3/day to seizure free\t\n4\tM\t18\t19.5\t6\t13\t0.5\tR cerebromalacia\tInfantile spasm\tVPA, CBZ, LEV\t3–15/day to seizure free\t\n5\tF\t93.5\t95\t12\t82\t1\tL temporal lesion\tTemporal epilepsy\tOXC, VPA\t3–4/day to seizure free\t\n6\tF\t26.3\t28\t12\t14.5\t1.5\tR frontal dysplasia\tFrontal epilepsy\tCBZ, VPA\t2–3/day to seizure free\t\n7\tM\t81\t83\t6\t76\t1\tL cerebromalacia\tAsymmetric tonic-closure seizures\tVPA, CBZ, TPM, LEV\t3–4/day to seizure free\t\n8\tM\t44\t48\t6\t38\t4\tR temporal lesion\tTemporal epilepsy\tCBZ, VPA\t1/day to seizure free\t\n9\tM\t27\t28.5\t14\t13\t1.5\tR frontal occupation lesions\tFrontal epilepsy\tOXC, VPA\t2–3/day to seizure free\t\n10\tM\t32\t35\t27\t6\t2\tL frontal occupation lesions\tAsymmetric tonic-closure seizures\tOXC, VPA\t7–8/day to seizure free\t\nF, female; M, male; L, left; R, right; Age 1, age of first scan in months; Age 2, age of second scan; Age 3, age of epilepsy onset; Interval 1, interval between epilepsy onset to surgery; Interval 2, interval between surgical procedure and second scan; CBZ, carbamazepine; LEV, levetiracetam; OXC, oxcarbazepine; TPM, topiramate; VPA, valproic acid.\n\nFigure 1 The post-surgical structural image of all patients. All images were achieved from the high-resolution T1-weighted 3D images. The images were showed in coronal or sagittal view of each subject. Surgery location: right hemisphere (Sub 1–4, Sub 6, Sub 8, and Sub 9), left hemisphere (Sub 5, Sub 7, and Sub 10). The detail of epilepsy type and the clinical information can be seen in Table 1. L, left; R, right.\n\nImage Acquisition\nImaging data were acquired on a 3 T Siemens scanner (MAGNETOM Trio Tim, Siemens, Germany) using an eight-channel head coil at the Shenzhen Children’s Hospital in Shenzhen, China. Foam cushions were used in the scanning procedures to reduce head translational and rotational movements. Resting blood oxygen level-dependent data were acquired from each subject using a same echo-planar imaging sequence with the following scan parameters: TR/TE = 2,000/30 ms, FOV = 220 mm × 220 mm, matrix = 94 × 94, flip angle = 90°, slice thickness = 3 mm, 36 interleaved axial slices, and 130 volumes. During the 260 s resting-state fMRI scan, all participants under the age of 4 were sedated with 10% chloral hydrate. Others were instructed to rest, to not think of anything, to keep their eyes open, and to not fall asleep. To avoid the subjects’ falling asleep, a relatively short scan was performed in this study. We also asked about their condition after the scan.\n\nData Preprocessing\nThe resting-state fMRI data were processed using Data Processing Assistant for Resting-State fMRI software (http://www.restfmri.net). Images from the three patients with left-side epileptic pathogency (Patients no. 5, 7, 10) were oriented around the midsagittal plane prior to data analyses, thereby lateralizing the epilepsy type to the right hemisphere in all patients. The first 10 functional images per subject were excluded from analyses to ensure equilibrium of magnetization. The preprocessing steps included slice timing, spatial realignment, normalization to the Montreal Neurological Institute template (resolution of 3 mm × 3 mm × 3 mm) and spatial smoothing with a 6-mm full width at half maximum Gaussian kernel. It was planned that subjects whose translational head motion exceeded 2 mm or rotational motion exceeded 2° during scanning would be excluded, but none of the participants in the present study were excluded based on this criterion. Finally, we removed linear trends from time courses, performed temporal bandpass filtering (0.01–0.08 Hz) and regressed out the nuisance signals such as the six head-motion parameters, global mean, white matter signals, and cerebrospinal fluid signals.\n\nALFF Analyses\nThe time courses were converted to a measure of frequency using a fast Fourier transform algorithm and the averaged square root of each spectrum across 0.01–0.08 Hz at each voxel was determined as the ALFF value. The framework for performing ALFF analyses can be seen in Figure S1 in Supplementary Material (an example of an ALFF analysis process in one voxel). The whole-brain voxel-wise ALFF was calculated in each participant in the patient group and healthy control group. Two-sample t-tests were performed to find areas that showed significant differences in ALFF between children with epilepsy, both before and after surgery, and the controls. The significance threshold of the two-sample t-test was set at p < 0.001 (t > 3.348) and a minimum cluster size of five voxels. The differences in ALFF between the pre- and postoperative scans in the patients group were also tested using paired samples t-tests. The significance threshold was set at p < 0.005 (t > 3.355) and a minimum cluster size of five voxels. We used this threshold in the paired samples t-tests considering a similar t value was used for both t-tests. Age and gender were controlled as covariates in all the above statistical analyses.\n\nCorrelations between the ALFF and Clinical Characteristics in Patients\nThe regions that showed significant changes in ALFF following surgery were selected as regions of interest (ROIs) for post hoc analyses. Average ALFF values in each ROI were extracted. The percentage changes following surgery in ALFF in each ROI were calculated with the following formula: (post–pre)/pre × 100.\n\nPartial correlation analyses were used to analyze the correlation between the percentage changes in ALFF values in each ROI and the age of epilepsy onset. The clinical factors, such as the interval between the two scans and the interval from epilepsy onset to surgery, were selected as control covariates. We used an uncorrected statistical significance level of p < 0.05, as these analyses were exploratory.\n\nFC Analyses\nThe filtered imaging data were then analyzed to remove the sources of spurious variance through linear regression, including the six parameters of head motion, the CSF signal, and the white matter signal. Time series of voxel within each ROI were averaged and corrected with the average time series of the other ROIs. Correlation values were then z-transformed to the mean of the whole sample. A two-sample t-test for statistical analysis of FC for each pair of ROIs was performed, comparing the patient and control groups both before and after treatment. To compare pre-surgical and post-surgical FC for each pair of ROIs in the patient group, we performed paired t-test analyses. We used an uncorrected statistical significance level of p < 0.05 as these analyses were exploratory.\n\nResults\nBetween-Group ALFF Analyses\nBefore surgery, the patient group showed a higher ALFF in the bilateral thalamus, putamen, temporal lobe, and cerebellum compared with the control group. An increased ALFF was also observed in the left pallidum, the left precuneus, the right fusiform, and the right hippocampus relative to the controls. In contrast, a decreased ALFF was observed only in the right post-central gyrus.\n\nAfter surgery, the patients showed an increased ALFF in the left parahippocampus, precuneus, orbital middle frontal gyrus, inferior parietal lobule (IPL), and insula relative to the controls. Additionally, an increased ALFF was seen in the bilateral pallidum and the right thalamus, the putamen, the precentral gyrus, the orbital middle temporal gyrus, and the cerebellum. A decreased ALFF was observed in the right hemisphere including the angular, pre- and post-central gyri. Figure 2 depicts the significantly different ALFF values between the control and patient groups.\n\nFigure 2 Abnormal spontaneous brain activity in children patients before and after epilepsy surgery. Increased amplitude of low frequency fluctuations (ALFF) are showed in hot color. In contrast, decreased ALFF are showed in cold color.\n\nPaired Samples t-Test Analyses in Patients\nFollowing epilepsy surgery, there were significant increases in ALFF in the bilateral IPL and right superior parietal lobule. The right post-central gyrus and inferior frontal gyrus (IFG) also showed significant increases in ALFF after epilepsy surgery. There were significant decreases in ALFF in the left putamen, the bilateral calcarine cortex, the right thalamus, and the middle cingulum after epilepsy surgery. There group differences are shown in Table 2 and Figure 3.\n\nTable 2 Summary of significant activations between pre- and postoperative conditions in the patient group from the whole-brain analysis.\n\nComparisons\tStatistical values\tCoordinates anatomical location\t\nCluster size\tt-Value\tp-Value\tx\ty\tz\tRegion\t\nAfter > before\t\t\t\t\t\t\t\t\n\t8\t4.09\t0.002\t51\t15\t9\tR Oper Inf frontal gyrus\t\n\t6\t4.56\t0.001\t54\t−6\t24\tR post-central gyrus\t\n\t6\t4.92\t0.001\t51\t−39\t48\tR Inf parietal lobule\t\n\t9\t4.64\t0.001\t18\t−69\t51\tR Sup parietal lobule\t\n\t8\t4.53\t0.001\t−48\t−48\t54\tL Inf parietal lobule\t\nBefore > after\t\t\t\t\t\t\t\t\n\t5\t5.43\t0.000\t−30\t3\t−3\tL putamen\t\n\t7\t5.57\t0.000\t15\t−6\t0\tR thalamus\t\n\t5\t6.01\t0.000\t−3\t−102\t3\tL calcarine\t\n\t13\t4.12\t0.002\t15\t−46\t6\tR calcarine\t\n\t7\t3.95\t0.002\t6\t−18\t30\tR mid cingulum\t\nThe MNI coordinates and t-values for the local maxima of the centers of the voxel clusters.\n\nR, right hemisphere; L, left hemisphere; Inf, inferior; Oper, operior; Sup, superior; Mid, middle.\n\nThreshold for significant clusters reported here was set at p < 0.005 and cluster size of 5.\n\nFigure 3 Longitudinal changes of spontaneous brain activity in children with medically refractory epilepsy from pre- to post-surgery.\n\nCorrelations between the ALFF and the Age of Epilepsy Onset\nTen clusters that showed significant changes in the ALFF following surgery were selected as ROIs for the correlation analyses. The mean ALFF values of each ROI were calculated as shown in Figure 4. The percent changes in ALFF and partial correlation analyses results are shown in Table 3. There was a significant positive correlation between the age of epilepsy onset and the percentage changes in ALFF values extracted from the left putamen (r = 0.808, p = 0.008), the left calcarine cortex (r = 0.812, p = 0.007), the right calcarine cortex (r = 0.625, p = 0.049), and the right middle cingulum (r = 0.894, p = 0.001).\n\nFigure 4 The mean amplitude of low frequency fluctuations (ALFF) values of each region of interest in children with medically refractory epilepsy from pre- to post-operation. pre, pre-surgery; post, post-surgery.\n\nTable 3 Partial correlation analyses between the percentage change of amplitude of low frequency fluctuations (ALFF) following surgery and age of epilepsy onset.\n\n\tRegions\tALFF values\t\nr-Value\tp-Value\t\nAge of epilepsy onset\tR Inf frontal gyrus\t−0.257\t0.270\t\n\tR post-central\t−0.204\t0.314\t\n\tR Inf parietal lobule\t0.091\t0.415\t\n\tR Sup parietal lobule\t0.124\t0.385\t\n\tL Inf parietal lobule\t−0.221\t0.300\t\n\tL putamen\t0.808\t0.008\t\n\tR thalamus\t0.043\t0.460\t\n\tL calcarine\t0.812\t0.007\t\n\tR calcarine\t0.625\t0.049\t\n\tR mid cingulum\t0.894\t0.001\t\nResults of partial correlation, control for the interval of two scannings, and the interval from epilepsy onset to surgery as covariates. Values in the table were Pearson’s coefficients (r) and the corresponding p-value (one-tailed). Significant correlation results were marked in bold.\n\nInf, inferior; Mid, middle; Sup, superior; R, right hemisphere; L, left hemisphere.\n\nFC Analyses within the ROIs\nConnectivity between the time courses within 10 ROIs was calculated. The pairs of ROIs showed significant changes between groups were selected and displayed in Figure 5. FC analyses in patients showed that the connectivity between the left IPL and the left putamen was decreased nearly to the level of normal controls after the surgery. The connectivity between the left IPL and the right calcarine was disrupted in the patient group before surgery. After surgical intervention, this disrupted intrahemispheric connectivity was restored nearly to the level of that in the normal control group. The connectivity between the left putamen and the right thalamus was disrupted in the patient group at the pre-surgical scan compared with that of the controls. This disrupted connectivity was reorganized after surgery. We found that patients with MRE showed a significantly decreased bilateral IPL connectivity at both pre- and post-surgical scans compared with the controls. Compared with the controls, the FC between the right IFG and the right post-central gyrus showed a nearly significant decrease in the patient group before surgery. With the surgical intervention, this connectivity was increased but not reached the level of the control group.\n\nFigure 5 Comparison of functional connectivity (FC) among groups. Two-sample t-test was used between the patient and the control group, while two-pair t-test was used in the patient groups from pre- to post-surgery.\n\nDiscussion\nThis study demonstrates the functional consequences of surgery on brain functional networks in children with MRE. We used a longitudinal method with resting-state fMRI to explore aberrant intrinsic brain activity from pre- to post-surgery. We found that the ALFF values were increased significantly in the bilateral parietal lobe and right frontal lobe after surgery. In contrast, the ALFF values decreased significantly in the deep nuclei (such as the left putamen, bilateral calcarine, right thalamus, and middle cingulate gyrus) with surgical intervention. The percentage changes in ALFF values showed decreases in these regions and these values were correlated with the age of epilepsy onset. FC analyses further demonstrated a reorganization of FC architecture after surgery, especially the pathways of the left IPL vs. the left putamen and the left IPL vs. the right calcarine. These changes in spontaneous brain activity and FC architecture after surgical intervention are consistent with each other, which might indicate that the disrupted functional interactions were reorganized after surgery. The correlation between brain activity and clinical characters implied that the age of epilepsy onset might affect the brain functional organization. Overall, our results suggest that early and successful surgery in children with MRE may potentially induce brain functional plasticity. The age of epilepsy onset may affect children’s brain functional reorganization after surgery.\n\nPostoperative Spontaneous Brain Activity Changes as Measured by ALFF\nGeneralized epileptic discharges that are related to activation in the thalamus along with deactivation in the default mode areas have been reported in a large body of literature, suggesting seizure generation, and the suspension of brain default function (15, 17, 20). In the present study, resting-state fMRI data in children with epilepsy were collected and brain activity patterns were measured using ALFF values. The patient group showed an increased ALFF in the subcortical structures and decreased ALFF in the post-central gyrus before surgery. The results were consistent with previous studies and implied functional brain damage caused by epilepsy seizures. After surgery, the seizures were controlled and the abnormal brain activity in the patient group showed an adaptive process. These results might implicate that epilepsy surgery is an established treatment for the selected patients with MRE in the present study, which can induce brain reorganization. In the functional domain, this adaptive process after epilepsy surgery can re-establish the normal brain function that is disrupted by epilepsy seizure. For example, Wong et al. (9) offered the neuroimaging evidence that the cortical language network is reorganized after an anterior temporal lobectomy. In our study, the brain activity patterns and connectivity patterns in some regions were altered after surgery. The brain activity changes following surgery in the present study may suggest the importance of epilepsy surgery in cases of MRE in infants and young children (21, 22). In the present study, the ALFF values in the deep nuclei were decreased after surgery, which implied that epilepsy damage of the putamen and the thalamus were prevented and even showed reorganization after surgery.\n\nThe significant changes in ALFF values within these regions after surgery can be explained by their functional role. The significantly decreased ALFF values seen in the thalamus after surgery are consistent with the known important role of subcortical structures in the generalization of epileptic seizures (23). The thalamus is an essential node involved in epilepsy networks. This region plays an important role in the initiation, propagation, and inhibition of epileptic activity (15, 24). Generalized epilepsy seizures spread out through the cortical–subcortical epilepsy network. This induces electrical discharges in the regions in the epilepsy network. In the present study, significantly increased ALFF values in the temporal lobe, cerebellum, and subcortical nuclei before surgery demonstrated that these regions would be affect by the epilepsy seizure. With surgical intervention, longitudinal changes in ALFF in the right thalamus implied that surgery intervention might control seizure activity in children. The ALFF values were decreased significantly after surgery, as no seizures generalized through the thalamus.\n\nIn addition, an increase in ALFF after surgery was found in the bilateral IPL, the right superior parietal area, and the frontal area. A large body of imaging studies have well-addressed the abnormalities of the frontal–parietal network in epilepsy patients (17, 20, 25, 26). The damage due to chronic seizures was controlled with epilepsy surgery. Functional impairments were recovered leading to increased brain activity in the parietal and frontal areas. Brain functional plasticity theory can also be used to explain these results. Previous studies have shown that human brain networks are plastic and can reorganize in response to the changes in the external environment or internal milieu (27, 28). Resting-state networks were reorganized after brain epilepsy surgery in parallel with the recovery of brain function (9, 10, 29). Longitudinal analyses showed that the ALFF values in the frontal–parietal network were increased significantly from pre- to post-surgery in our study. These results demonstrate that the parietal and frontal areas were sculpted by epilepsy surgery.\n\nCorrelations between the Percentage Changes in ALFF and Clinical Characteristics\nThe ALFF changes in fMRI signals have been suggested to be associated with clinical characteristics, such as the number of interictal epileptiform discharges or epilepsy duration (15, 17). Epilepsy duration was the most frequently used factor to calculate the neuroimaging prediction degree. In the present study, we used the patients’ age of epilepsy onset as a clinical factor to calculate the correlation with the neuroimaging results. We selected this clinical characteristic because our research subjects were children with MRE. Ongoing seizures would affect the normal developmental trajectory of these children’s brains. Our statistical results of the ALFF values between the pre-surgical group and the controls confirmed this expectation. The post-surgery seizure records indicate that all patients were seizure free after surgery. Once seizures are controlled after epilepsy surgery, the interrupted development in these children can potentially recover. Two prospective population-based observational studies have shown that early epilepsy surgery in infants and young children with MRE is important for improving brain activity (22, 30). A recent review in the domain of pediatric epilepsy also highlights the importance of early intervention of epilepsy surgery to brain recovery (21). Based on these previous studies, we speculated that children’s pre-surgical clinical condition might also have some predictive value regarding on brain reorganization after surgery.\n\nTherefore, we selected children’s age of epilepsy onset as our focus to study whether it is possible to predict children’s functional brain status after surgery. As expected, our correlation results demonstrate that the children with a younger age of epilepsy onset showed a large decrease in ALFF values from pre- to post-surgery in the bilateral calcarine, left putamen, and right middle cingulum. In these analyses, the age, sex, interval between the two scans, and the interval from epilepsy onset to surgery were all controlled. The partial correlation results implied that the age of epilepsy onset in children with MRE can, to some extent, predict the degree of brain activity change after epilepsy surgery. A child with an earlier epilepsy onset combined with an early referral for epilepsy surgery evaluation can potentially have improved brain activity after surgery.\n\nPostoperative Brain Changes in FC\nFunctional correlations between the epilepsy-related areas in each group were calculated in the present study. Compared with the controls, the patients with MRE showed a reduced connectivity between the right superior IFG and the right IPL. This difference was no longer significant post-surgery, which may represent a normalization of this functional pathway following surgery. Previous resting-state FC studies in epilepsy have shown disconnected connectivity to nodes within the diseased hemisphere (13). Another study in patients with mesial temporal lobe epilepsy showed that FC decreases bilaterally (31). In addition, they found the number of decreased links was significantly higher in the epileptogenic side. In the present study, we flipped the epilepsy type to the right hemisphere. Therefore, we consider the diseased hemisphere in the present study to be the right hemisphere. Decreased FC within the right hemisphere was consistent with previous studies and provides evidence that functional interactions are dependent upon structural connectivity. Postoperatively, FC between the right IFG and the right IPL was partially increased, which demonstrated the reorganization of FC architecture with epilepsy surgery.\n\nFurthermore, participants with epilepsy showed reduced connectivity between hemispheres, such as between the left IPL and the right calcarine, the left IPL and the right IPL, the left putamen and the right thalamus. The FC between the left IPL and the left putamen was increased significantly in patients before surgery. These results were consistent with the previous view of brain functional network changes after epilepsy or lesions (31–33). A previous study has shown that the interhemispheric FC in epilepsy patients was decreased compared with that in normal subjects (33). This study also showed that there was increased intrahemispheric FC within the healthy hemisphere in patients. Therefore, the decreased interhemispheric FC results found in the present study might imply that children’s brain functional integration between the hemispheres was damaged after epilepsy. In contrast, the increased intrahemispheric FC between the left IPL and left putamen indicated that the healthy hemisphere may be playing a compensatory role to support cognition (34). After surgery, these differences in interhemispheric FC were no longer significant except in the bilateral IPL. The increase in interhemispheric FC values after surgery might represent a reorganization of the functional pathway between the both hemispheres. The FC values between the left IPL and left putamen after surgery were decreased to a range similar to that of the controls. This may indicate that surgery can restore the functional pathways between the two hemispheres. The increased FC values between the functional cortexes within the diseased hemisphere after surgery would indicate brain functional reorganization. Therefore, compensation of the regions in the healthy hemisphere was no longer playing an important role after surgery. Taken together, these FC results suggest that surgery-induced brain functional recovery might be the main reason for the pathway reorganization between the hemispheres or in the functional areas within the seizure focus hemisphere.\n\nLimitations\nAlthough brain activity differences were identified from pre- to post-operation, the interpretations of these results should be made cautiously. The sample size of epilepsy patients in the current study is small. Larger numbers of patients will be required to identify consistent changes associated with successful epilepsy surgery across participants. The selected patients in the present study might suitable for surgery to controlling the seizure. Some children patients with MRE might not achieve satisfy results after surgery. This type of patients should also be considered in the future study. Another limitation of the current study was the use of the brain reversal method. Although this method is usually used in brain lesion studies, this operation can also introduce certain deviations to the analyses. In future studies, larger numbers of patients will be needed to divide the patients into left- and right-side types of epileptic pathogency. Third, imaging data in the epilepsy children were only collected at two-time points: pre-surgery and once post-surgery (mean of 79 days later). A longitudinal study with more time points should be designed to describe the long-term effects of epilepsy surgery on children’s brain development. Finally, the intervals between the surgery and the second fMRI scan varied from 0.5 to 7 months. The sedatives were used in some patients during the scanning but others were not. Same imaging protocol was used for the pre- and post-surgical scans in all patients. We realized that all of these factors might affect our final results. Future studies should consider and control for these factors to improve the reliability of the results.\n\nConclusion\nThe present study investigated epilepsy surgery-induced changes in brain activation and FC patterns in a group of 10 children with MRE using resting-state fMRI. Longitudinal analyses found that ALFF values in the parietal and frontal areas were increased significantly after surgery. In contrast, the ALFF values in the deep nuclei were decreased significantly after surgery. The percentage changes in ALFF values in the deep nuclei areas were correlated with the age of epilepsy onset. Here, FC analyses demonstrated a restoration of FC architecture after surgery, especially in the functional pathways between the both hemispheres or connecting the functional areas within the seizure focus hemisphere. These changes in brain activity and FC after surgical intervention might indicate that the disrupted functional interactions were reorganized after surgery. All these results provide preliminary evidence that the age of epilepsy onset might affect the brain functional organization. The current study can aid in understanding the neural mechanism underlying the functional plasticity following surgery in children with MRE.\n\nEthics Statement\nWritten informed consent was obtained from all parents in accordance with the standards of the Declaration of Helsinki. The Ethics Committee of the Shenzhen Children Hospital approved this study.\n\nAuthor Contributions\nYL, QC, KW, WH, and DA conceived and designed the experiments. ZT, QC, JW, FW, and YG performed the experiments. YL, KW, XM, and YW analyzed the data. YL, KW, and WH contributed reagents/materials/analysis tools. ZT, FW, QC, and DA responsible for patient management and conceptualized the study. YL, JW, and KW wrote and revised the paper.\n\nConflict of Interest Statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nWe would like to think all subjects who collocated in this study for their cooperation. We are also grateful to the radiographers at the Department of Pediatric Radiology of Shenzhen Children Hospital, who scanned the subjects.\n\nFunding. This work was supported by the National Natural Science Foundation of China (No. 81601483, No. 61427807), the Natural Science Foundation of Guangdong Province of China (No. 2016A030310402), and the China Postdoctoral Science Foundation (No. 2017M610538). This work was also supported by the Medical Scientific Research Foundation of Guangdong Province (Grant No. A2016317) and Shenzhen Science and Technology Innovation Committee (JCYJ20160429174426094). This work was also supported by the research startup foundation of Southern Medical University (PY2015N001).\n\nSupplementary Material\nThe Supplementary Material for this article can be found online at http://journal.frontiersin.org/article/10.3389/fneur.2017.00374/full#supplementary-material.\n\nFigure S1 Framework for performing amplitude of low frequency fluctuations (ALFF) analysis. The time courses of one voxel were converted to the frequency domain by using a fast Fourier transform. The averaged square root of the spectrum across 0.01–0.08 Hz at each voxel was taken as the ALFF value.\n\nClick here for additional data file.\n==== Refs\nReferences\n1 Ben-Menachem E \nMedical management of refractory epilepsy-practical treatment with novel antiepileptic drugs . Epilepsia (2014 ) 55 :3 –8 .10.1111/epi.12494 \n2 Gomez-Alonso J Bellas-Lamas P \nSurgical treatment for drug-resistant epilepsy . JAMA (2015 ) 313 :1572 10.1001/jama.2015.2883 \n3 Puka K Smith ML . Where are they now? Psychosocial, educational, and vocational outcomes after epilepsy surgery in childhood . Epilepsia (2016 ) 57 :574 –81 .10.1111/epi.13327 26858091 \n4 Fiest KM Sajobi TT Wiebe S . Epilepsy surgery and meaningful improvements in quality of life: results from a randomized controlled trial . Epilepsia (2014 ) 55 :886 –92 .10.1111/epi.12625 24735200 \n5 Zhang J Liu W Chen H Xia H Zhou Z Mei S \nMultimodal neuroimaging in presurgical evaluation of drug-resistant epilepsy . Neuroimage Clin (2014 ) 4 :35 –44 .10.1016/j.nicl.2013.10.017 24282678 \n6 Waites AB Briellmann RS Saling MM Abbott DF Jackson GD . Functional connectivity networks are disrupted in left temporal lobe epilepsy . Ann Neurol (2006 ) 59 :335 –43 .10.1002/ana.20733 16404743 \n7 Frings L Schulze-Bonhage A Spreer J Wagner K . Remote effects of hippocampal damage on default network connectivity in the human brain . J Neurol (2009 ) 256 :2021 –9 .10.1007/s00415-009-5233-0 19603243 \n8 Pataraia E Billingsley-Marshall RL Castillo EM Breier JI Simos PG Sarkari S \nOrganization of receptive language-specific cortex before and after left temporal lobectomy . Neurology (2005 ) 64 :481 –7 .10.1212/01.WNL.0000150900.71773.E6 15699379 \n9 Wong SWH Jong L Bandur D Bihari F Yen YF Takahashi AM \nCortical reorganization following anterior temporal lobectomy in patients with temporal lobe epilepsy . Neurology (2009 ) 73 :518 –25 .10.1212/WNL.0b013e3181b2a48e 19687453 \n10 Doucet GE Skidmore C Evans J Sharan A Sperling MR Pustina D \nTemporal lobe epilepsy and surgery selectively alter the dorsal, not the ventral, default-mode network . Front Neurol (2014 ) 5 :23 .10.3389/fneur.2014.00023 24653713 \n11 Johnston JM Vaishnavi SN Smyth MD Zhang DY He BJ Zempel JM \nLoss of resting interhemispheric functional connectivity after complete section of the corpus callosum . J Neurosci (2008 ) 28 :6453 –8 .10.1523/JNEUROSCI.0573-08.2008 18562616 \n12 Pizoli CE Shah MN Snyder AZ Shimony JS Limbrick DD Raichle ME \nResting-state activity in development and maintenance of normal brain function . Proc Natl Acad Sci U S A (2011 ) 108 :11638 –43 .10.1073/pnas.1109144108 21709227 \n13 Ibrahim GM Morgan BR Smith ML Kerr E Donner E Go CY \nThalamocortical connectivity is enhanced following functional hemispherotomy for intractable lateralized epilepsy . Epilepsy Behav (2015 ) 51 :281 –5 .10.1016/j.yebeh.2015.07.039 26318790 \n14 Zang Y Jiang T Lu Y He Y Tian L \nRegional homogeneity approach to fMRI data analysis . Neuroimage (2004 ) 22 :394 –400 .10.1016/j.neuroimage.2003.12.030 15110032 \n15 Zhang Z Lu G Zhong Y Tan Q Chen H Liao W \nfMRI study of mesial temporal lobe epilepsy using amplitude of low-frequency fluctuation analysis . Hum Brain Mapp (2010 ) 31 :1851 –61 .10.1002/hbm.20982 20225278 \n16 Yu R Chien Y-L Wang H-LS Liu C-M Liu C-C Hwang T-J \nFrequency-specific alternations in the amplitude of low-frequency fluctuations in schizophrenia . Hum Brain Mapp (2014 ) 35 :627 –37 .10.1002/hbm.22203 23125131 \n17 Zhu Y Yu Y Shinkareva SV Ji GJ Wang J Wang ZJ \nIntrinsic brain activity as a diagnostic biomarker in children with benign epilepsy with centrotemporal spikes . Hum Brain Mapp (2015 ) 36 :3878 –89 .10.1002/hbm.22884 26173095 \n18 Wang Y Li Y Wang H Chen Y Huang W . Altered default mode network on resting-state fMRI in children with infantile spasms . Front Neurol (2017 ) 8 :209 .10.3389/fneur.2017.00209 28579971 \n19 Friston KJ \nFunctional and effective connectivity in neuroimaging: a synthesis . Hum Brain Mapp (1994 ) 2 :56 –78 .10.1002/hbm.460020107 \n20 Zhang ZQ Xu Q Liao W Wang ZG Li Q Yang F \nPathological uncoupling between amplitude and connectivity of brain fluctuations in epilepsy . Hum Brain Mapp (2015 ) 36 :2756 –66 .10.1002/hbm.22805 25879781 \n21 Jayakar A Bolton J \nPediatric epilepsy surgery . Curr Neurol Neurosci Rep (2015 ) 15 :1 –8 .10.1007/s11910-015-0558-9 \n22 Reinholdson J Olsson I Edelvik A Hallbook T Lundgren J Rydenhag B \nLong-term follow-up after epilepsy surgery in infancy and early childhood—a prospective population based observational study . Seizure (2015 ) 30 :83 –9 .10.1016/j.seizure.2015.05.019 26216690 \n23 Norden AD Blumenfeld H . The role of subcortical structures in human epilepsy . Epilepsy Behav (2002 ) 3 :219 –31 .10.1016/S1525-5050(02)00029-X 12662601 \n24 Moeller F Maneshi M Pittau F Gholipour T Bellec P Dubeau F \nFunctional connectivity in patients with idiopathic generalized epilepsy . Epilepsia (2011 ) 52 :515 –22 .10.1111/j.1528-1167.2010.02938.x 21269293 \n25 Gotman J Grova C Bagshaw A Kobayashi E Aghakhani Y Dubeau F \nGeneralized epileptic discharges show thalamocortical activation and suspension of the default state of the brain . Proc Natl Acad Sci U S A (2005 ) 102 :15236 –40 .10.1073/pnas.0504935102 16217042 \n26 Zhang Z Lu G Zhong Y Tan Q Yang Z Liao W \nImpaired attention network in temporal lobe epilepsy: a resting FMRI study . Neurosci Lett (2009 ) 458 :97 –101 .10.1016/j.neulet.2009.04.040 19393717 \n27 May A . Experience-dependent structural plasticity in the adult human brain . Trends Cogn Sci (2011 ) 15 :475 –82 .10.1016/j.tics.2011.08.002 21906988 \n28 Herbet G Maheu M Costi E Lafargue G Duffau H . Mapping neuroplastic potential in brain-damaged patients . Brain (2016 ) 139 :829 –44 .10.1093/brain/awv394 26912646 \n29 Yogarajah M Focke NK Bonelli SB Thompson P Vollmar C Mcevoy AW \nThe structural plasticity of white matter networks following anterior temporal lobe resection . Brain (2010 ) 133 :2348 –64 .10.1093/brain/awq175 20826432 \n30 Rubinger L Chan C D’arco F Moineddin R Muthaffar O Rutka JT \nChange in presurgical diagnostic imaging evaluation affects subsequent pediatric epilepsy surgery outcome . Epilepsia (2016 ) 57 :32 –40 .10.1111/epi.13229 26715387 \n31 Bettus G Bartolomei F Confort-Gouny S Guedj E Chauvel P Cozzone PJ \nRole of resting state functional connectivity MRI in presurgical investigation of mesial temporal lobe epilepsy . J Neurol Neurosurg Psychiatry (2010 ) 81 (10 ):1147 –54 .10.1136/jnnp.2009.191460 20547611 \n32 Alstott J Breakspear M Hagmann P Cammoun L Sporns O . Modeling the impact of lesions in the human brain . PLoS Comput Biol (2009 ) 5 :e1000408 .10.1371/journal.pcbi.1000408 19521503 \n33 McCormick C Protzner AB Barnett AJ Cohn M Valiante TA Mcandrews MP . Linking DMN connectivity to episodic memory capacity: what can we learn from patients with medial temporal lobe damage? \nNeuroimage Clin (2014 ) 5 :188 –96 .10.1016/j.nicl.2014.05.008 25068108 \n34 Tracy JI Doucet GE . Resting-state functional connectivity in epilepsy: growing relevance for clinical decision making . Curr Opin Neurol (2015 ) 28 :158 –65 .10.1097/WCO.0000000000000178 25734954\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-2295",
"issue": "8()",
"journal": "Frontiers in neurology",
"keywords": "amplitude of low-frequency fluctuation; children; functional connectivity; medically refractory epilepsy; surgery",
"medline_ta": "Front Neurol",
"mesh_terms": null,
"nlm_unique_id": "101546899",
"other_id": null,
"pages": "374",
"pmc": null,
"pmid": "28824531",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "26216690;16217042;18562616;28579971;20225278;24282678;20826432;19603243;15699379;15110032;19393717;26912646;16404743;21906988;23125131;24653713;26858091;25068108;21269293;25879781;26173095;12662601;24735200;19687453;26318790;24400690;19521503;25898058;21709227;25734954;25893723;20547611;26715387",
"title": "Alterations in Spontaneous Brain Activity and Functional Network Reorganization following Surgery in Children with Medically Refractory Epilepsy: A Resting-State Functional Magnetic Resonance Imaging Study.",
"title_normalized": "alterations in spontaneous brain activity and functional network reorganization following surgery in children with medically refractory epilepsy a resting state functional magnetic resonance imaging study"
} | [
{
"companynumb": "CN-UCBSA-2017035277",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nRidaforolimus is a mammalian target of rapamycin inhibitor that has activity in solid tumors. Paclitaxel and carboplatin have broad antineoplastic activity in many cancers. This phase I trial was conducted to determine the safety profile, maximal tolerated dose, and recommended phase II dose and schedule of oral ridaforolimus combined with paclitaxel and carboplatin in patients with solid tumor cancers.\n\n\nMETHODS\nEligible patients with advanced solid tumor cancers received oral 10 to 30 mg ridaforolimus daily for 5 consecutive days per week combined with intravenous paclitaxel (175 mg/m2) and carboplatin (area under the curve [AUC] 5-6 mg/mL/min) in 3-week cycles. A standard 3 + 3 design was used to escalate doses, with predefined changes to an alternate dosing schedule and/or changes in carboplatin AUC doses based on dose-limiting toxicity (DLT). Secondary information was collected regarding response and time to progression. Patients were continued on treatment if therapy was tolerated and if stable disease or better was demonstrated.\n\n\nRESULTS\nThirty-one patients were consented, 28 patients were screened, and 24 patients met eligibility requirements and received treatment. Two patients were replaced for events unrelated to drug-related toxicity, resulting in 22 DLT-evaluable patients. Two grade 4 DLTs due to neutropenia were observed at dose level 1. The next cohort was changed to a predefined alternate dosing schedule (days 1-5 and 8-12). DLTs were neutropenia, sepsis, mucositis, and thrombocytopenia. The most common adverse events were neutropenia, anemia, thrombocytopenia, fatigue, alopecia, nausea, pain, and leukopenia. Twenty-four patients received a median of 4 cycles (range, 1-12). Evaluable patients for response (n = 18) demonstrated a median tumor measurement decrease of 25%. The best response in these 18 patients included 9 patients with partial response (50%), 6 with stable disease (33%), and 3 with progressive disease (17%). Thirteen of these patients received treatment for 4 or more cycles.\n\n\nCONCLUSIONS\nTreatment with ridaforolimus combined with paclitaxel and carboplatin had no unanticipated toxicities and showed antineoplastic activity. The recommended phase II dose and schedule is ridaforolimus 30 mg (days 1-5 and 8-12) plus day 1 paclitaxel (175 mg/m2) and carboplatin (AUC 5 mg/mL/min) on a 21-day cycle.\n\n\nBACKGROUND\nClinicalTrials.gov Identifier: NCT01256268 (trial registration date: December 1, 2010).",
"affiliations": "Department of Gynecologic Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, 33647, USA.;Division of Gynecologic Cancer Research, Center for Uterine Cancer, National Cancer Center, Ilsan-gu Madu-dong, Goyang, 410-768, Korea.;Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, 33647, USA.;Department of Gynecologic Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, 33647, USA.;Department of Gynecologic Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, 33647, USA.;Clinical Trials Office, Phase 1 Clinical trials, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, 33647, USA.;Department of Gynecologic Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, 33647, USA. Robert.Wenham@moffitt.org.",
"authors": "Chon|Hye Sook|HS|;Kang|Sokbom|S|;Lee|Jae K|JK|;Apte|Sachin M|SM|;Shahzad|Mian M|MM|;Williams-Elson|Irene|I|;Wenham|Robert M|RM|",
"chemical_list": "C515074:ridaforolimus; D016190:Carboplatin; D017239:Paclitaxel; D020123:Sirolimus",
"country": "England",
"delete": false,
"doi": "10.1186/s12885-017-3394-2",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 339410.1186/s12885-017-3394-2Research ArticlePhase I study of oral ridaforolimus in combination with paclitaxel and carboplatin in patients with solid tumor cancers Chon Hye Sook Hyesook.chon@moffitt.org 1Kang Sokbom Sokbom@gmail.com 2Lee Jae K. Jae.Lee@moffitt.org 3Apte Sachin M. Sachin.Apte@moffitt.org 1Shahzad Mian M. Mian.Shahzad@moffitt.org 1Williams-Elson Irene WilliaIJ@moffitt.org 4Wenham Robert M. (813) 745-3549Robert.Wenham@moffitt.org 11 0000 0000 9891 5233grid.468198.aDepartment of Gynecologic Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33647 USA 2 0000 0004 0628 9810grid.410914.9Division of Gynecologic Cancer Research, Center for Uterine Cancer, National Cancer Center, Ilsan-gu Madu-dong, Goyang, 410-768 Korea 3 0000 0000 9891 5233grid.468198.aDepartment of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33647 USA 4 0000 0000 9891 5233grid.468198.aClinical Trials Office, Phase 1 Clinical trials, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33647 USA 8 6 2017 8 6 2017 2017 17 40714 6 2016 30 5 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\nRidaforolimus is a mammalian target of rapamycin inhibitor that has activity in solid tumors. Paclitaxel and carboplatin have broad antineoplastic activity in many cancers. This phase I trial was conducted to determine the safety profile, maximal tolerated dose, and recommended phase II dose and schedule of oral ridaforolimus combined with paclitaxel and carboplatin in patients with solid tumor cancers.\n\nMethods\nEligible patients with advanced solid tumor cancers received oral 10 to 30 mg ridaforolimus daily for 5 consecutive days per week combined with intravenous paclitaxel (175 mg/m2) and carboplatin (area under the curve [AUC] 5–6 mg/mL/min) in 3-week cycles. A standard 3 + 3 design was used to escalate doses, with predefined changes to an alternate dosing schedule and/or changes in carboplatin AUC doses based on dose-limiting toxicity (DLT). Secondary information was collected regarding response and time to progression. Patients were continued on treatment if therapy was tolerated and if stable disease or better was demonstrated.\n\nResults\nThirty-one patients were consented, 28 patients were screened, and 24 patients met eligibility requirements and received treatment. Two patients were replaced for events unrelated to drug-related toxicity, resulting in 22 DLT-evaluable patients. Two grade 4 DLTs due to neutropenia were observed at dose level 1. The next cohort was changed to a predefined alternate dosing schedule (days 1–5 and 8–12). DLTs were neutropenia, sepsis, mucositis, and thrombocytopenia. The most common adverse events were neutropenia, anemia, thrombocytopenia, fatigue, alopecia, nausea, pain, and leukopenia. Twenty-four patients received a median of 4 cycles (range, 1–12). Evaluable patients for response (n = 18) demonstrated a median tumor measurement decrease of 25%. The best response in these 18 patients included 9 patients with partial response (50%), 6 with stable disease (33%), and 3 with progressive disease (17%). Thirteen of these patients received treatment for 4 or more cycles.\n\nConclusions\nTreatment with ridaforolimus combined with paclitaxel and carboplatin had no unanticipated toxicities and showed antineoplastic activity. The recommended phase II dose and schedule is ridaforolimus 30 mg (days 1–5 and 8–12) plus day 1 paclitaxel (175 mg/m2) and carboplatin (AUC 5 mg/mL/min) on a 21-day cycle.\n\nTrial registration\n\nClinicalTrials.gov Identifier: NCT01256268 (trial registration date: December 1, 2010).\n\nKeywords\nOral ridaforolimusPhase 1 trialPaclitaxel and carboplatin combinationSolid tumorshttp://dx.doi.org/10.13039/100000054National Cancer InstituteP30-CA076292issue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nBecause mammalian target of rapamycin (mTOR) inhibitors target the downstream effects of the PI3K/AKT/PTEN-related pathways, this class of drugs has broad antiproliferative activity [1]. Ridaforolimus (deforolimus; AP23573; MK 8669, AP 23573), a potent mTOR inhibitor with an IC50 in the nanomolar range, appears to be well tolerated in both intravenous and oral formulations as either a single agent or in combination with other chemotherapy agents [2]. In preclinical studies, ridaforolimus demonstrated antitumor activity against a broad range of human cancer cell lines in vitro and tumor xenograft models in vivo [3–6]. In phase I and II clinical trials, ridaforolimus displayed activity in various cancers, including sarcoma and hematologic malignancies [7–10]. In a phase III trial of patients with advanced sarcoma, single-agent ridaforolimus treatment (40 mg orally, once daily for 5 consecutive days every week) resulted in a statistically significant improvement in progression-free survival compared with placebo [11]. Ridaforolimus has shown additive or synergistic activity when combined with other single agents, such as paclitaxel, carboplatin, cisplatin, doxorubicin, imatinib, and trastuzumab [12, 13]. Therefore, combining chemotherapy regimens with an mTOR inhibitor with a different mechanism of action and reasonable toxicity may provide an advantageous clinical approach.\n\nThe combination of paclitaxel and carboplatin is one of the most commonly used chemotherapeutic combinations in cancer treatment, including head and neck cancer, advanced-stage non-small cell lung cancer, endometrial cancer, ovarian cancer, and others. Oral ridaforolimus has shown equivalent effectiveness comparable to the intravenous form [14]. Therefore, the potential benefit of a convenient oral dosing with paclitaxel plus carboplatin warranted investigation. In this phase I study, our aim was to determine the maximal tolerated dose (MTD) and the recommended phase 2 dose and schedule of oral ridaforolimus in combination with paclitaxel and carboplatin in patients with solid tumor cancers and to describe the safety and tolerability of this combination.\n\nMethods\nStudy eligibility\nPatients ≥18 years of age with solid tumor cancers not deemed curable by other therapies and who had measurable disease by Response Evaluation Criteria in Solid Tumor (RECIST) 1.1 or evaluable disease were eligible. Other eligibility criteria included Eastern Cooperative Oncology Group performance status of 0, 1, or 2; a life expectancy of at least 60 days; adequate bone marrow function, renal function, hepatic function, and neurologic function; serum cholesterol ≤350 mg/dL and triglyceride ≤400 mg/dL; and full recovery to baseline from acute toxicities of all prior chemotherapy regimens. Patients may have had up to 3 (0–3) prior cytotoxic chemotherapeutic regimens including prior treatment with carboplatin and paclitaxel (patients who had regimens switched for toxicity rather than progression, used for radiation sensitization only, or hormonal only were not eligible). No chemotherapy, radiotherapy, biologic, hormonal, or investigational drug therapy within 28 days before start of study treatment was permitted. Patients were excluded if they had any upper gastrointestinal illness that would impair swallowing or absorption of oral medication, any intercurrent illness, were known to have human immunodeficiency virus or AIDS, had received prior therapy with an mTOR inhibitor, or had concomitant treatment with inhibitors or inducers of cytochrome P450-3A. The study protocol was approved by the University of South Florida Institutional Review Board. All patients provided written informed consent before study participation.\n\nStudy design and treatment\nPatients received oral ridaforolimus daily on days 2–5, days 8–12, and days 15–19 during the first cycle of therapy and then 5 days a week (days 1–5, days 8–12, and days 15–19) throughout the remainder of therapy beginning with the second cycle of therapy. Oral ridaforolimus was administered in combination with day 1 intravenous paclitaxel (175 mg/m2) and carboplatin (AUC = 5–6 mg/mL/min) every 3 weeks, except for the first cycle of therapy where day 1 ridaforolimus was skipped to allow for blood samples to be collected day 1 of the first 2 cycles. These were held for potential PK analyses if specific drug and temporally related toxicities were noted. All patients received steroids, antiemetics, and antihistamines before the administration of paclitaxel and carboplatin. All patients were expected to continue study treatment in the absence of disease progression, complete response, unacceptable toxicity, or voluntary choice to withdraw participation. A 3 + 3 dose escalation design was used, with ridaforolimus dose levels of 10, 20, 30, and 40 mg orally in combination with intravenous paclitaxel and carboplatin based on a predefined dose escalation scheme. Carboplatin was dosed at an AUC of 5, with a planned escalation to an AUC of 6 mg/mL/min based on dose level cohort.\n\nThe maximal tolerated dose was defined as the highest dose at which no more than 1 of 6 evaluable patients experienced a dose-limiting toxicity (DLT) due to the combination of ridaforolimus, paclitaxel, and carboplatin during the first cycle of treatment. A patient who did not complete the first cycle of treatment for reasons other than a DLT was replaced. DLT was defined as ≥ grade 3 non-hematologic toxicity (specifically, rash, mucositis, pneumonitis) with the exceptions of fatigue, hypersensitivity reaction, nausea, and vomiting; ≥ grade 3 thrombocytopenia requiring platelet transfusion; grade 4 thrombocytopenia or neutropenia >7 days duration; any grade 4 neutropenic fever requiring hospitalization; unresolved toxicity resulting in delay of retreatment >2 weeks; grade 3 or 4 non-surgical hemorrhages; and failure of administration of ridaforolimus for 5 days or more (consecutive or nonconsecutive) due to any toxicity. Growth factor support was not allowed prophylactically for cycle 1 but could be subsequently used based on investigator discretion.\n\nA modification of the schedule that changed ridaforolimus administration to the first 2 weeks (days 1–5, days 8–12) versus all 3 weeks (days 1–5, days 8–12, days 15–18) of a cycle was predefined for 2 DLTs in a cohort that resulted from thrombocytopenia or neutropenia in the latter part of the cycle. The dose of ridaforolimus remained the same as the maximum achieved level in the prior cohort at which the DLTs were experienced. Dose escalation was to continue at each subsequent cohort until a maximum of 40 mg/day (days 1–5, days 8–12) of ridaforolimus was reached. Subsequent treatment cycles would not begin until absolute neutrophil count reached ≥1500 cells/mm3 and platelet count reached ≥75,000/mm3; mucositis, nausea, and vomiting were grade 1 or less; and bilirubin was ≤1.5 x institutional upper limit of normal. All drugs were held during the recovery period. Therapy was delayed for a maximum of 2 weeks until these values were achieved. Patients who failed to recover adequate counts within a 2-week delay were removed from study. Adverse events were graded according to the Common Terminology Criteria for Adverse Events version 4.0.\n\nEfficacy and safety assessments\nPatients were evaluated at baseline and before each subsequent treatment cycle to assess Eastern Cooperative Oncology Group performance status, vital signs, and adverse events. Hematologic and clinical chemistry assessments, including cholesterol, triglyceride, and glucose levels, were performed at baseline and at each treatment cycle. Tumor assessment by RECIST v1.1 was performed at baseline and every 2 cycles thereafter. Patients were required to have completed a minimum of 2 cycles of therapy to be evaluable for efficacy.\n\nResults\nPatients and study treatment\nThirty-one patients were consented and 24 patients were enrolled between June 2011 and May 2014. A total of 116 cycles were initiated until January 2015. All patients who received at least one dose of study medication were included in the toxicity analyses (n = 24 patients). Two patients were replaced for DLT evaluation (see below). Patients who completed required imaging after the second cycle were included for efficacy analyses (n = 18 patients). The mean age was 62 years (range, 30–72 years), and the median number of prior chemotherapy treatments was 2 (range, 0–3). Tumor types included ovarian/fallopian/primary peritoneal (n = 10), endometrial (n = 5), cervical (n = 3), esophageal (n = 2), and urethral, vaginal, mesothelial, and salivary (n = 1 for each). Number of cycles delivered to patients ranged from 1 to 12 (median of 5 cycles; n = 22 patients evaluable for DLT). Patient characteristics are summarized in Table 1.Table 1 Patient Characteristics (n = 24)\n\nCharacteristics\tNo. of Patients (%)\t\nAge, years\t\n Median\t62\t\n Range\t30–72\t\nSex\t\n Male\t4 (17)\t\n Female\t20 (83)\t\nRace\t\n White\t22 (90)\t\n Black\t0\t\n Other\t2 (10)\t\nECOG performance status\t\n ECOG 0\t16 (67)\t\n ECOG 1\t7 (29)\t\n ECOG 2\t1 (4)\t\nTumor type\t\n Ovarian/fallopian/peritoneal\t10 (42)\t\n Endometrial\t5 (21)\t\n Cervical\t3 (13)\t\n Esophageal\t2 (8)\t\n Urethral\t1 (4)\t\n Vaginal\t1 (4)\t\n Mesothelial\t1 (4)\t\n Salivary\t1 (4)\t\nPrior chemotherapiesa\n\t\n 0\t7 (29)\t\n 1\t1 (4)\t\n 2\t7 (29)\t\n 3\t9 (38)\t\n\nECOG Eastern Cooperative Oncology Group\n\n\naTherapies that included chemotherapy for radiation sensitization only (n = 4), were discontinued due to toxicity without progression (n = 2), were radiation alone (n = 4), or were hormonal only (n = 2) were not included for eligibility\n\n\n\n\nSafety\nThe number of patients enrolled and evaluable at each dose level and the DLTs are summarized in Table 2. Two DLTs of grade 4 neutropenia were observed at dose level 1 (ridaforolimus 10 mg from days 1–5, days 8–12, and days 15–18 combined with 175 mg/m2 paclitaxel and carboplatin (AUC 5 mg/mL/min)). A predefined alternate dosing cohort (days 1–5, days 8–12) was opened at the same dose of ridaforolimus (dose level 1A). There was one DLT with sepsis at alternate dose level 1A (1 of 6 patients). No DLTs were observed at alternate dose levels 2A (20 mg ridaforolimus) and 3A (30 mg ridaforolimus). Dose escalations were continued to cohort 4A (30 mg ridaforolimus, 175 mg/m2 paclitaxel, and AUC = 6 mg/mL/min carboplatin). At dose level 4A, 2 of 6 patients had DLTs (1 grade 3 mucositis and 1 grade 4 thrombocytopenia). Thus, the maximal tolerated dose was established as the 3A dose level (30 mg ridaforolimus combined with 175 mg/m2 paclitaxel and AUC = 5 mg/mL/min carboplatin). Two patients were replaced for DLT determination during cycle 1 (1 patient from cohort 2A for noncompliance and 1 patient from cohort 4A due to C. difficile diarrhea and diverticulitis deemed unrelated to treatment). Allowed drug-specific dose reductions after cycle 1 were done in 9 patients after a median of 5 cycles, including for paclitaxel + carboplatin (n = 4), paclitaxel only (n = 3), and ridaforolimus (n = 2).Table 2 Patients treated and DLTs by dose level\n\nDose Level\tRidaforolimus\nmg (days of cycle)\tCarboplatin (AUC)\tNo. of Patients Enrolled\tNo of Patients evaluable for DLTa\n\tDose-Limiting Toxicity\t\n1\t10 (days 1–5, 8–12, 15–19)\t5\t4\t4\tTwo grade 4 neutropenia\t\n1A\t10 (days 1–5, 8–12)\t5\t6\t6\tDeath from sepsis\t\n2A\t20 (days 1–5, 8–12)\t5\t4a\n\t3\tNone\t\n3A\t30 (days 1–5, 8–12)\t5\t3\t3\tNone\t\n4A\t30 (days 1–5, 8–12)\t6\t7b\n\t6\tGrade 3 mucositis; grade 4 thrombocytopenia requiring transfusion\t\nSlots replaced due to aprotocol non-compliance or bnon-treatment related issue\n\nPaclitaxel was at 175 mg/m2 for all cohorts\n\n\n\n\nTreatment-related adverse events observed in >20% of patients are shown in Table 3. The most common adverse events were neutropenia, anemia, thrombocytopenia, fatigue, alopecia, nausea, pain, and leukopenia. The most common grade 3 and grade 4 adverse events were hematologic, including neutropenia (92% of patients: 10 with grade 3 and 12 with grade 4), anemia (42%: 10 with grade 3), thrombocytopenia (67%: 8 with grade 3 and 8 with grade 4), and leukopenia (42%: 8 with grade 3 and 2 with grade 4). Non-hematologic grade 3 and 4 adverse events were infrequent, except hypokalemia (13%; 3 with grade 3 and 1 with grade 4). Of note, two grade 3 hyperglycemia and one grade 3 mucositis were among the less frequent (<10%) high-grade non-hematologic toxicities. One patient with recurrent fallopian tube cancer died. She initiated treatment 7 days before she presented with fever, chills, and abdominal pain. An autopsy showed the cause of death due to multiorgan failure, attributed to sepsis. With no other obvious cause, this was deemed at least possibly related to treatment. Table 4 demonstrates drug-related toxicities by dose level.Table 3 Number of cycles and patients with treatment-related adverse events in >20% of patients (N = 24 patients)\n\n\tGrade (number of cycles)\tPatients\t\n\t1\t2\t3\t4\tNumber\t%\t\nAlkaline phosphatase increased\t6\t\t\t\t5\t21%\t\nDysphagia\t2\t2\t1\t\t5\t21%\t\nDyspnea\t5\t3\t2\t\t5\t21%\t\nHypoalbuminemia\t3\t1\t1\t\t5\t21%\t\nDehydration\t3\t5\t1\t\t7\t29%\t\nFever\t8\t\t\t\t7\t29%\t\nHypokalemia\t11\t1\t4\t2\t7\t29%\t\nTransaminases increased\t11\t\t\t\t7\t29%\t\nHypertriglyceridemia\t7\t1\t1\t\t8\t33%\t\nPeripheral sensory neuropathy\t8\t3\t\t\t8\t33%\t\nVomiting\t7\t1\t4\t\t8\t33%\t\nAnorexia\t7\t4\t\t\t9\t38%\t\nUrinary tract infection\t1\t6\t2\t\t9\t38%\t\nDiarrhea\t8\t6\t1\t\t10\t42%\t\nHyperglycemia\t18\t6\t2\t\t10\t42%\t\nHypomagnesemia\t23\t6\t\t\t10\t42%\t\nMucositis oral\t10\t10\t2\t\t11\t46%\t\nWhite blood cell decreased\t14\t14\t29\t3\t12\t50%\t\nNausea\t17\t4\t3\t\t13\t54%\t\nPain\t7\t\t\t\t13\t54%\t\nAlopecia\t8\t12\t\t\t14\t58%\t\nFatigue\t14\t14\t1\t\t15\t63%\t\nAnemia\t21\t45\t15\t\t20\t83%\t\nPlatelet count decreased\t32\t26\t14\t14\t20\t83%\t\nNeutrophil count decreased\t8\t19\t26\t20\t21\t88%\t\nToxicities by grade seen in >20% of patients deemed possibly, probably, or definitely related in all patients eligible for toxicity evaluation. Under grade, this is listed as: Total Number of Cycles. Under Patients, this is listed as the: Total Number of Patients for any grade. There were 24 patients who received at least 1 dose of treatment and were part of the toxicity evaluation. A patient may be counted only once for each grade of toxicity but may appear under more than one grade for each toxicity\n\n\nTable 4 Drug-related toxicities by dose level for N = 24 Patients\n\n\t\nLevel 1: RIDA 10 mg; P 175 mg/m2; C 5 (n = 4)\t\nLevel 1A: RIDA 10 mg; P 175 mg/m2; C 5 (n = 6)\t\nLevel 2A: RIDA 20 mg; P 175 mg/m2; C 5 (n = 4)\t\nLevel 3A: RIDA 30 mg; P 175 mg/m2; C 5 (n = 3)\t\nLevel 4A: RIDA 30 mg; P 175 mg/m2; C 6 (n = 7)\t\nGrade\tTotal No. of Patients\tGrade\tTotal No. of Patients\tGrade\tTotal No. of Patients\tGrade\tTotal No. of Patients\tGrade\tTotal No. of Patients\t\n1\t2\t3\t4\t1\t2\t3\t4\t1\t2\t3\t4\t1\t2\t3\t4\t1\t2\t3\t4\t\nAlkaline phosphatase increased\t2\t\t\t\t2\t1\t\t\t\t1\t\t\t\t\t\t1\t\t\t\t1\t1\t\t\t\t1\t\nAlopecia\t\t1\t\t\t1\t1\t3\t\t\t4\t\t3\t\t\t3\t2\t2\t\t\t3\t2\t2\t\t\t2\t\nAnemia\t2\t2\t3\t\t4\t3\t4\t\t\t4\t3\t4\t2\t\t4\t1\t2\t\t\t2\t3\t4\t5\t\t6\t\nAnorexia\t\t\t\t\t\t1\t1\t\t\t2\t1\t\t\t\t1\t\t2\t\t\t2\t4\t\t\t\t4\t\nDehydration\t\t\t\t\t\t\t\t\t\t\t1\t\t\t\t1\t1\t3\t\t\t3\t1\t2\t1\t\t3\t\nDiarrhea\t\t1\t\t\t1\t1\t1\t\t\t2\t2\t1\t\t\t3\t\t\t\t\t\t3\t1\t1\t\t4\t\nDysphagia\t\t\t\t\t\t1\t\t\t\t1\t\t1\t\t\t1\t\t\t\t\t\t1\t1\t1\t\t3\t\nDyspnea\t1\t\t\t\t1\t\t\t2\t\t2\t\t\t\t\t\t\t\t\t\t\t2\t1\t\t\t2\t\nFatigue\t2\t2\t\t\t2\t1\t2\t\t\t3\t1\t2\t\t\t2\t2\t2\t\t\t3\t3\t3\t1\t\t5\t\nFever\t2\t\t\t\t2\t\t\t\t\t\t1\t\t\t\t1\t1\t\t\t\t1\t3\t\t\t\t3\t\nHyperglycemia\t\t1\t1\t\t1\t2\t2\t\t\t2\t2\t\t1\t\t2\t\t1\t\t\t1\t2\t2\t\t\t3\t\nHypertriglyceridemia\t\t1\t1\t\t1\t2\t\t\t\t2\t2\t\t\t\t2\t\t\t\t\t\t3\t\t\t\t3\t\nHypoalbuminemia\t1\t1\t\t\t2\t2\t\t1\t\t3\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nHypokalemia\t\t\t\t\t\t1\t\t\t\t1\t2\t1\t1\t1\t2\t1\t\t\t\t1\t2\t\t2\t\t3\t\nHypomagnesemia\t\t1\t\t\t1\t2\t\t\t\t2\t2\t1\t\t\t2\t1\t\t\t\t1\t4\t2\t\t\t4\t\nMucositis oral\t1\t1\t\t\t2\t\t\t\t\t\t2\t2\t\t\t3\t2\t1\t\t\t2\t3\t3\t1\t\t4\t\nNausea\t1\t\t\t\t1\t1\t\t\t\t1\t1\t2\t1\t\t3\t2\t2\t\t\t3\t5\t\t1\t\t5\t\nNeutrophil count decreased\t1\t1\t2\t2\t4\t4\t2\t\t4\t5\t\t1\t3\t1\t3\t\t2\t1\t2\t3\t2\t4\t4\t3\t6\t\nPain\t1\t\t\t\t1\t\t\t\t\t\t2\t\t\t\t2\t\t\t\t\t\t3\t\t\t\t3\t\nPeripheral sensory neuropathy\t1\t1\t\t\t1\t3\t1\t\t\t3\t\t1\t\t\t1\t1\t\t\t\t1\t2\t\t\t\t2\t\nPlatelet count decreased\t1\t4\t\t\t4\t3\t\t1\t1\t3\t4\t3\t2\t1\t4\t1\t1\t1\t2\t3\t3\t4\t4\t4\t6\t\nTransaminases increased\t\t\t\t\t\t\t\t\t\t\t1\t\t\t\t1\t3\t\t\t\t3\t1\t\t\t\t1\t\nUrinary tract infection\t\t1\t1\t\t2\t\t\t\t\t\t\t\t\t\t\t\t1\t\t\t1\t1\t3\t1\t\t4\t\nVomiting\t1\t\t\t\t1\t2\t\t\t\t2\t\t\t1\t\t1\t1\t\t\t\t1\t1\t1\t1\t\t3\t\nWhite blood cell decreased\t\t\t\t\t\t4\t2\t4\t\t5\t1\t2\t2\t1\t3\t\t\t\t1\t1\t1\t2\t2\t\t3\t\n\nRIDA Ridaforolimus, P paclitaxel, C carboplatin\n\n\n\n\nEfficacy\nEighteen of 24 patients were evaluable for antitumor response (5 were not evaluable because of DLTs and 1 patient was replaced due to discontinuation unrelated to treatment). Best response included 9 patients with partial response (50%), 6 with stable disease (33%), and 3 with progressive disease (17%). In 18 patients, 15 (83%) had stable disease or partial response at the time of first tumor assessment. Thirteen patients received 4 or more treatment cycles (range, 1–12). In the 18 patients evaluable for best response, 6 patients came off study before progression of disease was determined by RECIST. Of the remaining12 patients with RECIST-determined progressive disease, the median duration of response was 81 days (range, 0–236 days) and median time to progression from start of therapy was 166 days (range, 42–393 days). Five patients with partial response or stable disease discontinued treatment due to patient choice; however, these patients were deemed to have no treatment-defined toxicities at the time of discontinuation. One patient remained on treatment for 4 cycles with a partial response but was replaced at cycle 1 as a DLT determination due to noncompliance with drug schedule. The 18 evaluable patients demonstrated a median RECIST 1.1 tumor size decrease of 25% as the best response in target lesion (range, −83% to 232%; Fig. 1). Notably, responses among the 3 cervical and 1 vaginal cancer patients included 1 stable disease and 3 partial responses with a total of 29 cycles (median of 8) delivered. Figure 1 demonstrates best response by RECIST. As shown in Fig. 1, the majority of patients with partial response or stable disease had received prior paclitaxel and carboplatin or carboplatin-based chemotherapy.Fig. 1 Best response by Response Evaluation Criteria in Solid Tumor (RECIST), measured as maximum percent change of tumor RECIST measurements from baseline. Tumor type (and cohort) are denoted below each bar. Green denotes partial response, yellow denotes stable disease, and red denotes progressive disease. A, alternate dose schedule; CER, cervical; EM, endometrial; ESO, esophageal; MESO, mesothelial; OV, ovarian/fallopian/peritoneal; URE, urethral; VA, vaginal\n\n\n\n\nDiscussion\nThis phase I study of ridaforolimus combined with paclitaxel and carboplatin demonstrated tolerability at the defined maximal tolerated dose using doses of the 3 agents considered active in patients with solid tumor cancers. Treatment with ridaforolimus showed toxicities that were expected from its known profile. Mouth sores, rash, fatigue, stomatitis, and hypertriglyceridemia have been most prevalent in phase I and II clinical trials with ridaforolimus as a single agent, with incident rates ranging from 31% to 48% [7, 9]. Previous phase I and II studies have explored combinations of ridaforolimus with capecitabine [15], weekly paclitaxel [16], bevacizumab [16, 17], dalotuzumab [18, 19], and traztuzumab [20] and have demonstrated tolerability. Doses of up to 40 mg ridaforolimus once daily as a single agent for 5 consecutive days with 2 days rest each week have been shown to be tolerable in patients with metastatic or advanced solid tumors [14, 20]. When weekly intravenous ridaforolimus was combined with weekly paclitaxel, 2 recommended doses were determined: 37.5 mg ridaforolimus +60 mg/m2 paclitaxel and 12.5 mg ridaforolimus +80 mg/m2 paclitaxel [16]. At these recommended doses, a DLT of mucositis was observed, with grade 3/4 neutropenia shown in 14% to 37.5% of the cohorts. In our study, hematologic adverse events were somewhat more prominent, likely because of the nature of combination with two cytotoxic chemotherapies. Non-hematologic adverse events shown in our study were similar to other trials with single-agent ridaforolimus. We had anticipated that the use of these three agents together would have greater potential for bone marrow suppression, namely neutropenia and thrombocytopenia. Therefore, we had preplanned an alternate dosing schedule that shortened the administration of ridaforolimus to 2 weeks (10 days) instead of 3 weeks (15 days). Indeed, the two DLTs of grade 4 neutropenia were observed at the starting dose level of 10 mg ridaforolimus (days 1–5, days 8–12, and days 15–18) combined with paclitaxel (175 mg/m2) and carboplatin (AUC = 5 mg/mL/min). An alternate dosing cohort (dose level 1A; days 1–5 and days 8–12) was initiated at the same dose of ridaforolimus as the first cohort. This alternate dosing cohort (2 weeks on and 1 week off) was feasible for repeated cycles. This is similar to the results of the weekly paclitaxel study above in that patients had to switch from intravenous ridaforolimus in the latter part of the cycle (days 8 and 15) to earlier in the cycle (days 1 and 8) [16]. It appears that this earlier cycle dosing is sometimes necessary to allow sufficient marrow recovery when combined with cytotoxic chemotherapy.\n\nRidaforolimus has activity in cancer, particularly in disease stabilization in various tumor types. In a phase III trial of 702 patients with advanced metastatic sarcoma who had attained benefit with prior chemotherapy, administration of oral ridaforolimus as maintenance therapy resulted in a statistically significant improvement of 3.1 weeks in progression-free survival compared with placebo (hazard ratio of 0.72; 95% confidence interval, 0.61–0.85; P = 0.001) [11]. Various mTOR inhibitors, including everolimus (RA001), temsirolimus (CCI779), and ridaforolimus (AP2357), either as a single agent or combined with other chemotherapeutic or hormonal agents have been evaluated in patients with advanced or recurrent endometrial cancer with promising results [21–26]. Mutations or loss of function in PTEN (phosphatase and tensin homolog) plays a significant role in the pathogenesis of endometrial cancer. Downstream activation of the PI3K/AKT/mTOR signaling pathway triggered by the loss of function of PTEN suggests a therapeutic role of the mTOR inhibition. Paclitaxel plus carboplatin is a widely used regimen for this cancer; therefore, it would be of interest to study this combination with ridaforolimus at our recommended phase II dose and schedule in this disease. We also noted interesting activity in patients with cervical and vaginal cancer in our study. Among 3 patients with cervical cancer (1 with adenocarcinoma, 1 with squamous cell carcinoma) and 1 patient with vaginal cancer (squamous cell carcinoma), there were a total 29 cycles of treatment with 1 stable disease and 3 partial responses.\n\nIn a preclinical study, Molinolo et al. demonstrated that mTOR pathway activation was shown in most human papillomavirus-positive head and neck squamous cell carcinoma and cervical cancer squamous cell carcinoma tumor xenografts. mTOR inhibitors (rapamycin and everolimus) effectively decreased mTOR activity in vivo and caused a remarkable decrease in tumor burden (P < 0.001) [27]. In a phase II study of temsirolimus in patients with recurrent or metastatic cervical cancer, among 33 evaluable patients, 1 patient (3.0%) had a partial response and 19 patients (57.6%) had stable disease with a duration of 6.5 months [28]. There are trials in head and neck squamous cell carcinoma with rapamycin therapy and adding everolimus to definitive chemoradiation treatment in patients with locally advanced cervical cancer. Paclitaxel combined with carboplatin is also a regimen used for the treatment of these cancers; therefore, the addition of ridaforolimus to this combination may be considered for further study, perhaps with or without bevacizumab [29]. In our study, the combination of oral ridaforolimus with intravenous paclitaxel and carboplatin had no unanticipated toxicities with antitumor activity in patients with solid tumor cancers. Given the broad activity and use of paclitaxel and carboplatin in many tumor types, there is potential to explore this triplet therapy in multiple tumors in which mTOR inhibition may be relevant.\n\nConclusions\nTreatment with ridaforolimus in combination with paclitaxel and carboplatin had no unanticipated toxicities and showed antineoplastic activity. The recommended phase II dose and schedule is ridaforolimus 30 mg (days 1–5 and 8–12) plus day 1 paclitaxel (175 mg/m2) and carboplatin (AUC 5 mg/mL/min) on a 21-day cycle. There is potential to explore triplet therapy with ridaforolimus combined with paclitaxel and carboplatin in multiple tumors where mTOR inhibition is relevant.\n\nAbbreviations\nAUCArea under the curve\n\nDLTDose-limiting toxicity\n\nECOGEastern Cooperative Oncology Group\n\nmTORMammalian target of rapamycin\n\nRECISTResponse evaluation criteria in solid tumor\n\nAcknowledgements\nWe thank Rasa Hamilton (Moffitt Cancer Center) for editorial assistance.\n\nFunding\nThis work was supported in part by funds from the NCI comprehensive Cancer Center support grant P30-CA076292 and Moffitt Cancer Center. We thank Merck for supplying the study drug.\n\nAvailability of data and materials\nAll primary patient data are stored in a password-secured program at the H. Lee Moffitt Cancer Center and Research Institute.\n\nAuthors’ contributions\nRMW designed and led the study. HSC and RMW were involved in manuscript writing. SK and JKL were involved in data management and trial statistician. IWE provided study management. HSC, SMA, MS and RMW recruited patients and served on the trial management group. All authors participated in reviewing and revising the manuscript, and all agreed to the final version submitted.\n\nCompeting interests\nDr. Robert M. Wenham receives trial funding from Merck. Otherwise, the authors have no competing interests.\n\nConsent for publication\nNot applicable.\n\nEthics approval and consent to participate\nThe study protocol was approved by the University of South Florida Institutional Review Board. All patients provided written informed consent before study participation.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Schmelzle T Hall MN TOR, a central controller of cell growth Cell 2000 103 2 253 262 10.1016/S0092-8674(00)00117-3 11057898 \n2. Dancey JE Monzon J Ridaforolimus: a promising drug in the treatment of soft-tissue sarcoma and other malignancies Future Oncol 2011 7 7 827 839 10.2217/fon.11.57 21732754 \n3. Shaw RJ Cantley LC Ras, PI(3)K and mTOR signalling controls tumour cell growth Nature 2006 441 7092 424 430 10.1038/nature04869 16724053 \n4. Fasolo A Sessa C mTOR inhibitors in the treatment of cancer Expert Opin Investig Drugs 2008 17 11 1717 1734 10.1517/13543784.17.11.1717 18922108 \n5. Rivera VM Squillace RM Miller D Berk L Wardwell SD Ning Y Ridaforolimus (AP23573; MK-8669), a potent mTOR inhibitor, has broad antitumor activity and can be optimally administered using intermittent dosing regimens Mol Cancer Ther 2011 10 6 1059 1071 10.1158/1535-7163.MCT-10-0792 21482695 \n6. Squillace RM Miller D Cookson M Wardwell SD Moran L Clapham D Antitumor activity of ridaforolimus and potential cell-cycle determinants of sensitivity in sarcoma and endometrial cancer models Mol Cancer Ther 2011 10 10 1959 1968 10.1158/1535-7163.MCT-11-0273 21825008 \n7. Chawla SP Staddon AP Baker LH Schuetze SM Tolcher AW D'Amato GZ Phase II study of the mammalian target of rapamycin inhibitor ridaforolimus in patients with advanced bone and soft tissue sarcomas J Clin Oncol 2012 30 1 78 84 10.1200/JCO.2011.35.6329 22067397 \n8. Hartford CM Desai AA Janisch L Karrison T Rivera VM Berk L A phase I trial to determine the safety, tolerability, and maximum tolerated dose of deforolimus in patients with advanced malignancies Clin Cancer Res 2009 15 4 1428 1434 10.1158/1078-0432.CCR-08-2076 19228743 \n9. Mita MM Mita AC Chu QS Rowinsky EK Fetterly GJ Goldston M Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies J Clin Oncol 2008 26 3 361 367 10.1200/JCO.2007.12.0345 18202410 \n10. Rizzieri DA Feldman E Dipersio JF Gabrail N Stock W Strair R A phase 2 clinical trial of deforolimus (AP23573, MK-8669), a novel mammalian target of rapamycin inhibitor, in patients with relapsed or refractory hematologic malignancies Clin Cancer Res 2008 14 9 2756 2762 10.1158/1078-0432.CCR-07-1372 18451242 \n11. Demetri GD Chawla SP Ray-Coquard I Le Cesne A Staddon AP Milhem MM Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy J Clin Oncol 2013 31 19 2485 2492 10.1200/JCO.2012.45.5766 23715582 \n12. Mondesire WH Jian W Zhang H Ensor J Hung MC Mills GB Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells Clin Cancer Res 2004 10 20 7031 7042 10.1158/1078-0432.CCR-04-0361 15501983 \n13. Vignot S Faivre S Aguirre D Raymond E mTOR-targeted therapy of cancer with rapamycin derivatives Ann Oncol 2005 16 4 525 537 10.1093/annonc/mdi113 15728109 \n14. Mita MM Poplin E Britten CD Tap WD Rubin EH Scott BB Phase I/IIa trial of the mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) administered orally in patients with refractory or advanced malignancies and sarcoma Ann Oncol 2013 24 4 1104 1111 10.1093/annonc/mds602 23211938 \n15. Perotti A Locatelli A Sessa C Hess D Vigano L Capri G Phase IB study of the mTOR inhibitor ridaforolimus with capecitabine J Clin Oncol 2010 28 30 4554 4561 10.1200/JCO.2009.27.5867 20855840 \n16. Sessa C, Tosi D, Vigano L, Albanell J, Hess D, Maur M, et al. Phase Ib study of weekly mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) with weekly paclitaxel. Ann Oncol. 2010;21:1315–22.\n17. Nemunaitis J, Hochster HS, Lustgarten S, Rhodes R, Ebbinghaus S, Turner CD, et al. A phase I trial of oral ridaforolimus (AP23573; MK-8669) in combination with bevacizumab for patients with advanced cancers. Clin Oncol (R Coll Radiol). 2013;25:336–42.\n18. Di Cosimo S Sathyanarayanan S Bendell JC Cervantes A Stein MN Brana I Combination of the mTOR Inhibitor Ridaforolimus and the Anti-IGF1R Monoclonal Antibody Dalotuzumab: Preclinical Characterization and Phase I Clinical Trial Clin Cancer Res 2015 21 1 49 59 10.1158/1078-0432.CCR-14-0940 25320355 \n19. Seiler M Ray-Coquard I Melichar B Yardley DA Wang RX Dodion PF Oral Ridaforolimus Plus Trastuzumab for Patients With HER2(+) Trastuzumab-Refractory Metastatic Breast Cancer Clin Breast Cancer 2015 15 1 60 65 10.1016/j.clbc.2014.07.008 25239224 \n20. Seki Y Yamamoto N Tamura Y Goto Y Shibata T Tanioka M Phase I study for ridaforolimus, an oral mTOR inhibitor, in Japanese patients with advanced solid tumors Cancer Chemother Pharmacol 2012 69 4 1099 1105 10.1007/s00280-011-1788-4 22143378 \n21. Slomovitz BM Lu KH Johnston T Coleman RL Munsell M Broaddus RR A phase 2 study of the oral mammalian target of rapamycin inhibitor, everolimus, in patients with recurrent endometrial carcinoma Cancer 2010 116 23 5415 5419 10.1002/cncr.25515 20681032 \n22. Oza AM Elit L Tsao MS Kamel-Reid S Biagi J Provencher DM Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group J Clin Oncol 2011 29 24 3278 3285 10.1200/JCO.2010.34.1578 21788564 \n23. Colombo N McMeekin DS Schwartz PE Sessa C Gehrig PA Holloway R Ridaforolimus as a single agent in advanced endometrial cancer: results of a single-arm, phase 2 trial Br J Cancer 2013 108 5 1021 1026 10.1038/bjc.2013.59 23403817 \n24. Tsoref D Welch S Lau S Biagi J Tonkin K Martin LA Phase II study of oral ridaforolimus in women with recurrent or metastatic endometrial cancer Gynecol Oncol 2014 135 2 184 189 10.1016/j.ygyno.2014.06.033 25173583 \n25. Alvarez EA Brady WE Walker JL Rotmensch J Zhou XC Kendrick JE Phase II trial of combination bevacizumab and temsirolimus in the treatment of recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study Gynecol Oncol 2013 129 1 22 27 10.1016/j.ygyno.2012.12.022 23262204 \n26. Fleming GF Filiaci VL Marzullo B Zaino RJ Davidson SA Pearl M Temsirolimus with or without megestrol acetate and tamoxifen for endometrial cancer: a gynecologic oncology group study Gynecol Oncol 2014 132 3 585 592 10.1016/j.ygyno.2014.01.015 24456823 \n27. Molinolo AA Marsh C El Dinali M Gangane N Jennison K Hewitt S mTOR as a molecular target in HPV-associated oral and cervical squamous carcinomas Clin Cancer Res 2012 18 9 2558 2568 10.1158/1078-0432.CCR-11-2824 22409888 \n28. Tinker AV Ellard S Welch S Moens F Allo G Tsao MS Phase II study of temsirolimus (CCI-779) in women with recurrent, unresectable, locally advanced or metastatic carcinoma of the cervix. A trial of the NCIC Clinical Trials Group (NCIC CTG IND 199) Gynecol Oncol 2013 130 2 269 274 10.1016/j.ygyno.2013.05.008 23672928 \n29. Tewari KS Sill MW Long HJ 3rd Penson RT Huang H Ramondetta LM Improved survival with bevacizumab in advanced cervical cancer N Engl J Med 2014 370 8 734 743 10.1056/NEJMoa1309748 24552320\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "17(1)",
"journal": "BMC cancer",
"keywords": "Oral ridaforolimus; Paclitaxel and carboplatin combination; Phase 1 trial; Solid tumors",
"medline_ta": "BMC Cancer",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000740:Anemia; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005221:Fatigue; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms; D009503:Neutropenia; D017239:Paclitaxel; D012107:Research Design; D020123:Sirolimus; D013921:Thrombocytopenia",
"nlm_unique_id": "100967800",
"other_id": null,
"pages": "407",
"pmc": null,
"pmid": "28595616",
"pubdate": "2017-06-08",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article",
"references": "21732754;21788564;20681032;19228743;25239224;18922108;16724053;21482695;20855840;23672928;24456823;23715582;18451242;24552320;18202410;15728109;22067397;25320355;22409888;25173583;23403817;23615181;23262204;21825008;23211938;15501983;11057898;19901013;22143378",
"title": "Phase I study of oral ridaforolimus in combination with paclitaxel and carboplatin in patients with solid tumor cancers.",
"title_normalized": "phase i study of oral ridaforolimus in combination with paclitaxel and carboplatin in patients with solid tumor cancers"
} | [
{
"companynumb": "US-PFIZER INC-2017261559",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "The presentation of carbon monoxide poisoning is non-specific and highly variable. Hyperbaric oxygen therapy is used for the treatment of this condition. Various reports show the occurrence of self-limiting seizures after carbon monoxide poisoning and as a consequence of hyperbaric oxygen therapy. Contrary to the seizures, status epilepticus has been rarely observed in these conditions. The exact pathophysiology underlying seizures and status epilepticus associated with carbon monoxide poisoning and hyperbaric oxygen therapy is not really clear, and some elements appear to be common to both conditions. We describe a case of non-convulsive status epilepticus in a patient with carbon monoxide poisoning treated with hyperbaric oxygen therapy. The mechanism, MRI findings and implications are discussed.",
"affiliations": "Neuroradiology COU, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Italy.;Neuroradiology COU, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Italy francescadigiuliano@msn.com.;Neuroradiology COU, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Italy.;Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Italy.;Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Italy.;Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Italy.;Neuroradiology COU, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Italy.;Neuroradiology COU, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Italy.",
"authors": "Marziali|Simone|S|;Di Giuliano|Francesca|F|;Picchi|Eliseo|E|;Natoli|Silvia|S|;Leonardis|Carlo|C|;Leonardis|Francesca|F|;Garaci|Francesco|F|;Floris|Roberto|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1971400916665379",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1971-4009",
"issue": "29(6)",
"journal": "The neuroradiology journal",
"keywords": "Carbon monoxide poisoning; MRI; hyperbaric oxygen therapy; seizures; status epilepticus",
"medline_ta": "Neuroradiol J",
"mesh_terms": "D002249:Carbon Monoxide Poisoning; D004569:Electroencephalography; D005260:Female; D006801:Humans; D006931:Hyperbaric Oxygenation; D008279:Magnetic Resonance Imaging; D013226:Status Epilepticus",
"nlm_unique_id": "101295103",
"other_id": null,
"pages": "431-435",
"pmc": null,
"pmid": "27549147",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10788755;12362006;9610972;12034791;19297574;15946345;2884439;7247790;23241416;19270104;23598831;21192190;10541600;17438487",
"title": "Non-convulsive status epilepticus in a patient with carbon-monoxide poisoning treated with hyperbaric oxygen therapy.",
"title_normalized": "non convulsive status epilepticus in a patient with carbon monoxide poisoning treated with hyperbaric oxygen therapy"
} | [
{
"companynumb": "IT-ALSI-201600371",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OXYGEN"
},
"drugadditional": null,
"drugad... |
{
"abstract": "OBJECTIVE\nTo report a case of vancomycin-induced neutropenia and provide a review of the literature.\n\n\nMETHODS\nA 64-year-old white man was treated with intravenous vancomycin 1.5 g/day for finger osteomyelitis. He developed neutropenia after 21 days of vancomycin therapy. The absolute neutrophil count reached a nadir of 418 cells/mm(3) during vancomycin use and returned to normal 7 days after its discontinuation. The eosinophil count was also elevated during the neutropenic episode and probably related to vancomycin. Based on the Naranjo probability scale, the reaction was probably related to vancomycin use.\n\n\nCONCLUSIONS\nArticles describing cases of vancomycin-induced neutropenia were identified. All patients developed neutropenia as a result of vancomycin therapy >/=12 days. Neutrophil counts generally increased following discontinuation of vancomycin. One article reported successful resolution of neutropenia and infection by switching the patient's therapy to the structurally related antibiotic agent teicoplanin. Other patients were continued on vancomycin therapy, and neutropenia was treated with moderate to good success with filgrastim. Rechallenge was not generally attempted. The mechanism of neutropenia caused by vancomycin is unclear, but appears to be immune-mediated.\n\n\nCONCLUSIONS\nVancomycin therapy should not be prolonged unless absolutely necessary, and therapy should be reserved for patients with clear indications for the drug, such as infections due to gram-positive organisms resistant to other therapies. Patients should have periodic assessment of white blood cell and neutrophil counts with consideration to discontinue vancomycin if neutropenia develops.",
"affiliations": "Veterans Affairs Medical Center, West Palm Beach, FL, USA. marisel.segarra-newnham@med.va.gov",
"authors": "Segarra-Newnham|Marisel|M|;Tagoff|Shari S|SS|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin",
"country": "United States",
"delete": false,
"doi": "10.1345/aph.1E187",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "38(11)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007970:Leukopenia; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D010019:Osteomyelitis; D014640:Vancomycin",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "1855-9",
"pmc": null,
"pmid": "15466904",
"pubdate": "2004-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Probable vancomycin-induced neutropenia.",
"title_normalized": "probable vancomycin induced neutropenia"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2016SP011889",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional... |
{
"abstract": "Methemoglobinemia is a rare cause of neonatal cyanosis in the newborn. It is considered a medical emergency. Failure of recognition or appropriated treatment could result in serious disease and neonatal death. Neonatal methemoglobinemia can be caused by both hereditary and acquired factors.\n\n\n\nWe present two cases of newborns who developed severe cyanosis a few hours after birth due to methemoglobinemia. This was thought to be related to the local maternal perineal infiltration of prilocaine during childbirth. Though rare, prilocaine is the most potent agent to induce methemoglobinemia compared to other local aneasthetics. After intravenous administration of methylene blue, both newborns fully recovered.\n\n\n\nNeonatal methemoglobinemia is a rare and potentially fatal complication of local anesthetics, particularly prilocaine, administered to the mother during childbirth. Midwives, obstetricians, gynecologists and pediatricians should be aware of this complication. The use of other local anesthetics, including lidocaine, should be considered.",
"affiliations": "VieCuri Medisch Centrum, afd. Gynaecologie,Venlo.;VieCuri Medisch Centrum, afd. Kindergeneeskunde,Venlo.;VieCuri Medisch Centrum, afd. Kindergeneeskunde,Venlo.;VieCuri Medisch Centrum, afd. Gynaecologie,Venlo.;Maxima Medisch Centrum, afd. Kindergeneeskunde, Veldhoven.;VieCuri Medisch Centrum, afd. Gynaecologie,Venlo.",
"authors": "Wieland|Bernice V|BV|;Leijten|Alex|A|;van der Heijden|Hylke H A C M|HHACM|;van de Laar|Rafli|R|;Ten Brink|Fia|F|;Alers|Nicole O|NO|",
"chemical_list": "D000779:Anesthetics, Local; D011318:Prilocaine; D008012:Lidocaine",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2162",
"issue": "165()",
"journal": "Nederlands tijdschrift voor geneeskunde",
"keywords": null,
"medline_ta": "Ned Tijdschr Geneeskd",
"mesh_terms": "D000779:Anesthetics, Local; D003490:Cyanosis; D006801:Humans; D007231:Infant, Newborn; D008012:Lidocaine; D008708:Methemoglobinemia; D011318:Prilocaine",
"nlm_unique_id": "0400770",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34346590",
"pubdate": "2021-07-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Unexplained cyanosis in two newborns: neonatal methemoglobinemia after maternal perineal infiltration of prilocaine.",
"title_normalized": "unexplained cyanosis in two newborns neonatal methemoglobinemia after maternal perineal infiltration of prilocaine"
} | [
{
"companynumb": "NL-DENTSPLY PHARMACEUTICAL-2021SCDP000259",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PRILOCAINE"
},
"drugaddition... |
{
"abstract": "We report two cases of stroke associated with the use of finasteride at 1 mg/day, which is approved in Japan for the treatment of male-pattern hair loss. The first case involved a 35-year-old male taking 1 mg of finasteride daily for 6 months to prevent male-pattern hair loss. He was taken to a hospital and later admitted to our hospital owing to headache and seizures. Brain computed tomography (CT) images showed a low-density area in the right frontal lobe. CT venography (CTV) revealed sinus thrombosis and he was treated with an anticoagulant. As the headache gradually subsided, medications were tapered and terminated 10 months later when venous flow to the sagittal sinus and left transverse sinus was confirmed to be recanalized. The second case involved a 41-year-old male taking 1 mg of finasteride and 6 mg of minoxidil daily for 1 year for male-pattern hair loss. He started having headaches and was admitted to our hospital when diffusion-weighted images of brain magnetic resonance imaging (MRI) showed a high-intensity area in the left parietotemporal lobe. He was treated with antiplatelet and anticoagulation medicines. The Japan Pharmaceutical and Medical Devices Agency (PMDA) has reported 14 cases of thrombosis in patients taking finasteride in Japan; 4 cases of stroke (our 2 cases and 2 reported by PMDA), 6 cases of myocardial infarction, and 4 cases of other thrombotic diseases. Increases in estrone and estradiol levels in prostate cancer patients and controls receiving 5 mg of finasteride have been reported. Gynecomastia has also been reported as one of the adverse effects of finasteride at 1 mg or 5 mg daily. Taken together, we assume that the increases in estrone and estradiol levels induced by finasteride lead to thrombosis development.",
"affiliations": "Department of Neurology, Yokohama Rosai Hospital.",
"authors": "Tsuji|Yukio|Y|;Nakayama|Takahiro|T|;Bono|Keiko|K|;Kitamura|Mizuki|M|;Imafuku|Ichiro|I|",
"chemical_list": "D058891:5-alpha Reductase Inhibitors; D000925:Anticoagulants; D004970:Estrone; D004958:Estradiol; D018120:Finasteride",
"country": "Japan",
"delete": false,
"doi": "10.5692/clinicalneurol.54.423",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-918X",
"issue": "54(5)",
"journal": "Rinsho shinkeigaku = Clinical neurology",
"keywords": null,
"medline_ta": "Rinsho Shinkeigaku",
"mesh_terms": "D058891:5-alpha Reductase Inhibitors; D000284:Administration, Oral; D000328:Adult; D000505:Alopecia; D000925:Anticoagulants; D038524:Diffusion Magnetic Resonance Imaging; D017277:Drug Approval; D004958:Estradiol; D004970:Estrone; D018120:Finasteride; D006177:Gynecomastia; D006801:Humans; D007564:Japan; D008297:Male; D020521:Stroke; D013927:Thrombosis; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0417466",
"other_id": null,
"pages": "423-8",
"pmc": null,
"pmid": "24943080",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Two cases of stroke associated with the use of finasteride, an approved drug for male-pattern hair loss in Japan.",
"title_normalized": "two cases of stroke associated with the use of finasteride an approved drug for male pattern hair loss in japan"
} | [
{
"companynumb": "JP-CIPLA LTD.-2015JP03297",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MINOXIDIL"
},
"drugadditional": null,
... |
{
"abstract": "After allogeneic hematopoietic stem cell transplantation (HSCT), viral infections/reactivations are a frequent complication, sometimes with fatal outcome. Thus, early diagnosis is recommended by screening of whole blood or plasma preparations using highly sensitive molecular techniques that test for the most common viral pathogens, such as Epstein-Barr virus, cytomegalovirus, and adenoviruses (ADVs). Despite this approach, not every reactivation/infection can be adequately detected or excluded, even with highly sensitive polymerase chain reaction. Particularly after toxic treatment, uncommon infections or infections resistant to first-line treatment can occur, even in unusual locations. Herein, we present the case of a child with Philadelphia chromosome-positive acute lymphoblastic leukemia after allogeneic HSCT who suffered from 5 different viral reactivations/infections, including acyclovir-resistant herpes simplex virus type 1 esophagitis, human herpesvirus 6 encephalitis, rotavirus gastroenteritis, respiratory syncytial virus pneumonia, and ADV esophagitis, despite routinely performed blood examinations for viral pathogens remaining unrevealing at all times.",
"affiliations": "Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Jena, Germany.",
"authors": "Ernst|J|J|;Sauerbrei|A|A|;Krumbholz|A|A|;Egerer|R|R|;Mentzel|H-J|HJ|;Kurzai|M|M|;Häfer|R|R|;Beck|J F|JF|;Gruhn|B|B|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/j.1399-3062.2012.00778.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "14(5)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": null,
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000260:Adenoviruses, Human; D000293:Adolescent; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D018259:Herpesvirus 1, Human; D015654:Herpesvirus 6, Human; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012136:Respiratory Syncytial Viruses; D012401:Rotavirus; D014184:Transplantation, Homologous; D014775:Virus Activation; D014777:Virus Diseases",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "E82-8",
"pmc": null,
"pmid": "22862952",
"pubdate": "2012-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Multiple viral infections after haploidentical hematopoietic stem cell transplantation in a child with acute lymphoblastic leukemia.",
"title_normalized": "multiple viral infections after haploidentical hematopoietic stem cell transplantation in a child with acute lymphoblastic leukemia"
} | [
{
"companynumb": "DE-GLAXOSMITHKLINE-DE2018158269",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMPHOTERICIN B"
},
"drugadditional": "3... |
{
"abstract": "The diagnosis of acute promyelocytic leukemia (APL) in pregnancy is an uncommon, life-threatening emergency. Choice of treatment and management of complications are challenging.\n\n\n\nWe report the case of a patient with diagnosis of APL at gestational age (GA) 24 + 4. We describe the interdisciplinary management during pregnancy and delivery and provide a 2-year follow-up. Existing reports on APL in pregnancy are summarized.\n\n\n\nSingle-agent induction therapy with all-trans retinoic acid (ATRA) was started and resulted in normalization of blood cell counts after 32 days. Vaginal delivery of a healthy baby occurred at GA 34 + 4. Consolidation therapy consisted of four courses of ATRA and arsenic trioxide (ATO). Less than 100 cases of APL in pregnancy are published. Misdiagnosis as HELLP syndrome with fatal outcome may occur. Combination therapies (ATRA-plus anthracyclines) were used in the majority of reports.\n\n\n\nDiagnosis and treatment of APL during pregnancy continues to be a challenge requiring interdisciplinary team work. Single-agent ATRA therapy may evolve as a safe and less-toxic treatment modality.",
"affiliations": "Department of Internal Medicine III, Hematology/Oncology/Rheumatology, University Bonn Medical School, Sigmund-Freud-Str. 25, 53105, Bonn, Germany. cordula.nellessen@ukb.uni-bonn.de.;Department of Internal Medicine III, Hematology/Oncology/Rheumatology, University Bonn Medical School, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.;Department of Internal Medicine III, Hematology/Oncology/Rheumatology, University Bonn Medical School, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.;Department of Obstetrics and Prenatal Medicine, University Bonn Medical School, Bonn, Germany.;Department of Obstetrics and Prenatal Medicine, University Bonn Medical School, Bonn, Germany.;Department of Internal Medicine III, Hematology/Oncology/Rheumatology, University Bonn Medical School, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.;Department of Obstetrics and Prenatal Medicine, University Bonn Medical School, Bonn, Germany.",
"authors": "Nellessen|Cordula M|CM|;Janzen|Viktor|V|;Mayer|Karin|K|;Giovannini|Giulia|G|;Gembruch|Ulrich|U|;Brossart|Peter|P|;Merz|Waltraut M|WM|",
"chemical_list": "D000970:Antineoplastic Agents; D001152:Arsenicals; D014212:Tretinoin; D000077237:Arsenic Trioxide",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00404-017-4583-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0932-0067",
"issue": "297(2)",
"journal": "Archives of gynecology and obstetrics",
"keywords": "ATRA; Acute promyelocytic leukemia; Pregnancy",
"medline_ta": "Arch Gynecol Obstet",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D000077237:Arsenic Trioxide; D001152:Arsenicals; D005260:Female; D005865:Gestational Age; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D020360:Neoadjuvant Therapy; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D016896:Treatment Outcome; D014212:Tretinoin",
"nlm_unique_id": "8710213",
"other_id": null,
"pages": "281-284",
"pmc": null,
"pmid": "29110117",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Successful treatment of acute promyelocytic leukemia in pregnancy with single-agent all-trans retinoic acid.",
"title_normalized": "successful treatment of acute promyelocytic leukemia in pregnancy with single agent all trans retinoic acid"
} | [
{
"companynumb": "DE-BAUSCH-BL-2017-033180",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRETINOIN"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo assess the safety of the newer antiepileptic drugs (AEDs) during pregnancy.\n\n\nMETHODS\nThe study population was pregnant women who enrolled in the North American AED Pregnancy Registry between 1997 and 2011. Data on AED use and maternal characteristics were collected through phone interviews at enrollment, at 7 months' gestation, and postpartum. Malformations were confirmed by medical records. The risk of major malformations was calculated among infants exposed to specific AEDs in monotherapy during the first trimester of pregnancy and among an unexposed group. Risk ratios (RRs) and 95% confidence intervals (CIs) were estimated with logistic regression.\n\n\nRESULTS\nThe risk of major malformations was 9.3% (30 of 323) for valproate, 5.5% (11 of 199) for phenobarbital, 4.2% (15 of 359) for topiramate, 3.0% (31 of 1.033) for carbamazepine, 2.9% (12 of 416) for phenytoin, 2.4% (11 of 450) for levetiracetam, and 2.0% (31 of 1,562) for lamotrigine. Compared with lamotrigine, the RR was 5.1 (95% CI 3.0-8.5) for valproate, 2.9 (1.4-5.8) for phenobarbital, and 2.2 (1.2-4.0) for topiramate. The proportion of women with epilepsy who had seizures during pregnancy ranged from 23% for valproate to 31% for lamotrigine. Valproate was associated with a higher risk of neural tube defects, hypospadias, cardiac defects, and oral clefts and phenobarbital with a higher risk of cardiac defects and oral clefts; 5 infants exposed to topiramate (1.4%) had a cleft lip.\n\n\nCONCLUSIONS\nAEDs such as valproate and phenobarbital were associated with a higher risk of major malformations than newer AEDs such as lamotrigine and levetiracetam. Topiramate was associated with an increased risk of cleft lip compared with that of a reference population.",
"affiliations": "Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA. shernan@hsph.harvard.edu",
"authors": "Hernández-Díaz|S|S|;Smith|C R|CR|;Shen|A|A|;Mittendorf|R|R|;Hauser|W A|WA|;Yerby|M|M|;Holmes|L B|LB|;|||;|||",
"chemical_list": "D000927:Anticonvulsants",
"country": "United States",
"delete": false,
"doi": "10.1212/WNL.0b013e3182574f39",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3878",
"issue": "78(21)",
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000328:Adult; D000927:Anticonvulsants; D004827:Epilepsy; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D016017:Odds Ratio; D011247:Pregnancy; D011248:Pregnancy Complications; D011297:Prenatal Exposure Delayed Effects; D012042:Registries",
"nlm_unique_id": "0401060",
"other_id": null,
"pages": "1692-9",
"pmc": null,
"pmid": "22551726",
"pubdate": "2012-05-22",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Comparative safety of antiepileptic drugs during pregnancy.",
"title_normalized": "comparative safety of antiepileptic drugs during pregnancy"
} | [
{
"companynumb": "US-CIPLA LTD.-2016US02911",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"drugadditional": null,
... |
{
"abstract": "Pineal cysts of the third ventricle presenting with acute obstructive hydrocephalus due to internal cystic hemorrhage are a rare clinical entity. The authors report a case of a 61-year-old man taking antiplatelet medication who suffered from a hemorrhagic pineal cyst and was treated with endoscopic surgery. One month prior to treatment, the patient was diagnosed with a brainstem infarction and received clopidogrel in addition to aspirin. A small incidental pineal cyst was concurrently diagnosed using magnetic resonance (MR) imaging which was intended to be followed conservatively. The patient presented with a sudden onset of headache and diplopia. On admission, the neurological examination revealed clouding of consciousness and Parinaud syndrome. Computerized tomography (CT) scans demonstrated a hemorrhagic mass lesion in the posterior third ventricle. The patient underwent emergency external ventricular drainage with staged endoscopic biopsy and third ventriculostomy using a flexible videoscope. Histological examination revealed pineal tissue with necrotic change and no evidence of tumor cells. One year later MR imaging demonstrated no evidence of cystic lesion and a flow void between third ventricle and prepontine cistern. In patients with asymptomatic pineal cysts who are treated with antiplatelet therapy, it is important to be aware of the risk of pineal apoplexy. Endoscopic management can be effective for treatment of hemorrhagic pineal cyst with obstructive hydrocephalus.",
"affiliations": "Department of Neurosurgery, Osaka Medical College.",
"authors": "Tamura|Yoji|Y|;Yamada|Yoshitaka|Y|;Tucker|Adam|A|;Ukita|Tohru|T|;Tsuji|Masao|M|;Miyake|Hiroji|H|;Kuroiwa|Toshihiko|T|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors",
"country": "Japan",
"delete": false,
"doi": "10.2176/nmc.cr2012-0396",
"fulltext": "\n==== Front\nNeurol Med Chir (Tokyo)Neurol. Med. Chir. (Tokyo)NMCNeurologia medico-chirurgica0470-81051349-8029The Japan Neurosurgical Society 24067776nmc-53-625Case ReportEndoscopic Surgery for Hemorrhagic Pineal Cyst Following Antiplatelet Therapy: Case Report Tamura Yoji 1Yamada Yoshitaka 2Tucker Adam 12Ukita Tohru 2Tsuji Masao 2Miyake Hiroji 2Kuroiwa Toshihiko 11 Department of Neurosurgery, Osaka Medical College, Takatsuki, Osaka;2 Department of Neurosurgery, Nishinomiya Kyoritsu Neurosurgical Hospital, Nishinomiya, HyogoAddress reprint requests to: Yoji Tamura, MD, Department of Neurosurgery, Osaka Medical College, 2-7, Daigaku-machi, Takatsuki, Osaka 569-8686, Japan. e-mail: neu034@poh.osaka-med.ac.jpConflicts of Interest Disclosure\n\nNone declared.\n\n9 2013 25 9 2013 53 9 625 629 9 11 2012 22 2 2013 © 2013 The Japan Neurosurgical Society2013This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/Pineal cysts of the third ventricle presenting with acute obstructive hydrocephalus due to internal cystic hemorrhage are a rare clinical entity. The authors report a case of a 61-year-old man taking antiplatelet medication who suffered from a hemorrhagic pineal cyst and was treated with endoscopic surgery. One month prior to treatment, the patient was diagnosed with a brainstem infarction and received clopidogrel in addition to aspirin. A small incidental pineal cyst was concurrently diagnosed using magnetic resonance (MR) imaging which was intended to be followed conservatively. The patient presented with a sudden onset of headache and diplopia. On admission, the neurological examination revealed clouding of consciousness and Parinaud syndrome. Computerized tomography (CT) scans demonstrated a hemorrhagic mass lesion in the posterior third ventricle. The patient underwent emergency external ventricular drainage with staged endoscopic biopsy and third ventriculostomy using a flexible videoscope. Histological examination revealed pineal tissue with necrotic change and no evidence of tumor cells. One year later MR imaging demonstrated no evidence of cystic lesion and a flow void between third ventricle and prepontine cistern. In patients with asymptomatic pineal cysts who are treated with antiplatelet therapy, it is important to be aware of the risk of pineal apoplexy. Endoscopic management can be effective for treatment of hemorrhagic pineal cyst with obstructive hydrocephalus.\n\npineal cystpineal apoplexyendoscopic surgeryendoscopic third ventriculostomy\n==== Body\nIntroduction\nPineal cysts are often asymptomatic and encountered incidentally on computerized tomography (CT) scans or magnetic resonance (MR) imaging.1,2,22) However, infrequently these cysts can cause obstruction of cerebrospinal fluid (CSF) flow at the entrance of aqueduct due to cystic expansion and/or intracystic hemorrhage.3–6,8–11,13–21,23,24,26) The authors report a patient undergoing antiplatelet therapy for brainstem infarction who was presented with a symptomatic hemorrhagic pineal cyst.\n\nCase Report\nA 61-year-old man was presented with sudden onset of headache and diplopia. The patient had a prior history of uncontrollable diabetes mellitus. One month prior to admission, the patient was diagnosed with a brainstem infarction (Fig. 1A) and treated with clopidogrel (75 mg) in addition to his regular medications including aspirin (100 mg). At that time, MR images demonstrated an incidental small cyst in the pineal region without ventriculomegaly (Fig. 1B). The patient was treated conservatively with the intention of outpatient follow-up.\n\nOn admission, he complained of headache and the neurological examination revealed clouding of consciousness and Parinaud syndrome. Initial CT scans demonstrated a high density mass lesion in the pineal region and dilatation of the lateral/third ventricles with intraventricular hemorrhage (Fig. 2A). MR imaging suggested acute hemorrhage with iso intensity on T1-weighted (WI), low intensity on T2-WI without enhancement on Gd-enhanced T1-WI sequence (Fig. 2B, C). On Day 2, the patient’s consciousness level declined and CT scans demonstrated acute obstructive hydrocephalus which was emergently treated with external ventricular drainage.\n\nThree days later, the patient underwent endoscopic surgery via a right frontal burr hole using a flexible videoscope (VEF-V; Olympus Co., Tokyo). The cyst wall was observed after removal of clot of third ventricle (Fig. 3A). A tissue biopsy of the cyst wall was performed using grasping forceps. Although minor bleeding from the vascularized parts of the cyst occurred during removal of intracystic hematoma, complete hemostasis was obtained following artificial CSF irrigation (Fig. 3B). Finally, endoscopic third ventriculostomy (ETV) was performed in the standard manner.\n\nHistological assessment revealed pineal tissue with necrotic change and dispersed localized sections of vessel wall thickening. The typical three-layered pineal cystic structure was not observed. Inflammatory reaction was detected adjacent to the hemorrhagic area. There was no evidence of tumor cells in the any of the specimens (Fig. 3C). One year after surgery, MR imaging demonstrated membranous tissue obstruction at the entrance of the aqueduct, a post-ETV CSF flow void between the third ventricle and prepontine cistern, and evidence of any cystic lesion in the posterior third ventricle (Fig. 4A, B). During the follow-up period, the patient did not experience further headache or neurological deficits. Postoperatively antiplatelet medication was reduced to a single drug (clopidogrel) for prevention of brainstem infarction.\n\nDiscussion\nPineal cysts are typically asymptomatic and incidentally detected on neuroimaging studies. Sawamura et al. reported that asymptomatic pineal cysts more than 5 mm diameter account for 1.3% on MR imaging studies.22) These epidemiologic features were predominant in younger females. Recently Al-Holou et al. also reported similar findings of 2% and 1% prevalence in younger and adult patients, respectively.1,2)\n\nThese cysts usually become symptomatic due to compression of brain tissue or blockage of CSF flow from cystic expansion. Intracystic hemorrhage leading to pineal apoplexy has been reported only occasionally. Previous reported cases with progressive symptoms due to hemorrhage are summarized in Table 1.3,4,6,9–11,13–21,23) Hemorrhagic pineal cysts have been found in a broad spectrum in the age group from newborn infants to senile patients. The grade or extent of hemorrhage is also variable, ranging from minor intracystic xanthochromic fluid levels to intraventricular hemorrhage.\n\nIn 1976, Apuzzo et al. reported one case of pineal apoplexy due to hemorrhagic pineal cyst under anticoagulant therapy.3) Sarikaya-Seiwert et al. also suggested a potentially increased risk of anticoagulation-induced hemorrhage in pineal cysts.21) However, in the majority of reported cases to date, the precise etiology of bleeding has been unclear. In our case, the patient received dual antiplatelet therapy (clopidogrel in addition to aspirin) for brainstem infarction. In a multi-center trial of antiplatelet therapy for cerebral stroke, intracranial hemorrhage was more frequent in patients treated with both aspirin and clopidogrel than clopidogrel alone.7) Based on these rare cases, it is advisable to inform patients with pineal cysts treated with anticoagulant or antiplatelet therapy of the possible risk of intracystic hemorrhage and the potential associated complication of acute obstructive hydrocephalus. Furthermore, based on our case, we cannot ignore the possibility of the effect of uncontrolled diabetes as a contributing to the increased risk of hemorrhage.\n\nVarious surgical approaches, including microsurgical resection, stereotactic aspiration, and endoscopic approach have been employed for the treatment of symptomatic pineal cyst.5,6,9–17,20,21,23–26) Among these options, the cases of spontaneous cyst regression following only ventriculoperitonial shunt or ETV have been reported.4,6) A detailed explanation of the mechanism of this phenomenon has been described as follows: a change in the pressure gradient between the cyst and the ventricle cavity as a result of treatment to normalize ventricular pressure leads to displacement of cyst fluid into the third ventricle space.6) However, in hemorrhagic cases, it is important to differentiate from neoplasma such as glioma, pineocytoma, pineoblastoma, and germ cell tumors. Therefore, histological diagnosis is crucial, and we believe that microsurgical or endoscopic resection is an ideal approach to hemorrhagic pineal cysts.\n\nSeveral reports have shown that an endoscopic surgery can be useful for the treatment of symptomatic pineal cysts.5,11,16,24,25) Michielsen et al. reported 4 patients with pineal cyst who underwent endoscopic surgery via the ventricles.16) They described that the endoscope was an diagnostic and surgical tool, and even total cyst resection is possible by this method. In our case, only partial removal of the intracystic hematoma was performed because of the bleeding that encountered in vascularized parts of the cyst. Nevertheless, postoperatively, the clinical signs and symptoms of obstructive hydrocephalus resolve and almost complete radiological disappearance of the hematoma and cyst cavity was achieved. In this sense, hemorrhagic pineal cysts can be successfully treated only by partial endoscopic removal of the cyst wall.\n\nMichielsen et al. suggested that ETV for obstructive hydrocephalus due to cyst expansion was not necessary because normal CSF flow recovered immediately after cyst reduction.16) However, Uschold et al. who reported use of a supracerebellar infratentorial endoscopic approach claimed that posterior ETV (between third ventricle and quadrigeminal cistern) was beneficial for treatment of cases of the incomplete cyst resection.25) In our case, postoperative MR imaging revealed residual cyst wall adherent to the ependymal layer around the entrance of the aqueduct. ETV for persistent blockage of CSF flow in hemorrhagic pineal cysts can be an effective adjunctive treatment option.\n\nFig. 1 Magnetic resonance (MR) image 1 month before onset. A: Axial diffusion-weighted MR image showing a high intensity lesion in the brainstem. B: Axial fluid attenuated inversion recovery MR image showing a small high intensity lesion in the pineal region.\n\nFig. 2 A: Initial computerized tomography (CT) scan showing a high density mass lesion in the posterior third ventricle with evidence of intraventricular hemorrhage. B, C: Sagittal T1-weighted (B) and Gd-enhanced (C) magnetic resonance (MR) images showing an iso intensity mass lesion without enhancement.\n\nFig. 3 Intraoperative photogram of the endoscopic surgery for hemorrhagic pineal cyst. A: The cyst wall (asterisk) was exposed by removal of clot around cyst. B: After resection of the cyst wall, intracystic hematoma was removed with grasping forceps. C: Photomicrograph of cyst specimen revealing pineal tissue with necrotic change. H & E, ×400.\n\nFig. 4 Axial (A) and sagittal (B) T2-weighted magnetic resonance (MR) images 1 year after surgery. There was no evidence of residual cystic lesion in the posterior third ventricle. The entrance of the aqueduct was obstructed by membrane and a flow void was demonstrated between the third ventricle and the prepotine cistern.\n\nTable 1 Summary of reported cases of hemorrhagic pineal cyst with progressive symptoms\n\nAuthors (Year)\tAge/Sex\tSymptom & Sign\tCause of hemorrhage\tTreatment\tOutcome\t\nApuzzo (1976)\t56/M\tHA, lethargy, ataxic gait\tanticoagulant therapy\tcraniectomy, total excision\tnystagmus, ataxia\t\nHigashi et al. (1979)\t51/F\tHA, LOC\tunknown\tcraniotomy, total excision, V-P shunt\tgaze palsy\t\nOsborn et al. (1989)\t30/M\tHA, Parinaud syn\tunknown\tshunt, craniectomy, subtotal excision\tasymptomatic\t\nKlein & Rubinstein (1989)\t30/F\tHA, gaze palsy\tunknown\ttotal excision\tlost to follow-up\t\nTurtz et al. (1995)\t21/M\tHA, Parinaud syn\tunknown\tstereotactic endoscopic fenestration\tasymptomatic\t\nKoenigsberg et al. (1996)\t21/M\tHA, Parinaud syn\tdrug abuse\tendoscopic cyst incision\tasymptomatic\t\nMena et al. (1997)\t20/M\tParinaud syn, Papilledema\tunknown\texcision\t12 years alive\t\nSwaroop et al. (1998)\t35/F\tHA, papilledema, ataxia\tunknown\tcraniotomy, total excision\ttransient gaze palsy\t\nMukherjee et al. (1999)\t70/M\tHA, hearing loss, LOC\tunknown\tV-P shunt, partial excision\thearing recovery\t\nDi Chirico et al. (2001)\t16/F\tHA, papilledema\tunknown\tETV\tasymptomatic\t\nMichielsen et al. (2002)\t30/M\tHA, visual deficit\tunknown\tsterotactic endoscopic subtotal excision\tasymptomatic\t\n\t4/F\tHA, lethargy\tunknown\tendoscopic subtotal excision\tasymptomatic\t\nMcNeely et al. (2003)\t12/F\tHA, syncope\tunknown\tdrainage, ETV, craniotomy total excision\tasymptomatic\t\nAvery et al. (2004)\t71/F\tSyncope\tanticoagulant therapy\tshunt\tasymptomatic\t\nPatel et al. (2005)\t29/F\tHA, visual disturbance\tunknown\tcraniotomy, total excision\tasymptomatic\t\nNimmagadda et al. (2006)\t10D/F\tmacrocephaly\tunknown\tobservation\tasymptomatic\t\nMajeed et al. (2007)\t10/F\tHA, gaze palsy\tunknown\tcraniotomy, total excision\tasymptomatic\t\nSarikaya-Seiwert et al. (2009)\t16/F\tHA, impaired concentration\tunknown\tcraniotomy, total excision\tasymptomatic\t\n\t16/F\tHA, papilledema\tunknown\tcraniotomy, total excision\tasymptomatic\t\n\t38/F\tHA, impaired concentration\tanticoagulant therapy\tcraniotomy, total excision\tmalignant tumor\t\nPresent case\t61/M\tHA, Parinaud syn\tantiplatelet therapy\tendoscopic partial excision, ETV\tsymptoms due to brainstem infarction\t\nETV: endoscopic third ventriculostomy, HA: headache, LOC: loss of consciousness, V-P: ventriculoperitoneal.\n==== Refs\nReferences\n1) \nAl-Holou WN Garton HJ Muraszko KM Ibrahim M Maher CO : \nPrevalence of pineal cysts in children and young adults. Clinical article . \nJ Neurosurg Pediatr \n4 : \n230 –\n236 , \n2009 \n19772406 \n2) \nAl-Holou WN Terman SW Kilburg C Garton HJ Muraszko KM Chandler WF Ibrahim M Maher CO : \nPrevalence and natural history of pineal cysts in adults . \nJ Neurosurg \n115 : \n1106 –\n1114 , \n2011 \n21780858 \n3) \nApuzzo ML Davey LM Manuelidis EE : \nPineal apoplexy associated with anticoagulant therapy. Case report . \nJ Neurosurg \n45 : \n223 –\n226 , \n1976 \n59801 \n4) \nAvery GJ Lind CR Bok AP : \nSuccessful conservative operative management of pineal apoplexy . \nJ Clin Neurosci \n11 : \n667 –\n669 , \n2004 \n15261249 \n5) \nCosta F Fornari M Valla P Servello D : \nSymptomatic pineal cyst: case report and review of the literature . \nMinim Invasive Neurosurg \n51 : \n231 –\n233 , \n2008 \n18683116 \n6) \nDi Chirico A Di Rocco F Velardi F : \nSpontaneous regression of a symptomatic pineal cyst after endoscopic third ventriculostomy . \nChilds Nerv Syst \n17 : \n42 –\n46 , \n2001 \n11219622 \n7) \nDiener HC Bogousslavsky J Brass LM Cimminiello C Csiba L Kaste M Leys D Matias-Guiu J Rupprecht HJ MATCH investigators : \nAspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial . \nLancet \n364 : \n331 –\n337 , \n2004 \n15276392 \n8) \nFain JS Tomlinson FH Scheithauer BW Parisi JE Fletcher GP Kelly PJ Miller GM : \nSymptomatic glial cysts of the pineal gland . \nJ Neurosurg \n80 : \n454 –\n460 , \n1994 \n8113858 \n9) \nHigashi K Katayama S Orita T : \nPineal apoplexy . \nJ Neurol Neurosurg Psychiatr \n42 : \n1050 –\n1053 , \n1979 \n\n10) \nKlein P Rubinstein LJ : \nBenign symptomatic glial cysts of the pineal gland: a report of seven cases and review of the literature . \nJ Neurol Neurosurg Psychiatr \n52 : \n991 –\n995 , \n1989 \n\n11) \nKoenigsberg RA Faro S Marino R Turz A Goldman W : \nImaging of pineal apoplexy . \nClin Imaging \n20 : \n91 –\n94 , \n1996 \n8744815 \n12) \nKreth FW Schätz CR Pagenstecher A Faist M Volk B Ostertag CB : \nStereotactic management of lesions of the pineal region . \nNeurosurgery \n39 : \n280 –\n289 ; \ndiscussion 289–291 , \n1996 \n8832665 \n13) \nMajeed K Enam SA : \nRecurrent pineal apoplexy in a child . \nNeurology \n69 : \n112 –\n114 , \n2007 \n17606890 \n14) \nMcNeely PD Howes WJ Mehta V : \nPineal apoplexy: Is it a facilitator for the development of pineal cysts? \nCan J Neurol Sci \n30 : \n67 –\n71 , \n2003 \n12619788 \n15) \nMena H Armonda RA Ribas JL Ondra SL Rushing EJ : \nNonneoplastic pineal cysts: a clinicopathologic study of twenty-one cases . \nAnn Diagn Pathol \n1 : \n11 –\n18 , \n1997 \n9869821 \n16) \nMichielsen G Benoit Y Baert E Meire F Caemaert J : \nSymptomatic pineal cysts: clinical manifestations and management . \nActa Neurochir (Wien) \n144 : \n233 –\n242 , \n2002 \n11956936 \n17) \nMukherjee KK Banerji D Sharma R : \nPineal cyst presenting with intracystic and subarachnoid haemorrhage: report of a case and review of the literature . \nBr J Neurosurg \n13 : \n189 –\n192 , \n1999 \n10616590 \n18) \nNimmagadda A Sandberg DI Ragheb J : \nSpontaneous involution of a large pineal region hemorrhagic cyst in an infant. Case report . \nJ Neurosurg \n104 (\n4 Suppl ): \n275 –\n278 , \n2006 \n16619640 \n19) \nOsborn RE Deen HG Kerber CW Glass RF : \nA case of hemorrhagic pineal cyst: MR/CT correlation . \nNeuroradiology \n31 : \n187 –\n189 , \n1989 \n2747899 \n20) \nPatel AJ Fuller GN Wildrick DM Sawaya R : \nPineal cyst apoplexy: case report and review of the literature . \nNeurosurgery \n57 : \nE1066 , \n2005 \n16284546 \n21) \nSarikaya-Seiwert S Turowski B Hänggi D Janssen G Steiger HJ Stummer W : \nSymptomatic intracystic hemorrhage in pineal cysts. Report of 3 cases . \nJ Neurosurg Pediatr \n4 : \n130 –\n136 , \n2009 \n19645546 \n22) \nSawamura Y Ikeda J Ozawa M Minoshima Y Saito H Abe H : \nMagnetic resonance images reveal a high incidence of asymptomatic pineal cysts in young women . \nNeurosurgery \n37 : \n11 –\n15 ; \ndiscussion 15–16 , \n1995 \n8587669 \n23) \nSwaroop GR Whittle IR : \nPineal apoplexy: an occurrence with no diagnostic clinicopathological features . \nBr J Neurosurg \n12 : \n274 –\n276 , \n1998 \n11013695 \n24) \nTurtz AR Hughes WB Goldman HW : \nEndoscopic treatment of a symptomatic pineal cyst: technical case report . \nNeurosurgery \n37 : \n1013 –\n1014 ; \ndiscussion 1014–1015 , \n1995 \n8559325 \n25) \nUschold T Abla AA Fusco D Bristol RE Nakaji P : \nSupra cerebellar infratentorial endoscopically controlled resection of pineal lesions: case series and operative technique . \nJ Neurosurg Pediatr \n8 : \n554 –\n564 , \n2011 \n22132912 \n26) \nWisoff JH Epstein F : \nSurgical management of symptomatic pineal cysts . \nJ Neurosurg \n77 : \n896 –\n900 , \n1992 \n1432132\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0470-8105",
"issue": "53(9)",
"journal": "Neurologia medico-chirurgica",
"keywords": null,
"medline_ta": "Neurol Med Chir (Tokyo)",
"mesh_terms": "D001932:Brain Neoplasms; D020863:Central Nervous System Cysts; D004724:Endoscopy; D006801:Humans; D006849:Hydrocephalus; D020300:Intracranial Hemorrhages; D008297:Male; D008875:Middle Aged; D010870:Pineal Gland; D010975:Platelet Aggregation Inhibitors; D020542:Third Ventricle; D014696:Ventriculostomy",
"nlm_unique_id": "0400775",
"other_id": null,
"pages": "625-9",
"pmc": null,
"pmid": "24067776",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "1432132;17606890;8832665;11219622;12619788;16284546;501370;16619640;8587669;59801;8744815;18683116;15276392;8113858;2677249;15261249;10616590;22132912;9869821;19772406;21780858;8559325;19645546;11956936;2747899;11013695",
"title": "Endoscopic surgery for hemorrhagic pineal cyst following antiplatelet therapy: case report.",
"title_normalized": "endoscopic surgery for hemorrhagic pineal cyst following antiplatelet therapy case report"
} | [
{
"companynumb": "JP-ACCORD-024873",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": null,
... |
{
"abstract": "Kawasaki disease (KD) is a systemic vasculitis that can involve the nervous system, including the cranial nerves. Central nervous system findings, especially irritability, lethargy, and aseptic meningitis, occur in 1-30 % of KD patients (1). Cranial nerve palsies are seen rarely, and abducens nerve palsy has been reported in only three children. We describe a 2.5-year-old girl with incomplete KD who developed transient abducens nerve palsy after intravenous immunoglobulin (IVIG) treatment.",
"affiliations": "Department of Pediatric Infectious Diseases, Selcuk University Faculty of Medicine, Alaeddin Keykubat Campus, 42075, Selcuklu, Konya, Turkey. mkeser17@gmail.com.;Department of Pediatric Infectious Diseases, Selcuk University Faculty of Medicine, Alaeddin Keykubat Campus, 42075, Selcuklu, Konya, Turkey.;Department of Pediatric Neurology, Selcuk University Faculty of Medicine, Konya, Turkey.;Department of Pediatric Cardiology, Selcuk University Faculty of Medicine, Konya, Turkey.",
"authors": "Emiroglu|Melike|M|;Alkan|Gulsum|G|;Kartal|Ayse|A|;Cimen|Derya|D|",
"chemical_list": "D016756:Immunoglobulins, Intravenous",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00296-016-3515-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-8172",
"issue": "36(8)",
"journal": "Rheumatology international",
"keywords": "Abducens nerve; Central nervous system involvement; Kawasaki disease; Severity criteria",
"medline_ta": "Rheumatol Int",
"mesh_terms": "D020434:Abducens Nerve Diseases; D002675:Child, Preschool; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D009080:Mucocutaneous Lymph Node Syndrome",
"nlm_unique_id": "8206885",
"other_id": null,
"pages": "1181-3",
"pmc": null,
"pmid": "27329470",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": "7395511;10571450;20500489;23340202;25806679;26101056",
"title": "Abducens nerve palsy in a girl with incomplete Kawasaki disease.",
"title_normalized": "abducens nerve palsy in a girl with incomplete kawasaki disease"
} | [
{
"companynumb": "TR-BAXALTA-2016BLT005471",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": null,
"drugadditional": null,
"drugadministrationroute": "065",
"drugauth... |
{
"abstract": "Chronic Myelogenic Leukemia (CML) is a rare malignant disorder after solid organ transplantation, especially in renal transplant recipients. Imatinib Mesylate is currently approved as first line treatment of CML. Most reports on CML are from kidney recipients who received azathioprine in combination with cyclosporine and prednisolone as immunosuppressive therapy. We report a case with CML who was treated with Mycophenolate Mofetil.",
"affiliations": "Associate Professor of Hematology and Oncology, Uromia University of Medical Sciences, Iran. Makhdoomikhadijeh@yahoo.com.;Associate Professor of Nephrology, Nephrology and Kidney Transplant Research Center, Uromia, Iran.;Assistant professor of Nephrology , Uromia University of Medical Sciences, Uromia, Iran.;Resident of Internal Medicine, Uromia University of Medical Sciences, Iran.;Resident of Internal Medicine, Uromia University of Medical Sciences, Iran.",
"authors": "Eishei Oskuei|Ali|A|;Makhdoomi|Khadijeh|K|;Abkhiz|Saeed|S|;Vossoghian|Sara|S|;Farrokhpour|Mohsen|M|",
"chemical_list": "D000970:Antineoplastic Agents; D001549:Benzamides; D007166:Immunosuppressive Agents; D010879:Piperazines; D011743:Pyrimidines; D016572:Cyclosporine; D000068877:Imatinib Mesylate; D011239:Prednisolone",
"country": "Iran",
"delete": false,
"doi": "0141705/AIM.0015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1029-2977",
"issue": "17(5)",
"journal": "Archives of Iranian medicine",
"keywords": null,
"medline_ta": "Arch Iran Med",
"mesh_terms": "D000970:Antineoplastic Agents; D001549:Benzamides; D016572:Cyclosporine; D006801:Humans; D000068877:Imatinib Mesylate; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D010879:Piperazines; D011239:Prednisolone; D011743:Pyrimidines",
"nlm_unique_id": "100889644",
"other_id": null,
"pages": "388-90",
"pmc": null,
"pmid": "24784871",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of Chronic Myelogenic Leukemia (CML) with imatinib after renal transplantation.",
"title_normalized": "successful treatment of chronic myelogenic leukemia cml with imatinib after renal transplantation"
} | [
{
"companynumb": "IR-ACCORD-027739",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nWe performed electrophysiologic tests on two patients with digitalis toxicity who first had photophobia and xanthopsia and revealed reversible reduced visual acuity and binocular central scotoma.\n\n\nMETHODS\nThe patients were a 72-year-old male and a 54-year-old male who had symptoms of digitalis toxicity.\n\n\nRESULTS\nThe corrected visual acuity was severely decreased during digitalis toxicity, 0.02 oculus dexter (OD) and 0.1 oculus sinister (OS) in case 1 and 0.04 OD and 0.2 OS in case 2. But visual acuity recovered as the blood levels of digitalis decreased to the normal level and the corrected visual acuity was 0.7 OD and 0.8 OS in case 1 and 0.8 OD and 0.9 OS in case 2. We recorded 30 Hz-flicker electroretinogram (ERG), single flash ERG, photopic ERG, and scotopic ERG when digitalis blood levels were elevated and normal. Decreased amplitudes of 30 Hz-flicker ERG and photopic ERG suggested that photoreceptor function was disturbed at digitalis toxicity and cone dysfunction was more severely disturbed than rod dysfunction.\n\n\nCONCLUSIONS\n30 Hz-flicker ERG, as well as electrocardiogram and digitalis blood level, is a relatively convenient and useful measure of digitalis toxicity. It is necessary consiler toxicity when severe visual dysfunction is observed in patients with digitalis therapy.",
"affiliations": "Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.",
"authors": "Nagai|N|N|;Ohde|H|H|;Betsuin|Y|Y|;Matsukura|S|S|;Kigasawa|K|K|;Mashima|Y|Y|;Oguchi|Y|Y|",
"chemical_list": "D004077:Digoxin",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0029-0203",
"issue": "105(1)",
"journal": "Nippon Ganka Gakkai zasshi",
"keywords": null,
"medline_ta": "Nippon Ganka Gakkai Zasshi",
"mesh_terms": "D000368:Aged; D004077:Digoxin; D004596:Electroretinography; D006801:Humans; D008297:Male; D008875:Middle Aged; D012607:Scotoma; D014792:Visual Acuity",
"nlm_unique_id": "7505716",
"other_id": null,
"pages": "24-30",
"pmc": null,
"pmid": "11210783",
"pubdate": "2001-01",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Two cases of digitalis toxicity with reversible and severe decrease of visual acuity.",
"title_normalized": "two cases of digitalis toxicity with reversible and severe decrease of visual acuity"
} | [
{
"companynumb": "JP-CONCORDIA PHARMACEUTICALS INC.-GSH201706-003334",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DIGOXIN"
},
"drugadd... |
{
"abstract": "This case report presents a patient who, while undergoing oral isotretinoin therapy for acne vulgaris, developed onychocryptosis and asymptomatic external urethritis. These uncommon adverse events are not well-documented in medical literature. While his urethritis spontaneously resolved, his onychocryptosis symptoms necessitated surgical intervention. This report illustrates both cosmetic and functional adverse effects of isotretinoin and provides insight into the progression of these reactions over time.",
"affiliations": "Family Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.;Family Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.;Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.",
"authors": "Sivaraj|Krishan|K|http://orcid.org/0000-0002-4732-3574;Friedman|Jessica|J|;Morrell|Dean|D|",
"chemical_list": "D003879:Dermatologic Agents; D015474:Isotretinoin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-231387",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(8)",
"journal": "BMJ case reports",
"keywords": "dermatology; general practice / family medicine; skin; unwanted effects / adverse reactions; urinary and genital tract disorders",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000152:Acne Vulgaris; D000284:Administration, Oral; D000293:Adolescent; D003879:Dermatologic Agents; D003937:Diagnosis, Differential; D005533:Foot Dermatoses; D006801:Humans; D015474:Isotretinoin; D008297:Male; D014009:Onychomycosis; D014526:Urethritis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31413063",
"pubdate": "2019-08-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20676466;27015777;29512421;6192964;9228237;23617693;16575387;8737340;21114478;3280622;24173086;6227639;1460120;21198947;18786498;9252756;6461678;17376098;28295859;3720014;24099068;24964168;6454395;27192525;1533205;23839177;19588674",
"title": "Onychocryptosis and asymptomatic external urethritis as complications of oral isotretinoin therapy.",
"title_normalized": "onychocryptosis and asymptomatic external urethritis as complications of oral isotretinoin therapy"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/19/0113987",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ISOTRETINOIN"
},
"drugadditional": "1",
... |
{
"abstract": "A more complete understanding of immune-mediated damage to the coronary arteries in children with Kawasaki disease (KD) is required for improvements in patient treatment and outcomes. We recently reported the transcriptional profile of KD coronary arteritis, and in this study sought to determine protein expression of transcriptionally up-regulated immune genes in KD coronary arteries from the first 2 months after disease onset. We examined the coronary arteries of 12 fatal KD cases and 13 childhood controls for expression of a set of proteins whose genes were highly up-regulated in the KD coronary artery transcriptome: allograft inflammatory factor 1 (AIF1), interleukin 18 (IL-18), CD74, CD1c, CD20 (MS4A1), Toll-like receptor 7 (TLR-7) and Z-DNA binding protein 1 (ZBP1). Immunohistochemistry and immunofluorescence studies were performed to evaluate protein expression and co-localization, respectively. AIF1 was expressed transmurally in KD arteritis and localized to macrophages and myeloid dendritic cells. CD74, which interacts with major histocompatibility complex (MHC) class II on antigen-presenting cells, localized to the intima-media. CD1c, a marker of myeloid dendritic cells, was expressed in a transmural pattern, as were IL-18 and CD20. ZBP1 and TLR-7 were up-regulated compared to controls, but less highly compared to the other proteins. These findings provide evidence of antigen presentation and interferon response in KD arteritis. In combination with prior studies demonstrating T lymphocyte activation, these results demonstrate the complexity of the KD arterial immune response.",
"affiliations": "Department of Pediatrics/Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.;Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.;Northwestern University Feinberg School of Medicine, Chicago, IL, USA.;Northwestern University Feinberg School of Medicine, Chicago, IL, USA.;Northwestern University Feinberg School of Medicine, Chicago, IL, USA.",
"authors": "Cameron|S A|SA|0000-0003-4310-9287;White|S M|SM|;Arrollo|D|D|;Shulman|S T|ST|;Rowley|A H|AH|",
"chemical_list": "C112986:AIF1 protein, human; D015703:Antigens, CD; D018949:Antigens, CD1; D018951:Antigens, CD20; C437944:CD1C protein, human; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D006023:Glycoproteins; D020382:Interleukin-18; D008840:Microfilament Proteins; D016601:RNA-Binding Proteins; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; C485731:ZBP1 protein, human; D012799:Sialyltransferases; C093493:ST6GAL1 protein, human",
"country": "England",
"delete": false,
"doi": "10.1111/cei.13010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-9104",
"issue": "190(2)",
"journal": "Clinical and experimental immunology",
"keywords": "AIF1; Kawasaki Diseas; coronary aneurysm",
"medline_ta": "Clin Exp Immunol",
"mesh_terms": "D017951:Antigen Presentation; D015703:Antigens, CD; D018949:Antigens, CD1; D018951:Antigens, CD20; D001167:Arteritis; D002135:Calcium-Binding Proteins; D003323:Coronary Aneurysm; D003331:Coronary Vessels; D004268:DNA-Binding Proteins; D005260:Female; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D020869:Gene Expression Profiling; D006023:Glycoproteins; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D020382:Interleukin-18; D008297:Male; D008840:Microfilament Proteins; D009080:Mucocutaneous Lymph Node Syndrome; D016601:RNA-Binding Proteins; D012799:Sialyltransferases; D051199:Toll-Like Receptor 7",
"nlm_unique_id": "0057202",
"other_id": null,
"pages": "244-250",
"pmc": null,
"pmid": "28707750",
"pubdate": "2017-11",
"publication_types": "D016428:Journal Article",
"references": "1861216;6062087;6431411;11312119;16339580;17335804;25613900;2917369;27033518;2307451;26679344;9550392;20038800;23769880;17618271;28505365;8629302;14976261;12390951;3079804;28356445;22723916;11528596;25745177;22405251;15345916",
"title": "Arterial immune protein expression demonstrates the complexity of immune responses in Kawasaki disease arteritis.",
"title_normalized": "arterial immune protein expression demonstrates the complexity of immune responses in kawasaki disease arteritis"
} | [
{
"companynumb": "US-BIOVITRUM-2017US1037",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Hunter syndrome (HS) is a rare X-linked lysosomal storage disorder which affects multiple organ systems. Surgical intervention and general anesthesia should be used with caution because of significant airway complications.\n\n\n\nTwo HS patients underwent surgery with different prognosis are presented below. In the first case, symptoms of progressive disabilities on motor function, language, intelligence, and development last for 1 year in a 6-year-old boy; magnetic resonance imaging (MRI) showed severe hydrocephalus. Third ventriculostomy was performed in this patient to relieve the hydrocephalus. Unfortunately, this patient died postoperatively due to postsurgical tracheal collapse. In the second case, an 8-year-old girl was referred to our hospital with epidural hematoma because of a falling accident. Trephination surgery was performed under local anesthesia to remove the hematoma. Three days postsurgical, the patient was discharged uneventfully.\n\n\n\nGeneral anesthesia in HS patients was associated with poor prognosis due to respiratory complications. Local anesthesia and less intensified treatment should be recommended.",
"affiliations": "Department of Anesthesiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.;Emergency Department, Beijing Haidian Hospital, Beijing Haidian Section, Peking University, Beijing, 100080, China.;Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.;Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.;Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China. lichunde@hotmail.com.",
"authors": "Li|Jin|J|;Zhang|Xinyan|X|;Raynald|||;Jiang|Tao|T|;Li|Chunde|C|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00381-018-3998-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0256-7040",
"issue": "35(5)",
"journal": "Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery",
"keywords": "Complications; Hunter syndrome; Surgery; Treatment",
"medline_ta": "Childs Nerv Syst",
"mesh_terms": "D002648:Child; D017809:Fatal Outcome; D005260:Female; D006407:Hematoma, Epidural, Cranial; D006801:Humans; D006849:Hydrocephalus; D008297:Male; D016532:Mucopolysaccharidosis II",
"nlm_unique_id": "8503227",
"other_id": null,
"pages": "889-891",
"pmc": null,
"pmid": "30443672",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18207547;19901005;21107178;19773189;26937399;18339190;19597960;11490189;19111581;21045710;8509249;23311386;21319059;26046872;21458742;16912578;9514506",
"title": "Surgical consideration in Hunter syndrome: a case of hydrocephalus and a case of epidural hematoma.",
"title_normalized": "surgical consideration in hunter syndrome a case of hydrocephalus and a case of epidural hematoma"
} | [
{
"companynumb": "CN-ACCORD-128245",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MIDAZOLAM HYDROCHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "Serological activity may precede clinical flares of lupus nephritis (LN) but the management of asymptomatic serological reactivation (ASR) remains undefined.\n\n\n\nWe conducted a retrospective analysis of 138 episodes of ASR, which included 53 episodes in which immunosuppression was increased preemptively and 85 episodes in which treatment was unaltered. Preemptive immunosuppressive treatment comprised increasing the dose of prednisolone to ∼0.5 mg/kg/day, and in patients already on mycophenolate mofetil (MMF) or azathioprine (AZA), increasing the dose to 1.5 g/day and 100 mg/day, respectively.\n\n\n\nThirty-four episodes of renal flare occurred during follow-up (88.8 ± 77.3 and 82.8 ± 89.7 months in the preemptive group and controls, respectively), following 5 (9.4%) of preemptively treated ASR and 27 (31.8%) of untreated ASR [hazard ratio 0.3 (confidence interval 0.1-0.7), P = 0.012]. Preemptive treatment was associated with superior survival free of renal relapse (99, 92 and 90% at 6, 12 and 24 month, respectively, compared with 94, 69 and 64% in controls; P = 0.011), whereas survival rate free of extrarenal relapse was similar in the two groups. Preemptively treated patients who did not develop renal flares showed better renal function preservation (estimated glomerular filtration rate slope +0.54 ± 0.43 mL/min/1.73 m2/year, compared with -2.11 ± 0.50 and -1.00 ± 0.33 mL/min/1.73 m2/year, respectively, in controls who did and did not develop subsequent renal flares; P = 0.001 and 0.012, respectively). Preemptive treatment was associated with an increased incidence of gastrointestinal side effects attributed to MMF (P = 0.031), whereas infection rate did not differ between the two groups.\n\n\n\nA preemptive moderate increase of immunosuppression for ASR in LN patients may reduce renal flares and confer benefit to long-term renal function.",
"affiliations": "Division of Nephrology, Department of Medicine, University of Hong Kong, Hong Kong.;Division of Nephrology, Department of Medicine, University of Hong Kong, Hong Kong.;Division of Nephrology, Department of Medicine, University of Hong Kong, Hong Kong.;Division of Nephrology, Department of Medicine, University of Hong Kong, Hong Kong.;Division of Nephrology, Department of Medicine, University of Hong Kong, Hong Kong.;Division of Nephrology, Department of Medicine, University of Hong Kong, Hong Kong.",
"authors": "Yap|Desmond Y H|DYH|;Kwan|Lorraine P Y|LPY|;Ma|Maggie K M|MKM|;Mok|Maggie M Y|MMY|;Chan|Gary C W|GCW|;Chan|Tak Mao|TM|",
"chemical_list": "D007166:Immunosuppressive Agents; D011239:Prednisolone; D009173:Mycophenolic Acid; D001379:Azathioprine",
"country": "England",
"delete": false,
"doi": "10.1093/ndt/gfy024",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0931-0509",
"issue": "34(3)",
"journal": "Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association",
"keywords": "asymptomatic; immunology; lupus nephritis; preemptive treatment; serological reactivation",
"medline_ta": "Nephrol Dial Transplant",
"mesh_terms": "D000328:Adult; D001379:Azathioprine; D018450:Disease Progression; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007166:Immunosuppressive Agents; D007674:Kidney Diseases; D008181:Lupus Nephritis; D008297:Male; D009173:Mycophenolic Acid; D011239:Prednisolone; D012008:Recurrence; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome",
"nlm_unique_id": "8706402",
"other_id": null,
"pages": "467-473",
"pmc": null,
"pmid": "29509932",
"pubdate": "2019-03-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Preemptive immunosuppressive treatment for asymptomatic serological reactivation may reduce renal flares in patients with lupus nephritis: a cohort study.",
"title_normalized": "preemptive immunosuppressive treatment for asymptomatic serological reactivation may reduce renal flares in patients with lupus nephritis a cohort study"
} | [
{
"companynumb": "HK-EDENBRIDGE PHARMACEUTICALS, LLC-HK-2019EDE000041",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"d... |
{
"abstract": "BACKGROUND\nAdrenaline is the standard treatment for anaphylaxis but appropriate administration remains challenging, and iatrogenic overdose is easily overlooked. Despite the established importance of pediatric blood pressure measurement, its use remains inconsistent in clinical practice.\n\n\nMETHODS\nWe report a case of adrenaline overdose in a 9-year-old white boy with anaphylaxis, where signs of adrenaline overdose were indistinguishable from progressive shock until blood pressure measurement was taken.\n\n\nCONCLUSIONS\nThe consequences of under-dosing adrenaline in anaphylaxis are well-recognized, but the converse is less so. Blood pressure measurement should be a routine part of pediatric assessment as it is key to differentiating adrenaline overdose from anaphylactic shock.",
"affiliations": "Department of Emergency Medicine, Flinders Medical Centre, Flinders Drive, Bedford Park, 5042, Adelaide, Australia. Lily.P.Liew@gmail.com.;Department of Emergency Medicine, Flinders Medical Centre, Flinders Drive, Bedford Park, 5042, Adelaide, Australia.",
"authors": "Liew|Pui Yi Lily|PYL|http://orcid.org/0000-0001-5569-620X;Craven|John Andrew|JA|",
"chemical_list": "D004837:Epinephrine",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-017-1290-7",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 129010.1186/s13256-017-1290-7Case ReportAdrenaline overdose in pediatric anaphylaxis: a case report http://orcid.org/0000-0001-5569-620XLiew Pui Yi Lily Lily.P.Liew@gmail.com 12Craven John Andrew John.Craven@sa.gov.au 11 0000 0000 9685 0624grid.414925.fDepartment of Emergency Medicine, Flinders Medical Centre, Flinders Drive, Bedford Park, 5042 Adelaide, Australia 2 0000 0000 9295 3933grid.419789.aPresent address: Department of Obstetrics and Gynaecology, Monash Health, Casey Hospital, 62-70 Kangan Drive, Berwick, 3806 Victoria Australia 8 5 2017 8 5 2017 2017 11 1292 4 2017 10 4 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\nAdrenaline is the standard treatment for anaphylaxis but appropriate administration remains challenging, and iatrogenic overdose is easily overlooked. Despite the established importance of pediatric blood pressure measurement, its use remains inconsistent in clinical practice.\n\nCase presentation\nWe report a case of adrenaline overdose in a 9-year-old white boy with anaphylaxis, where signs of adrenaline overdose were indistinguishable from progressive shock until blood pressure measurement was taken.\n\nConclusions\nThe consequences of under-dosing adrenaline in anaphylaxis are well-recognized, but the converse is less so. Blood pressure measurement should be a routine part of pediatric assessment as it is key to differentiating adrenaline overdose from anaphylactic shock.\n\nKeywords\nPediatricChildrenAnaphylaxisAdrenalineEpinephrineOverdoseBlood pressureCase reportissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nAnaphylaxis, the most severe form of allergic reaction, is a life-threatening multi-systemic inflammatory process [1, 2] mediated by immunoglobulin E (IgE) [3]. The incidence of anaphylaxis in the pediatric group aged 5 to 14 has shown a marked upwards trend since 1990 [4, 5], and with the rapid onset and progression of the disease process, prompt action is key to successful management. Adrenaline is the recommended first line treatment in Australia, either through an autoinjector (commonly used in the community) or adrenaline ampoules and syringes [2]. Its use can be challenging due to non-intuitive dilution and dosing – particularly in the pediatric population.\n\nWe describe a case of adrenaline overdose in a child experiencing anaphylaxis, and discuss the role of blood pressure to differentiate progression of anaphylaxis symptoms from adrenaline toxicity.\n\nCase presentation\nA 9-year-old white boy (weight 32 kg), known to have multiple allergies, asthma, and a history of anaphylaxis to dairy products and nuts, developed generalized body rash, dyspnea, and confusion after inadvertently ingesting a school meal containing a dairy product. He was promptly given 300 μg intramuscular adrenaline via a fixed-dose autoinjector, as well as 600 μg of salbutamol via metered-dose inhaler (six puffs) by his teacher in the community.\n\nUpon ambulance arrival, he was drowsy, cyanosed, and had marked generalized body swelling. Observations suggested a shocked state: heart rate 120 beats/minute, respiratory rate 40 breaths/minute, air oxygen saturation 85 to 90%, loud respiratory wheeze, use of accessory muscles, and impalpable peripheral pulses. Further adrenaline was administered 300 μg intramuscularly without significant improvement, and this was followed by a bolus of 25 μg adrenaline administered intravenously. Twenty minutes into the event, on the presumption of refractory anaphylactic shock, an intravenous adrenaline infusion was commenced at 10 μg per minute. His blood pressure was not measured during the event or on the journey to the hospital.\n\nIn our emergency department, he was extremely agitated with repeated vomiting, but only had minimal respiratory distress. Oxygen saturation was difficult to record due to poor peripheral perfusion and clamminess, despite a blood pressure of 207/187 mmHg and heart rate of 160 beats/minute. Adrenaline toxicity was suspected and the adrenaline infusion was immediately ceased. He also received two separate doses of 2 mg intravenously administered ondansetron for the vomiting with little effect. Serial 12-lead electrocardiograms showed sinus tachycardia without other changes, and a normal chest X-ray excluded other causes.\n\nWithin 30 minutes his blood pressure returned to normal and he developed further respiratory symptoms (wheeze and dyspnea). The rapid improvement in his blood pressure, agitation, and vomiting following cessation of the adrenaline infusion supported the diagnosis of adrenaline overdose. In view of his asthma, he was given intravenously administered hydrocortisone and rescue nebulizers (salbutamol and ipratropium) to control his respiratory symptoms. He was admitted to our hospital, observed for 24 hours and discharged home with no further sequelae.\n\nDiscussion\nThis case highlights adrenaline overdose, an iatrogenic complication rarely reported in the pediatric population, as a potential pitfall in the management of pediatric anaphylaxis. While delaying and under-dosing adrenaline in anaphylaxis is widely recognized as detrimental, one should remain vigilant for adrenaline overdose because the risk of adverse effects, such as ventricular arrhythmias, hypertensive crises, pulmonary edema, and associated mortality [1] is significant. Avoiding overdose in anaphylaxis requires careful attention to the administration of adrenaline, guided by the clinical status and vital signs of the patient.\n\nEarly recognition is pivotal in managing anaphylaxis. Children commonly demonstrate symptoms from one or more of the following systems: cutaneous (80 to 90%), respiratory (70%), gastrointestinal tract (45%), cardiovascular (45%), and central nervous (15%) [1]. Once anaphylaxis is diagnosed or suspected, adrenaline is the first line treatment [1, 2]. Australasian guidelines generally recommend administration of 10 μg/kg (up to 500 μg) of 1:1000 adrenaline as an intramuscular injection into the lateral thigh, repeated after 5 minutes if required [1, 2, 6]. When an adrenaline autoinjector is used, a 150 μg device is prescribed for children age 1 to 5 (approximately 10 to 20 kg) and 300 μg for children age 5 and above [2]. If the symptoms of anaphylaxis remain refractory, an intravenously administered adrenaline infusion can be started at the rate of 0.05 to 1 μg/kg per minute after careful consideration and consultation with emergency care specialists [2, 6].\n\nIntramuscular injection is the standard route of administration. Skeletal muscle has an abundant supply of blood vessels and adrenaline is rapidly absorbed into the blood circulation [1, 2] but the risk of overdose and side effects are far lower compared with intravenously administered bolus or infusion. Adrenaline administered intravenously should only be administered in anaphylaxis if there is failure to respond to repeated intramuscular doses, or there is imminent or actual cardiorespiratory arrest [2, 6–8]. Other routes of administration are less reliable given the unpredictable absorption [9, 10].\n\nMonitoring pediatric vital signs can sometimes be challenging. Blood pressure has always been recognized as a vital part of pediatric assessment but routine measurement remains inconsistent [11, 12]. In Australia, blood pressure measurement is recommended in the assessment of anaphylaxis in all age groups [2, 3, 6, 8] as it is the prime differentiator between anaphylactic shock and adrenaline overdose, as well as being an essential guide to anaphylaxis progression and need for further adrenaline dosing. Other manifestations of adrenaline toxicity such as tachycardia, palpitations, dyspnea, cold peripheries, agitation, and pallor [13] could be mistaken for worsening anaphylaxis, and further adrenaline may be incorrectly administered.\n\nIn cases of anaphylaxis where there is no apparent improvement with repeated adrenaline dosing, other differential diagnoses need be considered and/or further management needs to be initiated. Intravenously administered volume expansion should always be given in anaphylactic shock with repeated boluses of 20 mL/kg normal saline. Bronchodilators can be considered adjuncts in children with respiratory distress or a known history of asthma. Current evidence suggests no proven benefit for glucocorticoids or antihistamines in managing anaphylaxis [1, 6].\n\nConclusions\nPrompt adrenaline administration remains the cornerstone of managing anaphylaxis in the pediatric population; however, like all therapies it needs to be administered judiciously and its effect assessed to ensure correct dosing. In episodes of anaphylactic shock, blood pressure will provide a guide to the effectiveness of treatment and allows shock to be differentiated from adrenaline overdose.\n\nAcknowledgements\nNot applicable.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nNot applicable.\n\nAuthors’ contributions\nBoth authors have been involved in the preparation of the manuscript and take public responsibility for the content. The preparation of this case report is in keeping with the CARE guidelines (2016 update). Both 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\nInformed consent for participation was taken retrospectively. Ethics review was not sought because the case report met criteria for exemption from such review according to the Southern Adelaide Clinical Human Research Ethics Committee policy (that is, the work is of “negligible risk”).\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Simons FE Ardusso LRF Bilò MB World Allergy Organization guidelines for the assessment and management of anaphylaxis World Allergy Organ J 2011 4 2 13 37 10.1097/WOX.0b013e318211496c 23268454 \n2. Australian Society of Clinical Immunology and Allergy. Guidelines: ADVANCED acute management of anaphylaxis. 2016. https://www.allergy.org.au/health-professionals. Accessed 20 Apr 2017.\n3. Kirkbright SJ Brown SGA Anaphylaxis: recognition and management Aust Fam Physician 2012 41 6 366 70 22675674 \n4. Mullins RJ Dear KB Tang ML Time trends in Australian hospital anaphylaxis admissions in 1998-1999 to 2011-2012 J Allergy Clin Immunol 2015 136 2 367 75 10.1016/j.jaci.2015.05.009 26187235 \n5. Liew WK Williamson E Tang MI Anaphylaxis fatalities and admissions in Australia J Allergy Clin Immunol 2009 123 434 42 10.1016/j.jaci.2008.10.049 19117599 \n6. Royal Children’s Hospital, Melbourne, Australia. Clinical practice guideline on Anaphylaxis. 2015. http://www.rch.org.au/clinicalguide/guideline_index/Anaphylaxis/. Accessed 20 Apr 2017.\n7. Campbell RL Bellolio MF Knutson BD Epinephrine in anaphylaxis: higher risk of cardiovascular complications and overdose after administration of intravenous bolus epinephrine compared with intramuscular epinephrine J Allergy Clin Immunol Pract 2015 3 1 76 80 10.1016/j.jaip.2014.06.007 25577622 \n8. Advanced Life Support Group Advanced Paediatric Life Support: The Practical Approach, Australia and New Zealand 2012 5 Australia Wiley-Blackwell \n9. Simons FE First-aid treatment of anaphylaxis to food: Focus on epinephrine J Allergy Clin Immunol 2004 113 837 44 15131564 \n10. Simons FE Roberts JR Gu X Epinephrine absorption in children with history of anaphylaxis J Allergy Clin Immunol 1998 101 1 33 7 10.1016/S0091-6749(98)70190-3 9449498 \n11. Bird C Michie C Measuring blood pressure in children BMJ 2008 336 1321 10.1136/bmj.a150 18556277 \n12. Gilhotra Y Willis F Blood pressure measurements on children in the emergency department Emerg Med Australas 2006 18 2 148 54 10.1111/j.1742-6723.2006.00824.x 16669941 \n13. Aspen Pharmacare Australia Pty Ltd. ASPEN Adrenaline Injection: product information. 2010. Retrieved from https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/PICMI. Accessed 20 Apr 2017.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "11(1)",
"journal": "Journal of medical case reports",
"keywords": "Adrenaline; Anaphylaxis; Blood pressure; Case report; Children; Epinephrine; Overdose; Pediatric",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000707:Anaphylaxis; D001794:Blood Pressure; D002648:Child; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine; D006801:Humans; D008297:Male; D019300:Medical Errors",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "129",
"pmc": null,
"pmid": "28482886",
"pubdate": "2017-05-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9449498;15131564;19117599;25577622;26187235;22675674;23268454;18556277;16669941",
"title": "Adrenaline overdose in pediatric anaphylaxis: a case report.",
"title_normalized": "adrenaline overdose in pediatric anaphylaxis a case report"
} | [
{
"companynumb": "AU-IMPAX LABORATORIES, INC-2017-IPXL-01511",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "EPINEPHRINE"
},
"drugadditio... |
{
"abstract": "Chromosome band 8q24 is the most frequently amplified locus in various types of cancers. MYC has been identified as the primary oncogene at the 8q24 locus, whereas a long noncoding gene, PVT1, which lies adjacent to MYC, has recently emerged as another potential oncogenic regulator at this position. In this study, we established and characterized a novel cell line, AMU-ML2, from a patient with diffuse large B-cell lymphoma (DLBCL), displaying homogeneously staining regions at the 8q24 locus. Fluorescence in situ hybridization clearly detected an elevation in MYC copy numbers corresponding to the homogenously staining region. In addition, a comparative genomic hybridization analysis using high-resolution arrays revealed that the 8q24 amplicon size was 1.4 Mb, containing the entire MYC and PVT1 regions. We also demonstrated a loss of heterozygosity for TP53 at 17p13 in conjunction with a TP53 frameshift mutation. Notably, AMU-ML2 cells exhibited resistance to vincristine, and cell proliferation was markedly inhibited by MYC-shRNA-mediated knockdown. Furthermore, genes involved in cyclin D, mTOR, and Ras signaling were downregulated following MYC knockdown, suggesting that MYC expression was closely associated with tumor cell growth. In conclusion, AMU-ML2 cells are uniquely characterized by homogenously staining regions at the 8q24 locus, thus providing useful insights into the pathogenesis of DLBCL with 8q24 abnormalities.",
"affiliations": "Division of Hematology Department of Internal Medicine Aichi Medical University Japan.;Division of Hematology Department of Internal Medicine Aichi Medical University Japan.;Department of Biochemistry Aichi Medical University Japan.;Department of Biochemistry Aichi Medical University Japan.;Division of Hematology Department of Internal Medicine Aichi Medical University Japan.;Division of Hematology Department of Internal Medicine Aichi Medical University Japan.;Division of Hematology Department of Internal Medicine Aichi Medical University Japan.;Division of Hematology Department of Internal Medicine Aichi Medical University Japan.;Division of Hematology Department of Internal Medicine Aichi Medical University Japan.;Division of Hematology Department of Internal Medicine Aichi Medical University Japan.;Division of Hematology Department of Internal Medicine Aichi Medical University Japan.;Division of Hematology Department of Internal Medicine Aichi Medical University Japan.;Division of Hematology Department of Internal Medicine Aichi Medical University Japan.;Division of Hematology Department of Internal Medicine Aichi Medical University Japan.;Department of Hematology Daiyukai General Hospital Aichi Japan.;Department of Biochemistry Aichi Medical University Japan.;Department of Hematology Mie University Japan.;Department of Hematology and Oncology Graduate School of Medical Science Kyoto Prefectural University of Medicine Japan.;Department of Tumor Immunology Aichi Medical University School of Medicine Japan.;Division of Hematology Department of Internal Medicine Aichi Medical University Japan.;Division of Hematology Department of Internal Medicine Aichi Medical University Japan.",
"authors": "Mizuno|Shohei|S|;Hanamura|Ichiro|I|0000-0002-6681-8927;Ota|Akinobu|A|;Karnan|Sivasundaram|S|;Kanasugi|Jo|J|;Nakamura|Ayano|A|;Takasugi|Souichi|S|;Uchino|Kaori|K|;Horio|Tomohiro|T|;Goto|Mineaki|M|;Murakami|Satsuki|S|;Gotou|Mayuko|M|;Yamamoto|Hidesuke|H|;Watarai|Masaya|M|;Shikami|Masato|M|;Hosokawa|Yoshitaka|Y|;Miwa|Hiroshi|H|;Taniwaki|Masafumi|M|;Ueda|Ryuzo|R|;Nitta|Masakazu|M|;Takami|Akiyoshi|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/2211-5463.12538",
"fulltext": "\n==== Front\nFEBS Open BioFEBS Open Bio10.1002/(ISSN)2211-5463FEB4FEBS Open Bio2211-5463John Wiley and Sons Inc. Hoboken 10.1002/2211-5463.12538FEB412538Research ArticleResearch ArticlesEstablishment and characterization of a novel vincristine‐resistant diffuse large B‐cell lymphoma cell line containing the 8q24 homogeneously staining region S. Mizuno et al.Mizuno Shohei \n1\nHanamura Ichiro http://orcid.org/0000-0002-6681-8927hanamura@aichi-med-u.ac.jp \n1\nOta Akinobu \n2\nKarnan Sivasundaram \n2\nKanasugi Jo \n1\nNakamura Ayano \n1\nTakasugi Souichi \n1\nUchino Kaori \n1\nHorio Tomohiro \n1\nGoto Mineaki \n1\nMurakami Satsuki \n1\nGotou Mayuko \n1\nYamamoto Hidesuke \n1\nWatarai Masaya \n1\nShikami Masato \n3\nHosokawa Yoshitaka \n2\nMiwa Hiroshi \n4\nTaniwaki Masafumi \n5\nUeda Ryuzo \n6\nNitta Masakazu \n1\nTakami Akiyoshi \n1\n\n1 \nDivision of Hematology\nDepartment of Internal Medicine\nAichi Medical University\nJapan\n\n2 \nDepartment of Biochemistry\nAichi Medical University\nJapan\n\n3 \nDepartment of Hematology\nDaiyukai General Hospital\nAichi\nJapan\n\n4 \nDepartment of Hematology\nMie University\nJapan\n\n5 \nDepartment of Hematology and Oncology\nGraduate School of Medical Science\nKyoto Prefectural University of Medicine\nJapan\n\n6 \nDepartment of Tumor Immunology\nAichi Medical University School of Medicine\nJapan\n* Correspondence\n\nI. Hanamura, Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, 1‐1 Yazako, Karimata, Nagakute, Aichi 480‐1195, Japan\n\nFax: +81 561 62 3401\n\nTel: +81 561 62 3311 ext. 23540\n\nE‐mail: hanamura@aichi-med-u.ac.jp\n20 11 2018 12 2018 8 12 10.1002/feb4.2018.8.issue-121977 1991 16 4 2018 02 10 2018 04 10 2018 © 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Chromosome band 8q24 is the most frequently amplified locus in various types of cancers. MYC has been identified as the primary oncogene at the 8q24 locus, whereas a long noncoding gene, PVT1, which lies adjacent to MYC, has recently emerged as another potential oncogenic regulator at this position. In this study, we established and characterized a novel cell line, AMU‐ML2, from a patient with diffuse large B‐cell lymphoma (DLBCL), displaying homogeneously staining regions at the 8q24 locus. Fluorescence in situ hybridization clearly detected an elevation in MYC copy numbers corresponding to the homogenously staining region. In addition, a comparative genomic hybridization analysis using high‐resolution arrays revealed that the 8q24 amplicon size was 1.4 Mb, containing the entire MYC and PVT1 regions. We also demonstrated a loss of heterozygosity for TP53 at 17p13 in conjunction with a TP53 frameshift mutation. Notably, AMU‐ML2 cells exhibited resistance to vincristine, and cell proliferation was markedly inhibited by MYC‐shRNA‐mediated knockdown. Furthermore, genes involved in cyclin D, mTOR, and Ras signaling were downregulated following MYC knockdown, suggesting that MYC expression was closely associated with tumor cell growth. In conclusion, AMU‐ML2 cells are uniquely characterized by homogenously staining regions at the 8q24 locus, thus providing useful insights into the pathogenesis of DLBCL with 8q24 abnormalities.\n\nchromosome 8q24diffuse large B‐cell lymphomahomogeneously staining regionMYConcogene amplificationpatient‐derived cell lineYOKOYAMA Foundation for Clinical PharmacologyJapan Blood Products OrganizationAichi Cancer Research FoundationResearch Grant from Aichi Medical University Aikeikai FoundationHori Sciences and Arts FoundationSENSHIN Medical Research FoundationNagao Memorial FundMinistry of Education, Culture, Sports and Technology of Japan15K19561 source-schema-version-number2.0component-idfeb412538cover-dateDecember 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.3 mode:remove_FC converted:03.12.2018\n==== Body\nAbbreviations\naCGHarray comparative genomic hybridization\n\nCCND1cyclin D1\n\nCNAcopy number alteration\n\nDLBCLdiffuse large B‐cell lymphoma\n\nFISHfluorescence in situ hybridization\n\nGSEAgene set enrichment analysis\n\nHSRhomogeneously staining region\n\nPBLperipheral blood leukocyte\n\nPVT1plasmacytoma variant translocation 1\n\nqRT‐PCRquantitative reverse transcription‐polymerase chain reaction\n\nR‐CHOPrituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone\n\nR‐Hyper‐CVAD/MAhigh‐dose methotrexate and cytarabine\n\nGene amplification, observed in the form of double‐minute chromosomes or homogeneously staining regions (HSRs), is recurrent and plays an important role in cancer 1. HSR is rarely seen in hematopoietic neoplasms compared with solid tumors and is observed at a lower frequency in lymphoid neoplasms than in myeloid neoplasms 2.\n\nChromosome 8q24 is the most frequently amplified locus in many cancers, with MYC being the most likely oncogene at this locus. The MYC gene encodes a transcription factor that regulates the expression of many target genes that control cell proliferation. The deregulation of MYC, resulting from t(8;14) and gene amplification, leads to the constitutive overexpression of MYC in numerous cancers and plays a pathogenetic role in oncogenesis 3, 4.\n\nPlasmacytoma variant translocation 1 (PVT1) is also located at 8q24, 57 kb downstream of MYC, and extends over 200 kb in the direction of the telomeres. PVT1 is a non‐protein‐coding gene and a homologue of mouse Pvt1\n5. The Pvt1 locus is a site of recurrent translocation in mouse plasmacytomas and a common integration site for the murine leukemia virus, which is capable of inducing T‐cell lymphomas in mice. In contrast to the typical Burkitt lymphoma (BL), in which the t(8;14) translocation contains a breakpoint within MYC, the t(2;8) or t(8;22) variant translocations in BL contain breakpoints in PVT1\n6.\n\n\nPVT1 produces a variety of noncoding RNAs, including several microRNAs 7. The precise functions of the PVT1 region and its noncoding RNAs remain unclear, although the long noncoding PVT1 RNA has a documented role in stabilization of the MYC protein 8. Moreover, several groups have reported that the amplification and subsequent overexpression of PVT1 have an oncogenic function in ovarian and breast cancers 9. A genomewide screen using array comparative genomic hybridization (array‐CGH) and gene expression profiling identified PVT1 as a candidate oncogene in breast and ovarian cancers, acute myeloid leukemia, and Hodgkin lymphoma 10, 11. Furthermore, we have previously reported two novel chimeric genes, PVT1‐NBEA and PVT1‐WWOX, in multiple myeloma cell lines 12.\n\nIn addition, a circular RNA obtained from exon 3 of PVT1 (circPVT1) has been shown to function as a promoter of cell proliferation in fibroblasts 13, an important prognostic factor in gastric cancer 14, and a diagnostic marker in osteosarcoma 15, and to have an oncogenic role in head and neck carcinoma and myeloid leukemia 16, 17. Hu et al. 18 have also described circPVT1 overexpression in B‐cell acute lymphoblastic leukemia and performed functional studies indicating its role in B‐cell proliferation. Taken together, these reports highlight the potential importance of the MYC/PVT1 locus in the pathophysiology of many cancers.\n\nDiffuse large B‐cell lymphoma (DLBCL) is the most common type of non‐Hodgkin lymphoma and is known as a biologically heterogeneous tumor. Although approximately 70% of patients with DLBCL survive longer than five years when treated with immunochemotherapy involving rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R‐CHOP), the remainder succumb to the disease 19. A high international prognostic index, extranodal lesions, a non‐germinal center B‐cell phenotype, BCL2 expression, the deletion of CDKN2A, and MYC rearrangements have been recognized as high‐risk features in DLBCL treated using R‐CHOP 20. The prognostic and biological significance of MYC rearrangements in DLBCL has been thoroughly investigated. However, the role of PVT1, which may be co‐amplified with MYC, remains unclear.\n\nWe herein report the AMU‐ML2 novel DLBCL cell line, obtained from a primary refractory patient. This cell line is uniquely characterized by a HSR at the 8q24 locus, containing MYC and PVT1 and displaying a high expression of PVT1 long noncoding RNAs. Here, we report the genetic and biological characteristics of this cell line in comparison with other B‐cell lymphoma cell lines.\n\nMaterials and methods\nCase history\nA 64‐year‐old man was referred to the clinic presenting pancytopenia, a 2‐month history of anorexia, and general fatigue in November 2011. The laboratory and chest X‐ray examinations revealed a white blood cell count of 1000 μL−1, hemoglobin of 9.6 g·dL−1, a platelet count of 5000 μL−1, LDH of 2397 U·L−1, and bilateral pleural effusion (Fig. S1A,B). Abnormal lymphocytes with Burkitt‐like morphology were observed in the pleural effusion and bone marrow (Fig. S1C,D). The patient was diagnosed with DLBCL and commenced treatment with R‐CHOP. G‐banding of cells revealed a complex karyotype; however, fluorescence in situ hybridization (FISH) using a MYC/IGH probe set revealed a significant increase in MYC copy number, in the absence of a fusion signal. Subsequently, the patient underwent a more intensive regimen involving rituximab plus hyperfractionated cyclophosphamide, doxorubicin, vincristine, and dexamethasone, alternating with high‐dose methotrexate and cytarabine (R‐Hyper‐CVAD/MA) 21 after one cycle of R‐CHOP. The patient responded to the treatment; however, he developed cytomegalovirus pneumonia after four cycles of R‐Hyper‐CVAD/MA and died of Trichosporon asahii sepsis at 6 months postdiagnosis.\n\nEstablishment of the AMU‐ML2 cell line\nThe patient provided written informed consent for his cells from the pleural effusion to be used in a procedure approved by the Institutional Review Board of Aichi Medical University. The study methodologies conformed to the standards set by the Declaration of Helsinki. The cells were collected at the time of initial diagnosis, prior to chemotherapy. The cells were cultured in RPMI 1640 medium (Sigma‐Aldrich, St. Louis, MO, USA) supplemented with 10% heat‐inactivated fetal bovine serum (Thermo Electron, Melbourne, Vic., Australia) and 1% penicillin/streptomycin (GIBCO‐BRL, Grand Island, NY, USA). Cultures were maintained at 37 °C in 5% CO2, and the medium was partially exchanged every 5–7 days. After 2 months in culture, cell proliferation became continuous. The cell line was designated as AMU‐ML2 after confirmation that cells had started growing again after the conventional freeze–thaw procedure.\n\nB‐cell lymphoma cell lines, cell culture, and drugs\nThe AMU‐ML2, SU‐DHL‐10, Raji, P3HR‐1, VAL, and Farage B‐cell lymphoma cell lines were cultured as previously described 22. Prednisolone, cyclophosphamide, vincristine, and doxorubicin were purchased from Wako Pure Chemical Industries (Osaka, Japan).\n\nChromosomal analyses and spectral karyotyping\nChromosome preparations for G‐banding, spectral karyotyping, and FISH were performed according to standard procedures (SRL Inc., Tokyo, Japan) 23, 24. A total of 20 metaphase spreads were analyzed by G‐banding, and the karyotype was defined according to the International System for Human Cytogenetic Nomenclature 25. Spectral karyotyping analyses were performed in metaphase spreads according to standard procedures (SRL Inc.) 26.\n\nMorphology and immunophenotype of bone marrow‐ and pleural effusion‐derived patient cells\nCells obtained from the patient's bone marrow and a pleural effusion were air‐dried on a glass slide. The cellular morphology was analyzed using May–Grunwald–Giemsa and immunohistochemistry (IHC) staining. The following antigens were examined by flow cytometry (SRL Inc.): CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD19, CD20, CD34, and CD56. The CD3, CD5, CD10, CD20, CD79a, cyclin D1, BCL2, BCL6, TP53, TdT and MIB‐1 labeling indices were examined by IHC. The anti‐TP53 antibody was purchased from DAKO Japan Inc. (clone DO‐7; Kyoto, Japan). The Epstein–Bar virus‐encoded RNA was examined by in situ hybridization.\n\nFISH analysis\nDetection of the 8q24 aberration and deletion of 17p in both metaphase and interphase nuclei was performed using the Vysis LSI IGH/MYC/CEP8 Tri‐Color Dual Fusion Probes (Fig. S1A) and the Vysis LSI TP53/CEP17 Dual Fusion Probes (Abbot Molecular, Des Plaines, IL, USA). Bacterial artificial chromosome (BAC) and P1‐derived artificial chromosome (PAC) clones RP1‐160A22, RP1‐193B12, RP1‐109F14, and RP11‐55J15 were obtained from Invitrogen (Carlsbad, CA, USA). FISH probes for the analysis of chromosome 6p and 8q breakpoints were prepared with DNA extracted from BAC clones and Poseidon Sub‐Telomeric Probes for chromosome 8 (KREATECH, Amsterdam, the Netherlands) (Fig. S1A,B). DNA extraction was performed using the NucleoBond Xtra Midi kit (Macherey‐Nagel, Düren, Germany). Labeling and hybridization of DNA were performed as previously described 27. BAC/PAC information was obtained from the National Center for Biotechnology Information website (https://www.ncbi.nlm.nih.gov/genome/gdv/), and the probes were confirmed to map to the precise chromosomal bands using metaphase spreads from peripheral blood lymphocytes of healthy donors.\n\nGenome copy number analyses\nArray‐CGH was performed using the SurePrint G3 Human CGH 2 × 400K, Oligo Microarray Kit (G4448A; Agilent Technologies, Santa Clara, CA, USA), which contains approximately 400 000 60‐mer oligonucleotides covering the entire human genome. Genomic DNA was extracted from AMU‐ML2 cells using the QIAamp DNA Mini Kit (Qiagen, Hilden, Germany). DNA labeling, hybridization, and washing were performed according to the manufacturer's protocols. Scanning analyses were performed using the Agilent Microarray Scanner (Agilent Technologies). The array data were analyzed to determine chromosomal copy numbers using the feature extractions version 11.0 software program (Agilent Technologies) and the analytical software program dna analytics, version 4.0 (Agilent Technologies). The ADM‐1 algorithm (Threshold 6.0) was adopted to detect genomic aberrations 28. The relationship between the log2 ratio (X), the copy number in the reference sample (A), the average copy number in tumor cells (B), and the ratio of tumor cells (C) was determined as X = Log2.\n\nDNA sequence analyses\nTotal RNA was isolated from AMU‐ML2 cells using the NucleoSpin RNA kit (TaKaRa Bio, Inc., Tokyo, Japan). Complementary DNA was synthesized from 2 μg of total RNA by using the High‐Capacity cDNA Reverse Transcription Kit (Invitrogen). PCR amplification of the open reading frame of TP53 was performed with a gene‐specific primer set as follows: forward primer, 5′‐ATGGAGGAGCCGCAGTCAGA; reverse primer, 5′‐TCAGTCTGAGTCAGGCCCTT. Sequence analysis was performed using the BigDye Terminator v3.1 Cycle Sequencing Kit and an Applied Biosystems 3130 Genetic Analyzer (Foster City, CA, USA).\n\nWestern blot analyses\nWestern blot analyses were performed as described previously 29. Briefly, proteins in the cell lysate were separated on 10% polyacrylamide gels, followed by transfer onto a polyvinylidene fluoride membrane (Merck Millipore, Darmstadt, Germany). The membrane was hybridized with a mouse monoclonal anti‐c‐Myc antibody (9E10; Wako) and a rabbit anti‐β‐actin antibody (13E5; Cell Signaling Technologies, Danvers, MA, USA). The membrane was visualized using ImmunoStar LD (Wako).\n\nReal‐time qRT‐PCR\nThe expression levels of the MYC and PVT1 transcripts were quantified by real‐time qRT‐PCR using TaqMan Gene Expression Assays (MYC, Hs00153408_m1; PVT1, Hs00413039_m1; β‐actin, Hs99999903_m1; Applied Biosystems) and the StepOnePlus™ Real‐Time PCR System (Applied Biosystems). In brief, total RNA was extracted using the RNeasy Mini Kit (Qiagen) and cDNA was synthesized from total RNA by using the SuperScript III First‐Strand Synthesis System (Invitrogen). The expression level of circPVT1 was quantified by real‐time qRT‐PCR using SYBR Green I (TaKaRa Bio, Inc.) with the StepOnePlus™Real‐Time PCR System, as previously described 13, 30, 31. cDNA was amplified using KOD FX Neo polymerase (Toyobo, Tokyo, Japan) with SYBR Green I. Primers for circPVT1 were follows: forward: 5′‐GGTTCCACCAGCGTTATTC; reverse: 5′‐CAACTTCCTTTGGGTCTCC 32. GAPDH was used as an internal standard for the SYBR Green I‐based analysis. Relative expression was determined using the 2−ΔΔCT method. The relative gene expression was determined using the gene expression in peripheral blood leukocytes (PBLs) from healthy donors as a control.\n\nMYC knockdown\nThe pRetrosuper Myc shRNA and pMKO.1‐puro GFP shRNA were gifts from Addgene (plasmids #15662 and #10675, respectively; Cambridge, MA, USA) 33, 34. To obtain cells stably expressing decreased levels of MYC, the MYC shRNA vector (AMU‐ML2/MYCsh) or the control GFP shRNA vector (AMU‐ML2/GFPsh) was introduced into AMU‐ML2 cells. The retroviral plasmids were packaged into 293T cells using the pCL10A vector. Viral supernatants were harvested 96 h after transfection and filtered before infection. The cells were infected with retroviruses in the presence of 8 μg·mL−1 Polybrene (Sigma‐Aldrich). Antibiotic selection (puromycin; 0.3 μg·mL−1; Wako) was begun 48 h after infection and continued for at least 3 days. Following infection and antibiotic selection, the cells were examined for MYC protein levels using western blotting.\n\nMicroarray gene expression analyses\nThe experimental procedure for the cDNA microarray analysis was based on the manufacturer's protocol (Agilent Technologies). In brief, cDNA synthesis and cRNA labeling with the cyanine 3 (Cy3) dye were performed using the Agilent Low Input Quick Amp Labeling Kit. The Cy3‐labeled cRNA was purified, fragmented, and hybridized on a Whole Human Genome 4 × 44k Oligo Microarray Chip containing 43 377 oligonucleotide probes, using a Gene Expression Hybridization kit. The microarray slide was washed and scanned using an Agilent DNA microarray scanner (Agilent Technologies). The scanned data were quantified using the feature extraction software program, version 11.0.1.1 (Agilent Technologies). The signal intensities were then normalized as described elsewhere 35.\n\nThe background signals were also normalized, and the microarray expression data were rank‐ordered based on the differential expression in AMU‐ML2/MYCsh cells versus AMU‐ML2/GFPsh cells as follows: Up‐ and downregulated genes were called when exhibiting a > 0.27 increase (fold change > 2.0) or < −0.27 decrease (fold change < 0.5), respectively, in AMU‐ML2/MYCsh cells versus AMU‐ML2/GFPsh cells.\n\nResults\nKaryotyping and FISH analysis of 8q24 abnormalities in AMU‐ML2 cells\nThe karyotyping of AMU‐ML2 cells by G‐banding and spectral karyotyping revealed the following karyotype: 46,XY,del(6)(p21p23),der(8)(8pter→8q24::hsr::6p21→6pter),add(9)(p13),del(17)(p?) 21 (Fig. 1A,B). The FISH analysis of AMU‐ML2 cells using a MYC/IGH probe set revealed no fusion signal for IGH and MYC; however, a significant increase in the MYC copy number was observed, corresponding to the HSR on chromosome 8q24 (Fig. 1C). The copy number of the amplicon at 8q24.21 was approximately 26 per tumor cell. A FISH analysis using RP11‐55J15, containing a segment of PVT1 but not the MYC gene (Fig. S2A), also showed a significant increase in the copy number at the PVT1 gene locus (Fig. 1D). The FISH analysis of AMU‐ML2 cells using an RP1‐160A22/RP11‐55J15 probe set revealed that chromosome 6p21.2‐22.2 translocated on chromosome 8q (white arrow), and a significant increase in the PVT1 copy number was observed (white triangle), corresponding to the HSR on chromosome 8q24 (Fig. 1D). RP11‐55J15 contained a segment of PVT1 but not the MYC gene (Fig. S2A), and also showed a significant increase in the copy number at the PVT1 gene locus. The FISH analysis of AMU‐ML2 cells using a RP1‐160A22/RP1‐193B12 probe set revealed fusion signal for both probes on chromosome 6p (white triangle); however, the other RP1‐193B12 was absent on chromosome 6p, and the other RP1‐160A22 translocated on chromosome 8q (white arrow) (Fig. 1E). The FISH analysis of AMU‐ML2 cells using a RP1‐160A22/Sub‐Telomere 8qter probe set revealed a fusion signal for both probes on chromosome 8q telomere (Fig. 1F). The FISH analysis of AMU‐ML2 cells using a TP53/ CEP17 set revealed that one of TP53 disappeared on chromosome 17p (Fig. 1G). The copy number of the amplicon at 8q24.21 was approximately 26 per tumor cell.\n\nFigure 1 Karyotype and FISH analyses of AMU‐ML2 cells. (A, B) Representative karyotype by G‐banding and spectral karyotyping indicated 46,XY,del(6)(p21p23),der(8)(8pter→8q24::hsr::6p21→6pter),add(9)(p13),del(17)(p?). (A) The black arrows indicate abnormal sites detected by G‐banding. (B) Spectral karyotyping analysis; the white arrow indicates the fusion of part of chromosome 6 (6ptel–6p21, red) with the telomeric region of 8q24. (C–F) FISH analysis of 8q24 containing the entire MYC and PVT1 regions (C), the 6p22–p21 breakpoint of t(6;8) (D–F) and the 17p13.2 locus, containing the TP53 gene (G) in AMU‐ML2 cells. Schematic illustrations of the FISH probes used in this study are presented beside each figure panel. (C) Interphase (left) and metaphase (right) FISH analyses using Vysis LSI IGH (green), MYC (red), and CEP8 (aqua) Tri‐Color Dual Fusion Probes are shown. The white arrow indicates the HSR on the MYC probe (red), without any IGH/MYC fusion signals. The copy number of the amplicon at 8q24.21 was approximately 26 per tumor cell. (D) The white arrow indicates the HSR on RP11‐55J15 (green), which covers part of PVT1 but not MYC, as depicted in Fig. S2A. The white arrowhead indicates a single copy signal on RP1‐160A22 (red) at 6p22. (E) The white arrowhead indicates a fusion signal on the normal chromosome 6. RP1‐160A22, shown in red; RP1‐193B12, shown in green. The white arrow indicates another red signal but no green signal on the derivative chromosome 8. (F) The white arrow indicates a fusion signal on the derivative chromosome 8. RP1‐160A22, shown in red; KREATECH Sub‐Telomere 8qter, shown in green. (G) The white arrow indicates a single copy signal at the TP53 gene locus. Vysis LSI CEP17, show in green; TP53 probe, shown in red. Ch, chromosome.\n\nArray‐CGH analyses and TP53 sequencing of AMU‐ML2 cells\nTo further investigate the genomewide copy number aberrations in AMU‐ML2 cells, we performed an array‐CGH (aCGH) analysis using an Agilent human CGH 400K Oligo Microarray format (Agilent Technologies; Fig. 2A, Table 1). The aCGH analysis identified several large deletions and amplifications as follows: a 7431‐kb deletion at 6p22.1–6p21.31, which contains the t(6;8) breakpoint detected by FISH (Fig. 2B); a 1462‐kb amplification at 8q24.21, which contains MYC and PVT1 (Fig. 2C); and a 7522‐kb deletion at 17p13.3–17p.13.1, which harbors the TP53 gene (Fig. 2D). The aCGH analysis also showed that the HIST1 gene locus, spanning 27.9–35.3 Mb on 6p22–6p21, contained a monoallelic deletion (Fig. 2B). Furthermore, our aCGH analysis detected 14 additional copy number alterations (CNAs). Segment gains were detected on chromosomes 6p21.31–p21.2, 8p11.23, 8q24.21, 8q24.3, 9p24.3–9p13.1, 14q11.2, and 19q13.2, whereas segment losses were detected on chromosomes 6p25.3, 6p22.1–6p21.31, 6p12.3, 7q31.33, 14q32.33, and 17p13.3–17p.13.1 (Table 1).\n\nFigure 2 High‐resolution aCGH analysis in AMU‐ML2 cells. Genomewide copy number aberrations in AMU‐ML2 cells were determined using an Agilent SurePrint G3 Human CGH 2× 400K Oligo Microarray (Agilent Technologies). The median probe spacing was approximately 4.6 kb. (A) Summary of the aCGH analysis. The x‐axis indicates the chromosome number, whereas the y‐axis indicates the log2 ratio (copy number aberrations). The red oval indicates a 1462‐kb highly amplified region, containing MYC and PVT1 at 8q24.21. The blue and green ovals indicate copy number changes at 6p22 to 6p21 and at 17p13, respectively. The other copy number alterations (CNAs) detected are summarized in Table 1. (B) The aCGH analysis shows a 7431‐kb deletion at 6p22.1–6p21.31, where the t(6;8) breakpoint was detected by FISH, as indicated in Fig. 4F. Blue rectangle, copy number changes at 6p22–6p21. (C) A 1462‐kb amplification detected by the aCGH analysis, containing MYC and PVT1 at 8q24.21, where 8q24.1 HSR was detected by FISH, as indicated in Fig. 4C. Red rectangle, copy number changes at 8q24. (D) A 7522‐kb deletion at 17p13.3–17p.13.1 detected by the aCGH analysis, where a single copy deletion of TP53 was detected by FISH, as indicated in Fig. 4F. Green rectangle, copy number changes at 17p13.\n\nTable 1 Copy number alteration (CNA) regions and estimated target genes detected by array‐CGH in AMU‐ML2 cells\n\nChromosome band\tStart (kb)\tEnd (kb)\tSize (kb)\tAverage log2 ratio\tNumber of genes\tCandidate genesa\n\t\nGains\t\n6p21.31–6p21.2\t35 339\t38 624\t3285\t0.62\t39\t\nMAPK14, MAPK13, ETV7, PIM1\n\t\n38 629\t39 800\t1171\t1.21\t9\t\t\n8p11.23\t39 354\t39 505\t151\t1.07\t0\t\t\n8q24.21\t126 515\t128 586\t2071\t0.55\t2\t\t\n8q24.21\t128 611\t130 073\t1462\t2.62\t2\t\nMYC, PVT1\n\t\n8q24.3\t138 653\t146 147\t7494\t1.04\t82\t\nEIF2C2, BOP1, MAPK15, MAF1\n\t\n9p24.3–9p13.1\t189\t390 481\t390 292\t0.45\t128\t\nJAK2, PAX5\n\t\n14q11.2\t21 523\t22 237\t714\t0.57\t2\t\t\n19q13.2\t46 947\t47 693\t746\t0.54\t22\t\nLYPD4, CD79A\n\t\nLosses\t\n6p25.3\t158\t318\t160\t−0.54\t1\t\nDUSP22\n\t\n6p22.1–6p21.31\t27 896\t35 327\t7431\t−0.52\t133\t\nHIST1H2AK, HIST1H2AL, HIST1H3I, HIST1H4L, HIST1H3J, HIST1H2AM, HIST1H2BO, HLA‐E, NOTCH4, HLA‐A, HLA‐B, HLA‐C, HLA‐DRA, HLA‐DRB5, HLA‐DRB1, HLA‐DQA1, HLA‐DQB1, HLA‐DQA2,\n\t\n6p12.3\t50 840\t50 944\t104\t−0.7\t2\t\nTFAP2D, TFAP2B\n\t\n7q31.33\t124 941\t125 414\t473\t−0.83\t0\t\t\n14q32.33\t105 314\t106 037\t723\t−1.12\t0\t\t\n17p13.3–17p13.1\t51\t7522\t7471\t−0.45\t110\t\nTP53\n\t\na Genes listed here are candidates based on their putative function.\n\nJohn Wiley & Sons, LtdIn addition, reverse transcription‐polymerase chain reaction (RT‐PCR) and Sanger sequencing analysis detected a frameshift mutation of TP53 in AMU‐ML2 cells (c.377_378delAC; Fig. S5).\n\n\nMYC, PVT1, and circPVT1 mRNA levels in AMU‐ML2 and other B‐cell lymphoma cell lines\nTo investigate the influence of the 8q24.21 amplification on MYC, PVT1, and circPVT1 expression, we performed quantitative RT‐PCR (qRT‐PCR) analysis in AMU‐ML2 cells and other B‐cell lymphoma cell lines, for which the chromosomal status at 8q24 is summarized in Fig. 3A. qRT‐PCR analysis showed that the expression of MYC, PVT1, and circPVT1 was significantly higher in AMU‐ML2 cells than that in PBLs from healthy donors. In addition, the expression of PVT1 and circPVT1 in AMU‐ML2 cells was the highest among the cell lines used in this study (Fig. 3B,C).\n\nFigure 3 \nMYC and PVT1 expression and the effect of chemotherapy on cell survival in AMU‐ML2 and other B‐cell lymphoma cell lines. (A) Chromosome 8q24 status in the B‐cell lymphoma cell lines used in this study. Amp, amplification. (B) MYC and PVT1 expression in B‐cell lymphoma cell lines (AMU‐ML2, SU‐DHL‐10, VAL, Raji, P3HR‐1, and Farage) and normal PBLs using TaqMan probe methodology. No association between the relative mRNA expression of MYC and that of PVT1 is observed. The relative gene expression is shown after normalization to GAPDH. The data are expressed relative to the mRNA levels found in the corresponding PBL samples, arbitrarily defined as 1. The values shown represent the means ± SE (n = 3). (C) circPVT1 expression in B‐cell lymphoma cell lines as determined by real‐time qRT‐PCR using SYBR Green methodology. The expression of circPVT1 in AMU‐ML2 cells was the highest among the cell lines used in this study. (D–G) Effect of chemotherapy on cell survival in AMU‐ML2 and other B‐cell lymphoma cell lines. AMU‐ML2 and other B‐cell lymphoma cell lines (SU‐DHL‐10, VAL, Raji, P3HR‐1, and Farage) were treated with the indicated concentration of vincristine (VCR, C) (1000, 500, 100, 50, 10, 1, 0.5, or 0.1 nm), doxorubicin (DXR, D) (5000, 1000, 500, 100, 50, 10, 1, 0.5, or 0.1 nm), prednisolone (PSL, E) (100 000, 50 000, 10 000, 5000, 1000, 500, 100, 50, or 10 nm), and cyclophosphamide (CY, F) (the same as prednisolone) for 72 h. After incubation, the cells were assayed using the MTT assay. Data are expressed relative to the mean optical density (595 nm) found in untreated cells, which was arbitrarily defined as 100%. Data are expressed as the means ± SE (n = 3).\n\nResistance of AMU‐ML2 cells to vincristine\nTo clarify the effect of anticancer drugs used in the chemotherapy of DLBCL on AMU‐ML2 cells, we performed an MTT assay using AMU‐ML2 and other B‐cell lymphoma cell lines following treatment with vincristine, doxorubicin, prednisolone, and cyclophosphamide. The MTT assay showed that AMU‐ML2 cells exhibited resistance to vincristine (at 100, 500, and 1000 nm), whereas cell survival in other B‐cell lymphoma cell lines was almost completely suppressed in a dose‐dependent manner (Fig. 3D). The MTT assay also showed that doxorubicin dose‐dependently decreased the cell survival rate in all cell lines used in this study (Fig. 3E). Prednisolone partially suppressed cell proliferation in AMU‐ML2 and B‐cell lymphoma cell lines, whereas cyclophosphamide did not exhibit any tumor‐suppressive effects (Fig. 3F,G).\n\nThe role of MYC in proliferation and gene expression in AMU‐ML2 cells\nAs our data showed that MYC expression was higher in AMU‐ML2 cells than that in PBLs from normal healthy volunteers, we next investigated the effects of MYC expression on cell proliferation using RNA interference. Our western blot analysis showed robust MYC expression in AMU‐ML2 cells expressing the control GFPsh vector; the expression of this protein decreased in cells expressing MYCsh (Fig. 4A). Therefore, we examined the effect of MYC knockdown on cell proliferation using an MTT assay. The MTT assay showed that the optical densities reflecting the cell numbers were significantly higher at both days 1 and 3 in cells expressing GFPsh than in those expressing MYCsh, strongly suggesting that MYC expression is closely associated with cell proliferation in AMU‐ML2 cells (Fig. 4B).\n\nFigure 4 Effect of MYC knockdown on cell proliferation and gene expression in AMU‐ML2 cells. (A) The MYC gene silencing shRNA vector (pRetrosuper Myc shRNA, plasmid 15662 from Addgene) or control GFPsh vector (pMKO.1‐puro GFP shRNA, plasmid 10675 from Addgene) was stably introduced into AMU‐ML2 cells using retroviral transduction. Cell clones were obtained after puromycin selection and subsequent single‐cell cloning. Five micrograms of cell lysate was subjected to a western blot analysis, to detect the MYC protein. β‐Actin was used as an internal control. (B) MTT analysis of the growth rate of AMU‐ML2/GFPsh and AMU‐ML2/MYCsh clones. The optical density (595 nm) at each time point (days 0, 1, and 3) is presented as the means ± SE (n = 4). Statistical significance between groups was determined using Student's t‐test. Statistical analyses were performed using spss 23.0 program (SPSS Inc.). The asterisk (*) indicates significant differences at P < 0.05, compared to the GFPsh clone. (C–E) Gene expression analysis. Total RNA from MYCsh and GFPsh clones was extracted and subjected to a cDNA microarray analysis using a SurePrint G3 Human 8 × 60K V3 format (Agilent Technologies). (C) Heatmap of downregulated (172 genes, fold change < 0.5) and upregulated genes (214 genes; fold change, > 2.0) following MYC knockdown. The heatmap was constructed using normalized values for each sample and the treeview software 43. The corresponding gene names are annotated on the right. (D) Gene ontology analyses using the PANTHER classification system. The downregulated genes were classified using the PANTHER‐Gene List Analysis (http://www.pantherdb.org). Pie chart showing the percentages of genes classified into each molecular pathway and/or cellular component. (E) The GSEA was conducted using the gsea software program, v2.2.4, and Molecular Signatures Database (Broad Institute). All raw data were formatted and applied to oncogenic signatures (C6). Representative GSEA enrichment plots and corresponding heatmap images of the indicated gene sets are shown for the MYCsh and GFPsh clones, respectively. Genes contributing to the enrichment are shown in rows, and the samples are shown in columns on the heatmap. Expression is shown as a gradient from high (red) to low (blue). FDR, false discovery rate; NES, normalized enrichment score. (F) Graphs showing the differential gene expression in cells expressing GFPsh and MYCsh. Raw fluorescence values obtained by scanning were utilized for the comparison of gene expression. The gene oligonucleotide probes corresponding to cyclin D1, STAT1, and BCL2 are shown. *P < 0.05, significant difference.\n\nTo further investigate the role of MYC in tumorigenesis in AMU‐ML2 cells, we performed a comprehensive gene expression analysis using Agilent cDNA microarrays. A heatmap analysis revealed different gene expression patterns between cells expressing GFPsh and those expressing MYCsh (Fig. 4C). We also observed that MYC knockdown downregulated the expression of 172 genes by < 0.5‐fold and upregulated the expression of 214 genes by > 2.0‐fold compared with that in cells expressing GFPsh (Tables S1 and S2). Moreover, we found that MYC knockdown significantly decreased the expression of cyclin D1 (CCND1), BCL2, and STAT1 but not that of GAPDH in AMU‐ML2 cells (Fig. 4F). By using a PANTHER classification analysis, we showed that 42.3% of the downregulated genes encoded binding proteins, including CCND2, BCL2, IRF4, SLAMF1, and SLAMF7 (Fig. 4D,E). Notably, this analysis also showed that 8.0% of the downregulated genes encoded either inflammation‐ or apoptosis‐related signaling molecules (Fig. S3). Therefore, we performed a gene set enrichment analysis (GSEA) to investigate whether the expression of a specific set of oncogenesis‐associated genes significantly differed between the MYC knockdown and control cells. Genes with oncogenic signatures showed a significant inactivation of cyclin D signaling‐related genes (NKG7, IFITM1, and PDE2), of genes induced by mTOR signaling (ITPR1, ATF3, and BATF), and of Ras signaling‐associated genes (NR4A3, DOCK4, and SATB1) (Fig. 4E). Furthermore, a GSEA using the Kyoto Encyclopedia of Genes and Genomes database showed a significant inactivation of genes associated with peroxisome proliferator‐activated receptor‐, hematopoietic‐, and cytokine–cytokine receptor‐related signaling (Fig. S4). Collectively, these results suggest that MYC expression is closely associated with tumor cell growth in AMU‐ML2 cells.\n\nDiscussion\nA HSR is occasionally observed in solid tumors, but rarely detected in DLBCL 36. In this study, we established a novel DLBCL cell line, AMU‐ML2, using patient cells, which was uniquely characterized by a HSR at the 8q24 locus, containing MYC and PVT1 (Fig. 1). Our aCGH analysis clearly identified the 8q24 amplicon size as ranging from 128 611 to 130 073 kb in the HSR (Fig. 2, Table 1). Moreover, we found that the amplicon contained the entire MYC and PVT1 sequences and was amplified at more than 20 copies per cell. To our knowledge, this is the first to report of a DLBCL cell line showing an amplicon containing the entire MYC and PVT1 genes at 8q24. As the patient‐derived cells were collected before the initiation of chemotherapy and established within 2 weeks, the detected chromosomal aberrations reflect the actual pathogenesis for the onset of aggressive DLBCL and do not reflect chemotherapy and/or long‐term cell culture.\n\nThe expression levels of both MYC and PVT1 were significantly higher in AMU‐ML2 and other B‐lymphoma cells with 8q24 abnormalities than those in PBLs from healthy donors and Farage cells lacking 8q24 abnormalities (Fig. 3B). The expression of MYC and PVT1 appears similar to that observed in gene amplification and translocation events at immunoglobulin loci.\n\n\nMYC, a candidate oncogene at the 8q24 amplification, has been reported to play an important role in the pathogenesis of lymphoma and leukemia 37. In this study, we show that the MYC‐shRNA‐mediated knockdown significantly suppressed cell proliferation in AMU‐ML2 cells (Fig. 4A,B). Furthermore, a cDNA microarray analysis revealed that the CCND2 cell‐cycle‐promoting gene, the IRF4 oncogenic transcription factor, and the BCL2 anti‐apoptotic gene were all downregulated following MYC knockdown (Fig. 4C). Although MYC is assumed to repress the transcription of BCL2 directly or through p53, BCL2 expression was repressed by MYC inhibition in AMU‐ML2 cells. This suggests the dysfunction of p53 in the AMU‐ML2 background. Our GSEA also showed that MYC knockdown inactivated gene expression for oncogenic gene sets, including the Ras, mTOR, and cyclin D signaling pathways (Fig. 4E). These results strongly suggest that the survival and proliferation of AMU‐ML2 cells strongly depend on the aberrant MYC expression.\n\nRecent reports have suggested that the deregulation of PVT1 consequent to gene amplification and chromosomal translocation may contribute to tumorigenesis and drug resistance 9, 38. Patients with DLBCL often suffer from resistance to chemotherapy, including R‐CHOP. Resistance to cisplatin by PVT1 overexpression has been reported in gastric and ovarian cancers 39. In addition, it has been reported that PVT1 promotes the development of multidrug resistance by mediating the mTOR/HIF‐1α/P‐glycoprotein pathway and/or the MRP1 signaling pathway 40. Moreover, overexpression of circPVT1 has been recently shown to serve as a prognostic factor in gastric cancer 14. In the present study, we found that AMU‐ML2 cells displayed vincristine resistance, in contrast to other B‐cell lymphoma cell lines (Fig. 3D). As the expression of PVT1 and circPVT1 in AMU‐ML2 cells was the highest among the cell lines tested (Fig. 3B,C), the overexpression of PVT1 and circPVT1 may contribute to vincristine resistance in AMU‐ML2 cells. Although the pathogenic role of PVT1 in lymphoma is not precisely known, the examination of whether the microRNAs and/or circPVT1 transcribed from the PVT1 locus are linked to tumorigenesis and drug sensitivity in AMU‐ML2 cells is worthy of further study.\n\nThe co‐amplification of MYC and PVT1 has been reportedly observed in several types of solid tumors and is associated with a shortened survival 9. However, the biological differences underlying the deregulation of MYC alone, or that of both MYC and PVT1, are not well characterized in DLBCL. Future clinical studies utilizing RNA‐seq, whole‐genome sequencing, and functional experiments will help clarify the precise incidence, clinical implications, and biological significance of the co‐amplification of MYC and PVT1 in DLBCL.\n\nIn addition to the HSR at 8q24, we have identified several other CNA loci (Table 1, Fig. 2A). TP53 is a well‐known tumor suppressor gene at the 17p13.1 locus. Loss of heterozygosity and inactivating mutations in the TP53 gene are frequently observed in many cancers and constitute a poor prognosis for DLBCL. In the present study, our aCGH analysis showed a monoallelic 7.8‐Mb deletion, which contains the TP53 gene (Fig. 2D). Moreover, the identification of a TP53 frameshift mutation in AMU‐ML2 cells suggested that p53 does not function in these cells. It has been reported that the disruption of the p14/ARF‐MDM2‐p53 pathway that accompanies MYC overexpression contributes to the pathogenesis of BL 41. It may therefore be possible that the pathophysiology of DLBCL is partly associated with the HSR at 8q24 as well as with the dysregulation of p53 in AMU‐ML2 cells. We also detected a chromosomal breakpoint and a single copy deletion in the HIST1 gene in AMU‐ML2 cells (Table 1, Fig. 2B). The HIST1 gene spans over 2 Mb and contains all the replication‐dependent H1 histone genes and other core histone genes at the 6p22–p21 locus. Moreover, it encodes histone proteins, which associate with the double‐stranded helical DNA molecule to form the chromatin, and play a role in gene regulation 42. In AMU‐ML2 cells, the deletion of a part of HIST1, after the t(6;8) translocation, may result in the haploinsufficiency of HIST1, which may influence chromatin remodeling and cellular gene expression.\n\nIn conclusion, the present study is the first to show a HSR containing both MYC and PVT1 at the 8q24 locus, in the AMU‐ML2 novel DLBCL cell line. We also demonstrated a loss of heterozygosity for TP53 at 17p13 with a frameshift mutation of TP53, suggesting that the high expression of MYC and TP53 dysfunction may contribute to cell survival in DLBCL. The AMU‐ML2 cell line is useful for investigating the roles of MYC and PVT1 and the interaction of the products of both genes in lymphomagenesis. Furthermore, it would be of interest to investigate the molecular mechanism through which AMU‐ML2 cells induce vincristine resistance. Our finding that MYC expression is closely related to the expression of oncogenic genes, including those in the Ras, mTOR, and CCND signaling pathways, provides new insights that may aid in the development of novel molecular‐targeted drugs for the treatment of patients with DLBCL. Further studies are required to clarify the role of PVT1 in the pathophysiology of DLBCL.\n\nAuthor contributions\nIH designed the study. SM, AO, SK, JK, and MT performed the experimental analyses. SM, IH, and AO wrote the manuscript. AN, ST, KU, TH, MG, SM, MG, HY, MW, and MS contributed reagents/materials/analysis tools. YH, HM, RU, MN, and AT contributed to overall project management.\n\nConflict of interest\nThe authors declare no conflict of interest.\n\nSupporting information\n\nFig. S1. Chest X‐ray and computed tomography (CT) findings of the patient with DLBCL on admission. (A) Chest X‐ray and B) CT findings revealing a bilateral moderate to severe pleural effusion. Morphology and immunohistochemistry (IHC) for the pleural effusion and bone marrow (BM) samples in the patient with DLBCL. (C, D) Cells from the pleural effusion and bone marrow showing medium to large cells with Burkitt‐like morphology (E‐H) IHC analysis of the patient‐derived BM cells. BM‐derived cells were incubated with anti‐BCL6 (E), anti‐cyclin D1 (F), anti‐MUM (G), and anti‐BCL2 (H) antibodies according to the manufacturer's instructions. Original magnification: 400×; MG: May–Grunwald–Giemsa staining.\n\nClick here for additional data file.\n\n \nFig. S2. Schema of the detected genomic aberrations and the BAC/PAC probes in the corresponding chromosomal gene locus. (A) Genomic features at 8q24. The amplicon detected by aCGH analysis (green), the gene structure of MYC and PVT1, the PVT1‐encoded microRNAs, BAC clone (RP11‐55J15, green bar), and Vysis FISH probe (LSI/MYC, shown in red) are depicted. The FISH probe for MYC (red bar) covers an 821‐kb region containing the entire MYC and PVT1 genes. The RP11‐55J15 BAC clone partially covers the PVT1 region, but not the MYC region. The size of the 8q24 amplicon (green bar) detected by aCGH approximately spans 1462 kb, containing the entire MYC and PVT1 genes. PVT1 encodes at least six microRNAs (miR‐1204, miR‐1205, miR‐1206, miR‐1207‐5p, miR‐1207‐3p, and miR‐1208; blue bar). The black horizontal bars indicate exons in each gene. (B) Genomic features at 6p22‐p21. The deletion detected by aCGH (purple), gene structure including a HIST1 gene cluster, and PAC clones (RP1‐97D16, black bar; RP1‐160A22, red bar; RP1‐193B12, green bar; RP3‐408B20 and RP1‐109F14, black bar) used for FISH analysis are depicted. The positional data for genes, microRNAs, and PAC/BAC clones were obtained from the NCBI website (https://www.ncbi.nlm.nih.gov/) and the dna analytics software (Agilent Technologies). The positions (Mb) indicate the distance from the telomeric end on the short arm of each chromosome. Mb, mega base.\n\nClick here for additional data file.\n\n \nFig. S3. Results of Panther Classification Analysis. Gene ontology analyses using the Panther Classification System. The downregulated genes in cells expressing MYCsh were classified using PANTHER‐Gene List Analysis (http://www.pantherdb.org). The percentages of genes classified into each pathway are shown as a pie chart.\n\nClick here for additional data file.\n\n \nFig. S4. GSEA with Kyoto Encyclopedia of Genes and Genomes (KEGG) gene sets. GSEA was conducted using GSEA v2.2.4 software and the Molecular Signatures Database (Broad Institute). All of the raw data were formatted and applied to the KEGG gene sets (C2).\n\nClick here for additional data file.\n\n \nFig. S5. Sequencing analysis of TP53 gene in AMU‐ML2 cells. (A) Total RNA was isolated from AMU‐ML2 cells using the NucleoSpin RNA kit (TaKaRa Bio, Inc.). After synthesizing complementary DNA, PCR amplification of TP53 gene was performed with a gene‐specific primer set, as described in Online Supplementary Data. Sequence analysis was performed by using an Applied Biosystems 3130 Genetic Analyzer. The TP53 frameshift mutation c.377_378delAC was detected in AMU‐ML2 cells (arrowhead). (B) Sequence alignment of TP53 with wild‐type (WT) TP53 gene. Nucleotide number is in reference to GenBank accession NM_000546.5 (TP53 transcript variant 1, mRNA).\n\nClick here for additional data file.\n\n \nTable S1. Downregulated genes under MYC knockdown in AMU‐ML2 cells.\n\n\nTable S2. Upregulated genes under MYC knockdown in AMU‐ML2 cells.\n\nClick here for additional data file.\n\n Acknowledgements\nThe authors would like to thank Ms. A Nakamura and Ms. T Nakamura for their valuable secretarial assistance and Editage for their editorial assistance. This study was supported by grants from the Aichi Cancer Research Foundation, Hori Sciences and Arts Foundation, Japan Blood Products Organization, the Ministry of Education, Culture, Sports and Technology of Japan (15K19561), the Nagao Memorial Fund, the Research Grant from Aichi Medical University Aikeikai Foundation, the SENSHIN Medical Research Foundation, and the YOKOYAMA Foundation for Clinical Pharmacology.\n==== Refs\nReferences\n1 \n\nCowell \nJK \n (1982 ) Double minutes and homogeneously staining regions: gene amplification in mammalian cells . Annu Rev Genet \n16 , 21 –59 .6760799 \n2 \n\nJin \nC \n, \nMertens \nF \n, \nJin \nY \n, \nWennerberg \nJ \n, \nHeim \nS \n and \nMitelman \nF \n (1995 ) Complex karyotype with an 11q13 homogeneously staining region in esophageal squamous cell carcinoma . Cancer Genet Cytogenet \n82 , 175 –176 .7664250 \n3 \n\nDang \nCV \n (2012 ) MYC on the path to cancer . Cell \n149 , 22 –35 .22464321 \n4 \n\nBoxer \nLM \n and \nDang \nCV \n (2001 ) Translocations involving c‐myc and c‐myc function . Oncogene \n20 , 5595 –5610 .11607812 \n5 \n\nPalumbo \nAP \n, \nBoccadoro \nM \n, \nBattaglio \nS \n, \nCorradini \nP \n, \nTsichlis \nPN \n, \nHuebner \nK \n, \nPileri \nA \n and \nCroce \nCM \n (1990 ) Human homologue of Moloney leukemia virus integration‐4 locus (MLVI‐4), located 20 kilobases 3ʹ of the myc gene, is rearranged in multiple myelomas . Cancer Res \n50 , 6478 –6482 .2208106 \n6 \n\nSun \nLK \n, \nShowe \nLC \n and \nCroce \nCM \n (1986 ) Analysis of the 3ʹ flanking region of the human c‐myc gene in lymphomas with the t(8;22) and t(2;8) chromosomal translocations . Nucleic Acids Res \n14 , 4037 –4050 .3714470 \n7 \n\nHuppi \nK \n, \nVolfovsky \nN \n, \nRunfola \nT \n, \nJones \nTL \n, \nMackiewicz \nM \n, \nMartin \nSE \n, \nMushinski \nJF \n, \nStephens \nR \n and \nCaplen \nNJ \n (2008 ) The identification of microRNAs in a genomically unstable region of human chromosome 8q24 . Mol Cancer Res \n6 , 212 –221 .18314482 \n8 \n\nTseng \nYY \n, \nMoriarity \nBS \n, \nGong \nW \n, \nAkiyama \nR \n, \nTiwari \nA \n, \nKawakami \nH \n, \nRonning \nP \n, \nReuland \nB \n, \nGuenther \nK \n, \nBeadnell \nTC \n\net al (2014 ) PVT1 dependence in cancer with MYC copy‐number increase . Nature \n512 , 82 ‐86 .25043044 \n9 \n\nGuan \nY \n, \nKuo \nWL \n, \nStilwell \nJL \n, \nTakano \nH \n, \nLapuk \nAV \n, \nFridlyand \nJ \n, \nMao \nJH \n, \nYu \nM \n, \nMiller \nMA \n, \nSantos \nJL \n\net al (2007 ) Amplification of PVT1 contributes to the pathophysiology of ovarian and breast cancer . Clin Cancer Res \n13 , 5745 –5755 .17908964 \n10 \n\nEnciso‐Mora \nV \n, \nBroderick \nP \n, \nMa \nY \n, \nJarrett \nRF \n, \nHjalgrim \nH \n, \nHemminki \nK \n, \nvan den Berg \nA \n, \nOlver \nB \n, \nLloyd \nA \n, \nDobbins \nSE \n\net al (2010 ) A genome‐wide association study of Hodgkin's lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24.21 and 10p14 (GATA3) . Nat Genet \n42 , 1126 –1130 .21037568 \n11 \n\nSircoulomb \nF \n, \nBekhouche \nI \n, \nFinetti \nP \n, \nAdélaïde \nJ \n, \nBen Hamida \nA \n, \nBonansea \nJ \n, \nRaynaud \nS \n, \nInnocenti \nC \n, \nCharafe‐Jauffret \nE \n, \nTarpin \nC \n\net al (2010 ) Genome profiling of ERBB2‐amplified breast cancers . BMC Cancer \n10 , 539 .20932292 \n12 \n\nNagoshi \nH \n, \nTaki \nT \n, \nHanamura \nI \n, \nNitta \nM \n, \nOtsuki \nT \n, \nNishida \nK \n, \nOkuda \nK \n, \nSakamoto \nN \n, \nKobayashi \nS \n, \nYamamoto‐Sugitani \nM \n\net al (2012 ) Frequent PVT1 rearrangement and novel chimeric genes PVT1‐NBEA and PVT1‐WWOX occur in multiple myeloma with 8q24 abnormality . Cancer Res \n72 , 4954 –4962 .22869583 \n13 \n\nPanda \nAC \n, \nDe \nS \n, \nGrammatikakis \nI \n, \nMunk \nR \n, \nYang \nX \n, \nPiao \nY \n, \nDudekula \nDB \n, \nAbdelmohsen \nK \n and \nGorospe \nM \n (2017 ) High‐purity circular RNA isolation method (RPAD) reveals vast collection of intronic circRNAs . Nucleic Acids Res \n45 , e116 .28444238 \n14 \n\nChen \nJ \n, \nLi \nY \n, \nZheng \nQ \n, \nBao \nC \n, \nHe \nJ \n, \nChen \nB \n, \nLyu \nD \n, \nZheng \nB \n, \nXu \nY \n, \nLong \nZ \n\net al (2017 ) Circular RNA profile identifies circPVT1 as a proliferative factor and prognostic marker in gastric cancer . Cancer Lett \n388 , 208 –219 .27986464 \n15 \n\nKun‐Peng \nZ \n, \nXiao‐Long \nM \n and \nChun‐Lin \nZ \n (2018 ) Overexpressed circPVT1, a potential new circular RNA biomarker, contributes to doxorubicin and cisplatin resistance of osteosarcoma cells by regulating ABCB1 . Int J Biol Sci \n14 , 321 –330 .29559849 \n16 \n\nVerduci \nL \n, \nFerraiuolo \nM \n, \nSacconi \nA \n, \nGanci \nF \n, \nVitale \nJ \n, \nColombo \nT \n, \nPaci \nP \n, \nStrano \nS \n, \nMacino \nG \n, \nRajewsky \nN \n\net al (2017 ) The oncogenic role of circPVT1 in head and neck squamous cell carcinoma is mediated through the mutant p53/YAP/TEAD transcription‐competent complex . Genome Biol \n18 , 237 .29262850 \n17 \n\nL′Abbate \nA \n, \nTolomeo \nD \n, \nCifola \nI \n, \nSevergnini \nM \n, \nTurchiano \nA \n, \nAugello \nB \n, \nSqueo \nG \n, \nD Addabbo \nP \n, \nTraversa \nD \n, \nDaniele \nG \n\net al (2018 ) MYC‐containing amplicons in acute myeloid leukemia: genomic structures, evolution, and transcriptional consequences . Leukemia \n32 , 2152 –2166 .29467491 \n18 \n\nHu \nJ \n, \nHan \nQ \n, \nGu \nY \n, \nMa \nJ \n, \nMcGrath \nM \n, \nQiao \nF \n, \nChen \nB \n, \nSong \nC \n and \nGe \nZ \n (2018 ) Circular RNA PVT1 expression and its roles in acute lymphoblastic leukemia . Epigenomics \n10 , 723 –732 .29693417 \n19 \n\nSweetenham \nJW \n (2005 ) Diffuse large B‐cell lymphoma: risk stratification and management of relapsed disease . Hematology Am Soc Hematol Educ Program \n2005 , 252 –259 .\n20 \n\nJardin \nF \n, \nJais \nJP \n, \nMolina \nTJ \n, \nParmentier \nF \n, \nPicquenot \nJM \n, \nRuminy \nP \n, \nTilly \nH \n, \nBastard \nC \n, \nSalles \nGA \n, \nFeugier \nP \n\net al (2010 ) Diffuse large B‐cell lymphomas with CDKN2A deletion have a distinct gene expression signature and a poor prognosis under R‐CHOP treatment: a GELA study . Blood \n116 , 1092 –1104 .20435884 \n21 \n\nThomas \nDA \n, \nFaderl \nS \n, \nO'Brien \nS \n, \nBueso‐Ramos \nC \n, \nCortes \nJ \n, \nGarcia‐Manero \nG \n, \nGiles \nFJ \n, \nVerstovsek \nS \n, \nWierda \nWG \n, \nPierce \nSA \n\net al (2006 ) Chemoimmunotherapy with hyper‐CVAD plus rituximab for the treatment of adult Burkitt and Burkitt‐type lymphoma or acute lymphoblastic leukemia . Cancer \n106 , 1569 –1580 .16502413 \n22 \n\nMizuno \nS \n, \nHanamura \nI \n, \nOta \nA \n, \nKarnan \nS \n, \nNarita \nT \n, \nRi \nM \n, \nMizutani \nM \n, \nGoto \nM \n, \nGotou \nM \n, \nTsunekawa \nN \n\net al (2015 ) Overexpression of salivary‐type amylase reduces the sensitivity to bortezomib in multiple myeloma cells . Int J Hematol \n102 , 569 –578 .26341959 \n23 \n\nSeabright \nM \n (1971 ) A rapid banding technique for human chromosomes . Lancet \n2 , 971 –972 .\n24 \n\nSiebert \nR \n, \nMatthiesen \nP \n, \nHarder \nS \n, \nZhang \nY \n, \nBorowski \nA \n, \nZühlke‐Jenisch \nR \n, \nMetzke \nS \n, \nJoos \nS \n, \nWeber‐Matthiesen \nK \n, \nGrote \nW \n\net al (1998 ) Application of interphase fluorescence in situ hybridization for the detection of the Burkitt translocation t(8;14)(q24;q32) in B‐cell lymphomas . Blood \n91 , 984 –990 .9446660 \n25 \n\nShaffer \nLG \n, \nMcGowan‐Jordan \nJ \n, \nSchmid \nM \n, International Standing Committee on Human Cytogenetic Nomenclature \n(2013 ) ISCN 2013: An International System for Human Cytogenetic Nomenclature . Karger , Basel, Switzerland and New York, NY, USA .\n26 \n\nVeldman \nT \n, \nVignon \nC \n, \nSchrock \nE \n, \nRowley \nJD \n and \nRied \nT \n (1997 ) Hidden chromosome abnormalities in haematological malignancies detected by multicolour spectral karyotyping . Nat Genet \n15 , 406 –610 .9090389 \n27 \n\nHanamura \nI \n, \nStewart \nJP \n, \nHuang \nY \n, \nZhan \nF \n, \nSantra \nM \n, \nSawyer \nJR \n, \nHollmig \nK \n, \nZangarri \nM \n, \nPineda‐Roman \nM \n, \nvan Rhee \nF \n\net al (2006 ) Frequent gain of chromosome band 1q21 in plasma‐cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem‐cell transplantation . Blood \n108 , 1724 –1732 .16705089 \n28 \n\nLipson \nD \n, \nAumann \nY \n, \nBen‐Dor \nA \n, \nLinial \nN \n and \nYakhini \nZ \n (2006 ) Efficient calculation of interval scores for DNA copy number data analysis . J Comput Biol \n13 , 215 –228 .16597236 \n29 \n\nGotou \nM \n, \nHanamura \nI \n, \nNagoshi \nH \n, \nWakabayashi \nM \n, \nSakamoto \nN \n, \nTsunekawa \nN \n, \nHorio \nT \n, \nGoto \nM \n, \nMizuno \nS \n, \nTakahashi \nM \n\net al (2012 ) Establishment of a novel human myeloid leukemia cell line, AMU‐AML1, carrying t(12;22)(p13;q11) without chimeric MN1‐TEL and with high expression of MN1 . Genes Chromosom Cancer \n51 , 42 –53 .21965128 \n30 \n\nTakahashi \nM \n, \nOta \nA \n, \nKarnan \nS \n, \nHossain \nE \n, \nKonishi \nY \n, \nDamdindorj \nL \n, \nKonishi \nH \n, \nYokochi \nT \n, \nNitta \nM \n and \nHosokawa \nY \n (2013 ) Arsenic trioxide prevents nitric oxide production in lipopolysaccharide‐stimulated RAW 264.7 by inhibiting a TRIF‐dependent pathway . Cancer Sci \n104 , 165 –170 .23106696 \n31 \n\nWahiduzzaman \nM \n, \nOta \nA \n, \nKarnan \nS \n, \nHanamura \nI \n, \nMizuno \nS \n, \nKanasugi \nJ \n, \nRahman \nML \n, \nHyodo \nT \n, \nKonishi \nH \n, \nTsuzuki \nS \n\net al (2018 ) Novel combined Ato‐C treatment synergistically suppresses proliferation of Bcr‐Abl‐positive leukemic cells in vitro and in vivo . Cancer Lett \n433 , 117 –130 .29944906 \n32 \n\nPanda \nAC \n and \nGorospe \nM \n (2018 ) Detection and analysis of circular RNAs by RT‐PCR . Bio‐protocol \n8 , e2775 .29644261 \n33 \n\nMasutomi \nK \n, \nPossemato \nR \n, \nWong \nJM \n, \nCurrier \nJL \n, \nTothova \nZ \n, \nManola \nJB \n, \nGanesan \nS \n, \nLansdorp \nPM \n, \nCollins \nK \n and \nHahn \nWC \n (2005 ) The telomerase reverse transcriptase regulates chromatin state and DNA damage responses . Proc Natl Acad Sci U S A \n102 , 8222 –8227 .15928077 \n34 \n\nPopov \nN \n, \nWanzel \nM \n, \nMadiredjo \nM \n, \nZhang \nD \n, \nBeijersbergen \nR \n, \nBernards \nR \n, \nMoll \nR \n, \nElledge \nSJ \n and \nEilers \nM \n (2007 ) The ubiquitin‐specific protease USP28 is required for MYC stability . Nat Cell Biol \n9 , 765 –774 .17558397 \n35 \n\nHuber \nW \n, \nvon Heydebreck \nA \n, \nSültmann \nH \n, \nPoustka \nA \n and \nVingron \nM \n (2002 ) Variance stabilization applied to microarray data calibration and to the quantification of differential expression . Bioinformatics \n18 , S96 –S104 .12169536 \n36 \n\nStorlazzi \nCT \n, \nLonoce \nA \n, \nGuastadisegni \nMC \n, \nTrombetta \nD \n, \nD'Addabbo \nP \n, \nDaniele \nG \n, \nL'Abbate \nA \n, \nMacchia \nG \n, \nSurace \nC \n, \nKok \nK \n\net al (2010 ) Gene amplification as double minutes or homogeneously staining regions in solid tumors: origin and structure . Genome Res \n20 , 1198 –1206 .20631050 \n37 \n\nAnderson \nNM \n, \nLi \nD \n, \nPeng \nHL \n, \nLaroche \nFJ \n, \nMansour \nMR \n, \nGjini \nE \n, \nAioub \nM \n, \nHelman \nDJ \n, \nRoderick \nJE \n, \nCheng \nT \n\net al (2016 ) The TCA cycle transferase DLST is important for MYC‐mediated leukemogenesis . Leukemia \n30 , 1365 –1374 .26876595 \n38 \n\nYou \nL \n, \nChang \nD \n, \nDu \nHZ \n and \nZhao \nYP \n (2011 ) Genome‐wide screen identifies PVT1 as a regulator of Gemcitabine sensitivity in human pancreatic cancer cells . Biochem Biophys Res Commun \n407 , 1 –6 .21316338 \n39 \n\nLiu \nE \n, \nLiu \nZ \n, \nZhou \nY \n, \nMi \nR \n and \nWang \nD \n (2015 ) Overexpression of long non‐coding RNA PVT1 in ovarian cancer cells promotes cisplatin resistance by regulating apoptotic pathways . Int J Clin Exp Med \n8 , 20565 –20572 .26884974 \n40 \n\nEischen \nCM \n, \nWeber \nJD \n, \nRoussel \nMF \n, \nSherr \nCJ \n and \nCleveland \nJL \n (1999 ) Disruption of the ARF‐Mdm2‐p53 tumor suppressor pathway in Myc‐induced lymphomagenesis . Genes Dev \n13 , 2658 –2669 .10541552 \n41 \n\nMarzluff \nWF \n, \nGongidi \nP \n, \nWoods \nKR \n, \nJin \nJ \n and \nMaltais \nLJ \n (2002 ) The human and mouse replication‐dependent histone genes . Genomics \n80 , 487 –498 .12408966 \n42 \n\nHarshman \nSW \n, \nYoung \nNL \n, \nParthun \nMR \n and \nFreitas \nMA \n (2013 ) H1 histones: current perspectives and challenges . Nucleic Acids Res \n41 , 9593 –9609 .23945933 \n43 \n\nPage \nRD \n (1996 ) TreeView: an application to display phylogenetic trees on personal computers . Comput Appl Biosci \n12 , 357 –358 .8902363\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2211-5463",
"issue": "8(12)",
"journal": "FEBS open bio",
"keywords": "MYC; chromosome 8q24; diffuse large B‐cell lymphoma; homogeneously staining region; oncogene amplification; patient‐derived cell line",
"medline_ta": "FEBS Open Bio",
"mesh_terms": null,
"nlm_unique_id": "101580716",
"other_id": null,
"pages": "1977-1991",
"pmc": null,
"pmid": "30524948",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article",
"references": "9446660;29559849;27986464;15928077;18314482;3714470;29944906;16304389;23106696;22464321;6760799;2208106;28444238;16597236;7664250;12408966;29262850;26884974;25043044;16502413;21037568;21965128;20435884;21316338;26876595;22869583;20631050;10541552;29693417;8902363;20932292;23945933;16705089;17558397;17908964;11607812;26341959;29467491;29644261;4107917;12169536;9090389",
"title": "Establishment and characterization of a novel vincristine-resistant diffuse large B-cell lymphoma cell line containing the 8q24 homogeneously staining region.",
"title_normalized": "establishment and characterization of a novel vincristine resistant diffuse large b cell lymphoma cell line containing the 8q24 homogeneously staining region"
} | [
{
"companynumb": "JP-BAUSCH-BL-2018-035731",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "3",
... |
{
"abstract": "Nephronophthisis is a progressive disease that affects development of the renal tubules and leads to end stage renal disease. Many affected children have isolated renal disease; however, there can be additional manifestations including heart defects, liver fibrosis, brain malformations, and situs inversus. There is no way to slow or modify the disease. We describe a patient who presented at birth with cholestatic jaundice and decreased kidney function, found by exome sequencing to have two NPHP3 variants. Her clinical status deteriorated rapidly, and two disease-modifying agents were given in hopes of slowing disease progression, the arginine vasopressin type II receptor antagonist tolvaptan to stabilize her renal function and isosorbide dinitrate to manage her poorly controlled hypertension. Tolvaptan therapy initiated at 82 days of life had limited effect on the rate of decline in renal function and was insufficient to abrogate the need for dialysis; however, isosorbide dinitrate therapy led to a dramatic improvement in blood pressure control and allowed for the discontinuation of multiple anti-hypertensive agents. This is the first report of the use of tolvaptan and isosorbide dinitrate for nephronophthisis management. We suggest that isosorbide dinitrate may represent a disease-modifying agent in nephronophthisis treatment.",
"affiliations": "Department of Pediatrics, St. Christopher's Hospital for Children, Philadelphia, Pennsylvania.;Department of Pediatrics, Section of Nephrology, St. Christopher's Hospital for Children, Philadelphia, Pennsylvania.;Department of Pediatrics, Section of Pharmacy, St. Christopher's Hospital for Children, Philadelphia, Pennsylvania.;Department of Pediatrics, Section of Pharmacy, St. Christopher's Hospital for Children, Philadelphia, Pennsylvania.;Department of Pediatrics, Section of Nephrology, St. Christopher's Hospital for Children, Philadelphia, Pennsylvania.",
"authors": "Strong|Alanna|A|0000-0001-9261-244X;Muneeruddin|Samina|S|;Parrish|Richard|R|;Lui|Daniel|D|;Conley|Susan B|SB|",
"chemical_list": "D014665:Vasodilator Agents; C528697:nephrocystin-3, human; D016547:Kinesins; D007548:Isosorbide Dinitrate",
"country": "United States",
"delete": false,
"doi": "10.1002/ajmg.a.38650",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1552-4825",
"issue": "176(4)",
"journal": "American journal of medical genetics. Part A",
"keywords": "ciliopathy; exome; nephronophthisis; primary cilia; tolvaptan",
"medline_ta": "Am J Med Genet A",
"mesh_terms": "D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007548:Isosorbide Dinitrate; D052177:Kidney Diseases, Cystic; D007677:Kidney Function Tests; D016547:Kinesins; D009154:Mutation; D010530:Peritoneal Dialysis; D010641:Phenotype; D016896:Treatment Outcome; D014665:Vasodilator Agents",
"nlm_unique_id": "101235741",
"other_id": null,
"pages": "1023-1026",
"pmc": null,
"pmid": "29575630",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Isosorbide dinitrate in nephronophthisis treatment.",
"title_normalized": "isosorbide dinitrate in nephronophthisis treatment"
} | [
{
"companynumb": "US-009507513-1804USA008374",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ATENOLOL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nVarious immune-related adverse events (irAEs) have been reported to be associated with the use of immune checkpoint inhibitors. We report a case of a patient with lung cancer treated with nivolumab who developed a bullous eruption and give a systematic review of the literature on irAEs in patients treated with immune checkpoint inhibitors for lung cancer.\n\n\nMETHODS\nA patient with lung adenocarcinoma developed a non-specific skin lesion at the time of his cancer diagnosis followed by flare episodes until the eighth cycle of nivolumab, when he developed a bullous lupus. As the first eruption had started a few months after his cancer diagnosis and was exacerbated during immunotherapy, a paraneoplastic origin is discussed. Since the patient also presented with flares under nivolumab, we reviewed reported irAEs. No bullous lupus was found but to date, 33 cases of paraneoplastic lupus and two of lupus erythematosus have been reported.\n\n\nCONCLUSIONS\nTo our knowledge, this is the first description of a bullous lupus exacerbated by nivolumab.",
"affiliations": "Internal Medicine Department, Jules Bordet Institute, Free University of Brussels (ULB), Brussels, Belgium.;Laboratory of Factual Medicine, Faculty of Medicine, Free University of Brussels (ULB), Brussels, Belgium.;Inter-Hospital Department of Dermatology, CHU Saint-Pierre, CHU Brugmann and HUDERF, Free University of Brussels (ULB), Brussels, Belgium.;Internal Medicine Department, Jules Bordet Institute, Free University of Brussels (ULB), Brussels, Belgium ap.meert@bordet.be.;Internal Medicine Department, Jules Bordet Institute, Free University of Brussels (ULB), Brussels, Belgium.",
"authors": "Wouters|Alicia|A|;Durieux|Valérie|V|;Kolivras|Athanassios|A|;Meert|Anne-Pascale|AP|;Sculier|Jean-Paul|JP|",
"chemical_list": "D000077594:Nivolumab",
"country": "Greece",
"delete": false,
"doi": "10.21873/anticanres.13432",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "39(6)",
"journal": "Anticancer research",
"keywords": "Bullous lupus; case report; lung cancer; nivolumab; paraneoplastic",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000077192:Adenocarcinoma of Lung; D001706:Biopsy; D001768:Blister; D006801:Humans; D008175:Lung Neoplasms; D008180:Lupus Erythematosus, Systemic; D008875:Middle Aged; D000077594:Nivolumab",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "3003-3008",
"pmc": null,
"pmid": "31177141",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D000078182:Systematic Review",
"references": null,
"title": "Bullous Lupus Under Nivolumab Treatment for Lung Cancer: A Case Report With Systematic Literature Review.",
"title_normalized": "bullous lupus under nivolumab treatment for lung cancer a case report with systematic literature review"
} | [
{
"companynumb": "BE-PFM-2019-08606",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINORELBINE TARTRATE"
},
"drugadditional": "3",
... |
{
"abstract": "We describe the case of a 42-year-old female who presented to our care 1 hour after ingesting 3.6 g of phenytoin. She was stuporous 48 hours after admission despite supportive therapy. She was treated with hemodialysis (HD) for nearly 6 hours in order to remove phenytoin. Her level of consciousness improved markedly during the procedure. During HD, phenytoin levels decreased by 47% and measured half-life was 6.8 hours as compared to 116 hours when not on HD. Finally, we were able to remove 547 mg of phenytoin (directly measured from the dialysate), representing approximately a third of estimated body stores. The use of extracorporeal therapy in phenytoin overdose is reviewed here. We believe that in severe cases of phenytoin intoxication, hemodialysis can be used to accelerate total body burden of the drug, even if protein binding is significant.",
"affiliations": "Division of Nephrology, Verdun Hospital, University of Montreal, Verdun, Quebec. marcghannoum@gmail.com",
"authors": "Ghannoum|M|M|;Troyanov|S|S|;Ayoub|P|P|;Lavergne|V|V|;Hewlett|T|T|",
"chemical_list": "D000927:Anticonvulsants; D001569:Benzodiazepines; D000078306:Clobazam; D000431:Ethanol; D010672:Phenytoin; D008140:Lorazepam",
"country": "Germany",
"delete": false,
"doi": "10.5414/cnp74059",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-0430",
"issue": "74(1)",
"journal": "Clinical nephrology",
"keywords": null,
"medline_ta": "Clin Nephrol",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D001569:Benzodiazepines; D000078306:Clobazam; D062787:Drug Overdose; D000431:Ethanol; D005260:Female; D006801:Humans; D008140:Lorazepam; D010672:Phenytoin; D011041:Poisoning; D006435:Renal Dialysis",
"nlm_unique_id": "0364441",
"other_id": null,
"pages": "59-64",
"pmc": null,
"pmid": "20557868",
"pubdate": "2010-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful hemodialysis in a phenytoin overdose: case report and review of the literature.",
"title_normalized": "successful hemodialysis in a phenytoin overdose case report and review of the literature"
} | [
{
"companynumb": "CA-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-280982",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": null,
"drugadditional": null,
"drugadministrationroute": ... |
{
"abstract": "Viral-associated trichodysplasia spinulosa is an unusual condition with distinctive clinical and histopathological features. Initially described in patients immunosupressed as a result of solid organ transplantation, it has also been reported in patients treated with immunosuppressive drugs other than cyclosporine or being treated for hematological malignancies. Patients presented with disseminated follicular, hyperkeratotic papules, and variable degrees of alopecia. Histopathological examination revealed shaftless bulbous and dilated hair follicles with keratotic plugging of the infundibulum. The authors reported a case of viral-associated trichodysplasia in a 5-year-old boy treated for a lymphoblastic leukemia. Eruption persisted, although treated with emollients and keratolytics, but resolved spontaneously after completing the antineoplastic medication.",
"affiliations": "Department of Pathology and *Dermatology, University Hospital and School of Medicine, Santiago de Compostela, Spain.",
"authors": "Celeiro-Muñoz|Catuxa|C|;González-Vilas|Daniel|D|;Sánchez-Aguilar|Dolores|D|;Suárez-Peñaranda|José Manuel|JM|",
"chemical_list": "D015122:Mercaptopurine; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1097/DAD.0000000000000005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0193-1091",
"issue": "36(6)",
"journal": "The American Journal of dermatopathology",
"keywords": null,
"medline_ta": "Am J Dermatopathol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002675:Child, Preschool; D006201:Hair Diseases; D006801:Humans; D007057:Ichthyosis; D016867:Immunocompromised Host; D008297:Male; D015122:Mercaptopurine; D008727:Methotrexate; D027601:Polyomavirus Infections; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma",
"nlm_unique_id": "7911005",
"other_id": null,
"pages": "e105-7",
"pmc": null,
"pmid": "24887966",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Viral-associated trichodysplasia secondary to antineoplastic treatment in a patient with lymphoblastic leukemia.",
"title_normalized": "viral associated trichodysplasia secondary to antineoplastic treatment in a patient with lymphoblastic leukemia"
} | [
{
"companynumb": "ES-FRESENIUS KABI-FK201502926",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MERCAPTOPURINE"
},
"drugadditional": nul... |
{
"abstract": "Gravid patient cardiopulmonary bypass remains a high-risk procedure with regard to fetal preservation. Maternal mortality is similar to that of the nonpregnant female at 1.5-5%. However, fetal mortality remains high at 16-33%, with an average of 19% over the past 25 years, with no correlation to gestational age. Teratogenesis is a major consideration in the first trimester. Variations in the timing of surgical intervention, gestational age, maternal health status, type of procedure, pre- or postorganogenesis, perfusion protocol, and pharmaceutical therapy are all factors that can influence fetomaternal outcome. In this report, we present a literature review along with our experience of a 26-year-old female who developed complications with her pregnancy at approximately 17 weeks gestation, with adverse neurological sequelae. The patient was 152 cm in height and weighed 48 kg, with a calculated body surface area of 1.40 M2. She had no prior history of cardiac disease and, upon admission to our institution, presented with a declining health status in pulmonary edema and was treated medically, with an ultimate requirement for mitral valve replacement. The total cardiopulmonary bypass time was 99 min with an aortic crossclamp time of 83 min. The literature, as expected, is limited to case reports and reviews since a controlled clinical trial during pregnancy is nonexistent, using extracorporeal circulation. This greatly challenges the medical staff in managing such difficult cases, with an incidence of heart disease during pregnancy of 1.2-3.7%.",
"affiliations": "Baylor University Medical Center, Dallas, USA. ssutton240@aol.com",
"authors": "Sutton|Steven W|SW|;Duncan|Michael A|MA|;Chase|Virginia A|VA|;Marce|Randy J|RJ|;Meyers|Thomas P|TP|;Wood|Richard E|RE|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1191/0267659105pf832oa",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0267-6591",
"issue": "20(6)",
"journal": "Perfusion",
"keywords": null,
"medline_ta": "Perfusion",
"mesh_terms": "D000328:Adult; D002315:Cardiopulmonary Bypass; D005260:Female; D019918:Heart Valve Prosthesis Implantation; D006801:Humans; D007231:Infant, Newborn; D008944:Mitral Valve Insufficiency; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D011256:Pregnancy Outcome; D011654:Pulmonary Edema",
"nlm_unique_id": "8700166",
"other_id": null,
"pages": "359-68",
"pmc": null,
"pmid": "16363322",
"pubdate": "2005-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Cardiopulmonary bypass and mitral valve replacement during pregnancy.",
"title_normalized": "cardiopulmonary bypass and mitral valve replacement during pregnancy"
} | [
{
"companynumb": "US-SA-2021SA135851",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MAGNESIUM SULFATE"
},
"drugadditional": "3",
... |
{
"abstract": "We herein describe the nosocomial transmission of a pre-XDR or MDR case of pulmonary tuberculosis in a HIV-negative health care worker in an area endemic for MDR and XDR tuberculosis. Following inadequate therapy and non-compliance, he presented with extra-pulmonary XDR tuberculosis in the form of multi-focal osteomyelitis and encysted pleural effusion. He was cured after two years of treatment with various anti-tuberculous drugs in addition to interferon gamma.",
"affiliations": "King Faisal Specialist Hospital and Research Centre, Department of Internal Medicine, PO BOX 40047, Jeddah 21499, Saudi Arabia. Electronic address: abeer_sh@doctor.com.;King Faisal Specialist Hospital and Research Center, Department of Internal Medicine, PO BOX 3354, Riyadh 11211, Saudi Arabia. Electronic address: rajhi@kfshrc.edu.sa.;King Abdulaziz Medical City, Department of Pathology and Lab Medicine, PO Box 9515, Jeddah 21324, Saudi Arabia. Electronic address: Fatah1234@hotmail.com.;King Abdulaziz Medical City, King Abdullah International Research Center, PO Box 22490, Riyadh 11426, Saudi Arabia. Electronic address: othmanaf@hotmail.com.",
"authors": "Alshukairi|Abeer N|AN|;Alrajhi|Abdulrahman A|AA|;Alamri|Abdulfattah W|AW|;Alothman|Adel F|AF|",
"chemical_list": "D000995:Antitubercular Agents; D007155:Immunologic Factors; D007371:Interferon-gamma",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1876-0341",
"issue": "9(4)",
"journal": "Journal of infection and public health",
"keywords": "Osteomyelitis; Therapy; XDR tuberculosis",
"medline_ta": "J Infect Public Health",
"mesh_terms": "D000995:Antitubercular Agents; D003428:Cross Infection; D054908:Extensively Drug-Resistant Tuberculosis; D006801:Humans; D007155:Immunologic Factors; D007371:Interferon-gamma; D010019:Osteomyelitis; D016896:Treatment Outcome",
"nlm_unique_id": "101487384",
"other_id": null,
"pages": "408-14",
"pmc": null,
"pmid": "26631433",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of multi-focal XDR tuberculous osteomyelitis.",
"title_normalized": "successful treatment of multi focal xdr tuberculous osteomyelitis"
} | [
{
"companynumb": "SA-LUPIN PHARMACEUTICALS INC.-2016-04053",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ISONIAZID"
},
"drugadditional... |
{
"abstract": "BACKGROUND\nThere is increasing recognition of distinct inflammatory eruptions associated with checkpoint inhibitors. A better understanding of their severity, therapeutic response, and impact on cancer treatment is needed.\n\n\nOBJECTIVE\nTo analyze the different rashes associated with immunotherapy referred to our institution's oncodermatology clinic and inpatient consultative service and to evaluate their therapeutic response and impact on immunotherapy.\n\n\nMETHODS\nWe retrospectively reviewed the medical records of patients referred to the oncodermatology clinic or inpatient dermatology service during 2016-2018 at Yale-New Haven Hospital for eruptions that developed during immunotherapy.\n\n\nRESULTS\nIn total, 98 patients (51 men, 47 women) treated with checkpoint inhibitors developed 103 inflammatory eruptions, with a range of mean latency of 0.2-17.7 months. A minority of patients (25/103; 24.3%) required immunotherapy interruption; most of these cases involved immunobullous (7/8; 87.5%), lichenoid (8/26; 30.8%), maculopapular (6/18; 33.3%), and Stevens-Johnson syndrome-like (2/2, 100%) reactions. Only 3 of 16 (18.8%) patients who had their immunotherapy interrupted had a grade 2 or 3 flare on rechallenge. Most reactions (93/103; 90.3%) responded to dermatologic therapy or immunotherapy interruption.\n\n\nCONCLUSIONS\nThis was a retrospective study from a single tertiary care center.\n\n\nCONCLUSIONS\nA variety of inflammatory reactions might occur from immunotherapy with differing degrees of severity. While most rashes responded to topical treatment, immunobullous and exfoliative presentations frequently interrupted immunotherapy. Increased awareness and early recognition could reduce the need for unnecessary immunotherapy interruption.",
"affiliations": "Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut.;Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut; Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.;Yale Center for Analytical Sciences, Yale University School of Medicine, New Haven, Connecticut.;Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut.;Internal Medicine (Medical Oncology), Yale University School of Medicine, New Haven, Connecticut.;Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut. Electronic address: jonathan.leventhal@yale.edu.",
"authors": "Coleman|Emily|E|;Ko|Christine|C|;Dai|Feng|F|;Tomayko|Mary M|MM|;Kluger|Harriet|H|;Leventhal|Jonathan S|JS|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D000074324:Ipilimumab; C000613593:durvalumab; D000077594:Nivolumab; C000594389:atezolizumab; C582435:pembrolizumab; C000609138:avelumab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaad.2018.10.062",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0190-9622",
"issue": "80(4)",
"journal": "Journal of the American Academy of Dermatology",
"keywords": "cutaneous adverse events; cytotoxic T-lymphocyte associated protein 4; dermatologic toxicities; immune checkpoint inhibitor; immune-related adverse events; immunotherapy; programmed cell death 1; programmed cell death ligand 1",
"medline_ta": "J Am Acad Dermatol",
"mesh_terms": "D000368:Aged; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D003875:Drug Eruptions; D005076:Exanthema; D005260:Female; D006801:Humans; D000074324:Ipilimumab; D017512:Lichenoid Eruptions; D008297:Male; D008875:Middle Aged; D000077594:Nivolumab; D012189:Retrospective Studies; D012878:Skin Neoplasms; D013262:Stevens-Johnson Syndrome; D028761:Withholding Treatment",
"nlm_unique_id": "7907132",
"other_id": null,
"pages": "990-997",
"pmc": null,
"pmid": "30399387",
"pubdate": "2019-04",
"publication_types": "D016428:Journal Article",
"references": "20525992;22658127;25755681;25918278;26027431;26371282;26629425;26793994;26957557;27031538;27043866;27411054;27486590;27570820;27739129;27859479;27981213;28000240;28430376;28817405;28881921;29221649;30025829;30112450",
"title": "Inflammatory eruptions associated with immune checkpoint inhibitor therapy: A single-institution retrospective analysis with stratification of reactions by toxicity and implications for management.",
"title_normalized": "inflammatory eruptions associated with immune checkpoint inhibitor therapy a single institution retrospective analysis with stratification of reactions by toxicity and implications for management"
} | [
{
"companynumb": "GB-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-048864",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "Central nervous system immune reconstitution inflammatory syndrome (CNS-IRIS) describes clinical characteristics that may be observed in previously immunocompromised patients during rapid restoration of immunity function in the presence of a pathogen. There have been no reports about CNS-IRIS related to bacterial meningitis so far. Here, we report a 24-year-old pregnant female patient with bacterial meningitis. Her clinical and neuroradiological condition worsened after induced labor despite great effective anti-infective therapy. CNS-IRIS was considered. Corticosteroids were administered, and the patient gradually recovered. We present the first case of CNS-IRIS associated with bacterial meningitis.",
"affiliations": "Department of Neurology, Center for Mental and Neurological Disorders and Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Neurology, Center for Mental and Neurological Disorders and Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Neurology, Center for Mental and Neurological Disorders and Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Dermatology, Guangzhou Women And Children's Medical Center, Guangzhou, China.;Department of Neurology, Center for Mental and Neurological Disorders and Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Neurology, Center for Mental and Neurological Disorders and Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Neurology, Center for Mental and Neurological Disorders and Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Neurology, Center for Mental and Neurological Disorders and Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.",
"authors": "Hu|Mengyan|M|;Liu|Sanxin|S|;Lu|Danli|D|;Zhong|Yi|Y|;Yu|Dafan|D|;Qiu|Wei|W|;Lu|Zhengqi|Z|;Zhang|Bingjun|B|",
"chemical_list": "D000305:Adrenal Cortex Hormones",
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fimmu.2021.585316",
"fulltext": "\n==== Front\nFront Immunol\nFront Immunol\nFront. Immunol.\nFrontiers in Immunology\n1664-3224\nFrontiers Media S.A.\n\n10.3389/fimmu.2021.585316\nImmunology\nCase Report\nCase Report: Central Nervous System Immune Reconstitution Inflammatory Syndrome Related to Bacterial Meningitis\nHu Mengyan 1 †\nLiu Sanxin 1 †\nLu Danli 1 †\nZhong Yi 2\nYu Dafan 1\nQiu Wei 1\n\nLu Zhengqi 1\n\nZhang Bingjun 1 *\n\n1 Department of Neurology, Center for Mental and Neurological Disorders and Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China\n2 Department of Dermatology, Guangzhou Women And Children’s Medical Center, Guangzhou, China\nEdited by: Sharon Glynn Lynch, University of Kansas Medical Center, United States\n\nReviewed by: Sonja Hochmeister, Medical University of Graz, Austria; Lars-Ove Brandenburg, University Hospital RWTH Aachen, Germany\n\n*Correspondence: Bingjun Zhang, gdbingjun@163.com\nThis article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Immunology\n\n†These authors have contributed equally to this work\n\n29 3 2021\n2021\n12 58531621 7 2020\n10 3 2021\nCopyright © 2021 Hu, Liu, Lu, Zhong, Yu, Qiu, Lu and Zhang\n2021\nHu, Liu, Lu, Zhong, Yu, Qiu, Lu and Zhang\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.\nCentral nervous system immune reconstitution inflammatory syndrome (CNS-IRIS) describes clinical characteristics that may be observed in previously immunocompromised patients during rapid restoration of immunity function in the presence of a pathogen. There have been no reports about CNS-IRIS related to bacterial meningitis so far. Here, we report a 24-year-old pregnant female patient with bacterial meningitis. Her clinical and neuroradiological condition worsened after induced labor despite great effective anti-infective therapy. CNS-IRIS was considered. Corticosteroids were administered, and the patient gradually recovered. We present the first case of CNS-IRIS associated with bacterial meningitis.\n\nimmune reconstitution inflammatory syndrome\nbacterial meningitis\nStaphylococcus aureus\npregnancy\ncase report\n==== Body\nIntroduction\n\nInfection of the central nervous system (CNS), usually presenting as meningitis or encephalitis, is linked to high mortality and morbidity rates throughout the world (1). During therapy of CNS infection, clinical deterioration may occur despite evidence of effective treatment. Known as CNS-immune reconstitution inflammatory syndrome (CNS-IRIS), this paradoxical heightened immune response was initially identified in human immunodeficiency virus (HIV)-infected patients following anti-infection therapy and reversal of immune deficiency with antiretroviral therapy (2). However, it is increasingly found in immunocompromised hosts (3). CNS-IRIS occurs in 9%–47% of persons with HIV infection and CNS opportunistic infection who start antiretroviral therapy and has a mortality rate of 13%–75% (4). These rates vary depending on the causative pathogen. Most common CNS-IRIS events develop in relation to cryptococcus, tuberculosis (TB), and John Cunningham (JC) virus, but several other viruses, mycobacteria, and fungi have been associated with CNS-IRIS.\n\nHowever, to the best of our knowledge, there has not been report about CNS-IRIS related to bacterial meningitis so far. We describe an interesting case of CNS-IRIS in a pregnant patient with bacterial meningitis, who developed deteriorated neurologic symptoms as seen by brain imaging after induced labor and effective anti-infective therapy.\n\nCase Report\n\nA 24-year-old pregnant female (G1P0) presented to the maternity ward of the local hospital, 12 weeks pregnant with a 14-day history of a mild headache and high fever for 2 days. After two generalized tonic-clonic seizure episodes, the female was transferred to our hospital. She had a 4-year history of hypothyroidism with irregular medication. The patient had no history of nasosinusitis, head trauma, or surgery. On admission, her vital signs revealed a temperature of 39.4°C, a blood pressure of 89/55 mmHg, a pulse of 120 beats/min, and a respiratory rate of 22 breaths/min. Physical examination revealed a lethargic patient with a Glasgow coma scale (GCS) score of 15/15. She had a normal physical examination except for nuchal rigidity and a positive Kernig’s sign. Blood tests showed that her leukocyte count was 22.7 × 109/L (neutrophil 85.4%), sedimentation rate (ESR) 105 mm/H, C-reactive protein (CRP) 99.1 mg/L, and procalcitonin (PCT) 0.5 ng/ml. Lumbar puncture showed that her cerebrospinal fluid (CSF) pressure was 330 mmH2O, leukocyte count 540 × 106/L (neutrophil 80.0%), protein 1.57 g/L, glucose 1.16 mmol/L, and chloride 117.1 mmol/L ( Figure 1 ). The patient was diagnosed with bacterial meningitis, and treated immediately with empirical antibiotic therapy with meropenem (2.0 q8h intravenous drip) and vancomycin (1.0 q8h intravenous drip). Levetiracetam (1.0) was administered twice daily for antiepileptic treatment. Brain magnetic resonance imaging (MRI) revealed diffuse hyperintensities on fluid attenuated inversion recovery (FLAIR) imaging, accompanying by meningeal enhancement on a T1 contrast image ( Figure 2A ). Brain magnetic resonance angiography (MRA) imaging exhibited normal findings. Head CT and MRI showed no bone destructions and fistulas. Later, blood and CSF culture indicated staphylococcus aureus, which was sensitive to vancomycin and linezolid. The results were consistent with the analysis of metagenomics next-generation sequencing (mNGS). Thereafter, temperature was gradually decreased. There was no recurrence of seizures. Repeated blood and CSF results were significantly improved. Serum and CSF antibodies were negative for all antibodies against nerve cell-surface antigens and intracellular antigens. Autoantibodies and mycoplasma pneumoniae antibody were also negative. The T-SPOT.TB test was normal. There were no cardiac valve destructions and vegetations on the echocardiography exam. A Doppler ultrasound suggested fetal growth restriction.\n\nFigure 1 The clinical and CSF evolutions of the patient.\n\nFigure 2 Brain MRI of the patient. (A) MRI revealed diffuse hyperintensities on fluid attenuated inversion recovery (FLAIR) imaging, accompanied by meningeal enhancement on the T1 contrast image. (B, C) Repeated MRI revealed that lesions were enlarged and meningeal enhancement was even more obvious after effective antibiotic therapy and induced labor. (D) Follow-up MRI showed marked improvement after corticosteroids treatment.\n\nThe patient selected to abort the pregnancy because the fetus had growth restriction and had undergone medical interventions, including medications and imaging examinations, that had the potential to result in the teratogenic effect for the fetus. After 20 days of antibiotic therapy, the patient underwent a successful medication abortion. However, she developed weakness of the right limb, and fever again. She deteriorated with a fluctuating mental condition (GCS ranging from 10 to 12 of 15). Although brain MRA imaging were still normal, brain MRI revealed lesions were enlarged and meningeal enhancement was even more obvious ( Figure 2B ). Repeated multiple blood and CSF culture were negative for any bacteria. Linezolid (0.6 g bid intravenous drip) was used to as a substitute to vancomycin.\n\nUnfortunately, the patient continued to deteriorate. She lapsed into a coma with a GCS 8 of 15. The repeated MRI was confirmed the progressive condition ( Figure 2C ). Antibodies related to autoimmune encephalitis were still negative in the serum and CSF. Therefore, CNS-IRIS was considered. The patient received high-dose intravenous methylprednisolone (20 mg/d/kg body weight, 5 days) followed by oral corticosteroids.\n\nThe neurologic abnormalities gradually improved, and follow-up MRI showed marked improvement ( Figure 2D ). She was discharged from hospital three months after her admission. Although weakness of the right limb continued, she was able to walk unaided.\n\nDiscussion\n\nThis case demonstrated the unusual characteristics of bacterial meningitis in a pregnant patient. The clinical evolution of the patient was characterized by a paradoxical clinical condition and neuroradiological worsening after induced labor, despite the use of greatly effective anti-infective therapy. CNS-IRIS induced by bacterial meningitis was diagnosed and treated with corticosteroids. To the best of our knowledge, this is the first case of CNS-IRIS related to bacterial meningitis.\n\nBacterial meningitis is a medical emergency, and is associated with high mortality and disease burden. The epidemiology of community-acquired bacterial meningitis worldwide has changed in the past decades as a result of vaccination (5). The majority of bacterial meningitis cases in adults are due to streptococcus agalactiae and streptococcus pneumonia (6). Lymphatic dissemination, hematogenous dissemination, and direct extension from the adjacent areas are considered the possible routes of pathogenesis invasion into the CNS. Staphylococcus aureus meningitis is a relatively uncommon but serious CNS infectious disease. It is a nosocomial infection usually associated with neurosurgical procedures and head trauma, but spontaneous infections may occasionally appear in communities (7, 8). In the present study, staphylococcus aureus meningitis in our patient was a spontaneous community-acquired infection. Staphylococcus aureus usually invades the CNS via hematogenous spread on the basis of positive blood culture.\n\nIRIS describes a series of symptoms and clinical characteristics that may be observed in previously immunocompromised patients during rapid restoration of immunity function in the presence of a pathogen or foreign antigen (2). However, there is no universally agreed-upon definition for IRIS. Immune deficiency is most frequently linked to HIV, a reversal of immunosuppressant states, and withdrawal of immunosuppressive drugs. IRIS can involve multiple organs, including the CNS, liver, lung, stomach, and intestine (9). The incidence of CNS-IRIS ranges widely according to CNS infection including TB, cryptococcus, and JC virus. An underlying mechanism of CNS-IRIS involves exposing large amounts of a foreign antigen to an immune system with improving ability which then responds and causes inflammation. Immune overactivation is caused by the hyper-responsiveness of the innate immune system as T lymphocyte function recovers (10). On brain biopsy or postmortem examinations, T lymphocytes and macrophages are found predominantly in the parenchyma and perivascular spaces (11). Brain MRI abnormalities, including new swelling with perilesional and perivascular edema, are often found in CNS-IRIS patients (12). The lesions might show contrast enhancement on MRI, due to local inflammation and breakdown of the blood–brain barrier (13, 14). Corticosteroids treatment is usually given to reduce the overactivation inflammatory response. In CNS-IRIS caused by TB and cryptococcus, corticosteroids treatment is recommended (4, 15, 16). However, use of corticosteroids in progressive multifocal leukoencephalopathy IRIS remains controversial (13). Furthermore, the dose and course of corticosteroids are still uncertain.\n\nWe believed that the patient met the definition of CNS-IRIS. First, the immunodeficient status was obvious during pregnancy in the patient. Second, immune function recovered rapidly after induced labor and effective antibiotic therapy. Third, deteriorated neurologic symptoms and brain imaging were found after treatment in the patient. Fourth, the deteriorated conditions were improved after use of corticosteroids. Fifth, the patient had no evidence of drug-resistant infection, bacterial superinfection, and drug allergy.\n\nIn conclusion, we present a rare case of a pregnant patient presenting with CNS-IRIS related to bacterial meningitis after effective antibiotic therapy and induced labor. Selection of the appropriate treatment regimen is challenging and is carefully considered in pregnant patients with severe infectious diseases.\n\nData Availability Statement\n\nAll datasets generated for this study are included in the article.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by the Medical Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin. Written informed consent was obtained from the participant’s next of kin for the publication of this case report, including any identifiable data or images included in this study.\n\nAuthor Contributions\n\nMH, SL, DL, and BZ designed the research. YZ performed the experiments and analyzed the data. DY and BZ wrote the main manuscript text and prepared the figures. ZL, WQ, and BZ edited and revised the manuscript. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThis study was supported by the National Natural Science Foundation of China (81971110, 81671178); the Guangdong Basic and Applied Basic Research Foundation (2020A1515010056); the Third Affiliated Hospital of Sun Yat-Sen University, Clinical Research Program (QHJH201907); and the Doctorial Starting Fund of Guangzhou Women and Children’s Medical Center (2018-293).\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 Beaman MH . Community-acquired acute meningitis and encephalitis: a narrative review. Med J Aust (2018) 209 (10 ):449–54. 10.5694/mja17.01073\n2 Haddow LJ Colebunders R Meintjes G Lawn SD Elliott JH Manabe YC . Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions. Lancet Infect Dis (2010) 10 (11 ):791–802. 10.1016/s1473-3099(10)70170-5 21029993\n3 Ecevit IZ Clancy CJ Schmalfuss IM Nguyen MH . The poor prognosis of central nervous system cryptococcosis among nonimmunosuppressed patients: a call for better disease recognition and evaluation of adjuncts to antifungal therapy. Clin Infect Dis (2006) 42 (10 ):1443–7. 10.1086/503570\n4 Bahr N Boulware DR Marais S Scriven J Wilkinson RJ Meintjes G . Central nervous system immune reconstitution inflammatory syndrome. Curr Infect Dis Rep (2013) 15 (6 ):583–93. 10.1007/s11908-013-0378-5\n5 McIntyre PB O’Brien KL Greenwood B van de Beek D . Effect of vaccines on bacterial meningitis worldwide. Lancet (2012) 380 (9854 ):1703–11. 10.1016/s0140-6736(12)61187-8\n6 van de Beek D Cabellos C Dzupova O Esposito S Klein M Kloek AT . ESCMID guideline: diagnosis and treatment of acute bacterial meningitis. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis (2016) 22 Suppl 3 :S37–62. 10.1016/j.cmi.2016.01.007\n7 Pintado V Pazos R Jiménez-Mejías ME Rodríguez-Guardado A Díaz-Pollán B Cabellos C . Staphylococcus aureus meningitis in adults: A comparative cohort study of infections caused by meticillin-resistant and meticillin-susceptible strains. J Hosp Infect (2019) 102 (1 ):108–15. 10.1016/j.jhin.2018.11.008\n8 Pintado V Meseguer MA Fortún J Cobo J Navas E Quereda C . Clinical study of 44 cases of Staphylococcus aureus meningitis. Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol (2002) 21 (12 ):864–8. 10.1007/s10096-002-0814-1\n9 Sueki H Mizukawa Y Aoyama Y . Immune reconstitution inflammatory syndrome in non-HIV immunosuppressed patients. J Dermatol (2018) 45 (1 ):3–9. 10.1111/1346-8138.14074 28944502\n10 Barber DL Andrade BB Sereti I Sher A . Immune reconstitution inflammatory syndrome: the trouble with immunity when you had none. Nat Rev Microbiol (2012) 10 (2 ):150–6. 10.1038/nrmicro2712\n11 Bauer J Gold R Adams O Lassmann H . Progressive multifocal leukoencephalopathy and immune reconstitution inflammatory syndrome (IRIS). Acta Neuropathol (2015) 130 (6 ):751–64. 10.1007/s00401-015-1471-7\n12 Ishii K Yamamoto F Homma S Okada Y Nakamichi K Saijo M . Probable progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome with immunosuppressant dose reduction following lung transplantation: a case report and literature review. BMC Neurol (2019) 19 (1 ):263. 10.1186/s12883-019-1493-1 31672142\n13 Tan CS Koralnik IJ . Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol (2010) 9 (4 ):425–37. 10.1016/s1474-4422(10)70040-5\n14 Wattjes MP Wijburg MT van Eijk J Frequin S Uitdehaag BMJ Barkhof F . Inflammatory natalizumab-associated PML: baseline characteristics, lesion evolution and relation with PML-IRIS. J Neurol Neurosurg Psychiatry (2018) 89 (5 ):535–41. 10.1136/jnnp-2017-316886\n15 Elsegeiny W Marr KA Williamson PR . Immunology of Cryptococcal Infections: Developing a Rational Approach to Patient Therapy. Front Immunol (2018) 9 :651. 10.3389/fimmu.2018.00651 29670625\n16 Walker NF Stek C Wasserman S Wilkinson RJ Meintjes G . The tuberculosis-associated immune reconstitution inflammatory syndrome: recent advances in clinical and pathogenesis research. Curr Opin HIV AIDS (2018) 13 (6 ):512–21. 10.1097/coh.0000000000000502\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-3224",
"issue": "12()",
"journal": "Frontiers in immunology",
"keywords": "Staphylococcus aureus; bacterial meningitis; case report; immune reconstitution inflammatory syndrome; pregnancy",
"medline_ta": "Front Immunol",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D002490:Central Nervous System; D002493:Central Nervous System Diseases; D005260:Female; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D016920:Meningitis, Bacterial; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101560960",
"other_id": null,
"pages": "585316",
"pmc": null,
"pmid": "33868222",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't",
"references": "31672142;23141619;22230950;29142146;30124473;24173584;29670625;12525921;27062097;21029993;30309300;28944502;16619158;30448277;20298966;26323992",
"title": "Case Report: Central Nervous System Immune Reconstitution Inflammatory Syndrome Related to Bacterial Meningitis.",
"title_normalized": "case report central nervous system immune reconstitution inflammatory syndrome related to bacterial meningitis"
} | [
{
"companynumb": "CN-SLATE RUN PHARMACEUTICALS-21CN000718",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VANCOMYCIN HYDROCHLORIDE"
},
"d... |
{
"abstract": "Primary gastrointestinal follicular lymphoma (FL) has an indolent clinical presentation and many of cases are diagnosed incidentally during routine endoscopic examinations. Herein, we present 3 cases with FL of the small intestine developed massive intestinal hemorrhage that necessitated blood transfusion. In all three patients, upper and lower endoscopic examinations failed to detect the bleeding sites. Eventually, video capsule endoscopies identified ulcerative lesions in the jejunum and biopsies using single- or double-balloon endoscopy confirmed the FL diagnosis in our three cases. The respective clinical stages according to the Lugano system were I, II-1 and II-1. PET-CT did not play a significant role in identifying the gastrointestinal lesions. Two patients received rituximab monotherapy and achieved a complete response. The other remains under observation after termination of antiplatelet drug therapy. Generally, the macroscopic appearance of multiple whitish nodules and the absence of symptoms represent the typical clinical picture of gastrointestinal FL. However, this study demonstrates that patients with ulcerative lesions may be at risk for massive bleeding. Further discussion is required to determine the optimal indications for total endoscopic examination of the small intestine.",
"affiliations": "Division of Hematology-Oncology, Chiba Cancer Center.",
"authors": "Sato|Akiyasu|A|;Tsujimura|Hideki|H|;Sugiyama|Takahiro|T|;Maruyama|Satoshi|S|;Yamada|Shuhei|S|;Ono|Keiko|K|;Wang|Xiaofei|X|;Sugawara|Takeaki|T|;Ise|Mikiko|M|;Itami|Makiko|M|;Kumagai|Kyouya|K|",
"chemical_list": "D000970:Antineoplastic Agents; D000069283:Rituximab",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.57.353",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "57(3)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": null,
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D004379:Duodenal Neoplasms; D005260:Female; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D007580:Jejunal Neoplasms; D008224:Lymphoma, Follicular; D008297:Male; D008875:Middle Aged; D012074:Remission Induction; D000069283:Rituximab",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "353-8",
"pmc": null,
"pmid": "27076249",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Primary gastrointestinal follicular lymphoma of the small intestine with massive hemorrhage: a report of three cases.",
"title_normalized": "primary gastrointestinal follicular lymphoma of the small intestine with massive hemorrhage a report of three cases"
} | [
{
"companynumb": "JP-BAYER-2016-076417",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Amplification or duplication of the AML1 gene at chromosome band 21q22 was detected by FISH using a locus-specific probe in three out of 171 unselected patients with therapy-related myelodysplasia (t-MDS) or t-AML (1.7%). In two patients AML1 signals were located tandemly on derivative chromosomes, in one patient on a dic(9;21) and in the the other patient on a derivative chromosome 18 made up of interchanging layers of material from chromosomes 9, 14, 18, and 21. In the third patient three single supernumerary copies of AML1 were located on derivatives of chromosomes 19 and 21. All three patients were older, had previously received therapy with alkylating agents without topoisomerase II inhibitors, had complex karyotypes including abnormalities of chromosomes 5 or 7, and presented acquired point mutations of the TP53 gene. No point mutations of the AML1 gene were observed. The results support a pivotal role of impaired TP53 function in the development of gene amplification or duplication in t-MDS and t-AML.",
"affiliations": "Department of Clinical Genetics, Section of Hematology/Oncology, The Juliane Marie Center, Rigshospitalet, Copenhagen, Denmark. mka@rh.dk",
"authors": "Andersen|M K|MK|;Christiansen|D H|DH|;Pedersen-Bjergaard|J|J|",
"chemical_list": "D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; D014157:Transcription Factors",
"country": "England",
"delete": false,
"doi": "10.1038/sj.leu.2403612",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-6924",
"issue": "19(2)",
"journal": "Leukemia",
"keywords": null,
"medline_ta": "Leukemia",
"mesh_terms": "D002874:Chromosome Mapping; D002891:Chromosomes, Human, Pair 21; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D005091:Exons; D005784:Gene Amplification; D020440:Gene Duplication; D016158:Genes, p53; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D009154:Mutation; D009190:Myelodysplastic Syndromes; D011518:Proto-Oncogene Proteins; D016019:Survival Analysis; D014157:Transcription Factors",
"nlm_unique_id": "8704895",
"other_id": null,
"pages": "197-200",
"pmc": null,
"pmid": "15618958",
"pubdate": "2005-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Amplification or duplication of chromosome band 21q22 with multiple copies of the AML1 gene and mutation of the TP53 gene in therapy-related MDS and AML.",
"title_normalized": "amplification or duplication of chromosome band 21q22 with multiple copies of the aml1 gene and mutation of the tp53 gene in therapy related mds and aml"
} | [
{
"companynumb": "DK-BAUSCH-BL-2018-012979",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Gemcitabine is not considered a cardiotoxic agent generally; so far only very few case reports have been reported in the literature on different aspects of cardiac side effects. Here we report a case series of 3 patients who developed congestive cardiac failure, when treated with gemcitabine monotherapy in the adjuvant setting for pancreatic cancers. Adjuvant chemotherapy with gemcitabine has been the standard of care for pancreatic cancer patients after successful surgery since the results of the CONKO-001 and ESPAC3 study were published. Gemcitabine was administered on days 1, 8, and 15 of a 28-day cycle at 1,000 mg/m2. All 3 patients developed symptoms suggestive of cardiac failure with a drop in ejection fraction on echocardiography, and responded to conservative treatment for heart failure after withdrawal of gemcitabine therapy. Early withdrawal of gemcitabine chemotherapy is recommended in addition to a need for studies required to evaluate the mechanism of cardiotoxicity. As per available literature, patients with diabetes and having received a total dose greater than 15,000 mg/m2 are generally at a higher risk and require close surveillance.",
"affiliations": "Queen Elizabeth Hospital, Birmingham, United Kingdom.;Queen Elizabeth Hospital, Birmingham, United Kingdom.;School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.;Queen Elizabeth Hospital, Birmingham, United Kingdom.",
"authors": "Alam|Salma|S|;Illo|Chidi|C|;Ma|Yuk Ting|YT|;Punia|Pankaj|P|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000488139",
"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000488139cro-0011-0221Case ReportGemcitabine-Induced Cardiotoxicity in Patients Receiving Adjuvant Chemotherapy for Pancreatic Cancer: A Case Series Alam Salma aIllo Chidi aMa Yuk Ting bPunia Pankaj a*aQueen Elizabeth Hospital, Birmingham, United KingdombSchool of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom*Dr. Pankaj Punia, Cancer Centre, Queen Elizabeth Hospital, Birmingham B152SY (UK), E-Mail Pankaj.Punia@uhb.nhs.ukJan-Apr 2018 5 4 2018 5 4 2018 11 1 221 227 5 3 2018 6 3 2018 Copyright © 2018 by S. Karger AG, Basel2018This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Gemcitabine is not considered a cardiotoxic agent generally; so far only very few case reports have been reported in the literature on different aspects of cardiac side effects. Here we report a case series of 3 patients who developed congestive cardiac failure, when treated with gemcitabine monotherapy in the adjuvant setting for pancreatic cancers. Adjuvant chemotherapy with gemcitabine has been the standard of care for pancreatic cancer patients after successful surgery since the results of the CONKO-001 and ESPAC3 study were published. Gemcitabine was administered on days 1, 8, and 15 of a 28-day cycle at 1,000 mg/m2. All 3 patients developed symptoms suggestive of cardiac failure with a drop in ejection fraction on echocardiography, and responded to conservative treatment for heart failure after withdrawal of gemcitabine therapy. Early withdrawal of gemcitabine chemotherapy is recommended in addition to a need for studies required to evaluate the mechanism of cardiotoxicity. As per available literature, patients with diabetes and having received a total dose greater than 15,000 mg/m2 are generally at a higher risk and require close surveillance.\n\nKeywords\nGemcitabineCardiotoxicityPancreatic cancer\n==== Body\nIntroduction\nAntineoplastic therapies have evolved considerably over the past decade, resulting in an overall survival, and improvement in morbidity and mortality for various different tumour types. Gemcitabine is a commonly used chemotherapy agent in the treatment of various solid malignancies including pancreatic, ovarian, breast, bladder, and non-small cell lung cancers. It is a nucleoside analogue and a pyrimidine antimetabolite that inhibits deoxyribonucleic acid (DNA) synthesis by inhibition of DNA polymerase and ribonucleotide reductase [1] resulting in apoptosis [2].\n\nGemcitabine is a relatively well-tolerated chemotherapy; the commonly reported side effects include bone marrow suppression, liver and kidney problems, nausea, fever, rash, shortness of breath, and hair loss. Its use during pregnancy increases the risk of teratogenesis. Cardiotoxicity, especially cardiomyopathy, has not been reported during early phase trials of drug development [3]. Although gemcitabine-induced cardiomyopathy is extremely rare, we report here 3 cases of gemcitabine-induced cardiomyopathy from a single tertiary centre in the United Kingdom.\n\nCase Report 1\nA 62-year-old Caucasian man first presented in November 2015 with recurrent epigastric and back pain, diarrhoea, vomiting, jaundice, and weight loss. Co morbidities included rheumatoid arthritis, peptic ulcer, hypertension, and myocardial infarction (15 years previously). He was on bisoprolol, piriton, simvastatin, amitriptyline, omeprazole, and adcal. He smoked 5 cigarettes per day and had a moderate alcohol intake.\n\nFollowing an initial work-up he underwent a Whipple procedure. Histological examination revealed pT3N0 pancreatic carcinoma. Adjuvant chemotherapy with IV gemcitabine (1,000 mg/m2 to the nearest 38 mg as 2,100 mg given on day 1, 8, and 15 on a 28-day cycle for 6 cycles) was recommended and commenced to reduce recurrence following a case discussion at the multi-disciplinary team meeting.\n\nFollowing the 4th cycle of chemotherapy he developed persistent peripheral oedema and myelosuppression with haemoglobin of 74. He was given 2 units of blood transfusion, and echocardiography at this point showed normal heart and valvular function. He was treated with furosemide and given the option of dose reduction or stopping treatment due to cumulative toxicity. The patient wanted to continue treatment and therefore received a 25% reduced dose at cycle 5. However on routine clinical follow-up, after cycle 5 for toxicity assessment, the peripheral oedema had worsened. Clinical examination revealed right-sided basal crepitation but normal JVP, his serum electrolytes were normal but haemoglobin was down to 73. The patient was adamant to continue and complete the treatment. It was therefore decided to delay treatment until symptoms improved. Despite a further 2 units of blood given as a day case and a higher dose of furosemide, oedema and shortness of breath got worse at home and he was admitted as an inpatient. His renal function began to deteriorate. A repeat echocardiogram showed an LVEF of 40% and moderate mitral valve regurgitation. Additionally, a high-resolution CT scan demonstrated multiple parenchymal infiltrates suggestive of possible pneumonitis with fluid overload. Nephrologists, cardiologists, and pulmonologists were involved in patient management.\n\nA decision was made to stop chemotherapy. He was treated with steroids, antibiotics with PCP cover, and diuretics, leading to symptomatic improvement and was discharged home.\n\nThe patient needed to be readmitted to hospital after a couple of weeks with worsening shortness of breath and pedal oedema. He was found to have pulmonary oedema and persistent deterioration in renal function requiring critical care review in the intensive therapy unit for respiratory support and haemofiltration. After a full renal screen by the renal medicine team, the patient's acute kidney injury was attributed to gemcitabine. A repeat high-resolution CT scan demonstrated a progression of possible drug-induced pneumonitis. He continued to receive steroids, diuretics, and antibiotics. He improved after a couple of weeks and was discharged. The Cardiology Team however attributed the patient's heart failure to ischaemic heart disease despite the likelihood of gemcitabine-induced cardiotoxicity. However, a repeat echocardiogram 3 weeks later showed an improvement in cardiac function; LVEF 50% and no valvular dysfunction were noted. He has not been readmitted since and is being followed up in the outpatient clinic by the oncology, nephrology, cardiology and respiratory medicine teams.\n\nFollowing completion of adjuvant chemotherapy, albeit treatment ceased early due to toxicity, post-treatment imaging did not demonstrate disease recurrence. His care was therefore handed back to the surgical colleagues for further follow-up.\n\nCase Report 2\nA 63-year-old Caucasian man initially presented with painless jaundice against the background of no significant past medical history. He underwent a Whipple procedure for carcinoma of the head of the pancreas. Histology showed a pT3 tumour with the involvement of 8 lymph nodes. He commenced on adjuvant gemcitabine (1,000 mg/m2 to the nearest 38 mg as 2,100 mg given on day 1, 8, 15 on a 28-day cycle, planned for 6 cycles).\n\nJust prior to his 3rd cycle, he gradually developed bilateral pedal oedema, with no other signs or symptoms. He was started on furosemide and chemotherapy continued. During his 4th cycle he received 2 units of blood. At the start of his 5th cycle he developed occasional shortness of breath, but by day 15 he was found to be anaemic and thrombocytopenic with acute kidney failure. Investigations ruled out urinary obstruction. He was treated with intravenous fluids and blood products. Patient was discharged home after renal team review. After a week at home, peripheral oedema and breathlessness increased and he was readmitted to hospital. Chest X-ray showed a mixed picture of fluid overload and right upper lobe consolidation. An echocardiogram demonstrated impaired systolic function with LVEF of 38%, mildly dilated left atrium, and mild mitral and tricuspid regurgitation. The patient was admitted to the coronary care unit by the cardiology team and was treated with antibiotics and diuretics, initially intravenously and later orally as he improved. It was decided to terminate adjuvant chemotherapy at the 5th cycle.\n\nThe CT scan at this stage was clear and the patient was placed on surveillance and continued outpatient follow-up by the cardiology and nephrology teams. A further cardiac MRI arranged by the cardiology team 2 months later demonstrated stable cardiac function, with an improvement in the EF to 67%, but demonstrated a suspicious retrocrural lymph node. To rule out recurrence a repeat CT staging scan was performed, additionally confirming that the retrocrural lymph nodes also showed multiple peritoneal metastases.\n\nHe was subsequently commenced on 2nd line FOLFOX (FOLFIRINOX modified due to renal and cardiac impairment) at a 75% reduced dose; treatment was well tolerated with only grade 1 peripheral neuropathy affecting fingertips and fatigue. The CT scan after 6 cycles and on completion of the 12th cycle showed stable disease. A surveillance scan after 3 months demonstrated disease progression again with worsening peritoneal and omental disease. He was re-challenged with FOLFOX. He continued to tolerate chemotherapy with minimal toxicity. Unfortunately he quickly deteriorated after cycle 5 of re-challenge FOLFOX chemotherapy, with severe cachexia and anorexia. A repeat CT confirmed significant progressive disease in the peritoneum and omentum with an enlarged metastatic node in the right groin. He passed away a few days later in February 2017.\n\nCase Report 3\nA 72-year-old Caucasian female presented with painless jaundice in November 2014. Comorbidities included type II diabetes mellitus, hypertension, and hypercholesterolaemia. She was on insulin, ramipril, rosuvastatin and lansoprazole. She was an ex-smoker but had no history of alcohol consumption.\n\nImaging showed pancreatic abnormality and a right-sided lung mass. Biopsy confirmed 2 separate primaries; she underwent right-sided lobectomy and Whipple procedure. Histology showed a lung adenocarcinoma (T2N0R0) and a poorly differentiated ductal adenocarcinoma of the head of the pancreas with lymph node, perineural, and vascular invasion (pT3pN1).\n\nShe was started on adjuvant gemcitabine, planned for 6 cycles. 75% of the standard dose (1,000 mg/m2) was given at the 1st cycle due to ongoing weakness after surgery, but then it was increased to 100% from 2nd cycle as the 1st cycle was well tolerated.\n\nFollowing the 2nd cycle, she developed peripheral oedema, cough, and shortness of breath, which were treated with furosemide and antibiotics. On completion of the 3rd cycle, shortness of breath and peripheral oedema worsened, clinically suggestive of congestive cardiac failure. She was admitted for investigations. CTPA showed subtle ground-glass appearance and an echocardiogram showed LVEF 60–65% with moderate aortic stenosis but no LVH. A diagnosis of chemotherapy-induced pneumonitis with underlying undiagnosed COPD was made, although clinical examination also favoured cardiac failure with somewhat preserved LVEF. Good left ventricular function on the echocardiogram may be misleading in this case as the patient had already been on diuretics for a couple of week at the time of the echocardiogram. She was treated with steroids, antibiotics, and diuretics, and was started on salbutamol inhalers. It was decided to stop further gemcitabine treatment due to significant toxicity; imaging showed stable disease, and the patient was placed under surveillance. Shortness of breath gradually improved over the next months.\n\nShe had confirmed disease progression after 6 months of surveillance, with local recurrence, omental nodules, and liver lesions. She was commenced on 2nd line FOLFOX. The 1st cycle of chemotherapy was not well tolerated with severe diarrhoea and nausea, leading to a dose reduction for 2nd cycle to 80%. She suffered similar toxicities after the 2nd cycle, including grade 3 mucositis. Following this, she was not prepared to continue with chemotherapy and opted for best supportive care.\n\nDiscussion\nCardiotoxicity is a well-known side effect of various antineoplastic agents like anthracyclines and 5-fluorouracil chemotherapy agents. Many newer biologic therapies are also considered potentially cardiotoxic, e.g. trastuzumab and rituximab, but cardiotoxicity is not a commonly reported side effect of gemcitabine monotherapy [4]. It should be used with caution in patients with liver, kidney, or cardiovascular disorders. In rare cases it may cause posterior reversible encephalopathy syndrome, capillary leak syndrome, severe lung conditions like pulmonary oedema, pneumonia, and adult respiratory distress syndrome [5, 6].\n\nThere have been case reports in the literature of acute myocardial infarction, arrhythmias like SVT and pericarditis following the use of gemcitabine but there is a paucity of data on gemcitabine-induced cardiomyopathy. Shrum et al. [7] published a retrospective analysis of the case notes of 156 patients to further investigate and assess clinical features which may predispose patients to developing new-onset gemcitabine-induced cardiomyopathy. All of the patients had received gemcitabine for various cancers in 1st or subsequent lines of treatment, 51 patients in ovarian cancer, and 105 patients with breast, lung, pancreas, and bladder cancer. Patients with new-onset congestive heart failure were compared with patients without new-onset congestive heart failure with the use of Wilcoxon rank-sum test and the Fisher exact test. 4.5% of patients developed new-onset congestive cardiac failure, which is more than previously reported (0.76% in the early phase trials) [8]. This patient cohort did not differ much in baseline characteristics such as age, weight, parity, body mass index, prior therapy with Adriamycin or smoking history. Interestingly, a comorbidity of diabetes mellitus and coronary artery disease was more common in addition to having received a total dose of > 17,000 mg/m2 in patients who developed new-onset congestive heart failure with gemcitabine. The authors therefore recommended additional follow-up for surveillance and screening of cardiac toxicity for all patients who have received > 15,000 mg/m2 of gemcitabine.\n\nThe French PharmacoVigilance Database (FPVD) also identified gemcitabine as one of the drugs [9] which causes drug-induced cardiomyopathy following a retrospective analysis of case reports over 16 years between 1 January 1990 and 30 June 2007; anthracyclines were used as control. A total of 258,729 adverse drug reactions were recorded; 47 were defined as dilated cardiomyopathy. A significant reporting odds ratio was found with cytotoxic agents such as epirubicin, mitoxantrone, cyclophosphamide, gemcitabine, and fluorouracil. Despite limitations of the retrospective analysis, the above study highlighted that agents like gemcitabine deemed safe from cardiotoxicity could represent a new pharmacovigilance signal and could contribute to establish further prospective studies in order to confirm such signals.\n\nKhan et al. [10] published a comprehensive literature review and case report of gemcitabine-induced cardiomyopathy as a late or chronic side effect and other acute cardiac events. Acute cardiac events were described as myocardial infarct, angina, and/or arrhythmias. The exact mechanism of cardiac damage causing cardiomyopathy remains unknown.\n\nRecently Mohebali et al. [11] described a case report of an elderly patient who had received multiple lines of chemotherapy, had stable cardiac function prior to commencing rituximab, gemcitabine, and oxaliplatin (R-Gem-Ox) for relapsed diffuse large B cell lymphoma and was admitted with symptoms of cardiac failure. The authors hypothesized that the patient was suffering from a multi-hit mechanism of cardiac muscle damage by potentially non-cardiotoxic agents resulting ultimately in cardiomyopathy.\n\nIn the current age of the availability of electronic information and social media, eHealthMe, a personalized health information app, has been available to patients to help them look up potential side effects reported by patients of the same gender, age, etc. Up to 1 May 2017, 13,900 people, reported to have experienced side effects when taking gemcitabine. Among them, 30 people (0.22%) had cardiomyopathy, especially male patients, 60+ years old (incidence 47.37%) who had been taking the drug for 1–6 months (66.67%), were on frusemide (23.33%), and had pancreatic carcinoma (13.33%).\n\nConclusion\nAll 3 patients in our case series with reported cardiac toxicity improved following withdrawal of gemcitabine treatment. Stopping gemcitabine treatment in cases of potential cardiotoxicity should be the 1st step in the management of these patients. An echocardiogram prior to starting treatment in patients more than 50 years of age with diabetes mellitus and previous coronary artery disease may also be warranted. Further research to look into the mechanism of gemcitabine cardiotoxicity is required. Additionally, as suggested in the literature, patients who have received a dose higher than 15,000 mg/m2 should be screened for cardiotoxicity whilst continuing surveillance.\n\nStatement of Ethics\nPatient consent was obtained for publication.\n\nDisclosure Statement\nWe have no conflict of interest to disclose.\n\nFunding Sources\nNo funding was required for this case series.\n==== Refs\nReferences\n1 Plunkett W Huang P Xu YZ Heinemann V Grunewald R Gandhi V Gemcitabine: metabolism, mechanisms of action, and self-potentiation. Semin Oncol. 1995 8 22 (4 Suppl 11) 3 10 \n2 Aapro MS Martin C Hatty S Gemcitabine – a safety review. Anticancer Drugs. 1998 3 9 (3) 191 201 9625429 \n3 Carmichael J Fink U Russell RC Spittle MF Harris AL Spiessi G Phase II study of gemcitabine in patients with advanced pancreatic cancer. Br J Cancer. 1996 1 73 (1) 101 105 8554969 \n4 Mattiucci GC Ippolito E D'Agostino GR Alfieri S Antinori A Crucitti A Long-term analysis of gemcitabine-based chemoradiation after surgical resection for pancreatic adenocarcinoma. Ann Surg Oncol. 2013 2 20 (2) 423 429 23208130 \n5 Gemcitabine ‘UK label.’ UK Electronic Medicines Compendium. 5 June 2014 [cited 2017 May 6].\n6 ‘Gemcitabine.’ Macmillan Cancer Support. 2017 [cited 2017 May 6].\n7 Shrum KJ Gill SE Thompson LK Blackhurst DW Puls LE New-onset congestive heart failure with gemcitabine in ovarian and other solid cancers. Am J Clin Oncol. 2014 8 37 (4) 364 368 23357971 \n8 Storniolo AM Allerheiligen SR Pearce HL Preclinical and phase I studies of gemcitabine. Semin Oncol. 1997 4 24 (2 Suppl 7) S7 2 \n9 Montastruc G Favreliere S Sommet A Pathak A Lapeyre-Mestre M Perault-Pochat MC French Association of Regional PharmacoVigilance Centres. Drugs and dilated cardiomyopathies: a case/noncase study in the French PharmacoVigilance Database. Br J Clin Pharmacol. 2010 3 69 3 287 294 20233200 \n10 Khan MF Gottesman S Boyella R Juneman E Gemcitabine-induced cardiomyopathy: a case report and review of the literature. J Med Case Reports. 2014 6 8 (1) 220 \n11 Mohebali D Matos J Chang JD Gemcitabine induced cardiomyopathy: a case of multiple hit cardiotoxicity. ESC Heart Fail. 2017 2 4 (1) 71 74 28217315\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "11(1)",
"journal": "Case reports in oncology",
"keywords": "Cardiotoxicity; Gemcitabine; Pancreatic cancer",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "221-227",
"pmc": null,
"pmid": "29805372",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "7481842;23357971;23208130;28217315;9194473;20233200;9625429;24957905;8554969",
"title": "Gemcitabine-Induced Cardiotoxicity in Patients Receiving Adjuvant Chemotherapy for Pancreatic Cancer: A Case Series.",
"title_normalized": "gemcitabine induced cardiotoxicity in patients receiving adjuvant chemotherapy for pancreatic cancer a case series"
} | [
{
"companynumb": "GB-DRREDDYS-USA/UKI/18/0098539",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
... |
{
"abstract": "We report a case of a new diagnosis of HIV with an extremely high viral load presenting with HIV encephalopathy, in a 54-year-old woman who had been treated with 2 years of extended high-dose immunosuppressant therapy for a recalcitrant pruritic rash before diagnosis.",
"affiliations": "Department of Infection and Immunology, Royal London Hospital, London, UK.;North Middlesex Hospital, London, UK.;Department of Sexual Health, Barking Community Hospital, London, UK.",
"authors": "Flanagan|Stuart|S|;De Saram|Sophia|S|;Dhairyawan|Rageshri|R|",
"chemical_list": "D019380:Anti-HIV Agents; D000069480:Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; D007166:Immunosuppressive Agents; D000068898:Raltegravir Potassium; D011239:Prednisolone; D019438:Ritonavir; D000069454:Darunavir",
"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": "D015526:AIDS Dementia Complex; D019380:Anti-HIV Agents; D044383:Blacks; D018791:CD4 Lymphocyte Count; D000069454:Darunavir; D057210:Delayed Diagnosis; D003876:Dermatitis, Atopic; D000069480:Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; D005260:Female; D015497:HIV-1; D006801:Humans; D007166:Immunosuppressive Agents; D008875:Middle Aged; D011237:Predictive Value of Tests; D011239:Prednisolone; D000068898:Raltegravir Potassium; D019438:Ritonavir; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26604225",
"pubdate": "2015-11-24",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24641299;24556869;16140574;7684876;12126821;25005147;15717259;9925811",
"title": "Extremely high HIV-1 viral load in a patient with undiagnosed clinical indicator disease for HIV infection.",
"title_normalized": "extremely high hiv 1 viral load in a patient with undiagnosed clinical indicator disease for hiv infection"
} | [
{
"companynumb": "PHHY2016GB010269",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Imatinib, a tyrosine kinase inhibitor has improved survival in pediatric patients with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia. There are no formal drug interactions listed between methotrexate and tyrosine kinase inhibitors. Four pediatric patients with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia had delayed methotrexate clearance during their first cycle of high-dose methotrexate while receiving imatinib, resulting in acute kidney injury. For subsequent high-dose methotrexate cycles, imatinib was withheld resulting in decreased acute kidney injury, shorter time to methotrexate clearance, less toxicity, and shorter hospitalizations. For pediatric patients with acute lymphoblastic leukemia receiving imatinib, we recommend escalated supportive care measures including increased hyperhydration and leucovoruin frequency. For patients with toxicities secondary to delayed clearance or need for glucarpidase, we recommend holding imatinib with subsequent high-dose methotrexate courses.",
"affiliations": "Department of Pediatrics, Division of Hematology/Oncology/Blood and Marrow Transplantation, Medical College of Wisconsin and Children's Milwaukee, Milwaukee, WI.;Department of Pediatrics, Division of Hematology/Oncology/Blood and Marrow Transplantation, Medical College of Wisconsin and Children's Milwaukee, Milwaukee, WI.;Department of Pharmacy, Wolfson Children's Hospital.;Department of Pharmacy, Wolfson Children's Hospital.;Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York, NY.;Department of Pediatrics, Division of Pediatric Hematology/Oncology, Nemours Children's Specialty Care and Wolfson Children's Hospital Jacksonville, FL.;Department of Pediatrics, Division of Hematology/Oncology/Blood and Marrow Transplantation, Medical College of Wisconsin and Children's Milwaukee, Milwaukee, WI.",
"authors": "Pommert|Lauren|L|;Liberio|Nicole|N|;Ng|John S|JS|;Egelund|Tosha A|TA|;Siver|Molly J|MJ|;Katzenstein|Howard M|HM|;Burke|Michael J|MJ|",
"chemical_list": "D000068877:Imatinib Mesylate; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000001816",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "43(2)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D058186:Acute Kidney Injury; D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000068877:Imatinib Mesylate; D015448:Leukemia, B-Cell; D008297:Male; D008727:Methotrexate; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011379:Prognosis; D055815:Young Adult",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e296-e300",
"pmc": null,
"pmid": "32398599",
"pubdate": "2021-03-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Concurrent Imatinib Dosing With High-dose Methotrexate Leads to Acute Kidney Injury and Delayed Methotrexate Clearance in Pediatric Patients With Philadelphia Chromosome-positive B-Cell Acute Lymphoblastic Leukemia.",
"title_normalized": "concurrent imatinib dosing with high dose methotrexate leads to acute kidney injury and delayed methotrexate clearance in pediatric patients with philadelphia chromosome positive b cell acute lymphoblastic leukemia"
} | [
{
"companynumb": "US-TEVA-2021-US-1914944",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPARAGINASE"
},
"drugadditional": "3",
... |
{
"abstract": "A 53-year-old male patient was diagnosed with squamous cell carcinoma of buccal mucosa with synchronous diffuse peritoneal carcinomatosis, a very rare presentation for oral cancer. His disease was highly resistant to intensive systemic chemotherapy and progressed rapidly. So far as we know, there were only five cases with peritoneal involvement by metastatic head and neck cancer reported prior to this patient in the English literature. Immunohistochemistry study revealed that tumour specimens from both oral cavity and peritoneum were negative for tumour necrosis factor alpha and CD24 but positive for CD44 and CD36. These four molecules have been disclosed to be involved in the process of peritoneal metastasis from ovarian cancer. Their roles in the metastatic pathway and possible therapeutic policy targeting at them will be thoroughly discussed.",
"affiliations": "Section of Haematology and Oncology, Department of Medicine, Ministry of Health and Welfare Changhua Hospital, 80, Sec. 2, Chung-Jeng Rd, Pu-Shin Township, Chang-Hua County, 51341, Taiwan.;Department of Pathology, Ministry of Health and Welfare Changhua Hospital, 80, Sec. 2, Chung-Jeng Rd, Pu-Shin Township, Chang-Hua County, 51341, Taiwan.",
"authors": "Fan|Frank S|FS|;Yang|Chung-Fan|CF|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3332/ecancer.2019.954",
"fulltext": "\n==== Front\nEcancermedicalscienceEcancermedicalscienceecancermedicalscienceecancermedicalscience1754-6605Cancer Intelligence 10.3332/ecancer.2019.954can-13-954Case ReportSynchronous peritoneal carcinomatosis from a buccal squamous cell carcinoma: a case report focusing on possible metastatic mechanisms and novel therapeutic modalities Fan Frank S 1Yang Chung-Fan 2\n1 Section of Haematology and Oncology, Department of Medicine, Ministry of Health and Welfare Changhua Hospital, 80, Sec. 2, Chung-Jeng Rd, Pu-Shin Township, Chang-Hua County, 51341, Taiwan\n2 Department of Pathology, Ministry of Health and Welfare Changhua Hospital, 80, Sec. 2, Chung-Jeng Rd, Pu-Shin Township, Chang-Hua County, 51341, Taiwan\na https://orcid.org/0000-0002-8123-6941\nb https://orcid.org/0000-0002-7366-4380Correspondence to: Frank S Fan fantast.fan@msa.hinet.net2019 29 7 2019 13 95403 2 2019 © the authors; licensee ecancermedicalscience.2019This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.A 53-year-old male patient was diagnosed with squamous cell carcinoma of buccal mucosa with synchronous diffuse peritoneal carcinomatosis, a very rare presentation for oral cancer. His disease was highly resistant to intensive systemic chemotherapy and progressed rapidly. So far as we know, there were only five cases with peritoneal involvement by metastatic head and neck cancer reported prior to this patient in the English literature. Immunohistochemistry study revealed that tumour specimens from both oral cavity and peritoneum were negative for tumour necrosis factor alpha and CD24 but positive for CD44 and CD36. These four molecules have been disclosed to be involved in the process of peritoneal metastasis from ovarian cancer. Their roles in the metastatic pathway and possible therapeutic policy targeting at them will be thoroughly discussed.\n\nperitoneal carcinomatosisbuccal cancersquamous cell carcinomametastatic mechanismCD44CD36\n==== Body\nIntroduction\nCancer metastasis to the peritoneal cavity is not an uncommon phenomenon. According to a study based on the Swedish Family-Cancer Database containing 179,581 patients with metastatic cancer, the most common primary sites of peritoneal metastasis are ovary, breast and other genital organs in females; liver and prostate in males; colorectum, pancreas and stomach in both genders [1]. The incidence of peritoneal metastasis from a primary site in the upper aerodigestive tract is, however, extremely rare. An analysis of the National Cancer Registry of Ireland database also shows that over three quarters of the extra-abdominal primary sites for peritoneal metastasis are breast, lung and melanoma without mention of head and neck cancer [2].\n\nIn this case report, we present a middle-aged male patient with synchronous extensive peritoneal carcinomatosis from a squamous cell carcinoma in the oral cavity at the time of diagnosis. To the best of our knowledge, there are only five cases with peritoneal cavity metastasis from squamous cell head and neck cancer reported previously in the English literature, four from hypopharynx and one from larynx, respectively [3–6]. We did a small study to investigate the possible mechanisms of this unusual type of metastasis with immunohistochemical staining focusing on four important molecules recently revealed to be involved in the process of peritoneal metastasis from ovarian cancer. Our purpose is to see whether a squamous cell carcinoma could adopt similar mechanisms in constituting its metastatic pathway.\n\nCase presentation\nA 53-year-old man was brought to our emergency unit with the chief complaint of abdomen fullness for 3 days in October 2018. There was no fever, vomiting, diarrhoea or constipation. He was a hepatitis B virus carrier and had a long history of hypertension without regular control. Alcohol abuse, cigarette smoking and betel nut chewing were all denied by himself. On physical examination, the abdomen was distended with detectable normal bowel sounds. Rebounding pain and muscle guarding were absent.\n\nLaboratory data were remarkable for a thrombocytosis and a leucocytosis with a shift-to-left phenomenon: white cell count 17,400/μl, haemoglobin 14.3, g/dl, platelet count 490,000/μl, segments 72%, lymphocytes 6%, band forms 9%, metamyelocytes 3% and myelocytes 3%. His liver and renal functions were within normal limits but the hypersensitive C-reactive protein level was ultrahigh: 37.262 mg/dl (normal 0 ~ 0.748).\n\nNo obvious active lung lesions were noted in the chest X-ray routine film but somewhat haziness shadow was detected over the central abdomen in the kidney-ureter-bladder film. A computed tomography (CT) disclosed ascites accumulation in addition to dirty thickening and heterogeneous fat stranding of peritoneum and mesentery (Figure 1). There were no tumours in the pancreas and biliary system.\n\nA diagnostic laparoscopy was performed under the impression of tuberculous peritonitis or peritoneal carcinomatosis. After drainage of intra-abdominal abscess-like fluid, excision biopsy of peritoneal nodules was done. Study of the ascites resulted in no evidence of tuberculous infection but a suspicion of malignancy with unidentified nature. On the other hand, serum tumour marker tests did not show any abnormality for alpha foetal protein, carcinoembryonic antigen, cancer antigen 19-9 and prostate specific antigen.\n\nSince the initial pathologic study of the peritoneum specimen was in favour of an epithelioid carcinoma, both upper gastrointestinal scopy and colonoscopy were arranged aiming at detecting a primary malignant lesion. However, only a shallow antral ulcer, moderate reflux esophagitis, mild internal haemorrhoids and several benign polyps along the whole colon and rectum were found.\n\nThe surgeon-in-charge then ordered a positron emission tomography/computed tomography (PET/CT) for discovering the hidden primary site. Much to his surprise and embarrassment, besides the predicted high uptake in the abdomen cavity (Figure 2), a 1.8-cm moderate uptake lesion over right lower buccal area appeared along with what presumed to be metastatic spots over right neck lymph nodes and vertebral bodies (Figure 3). A 2.5-cm right lower buccal ulcer with exophytic mass was subsequently disclosed by the oral surgeon and an incision biopsy led to a diagnosis of keratinizing squamous cell carcinoma (Figure 4).\n\nLater on, careful investigation of the peritoneal tumour let the pathologist decide that it was most likely also a squamous cell carcinoma with focal squamoid nests and severe acantholytic change very similar to the oral cavity lesion (Figure 5). The tumour cells were negative for cytokeratin 7 (CK7), cytokeratin 20 (CK20), thyroid transcription factor-1 (TTF-1) and muscarmine (Figure 6) but positive for cytokeratin 5/6 (CK5/6) and p40 (Figure 7) in histochemistry and immunohistochemistry studies. Thus, a diagnosis of peritoneal carcinomatosis from a buccal cancer was confidently established according to modern recommendations [7, 8]. Immunohistochemistry staining for p16INK4a, a surrogate biomarker for human papillomavirus infection [9], was negative in both the primary and peritoneal metastatic sites. The possibility of a primary peritoneal mesothelioma could be excluded based on the negative immunohistochemical staining results for calretinin, Wilms’ tumour 1 (WT1), Hector Battifora mesothelial-1 (HBME-1) and podoplanin (D2-40) [10] (Figure 8).\n\nAfter the patient’s surgical condition was over, he was transferred to the medical oncology ward for systemic chemotherapy. Intravenous cisplatin (50 mg/m2) and docetaxel (50 mg/m2) were given once, followed by continuous fluorouracil (1,000 mg/m2/day) for five consecutive days. This regimen was modified from what was adopted in the TAX 324 trial [11] for reducing toxicity in accordance with our past experience in treating patients who indulged in betel nut chewing, cigarette smoking, and heavy alcohol drinking. On the third day of chemotherapy, hypercalcemia was noted and the serum calcium level was immediately brought down by one dose of zoledronic acid (4 mg). Nevertheless, the tumour did not respond to chemotherapy and the patient’s general condition and conscious level deteriorated rapidly. A second course of chemotherapy with gemcitabine (1,000 mg/m2) and oxaliplatin (130 mg/m2) was given as a rescue 3 weeks after the first one. Unfortunately, there was still no response and the patient expired due to multiple organ failure.\n\nBased on our interest in the uncommon primary site for a peritoneal carcinomatosis, immunohistochemistry study of the tumour specimens was performed to see if the tumour had adopted some characteristics antecedently found functioning in the development of peritoneal metastasis from ovarian cancer. Tumour cells from both the primary site and the peritoneum turned out to be negative for tumour necrosis factor alpha (TNFα) and CD24 (Figure 9), but positive for CD44 and CD36 (Figure 10).\n\nDiscussion\nIntraperitoneal metastasis is a very complex outgrowth containing elements of cell proliferation, epithelial-mesenchymal transition, migration, adhesion, invasion and angiogenesis. Interaction between cancer cells and target site microenvirment involves matrix metalloproteinase, inflammatory cytokines, adhesion molecules, immunosuppressors, growth factors, vascular endothelial growth factors and their receptors in making the metastatic niches relatively compatible ‘soil’ for the ‘seeds’ [12].\n\nOvarian cancer is notably characterised by peritoneal carcinomatosis. The cellular and molecular processes including dissemination from primary tumour, haematogenous metastasis, signalling network between cancer cells and tumour-associated immune cells in the ascites and microenvironment have been intensively investigated [13, 14]. After reviewing recent literature, we focused our interest on TNFα, CD24, CD44, and CD36 to see if these four distinct molecules previously discovered to play important roles in ovarian cancer metastasis might also be detected in this patient’s oral cancer cells.\n\nA loop of cancer-stroma-cancer interaction in omental microenvironment has been proposed to promote peritoneal metastasis of ovarian cancer via TNFα-transforming growth factor-alpha (TGFa)-epidermal growth factor receptor (EGFR) communication [15]. As disclosed in the experiments, TNFα overexpressed and secreted by ovarian cancer cells induces TGFa expression in normal omental stromal fibroblasts through nuclear factor-κB (NF-κB) signalling. TGFa from the fibroblasts then promotes ovarian cancer colonisation in omentum through the activation of EGFR. Our patient’s oral cancer, however, does not express TNFα in either the primary site or the metastatic peritoneum, thus declining the presence of a TNFα-TNFα-EGFR loop in its metastatic process and also the possibility of using anti-TNFα agents as a therapeutic policy formerly reported to be beneficial in other cancer types [16, 17].\n\nCD24 is a small sialoglycoprotein localised on cell surface of many tumours including ovarian cancer. It has been identified to be a cancer stem cell marker in ovarian cancer [18] and a poor prognosis predictor associated with regulation of epithelial-mesenchymal-transition which facilitates migration of cancer cells [19]. After binding to its ligand, P-selectin, CD24 exerts its function through activation of JAK2 kinase and phosphorylation of STAT3. Inhibition of JAK2 induces cytotoxicity of CD24-expressed ovarian cancer cells and increases survival of animals carrying CD24-positive tumours, supporting JAK2 as a therapeutic target for cancer cells expressing CD24 [20]. Nonetheless, our patient’s peritoneal metastatic specimen is negative for CD24, making this strategy not applicable.\n\nCD44 is a cell membrane glycoprotein receptor with hyaluronan, a glycosaminoglycan component of the extracellular matrix, as its ligand. Upon activation, CD44 mediates and propagates self-renewal, stemness, epithelial-mesenchymal transition, migration, invasion, metastasis, and most importantly, resistance to chemotherapy, radiotherapy, endocrine and targeted therapy [21]. It has been recognised as a remarkable cancer stem cell marker for many kinds of malignancy including ovarian cancer and head and neck cancer [22]. Experiments have shown that inhibition of cancer cells’ CD44 function could reverse their malignant behaviour and sensitise them to therapy [23]. For example, antibody against CD44 was able to inhibit migration of breast cancer cells [24] and eradicate acute myeloid leukaemia stem cells [25]. Accordingly, the extraordinary chemoresistance of our patient’s carcinomatosis is thus reasonably assumed to be correlated well with its strong expression of CD44 and therapy aiming at CD44, once becoming a clinical reality, surely will provide great help for patients like ours.\n\nCD36 is a multifunctional glycoprotein on various types of cells. It has been disclosed to be a scavenger receptor for thrombospondin-1, specific oxidised phospholipids, modified low-density lipoproteins, apoptotic cells, certain bacterial and fungal pathogens [26]. CD36 also functions in uptake of long chain fatty acid and activates signal transduction upon binding with fatty acid [27]. In this regard, exogenous fatty acid absorption has been proved capable of promoting breast cancer cell growth via CD36 [28]. On the other hand, omental adipocytes were able to fuel gastric cancer cells and probably enhanced omentum metastasis through upregulation of CD36 [29].\n\nFurthermore, rather than only an energy supply, elevated fatty acid uptake through CD36 could also stimulate epithelial-mesenchymal transition in hepatocellular carcinoma and causatively facilitate metastasis [30]. Similar findings were detected in the experiment with ovarian cancer. CD36 expression induced by adipocytes drives ovarian cancer progression and metastasis to adipocyte-rich microenvironment in peritoneum. Intraperitoneal injection of anti-CD36 antibody effectively reduce tumour burden in mouse xenograft [31]. Most excitingly, in a human oral cancer model, anti-CD36 antibody treatment completely blocked the metastatic potential of CD36-positive cancer cells in mouse [32], reminding us of the hopeful capacity of anti-CD36 monoclonal antibody in treating malignancies like our patient’s.\n\nConclusion\nWhat we have not achieved well in the field of cancer treatment is to eradicate cancer stem cells, especially in metastatic sites and overcome drug resistance. Deeper understanding about metastatic mechanisms might reveal more key molecules in cancer stemness, migration, invasion and metastasis. Novel therapeutic modalities designed for attacking targets like TNFα, CD24, CD44 and CD36 are under aggressive development. Careful survey of cancer specimens for these biomarkers is expected to be helpful in identifying targetable antigens. The study in this patient provides an example of this ambitious kind of approach albeit awaiting more clinical trials to make efficacious treatments a reality.\n\nConflict of interest\nThe authors have no conflicts of interest.\n\nFunding\nThere is no financial support for this report.\n\nConsent\nThe patient was single. Written informed consent was obtained from the patient’s younger brother 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\nFigure 1. CT scan showing extensive dirty thickening of the peritoneum, fatty stranding and ascites accumulation in the abdomen cavity.\nFigure 2. PET/CT scan showing diffuse uptake over peritoneal space (SUVmax from 5.6 to 6.4).\nFigure 3. PET/CT scan. (A) A 1.8-cm lesion with moderate uptake over right lower buccal/gingival area with an avid metastatic lesion over spine. (B and C) Lymph node metastases over right neck.\nFigure 4. Squamous cell carcinoma of right lower buccal mucosa within oral cavity (haematoxylin and eosin stain). (A) Keratinizing large-sized polygonal tumour cells with abundant glassy/eosinophilic cytoplasm and pleomorphic nuclei, arranged in solid nests (×200). (B) Prominent acantholytic change in certain areas (×400).\nFigure 5. Metastatic squamous cell carcinoma over peritoneum (hematoxylin and eosin stain). (A) Neoplastic cells bearing high nucleus/cytoplasm ratio, pleomorphic nuclei and occasional nucleoli forming focal squamoid nests (×200). (B) Acantholytic change similar to that seen in buccal carcinoma specimen, resulting in glandular pattern with some detached or apoptotic tumour cells in the lumen-like structure (×400).\nFigure 6. Metastatic squamous cell carcinoma over peritoneum. Negative immunohistochemical staining for (A) CK7, (B) CK20 and (C) TTF-1. (D) Negative histochemical staining for mucicarmine.\nFigure 7. Metastatic squamous cell carcinoma over peritoneum. Positive immunohistochemical staining for (A) CK5/6 and (B) p40.\nFigure 8. Metastatic squamous cell carcinoma over peritoneum. Negative immunohistochemical staining for (A) calretinin, (B) WT1, (C) HBME-1 and (D) D2-40.\nFigure 9. Negative immunohistochemical staining for (A, B) TNFα and (C, D) CD24 in (A and C) primary buccal squamous cell carcinoma and (B and D) metastatic squamous cell carcinoma over peritoneum.\nFigure 10. Positive immunohistochemical staining for (A, B) CD44 and(C, D) CD36 in (A and C) primary buccal squamous cell carcinoma and (B and D) metastatic squamous cell carcinoma over peritoneum.\n==== Refs\nReferences\n1. Riihimäki M Thomsen H Sundquist K Clinical landscape of cancer metastases Cancer Med 2018 7 5534 5542 10.1002/cam4.1697 30328287 \n2. Flanagan M Solon J Chang KH Peritoneal metastases from extra-abdominal cancer—a population-based study Eur J Surg Oncol 2018 44 1811 1817 10.1016/j.ejso.2018.07.049 30139510 \n3. Hsu CL Wang HM Lee CS Hypopharyngeal carcinoma with clinical peritoneal carcinomatosis: a report of two patients Am J Clin Oncol 1998 21 362 365 10.1097/00000421-199808000-00009 9708634 \n4. Stebbing J Crane J Greenstein AS Atypical metastases from squamous cell cancers Ground Rounds 2002 2 43 45 \n5. Wong ZW Leong SS Tan T A case of metastatic squamous cell carcinoma of the hypopharynx manifesting as acute abdomen Ann Acad Med Singapore 2004 33 356 358 15175779 \n6. Wakasaki T Omori H Sueyoshi S A case of peritoneal metastasis during treatment for hypopharyngeal squamous cell carcinoma World J Surg Oncol 2016 14 265 10.1186/s12957-016-1025-z 27756320 \n7. Massard C Loriot Y Fizazi K Carcinomas of an unknown primary origin–diagnosis and treatment Nat Rev Clin Oncol 2011 8 701 710 10.1038/nrclinonc.2011.158 22048624 \n8. Lewis JS Jr Chernock RD Bishop JA Squamous and neuroendocrine specific immunohistochemical markers in head and neck squamous cell carcinoma: a tissue microarray study Head Neck Pathol 2018 12 62 70 10.1007/s12105-017-0825-y 28528398 \n9. Prigge ES Arbyn M von Knebel Doeberitz M Diagnostic accuracy of p16INK4a immunohistochemistry in oropharyngeal squamous cell carcinomas: a systematic review and meta-analysis Int J Cancer 2017 140 1186 1198 10.1002/ijc.30516 27859245 \n10. Husain AN Colby TV Ordóñez NG Guidelines for pathologic diagnosis of malignant mesothelioma 2017 update of the consensus statement from the international mesothelioma interest group Arch Pathol Lab Med 2018 142 89 108 10.5858/arpa.2017-0124-RA 28686500 \n11. Lorch JH Goloubeva O Haddad RI Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial Lancet Oncol 2011 12 153 159 10.1016/S1470-2045(10)70279-5 21233014 \n12. Mikuła-Pietrasik J Uruski P Tykarski A The peritoneal “soil” for a cancerous “seed”: a comprehensive review of the pathogenesis of intraperitoneal cancer metastases Cell Mol Life Sci 2018 75 509 525 10.1007/s00018-017-2663-1 28956065 \n13. Yeung TL Leung CS Yip KP Cellular and molecular processes in ovarian cancer metastasis. A review in the theme: cell and molecular processes in cancer metastasis Am J Physiol Cell Physiol 2015 309 C444 C456 10.1152/ajpcell.00188.2015 26224579 \n14. Worzfeld T Pogge von Strandmann E Huber M The unique molecular and cellular microenvironment of ovarian cancer Front Oncol 2017 7 24 10.3389/fonc.2017.00024 28275576 \n15. Lau TS Chan LK Wong EC A loop of cancer-stroma-cancer interaction promotes peritoneal metastasis of ovarian cancer via TNFα-TGFα-EGFR Oncogene 2017 36 3576 3587 10.1038/onc.2016.509 28166193 \n16. Zhao X Fan W Xu Z Inhibiting tumor necrosis factor-alpha diminishes desmoplasia and inflammation to overcome chemoresistance in pancreatic ductal adenocarcinoma Oncotarget 2016 7 81110 81122 10.18632/oncotarget.13212 27835602 \n17. Li W Jian YB Antitumor necrosis factor-α antibodies as a novel therapy for hepatocellular carcinoma Exp Ther Med 2018 16 529 536 30116311 \n18. Tarhriz V Bandehpour M Dastmalchi S Overview of CD24 as a new molecular marker in ovarian cancer J Cell Physiol 2019 234 2134 2142 10.1002/jcp.27581 30317611 \n19. Nakamura K Terai Y Tanabe A CD24 expression is a marker for predicting clinical outcome and regulates the epithelial-mesenchymal transition in ovarian cancer via both the Akt and ERK pathways Oncol Rep 2017 37 3189 3200 10.3892/or.2017.5583 28440503 \n20. Burgos-Ojeda D Wu R McLean K CD24+ ovarian cancer cells are enriched for cancer-initiating cells and dependent on JAK2 signaling for growth and metastasis Mol Cancer Ther 2015 14 1717 1727 10.1158/1535-7163.MCT-14-0607 25969154 \n21. Chanmee T Ontong P Kimata K Key roles of hyaluronan and its CD44 receptor in the stemness and survival of cancer stem cells Front Oncol 2015 5 180 10.3389/fonc.2015.00180 26322272 \n22. Bourguignon LYW Earle C Shiina M Activation of matrix hyaluronan-mediated CD44 signaling, epigenetic regulation and chemoresistance in head and neck cancer stem cells Int J Mol Sci 2017 18 E1849 10.3390/ijms18091849 28837080 \n23. Xu H Tian Y Yuan X The role of CD44 in epithelial-mesenchymal transition and cancer development Onco Targets Ther 2015 8 3783 3792 26719706 \n24. Uchino M Kojima H Wada K Nuclear beta-catenin and CD44 upregulation characterize invasive cell populations in non-aggressive MCF-7 breast cancer cells BMC Cancer 2010 10 414 10.1186/1471-2407-10-414 20696077 \n25. Jin L Hope KJ Zhai Q Targeting of CD44 eradicates human acute myeloid leukemic stem cells Nat Med 2006 12 1167 1174 10.1038/nm1483 16998484 \n26. Silverstein RL Febbraio M CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior Sci Signal 2009 2 72 re3 10.1126/scisignal.272re3 19471024 \n27. Pepino MY Kuda O Samovski D Structure-function of CD36 and importance of fatty acid signal transduction in fat metabolism Annu Rev Nutr 2014 34 281 303 10.1146/annurev-nutr-071812-161220 24850384 \n28. Zhao J Zhi Z Wang C Exogenous lipids promote the growth of breast cancer cells via CD36 Oncol Rep 2017 38 2105 2115 10.3892/or.2017.5864 28765876 \n29. Tan Y Lin K Zhao Y Adipocytes fuel gastric cancer omental metastasis via PITPNC1-mediated fatty acid metabolic reprogramming Theranostics 2018 8 5452 5468 10.7150/thno.28219 30555557 \n30. Nath A Li I Roberts LR Elevated free fatty acid uptake via CD36 promotes epithelial-mesenchymal transition in hepatocellular carcinoma Sci Rep 2015 5 14752 10.1038/srep14752 26424075 \n31. Ladanyi A Mukherjee A Kenny HA Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis Oncogene 2018 37 2285 2301 10.1038/s41388-017-0093-z 29398710 \n32. Pascual G Avgustinova A Mejetta S Targeting metastasis-initiating cells through the fatty acid receptor CD36 Nature 2017 541 41 45 10.1038/nature20791 27974793\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1754-6605",
"issue": "13()",
"journal": "Ecancermedicalscience",
"keywords": "CD36; CD44; buccal cancer; metastatic mechanism; peritoneal carcinomatosis; squamous cell carcinoma",
"medline_ta": "Ecancermedicalscience",
"mesh_terms": null,
"nlm_unique_id": "101392236",
"other_id": null,
"pages": "954",
"pmc": null,
"pmid": "31645882",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "26719706;15175779;28528398;16998484;25969154;9708634;28686500;26322272;20696077;28765876;28166193;28440503;19471024;30328287;21233014;27835602;27756320;30116311;28837080;30317611;26224579;27974793;28275576;27859245;30139510;30555557;22048624;28956065;24850384;26424075;29398710",
"title": "Synchronous peritoneal carcinomatosis from a buccal squamous cell carcinoma: a case report focusing on possible metastatic mechanisms and novel therapeutic modalities.",
"title_normalized": "synchronous peritoneal carcinomatosis from a buccal squamous cell carcinoma a case report focusing on possible metastatic mechanisms and novel therapeutic modalities"
} | [
{
"companynumb": "TW-MYLANLABS-2019M1093013",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GEMCITABINE"
},
"drugadditional": null,
... |
{
"abstract": "Pachychoroid pigment epitheliopathy (PPE) is considered to be a forme fruste of central serous chorioretinopathy. Tamoxifen (Soltamax; Midatech Pharma, Raleigh, NC) has an anti-estrogenic effect on cytoplasmic estrogen receptors. Serum total testosterone, cortisol, and cortisone levels increase during tamoxifen therapy. Tamoxifen may cause hormone disturbance leading to the development of disorders in the pachychoroid spectrum. The authors present two cases of PPE associated with tamoxifen therapy. A 65-year-old woman (Patient 1) and a 52-year-old woman (Patient 2) had a recent history of tamoxifen therapy. PPE lesions were seen in both eyes of Patient 1 and in the right eye of Patient 2. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:838-842.].",
"affiliations": null,
"authors": "Ersoz|Mehmet Giray|MG|;Arf|Serra|S|;Karacorlu|Murat|M|;Hocaoglu|Mumin|M|;Muslubas|Isil Sayman|IS|",
"chemical_list": "D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen",
"country": "United States",
"delete": false,
"doi": "10.3928/23258160-20170928-10",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2325-8160",
"issue": "48(10)",
"journal": "Ophthalmic surgery, lasers & imaging retina",
"keywords": null,
"medline_ta": "Ophthalmic Surg Lasers Imaging Retina",
"mesh_terms": "D000368:Aged; D018931:Antineoplastic Agents, Hormonal; D015862:Choroid Diseases; D005260:Female; D006801:Humans; D008875:Middle Aged; D012164:Retinal Diseases; D013629:Tamoxifen",
"nlm_unique_id": "101599215",
"other_id": null,
"pages": "838-842",
"pmc": null,
"pmid": "29020429",
"pubdate": "2017-10-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pachychoroid Pigment Epitheliopathy Associated With Tamoxifen.",
"title_normalized": "pachychoroid pigment epitheliopathy associated with tamoxifen"
} | [
{
"companynumb": "TR-TEVA-2017-TR-826098",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TAMOXIFEN"
},
"drugadditional": "3",
"... |
{
"abstract": "Over the past decade, treatment options for patients with multiple myeloma (MM) have improved substantially, resulting in better response rates and prolonged overall survival (OS). Nevertheless, MM remains a challenging disease, especially if renal insufficiency (RI) or extensive pre-treatment aggravates the assignment of the optimal treatment schedule. In this retrospective study, we analyzed the outcome of lenalidomide plus dexamethasone in 167 patients with relapsed or refractory MM with focus on RI. The baseline creatinine clearance (CLCr) was normal in 94 patients (CLCr≥80 ml/min), while RI was observed in 73 patients, including 40 patients with mild RI (50≤CLCr<80 ml/min) and 33 patients with moderate or severe RI (CLCr<50 ml/min). Response rates declined depending on the severity of RI, being 67% among patients with normal kidney function, 60% among patients with mild RI and 49% among patients with moderate or severe RI. Time to progression (TTP) was significantly reduced in patients with severe RI and in case of >2 previous treatment lines. OS was not significantly different between patients with normal and impaired renal function. In contrast, the number of previous treatment lines (2 vs. <2) and the use of novel agents like bortezomib or thalidomide prior to lenalidomide plus dexamethasone therapy had a more adverse effect on OS. In conclusion, lenalidomide plus dexamethasone is an effective regimen for relapsed or refractory patients with MM complicated by RI with manageable toxicity.",
"affiliations": "Department of Internal Medicine V, Hematology and Oncology, University of Heidelberg, INF 410, 69120, Heidelberg, Germany. Ulrike.Klein2@med.uni-heidelberg.de",
"authors": "Klein|Ulrike|U|;Neben|Kai|K|;Hielscher|Thomas|T|;Heiss|Christiane|C|;Ho|Anthony D|AD|;Goldschmidt|Hartmut|H|",
"chemical_list": "D000970:Antineoplastic Agents; D013792:Thalidomide; D003907:Dexamethasone; D000077269:Lenalidomide",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-010-1080-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "90(4)",
"journal": "Annals of hematology",
"keywords": null,
"medline_ta": "Ann Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D017326:Clinical Trials, Phase III as Topic; D003907:Dexamethasone; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D051437:Renal Insufficiency; D012189:Retrospective Studies; D013792:Thalidomide; D016896:Treatment Outcome",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "429-39",
"pmc": null,
"pmid": "20857112",
"pubdate": "2011-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Lenalidomide in combination with dexamethasone: effective regimen in patients with relapsed or refractory multiple myeloma complicated by renal impairment.",
"title_normalized": "lenalidomide in combination with dexamethasone effective regimen in patients with relapsed or refractory multiple myeloma complicated by renal impairment"
} | [
{
"companynumb": "DE-CELGENE-DEU-2015070827",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nRecent studies have demonstrated that a single episode of acute kidney injury from a number of causes can increase the risk of severe long-term outcomes, including major cardiovascular events and death. We tested the hypothesis that patients who develop acute kidney injury consistent with contrast-induced nephropathy after contrast-enhanced computed tomography (CT) imaging are at increased risk of major adverse events at 1 year.\n\n\nMETHODS\nWe followed a prospective, heterogeneous cohort of consecutive emergency department patients undergoing contrast-enhanced CT for the outcomes of acute kidney injury consistent with contrast-induced nephropathy and major adverse events, defined as the combined outcome of death (all cause), renal failure, myocardial infarction, and stroke or other arterial vascular events, in any anatomic territory, requiring invention within 1 year. The primary outcome, major adverse events, was determined by the consensus of 2 of 3 blinded adjudicators.\n\n\nRESULTS\nWe followed 633 patients undergoing contrast-enhanced CT, of whom 11% developed acute kidney injury consistent with contrast-induced nephropathy and 15% (95/633; 95% confidence interval [CI] 12% to 18%) experienced at least 1 major adverse event within 1 year, including 7% (46/633; 95% CI 5% to 9%) who died. The development of acute kidney injury after contrast-enhanced CT was associated with an increased risk of 1-year major adverse event: the incident risk ratio was 4.01 (95% CI 2.61 to 6.05) and was 2.36 (95% CI 1.49 to 3.75) after adjusting for age, existing coronary artery disease, active malignancy, and 1 or more additional exposures to intravascular iodinated contrast media.\n\n\nCONCLUSIONS\nThe development of acute kidney injury after contrast-enhanced CT was associated with a 2-fold increase in 1-year major adverse events. Further research is needed to validate this observation.",
"affiliations": "Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN. Electronic address: alimitch@iu.edu.;Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN.;Department of Emergency Medicine, University of Mississippi Medical Center, Jackson, MS.;University of Tennessee, Chattanooga College of Medicine, Chattanooga, TN.",
"authors": "Mitchell|Alice M|AM|;Kline|Jeffrey A|JA|;Jones|Alan E|AE|;Tumlin|James A|JA|",
"chemical_list": "D003287:Contrast Media",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0196-0644",
"issue": "66(3)",
"journal": "Annals of emergency medicine",
"keywords": null,
"medline_ta": "Ann Emerg Med",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D003287:Contrast Media; D004636:Emergency Service, Hospital; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D011446:Prospective Studies; D051437:Renal Insufficiency; D012307:Risk Factors; D020521:Stroke; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8002646",
"other_id": null,
"pages": "267-274.e4",
"pmc": null,
"pmid": "26004770",
"pubdate": "2015-09",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Major Adverse Events One Year After Acute Kidney Injury After Contrast-Enhanced Computed Tomography.",
"title_normalized": "major adverse events one year after acute kidney injury after contrast enhanced computed tomography"
} | [
{
"companynumb": "US-BRACCO-012672",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IOPAMIDOL"
},
"drugadditional": null,
"drug... |
{
"abstract": "OBJECTIVE\nTo investigate the effects of rituximab (RTX) in children with steroid-dependent nephrotic syndrome.\n\n\nMETHODS\nFive cases of children with steroid-dependent nephrotic syndrome seen from May 2012 to February 2013 in whom only steroid plus calcineurin inhibitor was effective and the disease recurred on reduction of dose were enrolled into this study, including 3 males and 2 females. Calcineurin inhibitors were stopped and steroids was changed to full dose. After the general condition improved, RTX was given at a dose of 375 mg/m(2), once a week for a total of three times for one course. After urine protein became negative for five days, the dose of steroid was changed to 2 mg/kg every other day, thereafter the dose was reduced by 5 mg per every 2 weeks, until discontinuation. After regular monitoring, when peripheral blood B cells were ≥ 3%, a second RTX was added.\n\n\nRESULTS\nUrine protein was negative in 2-7 days in 5 patients after the first RTX treatment. Before treatment B lymphocytes in peripheral blood was 7.8% to 13.0% and after the first course of RTX treatment decreased to 0 in the first 6 to 8 months at the beginning of recovery, while in the first 7 to 10 months to 3.3%-6.1%, after a second RTX was given, B lymphocytes were reduced to 0, but in two cases (cases 1 and 3) B lymphocytes rose again at 16 and 17 months, in the first 17 and 18 months rose to 4.16% and 4.17%, RTX was given once again respectively. B lymphocytes were reduced to 0 again. Currently the 5 patients continued to be negative for urine protein, maintaining remission for 12 to 20 months.RTX infusion had no significant side effects, and side effects of steroid and calcineurin inhibitor disappeared.\n\n\nCONCLUSIONS\nIn children with steroid-dependent and only calcineurin inhibitor effective nephritic syndrome, relapse may still occur after improvement of nephrotic syndrome, after the first RTX treatment, regular monitoring of B lymphocytes, RTX supplementary treatment in advance can help discontinuation of steroids and immunosuppressive agents and maintain remission.",
"affiliations": "Department of Nephrology and Rheumatology, Bayi Children's Hospital Affiliated to Beijing Military Region General Hospital, Beijing 100700, China.;Department of Nephrology and Rheumatology, Bayi Children's Hospital Affiliated to Beijing Military Region General Hospital, Beijing 100700, China.;Department of Nephrology and Rheumatology, Bayi Children's Hospital Affiliated to Beijing Military Region General Hospital, Beijing 100700, China.;Department of Nephrology and Rheumatology, Bayi Children's Hospital Affiliated to Beijing Military Region General Hospital, Beijing 100700, China.;Department of Nephrology and Rheumatology, Bayi Children's Hospital Affiliated to Beijing Military Region General Hospital, Beijing 100700, China.",
"authors": "Huang|Jianping|J|;Du|Juan|J|;Wang|Shuo|S|;Xiao|Lili|L|;Zhao|Xiaoyan|X|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D058846:Antibodies, Monoclonal, Murine-Derived; D018941:Antigens, CD19; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D000069283:Rituximab",
"country": "China",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0578-1310",
"issue": "52(7)",
"journal": "Zhonghua er ke za zhi = Chinese journal of pediatrics",
"keywords": null,
"medline_ta": "Zhonghua Er Ke Za Zhi",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D058846:Antibodies, Monoclonal, Murine-Derived; D018941:Antigens, CD19; D001402:B-Lymphocytes; D065095:Calcineurin Inhibitors; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents; D018655:Lymphocyte Count; D008297:Male; D009404:Nephrotic Syndrome; D011507:Proteinuria; D012008:Recurrence; D012074:Remission Induction; D000069283:Rituximab; D016896:Treatment Outcome",
"nlm_unique_id": "0417427",
"other_id": null,
"pages": "521-4",
"pmc": null,
"pmid": "25224058",
"pubdate": "2014-07",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Treatment of children with steroid-dependent nephrotic syndrome with rituximab.",
"title_normalized": "treatment of children with steroid dependent nephrotic syndrome with rituximab"
} | [
{
"companynumb": "CN-MYLANLABS-2015M1005584",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": n... |
{
"abstract": "As the list of anti-tumor immunotherapy agents and the list of cancers treated by these novel agents grow, a subset of patients are experiencing immune-related adverse events as a result of prolonged stimulation of the immune system. Many different immune related adverse events including colitis, hepatitis, pneumonitis, thyroiditis, hypophysitis, and cutaneous reactions can result from blocking these inhibitory pathways. The full spectrum of cutaneous immune related adverse events secondary to checkpoint inhibitor therapy is still being defined. The reported varied presentations include lichenoid reactions and bullous pemphigoid, amongst others. We present a severe cutaneous reaction, a case of debilitating erosive lichenoid dermatitis. This case emphasizes both the wide range of possible cutaneous reactions and the potential severity of these reactions.",
"affiliations": "Department of Dermatology, University of California Davis School of Medicine, Sacramento, California. DTartar@ucdavis.edu.",
"authors": "Davis|Michael J|MJ|;Wilken|Reason|R|;Fung|Maxwell A|MA|;Tartar|Danielle M|DM|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C000594389:atezolizumab",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "24(4)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D003875:Drug Eruptions; D006801:Humans; D017512:Lichenoid Eruptions; D008175:Lung Neoplasms; D008297:Male",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29906009",
"pubdate": "2018-04-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Debilitating erosive lichenoid interface dermatitis from checkpoint inhibitor therapy.",
"title_normalized": "debilitating erosive lichenoid interface dermatitis from checkpoint inhibitor therapy"
} | [
{
"companynumb": "US-ROCHE-2152510",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ATEZOLIZUMAB"
},
"drugadditional": null,
"dr... |
{
"abstract": "Cyclin dependent kinases 4/6 (CDK4/6) inhibitors gained an essential role in the treatment of metastatic breast cancer. Nevertheless, data regarding their use in combination with radiotherapy are still scarce. We performed a retrospective preliminary analysis of breast cancer patients treated at our Center with palliative radiation therapy and concurrent CDK4/6 inhibitors. Toxicities were measured according to CTCAE 4.0, local response according to RECIST 1.1 or PERCIST 1.0 and pain control using verbal numeric scale. 18 patients (32 treated sites) were identified; 50% received palbociclib, 33.3% ribociclib and 16.7% abemacliclib. Acute non-hematologic toxicity was fair, with the only exception of a patient who developed G3 ileitis. During 3 months following RT, 61.1% of patients developed G 3-4 neutropenia; nevertheless no patient required permanent suspension of treatment. Pain control was complete in 88.2% of patients three months after radiotherapy; 94.4% of patients achieved and maintained local control of disease. Radiotherapy concomitant to CDK4/6 inhibitors is feasible and characterized by a fair toxicity profile, with isolated episodes of high-grade reversible intestinal toxicity. Rate of G 3-4 neutropenia was comparable with that measured for CDK4/6 inhibitors alone. Promising results were reported in terms of pain relief and local control of disease.",
"affiliations": "Department of Radiation Oncology, Brescia University, Piazzale Spedali Civili, 1, 25123, Brescia, Italy.;Department of Radiation Oncology, ASST Spedali Civili of Brescia, P.le Spedali Civili 1, 25123, Brescia, Italy.;Department of Radiation Oncology, ASST Spedali Civili of Brescia, P.le Spedali Civili 1, 25123, Brescia, Italy. emiliano.salah@aol.com.;Medical Oncology Unit, University of Brescia, Spedali Civili of Brescia, P.le Spedali Civili 1, 25123, Brescia, Italy.;Department of Radiation Oncology, ASST Spedali Civili of Brescia, P.le Spedali Civili 1, 25123, Brescia, Italy.;Department of Radiation Oncology, ASST Spedali Civili of Brescia, P.le Spedali Civili 1, 25123, Brescia, Italy.;Medical Oncology Unit, University of Brescia, Spedali Civili of Brescia, P.le Spedali Civili 1, 25123, Brescia, Italy.;Medical Oncology Unit, University of Brescia, Spedali Civili of Brescia, P.le Spedali Civili 1, 25123, Brescia, Italy.;Radiation Oncology Service, ASST Valcamonica, 25040, Esine, Italy.;Department of Radiation Oncology, Brescia University, Piazzale Spedali Civili, 1, 25123, Brescia, Italy.;Department of Radiation Oncology, Brescia University, Piazzale Spedali Civili, 1, 25123, Brescia, Italy.;Department of Radiation Oncology, Brescia University, Piazzale Spedali Civili, 1, 25123, Brescia, Italy.;Advanced Radiation Oncology Department, Cancer Care Center, IRCCS Sacro Cuore Don Calabria Hospital, Via Don Sempreboni 5, 37034, Verona, Negrar, Italy.;Advanced Radiation Oncology Department, Cancer Care Center, IRCCS Sacro Cuore Don Calabria Hospital, Via Don Sempreboni 5, 37034, Verona, Negrar, Italy.;Department of Radiation Oncology, Brescia University, Piazzale Spedali Civili, 1, 25123, Brescia, Italy.;Department of Radiation Oncology, Brescia University, Piazzale Spedali Civili, 1, 25123, Brescia, Italy.",
"authors": "Guerini|Andrea Emanuele|AE|;Pedretti|Sara|S|;Salah|Emiliano|E|;Simoncini|Edda Lucia|EL|;Maddalo|Marta|M|;Pegurri|Ludovica|L|;Pedersini|Rebecca|R|;Vassalli|Lucia|L|;Pasinetti|Nadia|N|;Peretto|Gloria|G|;Triggiani|Luca|L|;Costantino|Gianluca|G|;Figlia|Vanessa|V|;Alongi|Filippo|F|;Magrini|Stefano Maria|SM|;Buglione|Michela|M|",
"chemical_list": "D000631:Aminopyridines; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011687:Purines; D011725:Pyridines; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib; C000589651:ribociclib",
"country": "England",
"delete": false,
"doi": "10.1038/s41598-020-70430-2",
"fulltext": "\n==== Front\nSci Rep\nSci Rep\nScientific Reports\n2045-2322 Nature Publishing Group UK London \n\n70430\n10.1038/s41598-020-70430-2\nArticle\nA single-center retrospective safety analysis of cyclin-dependent kinase 4/6 inhibitors concurrent with radiation therapy in metastatic breast cancer patients\nGuerini Andrea Emanuele a.e.guerini@gmail.com 1 Pedretti Sara sara.pedretti1984@gmail.com 2 Salah Emiliano emiliano.salah@aol.com 2 Simoncini Edda Lucia edda.simoncini@spedalicivili.brescia.it 3 Maddalo Marta marta.maddalo@gmail.com 2 Pegurri Ludovica ludovicapegurri@libero.it 2 Pedersini Rebecca rebecca.pedersini@gmail.com 3 Vassalli Lucia lucia.vassalli@libero.it 3 Pasinetti Nadia nadia_pasinetti@yahoo.it 4 Peretto Gloria gloriaper@hotmail.it 1 Triggiani Luca triggioluca@hotmail.it 1 Costantino Gianluca costantino.gianlu@gmail.com 1 Figlia Vanessa vanessa.figlia@sacrocuore.it 5 Alongi Filippo filippo.alongi@unibs.it 5 Magrini Stefano Maria stefano.magrini@unibs.it 1 Buglione Michela michela.buglione@unibs.it 1 1 grid.7637.50000000417571846Department of Radiation Oncology, Brescia University, Piazzale Spedali Civili, 1, 25123 Brescia, Italy \n2 grid.412725.7Department of Radiation Oncology, ASST Spedali Civili of Brescia, P.le Spedali Civili 1, 25123 Brescia, Italy \n3 Medical Oncology Unit, University of Brescia, Spedali Civili of Brescia, P.le Spedali Civili 1, 25123 Brescia, Italy \n4 Radiation Oncology Service, ASST Valcamonica, 25040 Esine, Italy \n5 grid.416422.70000 0004 1760 2489Advanced Radiation Oncology Department, Cancer Care Center, IRCCS Sacro Cuore Don Calabria Hospital, Via Don Sempreboni 5, 37034 Verona, Negrar Italy \n12 8 2020 \n12 8 2020 \n2020 \n10 1358925 4 2020 29 7 2020 © The Author(s) 2020Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.Cyclin dependent kinases 4/6 (CDK4/6) inhibitors gained an essential role in the treatment of metastatic breast cancer. Nevertheless, data regarding their use in combination with radiotherapy are still scarce. We performed a retrospective preliminary analysis of breast cancer patients treated at our Center with palliative radiation therapy and concurrent CDK4/6 inhibitors. Toxicities were measured according to CTCAE 4.0, local response according to RECIST 1.1 or PERCIST 1.0 and pain control using verbal numeric scale. 18 patients (32 treated sites) were identified; 50% received palbociclib, 33.3% ribociclib and 16.7% abemacliclib. Acute non-hematologic toxicity was fair, with the only exception of a patient who developed G3 ileitis. During 3 months following RT, 61.1% of patients developed G 3–4 neutropenia; nevertheless no patient required permanent suspension of treatment. Pain control was complete in 88.2% of patients three months after radiotherapy; 94.4% of patients achieved and maintained local control of disease. Radiotherapy concomitant to CDK4/6 inhibitors is feasible and characterized by a fair toxicity profile, with isolated episodes of high-grade reversible intestinal toxicity. Rate of G 3–4 neutropenia was comparable with that measured for CDK4/6 inhibitors alone. Promising results were reported in terms of pain relief and local control of disease.\n\nSubject terms\nBreast cancerCancer therapyissue-copyright-statement© The Author(s) 2020\n==== Body\nIntroduction\nSelective cyclin dependent kinases 4/6 (CDK4/6) inhibitors block tumor suppressor retinoblastoma protein phosphorylation, preventing the transition of cancer cells from G1 to S phase with consequent inhibition of cell cycle and proliferation1. To date, three CDK4/6 inhibitors are approved against hormone receptor positive, human epidermal growth factor receptor 2 negative metastatic or advanced breast cancer in combination with aromatase inhibitors or fulvestrant both in first and subsequent lines of therapy. After different phase III trials2–7 reporting significant improvements in response rate and progression free survival, palbociclib was the first CDK4/6 inhibitor authorized by European Medicines Agency in November 2016, followed by ribociclib in August 2017 and abemaciclib in September 2018.\n\nThe three compounds demonstrated comparable outcomes in terms of antitumoral efficacy, but are characterized by substantial differences in pharmacokinetics and few discrepancies in toxicity profiles8. Palbociclib and ribociclib showed a predominant bone marrow toxicity, with G 3–4 neutropenia reported in up to 66.7% of patients3. Abemaciclib determined lower rates of neutropenia, but a higher frequence of G 3–4 diarrhea (up to 19.7% compared to up to 4% for palbociclib)2,9. Ribociclib also determined G 3–4 aspartate aminotransferase and alanine aminotransferase elevations in 5–10% and QT interval prolongation in ~ 1–3% of treated patients4,5. Radiotherapy has a central and established role in the palliation of symptomatic lesions in metastatic cancer10 and is emerging as a mean to improve local control and prognosis of oligo-metastatic patients11,12. Despite the wide use of CDK4/6 inhibitors in the treatment of breast cancer, published data regarding possible contraindications and interactions with radiation treatment are still very limited. This, combined with isolated case reports13,14 of high grade radio-induced toxicity could raise concern in many clinicians and lead them to avoid the combination with radiotherapy in fear of an increase in toxicity and thus deprive the patient of an effective treatment.\n\nWe therefore performed a retrospective preliminary analysis of breast cancer patients treated at our Center with palliative radiation therapy to bone lesions and concurrent CDK4/6 inhibitors to assess the possible pitfalls of this combination.\n\nMethods and materials\nStudy population\nWe retrospectively reviewed the records of all patients affected by metastatic breast cancer that received external beam radiation therapy at our Center (Brescia University Radiation Therapy Department) from 2016 to 2020. Patients who were treated with CDK4/6 inhibitors concomitantly with palliative radiotherapy were included in this analysis: the maximum interval allowed between last drug administration and radiotherapy was 2 half lives (about 58 h for palbociclib15, 64 h for ribociclib16 and 37 h for abemaciclib17). Most of the patients underwent systemic treatment at Brescia University Oncology Department, in the context of our institutional Breast Unit.\n\nSystemic treatment\nPalbociclib was prescribed at the dose of 125 mg daily for 21 days followed by 7 days of pause, in association with either letrozole 2.5 mg daily or fulvestrant 500 mg every 28 days. Ribociclib was prescribed at the dose of 600 mg daily from day 1 to day 21 every 28 days, in combination with daily letrozole. Abemaciclib was prescribed at the dose of 150 mg bis in die, in association with either letrozole 2.5 mg daily or fulvestrant 500 mg every 28 days. Premenopausal patients also received LHRH agonists. Dosage reductions were allowed at prescriber’s discretion on the base of hematologic and clinical toxicities.\n\nRadiation therapy\nMost of the treatments (30 of 32) were prescribed with symptomatic or palliative intent, planned with 3D conformal techniques and patients were treated with 6 or 10 MV beams, generated from Elekta Synergy® linear accelerator. Two treatments for oligometastatic disease were prescribed with ablative intent, planned with stereotactic techniques one using VMAT and one using Tomotherapy and erogated respectively with Elekta Synergy® and Tomotherapy Hi-ART® systems. Clinical target volume (CTV) was defined on a case-by-case basis, generally including the osteolytic lesion and the eventual extension to the adjacent soft-tissues with a margin of 1–3 cm corrected for anatomical structures. For spinal lesions, the CTV usually included the involved vertebra plus half of the upper and lower vertebrae. Planning target volume (PTV) was generally outlined adding a 9 mm margin to the CTV. Prescribed dose was chosen according to guidelines for palliative radiotherapy18,19 and tailored to the characteristics of the patient, the tumor burden and the location of the lesion; in all the plans 95% of prescribed dose covered at least 95% of the PTV.\n\nOutcome measures and statistics\nToxicities were graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0). Tumor response was determined using CT scans, MRI or 18FDG-PET-CT scans and defined according to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) or Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST 1.0). Pain intensity was assessed by the patient’s self-rated pain verbal numeric scale (VNS), in which patients are asked to verbally state a number between 0 (no pain) and 10 (worst imaginable pain).\n\nEthical approval\nAll the procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent, when required according to institutional, national and international laws, was obtained from all subjects. This study was approved by the Ethics Committee of our Institution (ASST Spedali Civili di Brescia).\n\nDisclaimer\nThis manuscript has not been published and is not under consideration for publication elsewhere.\n\nResults\nStudy population\nEighteen metastatic breast cancer patients were selected, with a total of 32 treated sites. Baseline patients’ characteristics are detailed in Table 1. Median age at RT start was 64 years, four patients were metastatic at diagnosis and median interval between first diagnosis and metastatic progression was 6.8 years. Over 70% of the patients had not previously received endocrine therapy for metastatic disease. Nine patients (50%) received palbociclib, six (33.3%) ribociclib and three (16.7%) abemacliclib (concomitant RT on 19, 10 and 3 disease sites respectively). Most of the patients (66.7%) had both visceral and bone disease, while 33.3% presented with only osseous involvement. Concomitant hormone-therapy was represented by letrozole for 44.4% and fulvestrant for 55.6% of patients. Median and mean interval between CDK4/6 inhibitor start and RT were 1.5 and 3.2 months.Table 1 Main patients' characteristics.\n\nMedian age\t\nDiagnosis\t50.5 y (range 31.6–77.3 y)\t\nMetastasis\t60.9 y (range 35.8–77.3 y)\t\nRT start\t64.1 y (range 36.1–77.5 y)\t\nTime from diagnosis to metastasis\t6.8 y (range 0–24.4 y)\t\nHistology\t\nDuctal/NST carcinoma\t11 (72.2%)\t\nLobular carcinoma\t2 (11.1%)\t\nMicropapillary\t1 (5.6%)\t\nMixed ductal and lobular\t1 (5.6%)\t\nUnknown\t1 (5.6%)\t\nMetastatic at diagnosis\t\nYes\t4 (22.2%)\t\nNo\t14 (77.8%)\t\nSite of metastic disease\t\nBone only\t6 (33.3%)\t\nBone and visceral\t12 (66.7%)\t\nPrevious hormonal treatment for metastatic disease\t\nYes\t5 (27.8%)\t\nNo\t13 (72.2%)\t\nCDK4/6 inhibitor\t\nPalbociclib\t9 (50%)\t\nRibociclib\t6 (33.3%)\t\nAbemaciclib\t3 (16.7%)\t\nConcomitant hormonal treatment\t\nFulvestrant\t10 (55.6%)\t\nLetrozole\t8 (44.4%)\t\n\n\nTreatment characteristics\nDetails regarding radiation therapy are summarized in Tables 2 and 3. All the patient received radiation therapy to bone metastatic sites including the spine (61.1% of patients), the pelvis (50%), extremities (22.1%), sternum (11.1%), skull (5.6%) or ribs (5.6%). Prescribed dose was 30 Gy in 10 fractions for 40.6% of treatments, 20 Gy in 5 fractions for 37.5%, 8 Gy single fraction for 15.6% and 30 Gy in 3 fractions for 6.3%. The majority of treatments were performed with 3D conformal radiotherapy (90.6%), while two were calculated with VMAT and one with Tomotherapy.Table 2 Radiotherapy treatments characteristics.\n\nTime from CDK4/6 start to RT\t\nMedian 1.5 months\tRange 0–15. 6 months\t\nTotal number of treated sites\t\n32\tRange 1–4 per patient\t\nTreatment dose/fractions\t\n30 Gy/10 fr\t13 (40.6%)\t\n20 Gy/5 fr\t12 (37.5%)\t\n8 Gy/1 fr\t5 (15.6%)\t\n30 Gy/3 fr\t2 (6.3%)\t\nRT technique\t\n3D-CRT\t29 (90.6%)\t\nVMAT\t2 (6.3%)\t\nTomotherapy\t1 (3.1%)\t\nTreated site\t\nSpine\t61.1% of patients\t\nPelvis\t50%\t\nExtremities\t22.2%\t\nSternum\t11.1%\t\nSkull\t5.6%\t\nRibs\t5.6%\t\nTable 3 site and characteristics of radiotherapy treatment and pain and radiological response.\n\nPatient\tRT site\tConcomitant CDK4/6 inhibitor\tRT dose/technique\tVNS before RT\tVNS at RT end\tVNS at 1 mo\tResponse at 3 mo\tResponse at 6 mo\tLR\tAcute toxicity\t\n1\tL5 + sacrum + R ilium\tPalbociclib\t30 Gy/10 fr—3DCRT\t6\t4\t3\tSD\tSD\tNo\tG3 ileitis\t\n2\tL5 + sacrum + R sacroiliac joint\tPalbociclib\t30 Gy/10 fr—3DCRT\t4\t4\t3\t\tPR\tNo\tG1 diarrhea\t\n3\tL femur head; L IX rib\tPalbociclib\t20 Gy/5 fr—3DCRT\t0\t0\t0\t\tPR\tNo\tNone\t\n4\tR ischium + R ilium + R femur head + S2; C4; T2\tPalbociclib\t30 Gy/10 fr—3DCRT\t7\t5\t0\tPR\tPR\tNo\tG1 sore-throat + G1 diarrhea\t\n5\tR ilium + R sacral ala\tPalbociclib\t20 Gy/5 fr—3DCRT\t2\t1\t0\tPR\tPR\tYes\tNone\t\n6\tL acetabulum + L femur head; R sacral ala\n\nC5 vertebra\n\n\tPalbociclib\t30 Gy/10 fr—3DCRT\n\n30 Gy/3 fr—Tomo\n\n\t8\n\n0\n\n\t5\n\n0\n\n\t0\n\n0\n\n\t\tCR\n\nPR\n\n\tNo\n\nNo\n\n\tG1 nausea + G1 fatigue\n\nNone\n\n\t\n7\tSacrum + R ilium + bilateral femur head\tPalbociclib\t20 Gy/5 fr—VMAT\t7\t4\t2\t\t\tNo\tNone\t\n8\tT7 vertebra; T12 vertebra; S3-S5 tract\tRibociclib\t30 Gy/5 fr—3DCRT\t0\t0\t0\tSD\tPR\tNo\tG1 nausea\t\n9\tT6 vertebra\tRibociclib\t20 Gy/5 fr—3DCRT\t5\t3\t0\t\tSD\tNo\tG1 fatigue\t\n10\tT2-T4 vertebral tract\tPalbociclib\t20 Gy/5 fr—3DCRT\t6\t6\t0\tSD\t\tNo\tNone\t\n11\tT4 vertebra; T9 vertebra; R acetabulum\tRibociclib\t20 Gy/5 fr—3DCRT\t3\t0\t0\tSD\tPR\tNo\tG1 esophagitis\t\n12\tT2 vertebra\tPalbociclib\t20 Gy/5 fr—3DCRT\t0\t0\t0\tPR\tPR\tNo\tNone\t\n13\tL ischium + L pubic bone\tRibociclib\t8 Gy/1 fr—3DCRT\t0\t0\t0\tPR\t\tNo\tNone\t\n14\tsternum\tRibociclib\t8 Gy/1 fr—3DCRT\t2\t2\t0\t\t\tNo\tNone\t\n15\tT4 vertebra\tAbemaciclib\t8 Gy/1 fr—3DCRT\t0\t0\t0\tPR\t\tNo\tNone\t\n16\tL femur\tRibociclib\t8 Gy/1 fr—3DCRT\t4\t4\t0\tSD\tPR\tNo\tNone\t\n17\tT10-L1 vertebral tract\tAbemaciclib\t8 Gy/1 fr—3DCRT\t5\t5\t0\t\t\tNo\tNone\t\n18\tsternum\tAbemaciclib\t30 Gy/3 fr—VMAT\t0\t0\t0\t\t\tNo\tNone\t\nVNS, pain verbal numeric scale; mo, months; LR, local recurrence; L, left; R, right; fr, fraction; 3DCRT, 3D conformal radiotherapy; Tomo, Tomotherapy; VMAT, Volumetric Modulated Arc Therapy; SD, stable disease; PR, partial response.\n\n\n\nToxicity\nAcute toxicity data are summarized in Table 3. All radiotherapy courses were administered as planned without suspensions or dose reduction. Acute toxicity was limited and represented mainly by grade 1 side effects including sore throat (11.1% of patients), nausea/vomit (11.1%), diarrhea (11.1%), fatigue (11.1%) and esophagitis (5.6%).\n\nThe only exception was represented by one case of gastrointestinal G3 toxicity: 10 days after the end of RT (30 Gy in 10 fractions on a bulky bone localization involving L5 vertebra, sacrum and right ischium) the patient developed worsening diarrhea (up to 10 stools/day) and abdominal pain, that required hospitalization. A CT scan showed wall thickening and luminal narrowing of the distal ileum and colonoscopy confirmed the diagnosis of radiation-induced ileitis. Following conservative management with antibiotics and anti-inflammatory drugs, the toxicity completely resolved after 20 days. An abdominal CT-scan performed 3 months later confirmed the complete radiological resolution of ileitis. Palbociclib was suspended for a cycle and later resumed at full dosage and is still ongoing 29 months after this episode; dosage was reduced at 100 mg/die for G3 neutropenia more than 12 months after RT and subsequent isolated episodes of grade 1 diarrhea were reported. The patient later underwent stereotactic radiotherapy (30 Gy/3 fractions) on C5 vertebra: during this treatment, palbociclib was suspended to avoid excessive toxicity. Dosimetric parameters of the eight patients treated on pelvic sites are reported in Table 4. It has to be noted that the other seven patients treated to high-volume pelvic sites with similar dosimetric parameters did not develop high grade intestinal toxicity.Table 4 Dosimetric parameters of the eight patients treated on pelvic sites.\n\nPatient\tCTV (cc)\tPTV (cc)\tIntestinal Dmean (Gy)\tIntestinal Dmax (Gy)\tIntestinal D50 (Gy)\tIntestinal V10 (%)\tDose/fraction\tDiarrhea\t\nPt 1: L5 + sacrum + R ilium\t944.5\t1853.9\t10\t31\t16.7\t37\t30 Gy/10fr\n\nEQD2 32.5\n\n\tG 3\t\nPt 2: L5 + sacrum + R sacroiliac joint\t545\t1,138.9\t11.2\t30.9\t9.2\t45\t30 Gy/10fr\n\nEQD2 32.5\n\n\tG 1\t\nPt 4: R ischium + R ilium + S2\t491.8\t1,053.1\t7.7\t31.2\t2.8\t30\t30 Gy/10fr\n\nEQD2 32.5\n\n\tG 1\t\nPt 5: R ilium + R sacral ala\t151.7\t232.1\t1.5\t20\t0.2\t5\t20 Gy/5 fr\n\nEQD2 23.3\n\n\tNo\t\nPt 6: L acetabulum + R sacral ala\t257.4\t666.1\t6.7\t31.2\t1.3\t27\t30 Gy/10fr\n\nEQD2 32.5\n\n\tNo\t\nPt 7: Sacrum + R ilium\t933.7\t1819.4\t\t\t\t\t30 Gy/10fr\n\nEQD2 32.5\n\n\tNo\t\nPt 8: S3-S5 tract\t36.1\t109.7\t2.6\t30.3\t0.2\t6\t30 Gy/10fr\n\nEQD2 32.5\n\n\tNo\t\nPt 13: L ischium + L pubic bone\t89.6\t214.9\t2.5\t8\t1.9\t0\t8 Gy/1fr\n\nEQD2 12\n\n\tNo\t\n\n\nOnly one patient (5.6%) experienced “pain flare” during radiotherapy, that resolved before the end of treatment with anti-inflammatory drugs. Neutropenia was developed by 88.8% of the patients during 3 months following RT and was grade 3–4 in 61.1% of patients. Due to such toxicity, during the 3 months following RT CDK4/6 inhibitor was temporary suspended in 57.1% of the 14 patients with available data and the dose was temporary reduced in 28.6% and permanently reduced in 14.3% of patients; no permanent withhold was required and the median duration of drug suspension was 7 days (range 7–21 days). It has to be noted that all the four patients that were already on treatment with CDK4/6 inhibitors for more than three months before RT start already reported G ≥ 3 neutropenia during the previous cycles. Long term non-hematologic toxicity (median follow up 12 months) included G1 nausea/vomit (11.1% of patients), G1 diarrhea (11.1%) and G1 infections (5.6%).\n\nTreatment Outcome\nMedian VNS of the 12 patients presenting with pain was 5 (range 2–8) before RT and 4 (range 0–6) at the last day of RT; pain relief was complete in 8.3% and partial in 50% of patients, while the remaining 41.7% reported stable pain. One month after RT 83.3% of patients reported complete pain control and median VNS was 0 (mean 0.6 for previously symptomatic patients and 0.4 for the whole population) and after 3 and 6 months control was complete in 88.9% of patients and median VNS was 0 (mean 0.5 and 0.3 respectively). Only two patients still experienced pain after one and three months, both with a VNS reduction of at least 50% compared to baseline. No pain recurrence was reported. With a median follow up of 13.7 months (range 2–29 months) 15 patients (83.3%) are still alive, 6 (33.3%) developed progressive disease (resulting in 3 deaths) and the other 12 (66.7%) did not and are still on treatment with CDK4/6 inhibitors. Radiological and/or metabolic local response was evaluable for 11 patients at three months after RT (54.5% partial response, 45.5% stable disease) and for 12 patients after 6 months (8.3% complete response, 75% partial response and 16.7% stable disease compared to baseline). Considering the whole follow up period, 17 patients (94.4%) achieved local control of disease and maintained it until last evaluation and only one patient faced local recurrence 8 months after RT (20 Gy in 5 fractions to the right ilium and ala of sacrum).\n\nDiscussion\nBone represents the most frequent site of distant dissemination from breast cancer, as up to about 13% of patients diagnosed stage I-III disease develop bone metastasis, considering a median follow up of 12.5 years20. Complications depend on the site and the characteristics (osteolytic, osteoplastic or mixed) of bone lesions and include loss of structural function, fractures, spinal cord compression and pain. Up to 75% of the patients bearing bone metastases experience invalidating pain21. Radiotherapy provides pain relief to 50–85% of patients, with up to one third obtaining complete response22. Pain improvement is usually achieved within one month after RT, and mean duration of pain control is approximately 19 weeks, or even longer in breast cancer patients23. Unfortunately, a consistent proportion of patients might not obtain pain relief after radiotherapy and about half of initial responders experience pain relapse within 12 months after treatment24. The concurrent administration of a drug with radio-sensitizing activity could therefore be a valuable mean to improve symptomatic and disease control. CDK4/6 inhibitors demonstrated radio-sensitizing effects not only on breast cancer25, but also on several other tumor cell lines, including colorectal carcinoma25, lung cancer25,26, atypical teratoid rhabdoid tumor27, glioblastoma27,28, hepatocellular carcinoma29, cholangiocarcinoma29 and head and neck squamous carcinoma30. Despite these promising activity, the lack of a substantial body of clinical literature might persuade clinicians to avoid the concomitant administration of RT and CDK4/6 inhibitors, as radio-sensitizing effect could potentially involve also healthy tissues and lead to increased toxicity. This might determine unnecessary interruption of systemic treatment or even abstention from the benefits of RT. Therefore, we performed a retrospective analysis of the patient that underwent RT with concomitant CDK4/6 inhibitors at our Institution and a review of previously published clinical literature. The first reports of the combination of RT with CDK4/6 inhibitors are represented by preliminary data from very small patient samples.\n\nHans et. al. described an acceptable toxicity profile in five metastatic breast cancer patients treated with palbociclib and concurrent palliative RT31; all the patients experienced symptom improvement, but follow up time and local control were not reported. Meattini et al. analyzed ribociclib concomitant to palliative RT for bone metastases in the first five patients treated at their institution32. Two patients developed grade 3–4 side effects (one neutropenia and one vomit and diarrhea) and two needed temporary suspension of ribociclib, but radiotherapy was never suspended. At 3-month assessment, three stable disease and two partial response were observed. Larger subsequent series provided a broader perspective regarding the safety of concomitant treatment with CDK4/6 inhibitors and radiotherapy. Chowdary et al. evaluated the safety and efficacy of palbociclib in 16 breast cancer patients that received RT for symptomatic metastases33. No significant toxicity increase was observed compared to rates reported for palbociclib alone; prolonged pain control was achieved in all patients, and no local failures were described. It has to be noted that only 31.3% of the patients received palbociclib concomitantly, as an interval of 14 days between drug administration (before or after) RT was allowed, with a median interval of 5 days. Ippolito et. al. analyzed 16 metastatic breast cancer patients (24 radiotherapy treatments) that received palbociclib or ribociclib concurrently with RT34. Most of those patients (68.7%) underwent palliative RT to bone lesions with a median dose of 30 Gy, while the remaining received higher doses (median 50 Gy) to oligo-metastatic or oligo-progressive sites. Neutropenia was common but was already reported in previous cycles for most of the patients, thus radiotherapy did not appear to determine a relevant myelo-suppressive effect. No other relevant toxicities were developed. Pain relief was obtained by all patients that received RT on bone metastases. In patients treated at higher doses two complete response were observed (patient with extra-bone disease), while two partial responses and one stable disease were reported in patients with osseous lesions. The main limits of this study are represented by the short median follow up (only 6.3 months) and the fact that long term toxicities were not analyzed and local disease control was reported only for the five oligo-metastatic and oligo-progressive patients. The toxicities observed for combined treatment in these series and in our study are in line with published safety data of patients treated with CDK4/6 inhibitors alone2–7. Although high, the rate of grade 3–4 neutropenia we reported in the period between RT end and the three following cycles of CDK4/6 inhibitors (61.1%) is consistent with that described with palbociclib alone3. Moreover, no patient needed permanent suspension in the following cycles, with median duration of temporary interruption of 7 days and permanent dose reduction in only 14.3% of patients. Non-hematologic toxicity in our population was mild both in the acute and in the long term setting and represented mainly by grade 1 gastrointestinal toxicity. However, one of our patients also developed G3 ileitis 10 days after the end of RT with concurrent palbociclib on a bulky pelvic bone localization, that resolved completely after 20 days of conservative treatment. Another analogous case of severe radio-induced enterocolitis was reported after concomitant treatment with palbociclib and palliative radiotherapy (same dose, 30 Gy in 10 fractions) to left iliac bone and first sacral vertebra13. The patient developed worsening diarrhea and abdominal pain and a CT scan and colonoscopy confirmed the diagnosis. Following 3 weeks of conservative treatment, her symptoms abated. Biologically, 30 Gy in 10 fractions (EQD 2 Gy/fr 32.5 Gy) is a dose well below the normal bowel radiation tolerance dose, that is approximately 45–50 Gy in 2 Gy fractions35. Palbociclib might therefore act as a radiosensitizer on normal intestinal tissue, as palliative radiotherapy36 or palbociclib2 as single treatments are very unlikely to cause severe gastrointestinal side effects. In vivo data showed conflicting results, as palbociclib exposure resulted both in reduction37,38 and increase38 of acute gastrointestinal radiation syndrome in murine models, also depending on irradiation schedule38. Consequently, in case of concomitant CDK 4/6 inhibitor administration we advise the use of highly conformal treatment and optimization of the plan to maintain the dose as low as reasonably achievable to the gastrointestinal mucosa, especially in patients with high planning target volumes (PTVs) located in abdominal and pelvic areas and patients that experienced previous gastrointestinal toxicity. Only one patient (5.6%) experienced “pain flare” during radiotherapy, that resolved before the end of treatment with anti-inflammatory drugs: this compares favorably with the incidence reported in literature of up to 40% with RT alone39. In our population pain relief was complete in 8.3% and partial in 50% of patients at the last day of RT (median VNS 4 vs 5 at baseline), while the remaining 41.7% reported stable pain. One month after RT complete pain relief was experienced by 83.3% and after 3 months by 88.9% of patients and the remaining two patients obtained a VNS reduction of at least 50% compared to baseline. No pain recurrence was reported. Considering radiological and/or metabolic response, at three months 54.5% of patients achieved partial response and 45.5% stable disease and at 6 months 8.3% complete response, 75% partial response and 16.7% stable disease compared to baseline. With a median follow up of 13.7 months only one patient faced local recurrence while the other 94.4% of patients maintained local control. To our knowledge, this is the first report of concurrent treatment with radiation therapy and abemaciclib in metastatic breast cancer: in the three analyzed patients, no acute toxicity was observed.\n\nThe limits of our study must be acknowledged. Although our cohort, to the best of our knowledge, is the largest published up to date of metastatic breast cancer patients undergoing concurrent radiotherapy and CDK4/6 inhibitors, numbers are still limited. Results should therefore be interpreted with caution and should be confirmed by prospective studies enrolling larger samples of patients.\n\nConclusions\nConcomitant administration of palliative RT on bone lesions and CDK4/6 inhibitors is feasible and mostly characterized by a fair acute and long-term toxicity profile, with isolated episodes of high grade (although reversible) intestinal toxicity. Therefore, caution must be exercised when treating pelvic or abdominal sites, especially in case of high volume PTVs, and dose to the intestinal mucosa should be kept as low as reasonably achievable. In such scenarios, the use of highly conformal techniques is suggested. Rate of grade 3–4 neutropenia os high, but comparable with that measured for CDK4/6 inhibitors alone. Although the results of this study should be interpreted with caution, given the limited cohort,promising outcomes were reported both in terms of pain relief and local control of disease.\n\nPublisher's note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAuthor contributions\nA.E.G, E.S., S.P., S.M.M., M.B., F.A., E.L.S., L.T. and N.P. contributed substantially to the conception of the article; A.E.G., G.C., G.P., L.V., L.P., M.M., E.S., S.P., L.T. and R.P. contributed substantially to collection of clinical informations and data; all the authors contributed substantially to review of current literature; A.E.G, E.S., S.P., S.M.M., M.B., F.A., E.L.S., G.P., G.C., R.P., L.V., M.M., L.P., V.F. and N.P. contributed substantially to writing of the manuscript and data interpretation; all the authors contributed substantially to drafting and revisiting the manuscript. All authors have approved the manuscript and agree with its submission to “Scientific Reports”.\n\nCompeting interests\nThe authors declare no competing interests.\n==== Refs\nReferences\n1. Dukelow T Kishan D Khasraw M Murphy CG CDK4/6 inhibitors in breast cancer Anticancer Drugs. 2015 26 8 797 806 10.1097/CAD.0000000000000249 26053278 \n2. Finn RS Martin M Rugo HS Jones S Im SA Slamon DJ Palbociclib and letrozole in advanced breast cancer N. Engl. J. Med. 2016 375 20 1925 1936 10.1056/NEJMoa1607303 27959613 \n3. Cristofanilli M Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial Lancet Oncol. 2016 17 425 439 10.1016/S1470-2045(15)00613-0 26947331 \n4. O'Shaughnessy J Petrakova K Sonke GS Conte P Arteaga CL Hortobagyi GN Ribociclib plus letrozole versus letrozole alone in patients with de novo HR+, HER2- advanced breast cancer in the randomized MONALEESA-2 trial Breast Cancer Res. Treat. 2018 168 1 127 134 10.1007/s10549-017-4518-8 29164421 \n5. Tripathy D Im SA Colleoni M Franke F Bardia A Lu YS Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial Lancet Oncol. 2018 19 7 904 915 10.1016/S1470-2045(18)30292-4 29804902 \n6. Sledge GW Jr Toi M Neven P Sohn J Inoue K Llombart-Cussac A MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy J. Clin. Oncol. 2017 35 25 2875 2884 10.1200/JCO.2017.73.7585 28580882 \n7. Goetz MP Toi M Campone M Sohn J Paluch-Shimon S Di Leo A MONARCH 3: abemaciclib as initial therapy for advanced breast cancer J. Clin. Oncol. 2017 35 32 3638 3646 10.1200/JCO.2017.75.6155 28968163 \n8. Marra A Curigliano G Are all cyclin-dependent kinases 4/6 inhibitors created equal? NPJ Breast Cancer 2019 5 27 10.1038/s41523-019-0121-y 31482107 \n9. Dickler MN Tolaney SM Rugo HS Cortés J Diéras V Koustenis A Baselga J MONARCH 1, a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2- metastatic breast cancer Clin. Cancer Res. 2017 23 17 5218 5224 10.1158/1078-0432.CCR-17-0754 28533223 \n10. De Felice F Piccioli A Musio D Tombolini V The role of radiation therapy in bone metastases management Oncotarget 2017 8 15 25691 25699 10.18632/oncotarget.14823 28148890 \n11. Palma DA Olson R Harrow S Gaede S Louie AV Senan S Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial Lancet 2019 393 10185 2051 2058 10.1016/S0140-6736(18)32487-5 30982687 \n12. Triggiani L Alongi F Buglione M Detti B Santoni R Magrini SM Efficacy of stereotactic body radiotherapy in oligorecurrent and in oligoprogressive prostate cancer: new evidence from a multicentric study Br. J. Cancer 2017 116 12 1520 1525 10.1038/bjc.2017.103 28449007 \n13. Kawamoto T Shikama N Sasai K Severe acute radiation-induced enterocolitis after combined palbociclib and palliative radiotherapy treatment Radiother. Oncol. 2019 131 240 241 10.1016/j.radonc.2018.09.020 30336956 \n14. Messer JA Ekinci E Patel TA Teh BS Enhanced dermatologic toxicity following concurrent treatment with palbociclib and radiation therapy: a case report Rep. Pract. Oncol. Radiother. 2019 24 3 276 280 10.1016/j.rpor.2019.03.001 30948930 \n15. Beaver JA Amiri-Kordestani L Charlab R Chen W Palmby T Cortazar P FDA Approval: palbociclib for the treatment of postmenopausal patients with estrogen receptor-positive, HER2-negative metastatic breast cancer Clin. Cancer Res. 2015 21 21 4760 4766 10.1158/1078-0432.CCR-15-1185 26324739 \n16. Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Shapiro GI A phase I study of the cyclin-dependent kinase 4/6 inhibitor ribociclib (LEE011) in patients with advanced solid tumors and lymphomas Clin. Cancer Res. 2016 22 23 5696 5705 10.1158/1078-0432.CCR-16-1248 27542767 \n17. Patnaik A Rosen LS Tolaney SM Tolcher AW Goldman JW Shapiro GI Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors Cancer Discov. 2016 6 7 740 753 10.1158/2159-8290.CD-16-0095 27217383 \n18. Lutz S Berk L Chang E Chow E Hahn C Hartsell W Palliative radiotherapy for bone metastases: an ASTRO evidence-based guideline Int. J. Radiat. Oncol. Biol. Phys. 2011 79 4 965 976 10.1016/j.ijrobp.2010.11.026 21277118 \n19. Lutz S Balboni T Jones J Lo S Petit J Rich SE Wong R Hahn C Palliative radiation therapy for bone metastases: update of an ASTRO evidence-based guideline Pract. Radiat. Oncol. 2017 7 1 4 12 10.1016/j.prro.2016.08.001 27663933 \n20. Liede A Jerzak KJ Hernandez RK Wade SW Sun P Narod SA The incidence of bone metastasis after early-stage breast cancer in Canada Breast Cancer Res. Treat. 2016 156 3 587 595 10.1007/s10549-016-3782-3 27083181 \n21. Aielli F Ponzetti M Rucci N Bone metastasis pain, from the bench to the bedside Int. J. Mol. Sci. 2019 20 2 E280 10.3390/ijms20020280 30641973 \n22. Lutz S Berk L Chang E Chow E Hahn C von Gunten C Palliative radiotherapy for bone metastases: an ASTRO evidence-based guideline Int. J. Radiat. Oncol. Biol. Phys. 2011 79 965 976 10.1016/j.ijrobp.2010.11.026 21277118 \n23. Van der Linden YM, Lok JJ, Steenland E, Martijn H, van Houwelingen H, Marijnen CA et al. Dutch Bone Metastasis Study Group. Single fraction radiotherapy is efficacious: a further analysis of the Dutch Bone Metastasis Study controlling for the influence of retreatment. Int. J. Radiat. Oncol. Biol. Phys. 2004;59:528–37.\n24. Huisman M van den Bosch MA Wijlemans JW van Vulpen M van der Linden YM Verkooijen HM Effectiveness of reirradiation for painful bone metastases: a systematic review and meta-analysis Int. J. Radiat. Oncol. Biol. Phys. 2012 84 8 14 10.1016/j.ijrobp.2011.10.080 22300568 \n25. Fernández-Aroca DM Roche O Sabater S Pascual-Serra R Ortega-Muelas M Sánchez-Prieto R.mP53 pathway is a major determinant in the radiosensitizing effect of palbociclib: implication in cancer therapy Cancer Lett. 2019 451 23 33 10.1016/j.canlet.2019.02.049 30872077 \n26. Tao Z Le Blanc JM Wang C Zhan T Zhuang H Wang P Yuan Z Lu B Coadministration of trametinib and palbociclib radiosensitizes KRAS-mutant non-small cell lung cancers in vitro and in vivo Clin. Cancer Res. 2016 22 1 122 133 10.1158/1078-0432.CCR-15-0589 26728409 \n27. Hashizume R Zhang A Mueller S Prados MD Lulla RR Goldman S Saratsis AM James CD Inhibition of DNA damage repair by the CDK4/6 inhibitor palbociclib delays irradiated intracranial atypical teratoid rhabdoid tumor and glioblastoma xenograft regrowth Neuro Oncol. 2016 18 11 1519 1528 27370397 \n28. Whittaker S Madani D Joshi S Chung SA Johns T Day B McDonald KL Combination of palbociclib and radiotherapy for glioblastoma Cell Death Discov. 2017 3 17033 10.1038/cddiscovery.2017.33 28690875 \n29. Huang CY Hsieh FS Wang CY Chen LJ Chang SS Chen KF Palbociclib enhances radiosensitivity of hepatocellular carcinoma and cholangiocarcinoma via inhibiting ataxia telangiectasia-mutated kinase-mediated DNA damage response Eur. J. Cancer 2018 102 10 22 10.1016/j.ejca.2018.07.010 30103095 \n30. Göttgens EL Bussink J Leszczynska KB Peters H Span PN Hammond EM Inhibition of CDK4/CDK6 enhances radiosensitivity of HPV negative head and neck squamous cell carcinomas Int. J. Radiat. Oncol. Biol. Phys. 2019 105 3 548 558 10.1016/j.ijrobp.2019.06.2531 31271827 \n31. Hans S Cottu P Kirova YM Preliminary results of the association of Palbociclib and radiotherapy in metastatic breast cancer patients Radiother. Oncol. 2018 126 1 181 10.1016/j.radonc.2017.09.010 28964534 \n32. Meattini I Desideri I Scotti V Simontacchi G Livi L Ribociclib plus letrozole and concomitant palliative radiotherapy for metastatic breast cancer Breast 2018 42 1 2 10.1016/j.breast.2018.08.096 30118901 \n33. Chowdhary M Sen N Chowdhary A Usha L Cobleigh MA Wang D Patel KR Barry PN Rao RD Safety and efficacy of palbociclib and radiation therapy in patients with metastatic breast cancer: initial results of a novel combination Adv. Radiat. Oncol. 2019 4 3 453 457 10.1016/j.adro.2019.03.011 31360799 \n34. Ippolito E Greco C Silipigni S Dell'Aquila E Petrianni GM Ramella S Concurrent radiotherapy with palbociclib or ribociclib for metastatic breast cancer patients: Preliminary assessment of toxicity Breast 2019 46 70 74 10.1016/j.breast.2019.05.001 31100573 \n35. Hird A Chow E Zhang L Wong R Wu J Sinclair E Danjoux C Tsao M Barnes E Loblaw A Determining the incidence of pain flare following palliative radiotherapy for symptomatic bone metastases: results from three canadian cancer centers Int. J. Radiat. Oncol. Biol. Phys. 2009 75 193 197 10.1016/j.ijrobp.2008.10.044 19167840 \n36. Willett CG Goldberg S Shellito PC Grossbard M Clark J Fung C Does postoperative irradiation play a role in the adjuvant therapy of stage T4 colon cancer? Cancer J. Sci. Am. 1999 5 242 247 10439171 \n37. Sprave, T., Verma, V., Forster, R., Schlampp, I., Bruckner, T., Bostel, T., et al. Radiationinduced acute toxicities after image-guided intensity-modulated radiotherapy versus three-dimensional conformal radiotherapy for patients with spinal metastases (IRON-1 trial): first results of a randomized controlled trial. Strahlentherapie und Onkologie: Organ der Deutschen Rontgengesellschaft [et al] (2018).\n38. Wei L Leibowitz BJ Wang X Epperly M Greenberger J Zhang L Yu J Inhibition of CDK4/6 protects against radiation-induced intestinal injury in mice J. Clin. Invest. 2016 126 11 4076 4087 10.1172/JCI88410 27701148 \n39. Lee CL Oh P Xu ES Ma Y Kim Y Daniel AR Kirsch DG Blocking cyclin-dependent kinase 4/6 during single dose versus fractionated radiation therapy leads to opposite effects on acute gastrointestinal toxicity in mice Int. J. Radiat. Oncol. Biol. Phys. 2018 102 5 1569 1576 10.1016/j.ijrobp.2018.07.192 30056081\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2045-2322",
"issue": "10(1)",
"journal": "Scientific reports",
"keywords": null,
"medline_ta": "Sci Rep",
"mesh_terms": "D000631:Aminopyridines; D001943:Breast Neoplasms; D003131:Combined Modality Therapy; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D005260:Female; D006801:Humans; D007079:Ileitis; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D009503:Neutropenia; D017063:Outcome Assessment, Health Care; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011687:Purines; D011725:Pyridines; D011878:Radiotherapy; D012189:Retrospective Studies",
"nlm_unique_id": "101563288",
"other_id": null,
"pages": "13589",
"pmc": null,
"pmid": "32788596",
"pubdate": "2020-08-12",
"publication_types": "D016428:Journal Article",
"references": "26053278;27959613;26947331;29164421;29804902;28580882;28968163;31482107;28533223;28148890;30982687;28449007;30336956;30948930;26324739;27542767;27217383;21277118;27663933;27083181;30641973;21277118;22300568;30872077;26728409;27370397;28690875;30103095;31271827;28964534;30118901;31360799;31100573;19167840;10439171;27701148;30056081",
"title": "A single-center retrospective safety analysis of cyclin-dependent kinase 4/6 inhibitors concurrent with radiation therapy in metastatic breast cancer patients.",
"title_normalized": "a single center retrospective safety analysis of cyclin dependent kinase 4 6 inhibitors concurrent with radiation therapy in metastatic breast cancer patients"
} | [
{
"companynumb": "IT-PFIZER INC-2020329144",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PALBOCICLIB"
},
"drugadditional": "1",
... |
{
"abstract": "An 82-year-old man with a background of prostate carcinoma and bony metastases presented with bilateral discharging neck fistulae. Two years prior to presentation, the patient had been treated with intravenous zoledronic acid for 1 year as part of chemotherapy. Intraoral examination revealed extensive bilateral medication-related osteonecrosis, with orocutaneous fistulae within the neck. Treatment comprised removal of loose necrotic bone sequestrae, debridement of the fistulae and long-term administration of antibiotics, vitamin E and pentoxifylline. Four weeks later, the orocutaneous fistulae had healed.",
"affiliations": "Oral and Maxillofacial Surgery, West Hertfordshire Hospitals NHS Trust, Watford, Hertfordshire, UK.;Oral and Maxillofacial Surgery, West Hertfordshire Hospitals NHS Trust, Watford, Hertfordshire, UK.",
"authors": "Thavarajah|Meera|M|;Jayaram|Rahul|R|",
"chemical_list": "D000900:Anti-Bacterial Agents; D050071:Bone Density Conservation Agents; D016166:Free Radical Scavengers; D014810:Vitamin E; D000077211:Zoledronic Acid; D010431:Pentoxifylline",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-228238",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(2)",
"journal": "BMJ case reports",
"keywords": "dentistry and oral medicine; mouth; oncology; prostate cancer",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D050071:Bone Density Conservation Agents; D016166:Free Radical Scavengers; D006801:Humans; D008297:Male; D008334:Mandible; D010020:Osteonecrosis; D010431:Pentoxifylline; D011471:Prostatic Neoplasms; D014810:Vitamin E; D000077211:Zoledronic Acid",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30814104",
"pubdate": "2019-02-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25234529;28281587;16243172;18438586;27651287;29714695;29747794;26362367;25710950;29809272;23814591;27053542",
"title": "Uncommon presentation of medication-related osteonecrosis of the mandible in a patient with metastatic prostate cancer.",
"title_normalized": "uncommon presentation of medication related osteonecrosis of the mandible in a patient with metastatic prostate cancer"
} | [
{
"companynumb": "GB-PFIZER INC-2019117480",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nMannitol is the most commonly used intraoperative hypertonic solution in patients undergoing craniotomy. However, its use has been reported to be associated with hyperkalemia, which can occasionally be life threatening.\nIn this report, we discuss the case of a patient who had intraoperative cardiac arrest secondary to mannitol-induced hyperkalemia during a craniotomy for tumor resection. In addition, we provide a comprehensive review of the literature concerning similar cases previously reported, as well as a discussion of the pathophysiology of mannitol-induced hyperkalemia. Review of the literature suggests that patients prone to this phenomenon are young and healthy individuals with normal preoperative and postoperative cardiopulmonary and renal functions. The literature also suggests that the total dose of mannitol, as well as its rate of infusion, may play a role in the development of this phenomenon.\n\n\nCONCLUSIONS\nKnowledge of the existence of mannitol-induced hyperkalemia is paramount for the neurosurgeon and the anesthesiologist, because early treatment with insulin and calcium can quickly restore normal cardiac rhythm and prevent intraoperative death.",
"affiliations": "Department of Neurosurgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA.;Department of Anesthesiology, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA; Department of Anesthesiology and Pain Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA.;Department of Neurosurgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA; Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA.;Department of Neurosurgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA; Department of Neurosurgery, Roswell Park Cancer Institute, Buffalo, New York, USA. Electronic address: robert.fenstermaker@roswellpark.org.",
"authors": "Fanous|Andrew A|AA|;Tick|Robert C|RC|;Gu|Eugene Y|EY|;Fenstermaker|Robert A|RA|",
"chemical_list": "D006982:Hypertonic Solutions; D008353:Mannitol",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "91()",
"journal": "World neurosurgery",
"keywords": "Adverse event; Cardiac arrest; Craniotomy; Hyperkalemia; Intraoperative complication; Mannitol infusion",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D001932:Brain Neoplasms; D003110:Colonic Neoplasms; D003399:Craniotomy; D004562:Electrocardiography; D006801:Humans; D006947:Hyperkalemia; D006982:Hypertonic Solutions; D008297:Male; D008353:Mannitol",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "672.e5-9",
"pmc": null,
"pmid": "27086258",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Life-Threatening Mannitol-Induced Hyperkalemia in Neurosurgical Patients.",
"title_normalized": "life threatening mannitol induced hyperkalemia in neurosurgical patients"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201606831",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MANNITOL"
},
"drugadditional": null,
... |
{
"abstract": "Trastuzumab deruxtecan has been shown to have responses in heavily pretreated patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. However, the safety of this medication in patients with severe liver dysfunction and untreated or symptomatic central nervous system metastases is unknown. We describe a patient with metastatic HER2-positive breast cancer with liver failure and leptomeningeal metastases who was treated with dose-reduced trastuzumab deruxtecan. With treatment, the patient's hyperbilirubinemia resolved and she demonstrated a response on imaging. She was dose-escalated to full dose with minimal adverse events.",
"affiliations": "Baylor College of Medicine, Department of Internal Medicine, Section of Hematology-Oncology, One Baylor Plaza, Houston, TX, United States.;Baylor College of Medicine, Department of Internal Medicine, Section of Hematology-Oncology, One Baylor Plaza, Houston, TX, United States.;Baylor College of Medicine, Department of Internal Medicine, Section of Hematology-Oncology, One Baylor Plaza, Houston, TX, United States.;Baylor College of Medicine, Department of Internal Medicine, Section of Hematology-Oncology, One Baylor Plaza, Houston, TX, United States.;Baylor College of Medicine, Department of Internal Medicine, Section of Hematology-Oncology, One Baylor Plaza, Houston, TX, United States.;Baylor College of Medicine, Department of Internal Medicine, Section of Hematology-Oncology, One Baylor Plaza, Houston, TX, United States.;Baylor College of Medicine, Department of Internal Medicine, Section of Hematology-Oncology, One Baylor Plaza, Houston, TX, United States.",
"authors": "Higashiyama|Nicole|N|;Nangia|Julie|J|;Shafaee|Maryam Nemati|MN|;Chen|Nan|N|;Michael|Binu Liz|BL|;Rimawi|Mothaffar|M|;Hoyos|Valentina|V|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.cpccr.2020.100034",
"fulltext": "\n==== Front\n9918231203906676\n50827\nCurr Probl Cancer Case Rep\nCurr Probl Cancer Case Rep\nCurrent problems in cancer. Case reports\n2666-6219\n\n10.1016/j.cpccr.2020.100034\nnihpa1725845\nArticle\nDose-reduced trastuzumab deruxtecan can be safely used in liver failure and active leptomeningeal metastases\nHigashiyama Nicole a*\nNangia Julie ab\nShafaee Maryam Nemati ab\nChen Nan a\nMichael Binu Liz ab\nRimawi Mothaffar ab\nHoyos Valentina abc\na Baylor College of Medicine, Department of Internal Medicine, Section of Hematology-Oncology, One Baylor Plaza, Houston, TX, United States\nb Baylor College of Medicine, Lester and Sue Smith Breast Center, Dan L. Duncan Comprehensive Cancer Center, 7200 Cambridge St. 7th Floor, Houston, TX, United States\nc Baylor College of Medicine, Center for Cell and Gene Therapy, One Baylor Plaza, Room N1002, Houston, TX, United States\nCRediT authorship contribution statement\n\nNicole Higashiyama: Conceptualization, Writing - original draft, Writing - review & editing. Julie Nangia: Writing - review & editing. Maryam Nemati Shafaee: Writing - review & editing. Nan Chen: Writing - review & editing. Binu Liz Michael: Writing - review & editing. Mothaffar Rimawi: Writing - review & editing. Valentina Hoyos: Conceptualization, Writing - original draft, Writing - review & editing, Supervision.\n\n* Corresponding author. nicole.higashiyama@bcm.edu (N. Higashiyama).\n26 7 2021\n16 10 2020\n15 12 2020\n08 9 2021\n2 100034https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)\n\nTrastuzumab deruxtecan has been shown to have responses in heavily pretreated patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. However, the safety of this medication in patients with severe liver dysfunction and untreated or symptomatic central nervous system metastases is unknown. We describe a patient with metastatic HER2-positive breast cancer with liver failure and leptomeningeal metastases who was treated with dose-reduced trastuzumab deruxtecan. With treatment, the patient’s hyperbilirubinemia resolved and she demonstrated a response on imaging. She was dose-escalated to full dose with minimal adverse events.\n\nMetastatic breast cancer\nHER2\nAntibody-drug conjugate\nLiver failure\nLeptomeningeal metastases\n==== Body\npmcIntroduction\n\nTrastuzumab deruxtecan is an anti-HER2 humanized monoclonal antibody conjugated to a topoisomerase I inhibitor. In December 2019, the U.S. Food and Drug Administration (FDA) issued an accelerated approval for its use for the treatment of unresectable or metastatic HER2-positive breast cancer (mHER2+BC) after two or more anti-HER2-based regimens. This approval was granted based on the results of the DESTINY-Breast01 trial, an open-label, single-group, multicenter, phase 2 study showing a 60.9% overall response rate including 11 (6%) complete responses and a 16.4 month median progression-free survival in heavily pretreated patients (median 6 prior lines of therapy, including trastuzumab emtansine) with unresectable or mHER2+BC (Modi et al., 2020). These results are encouraging for patients with mHER2+BC, and trastuzumab deruxtecan has quickly been added to our anti-HER2 targeted treatment armamentarium. However, the role of trastuzumab deruxtecan in individuals with severe liver dysfunction or untreated or symptomatic central nervous system metastases (CNSm) is unclear since these patients were excluded from the study. Inclusion was limited to those with previously treated, stable CNSm and moderate hepatic dysfunction (total bilirubin ≤ 3 g/dL and aspartate transaminase (AST)/alanine transaminase (ALT) ≤ 5 times the upper limit of normal) (Modi et al., 2020). Thus, whether the administration of trastuzumab deruxtecan is safe in patients outside these parameters is unknown. This question is especially pertinent considering that 30–50% of mHER2+BC patients have or will develop brain metastases (Brufsky et al., 2011; Hurvitz et al., 2019; Pestalozzi et al., 2013) and 25–30% have liver involvement at initial metastatic presentation (Wu et al., 2017; Kennecke et al., 2010).\n\nHere we describe the case of a patient with both untreated leptomeningeal metastases and liver failure due to progressing liver metastases, who was treated with trastuzumab deruxtecan without significant toxicity and with an ongoing response to treatment, including normalization of her liver function tests and resolution of areas of leptomeningeal involvement.\n\nCase report\n\nA 45 year-old woman with estrogen receptor positive, progesterone receptor positive, HER2 positive (by fluorescent in situ hybridization), grade 3 invasive ductal carcinoma of the breast with metastases to the liver, bones, lymph nodes, pachymeninges, and leptomeninges, presented to the hospital in January 2020 with leg pain, right upper quadrant abdominal pain, and headache. At the time, she was being treated with trastuzumab, pertuzumab, goserelin, and exemestane. She had 4 lines of therapy previously including goserelin, letrozole, trastuzumab, and pertuzumab for 17 months; trastuzumab emtansine, goserelin, and letrozole for 2 months; capecitabine and lapatinib for 10 months; and docetaxel, trastuzumab, and pertuzumab for 4 months. She had also previously received radiation (3000 cGy in 10 fractions) to the bilateral mandibles for symptomatic inferior alveolar nerve involvement, as well as stereotactic radiosurgery (2700 cGy in 3 fractions) to a right parasagittal dural mass.\n\nWork-up for the abdominal and leg pain revealed stable bony metastases, but enlarging left axillary lymphadenopathy and multiple bilateral small pulmonary nodules. The hepatic metastases appeared stable on imaging. However, the liver appeared cirrhotic and she had acute cholestatic liver dysfunction (total bilirubin 2.5 mg/dL, alkaline phosphatase 620 U/L, ALT 51 U/L, and AST 216 U/L). Magnetic resonance cholangiopancreatography showed no evidence of obstruction. Hepatitis studies were negative. Exemestane was held due to concerns for cholestatic liver injury (LiverTox 2012) and she was discharged with follow-up.\n\nShe was re-admitted in February for anxiety and uncontrolled cancer-related pain. This time, her total bilirubin worsened to 3.8 mg/dL and her Eastern Cooperative Oncology Group performance status had declined to 3, so hospice was considered. However, the decision was made to reassess her treatment candidacy as an outpatient.\n\nAfter discharge, her total bilirubin continued to rise to 6.6 mg/dL with an alkaline phosphatase of 1188 U/L, AST of 250 U/L, and ALT of 42 U/L. Since she had been off exemestane for over four weeks, it was suspected that some degree of her liver dysfunction was attributable to worsened liver metastases. Brain imaging showed an increased 2.1 × 3.5 × 1.2 cm right occipitotemporal dural-based metastasis projecting into the leptomeninges, a new 1.1 × 0.9 cm dural-based metastasis along the parietal interhemispheric fissure, and mild increase in a right occipital calvarial metastasis (Fig. 1 A and 1 B). Radiation to these sites was considered, but with her worsening liver failure and improvement in her performance status to 2 with adequate pain control, the decision was made to treat her systemically. No lumbar puncture was performed for cerebral spinal fluid analysis prior to treatment since the imaging was highly suggestive of leptomeningeal involvement, she was rapidly deteriorating, and there were logistical constraints in obtaining a lumbar puncture in a timely manner. She was started on trastuzumab deruxtecan with a 25% dose-reduction (4 mg/kg). No next generation sequencing was available at this time to suggest other systemic treatment options.\n\nBy cycle 1 day 17, the patient’s leg pain resolved, bilirubin improved to 2.2 mg/dL, and performance status improved to 1. Imaging on cycle 2 day 6 showed a positive response with a 0.7 cm decrease in the left axillary lymphadenopathy and resolution of the pulmonary nodules. There was further improvement in the left axillary lymphadenopathy and hepatic metastases on imaging obtained after cycle 3. Additionally, the hyperbilirubinemia resolved (Fig. 2). Therefore, the patient’s treatment was escalated to full-dose trastuzumab deruxtecan. After 7 months of therapy, her disease continues to respond clinically with stable hepatic metastases on imaging after cycle 9 (Fig. 3) and reduced pain medication requirement. She has also shown near resolution of the dural metastases with no evidence of leptomeningeal and decreased pachymeningeal enhancement (Fig. 1 C and 1 D). Her only side effects have been a mild infusion reaction with cycle 1, asymptomatic grade 3 hypoproliferative anemia after cycle 1 with negative work-up for hemolysis or bleed, and worsening of her baseline anxiety requiring a serotonin-norepinephrine reuptake inhibitor.\n\nDiscussion\n\nIn the past year, the FDA has approved three new agents, trastuzumab deruxtecan, tucatinib, and neratinib, for the third-line treatment of patients with mHER2+BC, significantly increasing our therapeutic options in this poor prognosis setting. With the remarkable responses seen in the DESTINY-Breast01 trial, it will be necessary to determine the sequence of therapies that offers the most benefit to patients. This is particularly important in those who develop CNS and liver metastases, since they are associated with meaningful morbidity and mortality (Lee et al., 2008; Eichbaum et al., 2006). Moreover, they prove challenging, as not all drugs can penetrate the blood brain barrier and liver dysfunction limits our therapeutic options due to the high risk of toxicity.\n\nCNSm occur in up to 30–50% of mHER2+BC patients (Brufsky et al., 2011; Hurvitz et al., 2019; Pestalozzi et al., 2013). The mainstay of treatment has been surgery or radiation, which are associated with significant morbidity. Small molecule tyrosine kinase inhibitors lapatinib, neratinib, and tucatinib have the strongest evidence of CNS penetration and activity against CNSm with overall responses in combination with capecitabine between 30 and 65% (Murthy et al., 2020; Bachelot et al., 2013; Petrelli et al., 2017; Freedman et al., 2019). Therefore, these are the preferred systemic treatments in patients with active CNSm. However, in patients with concurrent high burden of systemic disease and visceral crisis (as was the case of our patient), probabilities of rapid systemic response are more promising with trastuzumab deruxtecan, making the decision between the two options challenging.\n\nThe role of anti-HER2 antibody-drug conjugates in treating CNSm is not established. Given their large molecular size, they have poor CNS penetration. However, studies have demonstrated that CNSm disrupt the blood brain barrier, which may contribute to some drug penetration (Lockman et al., 2010). Additionally, case series and retrospective studies have shown activity of the antibody-drug conjugate trastuzumab emtansine in CNSm, with response rates as high as 24–30% (Kalsi et al., 2015; Keith et al., 2016; Fabi et al., 2018; Bartsch et al., 2015). Thus far, trastuzumab deruxtecan has not been studied in untreated CNSm. The DESTINY-Breast01 trial included individuals with previously treated, stable CNSm and we eagerly await the full details on CNSm responses seen in this study (Jerusalem et al., 2020).\n\nAfter 5 cycles of trastuzumab deruxtecan, our patient had near resolution of her leptomeningeal involvement from a dural-based metastasis. It is possible that in this patient, the proximity of the metastasis to the blood brain barrier caused disruption to allow for drug penetration. Whether the same benefit of trastuzumab deruxtecan can be seen in parenchymal brain metastases warrants further investigation. Regardless, the ongoing response seen in our patient is remarkable given the particularly poor prognosis observed with leptomeningeal disease with a median survival of approximately 4 months (Franzoi and Hortobagyi, 2019).\n\nIn addition to leptomeningeal metastases, our patient exhibited a high burden of liver metastases with a cirrhotic appearance on imaging and liver failure. Hepatic dysfunction caused by liver metastases significantly limits our therapeutic options. Despite this, trastuzumab emtansine has been used in this setting with some evidence of benefit (Sharp and Johnston, 2015). However, which patients will benefit is unpredictable, since trastuzumab emtansine itself can cause severe hepatotoxicity (Diéras et al., 2013). Specifically, cases of liver failure and death have been associated with the development of nodular regenerative hyperplasia (Diéras et al., 2013).\n\nTransaminitis has been reported as a trastuzumab deruxtecan adverse effect. However, grade 3 or 4 AST elevations were only seen in 2% of patients (Modi et al., 2020) compared to 4.3% with trastuzumab emtansine (Verma et al., 2012). Though they are both antibody-drug conjugates, mouse models suggest that the hepatotoxicity of trastuzumab emtansine results from emtansine-associated intracellular damage of HER2 expressing hepatocytes due to upregulation of TNFα and apoptosis (Yan et al., 2015). Since trastuzumab deruxtecan is linked to a topoisomerase I inhibitor rather than a microtubule inhibitor, it remains to be seen whether a similar type of hepatotoxicity may occur. Irinotecan, another toposisomerase I inhibitor, has been associated with steatohepatitis, but not nodular regenerative hyperplasia (Robinson et al., 2012). This is the first reported use of trastuzumab deruxtecan in a patient with significant liver failure (Child-Pugh Class B). With treatment, her bilirubin normalized, indicating this might be the best choice of therapy for patients in this dire situation.\n\nConclusion\n\nHere we described a patient with mHER2+BC with liver failure and previously untreated leptomeningeal metastases who was safely treated with dose-reduced trastuzumab deruxtecan as fifth-line therapy. The patient’s hyperbilirubinemia resolved rapidly, enabling escalation to full-dose with minimal adverse events. She achieved both a significant systemic and CNS response. Therefore, the use of dose-reduced trastuzumab deruxtecan in severe liver dysfunction and in patients with leptomeningeal carcinomatosis should be investigated in prospective trials.\n\nFunding\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nFig. 1. Axial 3D brain volume (BRAVO) T1-weighted post-contrast brain magnetic resonance image (MRI) at baseline before trastuzumab deruxtecan treatment (A, B) and after 9 cycles of trastuzumab deruxtecan (C,D). (A), A 2.1 × 3.5 × 1.2 cm right occipitotemporal dural-based metastasis with projection into the leptomeninges and associated vasogenic edema (indicated by red arrow). (B), A 1.1 × 0.9 cm dural-based metastasis along the parietal interhemispheric fissure (indicated by red arrowhead). (C), Near resolution of the right occipitotemporal dural-based metastasis with leptomeningeal involvement. (D), Resolution of the dural-based metastasis along the parietal interhemispheric fissure.\n\nFig. 2. Total bilirubin levels during treatment with trastuzumab deruxtecan.\n\nFig. 3. Computed tomography of the liver with contrast at baseline before trastuzumab deruxtecan treatment (A, B) and after 9 cycles of trastuzumab deruxtecan (C, D). (A), Coronal view demonstrating a nodular liver contour and hepatomegaly with multiple subcentimeter hypoattenuating metastases throughout. (B), Axial view demonstrating multiple hypoattenuating liver lesions. (C), Coronal view demonstrating nodular contour but reduced hepatomegaly and less conspicuous hepatic metastases. (D), Axial view demonstrating decreased hepatic metastases.\n\nPatient consent statement\n\nWritten, informed consent for this publication was obtained from the patient.\n\nDeclaration of Competing Interest\n\nThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\n==== Refs\nReferences\n\nBachelot T , Romieu G , Campone M , , 2013. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol. 14 , 64–71. doi: 10.1016/S1470-2045(12)70432-1 . 23122784\nBartsch R , Berghoff AS , Vogl U , , 2015. Activity of T-DM1 in Her2-positive breast cancer brain metastases. Clin. Exp. Metastasis 32 , 729–737. doi: 10.1007/s10585-015-9740-3 . 26303828\nBrufsky AM , Mayer M , Rugo HS , , 2011. Central nervous system metastases in patients with HER2-positive metastatic breast cancer: incidence, treatment and survival in patients from registHER. Clin. Cancer Res 17 (14 ), 4834–4843. doi: 10.1148/1078-0432.CCR-10-2962 . 21768129\nDiéras V , Harbeck N , Budd GT , , 2013. Trastuzumab emtansine in human epidermal growth factor receptor 2-positive metastatic breast cancer: an integrated safety analysis. J. Clin. Oncol 32 , 2750–2757. doi: 10.1200/JCO.2012.43.3391 .\nEichbaum MHR , Kaltwasser M , Bruckner T , de Rossi TM , Schneeweiss A , Sohn C , 2006. Prognostic factors for patients with liver metastases from breast cancer. Breast Cancer Res. Treat 96 , 53–62. doi: 10.1007/s10549-005-9039-1 . 16319993\nFabi A , Alesini D , Valle E , , 2018. T-DM1 and brain metastases: clinical outcome in Her2-positive metastatic breast cancer. The Breast 41 , 137–143. doi: 10.1016/j.brast.2018.07.004 . 30092500\nFranzoi MA , Hortobagyi GN , 2019. Leptomeningeal carcinomatosis in patients with breast cancer. Crit. Rev. Oncol. Hemat 135 , 85–94. doi: 10.1016/j.critrevonc.2019.01.020 .\nFreedman RA , Gelman RS , Anders CK , , 2019. TBCRC 022: a phase II trial of neratinib and capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. J. Clin. Oncol 37 , 1081–1089. doi: 10.1200/JCO.18.01511 . 30860945\nHurvitz SA , O’Shaughnessy J , Mason G , , 2019. Central nervous system metastasis in patients with HER2-positive metastatic breast cancer: patient characteristics, treatment and survival from SystHERs. Clin. Cancer Res 25 (8 ), 2433–2441. doi: 10.1158/1078-0432.CCR-18-2366 . 30593513\nJerusalem G , Park YH , Yamashita T , , 2020. 138O CNS metastases in HER2-positive metastatic breast cancer treated with trastuzumab deruxtecan: DESTINY-Breast01 subgroup analyses. Ann. Oncol 31 (Supplement 2 ), S63–S64. doi: 10.1016/j.annonc.2020.03.239 .\nKalsi R , Feigenberg S , Kwok Y , Tkaczuk K , Mehta M , Chumsri S , 2015. Brain metastasis and response to ado-trastuzumab emtansine: a case report and literature review. Clin. Breast Cancer 15 (2 ), e163–e166. doi: 10.1016/j.clbc.2014.10.003 . 25454740\nKeith KC , Lee Y , Ewend MG , Zagar TM , Anders CK , 2016. Activity of trastuzumab-emtansine (TDM1) in HER2-positive breast cancer brain metastases: a case series. Cancer Treat. Commun 7 , 43–46. doi: 10.1016/j.ctrc.2016.03.005 . 27114895\nKennecke H , Yerushalmi R , Woods R , , 2010. Metastatic behavior of breast cancer subtypes. J. Clin. Oncol 28 , 327–377. doi: 10.1200/JCO.2009.25.9820 .\nLee SS , Ahn J−H , Kim MK , , 2008. Brain metastases in breast cancer: prognostic factors and management. Breast Cancer Res. Treat 111 , 523–530. doi: 10.1007/s10549-007-9806-2 . 17990100\nLiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Exemestane, 2012 (https://www.ncbi.nlm.nih.gov/books/NBK548926/)\nLockman PR , Mittapalli RK , Taskar KS , , 2010. Heterogeneous blood-tumor-barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. Clin. Cancer Res 16 (23 ), 5664–5678. doi: 10.1158/1078-0432.CCR-10-1564 . 20829328\nModi S , Saura C , Yamashita T , , 2020. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N. Engl. J. Med 382 , 610–621. doi: 10.1056/NEJMoa1914510 . 31825192\nMurthy RK , Loi S , Okines A , , 2020. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N. Engl. J. Med 382 (7 ), 597–609. doi: 10.1056/NEJMoa1914609 . 31825569\nPestalozzi BC , Holmes E , de Azambuja E , , 2013. CNS relapses in patients with HER2-positive early breast cancer who have and have not received adjuvant trastuzumab: a retrospective substudy of the HERA trial (BIG 1–01). Lancet Oncol. 14 , 244–248. doi: 10.1016/S1470-2045(13)70017-2 . 23414588\nPetrelli F , Ghidini M , Lonati V , , 2017. The efficacy of lapatinib and capecitabine in HER-2 positive breast cancer with brain metastases: a systematic review and pooled analysis. Eur. J. Cancer 84 , 141–148. doi: 10.1016/j.ejca.2017.07.024 . 28810186\nRobinson SM , Wilson CH , Burt AD , Manas DM , White SA , 2012. Chemotherapy-associated liver injury in patients with colorectal liver metastases: a systematic review and meta-analysis. Ann. Surg. Oncol 19 , 4287–4299. doi: 10.1245/s10434-012-2438-8 . 22766981\nSharp A , Johnston SRD , 2015. Dose-reduced trastuzumab emtansine: active and safe in acute hepatic dysfunction. Case Rep. Oncol 8 , 113–121. doi: 10.1159/000371720 . 25873876\nVerma S , Miles D , Gianni L , , 2012. Trastuzumab emtansine for HER2-positive advanced breast cancer. N. Engl. J. Med 367 (19 ), 1783–1791. doi: 10.1056/NEJ-Moa1209124 . 23020162\nWu Q , Li J , Zhu S , , 2017. Breast cancer subtypes predict the preferential site of distant metastases: a SEER based study. Oncotarget 8 (17 ), 27990–27996. doi: 10.18632/oncotarget.15856 . 28427196\nYan H , Endo Y , Shen Y , , 2015. Ado-trastuzumab emtansine targets hepatocytes via human epidermal growth factor receptor 2 to induce hepatotoxicity. Mol. Cancer Ther 15 (30 ), 480–490. doi: 10.1158/1535-7163.MCT-15-0580 . 26712117\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2666-6219",
"issue": "2()",
"journal": "Current problems in cancer. Case reports",
"keywords": "Antibody-drug conjugate; HER2; Leptomeningeal metastases; Liver failure; Metastatic breast cancer",
"medline_ta": "Curr Probl Cancer Case Rep",
"mesh_terms": null,
"nlm_unique_id": "9918231203906676",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34505091",
"pubdate": "2020-12-15",
"publication_types": "D016428:Journal Article",
"references": "31825192;25024070;30593513;28427196;16319993;27114895;30819451;30860945;20829328;23122784;21768129;28810186;23020162;31825569;17990100;25454740;25873876;26712117;30092500;22766981;20498394;26303828;23414588",
"title": "Dose-reduced trastuzumab deruxtecan can be safely used in liver failure and active leptomeningeal metastases.",
"title_normalized": "dose reduced trastuzumab deruxtecan can be safely used in liver failure and active leptomeningeal metastases"
} | [
{
"companynumb": "US-CELLTRION INC.-2021US012686",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRASTUZUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "The Polyomaviridae constitute a family of small DNA viruses infecting a variety of hosts. In humans, polyomaviruses can cause infections of the central nervous system, urinary tract, skin, and possibly the respiratory tract. Here we report the identification of a new human polyomavirus in plucked facial spines of a heart transplant patient with trichodysplasia spinulosa, a rare skin disease exclusively seen in immunocompromized patients. The trichodysplasia spinulosa-associated polyomavirus (TSV) genome was amplified through rolling-circle amplification and consists of a 5232-nucleotide circular DNA organized similarly to known polyomaviruses. Two putative \"early\" (small and large T antigen) and three putative \"late\" (VP1, VP2, VP3) genes were identified. The TSV large T antigen contains several domains (e.g. J-domain) and motifs (e.g. HPDKGG, pRb family-binding, zinc finger) described for other polyomaviruses and potentially involved in cellular transformation. Phylogenetic analysis revealed a close relationship of TSV with the Bornean orangutan polyomavirus and, more distantly, the Merkel cell polyomavirus that is found integrated in Merkel cell carcinomas of the skin. The presence of TSV in the affected patient's skin was confirmed by newly designed quantitative TSV-specific PCR, indicative of a viral load of 10(5) copies per cell. After topical cidofovir treatment, the lesions largely resolved coinciding with a reduction in TSV load. PCR screening demonstrated a 4% prevalence of TSV in an unrelated group of immunosuppressed transplant recipients without apparent disease. In conclusion, a new human polyomavirus was discovered and identified as the possible cause of trichodysplasia spinulosa in immunocompromized patients. The presence of TSV also in clinically unaffected individuals suggests frequent virus transmission causing subclinical, probably latent infections. Further studies have to reveal the impact of TSV infection in relation to other populations and diseases.",
"affiliations": "Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.",
"authors": "van der Meijden|Els|E|;Janssens|René W A|RW|;Lauber|Chris|C|;Bouwes Bavinck|Jan Nico|JN|;Gorbalenya|Alexander E|AE|;Feltkamp|Mariet C W|MC|",
"chemical_list": "D004270:DNA, Circular",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.ppat.1001024",
"fulltext": "\n==== Front\nPLoS PathogPLoS PathogplosplospathPLoS Pathogens1553-73661553-7374Public Library of Science San Francisco, USA 2068665910-PLPA-RA-2883R210.1371/journal.ppat.1001024Research ArticleDermatology/Skin Cancers, including Melanoma and LymphomaDermatology/Skin InfectionsEvolutionary Biology/Microbial Evolution and GenomicsVirologyVirology/Emerging Viral DiseasesVirology/Persistence and LatencyVirology/Virus Evolution and SymbiosisVirology/Viruses and CancerDiscovery of a New Human Polyomavirus Associated with Trichodysplasia Spinulosa in an Immunocompromized Patient Trichodysplasia Spinulosa-Associated Polyomavirusvan der Meijden Els \n1\nJanssens René W. A. \n2\nLauber Chris \n1\nBouwes Bavinck Jan Nico \n3\nGorbalenya Alexander E. \n1\nFeltkamp Mariet C. W. \n1\n\n*\n\n1 \nDepartment of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands\n\n2 \nDepartment of Dermatology, Jeroen Bosch Hospital, ‘s-Hertogenbosch, The Netherlands\n\n3 \nDepartment of Dermatology, Leiden University Medical Center, Leiden, The Netherlands\nImperiale Michael J. EditorUniversity of Michigan, United States of America* E-mail: m.c.w.feltkamp@lumc.nlConceived and designed the experiments: EvdM AEG MCWF. Performed the experiments: EvdM CL. Analyzed the data: EvdM CL AEG MCWF. Contributed reagents/materials/analysis tools: RWAJ JNBB AEG. Wrote the paper: EvdM RWAJ AEG MCWF.\n\n7 2010 29 7 2010 6 7 e100102419 3 2010 30 6 2010 van der Meijden et al.2010This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.The Polyomaviridae constitute a family of small DNA viruses infecting a variety of hosts. In humans, polyomaviruses can cause infections of the central nervous system, urinary tract, skin, and possibly the respiratory tract. Here we report the identification of a new human polyomavirus in plucked facial spines of a heart transplant patient with trichodysplasia spinulosa, a rare skin disease exclusively seen in immunocompromized patients. The trichodysplasia spinulosa-associated polyomavirus (TSV) genome was amplified through rolling-circle amplification and consists of a 5232-nucleotide circular DNA organized similarly to known polyomaviruses. Two putative “early” (small and large T antigen) and three putative “late” (VP1, VP2, VP3) genes were identified. The TSV large T antigen contains several domains (e.g. J-domain) and motifs (e.g. HPDKGG, pRb family-binding, zinc finger) described for other polyomaviruses and potentially involved in cellular transformation. Phylogenetic analysis revealed a close relationship of TSV with the Bornean orangutan polyomavirus and, more distantly, the Merkel cell polyomavirus that is found integrated in Merkel cell carcinomas of the skin. The presence of TSV in the affected patient's skin was confirmed by newly designed quantitative TSV-specific PCR, indicative of a viral load of 105 copies per cell. After topical cidofovir treatment, the lesions largely resolved coinciding with a reduction in TSV load. PCR screening demonstrated a 4% prevalence of TSV in an unrelated group of immunosuppressed transplant recipients without apparent disease. In conclusion, a new human polyomavirus was discovered and identified as the possible cause of trichodysplasia spinulosa in immunocompromized patients. The presence of TSV also in clinically unaffected individuals suggests frequent virus transmission causing subclinical, probably latent infections. Further studies have to reveal the impact of TSV infection in relation to other populations and diseases.\n\nAuthor Summary\nDiseases that occur exclusively in immunocompromized patients are often of an infectious nature. Trichodysplasia spinulosa (TS) is such a disease characterized by development of papules, spines and alopecia in the face. Fortunately this disease is rare, because facial features can change dramatically, as in the case of an adolescent TS patient who was on immunosuppressive drugs because of heart-transplantation. A viral cause of TS was suspected already for some time because virus particles had been seen in TS lesions. In pursuit of this unknown virus, we isolated DNA from collected TS spines and could detect a unique small circular DNA suggestive of a polyomavirus genome. Additional experiments confirmed the presence in these samples of a new polyomavirus that we tentatively called TS-associated polyomavirus (TSPyV or TSV). TSV shares several properties with other polyomaviruses, such as genome organization and proteome composition, association with disease in immunosuppressed patients and occurence in individuals without overt disease. The latter indicates that TSV circulates in the human population. Future studies have to show how this newly identified polyomavirus spreads, how it causes disease and if it is related to other (skin) conditions as well.\n==== Body\nIntroduction\nMembers of the polyomavirus family (Polyomaviridae) infect mammals (rodents, bovines, primates) and birds (fowl, psittacines), and can affect various organs. So far five human polyomaviruses have been described. Two of these, JC-polyomavirus (JCPyV or JCV) and BK-polyomavirus (BKPyV or BKV), are established pathogens in immunocompromized hosts causing progressive multifocal leukoencephalopathy in AIDS patients and nephropathy in renal transplant recipients, respectively. In 2007, two additional human polyomaviruses were described, KI-polyomavirus (KIPyV or KIV) and WU-polyomavirus (WUPyV or WUV) [1], [2], which were isolated from the respiratory tract and whose pathogenicity is still unclear. The most recently discovered human species concerns the Merkel cell polyomavirus (MCPyV or MCV) found to be integrated in a large proportion of Merkel cell carcinomas of the skin [3], but detected in apparently healthy skin, plucked eyebrow hairs and other cutaneous carcinomas as well [4]. The transforming, oncogenic potential of polyomaviruses was recognized long ago in rodents following natural infection, and after experimental infections with JCV or BKV causing tumors in newborn hamsters [5], [6]. Here we describe the identification of a new human polyomavirus that combines specific properties of other human polyomaviruses, as it infects the skin and seems to cause disease only in immunocompromized patients probably as the result of unrestricted virus and host cell proliferation, possibly the inner root sheath cells of hair follicles.\n\nTrichodysplasia spinulosa (TS), also known as pilomatrix dysplasia, cyclosporine-induced folliculodystrofy or virus-associated trichodysplasia, is a rare skin disease characterized by the development of follicular papules and keratin spines known as spicules [7], [8], [9], [10], [11], [12], [13], [14]. The lesions are most striking in the face, especially on the nose, eyebrows and auricles, but other parts of the body can be affected as well. The disease is accompanied by thickening of the skin and alopecia of eyebrows, sometimes also of lashes and scalp hairs, in some cases leading to distortion of facial features and a leonine appearance [8]. Histologically, TS is characterized by distended and abnormally maturated hair follicles with high numbers of inner root sheath cells containing excessive amounts of trichohyalin [7], [8], [9], [10], [11], [12], [13], [14]. From these aberrant follicles the keratin spicules originate that become 1–3 mm in length.\n\nTS is exclusively found in immunocompromized patients, such as solid organ transplant recipients and acute lymphocytic leukemia patients [7], [8], [9], [10], [11], [12], [13], [14]. Initially, the condition was described as a side-effect of cyclosporine treatment, but later it was also observed in patients treated with other immunosuppressive or chemotherapeutic drugs. In analogy with other diseases exclusively occurring in immunocompromized patients, an infectious etiology was suspected. In 1999, Haycox and coworkers for the first time by transmission electron microscopy (TEM) demonstrated the intracellular presence of virus particles probably belonging to the papovavirus family [8]. Since 2000 the papovaviruses are classified in separate families, the Papillomaviridae and Polyomaviridae. In subsequent TS case reports, the presence of crystalloid arranged clusters of 40-nm virus particles preferentially in the nuclei of inner root sheath cells was confirmed [11], [13], [14]. Shape, size and localization suggested the presence of a small, non-enveloped DNA virus, likely a polyomavirus, but attempts to culture or detect the virus using PCR methods based on polyomavirus or papillomavirus-specific primer sets failed [8], [13], [14].\n\nHere we describe a new case of TS and report the amplification, cloning and identification of a new human polyomavirus isolated from TS spicules. This virus was provisionally called TS-associated polyomavirus (TSPyV or TSV) and phylogenetic analysis was performed to determine its evolutionary position among the other known polyomaviruses. To investigate the putative causal relationship between TSV infection and TS, the clinical response after treatment with the anti-viral drug cidofovir was monitored, and TSV-specific quantitative PCR was developed to measure the TSV load in clinical samples before and after antiviral treatment. With this new PCR we also estimated the TSV prevalence in a group of unaffected immunosuppressed patients and provide evidence for TSV circulation outside TS patients as well.\n\nResults\nCase description\nIn the late spring of 2009, a 15 years old Caucasian male heart transplant patient was seen in the Dermatology outpatient clinic of the Jeroen Bosch Hospital because of spots and spines in the face. One and a half year prior to presentation, a year after transplantation and start of immune suppressive treatment, his skin condition had started to develop with desquamation of the eyebrows, gradually followed by the development of follicular, skin-colored, indurated papules on the eyebrows, nose, ears, malar-region and forehead (\nFigure 1A\n). Subsequent symptoms were loss of eyebrow hairs and partially of the eyelashes. From the enlarged follicular orifices, small hyperkeratotic white-yellowish spicules started to protrude on the eyebrows, nose and ears (\nFigure 1B\n). Comparable solitary hyperkeratotic papules and spicules also developed on the legs. Over a period of one year, as skin of his ears, eyebrows and nose had thickened, his overall facial appearance had changed dramatically.\n\n10.1371/journal.ppat.1001024.g001Figure 1 Clinical appearance and histology of the trichodysplasia spinulosa patient.\nFacial appearance at presentation is shown in panel A. Note the thickened skin, particularly on the nose and in the eyebrow region accompanied by central alopecia. Apart from the eyebrows and nose, papules are seen on the cheeks, chin, forehead and ears. Especially on the nose, but occasionally also in cheeks and chin, keratotic spicules protruded from the enlarged follicular orifices. Panel B shows a close-up of the nose at presentation with numerous papules and spicules. In panel C is shown a section of a formalin-fixed, paraffin-embedded biopsy of a hyperkeratotic follicular papule from the forehead. The epidermis reveals enlarged, hyperplastic hair bulbs and hypercornification within a distended follicular infundibulum (HE stain, 10×). Panel D shows a detail of the nose 3 months after topical cidofovir treatment. Papules and spicules have largely resolved and hairs have regained growth.\n\nIn the end of 2006 he had been transplanted elsewhere for dilated cardiomyopathy of unknown cause and was placed on immunosuppressive treatment. Transplantation was complicated by a cerebrovascular event and epilepsy due to embolization from the left ventricle. A year after transplantation he was treated for an EBV-positive large B-cell lymphoma with rituximab and lowering of the immunosuppressive treatment. At presentation in 2009, apart from the immunosuppressive regimen (tacrolimus 2.0 and 1.5 mg daily; mycophenolate mofetil 750 mg 2 dd; methylprednisolone 10 mg 1 dd), he was also using amplodipine (calcium-antagonist), pravastatine (statin) and levetiracetam (anti-epilepticum).\n\nAs the patient refused the taking of biopsies, an hematoxylin-eosin (HE)-stained section was retrieved, prepared from a biopsy taken previously of a hyperkeratotic papule from the eyebrow region, as well as a snap-frozen fragment thereof. The HE section showed substantially distended and enlarged hair follicles (\nFigure 1C\n). Some hair bulbs were hyperplastic and bulbous, encroaching on hair papillae that were diminished in size. Some hair follicles showed presence of poorly formed hairs. Attempts to demonstrate the presence of TSV particles by TEM in the biopsy fragment failed because of poor sample quality.\n\nThe constellation of findings was diagnostic of viral-associated TS in an immunosuppressed patient. Based on this diagnosis and the assumption that a polyomavirus was causing the disease, the patient was started on topical cidofovir 1% cream treatment twice a day. Gradually over the first three months the patient's condition improved considerably with diminution of the follicular spines, regrowth of eyebrow hair and reduction of the thickened skin of the ears and nose (\nFigure 1D\n), supporting the original diagnosis.\n\nIsolation, cloning and sequencing of the viral genome\nCombined with what has been described in the literature, the above observations indicated that the patient could carry a polyomavirus causing TS. To identify this virus, spicules collected from the nose were dissolved in lysis buffer and subjected to nucleic acid extraction. The extracted material was used as a template for rolling-circle amplification (RCA) [15]. Instead of taq-polymerase used in conventional PCR, the RCA-method employs the DNA-dependent φ29-polymerase, a proofreading enzyme that preferentially amplifies circular DNA while using random primers. The RCA product was cut with restriction enzymes and analyzed on gel revealing a number of bands (\nFigure 2\n). Based on the size of these fragments, the amplicon was estimated about 5000 base pairs (bp) in length. This size is typical for polyomavirus genomes; papillomavirus commonly have larger genomes of around 8000 bp. The presence and location of the specific enzyme restriction sites was later confirmed when the viral sequence was elucidated.\n\n10.1371/journal.ppat.1001024.g002Figure 2 Restriction analysis of the RCA product.\n\nEcoRV and XbaI digestion revealed one band of around 5000 bp. EcoRI digestion produced two bands of around 3600 and 1600 bp. After HindIII digestion 3 bands were visible of around 3000, 1500 and 400 bp. Sequence analysis later showed that HindIII digestion in fact produced four fragments of which the smallest, 378 and 364 bp, coincided on gel.\n\nThe 3600 and 1600-bp RCA fragments, obtained after EcoRI digestion (Figure 2), were ligated and cloned into plasmid pUC19. Sequencing of each fragment was started from primers located up and downstream of the pUC19 multiple cloning site. Sequential sequence reactions were performed on the cloned RCA fragments, each time using newly designed primers based on the previously obtained sequence. A list of primers used for this “primer walking” is shown in Table S1. Finally, all obtained sequences were assembled into one continuous (circular) DNA contig of 5232 nucleotides. With the use of the newly designed primers, the resolved sequence was verified and confirmed in the original RCA product by direct sequencing.\n\nTSV genome analysis\nBlast-mediated GenBank searches using the obtained 5232-bp circular DNA sequence as query consistently identified polyomaviruses as having most similar sequences. Analysis of this putative new viral genome revealed the presence of several open reading frames (ORFs) located on both strands. The orientation and relative size of these ORFs, as well as the presence of a non-coding control region (NCCR) in between, were similar to those of known polyomaviruses (\nFigure 3\n). Downstream of the NCCR that contains the origin of replication (ori), three putative late genes, VP1, VP2 and VP3, could be identified. Upstream of the NCCR, on the opposite strand, reside the candidate genes encoding the viral T antigens.\n\n10.1371/journal.ppat.1001024.g003Figure 3 Genome map of TSV.\nIndicated are the five identified ORFs representing the putative “early” genes encoding small and large T antigen, and the putative “late” genes encoding VP1, VP2 and VP3. The NCCR is placed on top and contains the putative ori. Nucleotide position 1 was chosen within the NCCR in the large T binding region. For a detailed view of the NCCR, see Figure 4A.\n\nIn the NCCR, a total of ten putative large T-binding sites could be identified, seven and three respectively on each strand (\nFigure 4\n). An A/T-rich domain, probably harboring the TATA box, is located downstream of the last large T-binding site. By analogy with most other human polyomaviruses and SV40, nucleotide position 1 of the genome was chosen within the NCCR, in large T-binding region.\n\n10.1371/journal.ppat.1001024.g004Figure 4 Detail of the TSV non-coding control region.\nIndicated are the putative large T-bindings sites located on both strands (gray-shaded boxes), the putative ori and putative TATA box (A/T-rich elements). Downstream of this area another two TSV putative large T-bindings sites are located, as well as one from KIV [1]. Nucleotide positions 1 are shown in white and underlined, except for MCV where the position 1 is shown in bold and underlined. For MCV two isolates are shown, MCV 339 and MCV350 [3].\n\nBecause of obvious similarities in genome length, organization and sequence, we propose to group this newly identified TS-associated virus among the polyomaviruses. Nucleotide positions, length and estimated mass of all putative viral genes and proteins, respectively, are listed in \nTable 1\n. The level of protein sequence similarity with other known (human) polyomaviruses in shown in \nTable 2\n. The TSV genome and putative gene sequences, as well as the putative protein amino acid sequences have been submitted to GenBank (accession number GU989205).\n\n10.1371/journal.ppat.1001024.t001Table 1 Overview of putative TSV genes and proteins.\nTSV\tCoding region (nt #)\tGC content (%)\tAmino acid number (n)\tCalculated mass (kDa)\t\nVP1\t1311-2438\t43,0\t376\t41,6\t\nVP2\t407-1345\t43,0\t313\t34,9\t\nVP3\t761-1345\t43,2\t195\t22,9\t\nSmall t\t5034-4438\t35,3\t199\t23,7\t\nLarge T 1\t5034-4795, 4363-2528\t37,0\t692\t79,7\t\nLarge T 2\t5034-4795, 4381-2528\t37,0\t698\t80,3\t\n For each of the putative TSV genes the coding region and GC-content is shown. For the putative TSV proteins the amino acid number and the estimated mass are shown.\n\n10.1371/journal.ppat.1001024.t002Table 2 Amino acid sequence similarities between putative TSV proteins and those of other polyomaviruses.\nTSV protein\tAmino acid sequence similarity (%)\t\n\tJCV\tBKV\tKIV\tWUV\tMCV\tSV40\tOPyV1\t\nVP1\t50,7\t52,5\t21,9\t24,1\t50,6\t52,9\t77,7\t\nVP2\t33,0\t33,0\t13,9\t13,0\t30,0\t32,0\t88,3\t\nVP3\t32,8\t32,2\t12,4\t11,4\t22,9\t31,1\t88,7\t\nSmall t\t34,0\t33,2\t32,0\t30,4\t34,7\t33,7\t70,9\t\nLarge T 1\t42,6\t41,1\t44,0\t43,9\t42,0\t39,6\t87,7\t\nLarge T 2\t42,3\t40,8\t43,6\t43,7\t43,0\t39,3\t88,4\t\n For each of the putative TSV proteins, the amino acid sequence similarity is shown in comparison to the proteins of other known human polyomaviruses, SV40 and the Bornean orangutan polyomavirus (OPV1).\n\nTSV T antigen analysis\nLike in all other polyomaviruses, the putative TSV small and large T antigens are expressed from a common primary transcript subject to alternative splicing [16], [17] (Figure 3), and share their N-terminal part of 80 amino acids in length. The most likely large T splice products were compared to the large T amino acid sequences of other known polyomaviruses producing two possible versions of the TSV large T antigen that differ only 6 amino acids in size. Version 1 was used for further analyses (Tables 1 and 2).\n\nThe putative TSV large T antigen contains characteristic sequence motifs in different domains, such as the J-domain, the ori DNA-binding domain and an ATPase/helicase domain (\nFigure 5\n). Within the N-terminal J-domain the highly conserved HPDKGG amino acid sequence is located, important for efficient polyomavirus DNA replication, transformation and virion assembly [18], [19]. Other characteristic polyomavirus large T sequence signatures are the pRb family-binding motif and a nuclear localization signal downstream of the J-domain [18]. In the ATPase/helicase domain, a zinc finger motif is recognized, two NTPase/helicase “Walker” motifs and an SF3 motif [20]. A sequence putatively involved in p53 complex formation that matches the p53-binding motif described by Pipas and coworkers (GPX1X2X3GKT [18]), overlaps with the “Walker” A motif located within the ATPase/helicase region shown in Figure 5\n[19], [21]. In addition to the N-terminal J-domain shared with the large T antigen and similar to other known polyomaviruses, the putative TSV small T antigen contains protein phosphatase 2A subunit-binding motifs (not shown) [19], [21].\n\n10.1371/journal.ppat.1001024.g005Figure 5 Amino acid sequence of the TSV large T protein.\nIndicated are three major domains found in the large T amino acid sequence; the J-domain (blue-shaded box), the ori DNA-binding domain (yellow-shaded box) and the helicase domain (green-shaded box). Within the J-domain the putative locations of conserved region 1 and the HPDKGG motif are depicted. Downstream of the J-domain, a pRb family-binding motif and nuclear localization signal are located. In the helicase domain, a zinc finger motif, NTPase-binding ‘Walker’ motifs A and B and an helicase SF3 (superfamily 3) motif C are located.\n\nPhylogenetic analysis\nComplete sequences of 20 polyomavirus genomes were selected to represent the Polyomaviridae family in the RefSeq database [22]. They include 5 human, 4 avian and 11 non-human mammalian polyomavirus species. Except for the hamster polyomavirus (sequence incomplete) and Simian agent 12 (almost identical to simian virus 12), all of these plus the genome of the recently sequenced Sumatran orangutan polyomavirus [23] species were included in our analysis. We produced multiple sequence alignments and conducted phylogenetic analyses to determine the evolutionary position of TSV with respect to other members of the family (\nFigure 6\n).\n\n10.1371/journal.ppat.1001024.g006Figure 6 Phylogenetic analysis of known polyomaviruses and TSV.\nBayesian posterior probability trees are shown for VP1 (A), VP2 (B), large T antigen (C) and a concatenation of all three (D). Numbers at branch points represent posterior probability support values and the scale bar is given in average number of substitutions per amino acid position. Major clades in the trees are highlighted using colored triangles. The following viruses are shown: Simian virus 40 (SV40), Goose hemorrhagic polyomavirus (GHPyV), Simian virus 12 (SV12), Squirrel monkey polyomavirus (SquiPyV), Finch polyomavirus (FPyV), Crow polyomavirus (CPyV), Bovine polyomavirus (BPyV), Merkel cell polyomavirus (MCPyV), WU Polyomavirus (WUPyV), KI polyomavirus Stockholm 60 (KIPyV), Budgerigar fledgling polyomavirus (BFPyV), African green monkey polyomavirus (AGMPyV), JC polyomavirus (JCPyV), BK polyomavirus (BKPyV), Murine polyomavirus (MPyV), Murine pneumotropic virus (MuPtV), Myotis polyomavirus VM-2008 (MyPyV), Bornean orangutan polyomavirus isolate Bo (OraPyV1), Sumatran orangutan polyomavirus isolate Pi (OraPyV2) and Trichodysplasia spinulosa-associated polyomavirus (TSPyV).\n\nThe phylogenetic analysis involving VP1, VP2 and large T antigen, as well as a merged set of these proteins, recognized seven clades among polyomaviruses (colored triangles in Figure 6). In all trees analyzed, TSV was found to form a tight monophyletic cluster with the Bornean orangutan polyomavirus (OraPyV1) (violet clade in Figure 6). The distances separating these two closely related viruses resemble those found between JCV, BKV, SV40 and SV12 that form another compact monophyletic cluster (dark green clade in Figure 6). These findings support the classification of TSV as a new polyomavirus species rather than a strain of any of the known species.\n\nIn trees based on the VP2, large T antigen or the combination of VP1, VP2 and large T proteins, TSV and OraPyV1 are found within a monophyletic group formed by MCV, Sumatran orangutan polyomavirus, murine polyomavirus and African green monkey polyomavirus (yellow clade in Figure 6). The position of the TSV/OraPyV1 branch within this clade somewhat varies between trees, but consistently splits off the cluster trunk after the basal African green monkey polyomavirus lineage. In the VP1 tree, TSV and OraPyV1 form a separate clade, although this separation should be viewed with some caution since VP1 is the least conserved protein and the lineage branching in the yellow cluster is poorly resolved (Figure 6).\n\nTSV prevalence\nThe rare occurrence of TS suggests the (sub-clinical) circulation of TSV in larger populations outside this patient cohort. To investigate this possibility we developed three TSV-targeted quantitative PCR assays. Primers and probes were chosen in the VP1 and Large T genes, and in the NCCR, respectively, and listed in Table S2. As expected on the basis of chosen primer and probe sequences, none of the TSV PCRs recognized any of the other human polyomaviruses when performed on JCV-positive cerebrospinal fluids (n = 5), BKV-positive blood plasmas (n = 20), KIV or WUV-positive respiratory samples (n = 20) and MCV-positive plucked eyebrow hairs (n = 30)(data not shown). In contrast, each TSV PCR detected the presence of TSV DNA in the patient's biopsy fragment and in the plucked spicules from the nose. Calculation of the viral load in both samples revealed a mean TSV copy number of 2×105 per cell.\n\nTo estimate the prevalence of TSV in immunosuppressed hosts, we analyzed a set of plucked eyebrows from long-term immunosuppressed renal transplant patients. Three out of 69 transplant patients (4%) were TSV-positive. The viral copy numbers detected in the plucked hairs of three of these patients were below one TSV copy per cell and, therefore, much lower than those detected in the patient's biopsy and spicules. Analysis of the patient's plucked eyebrow hairs collected six months after cidofovir treatment revealed a TSV load of 104 copies per cell in all three PCRs. Spicules collected from untreated solitary lesions located on the legs contained amounts of TSV comparable to those detected in the spicules from the patient's nose before treatment, 3×105 copies/cell.\n\nDiscussion\nWith the discovery of TSV the total number of described human polyomaviruses is brought to six. Pathogenicity profiles have been established for JCV and BKV, to some extent for MCV, but not yet for KIV and WUV [24], [25]. Although not definitive, the evidence presented for TSV with regard to the clinical entity of TS can be considered reasonably strong. Previously, electron micrographs have shown the presence of a polyoma-like virus in nuclei of inner root sheath cells [8], [11], [13], [14]. These cells lay at the base of the distended and enlarged hair follicles that give rise to papule and spicule formation, the clinical hallmarks of the disease. From these spicules we could isolate the TSV genome and detect large amounts of the virus.\n\nThe rapid response of clinical signs to cidofovir treatment, also suggested a causal relationship between TSV and disease. Concomitantly a reduction in viral load was observed, but not as pronounced as expected based on the clinical response. To what extent TSV loads measured in plucked hairs and in spicules can be compared, and whether the difference in load measured between the two reflect the actual reduction in TSV load is unclear at the moment. Whether a threshold exists in TSV load, above which the clinical signs of TSV infection start to develop, is not known. Detection of TSV in high copy numbers in samples from earlier reported TS cases should provide further evidence for the pathogenicity of TSV.\n\nOver the last years, different and often highly sophisticated methods for the detection of previously unknown viruses have been developed. RCA is a rather simple technique that takes advantage of the property of φ29-polymerase to preferentially amplify circular DNA while using random primers [15]. By strand displacement synthesis, a high molecular-weight DNA is produced containing multiple linear copies of the circular genome. The validity of this approach was demonstrated by the discovery of a number of newly identified papilloma and polyomaviruses [26], [27], [28], [29], [30]. Limitations of this method with respect to the minimal excess amount of viral over genomic DNA or maximum length of the viral genome are not exactly known. The absence of background smears or bands in our preparation shown in Figure 2 suggested a relative excess of circular (viral) DNA within the RCA product preparation, which was confirmed by qPCR on the spicules.\n\nAnalysis of the TSV genome revealed five putative genes probably encoding the VP1, VP2 and VP3 capsid antigens and the small and large T antigens. For the latter we have identified two putative splice variants, large T antigen 1 and 2. We found no ORF upstream of the TSV VP2 gene, indicating the absence of an LP1/Agno protein. Also the presence of alternative T proteins, such as middle T, seems unlikely. TSV lacks a third ORF within the T-antigen coding region as found in rodent polyomaviruses that encodes a middle T antigen, and no corresponding splice junctions were found. Further experimental investigation of TSV transcription is required to elucidate which (additional) TSV genes are expressed and how this is regulated.\n\nWithin the TSV large T protein several characteristic motifs could be located, including those required for binding the tumor-suppressor proteins pRb and p53. As shown for other well characterized polyomaviruses and also for papillomaviruses, binding and inactivation of these proteins promote cell transformation [19], [21], [31], a property that to some extent is shared by these small DNA (tumor) viruses. For high-risk human papillomaviruses oncogenicity has been established in the development of anogenital carcinomas. Integration of MCV probably plays a role in Merkel-cell carcinoma development [3]. If TSV possesses transformational properties and may play a part in carcinogenesis remains to be studied. In that respect, it is necessary to sort out whether TSV is potentially involved in other (hyper)proliferative (skin) diseases as well. For MCV for instance, observations have been made supporting a role also in development of cutaneous squamous-cell carcinomas [32].\n\nPhylogenetic analysis of 20 fully sequenced polyomaviruses, including TSV, suggests the existence of seven polyomavirus clades. In all trees in Figure 6, substantial protein and virus-specific differences in branch lengths representing evolutionary distances were observed, e.g. between KI and WU polyomavirus in the VP1 and VP2 tree, and goose hemorrhagic, crow, finch and budgerigar fledgling polyomavirus in the large T antigen tree. In combination with some topological incongruence of the three protein-specific trees, these observations are indicative of a complex evolutionary history for most polyomaviruses.\n\nOraPyV1 was isolated from blood of wild-caught and housed Bornean orangutans. Potentially, the properties of this virus, which remains poorly characterized beyond the genome sequence [23], could be insightful for understanding TSV. The murine and African green monkey polyomaviruses were isolated from leukemic extracts [33] and lymphoblastoid cells [34], respectively, also indicative of systemic infection. MCV was isolated from a Merkel-cell carcinoma and has been detected in other samples as well, including healthy skin biopsies, squamous-cell carcinomas, plucked hairs, and recently in respiratory samples as well [4], [32], [35], [36], [37], [38]. Initial attempts to detect TSV in other than skin-derived materials, such as blood plasma or serum, urine, cerebrospinal fluid failed. So far, we could detect TSV only in trichodysplasia tissue, spicules and plucked eyebrow hairs suggestive of a tropism specific for squamous epithelium, but larger studies are needed to confirm this finding.\n\nAlthough the occurrence of TS is limited to severely immunocompromized patients, this implies that TSV would be present in larger, probably immunocompetent populations as well. By analogy with most human polyomaviruses, one could anticipate that TSV is highly immunogenic and infects many people, probably early in life without apparent disease [39], [40]. Further (sero)epidemiological studies have to reveal if this indeed is the case and whether TSV causes low-level persistent (latent) infection, as described for other polyomaviruses.\n\nAlthough we have tested thus far only a limited number of individuals, TSV was detected in another three unrelated immunosuppressed patients without signs of trichodysplasia. This would be compatible with occasional infections from an unknown reservoir. In view of the lack of any epidemiological marker of the disease, however, it seems more likely the virus is common among humans but generally without causing disease, comparable to for instance JCV and BKV. In that case, at least in adults and in plucked eyebrow hairs, (latent) TSV loads may often be too low to be detected by our current assays. Although the eyebrow region is particularly affected in TS and eyebrow hairs were shown suitable material to detect (polyoma)viruses [4], [41], with 50% MCV-positivity in this study (data not shown) comparable to what Wieland and coworkers have found [4], it is not known at the moment whether eyebrow hairs represent a suitable clinical sample to detect low level TSV infections.\n\nIn conclusion, a new human polyomavirus was discovered and identified as the possible cause of TS in an immunocompromized patient. We provided evidence for the presence of TSV also among unaffected patients suggestive of subclinical, possibly latent infection. Additional studies in different populations and age groups using different clinical materials are needed to establish the (sero)prevalence and epidemiology of TSV infections, and its possible relation to the occurrence of other (skin) diseases, including cancer. For a general picture, these epidemiological studies should be complemented with experimental studies on TSV replication, transcription and transformation.\n\nMaterials and Methods\nEthics statement\nThe TS patient and his mother gave oral consent to collect spicules and eyebrow hairs for viral diagnosis and treatment monitoring. The Medical Ethics Committee of the LUMC declared in writing that no formal ethical approval was needed to analyze these clinically obtained materials. Written consent from the patient (minor) and his legal guardian (mother) was obtained for publication of his case and for showing his pictures.\n\nPlucked eyebrow hair samples from a population of renal transplant patients visiting the Dermatology outpatient clinic of the LUMC were obtained after informed oral consent from the subjects, which was documented in the patient files. Subject's written approval was not collected for this purpose (plucking of eyebrow hairs), as oral consent was considered appropriate in this case by the Medical Ethics Committee of the LUMC who approved of the study (Protocol P07.024: Risk factors for non-melanoma skin cancer/Genetic and environmental risk factors for the development of skin cancer in organ-transplant recipients).\n\nSample collection and DNA isolation\nTen spicules from the nose collected with sterile tweezers in a sterile vial were shipped to the Leiden University Medical Center (LUMC) at room temperature. Upon arrival the plugs were dissolved in a proteinase K-containing lysis buffer for overnight incubation at 56°C. Total DNA was isolated with the QIAamp DNA Mini Kit (Qiagen) according to the QIAmp tissue protocol, with some minor alterations [42]. In parallel, approximately 100 ng commercially available human genomic DNA (Promega) was extracted as a negative isolation control.\n\nRolling circle amplification (RCA)\nThe TempliPhi 100 RCA Kit (GE Healthcare, UK Limited) was used following manufacturer's instructions with some slight modifications. In brief, 1 µl, 1∶100 of the isolated total DNA, was diluted in 5 µl sample buffer, denatured at 95°C for 3 minutes and cooled down slowly to 4°C to allow primer annealing. Meanwhile a premix of 5 µl reaction buffer, 0.2 µl TempliPhi enzyme (bacteriophage ϕ29 DNA polymerase) and an extra 450 µM of each dNTP was prepared and added to the denatured DNA in sample buffer. The RCA reaction was preformed at 30°C for 16 hours followed by inactivation of the enzyme at 65°C for 10 minutes. The RCA product was stored at −20°C.\n\nGenomic sequencing, assembly and analysis\nThe RCA product was diluted 1∶1 in miliQ H2O and 2 µl was digested with EcoRV, HindIII, EcoRI or XbaI. The two fragments of the EcoRI digestion were isolated from gel, ligated and cloned into pUC19, and subsequently sequenced using M13 forward and reverse primers. The resulting sequences were used as a template to design new primers located at the end of the newly identified sequences and listed in Table S1. Sequence reactions were carried out with the BigDye Terminator kit (Applied Biosystems) and analyzed on an ABI Prism 3130 Genetic Analyzer (Applied Biosystems).\n\nContig sequence assembly was performed with ContigExpress, included in the vector NTI software package program, that uses CAP3 computations to drive the assembly process [43]. Putative splice donor and acceptor sites were identified based on consensus splice donor and acceptor sequences as published [44], [45], and automated splice-site predictions (http://zeus2.itb.cnr.it/~webgene/wwwspliceview.html). Putative large T binding sites within the NCCR were identified according to described motifs [46].\n\nDomain searches within the TSV large and small T antigen sequences were performed against the domain profile database SCOP [47] using the HHsearch software [48]. Hits against all 3 domains were strongly significant (E-values <E-12).\n\nSequence alignments and phylogenetic analysis\nAmino acid sequence similarities between the putative TSV gene products and those of other polyomaviruses, as shown in Table 2, were calculated with the AlignX program in vector NTI version 11, which uses the ClustalW algorithm with default alignment parameters.\n\nFor the phylogenic analyses all available polyomavirus genome sequences present in the RefSeq database in December 2009 were downloaded [22]. The Sumatran orangutan polyomavirus [23] and the identified TSV genome sequences were added to this set. The following genome sequences were included in the analysis: Simian virus 40 (NC_001669), Goose hemorrhagic polyomavirus (NC_004800), Simian virus 12 (NC_012122), Squirrel monkey polyomavirus (NC_009951), Finch polyomavirus (NC_007923), Crow polyomavirus (NC_007922), Bovine polyomavirus (NC_001442), Merkel cell polyomavirus (NC_010277), WU Polyomavirus (NC_009539), KI polyomavirus Stockholm 60 (NC_009238), Budgerigar fledgling polyomavirus (NC_004764), African green monkey polyomavirus (NC_004763), JC polyomavirus (NC_001699), BK polyomavirus (NC_001538), Murine polyomavirus (NC_001515), Murine pneumotropic virus (NC_001505), Myotis polyomavirus VM-2008 (NC_011310), Bornean orangutan polyomavirus isolate Bo (FN356900), Sumatran orangutan polyomavirus isolate Pi (FN356901) and Trichodysplasia spinulosa-associated polyomavirus (GU989205).\n\nMultiple amino acid alignments were compiled for VP1, VP2 and large T antigen using the Muscle program [49], followed by manual inspection assisted by the Viralis software platform [50]. For VP2 and large T antigen, only partial alignments were used covering, respectively, the part not overlapping with VP1 (positions 407 to 1307 in the TSV genome sequence) and the large exon including the helicase domain (positions 4130 to 2600 in the TSV genome sequence). The three protein-specific alignments and their concatenation were submitted to phylogenetic analyses.\n\nBayesian posterior probability trees were compiled utilizing the BEAST software [51]. MCMC chains (two per dataset) were run for 2 million steps (10% burn-in, sampled every 50 generations) under the WAG amino acid substitution model [52], and rate heterogeneity among sites (gamma distribution with 4 categories). For each analysis three molecular clock models (strict, relaxed with lognormal distribution, relaxed with exponential distribution) were tested [53]. The more complex model, e.g. relaxed molecular clock, was favored over the simpler model, e.g. strict molecular clock, if the Bayes factor (ratio of tree likelihoods) was bigger than five [54]. Convergence of runs was verified and Bayes factors were estimated using Tracer software (http://beast.bio.ed.ac.uk/Tracer).\n\nPCR development and testing\nFor the detection of TSV DNA, three real-time quantitative PCRs were developed with primers and Taqman probes located in the NCCR, and the VP1 and Large T ORFs, respectively (Table S2). Primers and probes were chosen with the help of Beacon Designer software (Premier Biosoft). The VP1 3′ primer had a 84% match with BKV, but none of the chosen TSV probes had similarities with any of the other known polyomaviruses.\n\nThe 50 µl PCR reactions consisted of 1× GeneAmp PCR buffer (15 mM Tris-HCl [pH 8,0], 50 mM KCl, 3,6 mM MgCl, 0,3 mM of each dNTP, 15 pmol of each primer, 7,5 pmol probe and 2 U of AmpliTaq Gold polymerase (Applied Biosystems). Real-time PCR was performed in the iCycler (Biorad) and cycle conditions are 9′ at 95°C, followed by 50 cycles of amplification (94°C for 1 min. and 65°C for 1 min.). TSV copy number was calculated against a plasmid titration series of pUC19-TSV included in each PCR assay that contains the full length TSV genome cloned in XbaI. Cell number was calculated with a PCR specific for the beta-actin gene, which was run in parallel on a dilution series of human genomic DNA (Promega). The sensitivity of each TSV PCR was found to be between 1–10 TSV genome copies.\n\nThe cerebrospinal fluids, blood plasmas and respiratory samples with proven JCV-, BKV-, KIV- or WUV-positivity used for validation of the developed TSV-specific PCRs were selected from clinical samples routinely send for viral diagnosis to the LUMC, Dept of Medical Microbiology. The plucked eyebrow hair samples were obtained with written permission from renal transplant patients visiting the Dermatology outpatient clinic of the LUMC.\n\nSupporting Information\nTable S1 List of TSV primers used for primer-walking and sequencing.\n\n(0.49 MB TIF)\n\nClick here for additional data file.\n\n Table S2 List of TSV primers and probes used for quantitative PCR.\n\n(0.24 MB TIF)\n\nClick here for additional data file.\n\n Ann Vossen is thanked for bringing the case under our attention, and Louis Kroes and Eric Snijder for critically reading the manuscript and helpful discussions. Futhermore, we thank Alexander Kravchenko, Dmitry Samborsky and Igor Sidorov for administrating Viralis software, and Eric Claas for quantitative PCR primer and probe design.\n\nThe authors have declared that no competing interests exist.\n\nAlexander E. Gorbalenya was partially supported by the Netherlands Bioinformatics Center BioRange SP 3.2.2 grant (http://www.nbic.nl/research/biorange/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n==== Refs\nReferences\n1 Allander T Andreasson K Gupta S Bjerkner A Bogdanovic G Persson MA Dalianis T Ramqvist T Andersson B 2007 Identification of a third human polyomavirus. J Virol 81 4130 4136 17287263 \n2 Gaynor AM Nissen MD Whiley DM Mackay IM Lambert SB Wu G Brennan DC Storch GA Sloots TP Wang D 2007 Identification of a novel polyomavirus from patients with acute respiratory tract infections. PLoS Pathog 3 e64 17480120 \n3 Feng H Shuda M Chang Y Moore PS 2008 Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 319 1096 1100 18202256 \n4 Wieland U Mauch C Kreuter A Krieg T Pfister H 2009 Merkel cell polyomavirus DNA in persons without merkel cell carcinoma. Emerg Infect Dis 15 1496 1498 19788824 \n5 Abend JR Jiang M Imperiale MJ 2009 BK virus and human cancer: Innocent until proven guilty. Seminars in Cancer Biology 19 252 260 19505653 \n6 Maginnis MS Atwood WJ 2009 JC Virus: An oncogenic virus in animals and humans? Seminars in Cancer Biology 19 261 269 19505654 \n7 Chastain MA Millikan LE 2000 Pilomatrix dysplasia in an immunosuppressed patient. J Am Acad Dermatol 43 118 122 10863236 \n8 Haycox CL Kim S Fleckman P Smith LT Piepkorn M Sundberg JP Howell DN Miller SE 1999 Trichodysplasia spinulosa–a newly described folliculocentric viral infection in an immunocompromised host. J Investig Dermatol Symp Proc 4 268 271 \n9 Heaphy MR Jr Shamma HN Hickmann M White MJ 2004 Cyclosporine-induced folliculodystrophy. J Am Acad Dermatol 50 310 315 14726894 \n10 Lee JS Frederiksen P Kossard S 2008 Progressive trichodysplasia spinulosa in a patient with chronic lymphocytic leukaemia in remission. Australas J Dermatol 49 57 60 18186853 \n11 Osswald SS Kulick KB Tomaszewski MM Sperling LC 2007 Viral-associated trichodysplasia in a patient with lymphoma: a case report and review. J Cutan Pathol 34 721 725 17696921 \n12 Sadler GM Halbert AR Smith N Rogers M 2007 Trichodysplasia spinulosa associated with chemotherapy for acute lymphocytic leukaemia. Australas J Dermatol 48 110 114 17535200 \n13 Sperling LC Tomaszewski MM Thomas DA 2004 Viral-associated trichodysplasia in patients who are immunocompromised. J Am Acad Dermatol 50 318 322 14726896 \n14 Wyatt AJ Sachs DL Shia J Delgado R Busam KJ 2005 Virus-associated trichodysplasia spinulosa. Am J Surg Pathol 29 241 246 15644782 \n15 Johne R Muller H Rector A van Ranst M Stevens H 2009 Rolling-circle amplification of viral DNA genomes using phi29 polymerase. Trends in Microbiology 17 205 211 19375325 \n16 Noble JCS Prives C Manley JL 1986 In vitro splicing of simian virus 40 early pre mRNA. Nucl Acids Res 14 1219 1235 3005968 \n17 White MK Safak M Khalili K 2009 Regulation of Gene Expression in Primate Polyomaviruses. J Virol 83 10846 10856 19640999 \n18 Pipas JM 1992 Common and unique features of T antigens encoded by the polyomavirus group. J Virol 66 3979 3985 1318392 \n19 Sullivan CS Pipas JM 2002 T Antigens of Simian Virus 40: Molecular Chaperones for Viral Replication and Tumorigenesis. Microbiol Mol Biol Rev 66 179 202 12040123 \n20 Gorbalenya AE Koonin EV Wolf YI 1990 A new superfamily of putative NTP-binding domains encoded by genomes of small DNA and RNA viruses. FEBS Letters 262 145 148 2156730 \n21 Ahuja D Saenz-Robles MT Pipas JM 2005 SV40 large T antigen targets multiple cellular pathways to elicit cellular transformation. Oncogene 24 7729 7745 16299533 \n22 Pruitt KD Tatusova T Maglott DR 2007 NCBI reference sequences (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic Acids Res 35 D61 D65 17130148 \n23 Groenewoud MJ Fagrouch Z van Gessel S Niphuis H Sasnauskas K Warren KS Heeney JL Verschoor EJ 2010 Characterization of novel polyomaviruses from Bornean and Sumatran orangutans. J Gen Virol 91 653 658 19923267 \n24 Dalianis T Ramqvist T Andreasson K Kean JM Garcea RL 2009 KI, WU and Merkel cell polyomaviruses: a new era for human polyomavirus research. Semin Cancer Biol 19 270 275 19416753 \n25 Jiang M Abend JR Johnson SF Imperiale MJ 2009 The role of polyomaviruses in human disease. Virology 384 266 273 18995875 \n26 Bennett MD Woolford L Stevens H van Ranst M Oldfield T Slaven M O'Hara AJ Warren KS Nicholls PK 2008 Genomic characterization of a novel virus found in papillomatous lesions from a southern brown bandicoot (Isoodon obesulus) in Western Australia. Virology 376 173 182 18440042 \n27 Johne R Wittig W Fernandez-de-Luco D Hofle U Muller H 2006 Characterization of Two Novel Polyomaviruses of Birds by Using Multiply Primed Rolling-Circle Amplification of Their Genomes. J Virol 80 3523 3531 16537620 \n28 Rector A Bossart GD Ghim SJ Sundberg JP Jenson AB van Ranst M 2004 Characterization of a Novel Close-to-Root Papillomavirus from a Florida Manatee by Using Multiply Primed Rolling-Circle Amplification: Trichechus manatus latirostris Papillomavirus Type 1. J Virol 78 12698 12702 15507660 \n29 Stevens H Rector A Bertelsen MF Leifsson PS van Ranst M 2008 Novel papillomavirus isolated from the oral mucosa of a polar bear does not cluster with other papillomaviruses of carnivores. Veterinary Microbiology 129 108 116 18215475 \n30 Verschoor EJ Groenewoud MJ Fagrouch Z Kewalapat A van Gessel S Kik MJL Heeney JL 2008 Molecular characterization of the first polyomavirus from a New World primate: squirrel monkey polyomavirus. J Gen Virol 89 130 137 18089736 \n31 Moens U Van Ghelue M Johannessen M 2007 Oncogenic potentials of the human polyomavirus regulatory proteins. Cellular and Molecular Life Sciences 64 1656 1678 17483871 \n32 Kassem A Technau K Kurz AK Pantulu D Loning M Kayser G Stickeler E Weyers W Diaz C Werner M Nashan D Zur HA 2009 Merkel cell polyomavirus sequences are frequently detected in nonmelanoma skin cancer of immunosuppressed patients. Int J Cancer 125 356 361 19384948 \n33 Ramqvist T Dalianis T 2009 Murine polyomavirus tumour specific transplantation antigens and viral persistence in relation to the immune response, and tumour development. Seminars in Cancer Biology 19 236 243 19505651 \n34 zur Hausen H Gissmann L 1979 Lymphotropic papovaviruses isolated from African green monkey and human cells. Med Microbiol Immunol 167 137 153 226854 \n35 Babakir-Mina M Ciccozzi M Lo PA Greco F Perno CF Ciotti M 2010 Identification of Merkel cell polyomavirus in the lower respiratory tract of Italian patients. J Med Virol 82 505 509 20087943 \n36 Dworkin AM Tseng SY Allain DC Iwenofu OH Peters SB Toland AE 2009 Merkel Cell Polyomavirus in Cutaneous Squamous Cell Carcinoma of Immunocompetent Individuals. J Invest Dermatol 129 2868 2874 19554019 \n37 Foulongne V Dereure O Kluger N Moles JP Guillot B Segondy M 2009 Merkel cell polyomavirus DNA detection in lesional and nonlesional skin from patients with Merkel cell carcinoma or other skin diseases. Br J Dermatol \n38 Goh S Lindau C Tiveljung-Lindell A Allander T 2009 Merkel cell polyomavirus in respiratory tract secretions. Emerg Infect Dis 15 489 491 19239773 \n39 Carter JJ Paulson KG Wipf GC Miranda D Madeleine MM Johnson LG Lemos BD Lee S Warcola AH Iyer JG Nghiem P Galloway DA 2009 Association of Merkel Cell Polyomavirus-Specific Antibodies With Merkel Cell Carcinoma. J Natl Cancer Inst 101 1510 1521 19776382 \n40 Kean JM Rao S Wang M Garcea RL 2009 Seroepidemiology of Human Polyomaviruses. PLoS Pathog 5 e1000363 19325891 \n41 de Koning MNC Struijk L Bavinck JNB Kleter B ter Schegget J Quint WGV Feltkamp MCW 2007 Betapapillomaviruses frequently persist in the skin of healthy individuals. J Gen Virol 88 1489 1495 17412978 \n42 de Koning M Quint W Struijk L Kleter B Wanningen P van Doorn LJ Weissenborn SJ Feltkamp M ter Schegget J 2006 Evaluation of a Novel Highly Sensitive, Broad-Spectrum PCR-Reverse Hybridization Assay for Detection and Identification of Beta-Papillomavirus DNA. J Clin Microbiol 44 1792 1800 16672409 \n43 Huang X Madan A 1999 CAP3: A DNA Sequence Assembly Program. Genome Research 9 868 877 10508846 \n44 Mount SM 1982 A catalogue of splice junction sequences. Nucleic Acids Res 10 459 472 7063411 \n45 Rogozin I Milanesi L 1997 Analysis of donor splice sites in different eukaryotic organisms. Journal of Molecular Evolution 45 50 59 9211734 \n46 Kwun HJ Guastafierro A Shuda M Meinke G Bohm A Moore PS Chang Y 2009 The minimum replication origin of merkel cell polyomavirus has a unique large T-antigen loading architecture and requires small T-antigen expression for optimal replication. J Virol 83 12118 12128 19759150 \n47 Murzin AG Brenner SE Hubbard T Chothia C 1995 SCOP: a structural classification of proteins database for the investigation of sequences and structures. J Mol Biol 247 536 540 7723011 \n48 Soding J 2005 Protein homology detection by HMM-HMM comparison. Bioinformatics 21 951 960 15531603 \n49 Edgar RC 2004 MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res 32 1792 1797 15034147 \n50 Gorbalenya AE Lieutaud P Harris MR Coutard B Canard B Kleywegt GJ Kravchenko AA Samborskiy DV Sidorov IA Leontovich AM Jones TA 2010 Practical application of bioinformatics by the multidisciplinary VIZIER consortium. Antiviral Research In Press, Corrected Proof. doi: DOI: 10.1016/j.antiviral.2010.02.005 \n51 Drummond AJ Rambaut A 2007 BEAST: Bayesian evolutionary analysis by sampling trees. BMC Evol Biol 7 214 17996036 \n52 Whelan S Goldman N 2001 A general empirical model of protein evolution derived from multiple protein families using a maximum-likelihood approach. Mol Biol Evol 18 691 699 11319253 \n53 Drummond AJ Ho SY Phillips MJ Rambaut A 2006 Relaxed phylogenetics and dating with confidence. PLoS Biol 4 e88 16683862 \n54 Goodman SN 1999 Toward evidence-based medical statistics. 2: The Bayes factor. Ann Intern Med 130 1005 1013 10383350\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1553-7366",
"issue": "6(7)",
"journal": "PLoS pathogens",
"keywords": null,
"medline_ta": "PLoS Pathog",
"mesh_terms": "D015266:Carcinoma, Merkel Cell; D004270:DNA, Circular; D005814:Genes, Viral; D016679:Genome, Viral; D006801:Humans; D016867:Immunocompromised Host; D010802:Phylogeny; D011120:Polyomavirus; D012871:Skin Diseases; D019562:Viral Load",
"nlm_unique_id": "101238921",
"other_id": null,
"pages": "e1001024",
"pmc": null,
"pmid": "20686659",
"pubdate": "2010-07-29",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "10674379;17130148;17535200;16683862;18089736;17996036;17696921;1318392;7063411;15507660;7723011;19776382;12040123;15531603;17483871;2156730;20153379;19325891;19640999;19505653;10383350;19554019;16672409;19923267;18202256;18215475;19416753;17287263;19375325;18440042;14726896;19239773;19678822;10863236;226854;11319253;18995875;19788824;19759150;9211734;19505654;17412978;18186853;10508846;20087943;17480120;16537620;16299533;19505651;15644782;19384948;15034147;3005968;14726894",
"title": "Discovery of a new human polyomavirus associated with trichodysplasia spinulosa in an immunocompromized patient.",
"title_normalized": "discovery of a new human polyomavirus associated with trichodysplasia spinulosa in an immunocompromized patient"
} | [
{
"companynumb": "NL-MYLANLABS-2017M1075612",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "With improved and prolonged survival of very and extremely low birth weight infants, invasive fungal infection has emerged as an important concern in the neonatal intensive care units. Candidiasis is the third leading cause of late onset sepsis in these neonates and is associated with 20-30% mortality. Extreme prematurity, central venous catheters, prolonged antibiotic exposure, parenteral nutrition are important risk factors. Various forms of cutaneous manifestations of candidiasis have been described ranging from local diaper dermatitis and oral thrush to widespread erosive and ulcerative lesions with extensive crusting in invasive fungal dermatitis. We report a series of four cases with cutaneous hyperpigmentation as manifestation of systemic candidiasis.",
"affiliations": "Department of Pediatrics, University College of Medical Sciences and Guru Teg Bahadur Hospital, Delhi, India.;Department of Pediatrics, University College of Medical Sciences and Guru Teg Bahadur Hospital, Delhi, India.;Department of Pediatrics, University College of Medical Sciences and Guru Teg Bahadur Hospital, Delhi, India.;Department of Pediatrics, University College of Medical Sciences and Guru Teg Bahadur Hospital, Delhi, India.",
"authors": "Prabhakar|P|P|;Batra|P|P|;Verma|C|C|;Harit|D|D|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D000666:Amphotericin B",
"country": "Netherlands",
"delete": false,
"doi": "10.3233/NPM-180196",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-4429",
"issue": "13(1)",
"journal": "Journal of neonatal-perinatal medicine",
"keywords": "Cutaneous hyperpigmentation; candidiasis; fungemia; neonates",
"medline_ta": "J Neonatal Perinatal Med",
"mesh_terms": "D000666:Amphotericin B; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D058387:Candidemia; D058365:Candidiasis, Invasive; D005260:Female; D006801:Humans; D017495:Hyperpigmentation; D007231:Infant, Newborn; D007234:Infant, Premature; D007363:Intensive Care Units, Neonatal; D008297:Male; D000071074:Neonatal Sepsis",
"nlm_unique_id": "101468335",
"other_id": null,
"pages": "143-148",
"pmc": null,
"pmid": "31771078",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Hyperpigmentation as a cutaneous manifestation of fungal sepsis in neonates: Case series report.",
"title_normalized": "hyperpigmentation as a cutaneous manifestation of fungal sepsis in neonates case series report"
} | [
{
"companynumb": "IN-PFIZER INC-2020191733",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMIKACIN"
},
"drugadditional": "3",
... |
{
"abstract": "Candida endocarditis (CE) is a rare and serious complication of candidemia. Using current diagnostic tools a confirmed diagnosis is often delayed and outcomes remain poor. The majority of new cases occur following cardiac valvular surgery, and/or in patients with the following risk factors: intravenous drug use, cancer chemotherapy, prolonged presence of central venous catheters, and prior history of bacterial endocarditis. It is not a common complication in non-neutropenic patients particularly with the absence of a prosthetic valve, and very few reports in the literature are available. Attempting to add to the limited data, 211 candidemia episodes from 172 nonneutropenic pediatric cases between January 2008 and December 2017 were evaluated. All patients were considered asymptomatic for underlying heart disease. However, 2 (0.9%) patients with a central venous catheter were determined as having endocarditis following echocardiography.",
"affiliations": "Division of Infectious Disease, Department of Pediatrics, Medical School of Ege University, Izmir, Turkey.;Division of Infectious Disease, Department of Pediatrics, Medical School of Ege University, Izmir, Turkey.;Division of Cardiology, Department of Pediatrics, Medical School of Ege University, Izmir, Turkey.;Division of Infectious Disease, Department of Pediatrics, Medical School of Ege University, Izmir, Turkey.;Division of Cardiology, Department of Pediatrics, Medical School of Ege University, Izmir, Turkey.;Department of Microbiology and Clinical Microbiology, Medical School of Ege University, Izmir, Turkey.;Division of Infectious Disease, Department of Pediatrics, Medical School of Ege University, Izmir, Turkey.;Division of Infectious Disease, Department of Pediatrics, Medical School of Ege University, Izmir, Turkey.",
"authors": "Guner|Gizem|G|;Bal|Zumrut Sahbudak|ZS|0000-0001-9189-8220;Dogan|Eser|E|;Umit|Zuhal|Z|;Levent|Erturk|E|;Hilmioglu Polat|Suleyha|S|;Ozkinay|Ferda|F|;Kurugol|Zafer|Z|",
"chemical_list": "D000935:Antifungal Agents",
"country": "United States",
"delete": false,
"doi": "10.1111/echo.14406",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0742-2822",
"issue": "36(7)",
"journal": "Echocardiography (Mount Kisco, N.Y.)",
"keywords": "endocarditis infective; intraatrial thrombus",
"medline_ta": "Echocardiography",
"mesh_terms": "D000935:Antifungal Agents; D058387:Candidemia; D004696:Endocarditis; D005260:Female; D006801:Humans; D006849:Hydrocephalus; D007223:Infant; D008297:Male; D016459:Prosthesis-Related Infections; D017287:Ventriculoperitoneal Shunt",
"nlm_unique_id": "8511187",
"other_id": null,
"pages": "1401-1404",
"pmc": null,
"pmid": "31215692",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Native valve endocarditis due to Candida albicans in two children: Two new case reports.",
"title_normalized": "native valve endocarditis due to candida albicans in two children two new case reports"
} | [
{
"companynumb": "TR-PFIZER INC-2019354259",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MEROPENEM"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nSmall cell lung cancer (SCLC) characterized by high degree of malignancy and rapid tumor progression. Intracranial metastases often appear at the time of the initial diagnosis or treatment. Besides of radiotherapy, chemotherapy is supposed to have limited effect.\nA 66-year-old male had blurred vision and unsteady step with moderate headache, nausea, vomit.\nThe patient was diagnosed with SCLC with intracranial metastases.\n\n\nMETHODS\nHigh dose of nimustine (ACNU) (300 mg/m) add to the regimen containing carboplatin and irinotecan.\n\n\nRESULTS\nAlthough the patient suffered severe myelosuppression, the intracranial lesion almost disappeared and maintained half a year.\n\n\nCONCLUSIONS\nACNU at a dose of 200 mg/m might be tolerable in combination with other chemotherapeutic drugs for the treatment of SCLC with intracranial metastases besides radiotherapy.",
"affiliations": "Department of Respiratory Medicine, The People's Hospital of Leshan, Leshan Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.",
"authors": "Luo|Wei|W|;Li|Ya-Lun|YL|;Chen|Ya Juan|YJ|;Xiang|Qing|Q|;Chen|Hong|H|",
"chemical_list": "D000970:Antineoplastic Agents; D015376:Nimustine",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000008218",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-7974",
"issue": "96(41)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D024221:Antineoplastic Protocols; D001921:Brain; D001932:Brain Neoplasms; D059248:Chemoradiotherapy; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D009367:Neoplasm Staging; D009460:Neurologic Examination; D015376:Nimustine; D055752:Small Cell Lung Carcinoma; D016896:Treatment Outcome; D014786:Vision Disorders",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e8218",
"pmc": null,
"pmid": "29019889",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016441:Retracted Publication",
"references": null,
"title": "High dose of nimustine as an add-on treatment for small cell lung cancer with intracranial metastasis: A case report and literature review.",
"title_normalized": "high dose of nimustine as an add on treatment for small cell lung cancer with intracranial metastasis a case report and literature review"
} | [
{
"companynumb": "CN-PFIZER INC-2017474052",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "1",
... |
{
"abstract": "Coagulation factor V inhibitors (FV-i) may occur in patients with congenital FV deficiency or previously hemostatically normal patients (autoimmune (AI)-FV-i). Most of the published literature is confined to case reports.\n\n\n\nDescribe clinical and laboratory features of AI-FV-i identified through the Special Coagulation Laboratory at Mayo Clinic, Rochester, Minnesota.\n\n\n\nIn this retrospective study individuals with FV-i screens performed from January 1999 to February 2017 were identified through the special coagulation laboratory database. Clinical presentation, management, and outcomes were collected for our institutional patients while detailed laboratory data was collected for all tested patients.\n\n\n\nOf patients with FV-i managed at our institution, 2/8 (25%) patients experienced no bleeding. There was no correlation between inhibitor titers and/or FV activity (FV:C) levels and clinical bleeding. Hemostatic management included fresh frozen plasma, platelet transfusion, activated prothrombin complex concentrates, and recombinant factor VIIa. Only 2 patients received immunomodulatory treatment. FV-i mixing studies with normal pooled plasma (n = 26) demonstrated inhibition on immediate mix but progressive inhibition after 1 h of incubation could not be demonstrated. 71% of platelet neutralization procedures were falsely positive while 59% of DRVVT assays were indeterminate.\n\n\n\nFV-i demonstrates immediate inhibition on mixing studies; however our limited data does not support a time dependent inhibition. Our clinical cohort confirms the variable clinical phenotype for individuals with FV-i and supports the notion that management of FV-i should be guided by clinical symptoms and not FV:C or FV-i titer.",
"affiliations": "Division of Hematology, Department of Internal Medicine, and the Division of Hematopathology and Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, Rochester, MN, United States of America.;Division of Hematology, Department of Internal Medicine, and the Division of Hematopathology and Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, Rochester, MN, United States of America.;Division of Hematology, Department of Internal Medicine, and the Division of Hematopathology and Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, Rochester, MN, United States of America.;Division of Hematology, Department of Internal Medicine, and the Division of Hematopathology and Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, Rochester, MN, United States of America.;Division of Hematology, Department of Internal Medicine, and the Division of Hematopathology and Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, Rochester, MN, United States of America.;Division of Hematology, Department of Internal Medicine, and the Division of Hematopathology and Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, Rochester, MN, United States of America.;Division of Hematology, Department of Internal Medicine, and the Division of Hematopathology and Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, Rochester, MN, United States of America.;Division of Hematology, Department of Internal Medicine, and the Division of Hematopathology and Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, Rochester, MN, United States of America.;Division of Hematology, Department of Internal Medicine, and the Division of Hematopathology and Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, Rochester, MN, United States of America. Electronic address: pruthi.rajiv@mayo.edu.",
"authors": "Sridharan|Meera|M|;Fylling|Kara A|KA|;Ashrani|Aneel A|AA|;Chen|Dong|D|;Marshall|Ariela L|AL|;Hook|C Christopher|CC|;Cardel|Laynalee K|LK|;Nichols|William L|WL|;Pruthi|Rajiv K|RK|",
"chemical_list": "D019774:Blood Coagulation Factor Inhibitors; D006490:Hemostatics; D007166:Immunosuppressive Agents; D005165:Factor V",
"country": "United States",
"delete": false,
"doi": "10.1016/j.thromres.2018.09.044",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0049-3848",
"issue": "171()",
"journal": "Thrombosis research",
"keywords": "Blood coagulation factor inhibitors; Factor V; Hemostasis; Lupus anticoagulant inhibitor; Thrombin",
"medline_ta": "Thromb Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015551:Autoimmunity; D019774:Blood Coagulation Factor Inhibitors; D001803:Blood Transfusion; D005165:Factor V; D005166:Factor V Deficiency; D005260:Female; D006470:Hemorrhage; D006490:Hemostatics; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "0326377",
"other_id": null,
"pages": "14-21",
"pmc": null,
"pmid": "30227314",
"pubdate": "2018-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical and laboratory diagnosis of autoimmune factor V inhibitors: A single institutional experience.",
"title_normalized": "clinical and laboratory diagnosis of autoimmune factor v inhibitors a single institutional experience"
} | [
{
"companynumb": "US-MYLANLABS-2018M1077288",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CEFAZOLIN"
},
"drugadditional": "3",
... |
{
"abstract": "IgA vasculitis (Henoch-Schönlein purpura) affects various organs, including the skin, gastrointestinal (GI) tract, joints and kidneys. Its clinical course typically consists of two phases: initial appearance of purpura and delayed onset of arthralgia, GI symptoms and haematuria. We report the case of an adult patient with IgA vasculitis of the small bowel, without skin involvement, complicated by cytomegalovirus (CMV) enteritis following prednisolone administration. Single-balloon enteroscopy revealed mucosal oedema, redness, erosions and transverse ulcers of the duodenum and jejunum. Jejunal biopsy specimens showed IgA deposition in the capillary walls. CMV reactivation was confirmed by PCR and immunostaining using jejunal biopsy specimens. This case report strongly suggests that adult patients with IgA vasculitis can present with isolated GI involvement, without characteristic skin purpura. Furthermore, CMV reactivation needs to be considered in patients with IgA vasculitis showing poor response to glucocorticoids.",
"affiliations": "Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine Hospital, Osaka-Sayama, Osaka, Japan.;Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine Hospital, Osaka-Sayama, Osaka, Japan y-komme@med.kindai.ac.jp.;Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine Hospital, Osaka-Sayama, Osaka, Japan.;Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine Hospital, Osaka-Sayama, Osaka, Japan.",
"authors": "Matsumura|Mariko|M|;Komeda|Yoriaki|Y|;Watanabe|Tomohiro|T|;Kudo|Masatoshi|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-235042",
"fulltext": "\n==== Front\nBMJ Case Rep\nBMJ Case Rep\nbmjcr\nbmjcasereports\nBMJ Case Reports\n1757-790X BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\nbcr-2020-235042\n10.1136/bcr-2020-235042\nReminder of Important Clinical Lesson\n1506\n1524\n532\n547\n1327\n102\nCase reportPurpura-free small intestinal IgA vasculitis complicated by cytomegalovirus reactivation\nMatsumura Mariko Komeda Yoriaki Watanabe Tomohiro Kudo Masatoshi \nDepartment of Gastroenterology and Hepatology, Kindai University Faculty of Medicine Hospital, Osaka-Sayama, Osaka, Japan\n\nCorrespondence to Dr Yoriaki Komeda; y-komme@med.kindai.ac.jp\n2020 \n6 7 2020 \n6 7 2020 \n13 7 e23504212 6 2020 © BMJ Publishing Group Limited 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2020http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.IgA vasculitis (Henoch-Schönlein purpura) affects various organs, including the skin, gastrointestinal (GI) tract, joints and kidneys. Its clinical course typically consists of two phases: initial appearance of purpura and delayed onset of arthralgia, GI symptoms and haematuria. We report the case of an adult patient with IgA vasculitis of the small bowel, without skin involvement, complicated by cytomegalovirus (CMV) enteritis following prednisolone administration. Single-balloon enteroscopy revealed mucosal oedema, redness, erosions and transverse ulcers of the duodenum and jejunum. Jejunal biopsy specimens showed IgA deposition in the capillary walls. CMV reactivation was confirmed by PCR and immunostaining using jejunal biopsy specimens. This case report strongly suggests that adult patients with IgA vasculitis can present with isolated GI involvement, without characteristic skin purpura. Furthermore, CMV reactivation needs to be considered in patients with IgA vasculitis showing poor response to glucocorticoids.\n\npurpura fulminansvasculitisendoscopyspecial-featureunlocked\n==== Body\nBackground\nIgA vasculitis, formerly known as Henoch-Schönlein purpura, is characterised by the deposition of IgA-immune complexes within small-vessel walls.1 This disease can develop at any age, but it commonly affects children.2 3 IgA vasculitis is the most common systemic vasculitis in childhood, with an annual incidence of 3–26 per 100 000 children.4 5 In contrast, adult IgA vasculitis is extremely rare, with an annual incidence of 0.1–14 per 100 000 individuals.6 IgA vasculitis affects multiple organs, including the skin, joints, gastrointestinal (GI) tract and kidneys.7 Reflecting a wide variety of affected organs, patients with IgA vasculitis show various clinical symptoms such as fever, purpura, arthralgia, abdominal pain and haematuria. Purpura is observed in almost all paediatric patients8 and is reportedly the initial symptom of IgA vasculitis in approximately three-quarters of affected children.9 Thus, typically, patients with IgA vasculitis initially present with purpura, followed by the development of arthralgia, haematuria and GI-related symptoms within the following few days. Both typical clinical signs and histopathological detection of leucocytoclastic vasculitis associated with IgA deposition are used to establish the diagnosis of IgA vasculitis.1 Glucocorticoids ameliorate GI-related symptoms, arthralgia and purpura in most patients with IgA vasculitis.\n\nDiagnosing IgA vasculitis is easy when paediatric patients exhibit characteristic purpura and joint-related, GI-related and renal symptoms. However, clinicians may need to consider a possibility of IgA vasculitis, even in the absence of purpura, if any of these symptoms are present. A lack of skin involvement may make it difficult to diagnose this disease. Considering that the delayed diagnosis of IgA vasculitis may sometimes lead to serious complications such as intestinal obstruction, intussusception, intestinal perforation and massive bleeding, a prompt diagnosis is necessary.6 Here, we report a case of an adult patient with IgA vasculitis of the small bowel, without concurrent skin involvement. Interestingly, this patient also developed cytomegalovirus (CMV) enteritis after receiving glucocorticoid therapy. To the best of our knowledge, this is the first reported case of purpura-free, small intestinal IgA vasculitis, complicated by CMV reactivation, in an adult.\n\nCase presentation\nA 68-year-old man, with no significant prior medical history, was admitted to our hospital after presenting with a 3-day history of abdominal pain, vomiting, diarrhoea and high fever (38.7°C). The bouts of vomiting and diarrhoea occurred several times a day. Physical abdominal examination revealed severe distention and tenderness.\n\nInvestigations\nLaboratory findings revealed an elevated C-reactive protein level, along with leucocytosis (table 1). Biochemical tests revealed elevated levels of serum transaminases (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase and creatine kinase). Abdominal CT showed thickening of the descending duodenal and jejunal walls, a finding that was consistent with the diagnosis of infectious gastroenteritis. Based on these data, we initially suspected infectious enteritis, and the patient was treated with antibiotics. However, he did not respond to bowel rest and antibiotic treatment. Thus, we considered the possibility of other diseases such as vasculitis, malignant lymphoma and malignant tumour since stool and blood cultures were negative for pathogenic microorganisms. To explore this possibility, we measured the serum concentrations of interleukin 2 receptor, carcinoembryonic antigen, carbohydrate antigen 19–9 and factor XIII activity levels. The soluble interleukin 2 receptor level was also elevated (1988 U/mL, normal range: 121–613 U/mL), whereas those of tumour markers were within the normal range. Serum factor XIII activity decreased to 37%. Contrast-enhanced abdominal CT imaging after antibiotic treatment revealed marked thickening of the small bowel wall originating from the duodenum to the proximal portion of the jejunum (figure 1A). Persistent high fever and abdominal pain, despite administration the antibiotic treatment, prompted us to examine the mucosa of the upper GI tract, including the jejunum, by balloon enteroscopy on the 11th day of hospitalisation. Mucosal oedema, redness, erosion and transverse ulcers were observed from the descending portion of the duodenum to the proximal jejunum (figure 1B). Jejunal biopsy specimens obtained during the first single-balloon enteroscopy (SBE) procedure revealed destruction of the crypt architecture, massive infiltration of immune cells and mucosal haemorrhage (figure 2A). Moreover, IgA deposition in the capillary vessel walls and IgA-expressing plasma cells were visualised in the immunohistochemical analysis (figure 2B). IgA expression not only in the lamina propria immune cells but also in the capillary vessel walls (figure 2C) led us to consider the possibility of enteric IgA vasculitis as IgA deposition in capillary walls is a specific finding of this immune disorder.10 A significant decrease in serum factor XIII activity was also consistent with IgA vasculitis. Thus, this patient was diagnosed with solitary enteric IgA vasculitis and then treated with prednisolone (PSL). PCR using jejunal biopsy samples did not detect tuberculosis. A second SBE was performed 2 weeks after initiation of PSL treatment to re-examine the small intestinal mucosa. Persistent mucosal oedema, erosions and transverse ulcers were still present within the GI tract, extending from the descending duodenum to the proximal jejunum. In addition, large shallow ulcers had appeared in the jejunum (figure 3A). Histopathological examination of the jejunal biopsy specimens, obtained during the second SBE, showed massive infiltration of immune cells, IgA deposition within the capillary walls and accumulation of IgA-expressing plasma cells (figure 3B). In addition to these pathological findings, giant cells with inclusion bodies as well as CMV-positive cells, characteristic of IgA vasculitis, were also found in the jejunal biopsy specimens (figure 3C). We also detected blood leucocytes expressing CMV pp65 antigen (5/50 000; normal, 0). The response to PSL during the first 7 days was quite effective, similar to the response in most cases of IgA vasculitis; subsequently, the effect was lost. Such alterations in responses to PSL can be explained by the occurrence of CMV reactivation after PSL treatment. Thus, it is likely that CMV enteritis developed owing to immunosuppression by PSL. Simultaneous occurrence of IgA vasculitis and CMV enteritis was less likely, as the CMV immunostaining test performed on the first jejunum biopsy specimen had a negative result. These findings strongly suggest that CMV reactivation had occurred after administration of high-dose PSL and that the abdominal symptoms had persisted owing to the development of CMV enteritis.\n\nTable 1 Laboratory findings\n\nBiochemistry\tCBC\tOthers\t\nCRP\t16.4 mg/dL\tWBC\t4080/μL\tIgG\t690 mg/dL\t\nNa\t133 mEq/L\tRBC\t404×104/μL\tIgA\t175 mg/dL\t\nK\t3.7 mEq/L\tHb\t13.4 g/dL\tIgM\t24 mg/dL\t\nCl\t100 mEq/L\tHt\t37.70%\tIgE\t295 IU/mL\t\nAST\t131 IU/L\tPlt\t17.6×104/μL\tRF\t4 U/mL\t\nALT\t69 IU/L\tNeut\t73.60%\tC3\t124 mg/dL\t\nLDH\t429 IU/L\tLymph\t17.60%\tC4\t28 mg/dL\t\nCK\t2922 U/L\tMono\t8.80%\tCH50\t82 U/mL\t\nCKMB\t11 U/L\tEosin\t0.00%\tsIL-2R\t1988 U/mL\t\nT-Bil\t0.8 mg/dL\tBaso\t0.00%\tCEA\t1.6 ng/mL\t\nTP\t5.8 g/dL\t\t\tCA19-9\t3 U/mL\t\nAlb\t3.2 g/dL\t\t\tANA\tNegative\t\nBUN\t43 mg/dL\t\t\tMPO-ANCA\t295 IU/mL\t\nCr\t1.38 mg/dL\t\t\tPR3-ANCA\t24 IU/mL\t\n\t\t\t\tBlood coagulation factor ⅩⅢ activity\t37.00%\t\nAlb, albumin; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate aminotransferase; Baso, basophils; BUN, blood urea nitrogen; C3, complement component 3; C4, complement component 4; CA19-9, carbohydrate antigen 19–9; CBC, complete blood count; CEA, carcinoembryonic antigen; CH50, total hemolytic complement; CK, creatine kinase; CKMB, creatine kinase-myoglobin; Cl, chlorine; Cr, creatinine; CRP, C-reactive protein; Eosin, eosinophils; Hb, haemoglobin; Ht, hematocrit; K, potassium; LDH, lactate dehydrogenase; Lymph, lymphcytes; MB, myoglobin; Mono, monocytes; MPO-ANCA, myeloperoxidase–antineutrophil cytoplasmic antibody; Na, sodium; Neut, neutophils; Plt, platelets; PR3-ANCA, proteinase 3–antineutrophil cytoplasmic antibody; RBC, red blood cells; RF, rheumatoid factor; sIL-2R, soluble interleukin 2 receptor; T-Bil, total bilirubin; TP, total protein; WBC, white blood cells.\n\nFigure 1 Endoscopic findings of the jejunal mucosa during single-balloon enteroscopy (SBE): (A) contrast-enhanced abdominal CT shows marked thickening of the descending duodenal (left) and proximal jejunal (right) walls. (B) SBE shows oedema, redness, erosions and transverse ulcers involving the duodenal (left) and jejunal (right) mucosae.\n\nFigure 2 IgA deposition within the jejunal mucosal capillary walls: (A) histopathological examination of the jejunal mucosa shows destruction of crypt architecture, massive infiltration by immune cells and mucosal haemorrhage (H&E, 40× magnification); (B) immunohistochemical examination of a jejunal biopsy sample shows deposition of IgA within the capillary walls along with aggregated IgA-expressing plasma cells (IgA immunostaining, 40× magnification); (C) high-magnification image of immunohistochemical staining shows IgA deposition in the capillary vessel walls (yellow arrow) (IgA immunostaining, 80× magnification).\n\nFigure 3 Jejunal mucosal findings indicating cytomegalovirus (CMV) reactivation: (A) single-balloon enteroscopy (SBE) shows mucosal oedema, redness, erosions and transverse ulcers involving the jejunal mucosa (left). Image taken after staining the jejunal mucosa with indigo carmine (right). (B) Jejunal biopsy samples obtained during the follow-up SBE show massive infiltration of immune cells within the jejunal mucosa (left) (H&E, 40× magnification) along with deposition of IgA in the capillary walls and high-magnification image of immunohistochemical staining shows accumulation of IgA-expressing plasma cells and IgA deposition in the capillary vessel walls (yellow arrow) (IgA immunostaining, 80× magnification) (right). (C) Histopathological examination of jejunal biopsy samples obtained during the follow-up SBE shows a giant cell with inclusion bodies (yellow arrow) (left) (H&E, 40× magnification) and positive immunoreactivity for CMV (right) (anti-CMV monoclonal immunostaining, 40× magnification).\n\nDifferential diagnosis\nConsidering the initial clinical presentation and investigation, the patient had been briefly considered to have infectious gastroenteritis, IgA vasculitis, eosinophilic gastroenteritis or CMV enteritis.\n\nTreatment\nThe patient was initially treated with fluid replacement and antibiotics for suspected infectious gastroenteritis. After the histopathological diagnosis of IgA vasculitis following the first SBE, PSL (60 mg/kg) therapy was initiated. Ganciclovir (5 mg/kg two times per day) was added to the PSL treatment according to the findings of the subsequent (second) jejunal biopsy, which confirmed the occurrence of CMV enteritis. This led to symptom relief, and PSL was gradually tapered to a dose of 30 mg/day by discharge.\n\nOutcome and follow-up\nA marked improvement in abdominal symptoms was observed after initiation of ganciclovir. Blood leucocytes expressing CMV pp65 were no longer detected 2 weeks after initiation of antiviral therapy. The patient was discharged on the 53rd day of hospitalisation.\n\nDiscussion\nIgA vasculitis, formerly known as Henoch-Schönlein purpura, commonly affects children, and an adult onset is relatively rare.3 6 The typical clinical course of IgA vasculitis comprises two phases: ~75% of patients initially exhibit purpura and this is followed by arthralgia, GI symptoms and haematuria.9 Diagnosing IgA vasculitis is straightforward if a paediatric patient manifests sequential clinical signs. However, diagnosis of IgA vasculitis could be difficult in patients presenting only with GI symptoms. In this report, we describe the case of an adult with IgA vasculitis presenting with isolated involvement of the small intestine. We arrived at the diagnosis based on several investigative findings. First, mucosal oedema, redness, erosions and ulcers were found localised to the duodenal and proximal jejunal mucosae, both of which are GI regions known to be involved in this condition.11 Second, serum factor XIII activity was found to be markedly decreased, which is considered indicative of IgA vasculitis.12 Third, massive infiltration of immune cells and mucosal haemorrhage were found in the jejunal biopsy specimens obtained during SBE. Finally, immunohistochemical analysis of the jejunal samples revealed deposition of IgA within the capillary walls. These histopathological findings supported the diagnosis of IgA vasculitis with isolated involvement of the small intestine, despite the absence of skin involvement. However, leucocytoclastic vasculitis was not detected in this case. Failure to detect leucocytoclastic vasculitis can be explained by the limited available extent of submucosal tissue that is suitable for detection of vasculitis in jejunal biopsy specimens. In line with this, the detection rate of vasculitis in biopsy specimens is very low (5.4%).11\n\n\nIgA vasculitis lesions can occur anywhere throughout the length of the GI tract, but most patients have small intestinal lesions, including those affecting the duodenum.9 Endoscopic findings in this disorder include redness, erosions, mucosal oedema, punctate bleeding, ulcers and purpura-like lesions affecting the intestinal mucosa,13–15 most of which were seen in the second SBE in our case. Considering that GI symptoms precede skin manifestations in 15%–35% of IgA vasculitis patients and that a significant proportion of patients are known to develop severe intestinal complications, such as ischaemia, obstruction, intussusception and perforation,9 recognition of the above-mentioned endoscopic findings is important for early diagnosis.13–15 In this case, the laboratory tests showed a markedly high creatine kinase level, which suggested the presence of small bowel ischaemia due to severe inflammation. In such severe cases, a prompt diagnosis, mainly based on endoscopic findings, is necessary even in the absence of typical skin purpura to avoid the development of complications requiring emergency surgery.\n\nCMV is a viral pathogen that causes opportunistic infections, leading to a severe and fatal disease in immunocompromised hosts.16 The prevalence of CMV infection in inflammatory bowel diseases has been examined, and the proportion of ulcerative colitis (UC) patients with CMV infection has been reported to be 6.3%.17 Such a high incidence of CMV reactivation in UC is related to the use of immunosuppressive agents, including PSL.18 As in the cases of UC with CMV reactivation, virus reactivation delayed mucosal healing in this patient with enteric IgA vasculitis after PSL treatment. To the best of our knowledge, this is the first case of small intestinal IgA vasculitis complicated by CMV enteritis. It is worth noting that mucosal oedema, erosions and transverse ulcers were seen in the small intestinal mucosa in this case, both before and after CMV reactivation. Therefore, in such cases, it might be challenging to diagnose CMV enteritis based only on endoscopic findings. Detection of CMV by PCR and immunostaining of intestinal biopsy specimens are required for diagnosing CMV enteritis after PSL administration for IgA vasculitis. Although the prognosis of IgA vasculitis is generally excellent owing to its high sensitivity to glucocorticoid therapy,5 this case report strongly suggests that CMV enteritis should be considered in patients with IgA vasculitis showing a poor response to glucocorticoids.\n\nLearning points\nAdult patients with IgA vasculitis can present with isolated gastrointestinal involvement, without characteristic skin manifestations.\n\nAn early diagnosis of this condition can be made on the basis of enteroscopic and histopathological findings to avoid emergence of surgical complications.\n\nThe possibility of cytomegalovirus (CMV) enteritis should be considered in IgA vasculitis patients showing a poor response to glucocorticoids.\n\nDetection of CMV on PCR and immunostaining of intestinal biopsy specimens are required for the diagnosis of CMV enteritis after administration of prednisolone for IgA vasculitis.\n\nContributors: YK and MM were involved in the study conception and design, drafted the article, and analysed and interpreted the data; TW and MK performed critical revision of the article for important intellectual content; all authors approved the final manuscript.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nPatient consent for publication: Obtained.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 \nMills JA , Michel BA , Bloch DA , et al \nThe American College of rheumatology 1990 criteria for the classification of Henoch-Schönlein purpura\n. Arthritis Rheum \n1990 ;33 :1114 –21\n. 10.1002/art.1780330809 \n2202310 \n2 \nPiram M , Mahr A \nEpidemiology of immunoglobulin A vasculitis (Henoch-Schönlein): current state of knowledge\n. Curr Opin Rheumatol \n2013 ;25 :171 –8\n. 10.1097/BOR.0b013e32835d8e2a \n23318735 \n3 \nBlanco R , Martínez-Taboada VM , Rodríguez-Valverde V , et al \nHenoch-Schönlein purpura in adulthood and childhood: two different expressions of the same syndrome\n. Arthritis Rheum \n1997 ;40 :859 –64\n. 10.1002/art.1780400513 \n9153547 \n4 \nGardner-Medwin JMM , Dolezalova P , Cummins C , et al \nIncidence of Henoch-Schönlein purpura, Kawasaki disease, and rare vasculitides in children of different ethnic origins\n. Lancet \n2002 ;360 :1197 –202\n. 10.1016/S0140-6736(02)11279-7 \n12401245 \n5 \nGonzález-Gay MA , García-Porrúa C \nEpidemiology of the vasculitides\n. Rheum Dis Clin North Am \n2001 ;27 :729 –49\n. 10.1016/S0889-857X(05)70232-5 \n11723761 \n6 \nDeshayes S , Moulis G , Pillebout E , et al \nPositive predictive value of hospital discharge diagnosis code to identify immunoglobulin A vasculitis in France: a validation study\n. Eur J Intern Med \n2017 ;43 :e18 –19\n. 10.1016/j.ejim.2017.05.025 \n28651748 \n7 \nChang W-L , Yang Y-H , Lin Y-T , et al \nGastrointestinal manifestations in Henoch-Schönlein purpura: a review of 261 patients\n. Acta Paediatr \n2004 ;93 :1427 –31\n. 10.1111/j.1651-2227.2004.tb02623.x \n15513566 \n8 \nSaulsbury FT \nHenoch-Schönlein purpura in children. Report of 100 patients and review of the literature\n. Medicine \n1999 ;78 :395 –409\n. 10.1097/00005792-199911000-00005 \n10575422 \n9 \nJauhola O , Ronkainen J , Koskimies O , et al \nClinical course of extrarenal symptoms in Henoch-Schonlein purpura: a 6-month prospective study\n. Arch Dis Child \n2010 ;95 :871 –6\n. 10.1136/adc.2009.167874 \n20371584 \n10 \nLouie CY , Gomez AJ , Sibley RK , et al \nHistologic features of gastrointestinal tract biopsies in IgA vasculitis (Henoch-Schönlein purpura)\n. Am J Surg Pathol \n2018 ;42 :529 –33\n. 10.1097/PAS.0000000000001036 \n29438165 \n11 \nGong EJ , Kim DH , Chun JH , et al \nEndoscopic findings of upper gastrointestinal involvement in primary vasculitis\n. Gut Liver \n2016 ;10 :542 –8\n. 10.5009/gnl15198 \n27226428 \n12 \nFukui H , Kamitsuji H , Nagao T , et al \nClinical evaluation of a pasteurized factor XIII concentrate administration in Henoch-Schönlein purpura. Japanese pediatric group\n. Thromb Res \n1989 ;56 :667 –75\n. 10.1016/0049-3848(89)90284-3 \n2699100 \n13 \nZhang Y , Huang X \nGastrointestinal involvement in Henoch-Schönlein purpura\n. Scand J Gastroenterol \n2008 ;43 :1038 –43\n. 10.1080/00365520802101861 \n18609159 \n14 \nKato S , Shibuya H , Naganuma H , et al \nGastrointestinal endoscopy in Henoch-Schönlein purpura\n. Eur J Pediatr \n1992 ;151 :482 –4\n. 10.1007/BF01957748 \n1396906 \n15 \nChen M-J , Wang T-E , Chang W-H , et al \nEndoscopic findings in a patient with Henoch-Schonlein purpura\n. World J Gastroenterol \n2005 ;11 :2354 –6\n. 10.3748/wjg.v11.i15.2354 \n15818753 \n16 \nCainelli F , Vento S \nInfections and solid organ transplant rejection: a cause-and-effect relationship? Lancet Infect Dis 2002;2:539–49. Review. Erratum in\n. Lancet Infect Dis \n2002 ;2 :645 .\n17 \nHendler SA , Barber GE , Okafor PN , et al \nCytomegalovirus infection is associated with worse outcomes in inflammatory bowel disease hospitalizations nationwide\n. Int J Colorectal Dis \n2020 ;35 :897 –903\n. 10.1007/s00384-020-03536-8 \n32124046 \n18 \nBeswick L , Ye B , van Langenberg DR \nToward an algorithm for the diagnosis and management of CMV in patients with colitis\n. Inflamm Bowel Dis \n2016 ;22 :2966 –76\n. 10.1097/MIB.0000000000000958 \n27763950\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1757-790X",
"issue": "13(7)",
"journal": "BMJ case reports",
"keywords": "endoscopy; purpura fulminans; vasculitis",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D004751:Enteritis; D006801:Humans; D011695:IgA Vasculitis; D007421:Intestine, Small; D008297:Male; D014775:Virus Activation",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32636227",
"pubdate": "2020-07-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20371584;28651748;11723761;32124046;9153547;27226428;29438165;2202310;27763950;1396906;15818753;15513566;12401245;18609159;23318735;2699100;10575422;12206970",
"title": "Purpura-free small intestinal IgA vasculitis complicated by cytomegalovirus reactivation.",
"title_normalized": "purpura free small intestinal iga vasculitis complicated by cytomegalovirus reactivation"
} | [
{
"companynumb": "JP-TEVA-2020-JP-1814976",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "1",
... |
{
"abstract": "Pancreatic acinar cell carcinoma (PACC) is a rare tumor, accounting for about 1% of all pancreatic exocrine cancers. Consensus on the management of metastatic PACC remains unclear.\nStarting from April 2019, a patient first received chemotherapy with two cycles of gemcitabine and nab-paclitaxel and two cycles of SOX regimen. After progression of disease evaluated based on RECIST 1.1, toripalimab and SOX regimen was administered because of PD-L1-positive expression, high tumor mutation burden (TMB), and somatic FANCA deletion in the tumor. Both the primary and metastatic tumor mass shrank significantly after two courses. The patient exhibited sustained partial response for at least six courses with well-controlled toxic effects. Then the treatment had to be stopped for 2 months because of the coronavirus disease 2019 pandemic. Computed tomography scan in March 2020 showed disease progression. Time from initiating treatment to tumor progression on toripalimab and SOX regimen treatment took up to at least 8 months.\nWe present the first case report where a PD-L1 positive, high TMB, and FANCA-deleted pancreatic acinar cell carcinoma was treated using chemotherapy combined with immunotherapy, in which the patient exhibited satisfactory response and tolerance.",
"affiliations": "Department of Abdominal Oncology, Cancer Center of West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.;Department of Abdominal Oncology, Cancer Center of West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.;Department of Abdominal Oncology, Cancer Center of West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.;Department of Abdominal Oncology, Cancer Center of West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.;Department of Abdominal Oncology, Cancer Center of West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.",
"authors": "Xu|Huanji|H|https://orcid.org/0000-0003-0314-5646;Wang|Xin|X|;Zhou|Sheng|S|;Hu|Qiancheng|Q|;Cao|Dan|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/0300891620980792",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8916",
"issue": "107(6)",
"journal": "Tumori",
"keywords": "PD-L1; Pancreatic acinar cell carcinoma; chemotherapy; immunotherapy",
"medline_ta": "Tumori",
"mesh_terms": null,
"nlm_unique_id": "0111356",
"other_id": null,
"pages": "NP24-NP27",
"pmc": null,
"pmid": "33345750",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy of chemotherapy combined with toripalimab in PD-L1-positive and high tumor mutation burden pancreatic acinar cell carcinoma: case report.",
"title_normalized": "efficacy of chemotherapy combined with toripalimab in pd l1 positive and high tumor mutation burden pancreatic acinar cell carcinoma case report"
} | [
{
"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-339430",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"dru... |
{
"abstract": "Patients with HIV are at an increased risk for cardiovascular disease, both as a result of treatment with protease inhibitors and from the disease itself. The medication regimens of patients with HIV and cardiovascular comorbidities are complex and require careful assessment for potentially serious drug-drug interactions. We report a case of clopidogrel non-responsiveness in a patient with HIV, latent tuberculosis and cardiovascular disease with a history of myocardial infarction. To our knowledge, this is the first report of significant drug interactions between clopidogrel, isoniazid and ritonavir. This case underscores the importance of a detailed drug interaction screening in infectious disease patients taking complex medication regimens, including clopidogrel.",
"affiliations": "Department of Pharmacy Practice, Mercer University College of Pharmacy, Atlanta, GA, USA Momary_km@mercer.edu.;Department of Pharmacy Practice, Mercer University College of Pharmacy, Atlanta, GA, USA.",
"authors": "Metzger|Nicole L|NL|;Momary|Kathryn M|KM|",
"chemical_list": "D000995:Antitubercular Agents; D017320:HIV Protease Inhibitors; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D019438:Ritonavir; D013988:Ticlopidine; D007538:Isoniazid",
"country": "England",
"delete": false,
"doi": "10.1177/0956462413516099",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0956-4624",
"issue": "25(7)",
"journal": "International journal of STD & AIDS",
"keywords": "AIDS; Antibiotic; HIV; antiviral; clopidogrel; drug--drug interactions; highly active antiretroviral therapy; isoniazid ritonavir",
"medline_ta": "Int J STD AIDS",
"mesh_terms": "D000995:Antitubercular Agents; D000077144:Clopidogrel; D004347:Drug Interactions; D004351:Drug Resistance; D015658:HIV Infections; D017320:HIV Protease Inhibitors; D006801:Humans; D007538:Isoniazid; D008297:Male; D009203:Myocardial Infarction; D010975:Platelet Aggregation Inhibitors; D019438:Ritonavir; D013988:Ticlopidine; D014376:Tuberculosis",
"nlm_unique_id": "9007917",
"other_id": null,
"pages": "532-4",
"pmc": null,
"pmid": "24352136",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A patient with HIV and tuberculosis with diminished clopidogrel response.",
"title_normalized": "a patient with hiv and tuberculosis with diminished clopidogrel response"
} | [
{
"companynumb": "US-ZYDUS-012317",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITONAVIR"
},
"drugadditional": "3",
"drugadm... |
{
"abstract": "Urinary incontinence is one of the principal reasons for visiting the urologist amongst paediatric patients, and an overactive bladder is the vesical dysfunction that most frequently provokes this. Currently the only medicine approved for managing an overactive bladder is oxybutynin; however, many patients respond partially to this therapy or are refractory to it. Vesical electrotherapy has emerged as a new alternative in the algorithm for managing patients with an overactive bladder refractory to anticholinergic medicines, but the evidence on this issue has to date been scant. We present the case of a 12-year-old patient with an overactive bladder refractory to oxybutynin and solifenacin who presented a good response to treatment with sacral vesical electrotherapy, with complete disappearance of the symptoms (diurnal incontinence and urgency of micturition) without adverse effects.",
"affiliations": "Servicio de Cirugía Pediátrica. Complejo Hospitalario Universitario A Coruña. La Coruña. España.. isabelcasalbe@gmail.com.",
"authors": "Casal-Beloy|I|I|;García-Novoa|M A|MA|;Casal Beloy|T|T|;García-González|M|M|;Somoza Argibay|I|I|",
"chemical_list": "D000069464:Solifenacin Succinate",
"country": "Spain",
"delete": false,
"doi": "10.23938/ASSN.0879",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1137-6627",
"issue": "43(3)",
"journal": "Anales del sistema sanitario de Navarra",
"keywords": null,
"medline_ta": "An Sist Sanit Navar",
"mesh_terms": "D002648:Child; D004599:Electric Stimulation Therapy; D006801:Humans; D000069464:Solifenacin Succinate; D016896:Treatment Outcome; D053201:Urinary Bladder, Overactive; D014549:Urinary Incontinence",
"nlm_unique_id": "9710381",
"other_id": null,
"pages": "417-421",
"pmc": null,
"pmid": "33180057",
"pubdate": "2020-12-22",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Sacral electrical neurostimulation in the refractory pediatric overactive bladder.",
"title_normalized": "sacral electrical neurostimulation in the refractory pediatric overactive bladder"
} | [
{
"companynumb": "ES-ALKEM LABORATORIES LIMITED-ES-ALKEM-2020-09586",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXYBUTYNIN CHLORIDE"
},
... |
{
"abstract": "Objective: The purpose of our study was to evaluate the alterations of bone metabolism and the prevalence of vertebral fractures in the population with HIV and hepatitis B and C seropositivity in treatment with antiretroviral drugs (HAART). Methods: We selected 83 patients with diagnosis of HIV, HBV, HCV infection. In all these patients biochemical examinations of phospho-calcium metabolism and a densitometry of lumbar spine were performed. We also evaluated lateral spine X-rays in order to analyze the presence of vertebral deformities and to define their severity. As a control group we analyzed the prevalence of vertebral fractures in a group of 40 non-infectious patients. Results: We selected 82 seropositive patients, 46 males and 37 females, with a median age of 55 ± 10 years. Out of these patients, 55 were infected by HIV, 12 were infected by HBV, 11 presented HIV and HCV co-infection and 4 were HCV+. The prevalence of hypovitaminosis D in the studied population was 53%, while the prevalence of osteoporosis and osteopenia was 14 and 48%, respectively. The average T-score in the fractured population was -1.9 SD. The viral load and the CD4+ cell count were respectively, directly, and inversely correlated with the number and severity of vertebral fractures. Antiretroviral therapy regimen containing TDF and PI was a significant determinant of the presence of vertebral deformities. The use of these drugs was also associated with lower levels of vitamin D and higher bone turnover levels compared to other antiretroviral drugs. Conclusions: HIV patients suffer from bone fragility, particularly at spine, independently by the level of bone mineral density. In this population, the T-score threshold for the risk of fracture is higher than that usually used in general population. For this reason, it would be indicated to perform an X-ray of the spine in order to detect vertebral deformities even in patients with a normal or slighlty reduced bone mineral density.",
"affiliations": "Internal Medicine Section D, Department of Medicine, University of Verona, Verona, Italy.;Department of Diagnostics and Public Health, University of Verona, Verona, Italy.;Department of Diagnostics and Public Health, University of Verona, Verona, Italy.;Department of Diagnostics and Public Health, University of Verona, Verona, Italy.;Internal Medicine Section D, Department of Medicine, University of Verona, Verona, Italy.;Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.;Internal Medicine Section D, Department of Medicine, University of Verona, Verona, Italy.;Internal Medicine Section D, Department of Medicine, University of Verona, Verona, Italy.",
"authors": "Dalla Grana|Elisa|E|;Rigo|Fabio|F|;Lanzafame|Massimiliano|M|;Lattuada|Emanuela|E|;Suardi|Silvia|S|;Mottes|Monica|M|;Valenti|Maria Teresa|MT|;Dalle Carbonare|Luca|L|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fendo.2019.00302",
"fulltext": "\n==== Front\nFront Endocrinol (Lausanne)Front Endocrinol (Lausanne)Front. Endocrinol.Frontiers in Endocrinology1664-2392Frontiers Media S.A. 10.3389/fendo.2019.00302EndocrinologyOriginal ResearchRelationship Between Vertebral Fractures, Bone Mineral Density, and Osteometabolic Profile in HIV and Hepatitis B and C-Infected Patients Treated With ART Dalla Grana Elisa 1Rigo Fabio 2Lanzafame Massimiliano 2Lattuada Emanuela 2Suardi Silvia 1Mottes Monica 3Valenti Maria Teresa 1Dalle Carbonare Luca 1*1Internal Medicine Section D, Department of Medicine, University of Verona, Verona, Italy2Department of Diagnostics and Public Health, University of Verona, Verona, Italy3Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, ItalyEdited by: Giacomina Brunetti, University of Bari Aldo Moro, Italy\n\nReviewed by: Marco Atteritano, University of Messina, Italy; Emma M. Clark, University of Bristol, United Kingdom\n\n*Correspondence: Luca Dalle Carbonare luca.dallecarbonare@univr.itThis article was submitted to Bone Research, a section of the journal Frontiers in Endocrinology\n\n14 5 2019 2019 10 30225 10 2018 26 4 2019 Copyright © 2019 Dalla Grana, Rigo, Lanzafame, Lattuada, Suardi, Mottes, Valenti and Dalle Carbonare.2019Dalla Grana, Rigo, Lanzafame, Lattuada, Suardi, Mottes, Valenti and Dalle CarbonareThis 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.Objective: The purpose of our study was to evaluate the alterations of bone metabolism and the prevalence of vertebral fractures in the population with HIV and hepatitis B and C seropositivity in treatment with antiretroviral drugs (HAART).\n\nMethods: We selected 83 patients with diagnosis of HIV, HBV, HCV infection. In all these patients biochemical examinations of phospho-calcium metabolism and a densitometry of lumbar spine were performed. We also evaluated lateral spine X-rays in order to analyze the presence of vertebral deformities and to define their severity. As a control group we analyzed the prevalence of vertebral fractures in a group of 40 non-infectious patients.\n\nResults: We selected 82 seropositive patients, 46 males and 37 females, with a median age of 55 ± 10 years. Out of these patients, 55 were infected by HIV, 12 were infected by HBV, 11 presented HIV and HCV co-infection and 4 were HCV+. The prevalence of hypovitaminosis D in the studied population was 53%, while the prevalence of osteoporosis and osteopenia was 14 and 48%, respectively. The average T-score in the fractured population was −1.9 SD. The viral load and the CD4+ cell count were respectively, directly, and inversely correlated with the number and severity of vertebral fractures. Antiretroviral therapy regimen containing TDF and PI was a significant determinant of the presence of vertebral deformities. The use of these drugs was also associated with lower levels of vitamin D and higher bone turnover levels compared to other antiretroviral drugs.\n\nConclusions: HIV patients suffer from bone fragility, particularly at spine, independently by the level of bone mineral density. In this population, the T-score threshold for the risk of fracture is higher than that usually used in general population. For this reason, it would be indicated to perform an X-ray of the spine in order to detect vertebral deformities even in patients with a normal or slighlty reduced bone mineral density.\n\nboneDXAfracturesspineHIVturnover\n==== Body\nIntroduction\nThe introduction of antiretroviral therapy (ART) has certainly improved the prognosis of HIV patients by reducing their mortality and morbidity, but has also revealed some complications related to the therapy. Among these, the evidence of a greater prevalence of reduced Bone Mineral Density (BMD), osteopenia and osteoporosis in the HIV+ population than the control population has emerged and has been widely studied (1–5).\n\nAn important meta-analysis of studies comparing BMD between HIV patients with normal population showed a prevalence of reduced BMD in 67% of people with HIV and a prevalence of 15% of osteoporosis in this population (6). A more recent study shows that even in newly diagnosed, therapy-naive HIV-infected patients, without any known secondary causes of osteoporosis, low BMD and high bone resorption are significantly prevalent (7).\n\nThe increased risk of osteopenia/osteoporosis in HIV+ patients is not only due to ART: in these patients there are ART-related, HIV-related, and even not-HIV not-ART-related risk factors for bone loss (8, 9). From this, it is clearly demonstrated that the pathogenesis of reduced bone mass is multifactorial. As a consequence of reduced BMD, patients with HIV infection are more likely to present with fragility fractures (10–14).\n\nNevertheless, data on the prevalence of fragility fractures in the HIV+ population are poor and often based on retrospective evaluation of clinical fractures, but this approach dramatically underestimates the phenomenon (14). Some studies report a moderate increase in prevalence of fractures in HIV+ patients compared to the general population, but data are statistically not significant considering that other risk factors for fractures, such as low BMI, smoking, and alcohol abuse, show a high prevalence in these patients (12–16). Other studies, however, show a significant increased prevalence of fractures, especially in relation to the high prevalence of frailty (10%, about twice as much as in the general population) and increased propensity to fall (16). Comparison of fracture prevalence rates among HIV+ individuals and not-infected individuals in a large US healthcare system reported a significantly high prevalence of all fractures in HIV+ males and females (2.87 per 100 infected persons vs. 1.77 per 100 people per year in not-infected persons) in all venues, but above all to the proximal femur, spine and wrist (14). Subsequent US studies have confirmed the association between HIV and increased risk of fractures, including the Veteran Aging Cohort Study (VACS) and the US HIV Outpatient Study (HOPS) (17, 18). In patients with HIV and HCV co-infection, the incidence rate for all fractures (traumatic and by fragility) varies from 26.8 to 62.3 per 1,000 people per year, while the incidence of fragility fractures is 2.6 per 1,000 people per year (19, 20). Hepatitis C co-infection would be, according to these data, an independent risk factor for fractures along with other documented risk factors: cigarette smoking, alcohol abuse, advanced age, white race, low BMI.\n\nAccording to two Italian studies, data on prevalence of fractures in the HIV-positive population would be even greater if we consider the vertebral deformities evaluable with a lateral spine X-Ray using a semi-quantitative evaluation of vertebral heights: according to Borderi et al. one HIV+ patient out of four would have a vertebral fracture and this data would be of potential clinical relevance, suggesting that bone damage is much more frequent than previously evaluated found by bone density evaluation (DXA) (21). The study of Torti et al. shows a prevalence of fractures in the male HIV+ population 2·5 times greater than a comparable age control group (22). A more recent study confirms that the prevalence of asymptomatic vertebral fractures is high in HIV-infected patients and it is not identified by the presence of osteoporosis in spine neither predicted by the FRAX equation (23). A low trabecular bone score (TBS) may be more associated with vertebral fractures than BMD, according with another recent Italian study (24).\n\nThe results of these studies, therefore, seem to indicate that lateral spine X-ray plays an important role in screening osteoporosis in this population, even before or independently from DXA. In fact, the measurement of bone mineral density alone cannot exclude the risk of fragility fractures, since many of these fractures occur in patients with normal BMD, as seen in other diseases, such as type 1 and 2 diabetes and acromegaly (25, 26).\n\nThe role of ART in increasing the incidence of fractures has not been completely established: up to now, data seems to converge on an increased incidence of fractures among HIV+ patients exposed to therapy than ART-naive patients, suggesting the role of certain antiretroviral agents, such as tenofovir disoproxil fumarate (TDF) and protease inhibitors (PI), in increasing the risk of fractures (27, 28). However, another recent case-control study does not support these data and suggests a reduction in the risk of fractures with prolonged exposure to tenofovir (29). In the light of this, further studies are needed to evaluate the effect of ART on fracture risk, especially for those patients who also present other risk factors.\n\nThe purpose of our study was to evaluate the alterations of bone metabolism and the prevalence of vertebral fractures in a population of patients with HIV and hepatitis B and C seropositivity in treatment with antiretroviral drugs.\n\nMethods\nA cross-sectional study of 82 patients infected by HIV or hepatitis B and C was performed. We enrolled both HIV-infected population and hepatitis-infected population, in order to see if there were any difference in the phospho-calcium metabolism and in the prevalence of vertebral fractures between the two groups. To do so, we considered the two populations to be comparable both for the inflammatory background and for the antiretroviral therapy that both groups experienced. A database was created using data from clinical charts of HIV-infected patients referring to the skeletal metabolism outpatient clinic of the Day Hospital of Infectious Diseases and from patients of the Infectious Diseases Department of Policlinico G.B. Rossi in Verona from November 2015 to June 2017. Inclusion criteria in the study were: male and female patients over the age of 40 with a previous or new diagnosis of HIV and/or HBV seropositivity. A minority of patients also had coinfection from HIV and HCV. For every patients we considered the principal epidemiological, clinical, immunological and virological risk factors for osteoporosis: sex, age, race, weight, CD4+ cell count, HIV viral load, AIDS diagnosis, protease inhibitors and NNRTI exposure, hepatitis C co-infection, vitamin D deficiency, chronic renal insufficiency, menopause.\n\nAll patients with independent risk factors for impaired bone metabolism, such as concomitant diseases or infections, anticonvulsant intake or steroid therapy, kidney failure, and those who had taken drugs that could affect skeletal metabolism or bone mass were excluded from the study. Patients with severe hepatic disease (defined as severe increase in hepatic cytolysis indices, severe alteration of liver function indices or end-stage cirrhosis) were also excluded from the study. All the patients had been supplemented with a single monthly dosage of 100,000 IU of cholecalciferol before our study.\n\nAll patients enrolled in the study performed biochemical examinations for dosing the following parameters of phospho-calcium metabolism in serum: 25-OH vitamin D, Creatinine, Phosphorus (P), Calcium (Ca), Parathyroid hormone (PTH), C-terminal fragment of type I collagen (s-CTX). Moreover, calcium excretion was evaluated in urine. In 71 patients, bone densitometry was performed using DXA (Dual Energy X-Ray Absorptiometry). In all of patients the lumbar spine densitometry was performed, considering L1-L4 segment of the lumbar spine. Given the young age of the patient enrolled, we considered lumbar densitometry in order to identify the presence of fractures. Vertebral deformities were detected on lateral spine X-ray using a semi-quantitative evaluation of vertebral heights and quantitative morphometric analysis of centrally digitized images. Fractures have been identified by manual measurement of 3 vertebral heights (anterior-Ha, middle-Hm, and posterior-Hp) and height ratios have been calculated (Ha/Hp, Hm/Hp, Hp/Hp of the upper vertebrae, Hp/Hp of the lower vertebrae). According to the classification of Genant, we defined the grade of each vertebral fracture, as follows: a decrease of 20–25% has been considered as a mild deformity (grade 1), of 26–40% as a moderate one (grade 2) and of >40% as a severe one (grade 3) (30). For each patient, the Spine Deformity Index (SDI) was calculated by summing the grade of vertebral deformities: SDI > 1 is indicative of vertebral fracture according to its definition (reduction in vertebral high of at least 4 mm or of 20%). All the measures were performed by the same physician. For X-rays, intraobserver agreement were 92.8% (κ = 0.79).\n\nWe also analyzed the prevalence of vertebral fractures in a group of 40 patients referring to the Osteoporosis Clinic of Internal Medicine of Policlinico G.B. Rossi in Verona, without HIV, HBV, or HCV infection, comparable to the studied population by sex, age and average T-score value.\n\nStatistical Analysis\nData were expressed as the mean ± standard deviation. Difference between groups were assessed by T-student test for uncoupled data. Frequencies were compared using Chi-square test, with Fisher correction where appropriate. Logistic regression models were used in the statistical analysis of factors associated with the presence of vertebral fractures. ROC analysis was performed in order to evaluate the best cut-off of DXA expressed as T-score in terms of sensibility and specificity to predict the presence of vertebral fractures in this specific setting. Statistical significance was assumed when P-values were < 0.05. Statistical analysis was carried out using SPSS for Windows version 22.0 (SPSS Inc., Chicago, IL, USA).\n\nResults\nWe selected 82 seropositive patients, 46 males and 37 females, with a median age of 55 ± 10 years. The average duration of the disease from the time of diagnosis in the selected patients was 17 ± 10 years. Results of anthropometric, biochemical and densitometric parameters grouped by the presence of fractures are reported in Table 1. Note that the only significant difference between the two groups was the CD4 cell count which was lower in the fractured patients. Out of these patients, 55 were infected by HIV, 12 were infected by HBV, 11 presented HIV and HCV co-infection, and 4 were HCV+. Most of the HIV+ and HBV+ patients were experienced to antiretroviral therapy, as showed in Table 2. The median age of HIV-infected population was 54 ± 9 years and, of these, 29 were males and 26 were females. In HBV-infected patients the median age was 56 ± 11 years, 7 were males and 5 females. The median age of HIV/HCV-positive people was 51 ± 4 years, 9 males and 2 females. The last group of HCV+ patients was composed of 1 male and 3 females, whose median age was 63 ± 10 years.\n\nTable 1 Characteristics of the studied population grouped by the presence of fractures.\n\nParameter\tFractured mean ± SD\tNot fractured mean ± SD\t\nAge (years)\t57 ± 11\t53 ± 8\t\nWeight (kg)\t66 ± 14\t62 ± 12\t\nHeight (m)\t1.65 ± 1.10\t1.63 ± 1.10\t\nCreatinine (mg/dL)\t0.83 ± 0.24\t0.80 ± 0.17\t\nPTH (pg/mL)\t33 ± 19\t28 ± 17\t\nVit.D (ng/mL)\t27 ± 7\t34 ± 8\t\nCalcium (mg/dL)\t9.3 ± 1.2\t9.3 ± 1.3\t\nCTX (ng/mL)\t0.52 ± 0.38\t0.52 ± 0.29\t\nPhosphorus (mg/dL)\t3.1 ± 0.6\t3.0 ± 0.4\t\nBMD lumbar spine (g/cm2)\t0.87 ± 0.11\t0.91 ± 0.14\t\nT-score of the lumbar spine\t−1.9 ± 0.9\t−1.5 ± 1.0\t\nZ-score lumbar spine\t−1.1 ± 1.0\t−0.8 ± 1.2\t\nCD 4 (cell/mm3)\t477 ± 261*\t720 ± 174\t\n* p < 0.001.\n\nTable 2 Distribution of ART in the population.\n\nDrug\tNumber of treated patients\t\nTenofovir\t36\t\nPI\t17\t\nTenofovir + PI\t11\t\nOther drugs\t11\t\nART-naïve\t8\t\nNo statistical differences in the main parameters of phospho-calcium metabolism have been detected between population infected by HIV and population infected by hepatitis viruses (HBV and HCV).\n\nAll of patients have been supplemented with cholecalciferol before our study with a single monthly dose of 100.000 IU; despite this, the median levels of vitamin D in the population were under the normal range (28.7 ± 14.4 ng/ml).\n\nAnalyzing data from densitometry, osteoporosis was present only in 17% of the population, osteopenia in 56.3%, while normal bone mass was present in 26.7% of the population. The prevalence of fractures was high: 34 patients presented at least one vertebral deformity (41% of the population). People with vertebral fractures were significantly older (>60 years old) and fractures were also more severe in older population than in younger population (p < 0.001). In the group of patients treated with bone-affecting drugs (tenofovir, protease inhibitors or a combination of them), the mean number of fractures was significantly higher than in the group who didn't receive these drugs (1.4 ± 0.9 vs. 0.7 ± 0.5, p < 0.05). Similarly, the median SDI (Spine Deformity Index) was higher in the first group than in the second one (2.2 ± 1.1 vs. 0.86 ± 1.00, p < 0.05). Of the fractured patients, 44% (15 patients) had grade 1 fractures, 41% (14 patients) had grade 2 fractures and 15% (5 patients) had grade 3 fractures. Multiple vertebral fractures were present in 25 patients (30.4%).\n\nBy the logistic regression considering the presence of fractures, the CD4+ cell count emerged as a predictive factor of the presence of fractures, after correction for bone mass, age, vitamin D levels and other parameters of phospho-calcium metabolism (Table 3). CD4+ cell count negatively correlated with the number of fractures and also with SDI (Spine Deformity Index) (p < 0.01 and R2 = −0.41). The viral load directly correlated with the presence and the severity of fractures (p < 0.001 and R2 < 0.45). It also directly correlated with PTH levels and negatively correlated with vitamin D levels. Furthermore, there was a negative correlation between CD4+ cell count and the viral load.\n\nTable 3 Logistic regression evaluating the predictive factors of vertebral fractures.\n\nVariables in the equation\t\n\t\tB\tS.E\tWald\tdf\tSig.\tExp(B)\t95% C.I. for Exp(B)\t\n\t\t\t\t\t\t\t\tLower\tUpper\t\nSTEP 1a\tAge\t−0.058\t0.043\t1.827\t1\t0.176\t0.943\t0.867\t1.027\t\n\tCD4 cell\t0.004\t0.002\t4.585\t1\t0.032\t1.004\t1.000\t1.008\t\n\tViralload\t−0.002\t0.008\t0.086\t1\t0.769\t0.998\t0.982\t1.014\t\n\tCreatinine\t−2.006\t1.951\t1.056\t1\t0.304\t0.135\t0.003\t6.165\t\n\tPTH\t−0.012\t0.030\t0.157\t1\t0.692\t0.988\t0.932\t1.048\t\n\tVit.D\t0.032\t0.035\t0.808\t1\t0.369\t1.032\t0.963\t1.106\t\n\tCalcium\t0.741\t1.162\t0.407\t1\t0.524\t2.098\t0.215\t20.472\t\n\tBMD lumbar spine\t2.279\t8.244\t0.076\t1\t0.782\t9.764\t0.000\t101595310\t\n\tT-score lumbar spine\t−0.194\t0.870\t0.049\t1\t0.824\t0.824\t0.150\t4.536\t\n\tConstant\t−7.493\t12.375\t0.367\t1\t0.545\t0.001\t\t\t\na Variable(s) entered on step 1:age, CD4 cell, vialload, creatinine, PTH, vit.D, calcium, BMD lumbar spine, T-score lumbar spine.\n\nNote that CD4 count was the main determinant after the correction for age, viral load, cretinine and the bone metabolism parameters.\n\nThe mean T-score in patients with fractures was −1.9 ± 0.9 and the mean Z-score was −1.1 ± 1.2, while the mean T-score in patients without any fracture was −1.5 ± 0.8 without statistically significant differences between the two groups. Bone Mass Density (BMD) didn't correlate with the presence of fractures.\n\nTo better evaluate the relationship between bone density and presence of vertebral fracture in this specific setting, we performed ROC analysis using lumbar spine T-score as test variable. The AUC for this diagnostic tool in this setting was 0.68 and the best cut-off was 1.7 SD showing 73% of sensitivity and 41% of specificity with a Yourden's index of 0.32 (Figure 1).\n\nFigure 1 The ROC analysis between bone density and presence of vertebral fracture. The AUC for this diagnostic tool in this setting was 0.68 and the best cut-of was 1.7 SD showing 73% of sensitivity and 41% of specificity.\n\nAnalyzing the main parameters of phospho-calcium metabolism, resorption marker (sCTX) in the group of patients receiving drugs inducing bone loss was significantly higher than that of patients who did not receive these drugs (0.52 ± 0.31 vs. 0.30 ± 0.08, p < 0.001) (Figure 2).\n\nFigure 2 Bone resorption marker (CTX) was significantly higher in patients treated with bone-affecting drugs compared to bone-sparing drugs treated patients (*p < 0.001).\n\nFinally, comparing the population with HIV+HCV+ co-infection with the population with only HIV+ infection (Table 4), the mean T-score was significantly lower in the first group than in the second one (−2.2 ± 0.8 vs. −1.6 ± 1.2) (p < 0.05). Furthermore, fractures were more severe in the first group than in the second one, since SDI was significantly higher in the HIV+HCV+ co-infected population (2.4 ± 2.0 vs. 1.7 ± 1.0) (Figure 3). Most of the fractures (about 60%) were dorsal, with a wedge morphology and of grade 2.\n\nTable 4 Differences between HIV and HIV + HCV population in parameters of phospho-calcic metabolism, features, and bone densitometry value.\n\n\tHIV (n°55) mean±SD\tHIV/HCV (n°11) mean ± SD\t\nAge (years)\t54 ± 9\t51 ± 4\t\nPTH (pg/mL)\t31 ± 14\t24 ± 15\t\nVit. D (ng/mL)\t28 ± 8\t28 ± 10\t\nCalcium (mg/dL)\t9.3 ± 0.3\t9.2 ± 0.4\t\nCTX (ng/mL)\t0.54 ± 0.34\t0.36 ± 0.20\t\nPhosphorus (mg/dL)\t3.0 ± 0.5\t3.1 ± 0.5\t\nBMD lumbar spine (g/cm2)\t0.91 ± 0.13\t0.84 ± 0.10\t\nT-score of the lumbar spine (SD)\t−1.7 ± 0.2\t−2.0 ± 0.8\t\nFigure 3 The severity of fractures was higher in HIV+HCV co-infected population compared to HIV-infected population (*p < 0.05).\n\nWe also analyzed the prevalence of vertebral fractures in a group of 40 patients referring to the Osteoporosis Clinic of Internal Medicine of Policlinico G.B. Rossi in Verona, without HIV, HBV or HCV infection, comparable to the studied population by sex, age and average T-score value. The main characteristics of the non-infectious group are described in Supplemental Table 1. The prevalence of fractures in these patients was significantly lower than that of the study population (17%).\n\nDiscussion\nComparing the HIV-infected population and the hepatitis-infected population, no statistical differences were found in the main parameters of phosphocalcic metabolism, suggesting a similar bone disease in these patients.\n\nOur study showed a very high prevalence of vertebral fractures in patients infected by HIV and hepatitis viruses: the 41% of the studied population showed at least one vertebral deformity. Despite the high prevalence of fractures, osteoporosis was present only in the 17% of the population enrolled in the study, while most of the population had a normal or a slightly reduced bone mass. In fact, the average T-score in fractured patients was −1.9 SD and the average Z-score −1.1 SD and these data were not statistically different from T-score measured in the non-fractured population (−1.5 SD). This means that bone mineral density could not be the best predictor of the risk of fragility fractures in these individuals and that a lateral X-rays at the spine could play an important role in detecting patients at a high risk of fracture even when DXA scan shows a normal BMD (22–24). In other words, these patients may experience vertebral fractures even when T-score levels are in the normal range. For this reason, in this population, it may be useful to define a threshold of fracture risk expressed in terms of T-score less negative than that traditionally considered for the general population. In our study, this T-score threshold was −1.7 SD, as expressed by ROC curve. In patients with T-score equal to or less than the proposed cut-off, it would be indicated to perform a radiographic study of the dorso-lumbar spine in latero-lateral projection in order to verify the presence of vertebral deformities and, where present, to define their severity.\n\nIn addition, bone mass levels correlated negatively with age: in older patients there were bone mineral density levels that were worse than in younger patients. The most plausible interpretation of this data might be that, on the one hand, age represents an independent risk factor for osteoporosis even in the general population, on the other hand, depending on the onset of the disease, elderly HIV patients may have suffered for more time the adverse effects of antiretroviral therapy, as many studies show (31–34).\n\nOur study suggested that there could be some other predictors of risk fractures in this specific population, such as infection-related factors: CD4+ cell count and the viral load. Indeed, we found a direct correlation between the HIV viremia and the number and the severity of fractures and, on the other hand, an inverse correlation between CD4+ cell count and the number of fractures. These data confirm an increased fracture rate in individuals with worse indices of infection, as other studies have suggested (31, 32). HIV and Hepatitis C co-infection have consistently been reported to be associated with an increased fracture risk: in our study, the bone mass was significantly lower in individuals with HIV and HCV co-infection and the severity of fractures was, consequently, greater than that of the population with only HIV infection (20, 31). Hepatitis C co-infection was confirmed to be an independent predictor of incident fracture and this is probably explained by the effect of chronic liver disease present in these patients (19, 35).\n\nFurthermore, we investigated the impact of antiretroviral therapy on the bone metabolism and also on the fracture risk. We compared the effect on bone metabolism of drugs recognized by the literature as mainly affecting the bone, i.e., tenofovir (TDF) and protease inhibitors (PI), with other drugs that did not appear to have this effect (32–35). We observed a significant increase in plasma CTX levels in the first group compared to the second group. Therefore, an antiretroviral therapy regimen that includes these drugs seems to increase bone resorption markers. Besides, patients in therapy with TDF and PI showed an increased fracture risk, since the average number of fractures as well as their degree of severity (SDI) were higher in this group of individuals than in the group who was not treated with such drugs.\n\nAnother interesting aspect in the use of antiretroviral therapy concerns the way it alters vitamin D metabolism lowering vitamin D levels in the blood (36–38) From the biochemical analyses of the patients, we found that the average levels of vitamin D were 28.7 ± 14.4 ng/ml and the prevalence of hypovitaminosis D was 53%, although all patients underwent supplementation with cholecalciferol before our study. Interestingly, a high viral load was associated with lower vitamin D levels: this could suggest that individuals with a worse progression of the disease have an impaired vitamin D metabolism. Furthermore, low levels of vitamin D in the blood have been correlated with an increased risk of vertebral fractures in HIV-infected patients, as some studies show (39). These findings, in line with what is reported in the literature, confirm the hypothesis that vitamin D metabolism is probably altered in these patients and that the normalization of 25-OH-D levels is achievable with higher doses of cholecalciferol than those usually used in the general population (40).\n\nA limitation of the study is that this is a cross-sectional study, since we didn't take into account the duration of disease or even the duration of antiretroviral therapy in the patients considered. Furthermore, for some subgroups of patients, such as people with HIV and HCV coinfection or the HCV infected patients, the number of the population was significantly lower than the population of HIV infected patients. Another limit of the study is the lack of a control group. However, we compared the results from this study with those obtained from a population without HIV, HBV, HCV seropositivity matched by age, sex, and T-score value and we found that in these patients the prevalence of fractures was significantly lower than that of the studied population (17%).\n\nConclusion\nAdults with HIV, HBV, and HCV infection have an increased fracture risk compared to the general population age-matched, which is associated to an increased bone turnover due to the underlying disease and the antiretroviral therapy (ART). The role of antiretroviral treatment in genesis and maintenance of hypovitaminosis D and in the increase in skeletal turnover is also confirmed. A better control of the disease activity seems to be the first goal to reduce the impact on bone caused by the inflammatory background in these patients. On the other hand, the ART itself could lead to a worse outcome of bone metabolism as well as increased fracture risk.\n\nThe best approach to these patients should provide a detailed assessment of the parameters of bone metabolism including bone turnover markers. In addition, densitometry (DXA) is confirmed to be a useful tool for assessing possible bone mineral density impairment, although, in this particular setting, even moderately reduced bone mass levels may be associated with increased fracture risk. For this reason it should be necessary to define a different T-score threshold associated with an increased fracture risk. Consequently, in these patients it could be important to perform radiographs of the dorso-lumbar spine in order to detect vertebral fractures even in patients with a normal or slightly reduced bone mass.\n\nThe early detection of patients at a high risk of fractures allow to introduce a bone sparing treatment already in the first phases of the disease, by using wherever possible a low-impact antiretroviral therapy and by monitoring the presence of vertebral fractures.\n\nEthics Statement\nThe study was carried out in accordance of normal clinical practice. No additional procedures were included in the study.\n\nAuthor Contributions\nED: patient selection and writing. FR: patient selection and data collection. ML: study design, data interpretation. EL: literature search, data collection. SS: patient selection and data collection. MM: study design, data interpretation. MV: study design, data collection. LD: data analysis, data interpretation, writing.\n\nConflict of Interest Statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nSupplementary Material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fendo.2019.00302/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\n1. Tebas P Powderly WG Claxton S Marin D Tantisiriwat W Teitelbaum SL \nAccelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy . AIDS. (2000 ) 14 :F63 –7 . 10.1097/00002030-200003100-00005 10770534 \n2. Mondy K Yarasheski K Powderly WG Whyte M Claxton S DeMarco D . Longitudinal evolution of bone mineral density and bone markers in human immunodeficiency virus-infected individuals . Clin Infect Dis. (2003 ) 36 :482 –90 . 10.1086/367569 12567307 \n3. Madeddu G Spanu A Solinas P Calia GM Lovigu C Chessa F . Bone mass loss and vitamin D metabolism impairment in HIV patients receiving highly active antiretroviral therapy . Q J Nucl Med Mol Imaging. (2004 ) 48 :39 –48 . 15195003 \n4. Moore AL Vashisht A Sabin CA Mocroft A Madge S Phillips AN . Reduced bone mineral density in HIV-positive individuals . AIDS. (2001 ) 15 :1731 –3 . 10.1097/00002030-200109070-00019 11546951 \n5. Cazanave C Dupon M Lavignolle-Aurillac V Barthe N Lawson-Ayayi S Mehsen N . Reduced bone mineral density in HIV-infected patients: prevalence and associated factors . AIDS. (2008 ) 22 :395 –402 . 10.1097/QAD.0b013e3282f423dd 18195566 \n6. Brown TT Cofrancesco J . Metabolic abnormalities in HIV-infected patients: an update . Curr Infect Dis Rep. (2006 ) 8 :497 –504 . 10.1007/s11908-006-0025-5 17064644 \n7. Ceballos ME Carvajal C Jaramillo J Dominiquez A Gonzàlez G . Vitamin D and bone mineral density in HIV newly diagnosed therapy-naive patients without any secondary causes of osteoporosis . Calcif. Tissue Int. (2019 ) 104 :42 –49 . 10.1007/s00223-018-0474-5 30209528 \n8. Warriner AH Mugavero M Overton ET . Bone alterations associated with HIV. \nCurr HIV/AIDS Rep. (2014 ) 11 :233 –40 . 10.1007/s11904-014-0216-x 25064454 \n9. Hileman CO Eckard AR McComsey GA . Bone loss in HIV: a contemporary review . Curr Opin Endocrinol Diabetes Obes. (2015 ) 22 :446 –51 . 10.1097/MED.0000000000000200 26414081 \n10. Bolland MJ Grey A Reid IR . Skeletal health in adults with HIV infection . Lancet Diabetes Endocrinol. (2015 ) 3 :63 –74 . 10.1016/S2213-8587(13)70181-5 24731663 \n11. Compston J . HIV infection and osteoporosis . Bonekey Rep. (2015 ) 4 :636 . 10.1038/bonekey.2015.3 25709813 \n12. Collin F Duval X Le Moing V Piroth L Al Kaied F Massip P . Ten-year incidence and risk factors of bone fractures in a cohort of treated HIV1-infected adults . AIDS. (2009 ) 23 :1021 –4 . 10.1097/QAD.0b013e3283292195 19300202 \n13. Prior J Burdge D Maan E Milner R Hankins C Klein M . Fragility fractures and bone mineral density in HIV positive women: a case-control population-based study . Osteoporos Int. (2007 ) 18 :1345 –53 . 10.1007/s00198-007-0428-7 17665239 \n14. Triant VA Brown TT Lee H Grinspoon SK . Fracture prevalence among human immunodeficiency virus (HIV)-infected versus non-HIV-infected patients in a large U.S. healthcare system . J Clin Endocrinol Metab. (2008 ) 93 :3499 –504 . 10.1210/jc.2008-0828 18593764 \n15. Yin MT Shi Q Hoover DR Anastos K Sharma A Young M . Fracture incidence in HIV-infected women: results from the women's interagency HIV study . AIDS. (2010 ) 24 :2679 –86 . 10.1097/QAD.0b013e32833f6294 20859192 \n16. Hoy J Young B . Do people with HIV infection have a higher risk of fracture compared with those without HIV infection? \nCurr Opin HIV AIDS. (2016 ) 11 :301 –5 . 10.1097/COH.0000000000000249 26882459 \n17. Womack JA Goulet JL Gibert C Brandt C Chang CC Gulanski B . Increased risk of fragility fractures among HIV infected compared to uninfected male veterans . PLoS ONE. (2011 ) 6 :e17217 . 10.1371/journal.pone.0017217 21359191 \n18. Young B Dao CN Buchacz K Baker R Brooks JT . Increased rates of bone fracture among HIV-infected persons in the HIV Outpatient Study (HOPS) compared with the US general population, 2000-2006 . Clin Infect Dis. (2011 ) 52 :1061 –8 . 10.1093/cid/ciq242 21398272 \n19. Dong HV Cortes YI Shiau S Yin MT . Osteoporosis and fractures in HIV/hepatitis C virus coinfection: a systematic review and meta-analysis . AIDS. (2014 ) 28 :2119 –31 . 10.1097/QAD.0000000000000363 24977441 \n20. Maalouf NM Zhang S Drechsler H Brown GR Tebas P Bedimo R . Hepatitis C co-infection and severity of liver disease as risk factors for osteoporotic fractures among HIV-infected patients . J Bone Miner Res. (2013 ) 28 :2577 –83 . 10.1002/jbmr.1988 23677838 \n21. Borderi M Calza L Colangeli V Vanino E Viale P Gibellini D . Prevalence of sub-clinical vertebral fractures in HIV-infected patients . New Microbiol. (2014 ) 37 :25 –32 . 24531168 \n22. Torti C Mazziotti G Soldini PA Foca E Maroldi R Gotti D . High prevalence of radiological vertebral fractures in HIV-infected males . Endocrine. (2012 ) 41 :512 –7 . 10.1007/s12020-011-9586-7 22198528 \n23. Llop M Sifuentes WA Bañón S Macia-Villa C Perez-Elías MJ Rosillo M . Increased prevalence of asymptomatic vertebral fractures in HIV-infected patients over 50 years of age . Arch Osteoporos. (2018 ) 13 :56 . 10.1007/s11657-018-0464-2 29736771 \n24. Ciullini L Pennica A Argento G Novarini D Teti E Pugliese G . Trabecular bone score (TBS) is associated with sub-clinical vertebral fractures in HIV-infected patients . J Bone Miner Metab. (2018 ) 36 :111 –8 . 10.1007/s00774-017-0819-6 28233186 \n25. Vestergaard P . Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes–a meta-analysis . Osteoporos Int. (2007 ) 18 :427 –44 . 10.1007/s00198-006-0253-4 17068657 \n26. Mazziotti G Bianchi A Bonadonna S Cimino V Patelli I Fusco A . Prevalence of vertebral fractures in men with acromegaly . J Clin Endocrinol Metab. (2008 ) 93 :4649 –55 . 10.1210/jc.2008-0791 18827004 \n27. Bedimo R Maalouf NM Zhang S Drechsler H Tebas P . Osteoporotic fracture risk associated with cumulative exposure to tenofovir and other antiretroviral agents . AIDS. (2012 ) 26 :825 –31 . 10.1097/QAD.0b013e32835192ae 22301411 \n28. Hansen AB Gerstoft J Kronborg G Larsen CS Pedersen C Pedersen G . Incidence of low and high-energy fractures in persons with and without HIV infection: a Danish population-based cohort study . AIDS. (2012 ) 26 :285 –93 . 10.1097/QAD.0b013e32834ed8a7 22095195 \n29. Mundy LM Youk AO McComsey GA Bowlin SJ . Overall benefit of antiretroviral treatment on the risk of fracture in HIV: nested case-control analysis in a health-insured population . AIDS. (2012 ) 26 :1073 –82 . 10.1097/QAD.0b013e328351997f 22301413 \n30. Genant HK Wu CY van Kuijk C Nevitt MC . Vertebral fracture assessment using a semiquantitative technique . J Bone Miner Res . (1993 ). 8 :1137 –48 . 10.1002/jbmr.5650080915 8237484 \n31. Pinto Neto LF Ragi-Eis S Vieira NF Soprani M Neves MB Ribeiro-Rodrigues R . Low bone mass prevalence, therapy type, and clinical risk factors in an HIV-infected Brazilian population . J Clin Densitom. (2011 ) 14 :434 –9 . 10.1016/j.jocd.2011.06.004 22051092 \n32. Li Vecchi V Soresi M Giannitrapani L Mazzola G La Sala S Tramuto F . Dairy calcium intake and lifestyle risk factors for bone loss in hiv-infected and uninfected Mediterranean subjects . BMC Infect Dis. (2012 ) 12 :192 . 10.1186/1471-2334-12-192 22894751 \n33. Brown TT Moser C Currier JS Ribaudo HJ Rothenberg J Kelesidis T \nChanges in bone mineral density after initiation of antiretroviral treatment with Tenofovir Disoproxil Fumarate/Emtricitabine Plus Atazanavir/Ritonavir, Darunavir/Ritonavir, or Raltegravir . J Infect Dis. (2015 ) 212 :1241 –9 . 10.1093/infdis/jiv194 25948863 \n34. Zhang L Su Y Hsieh E Xia W Xie J Han Y . Bone turnover and bone mineral density in HIV-1 infected Chinese taking highly active antiretroviral therapy -a prospective observational study . BMC Musculoskelet Disord. (2013 ) 14 :224 . 10.1186/1471-2474-14-224 23899016 \n35. Shiau S Broun EC Arpadi SM Yin MT . Incident fractures in HIVinfected individuals: a systematic review and meta-analysis . AIDS. (2013 ) 27 :1949 –57 . 10.1097/QAD.0b013e328361d241 24126140 \n36. Theodorou M Serste T Van Gossum M Dewit S . Factors associated with vitamin D deficiency in a population of 2044 HIV-infected patients . Clin Nutr. (2014 ) 33 :274 –9 . 10.1016/j.clnu.2013.04.018 23680190 \n37. Brown TT McComsey GA . Association between initiation of antiretroviral therapy with efavirenz and decreases in 25-hydroxyvitamin D. \nAntivir Ther (Lond). (2010 ) 15 :425 –9 . 10.3851/IMP1502 20516561 \n38. Wohl DA Orkin C Doroana M Pilotto JH Sungkanuparph S Yeni P . Change in vitamin D levels and risk of severe vitamin D deficiency over 48 weeks among HIV-1-infected, treatment-naive adults receiving rilpivirine or efavirenz in a Phase III trial (ECHO) . Antivir Ther (Lond). (2014 ) 19 :191 –200 . 10.3851/IMP2721 24430534 \n39. Atteritano M Mirarchi L Venanzi-Rullo E Santoro D Iaria C Catalano A . Vitamin D status and the relationship with bone fragility fractures in HIV-infected patients: a case control study . Int J Mol Sci. \n19 :E119 . 10.3390/ijms19010119 29301284 \n40. Piso RJ Rothen M Rothen JP Stahl M Fux C . Per oral substitution with 300000 IU vitamin D (Cholecalciferol) reduces bone turnover markers in HIV-infected patients . BMC Infect Dis. (2013 ) 13 :577 . 10.1186/1471-2334-13-577 24314015\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-2392",
"issue": "10()",
"journal": "Frontiers in endocrinology",
"keywords": "DXA; HIV; bone; fractures; spine; turnover",
"medline_ta": "Front Endocrinol (Lausanne)",
"mesh_terms": null,
"nlm_unique_id": "101555782",
"other_id": null,
"pages": "302",
"pmc": null,
"pmid": "31139152",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "10770534;11546951;12567307;15195003;17064644;17068657;17665239;18195566;18593764;18827004;19300202;20516561;20859192;21359191;21398272;22051092;22095195;22198528;22301411;22301413;22894751;23677838;23680190;23899016;24126140;24314015;24430534;24531168;24731663;24977441;25064454;25709813;25948863;26414081;26882459;28233186;29301284;29736771;30209528;8237484",
"title": "Relationship Between Vertebral Fractures, Bone Mineral Density, and Osteometabolic Profile in HIV and Hepatitis B and C-Infected Patients Treated With ART.",
"title_normalized": "relationship between vertebral fractures bone mineral density and osteometabolic profile in hiv and hepatitis b and c infected patients treated with art"
} | [
{
"companynumb": "IT-GILEAD-2019-0415404",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TENOFOVIR DISOPROXIL FUMARATE"
},
"drugadditiona... |
{
"abstract": "We describe a case of pneumonia and empyema thoracis caused by trimethoprim-sulfamethoxazole-susceptible, but imipenem-resistant Nocardia abscessus in a cancer patient. The isolate was confirmed to the species level by 16S rRNA sequencing analysis. The patient did not respond to antibiotic therapy, including ceftriaxone and imipenem, and died of progressing pneumonia and multiple organ failure.",
"affiliations": "Department of Intensive Care Medicine, Chi-Mei Medical Center, Liouying, Tainan, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.;Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan.;Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, National Taiwan University, College of Medicine, Taipei, Taiwan. Electronic address: hsporen@ntu.edu.tw.",
"authors": "Lai|Chih-Cheng|CC|;Tsai|Hsih-Yeh|HY|;Ruan|Sheng-Yuan|SY|;Liao|Chun-Hsing|CH|;Hsueh|Po-Ren|PR|",
"chemical_list": "D000900:Anti-Bacterial Agents; D012336:RNA, Ribosomal, 16S; D015378:Imipenem; D002443:Ceftriaxone; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1684-1182",
"issue": "48(6)",
"journal": "Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi",
"keywords": "16S rRNA sequencing; Empyema thoracis; Imipenem-resistant; Nocardia abscessus",
"medline_ta": "J Microbiol Immunol Infect",
"mesh_terms": "D000900:Anti-Bacterial Agents; D002443:Ceftriaxone; D024901:Drug Resistance, Multiple, Bacterial; D016724:Empyema, Pleural; D006394:Hemangiosarcoma; D006801:Humans; D015378:Imipenem; D016867:Immunocompromised Host; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure; D009615:Nocardia; D009617:Nocardia Infections; D011014:Pneumonia; D012336:RNA, Ribosomal, 16S; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "100956211",
"other_id": null,
"pages": "706-8",
"pmc": null,
"pmid": "23523047",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal pneumonia and empyema thoracis caused by imipenem-resistant Nocardia abscessus in a cancer patient.",
"title_normalized": "fatal pneumonia and empyema thoracis caused by imipenem resistant nocardia abscessus in a cancer patient"
} | [
{
"companynumb": "TW-HQ SPECIALTY-TW-2016INT000029",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": nul... |
{
"abstract": "BACKGROUND\nFor colorectal liver metastasis (CRLM) patients, hepatic resection is currently the sole cure offering the chance of long-term survival. Tumor shrinkage and planned liver remnant hypertrophy are the two key strategies for conversion of initially unresectable CRLM. First conducted in 2012, associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) allows rapid liver growth. As a means to induce hypertrophy, portal vein embolization (PVE) has been widely applied before extending hepatectomy. Recently, Peng et al. present a new approach of terminal branches portal vein embolization (TBPVE), offering an efficient way to amplify FLR and making chances for surgery in 2 weeks.\n\n\nMETHODS\nWe reported a 61-year-old woman with synchronous hepatic metastasized carcinoma of the colon sigmoideum underwent TBPVE after 6 cycles of neoadjuvant therapy in order to perform a planned right trisectionectomy. Rapid liver remnant hypertrophy and remarkable tumor shrinkage were achieved, and laparoscopic sigmoidectomy and right trisectionectomy were successfully performed. The postsurgical course was uneventful and 7 months of recurrence-free survival have been witnessed.\n\n\nCONCLUSIONS\nThe dual tactics of tumor shrinkage and planned rapid liver remnant hypertrophy will make concerted efforts to further increase the clinical candidacy for curative resection, which are valuable for further investigation.",
"affiliations": "Department of Surgical Oncology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China.;Department of Surgical Oncology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China.;Department of Surgical Oncology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China.;Department of Radiology and Intervention, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.;Department of Surgical Oncology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China.;Department of Surgical Oncology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China.;Department of Surgical Oncology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China.;Department of Radiology and Intervention, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.;Department of Surgical Oncology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China. sypzju@zju.edu.cn.;Department of General Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.",
"authors": "Xiao|Nan|N|;Yu|Kailin|K|;Yu|Shaojun|S|;Wu|Jianjun|J|;Wang|Jian|J|;Shan|Siyang|S|;Zheng|Shuchun|S|;Wang|Liuhong|L|;Wang|Jianwei|J|;Peng|Shuyou|S|",
"chemical_list": "D002272:Carcinoembryonic Antigen; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "England",
"delete": false,
"doi": "10.1186/s12957-017-1212-6",
"fulltext": "\n==== Front\nWorld J Surg OncolWorld J Surg OncolWorld Journal of Surgical Oncology1477-7819BioMed Central London 121210.1186/s12957-017-1212-6Case ReportThe paradigm of tumor shrinkage and rapid liver remnant hypertrophy for conversion of initially unresectable colorectal liver metastasis: a case report and literature review Xiao Nan 1Yu Kailin 1Yu Shaojun 1Wu Jianjun 2Wang Jian 1Shan Siyang 1Zheng Shuchun 1Wang Liuhong 2Wang Jianwei sypzju@zju.edu.cn 1Peng Shuyou 31 grid.412465.0Department of Surgical Oncology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009 China 2 grid.412465.0Department of Radiology and Intervention, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China 3 grid.412465.0Department of General Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China 3 8 2017 3 8 2017 2017 15 14818 4 2017 22 7 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\nFor colorectal liver metastasis (CRLM) patients, hepatic resection is currently the sole cure offering the chance of long-term survival. Tumor shrinkage and planned liver remnant hypertrophy are the two key strategies for conversion of initially unresectable CRLM. First conducted in 2012, associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) allows rapid liver growth. As a means to induce hypertrophy, portal vein embolization (PVE) has been widely applied before extending hepatectomy. Recently, Peng et al. present a new approach of terminal branches portal vein embolization (TBPVE), offering an efficient way to amplify FLR and making chances for surgery in 2 weeks.\n\nCase presentation\nWe reported a 61-year-old woman with synchronous hepatic metastasized carcinoma of the colon sigmoideum underwent TBPVE after 6 cycles of neoadjuvant therapy in order to perform a planned right trisectionectomy. Rapid liver remnant hypertrophy and remarkable tumor shrinkage were achieved, and laparoscopic sigmoidectomy and right trisectionectomy were successfully performed. The postsurgical course was uneventful and 7 months of recurrence-free survival have been witnessed.\n\nConclusions\nThe dual tactics of tumor shrinkage and planned rapid liver remnant hypertrophy will make concerted efforts to further increase the clinical candidacy for curative resection, which are valuable for further investigation.\n\nKeywords\nTumor shrinkageLiver remnant hypertrophyUnresectable colorectal liver metastasisPreoperative chemotherapythe Natural Science Fund of ChinaNo. 81672364the Zhejiang Province Natural Science Foundation of ChinaNo. LY15H160023issue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nColorectal cancer is the third leading cause of malignancy-related death worldwide. The liver is the most common metastatic site of colorectal cancer and liver metastasis occurs in 20–40% of patients at the time of primary diagnosis [1]. Liver resection is the sole curative approach to colorectal liver metastasis (CRLM). Nevertheless, only less than 25% of patients with CRLM are eligible for curative resection, of which insufficient future liver remnant (FLR) volume is the main cause [2]. Currently, systemic therapy is the only established treatment for patients with unresectable CRLM. Tumor shrinkage and liver remnant hypertrophy are the two key strategies for conversion of initially unresectable CRLM.\n\nFirst conducted in 2012, associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) allows rapid liver growth in a short time and has a strong impact on surgery for liver cancer. However, high morbidity and mortality after the surgery cannot be ignored. Classic portal vein embolization (PVE) has been widely applied before extending hepatectomy, but the slow growth of FLR renders a longish waiting time of 4–6 weeks between PVE and liver resection, which embraces the risk of tumor progression. Recently, Peng et al. [3] presented a new approach of terminal branches portal vein embolization liver partition for planned hepatectomy (TELPP), offering an efficient way to amplify the FLR and making chances for surgery in 2 weeks.\n\nCase presentation\nA 61-year-old woman was referred to our department because of synchronous hepatic metastasized carcinoma of the colon sigmoideum. Physical examination revealed no significant abnormalities. Blood investigations were within normal range except for mild anemia and serum carcinoembryonic antigen level of 10 ng/ml. Fecal occult blood test was strongly positive.\n\nColonoscopy found a sigmoid lesion 20 cm from the anus, and pathological result of the biopsy specimen demonstrated a moderately differentiated adenocarcinoma. The gene detection found no mutation in KRAS, NRAS, and BRAF. Magnetic resonance imaging of the liver revealed multiple metastases and the largest measured 15 cm × 11 cm × 13 cm (staging according the seventh edition of the UICC: cT3, cN1, cM1a) (Fig. 1).Fig. 1 MRI imaging of the mass revealed tumor distributed at the right hepatic trisection, adjacent to the left branch of portal vein at primary diagnosis\n\n\n\n\nThe multi-disciplinary team (MDT) suggested a conversion strategy consisting of preoperative FOLFIRI (irinotecan, fluoruracil) regimen with cetuximab for the initially unresectable colorectal liver metastasis. If the conversion of liver metastasis was achieved, a right trisectionectomy would be performed.\n\nAfter 6 cycles, the liver metastasis significantly shrank (staging according to RECIST version 1.1: PR), but the largest metastasis was adjacent to the left branch of portal vein (Fig. 2). The CT volumetry revealed that total liver volume (TLV) was 1495 ml, and the volume of the future liver remnant (FLR) was 415 ml, which was below the volume cutoff value for safe resection (more than 40% of TLV) [4]. So, according to MDT, terminal branches portal vein embolization (TBPVE) was performed to block the anterior and posterior branch of the right portal vein as previously reported [3] for sufficient hypertrophy of the left lateral lobe (Fig. 3).Fig. 2 Tumor shrunk significantly after 6 cycles of FOLFIRI with cetuximab\n\n\nFig. 3 Effect of terminal branch portal vein embolization. a Post-embolization venogram with coils visible in the anterior and posterior right portal vein (black arrows). b CT scan showing embolized terminal branches of the right portal vein. c CT scan showing lipiodol deposition\n\n\n\n\nFive days after the TBPVE, the FLR was 513 ml (47.5% of TLV). On the 11th day, the FLR was 550 ml (50.9% of TLV) (Fig. 4) and laparoscopic sigmoidectomy and right trisectionectomy were performed (Fig. 5). There were no intraoperative complications, and the histology of the FLR showed a low-grade steatohepatitis after chemotherapy. The postoperative histology revealed pT3, pN2b (11/17), pM1, L0, V1, G2, and R0 resection margin. The postsurgical course was uneventful and the patient continued to undertake 6 cycles of systemic therapy of FOLFIRI with cetuximab. Heretofore, 7 months of recurrence-free survival have been witnessed.Fig. 4 Volume of the left lateral external lobe of the liver. a Before the TBPVE. b Hypertrophy on the 5th and c 11th day after the TBPVE\n\n\nFig. 5 Right trisectionectomy a hypertrophy of the left lateral external lobe of the liver b pars sagitalis of the left branch of portal vein c right trisectionectomy specimen\n\n\n\n\nDiscussion\nFor CRLM patients, hepatic resection is the only treatment with a curative intent offering the chance of long-term survival at present. Nevertheless, at the time of diagnosis, only fewer than 25% of CRLM patients are eligible for liver resection. The main limitations to the resection are inadequate future liver remnant (FLR) volume and poor oncological prognosis of advanced diseases. The former increases the risk of postoperative liver failure, while the latter is associated with early recurrence.\n\nThe past few decades have seen surgeons struggling to achieve rapid liver remnant hypertrophy. As a classic way to induce hypertrophy of the FLR, PVE is now routinely applied to improve the rate of R0 resection. But it takes 3–8 weeks to expand the volume of FLR by up to 40% and the second stage of the surgery is not always accomplished [5]. First performed by Schnitzbauer in 2012, ALPPS led to 74% increase of the FLR in a mean time of 9 days, making initially unresectable hepatic lesions resectable. Despite its advantages, ALPPS caused high morbidity (64%) and liver-related mortality (12%), which has been evoking violent controversy [6].\n\nTo overcome the aforementioned disadvantages, Peng et al. [3] presented a new approach of TBPVE, which deflowered the essence of PVE and ALPPS. It is reported that this new technique could induce rapid liver remnant hypertrophy and make chances for surgery in 14 days. Increasing FLR by 33% to 68%, four cases of huge hepatocellular carcinoma with liver cirrhosis acquired chances of right hepatectomy 2 weeks after the TBPVE. His group recently reported the safety and efficacy data of tentative application of TBPVE liver partition for planned hepatectomy (TELPP). Similar to that of ALPPS, the philosophy behind TBPVE is the thorough separation of the left and right hemi-liver (ramus communicans of the right and left portal vein). Moreover, complete and enduring embolism of the terminal branches to segment V, VIII or IV is indispensible in order to rapidly promote the regeneration of remnant liver parenchyma. Technically, to achieve this goal, they first embolized the terminal branches with lipiodol and cyanoacrylate, then blocked the main branch of portal vein with coils. Compared with classic PVE, the new technique could increase the FLR more significantly in a short period of time. The specific physiopathological mechanisms underlying this enhanced liver remnant hypertrophy are still unconfirmed. The explanation for this phenomenon might be that, in comparison to PVE, TBPVE attains more thorough partitions of communicating branches between the planned resected segments and FLR, which lead to increasing portal flow and hepatotropic factors to the FLR [7].\n\nThe use of first-line chemotherapy to shrink hepatic metastases is an ideal strategy for patients with initially unresectable CLRM, but only about 20% of the patients with initially unresectable liver-limited metastases become resectable after chemotherapy [8]. Considering the low tumor response rate yielded by second-line chemotherapy after the failure of first-line regimen [9], we believe TBPVE could be a better choice for these patients as a fast and efficient way to amplify FLR and create chances for surgery in a short time.\n\nThere is growing evidence that PVE not only does stimulate the growth of FLR but also induces significant tumor growth in patients with CRLM [10, 11]. The longish time between PVE and liver resection required to achieve adequate FLR volume embraces the risk of progressive disease [12]. Moreover, potential promotion of tumor growth after PVE and consequent acceleration of tumor progression in the waiting time are primary concerns possibly confining the use of PVE in patients with multifocal tumors [13]. A recent meta-analysis [5] reviewing 44 publications and including 1791 patients undergoing PVE demonstrated that the hypertrophy response was insufficient in 51 patients (2.8%) to perform liver resection and 6.1% of those patients treated ultimately were not able to undergo resection because of local tumor progression after PVE. Another study by Fischer et al. [14] based on 208 tumors measured in 64 patients found that, without post-PVE chemotherapy, 34.2% of the liver lesions progressed. However, there was a remarkable lower risk of tumor progression (18.9%, p = .03) when chemotherapy was applied.\n\nConsequently, it has sparked controversy over whether preoperative chemotherapy could cooperate with PVE.\n\nSurely, there are sufficient practical and academic justifications for preoperative chemotherapy. Approximately 15% of patients with initially unresectable hepatic colorectal metastases are now conventionally converted to resectable cases by chemotherapy. The chemotherapy and biologic treatments given while the tumor is in situ can not only help to decide the appropriate therapies after surgery but also eliminate microscopic tumor cells.\n\nNevertheless, it was suggested that preoperative chemotherapy would hinder liver regeneration [15] and increase postoperative complications [16]. Therefore, chemotherapy was interrupted several weeks before embolization, leaving the potential for tumor progression at liberty.\n\nProlonged peri-procedure chemotherapy has been associated with reduced hypertrophy [17, 18]. Yet, some studies [19–21] were unable to show any influence of chemotherapy on liver regeneration after PVE. On the other hand, Covey et al. [22] in a study with a series of 100 patients concluded that liver could still hypertrophy in a toxic environment and preoperative chemotherapy during PVE had no negative effects on liver regeneration. Most recently, Fischer et al. [14] reported the combination of PVE and chemotherapy was not only effective in terms of liver hypertrophy but also related to retarded tumor growth and improved long-term survival. Additionally, it is indicated that short chemical-free intervals (CFI) improved outcomes, whereas long CFI resulted in poor oncological endings. Kambakamba et al. [23] found that short CFI is closely associated with significantly better prognosis in terms of overall survival and disease-free survival based on 74 patients suffering from CRLM who received operations. Spelt and his colleagues [24] also came to the conclusion that long intervals between the end of chemotherapy and PVE could enhance tumor progression in CRLM patients.\n\nConclusion\nIn conclusion, TBPVE was a promising approach to shorten the waiting time between embolization and surgery. Preliminary study indicated that TBPVE could rival ALPPS in respect of inducing rapid liver remnant hypertrophy and, meanwhile, be on a par with PVE in terms of post-operation complications. To confirm its safety and efficacy, further large-scale and multi-centered studies are needed.\n\nThe threat of progressive disease after PVE highlights the value of minimizing the waiting time between PVE and resection and of devising therapeutic strategies using preoperative chemotherapy to control tumor growth after PVE. Besides, given that the liver can still regenerate when cytotoxic chemotherapy is administered, the modality combining preoperative chemotherapy with TBPVE would attain lesion shrinkage while also achieving rapid liver remnant expansion. The dual tactics of tumor shrinkage and planned rapid liver remnant hypertrophy will make concerted efforts to further increase the clinical candidacy for curative resection, which are valuable for further investigation.\n\nAbbreviations\nALPPSAssociated liver partition and portal vein ligation for staged hepatectomy\n\nCFIChemical-free intervals\n\nCRLMColorectal liver metastasis\n\nFLRFuture liver remnant\n\nMDTMulti-disciplinary team\n\nPVEPortal vein embolization\n\nTBPVETerminal branches portal vein embolization\n\nTELPPTerminal branches portal vein embolization liver partition for planned hepatectomy\n\nTLVTotal liver volume\n\nAcknowledgements\nNot applicable.\n\nFunding\nThis study was supported by the Natural Science Fund of China under Grant No. 81672364 and the Zhejiang Province Natural Science Foundation of China under Grant No. LY15H160023.\n\nAvailability of data and materials\nData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\n\nAuthors’ contributions\nNX and KLY are the co-first author. JWW is the corresponding author of the manuscript. SJY, JJW, JW and LHW collected the patient’s data and provided the figures. SYS, SCZ, and SYP were involved in drafting and revising the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nEthical approval was given by the medical ethics committee of Second Affiliated Hospital School of Medicine, Zhejiang University.\n\nConsent for publication\nWritten informed consent for publication of this case report and the associated images were obtained from the patient.\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. Siegel RL Miller KD Jemal A Cancer statistics, 2016 CA Cancer J Clin 2016 66 7 30 10.3322/caac.21332 26742998 \n2. Lam VW Laurence JM Johnston E Hollands MJ Pleass HC Richardson AJ A systematic review of two-stage hepatectomy in patients with initially unresectable colorectal liver metastases HPB (Oxford) 2013 15 483 491 10.1111/j.1477-2574.2012.00607.x 23750490 \n3. Peng SY Huang CY Li JT Zhang YY He XW Wang YF Hong DF Cai XJ Terminal branches portal vein embolization for planed hepatectomy Zhonghua Wai Ke Za Zhi 2016 54 9 664 668 27587208 \n4. Abdalla EK Adam R Bilchik AJ Jaeck D Vauthey JN Mahvi D Improving resectability of hepatic colorectal metastases: expert consensus statement Ann Surg Oncol 2006 13 1271 1280 10.1245/s10434-006-9045-5 16955381 \n5. van Lienden KP van den Esschert JW de Graaf W Bipat S Lameris JS van Gulik TM van Delden OM Portal vein embolization before liver resection: a systematic review Cardiovasc Intervent Radiol 2013 36 25 34 10.1007/s00270-012-0440-y 22806245 \n6. Schnitzbauer AA Lang SA Goessmann H Nadalin S Baumgart J Farkas SA Fichtner-Feigl S Lorf T Goralcyk A Horbelt R Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings Ann Surg 2012 255 405 414 10.1097/SLA.0b013e31824856f5 22330038 \n7. Yokoyama Y Nagino M Nimura Y Mechanisms of hepatic regeneration following portal vein embolization and partial hepatectomy: a review World J Surg 2007 31 367 374 10.1007/s00268-006-0526-2 17219273 \n8. Maeda Y Shinohara T Nagatsu A Futakawa N Hamada T Long-term outcomes of conversion hepatectomy for initially unresectable colorectal liver metastases Ann Surg Oncol 2016 23 Suppl 2 S242 S248 10.1245/s10434-015-4460-0 25749931 \n9. Mocellin S Baretta Z Roque IFM Sola I Martin-Richard M Hallum S Bonfill Cosp X Second-line systemic therapy for metastatic colorectal cancer Cochrane Database Syst Rev 2017 1 Cd006875 28128439 \n10. Hoekstra LT van Lienden KP Doets A Busch OR Gouma DJ van Gulik TM Tumor progression after preoperative portal vein embolization Ann Surg 2012 256 812 817 10.1097/SLA.0b013e3182733f09 23095626 \n11. Simoneau E Aljiffry M Salman A Abualhassan N Cabrera T Valenti D El Baage A Jamal M Kavan P Al-Abbad S Portal vein embolization stimulates tumour growth in patients with colorectal cancer liver metastases HPB (Oxford) 2012 14 461 468 10.1111/j.1477-2574.2012.00476.x 22672548 \n12. de Graaf W van den Esschert JW van Lienden KP van Gulik TM Induction of tumor growth after preoperative portal vein embolization: is it a real problem? Ann Surg Oncol 2009 16 423 430 10.1245/s10434-008-0222-6 19050974 \n13. van Gulik TM van den Esschert JW de Graaf W van Lienden KP Busch OR Heger M van Delden OM Lameris JS Gouma DJ Controversies in the use of portal vein embolization Dig Surg 2008 25 436 444 10.1159/000184735 19212116 \n14. Fischer C Melstrom LG Arnaoutakis D Jarnagin W Brown K D'Angelica M Covey A DeMatteo R Allen P Kingham TP Chemotherapy after portal vein embolization to protect against tumor growth during liver hypertrophy before hepatectomy JAMA Surg 2013 148 1103 1108 10.1001/jamasurg.2013.2126 24173207 \n15. Kremer M Manzini G Hristov B Polychronidis G Mokry T Sommer CM Mehrabi A Weitz J Buchler MW Schemmer P Impact of neoadjuvant chemotherapy on hypertrophy of the future liver remnant after associating liver partition and portal vein ligation for staged hepatectomy J Am Coll Surg 2015 221 717–728.e711 10.1016/j.jamcollsurg.2015.05.017 26232303 \n16. Karoui M Penna C Amin-Hashem M Mitry E Benoist S Franc B Rougier P Nordlinger B Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases Ann Surg 2006 243 1 7 10.1097/01.sla.0000193603.26265.c3 16371728 \n17. de Baere T Teriitehau C Deschamps F Catherine L Rao P Hakime A Auperin A Goere D Elias D Hechelhammer L Predictive factors for hypertrophy of the future remnant liver after selective portal vein embolization Ann Surg Oncol 2010 17 2081 2089 10.1245/s10434-010-0979-2 20237856 \n18. Sturesson C Keussen I Tranberg KG Prolonged chemotherapy impairs liver regeneration after portal vein occlusion—an audit of 26 patients Eur J Surg Oncol 2010 36 358 364 10.1016/j.ejso.2009.12.001 20100648 \n19. Spelt L Norman P Tornqvist L Tingstedt B Andersson R Combined portal vein embolization and preoperative chemotherapy prior to liver resection for colorectal cancer metastases Scand J Gastroenterol 2012 47 975 983 10.3109/00365521.2012.685751 22631611 \n20. Hasselgren K Malago M Vyas S Campos RR Brusadin R Linecker M Petrowsky H Clavien PA Machado MA Hernandez-Alejandro R Neoadjuvant chemotherapy does not affect future liver remnant growth and outcomes of associating liver partition and portal vein ligation for staged hepatectomy Surgery 2017 161 1255 1265 10.1016/j.surg.2016.11.033 28081953 \n21. Nafidi O Desy D Letourneau R Cote J Plasse M Vandenbroucke F Roy A Dagenais M Lapointe RW Hypertrophy of the non-embolized liver after chemotherapy HPB (Oxford) 2009 11 103 107 10.1111/j.1477-2574.2009.00004.x 19590632 \n22. Covey AM Brown KT Jarnagin WR Brody LA Schwartz L Tuorto S Sofocleous CT D'Angelica M Getrajdman GI DeMatteo R Combined portal vein embolization and neoadjuvant chemotherapy as a treatment strategy for resectable hepatic colorectal metastases Ann Surg 2008 247 451 455 10.1097/SLA.0b013e31815ed693 18376189 \n23. Kambakamba P Linecker M Alvarez FA Samaras P Reiner CS Raptis DA Kron P de Santibanes E Petrowsky H Clavien PA Lesurtel M Short chemotherapy-free interval improves oncological outcome in patients undergoing two-stage hepatectomy for colorectal liver metastases Ann Surg Oncol 2016 23 3915 3923 10.1245/s10434-016-5419-5 27431413 \n24. Spelt L Sparrelid E Isaksson B Andersson RG Sturesson C Tumour growth after portal vein embolization with pre-procedural chemotherapy for colorectal liver metastases HPB (Oxford) 2015 17 529 535 10.1111/hpb.12397 25726854\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1477-7819",
"issue": "15(1)",
"journal": "World journal of surgical oncology",
"keywords": "Liver remnant hypertrophy; Preoperative chemotherapy; Tumor shrinkage; Unresectable colorectal liver metastasis",
"medline_ta": "World J Surg Oncol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D002272:Carcinoembryonic Antigen; D002277:Carcinoma; D012809:Colon, Sigmoid; D003113:Colonoscopy; D015179:Colorectal Neoplasms; D004621:Embolization, Therapeutic; D005260:Female; D005472:Fluorouracil; D006498:Hepatectomy; D006801:Humans; D006984:Hypertrophy; D010535:Laparoscopy; D002955:Leucovorin; D008026:Ligation; D008099:Liver; D008113:Liver Neoplasms; D008115:Liver Regeneration; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D011169:Portal Vein; D011379:Prognosis; D016896:Treatment Outcome; D014656:Vascular Surgical Procedures",
"nlm_unique_id": "101170544",
"other_id": null,
"pages": "148",
"pmc": null,
"pmid": "28774330",
"pubdate": "2017-08-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "17219273;25726854;19212116;27431413;22330038;23095626;19590632;28081953;22672548;22631611;16371728;18376189;20237856;16955381;24173207;25749931;27587208;23750490;20100648;22806245;19050974;26232303;26742998;28128439",
"title": "The paradigm of tumor shrinkage and rapid liver remnant hypertrophy for conversion of initially unresectable colorectal liver metastasis: a case report and literature review.",
"title_normalized": "the paradigm of tumor shrinkage and rapid liver remnant hypertrophy for conversion of initially unresectable colorectal liver metastasis a case report and literature review"
} | [
{
"companynumb": "CN-ACCORD-057964",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CETUXIMAB"
},
"drugadditional": null,
"druga... |
{
"abstract": "Inguinal hernia repair belongs to the most frequently performed surgical procedures. Endoscopic techniques like TAPP and TEP have become standard of care together with the conventional open techniques. Especially in endoscopic techniques, there is a confusing amount of different meshes and fixation techniques with impact on perioperative and long-term outcome. We present the first single-center data on the use of titanized extra lightweight meshes and fibrin glue fixation compared to staple fixation regarding long-term outcome, especially chronic pain.\n\n\n\nA clinical trial with retrospective analysis of patient- and procedure-related data and questionnaire-based follow-up of TAPP procedures performed in 2012-2014 was conducted in a specialized hernia center. Standard TAPP technique was used with placement of TiMesh extra light (16 g/m2) and either fibrin glue or staple fixation. Procedure- and patient-related data are compared after propensity score matching regarding perioperative complications and long-term outcome.\n\n\n\nOf 612 TAPP procedures 372 procedures were included in analysis after propensity score matching. Fibrin glue was used in n = 279 and staple fixation in n = 93 cases. There were significant differences regarding duration of the surgical procedures (p = 0.001) and distribution of mesh size. No differences were noted regarding perioperative complications such as seroma or hematoma formation and need for re-laparoscopy. During a mean follow-up of 32.1 ± 20.6 month with a follow-up rate of 79%, there was no difference in long-term outcome, especially for rate of recurrence (p = 0.112) and development of chronic pain (p = 0.846). The overall rate of recurrence was 3.0% (n = 11), and in 2.4% (n = 9) patients complained of chronic pain.\n\n\n\nInguinal hernia repair using extra lightweight titanized meshes and fibrin glue fixation is safe and feasible compared to staple fixation even in large and combined hernia defects, if mesh size is adjusted to size of hernia defect. The rate of chronic pain was extremely low at 2.4%.",
"affiliations": "Department of General and Vascular Surgery, Agatharied Hospital, Hausham, Germany. Ulrich.Wirth@med.uni-muenchen.de.;Department of Rehabilitation Medicine, International Medical Center, Schön Klinik Vogtareuth, Vogtareuth, Germany.;Department of General and Vascular Surgery, Agatharied Hospital, Hausham, Germany.;Department of Surgery and Center for Minimally Invasive Surgery, Academic Teaching Hospital of Charité Medical School, Vivantes Hospital, Neue Bergstrasse 6, 13585, Berlin, Germany.;Department of General and Vascular Surgery, Agatharied Hospital, Hausham, Germany.;Department of General and Vascular Surgery, Agatharied Hospital, Hausham, Germany.",
"authors": "Wirth|Ulrich|U|0000-0003-2366-8524;Saller|Marie Luise|ML|;von Ahnen|Thomas|T|;Köckerling|Ferdinand|F|;Schardey|Hans Martin|HM|;Schopf|Stefan|S|",
"chemical_list": "D015718:Fibrin Tissue Adhesive",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00464-019-06965-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0930-2794",
"issue": "34(5)",
"journal": "Surgical endoscopy",
"keywords": "Chronic pain; Fibrin sealant fixation; Inguinal hernia; Laparoscopic hernia repair; TAPP; TiMesh® extra light",
"medline_ta": "Surg Endosc",
"mesh_terms": "D059350:Chronic Pain; D005260:Female; D015718:Fibrin Tissue Adhesive; D006552:Hernia, Inguinal; D059685:Herniorrhaphy; D006801:Humans; D010535:Laparoscopy; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013526:Surgical Mesh; D013536:Suture Techniques",
"nlm_unique_id": "8806653",
"other_id": null,
"pages": "1929-1938",
"pmc": null,
"pmid": "31300910",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "23355162;21607821;25786904;24647885;10460281;21853390;29888245;11922736;29330835;21103989;27232253;27334968;29075973;20526620;10663001;24253381;14691711;27351657;21751060;28451730;26316363;25805239;28953552;28233095;15359095;29075969;26092012",
"title": "Long-term outcome and chronic pain in atraumatic fibrin glue versus staple fixation of extra light titanized meshes in laparoscopic inguinal hernia repair (TAPP): a single-center experience.",
"title_normalized": "long term outcome and chronic pain in atraumatic fibrin glue versus staple fixation of extra light titanized meshes in laparoscopic inguinal hernia repair tapp a single center experience"
} | [
{
"companynumb": "DE-JNJFOC-20191230279",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FIBRINOGEN HUMAN\\THROMBIN HUMAN"
},
"drugadditio... |
{
"abstract": "Myastenia-Inflammatory Myopathy (MG-IM) association has been described in less than 50 cases, as isolated reports or in few case series. In most cases, MG and IM onset occur simultaneously even if the overlapping clinical manifestations could lead to delay the diagnosis in the early stage of disease. In these cases, thymic pathology is present in more than 50% of cases. Pathological findings can be consistent of polymyositis (63%), dermatomyositis (25%) or granulomatosis (12%). Accurate clinical manifestations and severity of IM in MG, including muscle specific antibodies (MSA) and muscle MRI, have not been systematically investigated and focal or mild subclinical myositis have not been reported. We observed that focal myositis or asymptomatic CK elevation can also occur in MG. In this review we have also retrospectively re-analyzed the clinical, serological, pathological and muscle imaging data from 13 patients with MG- IM from our cohort of 441 MG patients (2,9%). Clinical onset occurred simultaneously in 10/13 patients, whereas in 2 patients the IM appeared later in MG disease course (range 10-14 years) and conversely in 1 patient MG symptoms occurred later in IM disease course (4 years). Median age at disease onset was 51 year (range 24-73 years) regardless of clinical onset (MG or IM). Median clinical follow-up was 88 months (range 31-237 months). IM was suspected by CK elevation in all patients (ranging 800-3000 UI/L at first detection) and non-fatigable muscle weakness unresponsive to acetylcholinesterase inhibitors. All the patients presented mild to moderate MG symptoms. Three main categories of muscle involvement, sometimes overlapping, were recognizable: distal, proximal and subclinical myositits, leading to three main clinical groups (A,B,C) and two overlapping subgroups (A/B and B/C). Thymus pathology was present in 10/13 patients. Anti-AChR was detected in al all patients associated with anti-Titin and -RyR1 in those patients with thymoma. No MSA, nor MAA antibodies were detected. Muscle biopsy confirmed IM in all patients. In conclusion we redefined the clinical spectrum of muscle involvement in MG-IM association, which represent a continuum among 3 main clinical groups: distal, proximal and subclinical muscle involvement. Minimal muscle involvement and focal myositis could be underestimated among myasthenic patients and early aggressive immunotherapy could be required in focal group.",
"affiliations": "Neuromuscular and Rare Disease Center, Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), SAPIENZA University, Sant'Andrea Hospital, Rome, Italy. Electronic address: matteo.garibaldi@uniroma1.it.;Neuromuscular and Rare Disease Center, Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), SAPIENZA University, Sant'Andrea Hospital, Rome, Italy.;Neuromuscular and Rare Disease Center, Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), SAPIENZA University, Sant'Andrea Hospital, Rome, Italy.;Neuromuscular and Rare Disease Center, Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), SAPIENZA University, Sant'Andrea Hospital, Rome, Italy.;Neuromuscular and Rare Disease Center, Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), SAPIENZA University, Sant'Andrea Hospital, Rome, Italy.;Neuromuscular and Rare Disease Center, Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), SAPIENZA University, Sant'Andrea Hospital, Rome, Italy.;Neuromuscular and Rare Disease Center, Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), SAPIENZA University, Sant'Andrea Hospital, Rome, Italy.;Neuromuscular and Rare Disease Center, Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), SAPIENZA University, Sant'Andrea Hospital, Rome, Italy.;Neuromuscular and Rare Disease Center, Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), SAPIENZA University, Sant'Andrea Hospital, Rome, Italy.;Neuromuscular and Rare Disease Center, Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), SAPIENZA University, Sant'Andrea Hospital, Rome, Italy.;Rare Neuromuscular Diseases Centre, Department of Human Neuroscience, SAPIENZA University, Rome, Italy.;Fondazione Policlinico Universitario \"A. Gemelli\" IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.;Fondazione Policlinico Universitario \"A. Gemelli\" IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.;Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS Neurological Institute \"C. Besta\", Milan, Italy.;Unit of Neuromuscular Disorders, Neurology, San Filippo Neri Hospital, Rome, Italy.;Neuroscience Department, San Camillo-Forlanini Hospital, Rome, Italy.;Neuromuscular and Rare Disease Center, Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), SAPIENZA University, Sant'Andrea Hospital, Rome, Italy.;Neuromuscular and Rare Disease Center, Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), SAPIENZA University, Sant'Andrea Hospital, Rome, Italy.",
"authors": "Garibaldi|Matteo|M|;Fionda|Laura|L|;Vanoli|Fiammetta|F|;Leonardi|Luca|L|;Loreti|Simona|S|;Bucci|Elisabetta|E|;Di Pasquale|Antonella|A|;Morino|Stefania|S|;Vizzaccaro|Elisa|E|;Merlonghi|Gioia|G|;Ceccanti|Marco|M|;Lucchini|Matteo|M|;Mirabella|Massimiliano|M|;Andreetta|Francesca|F|;Pennisi|Elena Maria|EM|;Petrucci|Antonio|A|;Salvetti|Marco|M|;Antonini|Giovanni|G|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.autrev.2020.102498",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1568-9972",
"issue": "19(4)",
"journal": "Autoimmunity reviews",
"keywords": "Distal myopathy; Idiopathic inflammatory myopathy (IM); Myasthenia gravis (MG); Myositis; Polymyositis; Thymoma",
"medline_ta": "Autoimmun Rev",
"mesh_terms": "D006801:Humans; D018908:Muscle Weakness; D009157:Myasthenia Gravis; D009220:Myositis; D012189:Retrospective Studies; D013945:Thymoma",
"nlm_unique_id": "101128967",
"other_id": null,
"pages": "102498",
"pmc": null,
"pmid": "32062029",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Muscle involvement in myasthenia gravis: Expanding the clinical spectrum of Myasthenia-Myositis association from a large cohort of patients.",
"title_normalized": "muscle involvement in myasthenia gravis expanding the clinical spectrum of myasthenia myositis association from a large cohort of patients"
} | [
{
"companynumb": "IT-MYLANLABS-2020M1044172",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "Allogeneic hematopoietic cell transplant (HCT) recipients are at risk for herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. Routine prophylaxis with acyclovir is recommended during periods of immunosuppression. Brincidofovir (BCV, CMX001), a lipid conjugate of cidofovir, has shown in vitro activity against HSV/VZV, but has not been formally studied for HSV/VZV prophylaxis. We report our clinical experience of BCV for HSV/VZV prophylaxis in HCT recipients. This was a retrospective review of 30 hematopoietic cell transplant (HCT) recipients between 8/2010 and 8/2015 who received BCV doses not exceeding 200 mg/week for adults/adolescents and 4 mg/kg/week for pediatric (<12 years) patients, for ≥14 days BCV without concomitant acyclovir under clinical trials or single patient use. HSV/VZV cases during BCV treatment were confirmed by viral culture or PCR and clinical symptoms. Of 30 patients who met the inclusion criteria, 27 (90%) patients were adults and 22 (73%) patients received T-cell depleted HCT. The most common indications for BCV were cytomegalovirus in 12 patients (40%) and adenovirus in 11 patients (37%). One patient was treated for acyclovir-resistant HSV and one for disseminated VZV. There were two breakthrough cases of HSV infection during 2170 patient-days. There were no cases of breakthrough VZV infection. The overall rate of breakthrough HSV infection was 1.0 per 1000 patient-days, without any breakthrough VZV infections. Our study provides the only available-albeit limited-evidence on the potential efficacy of BCV for HSV/VZV prophylaxis in HCT patients. Additional studies are needed to further assess the efficacy and safety of BCV in the setting.",
"affiliations": "Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Weill Cornell Medical College, Cornell University, New York, New York.;Weill Cornell Medical College, Cornell University, New York, New York.;Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.",
"authors": "Lee|Yeon Joo|YJ|http://orcid.org/0000-0002-2997-0217;Neofytos|Dionysios|D|;Kim|Seong Jin|SJ|;Cheteyan|Leslie|L|;Huang|Yao-Ting|YT|;Papadopoulos|Esperanza B|EB|;Jakubowski|Ann A|AA|;Papanicolaou|Genovefa A|GA|",
"chemical_list": "D063065:Organophosphonates; C525733:brincidofovir; D003596:Cytosine",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12977",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "20(6)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "brincidofovir; hematopoietic cell transplant; herpes simplex virus (HSV); varicella-zoster virus (VZV)",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D019072:Antibiotic Prophylaxis; D002648:Child; D002675:Child, Preschool; D003596:Cytosine; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006561:Herpes Simplex; D014645:Herpesvirus 3, Human; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates; D012189:Retrospective Studies; D018139:Simplexvirus; D016896:Treatment Outcome; D000073618:Varicella Zoster Virus Infection; D055815:Young Adult",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e12977",
"pmc": null,
"pmid": "30120866",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "11859400;15572000;17570114;19861977;24066743;25120093;25218782;26187863;27482652;27582067;27997653;28063938;28209721;28453848;28668490",
"title": "Efficacy of brincidofovir as prophylaxis against HSV and VZV in hematopoietic cell transplant recipients.",
"title_normalized": "efficacy of brincidofovir as prophylaxis against hsv and vzv in hematopoietic cell transplant recipients"
} | [
{
"companynumb": "US-TEVA-2019-US-994640",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",... |
{
"abstract": "Post-radiation soft tissue sarcomas (PRSTSs) are rare secondary malignancies. In this report, we describe the clinical presentation of a 52-year-old woman who underwent postmastectomy radiation therapy (PMRT) for left-sided breast cancer 2.7 years ago and presented with a left internal mammary mass and left interpectoral nodule on computed tomography. On further evaluation, she was diagnosed with internal mammary rhabdomyosarcoma and interpectoral nodal breast cancer relapse, and was treated with chemotherapy, followed by surgery and endocrine therapy. She developed left pleural metastases and is currently receiving targeted therapy. Internal mammary rhabdomyosarcomas are rare among PRSTSs and pose a diagnostic challenge for patients with breast cancer. Histological evaluation is important for the differential diagnosis of breast cancer relapses with secondary malignancies. The management of post-radiation thoracic rhabdomyosarcomas is challenging, and the prognosis is poor.",
"affiliations": "Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Breast Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.",
"authors": "Wang|Dan-Qiong|DQ|;Zhang|Jing-Yi|JY|;Li|Jing|J|;Ying|Jian-Ming|JM|;Wang|Xiang|X|;Fan|Ying|Y|;Wang|Shu-Lian|SL|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2021.751758",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X\nFrontiers Media S.A.\n\n10.3389/fonc.2021.751758\nOncology\nCase Report\nCase Report: An Internal Mammary Rhabdomyosarcoma After Mastectomy and Systemic and Radiation Therapy in a Patient With Breast Cancer\nWang Dan-Qiong 1\n\nZhang Jing-Yi 2\n\nLi Jing 3\nYing Jian-Ming 4\nWang Xiang 5\nFan Ying 2 *\n\nWang Shu-Lian 1 *\n\n1 Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China\n2 Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China\n3 Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China\n4 Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China\n5 Department of Breast Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China\nEdited by: Susanne Rogers, Aarau Cantonal Hospital, Switzerland\n\nReviewed by: Vikram Jairam, Yale University, United States; Christin A. Knowlton, Yale University, United States\n\n*Correspondence: Ying Fan, fanyingfy@medmail.com.cn; Shu-Lian Wang, wsl20040118@yahoo.com\nThis article was submitted to Radiation Oncology, a section of the journal Frontiers in Oncology\n\n26 10 2021\n2021\n11 75175802 8 2021\n11 10 2021\nCopyright © 2021 Wang, Zhang, Li, Ying, Wang, Fan and Wang\n2021\nWang, Zhang, Li, Ying, Wang, Fan and Wang\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.\nPost-radiation soft tissue sarcomas (PRSTSs) are rare secondary malignancies. In this report, we describe the clinical presentation of a 52-year-old woman who underwent postmastectomy radiation therapy (PMRT) for left-sided breast cancer 2.7 years ago and presented with a left internal mammary mass and left interpectoral nodule on computed tomography. On further evaluation, she was diagnosed with internal mammary rhabdomyosarcoma and interpectoral nodal breast cancer relapse, and was treated with chemotherapy, followed by surgery and endocrine therapy. She developed left pleural metastases and is currently receiving targeted therapy. Internal mammary rhabdomyosarcomas are rare among PRSTSs and pose a diagnostic challenge for patients with breast cancer. Histological evaluation is important for the differential diagnosis of breast cancer relapses with secondary malignancies. The management of post-radiation thoracic rhabdomyosarcomas is challenging, and the prognosis is poor.\n\npost-radiation soft tissue sarcomas\nrhabdomyosarcomas\nbreast cancer\nradiation therapy\ncase report\n==== Body\npmcIntroduction\n\nPost-radiation soft tissue sarcomas (PRSTSs) occur in <1% of post-radiation patients. The most common site of PRSTSs is the thoracic region, which is frequently irradiated due to breast cancer or Hodgkin’s lymphoma (1). Breast cancer is known to be the most frequent original cancer of PRSTSs (1–3). The 15-year cumulative incidence of PRSTSs for breast cancer is 0.28% (4). Although PRSTSs of breast cancer are generally rare, they are increasing in number given the long-term survival of patients receiving radiation therapy (RT). Meanwhile, the use of systemic therapy may also contribute to an increase in the risk of PRSTSs (5). Therefore, clinicians should be aware of the differential diagnosis between PRSTSs and locoregional relapse.\n\nIn 1948, Cahan et al. established some criteria to define the essential characteristics of radiation-induced sarcomas of the bone (6), namely: i) the tumor must arise within, or adjacent to, a previously irradiated field; ii) the tumor should arise at least 6 months after the cessation of RT; and iii) histological confirmation of a sarcoma, distinct from the patient’s prior malignancy. These criteria have been modified over time, especially the duration of latency and the inclusion of soft-tissue sarcomas. Here, we report a rare case of internal mammary rhabdomyosarcoma and interpectoral nodal breast cancer relapse in a 52-year-old woman 2.7 years after postmastectomy radiation therapy (PMRT) and systemic therapy for breast cancer. The article was written according to the CAse REport (CARE) guidelines, and the CARE checklist is provided in Supplementary Table 1 .\n\nCase Description\n\nThe patient was a 52-year-old healthy woman who was originally diagnosed with left-sided breast cancer in May 2017 (then age, 48 years). She underwent mastectomy and axillary lymph node dissection. Pathology indicated grade II, non-specific, invasive carcinoma, with a tumor size measuring 1.2×1.0 cm, and the presence of lymphovascular invasion. Immunohistochemistry (IHC) showed that the tumor was positive for estrogen receptor (ER) (80%), progesterone receptor (PR) (70%), Ki-67 (25%), and negative for HER2 (1+). Two out of 23 removed lymph nodes showed metastases, with extracapsular extension. The patient’s disease was staged as pT1cN1aM0.\n\nFrom June to October 2017, she received six cycles of chemotherapy (epirubicin 60 mg d1, 2 + paclitaxel liposome 270 mg d3, q21d). Because of the grade 4 agranulocytosis with fever after the first cycle, the regimens were adjusted to epirubicin 60 mg d1, 50 mg d2 + paclitaxel liposome 240 mg d3 for the remaining five cycles.\n\nIn November 2017, she received PMRT, which consisted of 43.5 Gy in 15 daily fractions to the chest wall and supra/infraclavicular fossa, but did not intend to include the internal mammary nodal region. The chest wall was irradiated with 6 MeV electron, while the supra/infraclavicular fossa was irradiated with 6 MV x-rays by using three-dimensional conformal radiation therapy (3D-CRT) technique. Then, she was prescribed oral tamoxifen and underwent regular follow-up.\n\nIn July 2020, 2.7 years after the PMRT, chest computed tomography (CT) for routine examination revealed a 2.7 cm×1.7 cm nodule in the left interpectoral region, and a 3.5 cm×3.0 cm mass in the left internal mammary area ( Figure 1 ). She had no symptoms and there were no palpated nodules on physical examination. Ultrasound-guided 22-gauge needle biopsy of the interpectoral nodule was performed and histological examination revealed carcinoma cells. On IHC, the tumor was positive for AE1/AE3 and ER (10%). To further elucidate the molecular subtype of the recurrence, ultrasound-guided 16-gauge needle biopsy of the left internal mammary mass was performed, which showed few malignant tumor cells on hematoxylin-eosin (HE) staining. IHC showed that the tumor was positive for vimentin, desmin, myogenic differentiation 1 (myoD1), and Ki-67 (70%), and negative for S-100, smooth muscle actin (SMA), cytokeratin 18 (CK18), AE1/AE3, ER, and PR, suggesting spindle cell rhabdomyosarcoma. Then, ultrasound-guided 16-gauge needle biopsy of the interpectoral nodule was performed, and histology suggested grade II, non-specific, invasive carcinoma, and IHC showed that the tumor was positive for ER (70%), PR (20%), Ki-67 (70%), and androgen receptor (AR) (60%) and negative for HER2, cytokeratin 5/6 (CK5/6), EGFR, vimentin, myoD1, and desmin, confirming breast cancer recurrence. Bone-emission CT showed slightly increased intake of the medial anterior segment of the left second rib, which was considered as tumor erosion. Next-generation sequencing (NGS) revealed that she did not carry germline mutations in BRCA1, BRCA2, MLH1, and MSH2 genes. After staging workup with abdominal ultrasonography, she was diagnosed with post-radiation rhabdomyosarcoma cT1N0M0Gx, stage IA, and interpectoral nodal recurrence from breast cancer.\n\nFigure 1 Chest CT images. (A) At baseline (July 2020), CT indicated a 2.7 cm×1.7 cm nodule in the left interpectoral region, and a 3.5 cm×3.0 cm mass in the left internal mammary area. (B) After two cycles of chemotherapy (September 2020), CT indicated stable disease (SD) with a decreased nodule size (2.4×1.5 cm) and a slight increase in the mass size (4.5×3.3 cm). (C) After four cycles of chemotherapy (November 2020), CT indicated SD with a decreased nodule size (2.2×1.2 cm) and mass (4.4×3.1 cm). (D) After six cycles of chemotherapy (February 2021), CT indicated SD with a decreased nodule size (1.5×0.7 cm) and mass (3.6×3.1 cm). (E) After surgery, E1 shows the left interpectoral node shrinkage to 1.2×0.8 cm in size, and E2, E3, E4 show appearance of multiple left pleural metastatic nodules.\n\nFrom September 2020 to January 2021, she received six cycles of chemotherapy, consisting of albumin paclitaxel 40 mg and carboplatin 700 mg, q21d. She tolerated the treatment well, developing grade I anemia, grade II vomiting, and grade II hyperlipidemia after chemotherapy. CT evaluation showed stable disease (SD) after 2, 4, and 6 cycles ( Figure 1 ). After multidisciplinary team discussion in February 2021, she underwent a wide local resection of internal mammary mass along with adjacent ribs, sternum, and left upper lung. After the tumor was completely resected with 4-cm margins, intraoperative frozen section confirmed a negative margin. Macroscopically, the resected tumor measured 3 cm in diameter, and involved the sternum, rib, and left upper lung. Microscopically, the lesion consisted of spindle malignant cells, and IHC revealed that the tumor was positive for desmin (focal +), myoD1 (+), myogenin (focal +), Ki-67 (40%), and CK (focal +), and negative for CK7, SMA, ER, and PR, indicating rhabdomyosarcoma ( Figure 2 ). After a normal recovery from surgery, she received goserelin and letrozole from March 2021. In May 2021, her chest CT showed that the left interpectoral node shrank to 1.2×0.8 cm in size; however, multiple left pleural metastatic nodules appeared ( Figure 1 ). She refused any further chemotherapy because of fear of vomiting and disappointment with progression on chemotherapy. A complementary IHC revealed that the internal mammary tumor was positive for programmed cell death ligand 1 (PD-L1) (22C3): combined positive score (CPS) 10. From May 2021, she received programmed cell death protein 1 (PD1) antibody toripalimab 240 mg d1 and bevacizumab 400 mg d1, q21d, and has meanwhile continued her endocrine therapy. The timeline of her historical and current treatments is illustrated in Figure 3 . Her PMRT treatment plan was retrieved, and the unintentional mean radiation dose to the left internal mammary region, where the rhabdomyosarcoma originated, was estimated as 32.5 Gy in 15 fractions ( Figure 4 ).\n\nFigure 2 Representative histologic images of rhabdomyosarcoma. (A) Malignant mesenchymal tumor, mainly spindle cells, clear cytoplasm or acidophilic tumor cells, severe atypia, large and hyperchromatic nuclei, irregular karyotype, and visible mitotic image. (B) MyoD1 (+) by immunohistochemistry. (C) Myogenin (focal +) by immunohistochemistry.\n\nFigure 3 Timeline of historical and current treatments.\n\nFigure 4 The dose distribution of PMRT the patient received for breast cancer. Upper image, horizontal view; left image, sagittal view; and right image, coronal view.\n\nDiscussion\n\nOur case report is significant, because we believe it is extremely rare for a patient to develop both breast cancer recurrence and PRSTSs in two different lymphatic drainage regions that had been exposed to radiation 2.7 years ago. The post-radiation rhabdomyosarcoma was an accidental finding, as the specimen from the first biopsy of the interpectoral node was not adequate for elucidating the molecular subtype and hence, a second biopsy of the internal mammary mass was performed. Routinely, it is not required to perform histological analysis for all recurrent lesions. However, the present case suggests that because all lesions occurred in the previous radiation field, histological confirmation could be useful because of the possible development of PRSTSs.\n\nRadiation therapy is associated with an increased risk of developing a secondary in-field PRSTSs (HR, 4.1), especially angiosarcomas (HR, 8.97), in breast cancer patients within a median latent period of 7 years. The risk for development of PRSTSs (at all sites) increased in the third year after diagnosis of breast cancer, peaked at 8–12 years, and then decreased again (7). Similarly, it has been reported that the median time from the diagnosis of original cancer to PRSTSs was 11 years (1–3). As for the present case, thoracic rhabdomyosarcoma is rare not only as PRSTSs but also as sporadic sarcoma (8). The most common histological type of PRSTSs was undifferentiated pleomorphic sarcoma, followed by angiosarcoma (2), whereas sporadic rhabdomyosarcoma occurred frequently in the head and neck region and the genitourinary tract. There is a relationship between the dose of radiation received by soft tissue sarcoma sites during breast cancer RT and the risk of developing these secondary sarcomas. Hang et al. found that the risk of angiosarcomas was 15.9-fold higher and the risk of other soft tissue sarcomas was 2.2-fold higher among women treated by RT than among those who were not (9). Rubino et al. reported that among women treated with RT, those who received >14 Gy had a higher risk of sarcoma than those who received <14 Gy, and the odds-ratios (ORs) were 1.6 and 30.6 for women who received 14–44 Gy and at least 45 Gy at the site of the sarcoma, respectively (4). Henderson et al. reported that anthracycline exposure was associated with sarcoma risk (OR=3.5) in childhood cancer survivors, after adjusting for radiation dose, other chemotherapy, and primary cancers (5). In addition, genetic susceptibility was associated with increased risk of malignancies. There was a significantly higher prevalence of post-radiation sarcoma in patients with breast cancer and Li-Fraumeni syndrome (LFS) than non-LFS breast cancer patients (6% vs. 0.03%, p<0.001) (10). Our patient was not BRCA1, BRCA2, MLH1, and MSH2 germline mutations carrier but had received anthracycline-based chemotherapy and 32.5 Gy of radiation in left internal mammary site, therefore her rhabdomyosarcoma is likely attributed to previous RT and chemotherapy.\n\nPRSTSs has worse outcomes than sporadic sarcomas (2, 11). Patients with PRSTSs had a 5-year OS of 38%–68% (2, 7). Surgery with curative intent is the mainstay of therapy. Negative surgical margins are usually associated with better OS (1, 2, 12). The management of the present case is rather complicated and both secondary rhabdomyosarcoma and breast cancer recurrence were taken into consideration. Our patient received chemotherapy followed by curative surgery. Unfortunately, she developed multi-pleural metastases shortly after surgery. Patients with thoracic rhabdomyosarcoma have a poorer prognosis than those with rhabdomyosarcoma at other sites, which might be due to the higher percentage of advanced-stage tumors and technical difficulties of local therapy at the thoracic site. The rhabdomyosarcoma had involved the left upper lung and pleura in the present case. Tumors may extend or disseminate along pleural surfaces and be deceiving in their size and boundaries; hence, more vigorous measures to ensure local and distant control may be needed. Based on the evidence that PD-1 blockade combined with vascular endothelial growth factor (VEGF) inhibitor showed acceptable toxic effects and preliminary activity in advanced sarcomas (13), our patient was willing to try PD1 antibody and bevacizumab, but further follow-up is warranted.\n\nThe present study indicates the importance of differential diagnosis between tumor relapse and PRSTSs for a mass developed in the lymph drainage site for breast cancer patients with a history of RT. We highlight this case with the intention of alerting clinicians to obtain histological confirmation for any in-field relapse.\n\nConclusion\n\nInternal mammary rhabdomyosarcomas are extremely rare among PRSTSs and pose a diagnostic challenge for patients with breast cancer. Histological evaluation is important for differential diagnosis of breast cancer relapses with secondary malignancies.\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 authors.\n\nEthics Statement\n\nWritten informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nD-QW, S-LW, and YF performed image acquisition and completed the manuscript. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThis work was supported by the CAMS Innovation Fund for Medical Sciences (2020-I2M-C&T-B-075).\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublisher’s Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.751758/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1 Spalek MJ Czarnecka AM Rutkowski P . The Management of Radiation-Induced Sarcomas: A Cohort Analysis From a Sarcoma Tertiary Center. J Clin Med (2021) 10 (4 ):694. doi: 10.3390/jcm10040694 33578934\n2 Mito JK Mitra D Barysauskas CM . A Comparison of Outcomes and Prognostic Features for Radiation-Associated Angiosarcoma of the Breast and Other Radiation-Associated Sarcomas. Int J Radiat Oncol Biol Phys (2019) 104 (2 ):425–35. doi: 10.1016/j.ijrobp.2019.01.082\n3 Callesen LB Safwat A Rose HK . Radiation-Induced Sarcoma: A Retrospective Population-Based Study Over 34 Years in a Single Institution. Clin Oncol (R Coll Radiol) (2021) 33 (5 ):e232–e8. doi: 10.1016/j.clon.2020.12.009\n4 Rubino C Shamsaldin A Lê M . Radiation Dose and Risk of Soft Tissue and Bone Sarcoma After Breast Cancer Treatment. Breast Cancer Res Treat (2005) 89 (3 ):277–88. doi: 10.1007/s10549-004-2472-8\n5 Henderson TO Rajaraman P Stovall M . Risk Factors Associated With Secondary Sarcomas in Childhood Cancer Survivors: A Report From the Childhood Cancer Survivor Study. Int J Radiat Oncol Biol Phys (2012) 84 (1 ):224–30. doi: 10.1016/j.ijrobp.2011.11.022\n6 Cahan WG Woodard HQ Higinbotham NL . Sarcoma Arising in Irradiated Bone: Report of Eleven Cases. 1948. Cancer (1998) 82 (1 ):8–34. doi: 10.1002/(sici)1097-0142(19980101)82:1<8::aid-cncr3>3.0.co;2-w 9428476\n7 Mery CM George S Bertagnolli MM . Secondary Sarcomas After Radiotherapy for Breast Cancer: Sustained Risk and Poor Survival. Cancer (2009) 115 (18 ):4055–63. doi: 10.1002/cncr.24462\n8 Andrassy RJ Wiener ES Raney RB . Thoracic Sarcomas in Children. Ann Surg (1998) 227 (2 ):170–3. doi: 10.1097/00000658-199802000-00003\n9 Huang J Mackillop WJ . Increased Risk of Soft Tissue Sarcoma After Radiotherapy in Women With Breast Carcinoma. Cancer (2001) 92 (1 ):172–80. doi: 10.1002/1097-0142(20010701)92:1<172::aid-cncr1306>3.0.co;2-k\n10 Le AN Harton J Desai H . Frequency of Radiation-Induced Malignancies Post-Adjuvant Radiotherapy for Breast Cancer in Patients With Li-Fraumeni Syndrome. Breast Cancer Res Treat (2020) 181 (1 ):181–8. doi: 10.1007/s10549-020-05612-7\n11 Bjerkehagen B Smastuen MC Hall KS . Why do Patients With Radiation-Induced Sarcomas Have a Poor Sarcoma-Related Survival? Br J Cancer (2012) 106 (2 ):297–306. doi: 10.1038/bjc.2011.559 22173669\n12 Fang Z Matsumoto S Ae K . Postradiation Soft Tissue Sarcoma: A Multiinstitutional Analysis of 14 Cases in Japan. J Orthop Sci (2004) 9 (3 ):242–6. doi: 10.1007/s00776-004-0768-5\n13 Wilky BA Trucco MM Subhawong TK . Axitinib Plus Pembrolizumab in Patients With Advanced Sarcomas Including Alveolar Soft-Part Sarcoma: A Single-Centre, Single-Arm, Phase 2 Trial. Lancet Oncol (2019) 20 (6 ):837–48. doi: 10.1016/S1470-2045(19)30153-6\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "11()",
"journal": "Frontiers in oncology",
"keywords": "breast cancer; case report; post-radiation soft tissue sarcomas; radiation therapy; rhabdomyosarcomas",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
"other_id": null,
"pages": "751758",
"pmc": null,
"pmid": "34765557",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "11443624;31078463;30703514;32246378;33386215;22173669;9428476;15168177;9488512;22795729;19526590;33578934;15754127",
"title": "Case Report: An Internal Mammary Rhabdomyosarcoma After Mastectomy and Systemic and Radiation Therapy in a Patient With Breast Cancer.",
"title_normalized": "case report an internal mammary rhabdomyosarcoma after mastectomy and systemic and radiation therapy in a patient with breast cancer"
} | [
{
"companynumb": "CN-MLMSERVICE-20211125-3242796-1",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "EPIRUBICIN HYDROCHLORIDE"
},
"drugaddi... |
{
"abstract": "BACKGROUND\nThe cutaneous effects of rapidly accelerated fibrosarcoma kinase B (BRAF) inhibitors are not well understood. Squamous cell carcinoma (SCC), keratoacanthoma, and photosensitivity have been described in patients taking BRAF inhibitors.\n\n\nMETHODS\nTo characterize the timing and frequency of skin lesions in patients receiving BRAF inhibitor therapy, we utilized a retrospective case review of 53 patients undergoing treatment with BRAF inhibitors for 4-92 weeks of therapy. Patients were evaluated at baseline, and then followed at 4- to 12-week intervals. Charts were retrospectively reviewed, and the morphology and timing of cutaneous events were recorded.\n\n\nRESULTS\nThirty-three of the 53 charts met exclusion/inclusion criteria, 15 were treated with vemurafenib, and 18 were treated with GSK 2118436/GSK 1120212. Of 33 patients treated with BRAF inhibitor, 13 developed photosensitivity (39.4%), 10 developed actinic keratoses (30.3%), 10 developed warts (30.3%), and 6 developed SCC (18.2%).\n\n\nCONCLUSIONS\nMultiple cutaneous findings were observed in the 33 patients taking BRAF inhibitors. The previously described association with SCC and photosensitivity was observed in these patients as well. Over half of the observed SCCs were invasive in nature. Photosensitivity continues to be frequent with BRAF inhibitors. Patients taking BRAF inhibitors should have regular full body skin exams. Further studies are necessary to better elucidate the rates of these adverse cutaneous effects.",
"affiliations": "Departments of Dermatology.;Departments of Dermatology.;Departments of Pathology.;Oncology, Massachusetts General Hospital, Boston, USA.;Oncology, Massachusetts General Hospital, Boston, USA.;Departments of Dermatology. Electronic address: harvardskinstudies@partners.org.",
"authors": "Mattei|P L|PL|;Alora-Palli|M B|MB|;Kraft|S|S|;Lawrence|D P|DP|;Flaherty|K T|KT|;Kimball|A B|AB|",
"chemical_list": "D000970:Antineoplastic Agents; D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D011728:Pyridones; D011744:Pyrimidinones; D013449:Sulfonamides; D000077484:Vemurafenib; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib",
"country": "England",
"delete": false,
"doi": "10.1093/annonc/mds292",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0923-7534",
"issue": "24(2)",
"journal": "Annals of oncology : official journal of the European Society for Medical Oncology",
"keywords": null,
"medline_ta": "Ann Oncol",
"mesh_terms": "D000970:Antineoplastic Agents; D002294:Carcinoma, Squamous Cell; D005260:Female; D006801:Humans; D007093:Imidazoles; D007211:Indoles; D007636:Keratoacanthoma; D055623:Keratosis, Actinic; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D009369:Neoplasms; D010091:Oximes; D010787:Photosensitivity Disorders; D048493:Proto-Oncogene Proteins B-raf; D011728:Pyridones; D011744:Pyrimidinones; D012189:Retrospective Studies; D012871:Skin Diseases; D013449:Sulfonamides; D000077484:Vemurafenib; D014860:Warts",
"nlm_unique_id": "9007735",
"other_id": null,
"pages": "530-537",
"pmc": null,
"pmid": "23035153",
"pubdate": "2013-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Cutaneous effects of BRAF inhibitor therapy: a case series.",
"title_normalized": "cutaneous effects of braf inhibitor therapy a case series"
} | [
{
"companynumb": "US-GLAXOSMITHKLINE-US2015GSK085595",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABRAFENIB"
},
"drugadditional": nul... |
{
"abstract": "The present case involved a 60-year-old man with autoimmune pancreatitis (AIP). While his AIP was in remission for 6 years, a follow-up CE-CT revealed a dilated main pancreatic duct (MPD) and an enhanced mural nodule. Fluorodeoxyglucose uptake was positive on positron emission tomography. Endoscopic retrograde pancreatography showed a filling defect of the MPD, and pancreatoscopy revealed a nodule partially covered with papillary lesions. Although a repeat biopsy revealed no evidence of malignancy, we speculated that there was a high likelihood of main-duct-type intraductal papillary mucinous neoplasm (IPMN)-derived carcinoma concomitant with AIP. Subsequently, the patient underwent subtotal stomach-preserving pancreaticoduodenectomy. A surgical specimen showed a 35 mm protuberant papillary lesion with abundant stroma, located in the main duct of the pancreas. Further histological evaluation revealed that the nodule was predominantly composed of IPMN with low-grade dysplasia, which was accompanied by abundant IgG4-positive lymphoplasmacytic infiltration, and fibrosis existed predominantly around the IPMN. The epithelium of the cyst showed mucinous hyperplasia with focal papillary structures of gastric phenotype (MUC5A+, MUC6+, MUC1-, MUC2-, CDX-). After surgical resection, we did not find any imaging evidence suggesting a recurrent tumor and AIP relapse in the remnant pancreas. In conclusion, we report a case of IPMN coincidentally found in a patient with type 1 AIP. Active AIP may exaggerate the morphology of IPMN, and careful evaluation should be performed to select appropriate management.",
"affiliations": "Department of Gastroenterology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295, Japan. subaru@fmu.ac.jp.;Department of Hepato-Biliary-Pancreatic and Transplant Surgery, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan.;Department of Hepato-Biliary-Pancreatic and Transplant Surgery, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan.;Department of Gastroenterology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295, Japan.;Department of Gastroenterology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295, Japan.;Department of Gastroenterology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295, Japan.;Department of Endoscopy, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan.;Department of Gastroenterology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295, Japan.;Department of Endoscopy, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan.;Department of Endoscopy, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan.;Department of Anatomic Pathology, Kurashiki Central Hospital, Kurashiki, 710-8602, Japan.;Department of Pathology, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan.;Department of Pathology, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan.;Department of Endoscopy, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan.;Department of Hepato-Biliary-Pancreatic and Transplant Surgery, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan.;Department of Gastroenterology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295, Japan.",
"authors": "Suzuki|Rei|R|http://orcid.org/0000-0002-4049-0484;Okada|Ryo|R|;Muto|Makoto|M|;Takagi|Tadayuki|T|;Sugimoto|Mitsuru|M|;Irie|Hiroki|H|;Nakamura|Jun|J|;Takasumi|Mika|M|;Kato|Tsunetaka|T|;Hashimoto|Minami|M|;Notohara|Kenji|K|;Suzuki|Osamu|O|;Hashimoto|Yuko|Y|;Hikichi|Takuto|T|;Marubashi|Shigeru|S|;Ohira|Hiromasa|H|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-020-01162-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "13(6)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Autoimmune pancreatitis; Gastric type; Intraductal papillary mucinous neoplasm",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D002288:Adenocarcinoma, Mucinous; D000081012:Autoimmune Pancreatitis; D021441:Carcinoma, Pancreatic Ductal; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010190:Pancreatic Neoplasms",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "1315-1321",
"pmc": null,
"pmid": "32594422",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rare coincidence of intraductal papillary mucinous neoplasm and type 1 autoimmune pancreatitis.",
"title_normalized": "rare coincidence of intraductal papillary mucinous neoplasm and type 1 autoimmune pancreatitis"
} | [
{
"companynumb": "NVSC2020JP197913",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Gastric small cell carcinoma (GSCC) is a rare entity in the western hemisphere. GSCC's typically arise in the upper one-third of the stomach and have histologic features similar to those of small-cell lung carcinoma (SCLC). They have an aggressive natural history that is characterized by early and widespread metastases. Prognosis is dismal with an overall survival of less than 12 months. We present the case of a 79-year-old African-American woman who presented with two weeks of progressive dysphagia associated with nausea, vomiting and a foreign body sensation in the throat. Computed tomography (CT) imaging showed multiple hepatic and lymph node lesions but revealed no gastric thickening. Endoscopy revealed a large ulcer on the lesser curvature of the stomach. Biopsy proved the diagnosis of pure-type GSCC. Bone scan identified multiple focal bony lesions at the thoracolumbar vertebrae, ribcage, bilateral scapulae, pelvic bones and right proximal femur. Treatment was started with cisplatin and etoposide. To our knowledge, this is the one of the first reported cases of gastric small cell cancer with bone metastases in the western hemisphere. Our report shows the importance of doing a full metastatic workup in these patients to identify sites of metastases.",
"affiliations": "Department of Hematology Oncology, The Brooklyn Hospital Center, Brooklyn, NY, USA.;Department of Internal Medicine, The Brooklyn Hospital Center, Brooklyn, NY, USA.;Department of Gastroenterology, The Brooklyn Hospital Center, Brooklyn, NY, USA.;Department of Pathology, The Brooklyn Hospital Center, Brooklyn, NY, USA.;Department of Hematology Oncology, The Brooklyn Hospital Center, Brooklyn, NY, USA.;Department of Hematology Oncology, The Brooklyn Hospital Center, Brooklyn, NY, USA.",
"authors": "Rajasekaran Rathnakumar|Geethapriya|G|;Gupta|Ashish|A|;John|Febin|F|;Liu|Yingxian|Y|;Shakil|Shams|S|;Guevara|Elizabeth|E|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/jgo.2019.06.10",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2078-6891",
"issue": "10(5)",
"journal": "Journal of gastrointestinal oncology",
"keywords": "Gastric small cell cancer; bone metastases; neuroendocrine tumor (NET)",
"medline_ta": "J Gastrointest Oncol",
"mesh_terms": null,
"nlm_unique_id": "101557751",
"other_id": null,
"pages": "1027-1031",
"pmc": null,
"pmid": "31602342",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports",
"references": "15226341;20848201;29896397;19893606;15150595;22076200;25550603;25932087;23662228;16022138",
"title": "A case of gastric small cell carcinoma with metastases to bone and liver.",
"title_normalized": "a case of gastric small cell carcinoma with metastases to bone and liver"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-19-49685",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"dru... |
{
"abstract": "BACKGROUND\nThrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder. Drug-induced TTP is uncommon and we report a TTP associated with the use of clopidogrel.\n\n\nMETHODS\nWe report a 50-year-old man who presented with acute myocardial infarction and received clopidogrel therapy. He developed acute TTP ten days after clopidogrel onset. Imputability of the drug was demonstrated during a reintroduction test. Deficiency of ADAMTS 13 was confirmed and autoantibodies against ADAMTS 13 were detected. Complete remission was obtained after 24 plasma exchange sessions and adjunction of corticosteroids.\n\n\nCONCLUSIONS\nDrug-induced TTP are probably immunologic, as was demonstrated in our patient. Clinicians should be aware of this possible uncommon adverse effect of clopidogrel because prompt therapy is imperative for life saving.",
"affiliations": "Service de médecine interne, hôpital Édouard-Herriot, Lyon 69003 cedex, France. ludovickarkowski@hotmail.fr",
"authors": "Karkowski|L|L|;Wolf|M|M|;Lescampf|J|J|;Coppérré|B|B|;Veyradier|A|A|;Ninet|J|J|;Hot|A|A|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine",
"country": "France",
"delete": false,
"doi": "10.1016/j.revmed.2011.10.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0248-8663",
"issue": "32(12)",
"journal": "La Revue de medecine interne",
"keywords": null,
"medline_ta": "Rev Med Interne",
"mesh_terms": "D000077144:Clopidogrel; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D010975:Platelet Aggregation Inhibitors; D011697:Purpura, Thrombotic Thrombocytopenic; D013988:Ticlopidine",
"nlm_unique_id": "8101383",
"other_id": null,
"pages": "762-5",
"pmc": null,
"pmid": "22093796",
"pubdate": "2011-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Clopidogrel induced thrombotic thrombocytopenic purpura.",
"title_normalized": "clopidogrel induced thrombotic thrombocytopenic purpura"
} | [
{
"companynumb": "FR-RANBAXY-2012RR-52737",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": nul... |
{
"abstract": "The gastrointestinal stromal tumor (GIST) is a digestive neoplasm of mesenchymal lineage. The treatment strategy for receptor tyrosine kinase-mutated GISTs is well defined. Wild-type GISTs (WT-GISTs) respond unsatisfactorily to specific kinase inhibitors. Moreover, evidence shows that repeat surgery has limited benefit. We report the case of a young female patient who was diagnosed with liver metastatic WT-GIST, after initial radical resection and adjuvant therapy with molecular targeted drugs. Due to the disease progression, a two-stage surgery was performed, with the removal of extrahepatic lesions followed by a total hepatectomy. The patient is disease-free after 4 years from liver transplantation (LT), performed under everolimus-based immunosuppression. The treatment of WT-GISTs remains a significant challenge due to the frequent resistance to tyrosine kinase inhibitors (TKIs). Liver transplantation might represent an effective treatment option for such disease.",
"affiliations": "Hepato-Pancreato-Biliary Surgery and Transplantation, Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy.;Hepato-Pancreato-Biliary Surgery and Transplantation, Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy.;Hepato-Pancreato-Biliary Surgery and Transplantation, Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy.;Hepato-Pancreato-Biliary Surgery and Transplantation, Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy.;Hepato-Pancreato-Biliary Surgery and Transplantation, Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy.;Hepato-Pancreato-Biliary Surgery and Transplantation, Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy.;Pathological Anatomy, Department of Biomedical Sciences and Public Health, Polytechnic University of Marche, Ancona, Italy.;Pôle de Chirurgie Expérimentale et Transplantation, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.;Hepato-Pancreato-Biliary Surgery and Transplantation, Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy.",
"authors": "Iesari|Samuele|S|0000-0002-6918-945X;Mocchegiani|Federico|F|0000-0002-8833-5360;Nicolini|Daniele|D|;Benedetti Cacciaguerra|Andrea|A|;Coletta|Martina|M|;Montalti|Roberto|R|;Mandolesi|Alessandra|A|;Lerut|Jan|J|;Vivarelli|Marco|M|",
"chemical_list": "D047428:Protein Kinase Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.15377",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "19(10)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "cancer/malignancy/neoplasia: metastatic disease; clinical research/practice; immunosuppressive regimens; liver disease: malignant; liver transplantation/hepatology; organ allocation",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000328:Adult; D005260:Female; D005770:Gastrointestinal Neoplasms; D046152:Gastrointestinal Stromal Tumors; D006801:Humans; D008113:Liver Neoplasms; D016031:Liver Transplantation; D058990:Molecular Targeted Therapy; D011379:Prognosis; D047428:Protein Kinase Inhibitors",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "2939-2943",
"pmc": null,
"pmid": "30943317",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Liver transplantation for metastatic wild-type gastrointestinal stromal tumor in the era of molecular targeted therapies: Report of a first case.",
"title_normalized": "liver transplantation for metastatic wild type gastrointestinal stromal tumor in the era of molecular targeted therapies report of a first case"
} | [
{
"companynumb": "IT-MYLANLABS-2019M1088908",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
... |
{
"abstract": "Posterior reversible encephalopathy syndrome (PRES) is the most common neurological complication occurring in children undergoing induction chemotherapy for acute lymphoblastic leukaemia (ALL) but is increasingly recognised to occur in adults as well. Here, we report a woman who presented with B-cell ALL (B-ALL) at the time of delivery and developed PRES 1 day after receiving intrathecal (IT) methotrexate (MTX) that rapidly resolved. She subsequently received IT MTX without recurrence of neurological symptoms. This case represents the first case of PRES in a postpartum B-ALL patient receiving IT MTX, demonstrates that re-treatment with MTX in this case could be done safely and highlights the risk of PRES in adults treated for B-ALL.",
"affiliations": "Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.;Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.",
"authors": "Mescher|Craig|C|http://orcid.org/0000-0002-9478-6926;Slungaard|Arne|A|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-220429",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "chemotherapy; haematology (drugs and medicines); haematology (incl blood transfusion); pregnancy; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D007278:Injections, Spinal; D008279:Magnetic Resonance Imaging; D008727:Methotrexate; D054038:Posterior Leukoencephalopathy Syndrome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D055815:Young Adult",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28978582",
"pubdate": "2017-10-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20470218;23617825;21924823;12552054;22225972;21210832;15756541;25999210;26012245;8559202",
"title": "Posterior reversible encephalopathy syndrome in a postpartum woman with acute lymphoblastic leukaemia after intrathecal methotrexate.",
"title_normalized": "posterior reversible encephalopathy syndrome in a postpartum woman with acute lymphoblastic leukaemia after intrathecal methotrexate"
} | [
{
"companynumb": "US-MYLANLABS-2017M1069621",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
... |
{
"abstract": "Bacteremia is often caused by gram-negative bacteria (represented by EKP; Escherichia coli, Klebsiella species, and Proteus mirabilis), and the excessive use of cefazolin, as the first-line antimicrobial in its treatment, has been a source of concern in the emergence of resistant strains. As an antimicrobial, cefotiam may be an alternative to cefazolin; however, little evidence is available for its use in the treatment of bacteremia. The purpose of this non-inferiority study was to retrospectively compare the therapeutic efficacy of cefotiam with some antimicrobials of narrow spectrum (cefazolin, cefmetazole, and flomoxef) in the treatment of EKP-induced bacteremia. The number of patients recruited was 32 in the cefotiam group and 29 in the control group. In the primary endpoint, the survival rate on day 28 for the cefotiam group and the control group was 93.5% and 89.3%, respectively (relative risk at day 28, 1.048; 95% confidence interval, 0.894-1.227). In the secondary end point, treatment success rate in the two groups was 71.9% and 69.0%, respectively (relative risk, 1.042; 95% confidence interval, 0.752-1.445). Intensive care unit admission, low body weight, hypoalbuminemia, and infections unassociated with the urinary tract were identified to be the risk factors responsible for treatment failure. We demonstrated cefotiam may be non-inferior to other antimicrobials of similar spectrum, in terms of survival rate, in EKP-induced bacteremia.",
"affiliations": "Department of Pharmacy, Kumamoto University Hospital, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan. Electronic address: yumihashi@kuh.kumamoto-u.ac.jp.;Department of Pharmacy, Kumamoto University Hospital, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan; Department of Infection Control, Kumamoto University Hospital, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan. Electronic address: kazutakaoda@kuh.kumamoto-u.ac.jp.;Department of Pharmacy, Kumamoto University Hospital, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan; Department of Infection Control, Kumamoto University Hospital, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan. Electronic address: sy05044@kuh.kumamoto-u.ac.jp.;Department of Infection Control, Kumamoto University Hospital, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan. Electronic address: knosaka@kumamoto-u.ac.jp.;Department of Pharmacy, Kumamoto University Hospital, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan; Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan. Electronic address: hjono@kuh.kumamoto-u.ac.jp.;Department of Pharmacy, Kumamoto University Hospital, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan; Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan. Electronic address: saitohide@kuh.kumamoto-u.ac.jp.",
"authors": "Hashiguchi|Yumi|Y|;Oda|Kazutaka|K|;Katanoda|Tomomi|T|;Nosaka|Kisato|K|;Jono|Hirofumi|H|;Saito|Hideyuki|H|",
"chemical_list": "D000900:Anti-Bacterial Agents; D015310:Cefotiam",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2020.06.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "26(11)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Antimicrobial resistance; Bacteremia; Cefazolin; Cefotiam",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000900:Anti-Bacterial Agents; D016470:Bacteremia; D015310:Cefotiam; D004926:Escherichia coli; D006801:Humans; D007709:Klebsiella; D011513:Proteus mirabilis; D012189:Retrospective Studies",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "1158-1163",
"pmc": null,
"pmid": "32828676",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical evaluation of cefotiam in the treatment of bacteremia caused by Escherichia coli, Klebsiella species, and Proteus mirabilis: A retrospective study.",
"title_normalized": "clinical evaluation of cefotiam in the treatment of bacteremia caused by escherichia coli klebsiella species and proteus mirabilis a retrospective study"
} | [
{
"companynumb": "JP-PFIZER INC-2020475107",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MEROPENEM"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nFatal poisonings among drug addicts in Denmark in 2012 were examined. Cause of death, abuse pattern and geographic differences are discussed and data are compared with previous studies.\n\n\nMETHODS\nAll fatal poisonings examined at the three institutes of forensic medicine in Denmark in 2012 were included in the study.\n\n\nRESULTS\nA total of 188 fatal intoxications were recorded. The median age increased from 37.5 in 2007 to 41.5 in 2012. The majority were men (77%). Methadone (59%) was the main intoxicant. The decrease in the frequency of heroin/morphine deaths since 1997 (71%) continued, declining to 44% in 2002, 33% in 2007 and finally to 27% in 2012. Few deaths from central stimulants (amphetamine and cocaine) occurred. Multiple drug use was common and consisted mainly of opioids, cocaine, amphetamine, cannabis, benzodiazepines and alcohol. Heroin/morphine use was most frequent on Funen and in South Jutland. Cocaine was most frequently detected in East Denmark, while amphetamine was more frequent in West Denmark.\n\n\nCONCLUSIONS\nThe number of fatal poisonings among drug addicts has stabilised around 200. The increase in methadone deaths continued and, as in 2007, methadone was the main intoxicant. The increase in methadone deaths seems to be associated with use of methadone in substitution treatment. Nevertheless, methadone treatment also seems to save lives, as indicated by the increasing median age. Use of antidepressants and antipsychotics increased to a high level compared with 2007, indicating that a considerable number of drug addicts also have psychiatric illness.\n\n\nBACKGROUND\nnone.\n\n\nBACKGROUND\nnot relevant.",
"affiliations": "kirsten.wiese@sund.ku.dk.",
"authors": "Simonsen|Kirsten Wiese|KW|;Christoffersen|Dorte J|DJ|;Banner|Jytte|J|;Linnet|Kristian|K|;Andersen|Ljubica V|LV|",
"chemical_list": "D000701:Analgesics, Opioid; D009020:Morphine; D008691:Methadone",
"country": "Denmark",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2245-1919",
"issue": "62(10)",
"journal": "Danish medical journal",
"keywords": null,
"medline_ta": "Dan Med J",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D000701:Analgesics, Opioid; D002423:Cause of Death; D003718:Denmark; D005260:Female; D005554:Forensic Medicine; D006801:Humans; D008297:Male; D008691:Methadone; D008875:Middle Aged; D009020:Morphine; D017678:Sex Distribution; D019966:Substance-Related Disorders; D055815:Young Adult",
"nlm_unique_id": "101576205",
"other_id": null,
"pages": "A5147",
"pmc": null,
"pmid": "26441394",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Fatal poisoning among patients with drug addiction.",
"title_normalized": "fatal poisoning among patients with drug addiction"
} | [
{
"companynumb": "DK-JNJFOC-20151120068",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "COCAINE"
},
"drugadditional": null,
"d... |
{
"abstract": "Valproic acid is commonly used to treat pediatric epilepsy. This drug is usually well-tolerated; its side effects are typically mild, with hepatotoxicity being the most widely recognized one. Bone marrow suppression is a rarely seen complication in patients with valproic acid levels more than 125 mcg/mL. Reported cases indicate an increased incidence of hematologic toxicity; however, evidence for management is limited. We report a case of bone marrow suppression induced by a high dose of valproic acid in a 10-year-old male.",
"affiliations": "Pediatrics, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, USA.;Pediatrics, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, USA.",
"authors": "Wahba|Andrew|A|;Bergez|Emmalee|E|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.11252",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.11252\nNeurology\nPediatrics\nHematology\nSevere Pancytopenia Induced by Valproic Acid\nMuacevic Alexander Adler John R Wahba Andrew 1 Bergez Emmalee 1 \n1 \nPediatrics, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, USA \n\nAndrew Wahba andrew.a.wahba@uth.tmc.edu\n30 10 2020 \n10 2020 \n12 10 e1125230 10 2020 Copyright © 2020, Wahba et al.2020Wahba et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/44750-severe-pancytopenia-induced-by-valproic-acidValproic acid is commonly used to treat pediatric epilepsy. This drug is usually well-tolerated; its side effects are typically mild, with hepatotoxicity being the most widely recognized one. Bone marrow suppression is a rarely seen complication in patients with valproic acid levels more than 125 mcg/mL. Reported cases indicate an increased incidence of hematologic toxicity; however, evidence for management is limited. We report a case of bone marrow suppression induced by a high dose of valproic acid in a 10-year-old male.\n\nbone marrow suppressionpancytopeniavalproic acidThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nValproic acid (VPA) is the most commonly used anticonvulsant, initially approved by the U.S. Food and Drug Administration (FDA) in 1978 to be used as a monotherapy or adjunctive therapy for complex partial and absence seizures. Recently, it has been approved for use in bipolar disorder and migraine prophylaxis. VPA is a small-branched chain fatty acid that is highly protein-bound (>85%) in a saturable manner, which results in lower clearance rate and urine excretion. The percentage of protein binding decreases with higher VPA levels. VPA decreases neuronal hyperexcitability through several mechanisms. These include increasing the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) by inhibiting its degradation and increasing synthesis, blockage of the calcium channel voltage-dependent, inhibiting the synthesis of inositol, and modulating glutamatergic transmission [1,2]. VPA is mainly metabolized in the liver through microsomal glucuronidation, which becomes fully effective by the age of four years, mitochondrial beta-oxidation, and, to a lesser extent, cytochrome P450-dependent oxidation [3]. It has an average elimination half-life of 4-16 hours depending on patient age and combined use with enzyme-inducing agents such as phenytoin, carbamazepine, and barbiturates [4,5]. Plasma clearance is 50% higher in the age of 2-10 years compared to adults [6]. VPA has a wide therapeutic trough level concentration between 50 and 100 mcg/mL for seizures and 125 mcg/mL for manic episodes in bipolar disease. Therapeutic daily dose ranges between 15 and 60 mg/kg. VPA is usually well-tolerated; its side effects are typically mild, with hepatotoxicity being the most widely recognized one. Hepatotoxicity usually happens during the first six months of treatment; children under the age of 2 years are at higher risk of developing fatal hepatotoxicity. Other known side effects are pancreatitis, hyperammonemia, hypothermia, suicidal ideations, and birth defects particularly neural tube defects. However, as levels exceed 125 mcg/mL, few cases of hematologic toxicity such as thrombocytopenia, platelet dysfunction, neutropenia, pure red cell aplasia, and acute leukemia have been reported. In this report, we identify a case of severe pancytopenia induced by VPA in a pediatric patient.\n\nCase presentation\nAn 11-year-old Hispanic male with a history of autism spectrum disorder (ASD), Dravet syndrome due to SCN1A gene mutation, and intractable epilepsy presented with five days of lethargy, decreased oral intake, and seven pounds weight loss. The patient’s mother denied any fever, abdominal pain, vomiting, headache, or sick contacts. His last seizure was six months prior. He previously failed multiple anti-seizure medications such as levetiracetam and clobazam. He had a vagus nerve stimulator placed at the age of five years. He was developmentally delayed with speech and learning difficulties. He had no past medical history of any hematologic disorders. Family history was negative for seizures, developmental, or bleeding disorders. The patient was taking VPA 31 mg/kg/day and lacosamide 7 mg/kg/day for seizure control. He had been on this regimen for the past eight years without any recent new medications or changes.\n\nOn physical examination, oral temperature was 98.1°F, heart rate was 85 beats per minute, blood pressure was 97/60 mmHg, respiratory rate was 20 breaths per minute, and oxygen saturation was 99% on room air. Weight was 28.9 kg, with a body mass index (BMI) of 16.59 kg/m2. The abdomen was soft, non-distended, non-tender with no hepatosplenomegaly. Heart and lung exams were clear, and no skin rash or lesions were seen. On a neurological exam, he was awake and followed commands, and was able to move all extremities with intact cranial nerves, sensations, and reflexes. No jaundice, oral ulcers, thrush, lymphadenopathy, petechiae, ecchymosis, or signs of bleeding were present.\n\nIn the emergency room, lab workup was notable for pancytopenia (Table 1), with a VPA level of 255 mcg/mL (therapeutic range: 50-125 mcg/mL). This VPA level was drawn approximately three hours after the last dose was given. VPA was discontinued, topiramate was initiated with lacosamide for proper seizure prophylaxis, and the patient was admitted for further workup of pancytopenia. Reticulocyte count on admission was 1.5 %, demonstrating inadequate bone marrow response to pancytopenia. On the following day, the patient developed conjunctival pallor and bilateral lower extremities petechiae. Vital signs remained within normal limits. On repeat lab tests, the patient had worsening pancytopenia (Table 1), with an absolute neutrophil count (ANC) of 300/mm3. Due to concerns for altered mental status in the setting of severe thrombocytopenia, a CT of the head was obtained, which showed no signs of intracranial bleeding. The peripheral smear showed evidence of thrombocytopenia and leukopenia, but no blasts or other concerns for leukemia were identified.\n\nTable 1 Laboratory values at different time points\nWBC, white blood cell; RBC, red blood cell; MPV, mean platelet volume; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen\n\n\nLab Test\n\t\nDay 1\n\t\nDay 2\n\t\nDay 4\n\t\nDay 5\n\t\nDay 6\n\t\nDay 8\n\t\nDay 9\n\t\n\nValproic acid (mcg/mL)\n\t\n255\n\t\n214\n\t\n102\n\t\n53\n\t\n31\n\t\n6\n\t\n \n\t\n\nWBC x 103/mm3\n\t\n5.1\n\t\n3.6\n\t\n3.6\n\t\n2.3\n\t\n4.9\n\t\n6.8\n\t\n7\n\t\n\nRBC x 106/mm3\n\t\n3\n\t\n2.2\n\t\n2.2\n\t\n1.7\n\t\n3.2\n\t\n3.2\n\t\n3.1\n\t\n\nHemoglobin (g/dL)\n\t\n10.7\n\t\n7.9\n\t\n7.9\n\t\n6.4\n\t\n11.2\n\t\n11.3\n\t\n11\n\t\n\nHematocrit (%)\n\t\n31.9\n\t\n22.6\n\t\n23.1\n\t\n18.4\n\t\n32.5\n\t\n33.2\n\t\n31.1\n\t\n\nPlatelet x 103/mm3\n\t\n10\n\t\n4\n\t\n7\n\t\n3\n\t\n124\n\t\n103\n\t\n143\n\t\n\nMPV (fL)\n\t\n9.7\n\t\n9.4\n\t\n9.2\n\t\n8.2\n\t\n7.8\n\t\n9.4\n\t\n9.5\n\t\n\nNeutrophil x 103/mm3\n\t\n0.9\n\t\n0.3\n\t\n0.7\n\t\n0.4\n\t\n1.7\n\t\n1.6\n\t\n1.5\n\t\n\nMonocytes x 103/mm3\n\t\n0.3\n\t\n0.1\n\t\n0.4\n\t\n0.8\n\t\n1.4\n\t\n1.6\n\t\n1.2\n\t\n\nLymphocyte x 103/mm3\n\t\n3.9\n\t\n3.2\n\t\n2.5\n\t\n1.6\n\t\n2.3\n\t\n3.6\n\t\n4.2\n\t\n\nReticulocyte count (%)\n\t\n1.5\n\t\n \n\t\n \n\t\n \n\t\n3.6\n\t\n5.4\n\t\n4.7\n\t\n\nALT (unit/L)\n\t\n \n\t\n12\n\t\n \n\t\n \n\t\n17\n\t\n25\n\t\n \n\t\n\nAST (unit/L)\n\t\n \n\t\n22\n\t\n \n\t\n \n\t\n45\n\t\n64\n\t\n \n\t\n\nAmmonia (μg/dL)\n\t\n \n\t\n147\n\t\n103\n\t\n79\n\t\n66\n\t\n78\n\t\n74\n\t\n\nTotal bilirubin (mg/dL)\n\t\n \n\t\n0.8\n\t\n \n\t\n \n\t\n0.7\n\t\n0.5\n\t\n \n\t\n\nAlbumin (g/dL)\n\t\n \n\t\n3\n\t\n \n\t\n \n\t\n2.9\n\t\n2.9\n\t\n \n\t\n\nSodium (mEq/L)\n\t\n140\n\t\n141\n\t\n \n\t\n \n\t\n140\n\t\n139\n\t\n \n\t\n\nPotassium (mEq/L)\n\t\n3.7\n\t\n3.9\n\t\n \n\t\n \n\t\n4.2\n\t\n4\n\t\n \n\t\n\nCreatinine (mg/dL)\n\t\n0.50\n\t\n0.43\n\t\n \n\t\n \n\t\n0.42\n\t\n0.39\n\t\n \n\t\n\nBUN (mg/dL)\n\t\n15\n\t\n13\n\t\n \n\t\n \n\t\n \n\t\n16\n\t\n \n\t\nThe underlying reason for elevated VPA levels was unclear despite the patient's medication compliance. Since VPA is mainly metabolized in the liver, factor V level was obtained to assess liver function, which returned within normal limits, and abdominal ultrasound showed normal size liver with normal echogenicity. The patient had previous outpatient liver enzyme levels that were within normal limits, the most recent of which was six months prior.\n\nA trial of intravenous immunoglobulin (IVIG) 1 g/kg was given on admission day 3 to determine if the process was immune-mediated. However, follow-up laboratory values continued to show pancytopenia despite the VPA level progressively decreasing to 102 mcg/mL. To rule out other causes of bone marrow aplasia, Epstein-Barr virus (EBV), cytomegalovirus (CMV), human immunodeficiency virus (HIV), and parvovirus B19 serology were negative. He had normal vitamin B12, erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), haptoglobin, and D-dimer levels. Neutrophil antibody was undetected by flow cytometry.\n\nDue to persistent anemia and severe thrombocytopenia, a single transfusion of 10 mL/kg packed red blood cells and 10 mL/kg platelets were given for supportive measures on admission day 5. On the following days, the patient’s laboratory values showed evidence of gradual bone marrow recovery, and the patient was discharged on day 9.\n\nDiscussion\nWe report a case of a pediatric patient with a history of intractable epilepsy and SCN1A mutation causing Dravet syndrome who has been receiving VPA for eight years with no reported side effects. He presented with toxic VPA levels and severe pancytopenia. VPA affected all the three bone marrow cell lines, which started to recover around day 6 after discontinuation of the drug.\n\nSCN1A gene, located on chromosome 2q24, is one of the most commonly known epilepsy genes. Our patient has a missense variant c.1096G>C; p.Asp366His (one guanine ribonucleotide was altered to cytosine in codon 1096, which caused a change in the reading frame from aspartate to histidine). SCN1A mutations have been linked to multiple epilepsy disorders such as Dravet syndrome, which is also known as severe myoclonic epilepsy in infancy (MIM# 607208). Dravet syndrome usually presents as a refractory seizure during the first year of life and developmental delay. SCN1A mutations impair the inhibition of neuronal sodium channel activity, which increases neuronal excitability [7,8].\n\nOur patient had severe pancytopenia, hyperammonemia with normal liver enzymes, and kidney function levels. L-carnitine has been shown to be effective in VPA-induced hepatotoxicity and hyperammonemia above 80 μg/dL [9]. Exogenous carnitine binds to VPA, enhancing the beta-oxidation and urea synthesis process, thus decreasing ammonia levels. Since the repeat ammonia level for our patient dropped below 80 μg/dL, the decision was to trend the ammonia level without giving carnitine.\n\nUpon admission, differential diagnoses for pancytopenia included drug-induced myelosuppression, autoimmune-mediated pancytopenia, and other causes of bone marrow failure such as idiopathic acquired aplastic anemia, hypoplastic myelodysplastic syndrome, infections, nutritional deficiencies, hematopoietic and lymphoid neoplasms, and myelofibrosis. Peripheral smear findings, negative viral serology, negative neutrophil antibody, poor response to IVIG, and spontaneous recovery after discontinuation of VPA support that the cause was most likely drug-induced bone marrow suppression.\n\nVPA can cause a wide spectrum of hematologic toxicities such as thrombocytopenia, acquired Von Willebrand disease, neutropenia, Pelger-Huet anomalies, macrocytosis, pure red cell aplasia, and acute leukemia. These toxicities appear to be reversible and dose-related with the female gender being at higher risk [10,11]. Mild thrombocytopenia is the most commonly reported toxicity, and it usually does not require immediate discontinuation of the drug [12]. Few cases of severe pancytopenia have been reported. Direct bone marrow suppression and immune-mediated destruction are the two known mechanisms. In an in vitro study to assess direct bone marrow suppression, VPA markedly inhibited the growth of bone marrow progenitor cells at a concentration of 200 mcg/mL, and normal growth was seen at a concentration of 100 mcg/mL [13]. We believe the patient's supra-therapeutic VPA levels have led to the severity of his symptoms. Management is mainly supportive through discontinuing VPA in severe cases or lowering the daily dose in mild cases, use of IVIG in immune-mediated toxicity, desmopressin or aminocaproic acid in patients with bleeding diathesis, granulocyte colony-stimulating factor (GCSF) in neutropenic patients, and blood transfusion in life-threatening conditions [14,15].\n\nConclusions\nVPA-induced hematologic toxicity is becoming more frequently encountered; however, evidence for management is limited. Bone marrow suppression is a rarely seen complication in patients with VPA levels > 125 mcg/mL. In these patients, immediate discontinuation of the drug is recommended. Resolution of the bone marrow suppression is expected to occur within 10 days of VPA withdrawal. Patients taking VPA may benefit from periodic monitoring of cell line counts, and caution should be taken when prescribing high doses.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience CNS Drugs Perucca E 695 714 16 2002 12269862 \n2 Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy CNS Drugs Löscher W 669 694 16 2002 12269861 \n3 Valproic acid pathway: pharmacokinetics and pharmacodynamics Pharmacogenet Genomics Ghodke-Puranik Y Thorn CF Lamba JK 236 241 4 2013 \n4 Functional half-life is a meaningful descriptor of steady-state pharmacokinetics of an extended-release formulation of a rapidly cleared drug: as shown by once-daily divalproex-ER Clin Drug Investig Dutta S Reed RC 681 690 26 2006 \n5 Population pharmacokinetics of valproic acid in pediatric patients with epilepsy: considerations for dosing spinal muscular atrophy patients J Clin Pharmacol Williams JH Jayaraman B Swoboda KJ Barrett JS 1676 1688 52 2012 22167565 \n6 Valproate as a mainstay of therapy for pediatric epilepsy Paediatr Drugs Guerrini R 113 129 8 2006 16608372 \n7 Altered function of the SCN1A voltage-gated sodium channel leads to gamma-aminobutyric acid-ergic (GABAergic) interneuron abnormalities J Biol Chem Martin MS Dutt K Papale LA 9823 9834 26 2010 \n8 Sodium channel SCN1A and epilepsy: mutations and mechanisms Epilepsia Escayg A Goldin AL 1650 1658 51 2010 20831750 \n9 Science review: carnitine in the treatment of valproic acid-induced toxicity - what is the evidence? Crit Care Lheureux PE Penaloza A Zahir S Gris M 431 440 5 2005 \n10 Valproate-induced thrombocytopenia: a prospective monotherapy study Epilepsia Nasreddine W Beydoun A 438 445 49 2008 18031547 \n11 The risk of thrombocytopenia during valproic acid therapy: a critical summary of available clinical data Drugs RD Buoli M Serati M Botturi A Altamura AC 1 5 18 2018 \n12 Valproic acid and thrombocytopenia in children: a case-controlled retrospective study Pediatr Neurol Allarakhia IN Garofalo EA Komarynski MA Robertson PL 303 307 14 1996 8805173 \n13 Bone marrow suppression induced by high dose valproic acid Arch Dis Child Kishi T Fujita N Kawaguchi H Ishimae M Watanabe K Tanaka T 153 155 71 1994 7944539 \n14 Hematologic toxicity of sodium valproate J Pediatr Hematol Oncol Acharya S Bussel JB 62 65 22 2000 10695824 \n15 Valproic acid-induced neutropenia Ann Pharmacother Vesta KS Medina PJ 819 821 37 2003 12773069\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "12(10)",
"journal": "Cureus",
"keywords": "bone marrow suppression; pancytopenia; valproic acid",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e11252",
"pmc": null,
"pmid": "33269170",
"pubdate": "2020-10-30",
"publication_types": "D002363:Case Reports",
"references": "18031547;16608372;17274675;22167565;29260458;16277730;20100831;10695824;7944539;12269862;23407051;8805173;12773069;20831750;12269861",
"title": "Severe Pancytopenia Induced by Valproic Acid.",
"title_normalized": "severe pancytopenia induced by valproic acid"
} | [
{
"companynumb": "US-CATALENT PHARMA SOLUTIONS-CAT-000311-2020",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VALPROIC ACID"
},
"drugadd... |
{
"abstract": "OBJECTIVE\nDescribe use and predictive potential of an intracellular cytokine staining (ICS) cytomegalovirus cell-mediated immunity (CMV CMI) assay and a risk factor screening tool on CMV reactivation in a real-world clinical setting and compare this to serologically demonstrated immunity by CMV IGG.\n\n\nMETHODS\nAdult transplant patients at our center with the ICS assay resulted between 10/1/2018 and 9/1/2019 were included. Assays were considered positive per manufacturer specifications.\n\n\nRESULTS\nTwenty-five patients underwent ICS CMV CMI testing at our institution during the study period. The majority were kidney transplant recipients, 76% were D+/R-, and 76% were receiving CMV treatment. The positive predictive value (PPV) of the assay to predict lack of CMV was 87%; 93% when patients with antiviral resistance were excluded and 91% in only those receiving treatment. The presence of ≤2 clinical risk factors on the screening tool had a PPV of 92% in predicting lack of recurrence. In comparison, serologically demonstrated immunity by CMV IGG had a PPV of 62%.\n\n\nCONCLUSIONS\nIn our study representing real-world clinical use, the ICS CMV CMI assay and the risk factor screening tool had predictive potential that was superior to serologically demonstrated immunity. The reliability of the assay seemed to decrease with higher degrees of clinical risk suggesting a multimodal screening approach is warranted.",
"affiliations": "Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, WI, USA.;Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, WI, USA.;Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, WI, USA.;Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, WI, USA.;Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, WI, USA.;Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, WI, USA.",
"authors": "Jorgenson|Margaret R|MR|https://orcid.org/0000-0001-6088-9727;Hillis|Mikala I|MI|;Saddler|Christopher M|CM|https://orcid.org/0000-0002-6656-981X;Smith|Jeannina A|JA|;Parajuli|Sandesh|S|https://orcid.org/0000-0003-1667-7465;Mandelbrot|Didier A|DA|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13311",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "22(4)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "clinical decision making; cytomegalovirus; infection and infectious agents; risk assessment; risk stratification; viral",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D057286:Electronic Health Records; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007111:Immunity, Cellular; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation; D015203:Reproducibility of Results; D012307:Risk Factors; D012698:Serologic Tests; D066027:Transplant Recipients; D019562:Viral Load",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13311",
"pmc": null,
"pmid": "32386076",
"pubdate": "2020-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Prediction of cytomegalovirus infection: A single-center experience utilizing a newly available cell-mediated immunity assay by flow cytometry, a risk factor screening tool, and serologically demonstrated immunity.",
"title_normalized": "prediction of cytomegalovirus infection a single center experience utilizing a newly available cell mediated immunity assay by flow cytometry a risk factor screening tool and serologically demonstrated immunity"
} | [
{
"companynumb": "NVSC2020US150436",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
},
"drugadditional": "3",
... |
{
"abstract": "Temporal inference from laboratory testing results and triangulation with clinical outcomes extracted from unstructured electronic health record (EHR) provider notes is integral to advancing precision medicine. Here, we studied 246 SARS-CoV-2 PCR-positive (COVIDpos) patients and propensity-matched 2460 SARS-CoV-2 PCR-negative (COVIDneg) patients subjected to around 700,000 lab tests cumulatively across 194 assays. Compared to COVIDneg patients at the time of diagnostic testing, COVIDpos patients tended to have higher plasma fibrinogen levels and lower platelet counts. However, as the infection evolves, COVIDpos patients distinctively show declining fibrinogen, increasing platelet counts, and lower white blood cell counts. Augmented curation of EHRs suggests that only a minority of COVIDpos patients develop thromboembolism, and rarely, disseminated intravascular coagulopathy (DIC), with patients generally not displaying platelet reductions typical of consumptive coagulopathies. These temporal trends provide fine-grained resolution into COVID-19 associated coagulopathy (CAC) and set the stage for personalizing thromboprophylaxis.",
"affiliations": "nference, inc, Cambridge, United States.;nference, inc, Cambridge, United States.;nference, inc, Cambridge, United States.;nference, inc, Cambridge, United States.;nference, inc, Cambridge, United States.;nference, inc, Cambridge, United States.;Mayo Clinic, Rochester, United States.;Mayo Clinic, Rochester, United States.;Mayo Clinic, Rochester, United States.;Mayo Clinic, Rochester, United States.;Mayo Clinic, Rochester, United States.;Mayo Clinic, Rochester, United States.;Mayo Clinic, Rochester, United States.;Mayo Clinic, Rochester, United States.;Janssen pharmaceutical companies of Johnson & Johnson (J&J), Spring House, United States.;Janssen pharmaceutical companies of Johnson & Johnson (J&J), Spring House, United States.;Janssen pharmaceutical companies of Johnson & Johnson (J&J), Spring House, United States.;nference, inc, Cambridge, United States.",
"authors": "Pawlowski|Colin|C|https://orcid.org/0000-0003-2781-7507;Wagner|Tyler|T|;Puranik|Arjun|A|;Murugadoss|Karthik|K|;Loscalzo|Liam|L|;Venkatakrishnan|A J|AJ|;Pruthi|Rajiv K|RK|;Houghton|Damon E|DE|;O'Horo|John C|JC|;Morice|William G|WG|;Williams|Amy W|AW|;Gores|Gregory J|GJ|;Halamka|John|J|;Badley|Andrew D|AD|;Barnathan|Elliot S|ES|;Makimura|Hideo|H|;Khan|Najat|N|;Soundararajan|Venky|V|https://orcid.org/0000-0001-7434-9211",
"chemical_list": "D015415:Biomarkers; D005340:Fibrinogen",
"country": "England",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\neLife\nElife\neLife\neLife\n2050-084X eLife Sciences Publications, Ltd \n\n32804081\n59209\n10.7554/eLife.59209\nResearch Article\nMedicine\nInference from longitudinal laboratory tests characterizes temporal evolution of COVID-19-associated coagulopathy (CAC)\nPawlowski Colin https://orcid.org/0000-0003-2781-75071 Wagner Tyler 1 Puranik Arjun 1 Murugadoss Karthik 1 Loscalzo Liam 1 Venkatakrishnan AJ 1 Pruthi Rajiv K 2 Houghton Damon E 2 O'Horo John C 2 Morice William G II23 Williams Amy W 2 Gores Gregory J 2 Halamka John 24 Badley Andrew D 2 Barnathan Elliot S 5 Makimura Hideo 5 Khan Najat 5 Soundararajan Venky https://orcid.org/0000-0001-7434-9211venky@nference.net1 1 nference, incCambridgeUnited States\n2 Mayo ClinicRochesterUnited States\n3 Mayo Clinic LaboratoriesRochesterUnited States\n4 Mayo Clinic PlatformRochesterUnited States\n5 Janssen pharmaceutical companies of Johnson & Johnson (J&J)Spring HouseUnited States\nvan der Meer Jos WM Senior EditorRadboud University Medical CenterNetherlands\n van de Veerdonk Frank L Reviewing EditorRadboud University Medical CenterNetherlands\n 17 8 2020 \n2020 \n9 e5920922 5 2020 14 8 2020 © 2020, Pawlowski et al2020Pawlowski et alhttp://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.Temporal inference from laboratory testing results and triangulation with clinical outcomes extracted from unstructured electronic health record (EHR) provider notes is integral to advancing precision medicine. Here, we studied 246 SARS-CoV-2 PCR-positive (COVIDpos) patients and propensity-matched 2460 SARS-CoV-2 PCR-negative (COVIDneg) patients subjected to around 700,000 lab tests cumulatively across 194 assays. Compared to COVIDneg patients at the time of diagnostic testing, COVIDpos patients tended to have higher plasma fibrinogen levels and lower platelet counts. However, as the infection evolves, COVIDpos patients distinctively show declining fibrinogen, increasing platelet counts, and lower white blood cell counts. Augmented curation of EHRs suggests that only a minority of COVIDpos patients develop thromboembolism, and rarely, disseminated intravascular coagulopathy (DIC), with patients generally not displaying platelet reductions typical of consumptive coagulopathies. These temporal trends provide fine-grained resolution into COVID-19 associated coagulopathy (CAC) and set the stage for personalizing thromboprophylaxis.\n\nlaboratory testsCOVID-19electronic health record (EHR)SARS-CoV-2coagulationthrombolytic agentsResearch organism\nHumanNo external funding was received for this work.Author impact statementLongitudinal laboratory testing results tied to SARS-CoV-2 diagnostic PCR results of more than 2500 patients reveal the temporal evolution of COVID-associated coagulopathy.\n==== Body\nIntroduction\nThere is a growing body of evidence suggesting that severe COVID-19 outcomes may be associated with dysregulated coagulation (Tang et al., 2020), including stroke, pulmonary embolism, myocardial infarction, and other venous or arterial thromboembolic complications (Klok et al., 2020). This so-called COVID-19 associated coagulopathy (CAC) shares similarities with disseminated intravascular coagulation (DIC) and thrombotic microangiopathy but also has distinctive features (Levi et al., 2020). Given the significance of CAC to COVID-19 mortality, there is an urgent need for fine-grained resolution into the temporal manifestation of CAC, particularly in comparison to the broad-spectrum of other, better characterized coagulopathies. While there are studies suggesting associations between COVID-19 infection and mortality with thrombocytopenia, D-dimer levels, and prolongation of prothrombin time, the signatures of CAC onset and progression as well as their connection to clinical outcomes are not well defined (Tang et al., 2020; Gao et al., 2020; Panigada et al., 2020). An advanced understanding of this phenotype may aid in the risk stratification of patients, thus facilitating optimal monitoring strategies during disease evolution through the paradigm of precision medicine.\n\nTo this end, we instituted a holistic data science platform across an academic medical center that enables machine intelligence to augment the curation of phenotypes and outcomes from over 10 million electronic health record (EHR) clinical notes and associated 3.2 million lab tests from 2232 SARS-CoV-2 positive (COVIDpos) and 72,354 confirmed SARS-CoV-2 negative (COVIDneg) patients over a retrospectively defined 2-month observation period straddling the date of the PCR test. For the COVIDpos cohort, we center the 2-month observation period around the date of the first positive PCR test for SARS-CoV-2, and for the COVIDneg cohort, we center the 2-month observation period around the date of the first PCR test for SARS-CoV-2 (see Materials and methods). It is important to note that not all individuals infected by SARS-CoV-2 develop symptoms of COVID-19, but rather that a majority of patients are either asymptomatic or have mild-to-moderate symptoms not requiring hospitalization for COVID-19 (Wagner et al., 2020). Furthermore, the guidelines followed for PCR-testing included a routine screening of individuals, patients displaying COVID-19 symptoms as per the Mayo Clinic (Coronavirus disease, 2019) and CDC definitions (Website, 2020), and possibly contact with infected persons or underlying predisposing conditions (Wagner et al., 2020).\n\nBy compiling all available laboratory testing data for the 30 days preceding the first SARS-CoV-2 PCR positive diagnostic testing date (day 0), as well as the 30 days following the diagnostic testing date, and triangulating this information with medications and clinical outcomes, we were able to identify laboratory abnormalities significantly associated with the COVIDpos group. We identified coagulation-related parameters among this set of abnormalities and then studied aggregate as well as individual patient trajectories that could aid in extracting a temporal signature of CAC onset and progression. We also correlated these signals with the clinical outcomes of these patients.\n\nIn order to hone into longitudinal lab test trends that would apply at the individual patient level, we restricted our analysis to patients with available serial testing data, which had at least three test results of the same type during the observation period. After applying these inclusion criteria, 246 COVIDpos and 13,666 COVIDneg patients met study the inclusion criteria. The need for longitudinal data on the testing results, while constraining the study population size greatly, enables us to provide a fine-grained temporal resolution of CAC for the first time.\n\nAfter filtering the patients with the available longitudinal testing data, the median age in the COVIDpos and COVIDneg groups were 60.8 years and 64.1 years, respectively (see Materials and methods and Table 1), and the numbers of males were 137 (56%) and 7129 (52%), respectively. The total numbers of pre-existing coagulopathies in the COVIDpos and COVIDneg groups were 31 (13%) and 3901 (29%), respectively. These counts of coagulopathies include the following phenotypes identified in the clinical notes from day −365 to day −31 relative to the PCR testing date: deep vein thrombosis, pulmonary embolism, myocardial infarction, venous thromboembolism, thrombotic stroke, cerebral venous thrombosis, and disseminated intravascular coagulation (see Table 1 for detailed breakdown). The number of COVIDpos patients hospitalized in the month prior to the SARS-CoV-2 PCR testing date was 41 (17%), compared to 1247 (9.1%) for the COVIDneg cohort.\n\nTable 1. Summary of patient characteristics for the overall COVIDpos, COVIDneg (matched), and COVIDneg cohorts.\nThe COVIDneg (matched) cohort was constructed using 1:10 propensity score matching to balance each of the clinical covariates, including demographics (age, gender, race), medication use (anticoagulant/antiplatelet use in the preceding 30 days/1 year of PCR testing date), medical history of thrombotic events from the past year, and hospitalization status in the month prior to the date of PCR testing.\n\nPatient characteristics\tCOVIDpos\tCOVIDneg (matched)\tCOVIDneg\t\nNumber of patients\t246\t2460\t13,666\t\nAge in years\t60.8\t60.9\t64.1\t\nGender:\t\nMale\t137 (56%)\t1388 (56%)\t7129 (52%)\t\nRace:\t\nWhite\t154 (63%)\t1540 (63%)\t12,241 (90%)\t\nBlack\t24 (9.8%)\t313 (13%)\t569 (4.2%)\t\nAsian\t18 (7.3%)\t207 (8.4%)\t274 (2.0%)\t\nAmerican Indian\t23 (9.3%)\t81 (3.3%)\t81 (0.59%)\t\nOther\t27 (11%)\t319 (13%)\t501 (3.7%)\t\nMedication use in the preceding 30 days of PCR testing date:\t\nAnticoagulants\t63 (26%)\t596 (24%)\t5171 (38%)\t\nAntiplatelets\t30 (12%)\t298 (12%)\t2230 (16%)\t\nMedication use in the preceding 1 year of PCR testing date:\t\nAnticoagulants\t86 (35%)\t819 (33%)\t7476 (55%)\t\nAntiplatelets\t40 (16%)\t419 (17%)\t3620 (26%)\t\nMedical history of thrombotic events in 1 year prior to study period:\t\nDeep vein thrombosis\t15 (6.1%)\t153 (6.2%)\t2,110 (15%)\t\nPulmonary embolism\t12 (4.9%)\t112 (4.6%)\t1258 (9.2%)\t\nMyocardial infarction\t11 (4.5%)\t142 (5.8%)\t1468 (11%)\t\nVenous thromboembolism\t4 (1.6%)\t44 (1.8%)\t615 (4.5%)\t\nThrombotic stroke\t1 (0.41%)\t3 (0.12%)\t143 (1.0%)\t\nCerebral venous thrombosis\t0\t1 (0.04%)\t7 (0.05%)\t\nDisseminated intravascular coagulation\t0\t1 (0.04%)\t30 (0.22%)\t\nAny thrombotic event\t31 (13%)\t308 (13%)\t3901 (29%)\t\nHospitalized in the month prior to PCR testing date\t41 (17%)\t304 (12%)\t1247 (9%)\t\nTo balance these clinical covariates and others between the two cohorts, we applied 1:10 propensity score matching to define a subset of 2460 patients from the COVIDneg cohort to use for the final statistical analysis (see Materials and methods). In particular, the general categories of covariates considered for balancing included: demographics, anticoagulant/antiplatelet medication use, medical history of pre-existing coagulopathies, and hospital admission status. Population-level characteristics of the COVIDpos, COVIDneg, and the final propensity score-matched COVIDneg (matched) cohorts are summarized in Table 1. We observe that the COVIDpos and COVIDneg (matched) cohorts are well-balanced along these covariates which are potential confounding variables for thrombotic events and coagulopathy-related lab tests during the study period.\n\nResults\nLongitudinal analysis identifies lab test results characteristic of COVID-19 at specific prognostic time intervals\nTo identify laboratory test results that differ between COVIDpos and COVIDneg (matched) patients, we analyzed longitudinal trends of 194 laboratory test results in the 30 days before and after the day of PCR testing (designated as day 0). As most patients did not undergo laboratory testing for each assay on a daily basis, we grouped the measurements into nine time windows reflecting potential stages of infection as follows: pre-infection (days −30 to −11), pre-PCR (days −10 to −2), time of clinical presentation (days −1 to 0), and post-PCR phases 1 (days 1 to 3), 2 (days 4 to 6), 3 (days 7 to 9), 4 (days 10 to 12), 5 (days 13 to 15), and 6 (days 16 to 30). We only considered test-time window pairs in which at least three patients contributing to laboratory test results in both groups. During each time window, we then compared the distribution of results from COVIDpos versus COVIDneg (matched) patients, allowing us to identify any lab tests which were significantly altered in COVIDpos patients during any time of disease acquisition, onset, and/or progression.\n\nOf the 1709 lab test-time window pairs with adequate data points for comparison, we identified 130 such pairs (comprising 66 unique lab tests) which met our thresholds for statistical significance (Cohen’s D >0.35, BH-adjusted Mann-Whitney p-value <0.05; Table 2). Among these were lab tests that may be considered positive controls for our analysis. From the time of clinical presentation onward, elevated titers of SARS-CoV-2 IgG antibodies (Figure 1A) and a reduction in blood oxygenation in COVIDpos patients were observed (Figure 1B). We also identified abnormalities in several other classes of lab tests, including immune cell counts (Figures 1C–E and 2A–B), red blood cell counts (Figure 2C), mean corpuscular volume (Figure 2D), calcium and magnesium levels (Figure 2E–F), and coagulation-related tests (Figure 3).\n\nFigure 1. Longitudinal and temporally resolved analysis highlights positive control lab tests elevated in COVIDpos patients along with distinctive immune signatures.\nLongitudinal trends in COVIDpos versus COVIDneg (matched) patients for the following lab tests: (A) SARS-CoV-2 IGG ratio, (B) oxygen saturation in arterial blood, (C) white blood cells, (D) monocytes absolute, and (E) neutrophils, blood. For any window of time during which at least three patients in each cohort had test results, data are shown as mean with standard errors. The normal range for each lab test is shaded in green. Values given horizontally along the top of the plot are Cohen’s D statistics comparing the COVIDpos and COVIDneg (matched) cohorts along with the BH-adjusted Mann-Whitney test p-values. Significant differences (adjusted p-value <0.05) are shown in black, while non-significant values are shown in gray. Values given horizontally along the bottom of the plot are the numbers of patients in the COVIDpos and COVIDneg cohorts, respectively (i.e. # COVIDpos | # COVIDneg). For certain lab tests, some data points are missing because these time windows had fewer than three data points in the COVIDpos cohort.\n\nFigure 2. Longitudinal trends of COVIDpos patients’ lab tests show distinctive immune, hematologic, and serum chemistry signatures within normal ranges.\nLongitudinal trends in COVIDpos versus COVIDneg (matched) patients for the following lab tests: (A) eosinophils absolute, (B) basophils absolute, (C) red blood cell count, (D) mean corpuscular volume, (E) calcium total, plasma, and (F) magnesium total, serum/plasma. For any window of time during which at least three patients in each cohort had test results, data are shown as mean with standard errors. The normal range for each lab test is shaded in green. Values given horizontally along the top of the plot are Cohen’s D statistics comparing the COVIDpos and COVIDneg (matched) cohorts along with the BH-adjusted Mann-Whitney test p-values. Significant differences (adjusted p-value <0.05) are shown in black, while non-significant values are shown in gray. Values given horizontally along the bottom of the plot are the numbers of patients in the COVIDpos and COVIDneg cohorts, respectively (i.e. # COVIDpos | # COVIDneg). For certain lab tests, some data points are missing because these time windows had fewer than three data points in the COVIDpos cohort.\n\nFigure 3. COVIDpos patients show distinctly opposite temporal trends in fibrinogen and platelet counts starting at the time of diagnosis.\nLongitudinal trends of COVIDpos versus COVIDneg (matched) patients for the following lab tests: (A) fibrinogen, plasma, (B) platelets, and (C) other coagulation-related tests including prothrombin time (PT), activated partial thromboplastic time (aPTT), and D-dimers. For any window of time during which at least three patients in each cohort had test results, data are shown as mean with standard errors. The normal range for each lab test is shaded in green. Values given horizontally along the top of the plot are Cohen’s D statistics comparing the COVIDpos and COVIDneg (matched) cohorts along with the BH-adjusted Mann-Whitney test p-values. Significant differences (adjusted p-value <0.05) are shown in black, while non-significant values are shown in gray. Values given horizontally along the bottom of the plot are the numbers of patients in the COVIDpos and COVIDneg cohorts, respectively (i.e. # COVIDpos | # COVIDneg). For certain lab tests, some data points are missing because these time windows had fewer than three data points in the COVIDpos cohort.\n\nTable 2. Summary of lab tests significantly different between COVIDpos and propensity score-matched COVIDneg cohorts during at least one clinical time window.\nData from individual patients were averaged over the defined time windows, and the mean values were compared between COVIDpos and COVIDneg patients. The lab test-time window pairs shown are those which met our defined thresholds for statistical significance and substantial effect (BH-adjusted Mann-Whitney p-value <0.05 and Cohen’s D absolute value >0.35). In particular, 130 of the initial 1709 (test, time window) pairs with at least one patient met these thresholds. Rows are sorted alphabetically by test and then time window (from earliest to latest). Coagulation-related tests of particular interest (fibrinogen, platelets, prothrombin time, activated partial thromboplastin time, and D-dimer) are highlighted in gray. Sample sources are denoted as: P = plasma, S = serum, S/P = serum/plasma, B = blood, U = urine.\n\nTest\tUnits\tTime window\tCount COVIDpos\tCount COVIDneg\tMean COVIDpos\tMean COVIDneg\tCohen's D\tBH-adj M-W p-value\t\nABGRS pH Arterial\tpH\tDays 16–30 Post-Dx\t18\t91\t7.45\t7.4\t0.775\t0.02\t\nABGRS PO2 Arterial\tmm Hg\tDays 1–3 Post-Dx\t16\t204\t81.9\t129.6\t−0.797\t3.1E-03\t\nABGRS PO2 Arterial\tmm Hg\tDays 4–6 Post-Dx\t25\t82\t78.1\t113.2\t−0.712\t8.8E-03\t\nABGRS PO2 Arterial\tmm Hg\tDays 7–9 Post-Dx\t23\t58\t77.2\t121.9\t−0.807\t1.0E-03\t\nABGRS PO2 Arterial\tmm Hg\tDays 10–12 Post-Dx\t18\t37\t76.4\t104.2\t−0.965\t2.6E-03\t\nABGRS PO2 Arterial\tmm Hg\tDays 13–15 Post-Dx\t15\t31\t73.1\t112.3\t−0.964\t6.0E-03\t\nActivated Partial Thrombopl Time, P\tsec\tDays 7–9 Post-Dx\t22\t66\t50.5\t36.7\t0.727\t0.026\t\nActivated Partial Thrombopl Time, P\tsec\tDays 10–12 Post-Dx\t14\t54\t63.3\t39.2\t1.085\t2.4E-03\t\nActivated Partial Thrombopl Time, P\tsec\tDays 13–15 Post-Dx\t16\t48\t53.1\t37.6\t1.065\t5.6E-03\t\nActivated Partial Thrombopl Time, P\tsec\tDays 16–30 Post-Dx\t19\t149\t56.2\t37.5\t0.884\t0.027\t\nAlanine Aminotransferase (ALT), P\tU/L\tDays 10–12 Post-Dx\t27\t104\t77.3\t46\t0.512\t0.015\t\nAlbumin, P\tg/dL\tDays 7–9 Post-Dx\t42\t188\t3.06\t3.41\t−0.54\t5.6E-03\t\nAlbumin, S/P\tg/dL\tClinical presentation\t85\t812\t3.43\t3.81\t−0.591\t4.8E-06\t\nAlbumin, S/P\tg/dL\tDays 1–3 Post-Dx\t77\t525\t3.26\t3.6\t−0.541\t3.8E-05\t\nAlbumin, S/P\tg/dL\tDays 10–12 Post-Dx\t61\t254\t3.35\t3.66\t−0.47\t2.6E-03\t\nAlkaline Phosphatase, P\tU/L\tDays 4–6 Post-Dx\t42\t139\t88.8\t126.7\t−0.395\t3.7E-03\t\nArterial O2 PP Diff\tNone\tClinical presentation\t21\t106\t268.1\t152.1\t0.924\t9.7E-03\t\nArterial O2 PP Diff\tNone\tDays 1–3 Post-Dx\t22\t112\t225.9\t147.4\t0.639\t0.017\t\nArterial O2 PP Diff\tNone\tDays 4–6 Post-Dx\t17\t49\t271.4\t155\t0.891\t4.8E-03\t\nAspartate Aminotransferase (AST), P\tU/L\tDays 10–12 Post-Dx\t27\t107\t67.6\t44.7\t0.404\t3.6E-04\t\nBasophils Absolute\t×10(9)/L\tClinical presentation\t133\t1400\t0.0251\t0.0379\t−0.412\t5.8E-06\t\nBicarbonate [MMOL/L] in Arterial Blood\tmmol/L\tDays 16–30 Post-Dx\t18\t91\t28.6\t24.3\t0.857\t7.6E-03\t\nBicarbonate in Arterial Blood\tmmol/L\tDays 1–3 Post-Dx\t26\t193\t23.2\t21.4\t0.513\t0.027\t\nBUN, P\tmg/dL\tDays 16–30 Post-Dx\t49\t562\t31.4\t21.9\t0.555\t3.9E-03\t\nC-reactive Protein Quantative, S\tmg/L\tClinical presentation\t85\t666\t100.2\t68.2\t0.375\t6.8E-05\t\nCalcium, Ionized, B\tmg/dL\tClinical presentation\t14\t201\t4.36\t4.77\t−0.67\t0.015\t\nCalcium, Ionized, B\tmg/dL\tDays 1–3 Post-Dx\t18\t270\t4.42\t4.73\t−0.783\t8.5E-04\t\nCalcium, Total, P\tmg/dL\tClinical presentation\t89\t1144\t8.71\t9.05\t−0.468\t5.5E-06\t\nCalcium, Total, P\tmg/dL\tDays 1–3 Post-Dx\t77\t910\t8.52\t8.81\t−0.459\t3.2E-04\t\nCalcium, Total, P\tmg/dL\tDays 7–9 Post-Dx\t71\t353\t8.61\t8.93\t−0.457\t1.8E-03\t\nCalcium, Total, S\tmg/dL\tClinical presentation\t83\t941\t8.29\t8.91\t−0.854\t1.9E-13\t\nCalcium, Total, S\tmg/dL\tDays 1–3 Post-Dx\t98\t1025\t8.28\t8.77\t−0.717\t2.2E-10\t\nCalcium, Total, S\tmg/dL\tDays 4–6 Post-Dx\t87\t568\t8.4\t8.69\t−0.435\t2.3E-03\t\nCalcium, Total, S\tmg/dL\tDays 7–9 Post-Dx\t82\t433\t8.49\t8.76\t−0.384\t0.011\t\nCarboxyhemoglobin, ARTERIAL\t%\tClinical presentation\t34\t356\t0.507\t0.991\t−0.71\t2.0E-04\t\nCarboxyhemoglobin, Arterial\t%\tDays 1–3 Post-Dx\t44\t436\t0.535\t0.9\t−0.711\t5.9E-05\t\nCarboxyhemoglobin, Arterial\t%\tDays 4–6 Post-Dx\t58\t166\t0.678\t0.974\t−0.544\t3.0E-03\t\nCarboxyhemoglobin, Arterial\t%\tDays 7–9 Post-Dx\t45\t102\t0.704\t0.97\t−0.472\t0.048\t\nCarboxyhemoglobin, Venous\t%\tDays 1–3 Post-Dx\t10\t73\t0.701\t1.16\t−0.862\t0.02\t\nCarboxyhemoglobin, Venous\t%\tDays 4–6 Post-Dx\t14\t47\t0.725\t1.29\t−0.837\t3.7E-03\t\nChloride, P\tmmol/L\tDays 1–3 Post-Dx\t77\t906\t100.1\t101.9\t−0.363\t7.7E-03\t\nEosinophils Absolute\t×10(9)/L\tPre-diagnosis\t28\t547\t0.0689\t0.161\t−0.45\t1.7E-03\t\nEsosinophils Absolute\t×10(9)/L\tDays 4–6 Post-Dx\t133\t559\t0.0906\t0.172\t−0.358\t2.4E-06\t\nFibrinogen, P\tmg/dL\tClinical presentation\t51\t233\t528.9\t360.7\t0.859\t8.9E-07\t\nFibrinogen, P\tmg/dL\tDays 1–3 Post-Dx\t18\t319\t432.6\t297.4\t0.836\t1.7E-03\t\nFibrinogen, P\tmg/dL\tDays 4–6 Post-Dx\t26\t116\t477.8\t333.7\t0.744\t0.014\t\nGlucose, Random, S\tmg/dL\tDays 13–15 Post-Dx\t49\t314\t150\t126.5\t0.544\t0.013\t\nHematocrit, B\t%\tDays 1–3 Post-Dx\t158\t1582\t36.5\t33.8\t0.433\t9.6E-06\t\nHematocrit, B\t%\tDays 4–6 Post-Dx\t152\t851\t36\t32.1\t0.621\t2.2E-10\t\nHematocrit, B\t%\tDays 7–9 Post-Dx\t132\t639\t35.5\t31.8\t0.587\t5.8E-08\t\nHematocrit, B\t%\tDays 10–12 Post-Dx\t110\t505\t35.1\t31.8\t0.511\t1.7E-05\t\nHemoglobin Arterial\tg/dL\tDays 1–3 Post-Dx\t31\t208\t12.1\t10.8\t0.651\t0.025\t\nHemoglobin, B\tg/dL\tDays 1–3 Post-Dx\t158\t1682\t11.9\t11.1\t0.358\t2.2E-04\t\nHemoglobin, B\tg/dL\tDays 4–6 Post-Dx\t152\t873\t11.8\t10.4\t0.636\t1.4E-10\t\nHemoglobin, B\tg/dL\tDays 7–9 Post-Dx\t132\t653\t11.6\t10.4\t0.56\t2.0E-07\t\nHemoglobin, B\tg/dL\tDays 10–12 Post-Dx\t110\t516\t11.4\t10.3\t0.49\t2.6E-05\t\nIonized Calcium, Arterial\tmg/dL\tDays 16–30 Post-Dx\t8\t36\t4.93\t4.48\t1.561\t0.022\t\nLactate Dehydrogenase, S\tU/L\tDays 10–12 Post-Dx\t21\t88\t406.2\t295.2\t0.463\t1.4E-03\t\nLactate, P\tmmol/L\tClinical presentation\t89\t954\t1.37\t1.93\t−0.462\t3.1E-06\t\nLymphocytes Percent\t%\tDays 13–15 Post-Dx\t5\t66\t33.2\t15\t1.514\t0.048\t\nLymphs Absolute\t×10(9)/L\tDays 13–15 Post-Dx\t56\t349\t3.12\t1.11\t0.44\t0.018\t\nMagnesium, Plasma\tmg/dL\tDays 10–12 Post-Dx\t20\t87\t2.14\t1.91\t0.772\t0.015\t\nMagnesium, S/P\tmg/dL\tDays 4–6 Post-Dx\t47\t279\t2.22\t1.98\t0.743\t3.0E-03\t\nMagnesium, S/P\tmg/dL\tDays 7–9 Post-Dx\t40\t215\t2.31\t1.97\t1.06\t4.1E-06\t\nMagnesium, S/P\tmg/dL\tDays 10–12 Post-Dx\t36\t187\t2.26\t1.91\t1.005\t2.9E-06\t\nMagnesium, S/P\tmg/dL\tDays 13–15 Post-Dx\t35\t179\t2.22\t1.89\t0.904\t1.8E-07\t\nMagnesium, S/P\tmg/dL\tDays 16–30 Post-Dx\t33\t317\t2.13\t1.89\t0.906\t1.6E-04\t\nManual Diff Promyelocytes\t%\tDays 1–3 Post-Dx\t6\t55\t0.25\t0\t1.402\t0.027\t\nMean Corpuscular Volume\tfL\tDays 10–12 Post-Dx\t110\t502\t89.5\t92\t−0.38\t8.8E-03\t\nMethemoglobin, ABG\t%\tClinical presentation\t34\t356\t0.335\t0.571\t−0.629\t6.0E-03\t\nMethemoglobin, ABG\t%\tDays 1–3 Post-Dx\t44\t436\t0.425\t0.697\t−0.463\t1.5E-03\t\nMonocytes Absolute\t×10(9)/L\tDays 1–3 Post-Dx\t131\t1079\t0.447\t0.748\t−0.502\t2.6E-16\t\nMonocytes Absolute\t×10(9)/L\tDays 4–6 Post-Dx\t135\t584\t0.475\t0.715\t−0.597\t2.2E-10\t\nN-terminal-PRO-Brain Type Natriuretic Peptide, S\tpg/mL\tDays 4–6 Post-Dx\t10\t63\t415.6\t7609.7\t−0.525\t2.9E-03\t\nNeutrophils, B\t×10(9)/L\tClinical presentation\t136\t1382\t5.31\t7.12\t−0.396\t6.3E-06\t\nNeutrophils, B\t×10(9)/L\tDays 1–3 Post-Dx\t130\t1141\t4.73\t6.32\t−0.385\t5.8E-05\t\nNT-PRO BNP, P\tpg/mL\tClinical presentation\t25\t372\t1372.4\t5327.9\t−0.385\t0.046\t\nNT-PRO BNP, P\tpg/mL\tDays 4–6 Post-Dx\t14\t20\t815.3\t4388.8\t−0.929\t0.02\t\nNucleated RBC\t/100 WBC\tDays 13–15 Post-Dx\t23\t189\t1.24\t0.447\t0.561\t1.7E-03\t\nO2 HB\t%\tDays 1–3 Post-Dx\t13\t242\t88.6\t95\t−1.37\t2.2E-03\t\nO2 HB\t%\tDays 4–6 Post-Dx\t32\t90\t92.1\t93.7\t−0.356\t0.013\t\nO2 HB\t%\tDays 7–9 Post-Dx\t24\t46\t91.5\t94.5\t−0.701\t3.3E-04\t\nOsmolality, U\tmOsm/kg\tPre-diagnosis\t4\t80\t231.5\t478.8\t−1.509\t0.044\t\nOxygen Content, Arterial\tvol %\tDays 4–6 Post-Dx\t32\t89\t16\t13.7\t0.839\t2.4E-03\t\nOxygen Saturation (%) in Arterial Blood\t%\tClinical presentation\t27\t189\t94.2\t96.2\t−0.52\t3.1E-03\t\nOxygen Saturation (%) in Arterial Blood\t%\tDays 1–3 Post-Dx\t31\t216\t94.3\t97.1\t−1.293\t8.4E-09\t\nOxygen Saturation (%) in Arterial Blood\t%\tDays 4–6 Post-Dx\t26\t70\t94.3\t95.7\t−0.578\t0.014\t\nOxygen Saturation (%) in Arterial Blood\t%\tDays 10–12 Post-Dx\t18\t29\t93.4\t96.5\t−1.254\t3.1E-03\t\nOxygen Saturation (%) in Arterial Blood\t%\tDays 13–15 Post-Dx\t17\t28\t94.8\t96.4\t−0.671\t0.043\t\npH Blood Arterial\tNone\tDays 1–3 Post-Dx\t26\t193\t7.42\t7.39\t0.539\t0.035\t\npH Blood Venous\tpH\tDays 1–3 Post-Dx\t10\t82\t7.42\t7.36\t0.963\t0.031\t\npH, POCT, B\tNone\tClinical presentation\t13\t202\t7.41\t7.33\t0.708\t0.042\t\nPlatelets\t×10(9)/L\tPre-diagnosis\t39\t649\t184.8\t225.9\t−0.393\t0.024\t\nPO2\tmm Hg\tDays 1–3 Post-Dx\t8\t145\t67.2\t179.7\t−1.301\t1.7E-03\t\nPO2\tmm Hg\tDays 7–9 Post-Dx\t14\t16\t71.1\t121.1\t−0.949\t0.027\t\nPO2 Arterial\tmm Hg\tDays 1–3 Post-Dx\t26\t193\t100.4\t150.9\t−0.87\t8.2E-05\t\nPO2 Arterial\tmm Hg\tDays 10–12 Post-Dx\t17\t25\t93.6\t134\t−0.755\t0.019\t\nPotassium, S\tmmol/L\tPre-diagnosis\t10\t398\t3.93\t4.35\t−0.836\t0.049\t\nRABG Calculated O2 Hemoglobin\t%\tDays 1–3 Post-Dx\t22\t109\t93.6\t95\t−0.464\t2.9E-03\t\nRABG Calculated O2 Hemoglobin\t%\tDays 4–6 Post-Dx\t16\t49\t93.2\t95.3\t−0.859\t2.3E-03\t\nRABG Calculated O2 Hemoglobin\t%\tDays 10–12 Post-Dx\t13\t22\t94\t96.3\t−1.269\t0.038\t\nRABG PF Ratio\tNone\tDays 4–6 Post-Dx\t17\t49\t1.46\t2.68\t−1.489\t6.9E-05\t\nRABG PF Ratio\tNone\tDays 7–9 Post-Dx\t13\t22\t1.75\t2.56\t−1.006\t0.038\t\nRABG PF Ratio\tNone\tDays 10–12 Post-Dx\t13\t22\t1.83\t3.22\t−1.518\t3.9E-03\t\nRBC (Red Blood Cell) Count\t×10(12)/L\tClinical presentation\t151\t1671\t4.32\t3.99\t0.409\t2.0E-04\t\nRBC (Red Blood Cell) Count\t×10(12)/L\tDays 1–3 Post-Dx\t158\t1562\t4.13\t3.73\t0.524\t5.8E-08\t\nRBC (Red Blood Cell) Count\t×10(12)/L\tDays 4–6 Post-Dx\t152\t846\t4.08\t3.55\t0.693\t3.2E-12\t\nRBC (Red Blood Cell) Count\t×10(12)/L\tDays 7–9 Post-Dx\t132\t635\t4\t3.49\t0.656\t2.4E-09\t\nRBC (Red Blood Cell) Count\t×10(12)/L\tDays 10–12 Post-Dx\t110\t502\t3.95\t3.48\t0.587\t6.1E-07\t\nRed Cell Distribution Width CV\t%\tDays 4–6 Post-Dx\t137\t722\t14.1\t15.1\t−0.373\t3.4E-04\t\nRed Cell Distribution Width CV\t%\tDays 7–9 Post-Dx\t119\t552\t14.2\t15.4\t−0.431\t9.8E-05\t\nRed Cell Distribution Width CV\t%\tDays 10–12 Post-Dx\t97\t429\t14.5\t15.7\t−0.394\t1.2E-03\t\nSodium, P\tmmol/L\tClinical presentation\t89\t1141\t135.6\t137.3\t−0.375\t7.3E-03\t\nSodium, P\tmmol/L\tDays 1–3 Post-Dx\t77\t927\t136.6\t138.1\t−0.377\t4.7E-03\t\nSodium, S\tmmol/L\tDays 10–12 Post-Dx\t69\t334\t140.8\t138.3\t0.651\t2.0E-04\t\nSpont. Breaths/min\tNone\tDays 4–6 Post-Dx\t23\t67\t25\t20.2\t0.767\t0.016\t\nTacrolimus, B\tng/mL\tDays 7–9 Post-Dx\t8\t81\t4.22\t8.12\t−1.102\t8.8E-03\t\nTacrolimus, B\tng/mL\tDays 10–12 Post-Dx\t8\t79\t3.8\t9.24\t−1.468\t2.5E-03\t\nTacrolimus, B\tng/mL\tDays 13–15 Post-Dx\t7\t71\t3.7\t8.52\t−1.47\t7.5E-03\t\nTacrolimus, B\tng/mL\tDays 16–30 Post-Dx\t10\t110\t4.93\t7.8\t−1.094\t0.022\t\nTemperature\tNone\tClinical presentation\t23\t136\t37\t36.7\t0.591\t0.042\t\nTemperature\tNone\tDays 1–3 Post-Dx\t23\t189\t37\t36.4\t0.765\t4.8E-04\t\nTriglycerides, S/P\tmg/dL\tDays 4–6 Post-Dx\t16\t41\t326.2\t173\t1.196\t7.3E-03\t\nTriglycerides, S/P\tmg/dL\tDays 7–9 Post-Dx\t17\t24\t310.6\t191.5\t0.945\t0.016\t\nTriglycerides, S/P\tmg/dL\tDays 10–12 Post-Dx\t17\t35\t364.5\t174.4\t1.217\t4.0E-03\t\nTriglycerides, S/P\tmg/dL\tDays 16–30 Post-Dx\t10\t77\t276.1\t166.4\t0.83\t0.024\t\nTroponin T, 5TH GEN, P\tng/L\tDays 4–6 Post-Dx\t18\t54\t21.4\t245.3\t−0.499\t7.5E-03\t\nTroponin T, Baseline, 5TH Gen, P\tng/L\tDays 7–9 Post-Dx\t11\t43\t15.1\t53.7\t−0.538\t0.037\t\nVBGRS HGB\tg/dL\tDays 4–6 Post-Dx\t36\t99\t12.3\t10.5\t0.932\t3.6E-04\t\nWhite Blood Cells\t×10(9)/L\tDays 1–3 Post-Dx\t158\t1650\t6.67\t9.08\t−0.439\t3.2E-12\t\nWith respect to coagulation, we found that plasma fibrinogen was significantly elevated in COVIDpos patients at the time of diagnosis (Cohen’s D = 0.859, BH-adjusted Mann-Whitney p-value = 8.9e-7, Table 2, Figure 3A). This hyperfibrinogenemia generally resolved during the 7 days following diagnosis (Figure 3A). Conversely, platelet counts were lower in the COVIDpos cohort at the time of clinical presentation but tended to increase over the subsequent 10 days to levels significantly higher than those in COVIDneg patients (Cohen’s D = 0.229, BH-adjusted Mann-Whitney p-value = 3.6e-3, Table 2, Figure 3B). While thrombocytopenia has been reported in COVID-19 patients before (Xu et al., 2020; Yang et al., 2020), an upward trend in platelet counts after diagnosis has not been described to our knowledge. We observe extended prothrombin times in both the COVIDpos and COVIDneg (matched) cohorts significantly above the normal range; however, there was no differentiation between the cohorts. We observe extended activated partial thromboplastin times (aPTT) in the COVIDpos significantly above normal levels from day 7 onward (Figure 3D). D-dimer levels were frequently above normal limits in both the COVIDpos and COVIDneg cohorts and were not significantly different between these cohorts during any time window (Figure 3E). The above trends hold up even when the time windows are perturbed (Table 3).\n\nTable 3. Sensitivity analysis of clinical time intervals for significant coagulation-related lab test trends.\nResults from sensitivity analysis perturbing the time intervals for the significant (coagulation-related lab test, time interval) pairs (i.e. highlighted rows of Table 2). Perturbed results that met both of the significance thresholds (BH-adjusted Mann-Whitney p-value <0.05 and Cohen’s D absolute value >0.35) are highlighted in light green, and perturbed results that only met one of the thresholds for either effect size or statistical significance are highlighted in yellow.\n\nTest\tUnits\tPerturbation\tOriginal time window\tCount COVIDpos\tCount COVIDneg\tMean COVIDpos\tMean COVIDneg\tCohen's D\tBH-adjusted \nM-W p-value\t\nActivated Partial Thrombopl Time, P\tsec\t−1 day\tDays 7−9 Post-Dx\t26\t72\t50.1\t38\t0.57\t0.034\t\nActivated Partial Thrombopl Time, P\tsec\t+1 day\tDays 7−9 Post-Dx\t17\t58\t55\t37.5\t0.81\t0.014\t\nActivated Partial Thrombopl Time, P\tsec\t−1 day\tDays 10−12 Post-Dx\t16\t57\t56.9\t38.4\t0.808\t9.10E-03\t\nActivated Partial Thrombopl Time, P\tsec\t+1 day\tDays 10−12 Post-Dx\t15\t60\t56.9\t38\t1.106\t2.60E-03\t\nActivated Partial Thrombopl Time, P\tsec\t−1 day\tDays 13−15 Post-Dx\t15\t52\t55.5\t37.8\t1.041\t0.014\t\nActivated Partial Thrombopl TIME, P\tsec\t+1 day\tDays 13−15 Post-Dx\t14\t48\t51.8\t37.1\t0.962\t0.015\t\nActivated Partial Thrombopl Time, P\tsec\t−1 day\tDays 16−30 Post-Dx\t22\t156\t55.2\t37\t0.913\t5.70E-03\t\nActivated Partial Thrombopl Time, P\tsec\t+1 day\tDays 16−30 Post-Dx\t19\t139\t56\t38.2\t0.725\t3.80E-02\t\nFibrinogen, P\tmg/dL\t−1 day\tClinical presentation\t25\t92\t584.9\t370.7\t1.067\t1.20E-04\t\nFibrinogen, P\tmg/dL\t+1 day\tClinical presentation\t37\t292\t488.2\t326.2\t0.885\t8.80E-06\t\nFibrinogen, P\tmg/dL\t−1 day\tDays 1−3 Post-Dx\t41\t381\t494.5\t318\t1.023\t3.90E-07\t\nFibrinogen, P\tmg/dL\t+1 day\tDays 1−3 Post-Dx\t21\t244\t420.3\t312.2\t0.616\t7.90E-03\t\nFibrinogen, P\tmg/dL\t−1 day\tDays 4−6 Post-Dx\t27\t156\t432.2\t336\t0.495\t0.045\t\nFibrinogen, P\tmg/dL\t+1 day\tDays 4−6 Post-Dx\t24\t105\t472.2\t333.2\t0.712\t0.025\t\nPlatelets\tx10(9)/L\t−1 day\tPre-diagnosis\t34\t575\t187.3\t225.6\t-0.357\t0.057\t\nPlatelets\tx10(9)/L\t+1 day\tPre-diagnosis\t118\t1533\t201.3\t234.4\t-0.328\t7.30E-04\t\nWe also performed similar analyses comparing the COVIDpos and COVIDneg (matched) cohorts using different time window definitions including daily trends (Figure 4). This approach offers the advantage of increased granularity at the cost of sample size per time point, but we did identify similar lab tests as altered in COVIDpos patients using each approach including the fibrinogen decline and platelet increase in the COVIDpos cohort after diagnosis (Figure 4).\n\nFigure 4. Longitudinal trends of lab tests with daily resolution.\nLongitudinal trends of COVIDpos versus COVIDneg (matched) patients for the following lab tests: (A) platelets; (B) fibrinogen, plasma; (C) prothrombin time, plasma; (D) activated partial thromboplastin time; (E) D-dimer; (F) magnesium, serum/plasma; (G) basophils absolute; (H) neutrophils, blood; (I) alkaline phosphatase, serum. The reference ranges are shown at the top of each plot. For each cohort, average lab values and standard errors are shown for each day with at least three observations. For certain lab tests, some data points are missing because these days had fewer than three data points in the COVIDpos cohort.\n\nThrombosis is enriched among COVID-19 patients undergoing longitudinal lab testing\nGiven the recently described coagulopathies associated with COVID-19 (Tang et al., 2020; Klok et al., 2020; Levi et al., 2020), we were intrigued by the temporal trends in fibrinogen levels and platelet counts in the COVIDpos cohort (Figure 3). Next, we asked whether the observed coagulation-related laboratory trends were associated with clinical manifestations of thrombosis. To do so, we employed a BERT-based neural network (Devlin et al., 2018; see Materials and methods) to identify patients who experienced a thrombotic event after their SARS-CoV-2 PCR testing date. Specifically, we extracted diagnostic sentiment from EHR notes (e.g. whether a patient was diagnosed with a phenotype, suspected of having a phenotype, ruled out for having a phenotype, or other) regarding specific thromboembolic phenotypes including deep vein thrombosis, pulmonary embolism, myocardial infarction, venous thromboembolism, thrombotic stroke, cerebral venous thrombosis, and disseminated intravascular coagulation.\n\nWe found that 101 of the total 2232 COVIDpos cohort (4.5%) were positively diagnosed with one or more of the above-mentioned thrombotic phenotypes in the 30 days after PCR testing, with the majority of these patients (53 of 101) experiencing a deep vein thrombosis. Interestingly, we found that after creating subsets of the patients with longitudinal lab testing data (i.e. the patients meeting the criteria for inclusion in our study), 76 of the 246 patients (31%) had at least one EHR-derived clot diagnosis, including 47 patients with deep vein thrombosis (Table 4). Thus, the cohort under consideration here is highly enriched (Table 5; hypergeometric p-value <1×10−50) for patients experiencing thrombotic events compared to the overall COVIDpos cohort.\n\nTable 4. Prevalence of thrombotic phenotypes after the clinical presentation in COVIDpos patients with and without available longitudinal lab testing data.\nFor each clotting phenotype listed, a BERT-based neural network was used to extract diagnostic sentiment from individual EHR patient notes in which the phenotype (or a synonym thereof) was present. This automated curation was applied to clinical notes for each patient from day = −1 (clinical presentation) to day = 30 (end of the study period) relative to the PCR testing date. In this table, we show the absolute number of patients with each phenotype along with the percentage of patients in each cohort with the given specific thrombotic phenotype in parentheses.\n\nClotting phenotype\tCohort 1: COVIDpos with longitudinal data\tCohort 2: COVIDpos without longitudinal data\tCohort 3: Complete COVIDpos cohort\t\nDeep vein thrombosis\t47 (19%)\t6 (0.30%)\t53 (2.4%)\t\nPulmonary embolism\t22 (8.9%)\t9 (0.45%)\t31 (1.4%)\t\nMyocardial infarction\t10 (4.1%)\t8 (0.40%)\t18 (0.81%)\t\nVenous thromboembolism\t7 (2.8%)\t0\t7 (0.31%)\t\nThrombotic stroke\t2 (0.81%)\t2 (0.10%]\t4 (0.18%)\t\nCerebral venous thrombosis\t0\t0\t0\t\nDisseminated intravascular coagulation\t5 (2.0%)\t0\t5 (0.22%)\t\nTotal unique patients with clot\t76 (31%)\t25 (1.3%)\t101 (4.5%)\t\nTotal patients\t246\t1986\t2232\t\nTable 5. Enrichment of thrombotic phenotypes among COVIDpos patients with longitudinal lab testing data.\nContingency table to calculate hypergeometric enrichment significance of thrombosis among patients with longitudinal lab testing data. The 246 patients with longitudinal testing data are those considered in this study, while the 1986 patients who did not have at least three results from one lab test over the defined 60-day window were excluded from this longitudinal analysis.\n\n\tPatient has longitudinal data\tPatient does NOT have longitudinal data\tTotal\t\nThrombosis\t76\t25\t101\t\nNo thrombosis\t170\t1961\t2131\t\nTotal\t246\t1986\t2232\t\nHypergeometric enrichment: p-value <1×10−50.\n\nTable 6. Validation of the BERT model to identify the sentiment of thrombotic phenotypes in clinical notes.\nOut-of-sample accuracy results of the BERT model to identify thrombotic phenotypes in 1000 randomly selected sentences from clinical notes which contained at least one mention of a thrombotic phenotype. The columns are (1) Clotting phenotype: thrombotic phenotype identified in the sentence, (2) TP (true positives): count of sentences in which the BERT model correctly identified the sentiment as ‘Yes’, (3) TN (true negatives): count of sentences in which the BERT model correctly identified the sentiment as not ‘Yes’, (4) FP (false positives): count of sentences in which the BERT model incorrectly identified the sentiment as ‘Yes’, (5) FN: (false negatives): count of sentences in which the BERT model incorrectly identified the sentiment as not ‘Yes’, (6) Recall: recall of the BERT model, equal to TP/(TP+FN), (7) Precision: precision of the BERT model, equal to TP/(TP+FP), (8) Accuracy: accuracy of the BERT model, equal to (TP+TN)/(TP+TN+FP+FN).\n\nClotting phenotype\tTP\tTN\tFP\tFN\tRecall\tPrecision\tAccuracy\t\nDeep vein thrombosis\t136\t178\t24\t3\t98%\t85%\t92%\t\nPulmonary embolism\t164\t78\t7\t6\t96%\t96%\t95%\t\nMyocardial infarction\t212\t65\t3\t3\t99%\t99%\t98%\t\nVenous thromboembolism\t3\t97\t7\t0\t100%\t30%\t93%\t\nThrombotic stroke\t5\t0\t0\t0\t100%\t100%\t100%\t\nCerebral venous thrombosis\t1\t0\t0\t0\t100%\t100%\t100%\t\nDisseminated intravascular coagulation\t4\t4\t0\t0\t100%\t100%\t100%\t\nOverall\t525\t422\t41\t12\t97.8%\t92.8%\t94.7%\t\nLongitudinal platelet count trends are not strongly associated with the development of thrombosis in COVID-19 patients\nAmong the 246 COVIDpos patients with longitudinal lab testing data, 81 were serially tested starting at clinical presentation for fibrinogen versus 245 tested for platelets. As such, we first analyzed whether associations exist between platelet counts (or temporal alterations thereof) and clotting propensity in this cohort. Among these 245, there were 169 patients without thrombosis after PCR-based diagnosis (non-thrombotic) and 76 patients with thrombosis (thrombotic). There is a statistically significant difference between the COVIDpos and COVIDneg cohorts in the platelet count at clinical presentation (Figure 5A). In particular, thrombocytopenia (platelet count <150×109/L) was observed in 29% (46 out of 154) COVIDpos and 21% (346 of 1661) COVIDneg patients at the time of diagnosis (Figure 5A). However, the platelet levels at this time point were not associated with the subsequent formation of a blood clot in the COVIDpos cohort (Figure 5B).\n\nFigure 5. Association between platelet counts and thrombosis in the COVIDpos cohort.\nBox plots of platelet counts, min/max values, and maximum levels of increase/decline at specific time intervals for COVIDpos and COVIDneg cohorts and subgroups of the COVIDpos cohort with and without thrombotic events after SARS-CoV-2 diagnosis. In the subplot (A), we show platelet counts for COVIDpos (red) and COVIDneg (blue) cohorts. In subplots (B-F), we show platelet counts for COVIDpos patients who did and did not subsequently develop thromboses (purple and black, respectively). Horizontal dotted gray lines correspond to upper and lower limits of normal platelet counts (150−450 × 109/L), and horizontal red line shows 100 × 109/L. At the top of each plot, Cohen’s D effect size and p-value from the Mann-Whitney statistical test are shown. (A) Platelet counts at the time of PCR testing for COVIDpos and COVIDneg cohorts. (B) Platelet counts at the time of PCR testing for COVIDpos patients who did and did not subsequently develop thromboses. (C) Maximum platelet counts (considering counts at and after positive PCR test date) for COVIDpos patients who did and did not subsequently develop thromboses. (D) Minimum platelet counts (considering counts at and after positive PCR test date) for COVIDpos patients who did and did not subsequently develop thromboses. (E) Maximum degree of platelet increases after positive PCR test date for COVIDpos patients who did and did not subsequently develop thromboses. (F) Maximum degree of platelet declines after positive PCR test date for COVIDpos patients who did and did not subsequently develop thromboses.\n\nWe hypothesized that the previously discussed increase in platelet counts after COVID-19 diagnosis may be associated with the development of blood clots. If true, then we would expect the thrombotic COVIDpos cohort to show significantly higher maximum platelet counts during their course of disease progression compared to the non-thrombotic COVIDpos cohort. We found that this was not the case, as maximum platelet counts were similar in the two groups (Figure 5C). Similarly, among the 147 COVIDpos patients with platelet counts both at the time of clinical presentation and post-diagnosis, the degree of maximal platelet increase was not associated with the development of thrombosis (Figure 5E). It would certainly be of interest to perform this same analysis on a larger COVIDpos cohort (n = 2232; 101 thrombotic vs. 2131 non-thrombotic), but we were not able to do so given the lack of longitudinal testing available for a large majority of non-thrombotic COVIDpos patients (Table 4).\n\nConversely, we explored whether some COVIDpos patients may experience clotting in the setting of low or declining platelets (e.g. consumptive coagulopathy) despite the population-level trend of increasing platelets over time. Indeed, we found that nine of 74 thrombotic patients showed absolute platelet counts below 100 × 109/L during at least one post-diagnosis time window (below dotted red line in Figure 5D). In addition, we analyzed post-diagnosis platelet reductions among COVIDpos patients. While the maximum degree of absolute platelet reduction was not associated with clot development in aggregate (Figure 5F), we did find that six of the 52 thrombotic patients experienced a reduction of at least 100 × 109/L relative to the time of diagnosis. Of note, similar fractions of non-thrombotic COVIDpos patients also showed these low or declining platelet counts, indicating that these trends are not specific indicators of thrombosis (Figure 5D,F).\n\nConsumptive coagulopathy contributes to only a small fraction of COVID-19 associated thromboses\nThe observed declining platelet counts and thrombocytopenia in the context of thrombosis in a small fraction of COVIDpos patients are consistent with previous reports that fewer than 1% of survivors, but over 70% of non-survivors, meet the International Society on Thrombosis and Hemostasis (ISTH) criteria for disseminated intravascular coagulation (DIC; Tang et al., 2020). As was previously noted, hyperfibrinogenemia was among the strongest lab test features distinguishing COVIDpos from COVIDneg patients at diagnosis, but the subsequent downward trend (Figure 3A) could be attributed to a resolving acute phase response and/or consumption of fibrinogen in a systemic coagulopathy. Using our BERT-based sentiment extraction, we found that only five of the 2232 COVIDpos patients that exhibited DIC-like symptoms, all of whom were included in our longitudinal cohort of 246 COVIDpos patients (Table 4). Upon manual review of the EHR data for each patient, we found that two out of these five patients had confirmed diagnosis of DIC, while the remaining had high clinical suspicion and pending tests for DIC. This finding suggests that declining fibrinogen after COVID-19 diagnosis typically represents a physiologic return to normal range rather than pathologic coagulation factor consumption. To further examine the plasma fibrinogen trends among COVID-19 patients with DIC, with non-DIC thrombosis, and without thrombosis, we examined patient-level lab test trends from 10 individuals who were tested for fibrinogen both at the time of diagnosis and at least two times subsequently. The 10 patients for individual analysis were selected as the first 10 individuals with longitudinal fibrinogen lab testing data available.\n\nThis patient-level analysis indeed revealed multiple distinct trajectories with respect to fibrinogen and other coagulation parameters in COVIDpos patients. Four of these ten individuals developed at least one blood clot during their hospital course. Only one was identified by our BERT model (and confirmed by manual EHR review) to have low-grade DIC, and as expected we found this patient’s longitudinal lab test pattern to be consistent with consumptive coagulopathy (Patient 124; Figure 6A). At the time of diagnosis, this patient showed significant hyperfibrinogenemia with elevated D-dimers (1304.5 ng/mL) and a borderline normal platelet count (153 × 109/L). Over the next 10 days, this patient’s fibrinogen levels consistently decreased, reaching a minimum of 110 mg/dL on day 9. Similarly, after an initial recovery to 190 × 109/L the platelet counts consistently declined starting on day 2 post-diagnosis, reaching a minimum of 117 × 109/L on day 11. D-dimer levels exponentially increased after 5 days, reaching a maximum of 41,300 ng/mL on day 10. Phenotypically, this patient experienced both thrombotic (right internal jugular vein and right superior thyroid artery) and hemorrhagic (oropharyngeal and pulmonary) events. This combination of lab results and clinical manifestations is consistent with the diagnosis of DIC-like consumptive coagulopathy during the first week after COVID-19 diagnosis.\n\nFigure 6. Longitudinal analyses of platelet counts, plasma fibrinogen, and D-dimer levels in individual patients with or without thrombotic disease.\nIn each plot, shaded regions represent time periods when the patient was taking a specific anticoagulant or antiplatelet medication. Medications taken for prophylaxis are denoted in the legend with (ppx). (A) Patient 124 developed hemorrhagic and thrombotic phenotypes in the context of declining fibrinogen, declining platelets, and increasing D-dimers. This is consistent with a DIC-like coagulopathy. (B) Patient 23 developed clots in the setting of declining fibrinogen and elevated D-dimers but stable platelet counts which increased shortly thereafter. (C) Patient 79 developed clots while showing increases in platelet counts along with plasma fibrinogen and D-dimers. (D) Patient 94 developed clots with relatively stable platelet counts and steadily declining plasma fibrinogen. (E) Patient 13 did not develop clots or bleeding despite a coordinate decrease in platelet counts and fibrinogen which may be mistaken for a DIC-like coagulopathy. (F) Patient 51 did not develop clots despite showing a post-diagnosis decline in plasma fibrinogen similar to several patients in the thrombotic cohort.\n\nLab test results from three other non-DIC thrombotic patients with longitudinal fibrinogen testing confirm the presence of alternative forms of coagulopathy in the COVID-19 population. Patient 23 developed a clot on day 4 post-diagnosis in the context of a declining fibrinogen level and increasing D-dimers but steady platelet counts, which actually increased shortly thereafter (Figure 6B). Patient 79 developed several clots after day 3 post-diagnosis in the setting of upward trending platelets (which eventually exceed the upper limit of normal) and elevated levels of both fibrinogen and D-dimers (Figure 6C). Patient 94 developed a clot on day 8 post-diagnosis with relatively stable platelet counts within normal limits and steadily declining fibrinogen levels (Figure 6D).\n\nOne hypothesis is that early elevations in plasma fibrinogen contribute to the clotting observed in the non-DIC like COVIDpos cohort. This hypothesis may warrant further analysis in cohorts with more longitudinal fibrinogen data, but again it is important to note that several COVIDpos patients who presented with hyperfibrinogenemia did not go on to develop thromboses (Figure 6E–F). This emphasizes that a steady post-diagnosis decline in plasma fibrinogen may represent physiologic resolution of the acute phase response rather than a pathologic consumption of fibrinogen and other coagulation factors (Figure 6B,D–F).\n\nTaken together, this analysis affirms that a DIC-like coagulopathy resulting in a combination of hemorrhage and thrombosis can develop in the setting of COVID-19 infection. However, the observations that DIC was formally diagnosed in only five of 2232 COVIDpos patients and emphasizes that consumptive coagulopathy is an exception rather than the rule as it pertains to thrombotic phenotypes in COVID-19 patients. These results should be considered as a preliminary characterization of COVID-associated coagulopathies (CAC) and will be updated as patient counts increase with the continued evolution of the COVID-19 pandemic.\n\nDiscussion\nMany studies on clinical characteristics and lab tests are shedding light on the spectrum of hematological parameters associated with COVID-19 patients. In an initial study of 41 patients from Wuhan, the blood counts in COVIDpos patients showed leukopenia and lymphopenia, and prothrombin time and D-dimer levels were higher in ICU patients than in non-ICU patients (Huang et al., 2020). Another study based on 343 Wuhan COVIDpos patients found that a D‐dimer level of at least 2.0 µg/mL could predict mortality with a sensitivity of 92.3% and a specificity of 83.3% (Zhang et al., 2020). An independent study of 43 COVID-19 patients found significant differences between mild and severe cases in plasma interleukin‐6 (IL‐6), D‐dimers, glucose, thrombin time, fibrinogen, and C‐reactive protein (p<0.05; Gao et al., 2020). While such studies indeed highlight that hematological and inflammatory abnormalities are prevalent in COVIDpos, a high-resolution temporal understanding of how these parameters evolve in COVID-19 patients post diagnosis has not been established. Specifically, in the wake of accumulating evidence for hypercoagulability in COVIDpos patients, there are important clinical questions emerging regarding the necessity of and guidelines for thromboprophylaxis in patient management.\n\nDIC-like consumptive coagulopathy in COVID-19 has been a point of concern in severely ill COVID-19 patients. Particularly in patients with ARDS, multiple organ dysfunction syndrome (MODS) is the predominant cause of death. A recent study suggested that DIC was associated with MODS during the early stage of ARDS and that persistent DIC may also have a role in this association (Gando et al., 2020). Our study focusing on COVID-19 patients with longitudinal lab data suggests that COVID-19 is indeed associated with modulation of coagulation related parameters such as platelet counts, fibrinogen levels, and clotting time (Figure 2). However, the majority of thrombotic events in COVID-19 patients with longitudinal lab testing are not the result of a DIC-like consumptive coagulopathy, as this only occurs in a small subset (Table 4).\n\nThe ability to derive this longitudinal understanding of COVID-19 progression, including laboratory abnormalities and their associated clinical manifestations, mandates the synthesis of structured and unstructured EHR data (e.g. lab tests and clinical notes) at a large scale. The fact that tens of thousands of patients have undergone SARS-CoV-2 testing at major academic medical centers (AMCs) provides an abundance of potential data to perform this analysis but also poses significant challenges from a practicality standpoint. Manual review and curation of patient trajectories and associated testing results is not practical. It is not likely to provide comprehensive or even entirely accurate individual patient records. Rather, triangulation across datasets, including lab measurements, clinical notes, and prescription information, using a scalable digitized approach to extract structured data along with sentiment-surrounded clinical phenotypes and outcomes enables us to efficiently perform this analysis in a timely fashion.\n\nBy developing and deploying such a digitized platform on the entirety of EHR data from a large AMC, we have identified in an unbiased manner, laboratory test-based abnormalities that differentiate COVIDpos patients from COVIDneg patients. The abnormalities in coagulation-related tests, including fibrinogen and platelets, were intriguing in the context of literature reporting the occurrence of various clotting phenotypes in COVID-19 patients, including DIC-like consumptive coagulopathies along with more isolated clotting events in the lungs, central nervous system, and other tissues (Tang et al., 2020; Klok et al., 2020; Levi et al., 2020). Our finding that consumptive coagulopathy represents a minority of COVID-19 associated clotting events provides context for other studies, which have reported overt DIC or DIC-like disease in over 70% of non-survivors but far lower fractions of survivors (Tang et al., 2020). As the pandemic continues to evolve and the patient counts increase over the coming months, we will be monitoring and reporting any updates to the clinical and laboratory observations drawn in this study.\n\nNotwithstanding the preliminary nature of the analysis presented in this study, the results highlight that consumptive coagulopathy should be considered in the minority of COVIDpos patients with significant serial reductions in platelet counts. It remains to be seen whether the post-diagnosis platelet increases or early hyperfibrinogenemia which we observed may contribute mechanistically to the clotting in the much larger non-DIC thrombotic COVID-19 population. It is important to note that despite the trend of increasing platelets, the platelet count only extended above the normal range (>450×109/L) after the PCR date in few COVIDpos patients with serial measurements, and the development of such outright thrombocytosis was observed with similar frequencies in the thrombotic and non-thrombotic cohorts (Figure 5C). Further, the fact that several patients with elevated fibrinogen (i.e. >400 mg/dL) at presentation did not develop thromboses suggests that early hyperfibrinogenemia is not a singular driver of subsequent clotting events, but a small sample size (n = 10 patients; nine non-thrombotic vs. one thrombotic) limited the power of this analysis (Figure 6).\n\nDespite these caveats, this linking of longitudinal trends to patient outcomes provides several useful pieces of clinical information. First, hyperfibrinogenemia is to be expected in COVID-19 patients around the time of diagnostic testing. Furthermore, declining fibrinogen levels shortly after diagnosis are also expected and likely represent the resolution of acute phase response in most patients rather than a decline secondary to the onset of consumptive coagulation. In addition, borderline or overt thrombocytopenia is common in COVID-19 patients at the time of clinical presentation, and the initial platelet count does not robustly predict patients who are likely to develop thromboses. After diagnosis, COVID-19 patients generally show an upward trend in platelets. Patients whose platelets trend down after diagnosis should be monitored, as platelet reductions after clinical presentation are associated with thromboses and significant reductions may be indicative of ongoing consumptive coagulopathy.\n\nOne unavoidable limitation of this study is that we restrict our analysis to patients which have longitudinal lab testing data available. While the inclusion criteria is naturally biased, we consider this study population to be of high clinical interest because these patients are highly enriched for severe thrombotic events during the study period (see Table 5). Further, in the propensity score matching step of the analysis, we are able to construct a control cohort that is similar to the COVIDpos cohort in these enriched dimensions. To provide additional color on the distinctive attributes of the study population, we provide a summary of the clinical characteristics of the study population versus all patients with PCR tests during the same time period (see Table 7). In addition, we provide the median numbers of lab tests per patient for selected coagulation-related lab tests (fibrinogen, platelets, PTT, APTT, D-dimer) and total lab tests (Tables 8 and 9).\n\nTable 7. General characteristics of patients with SARS-CoV-2 PCR testing.\nGeneral demographic characteristics of all patients who underwent SARS-CoV-2 PCR testing in the Mayo Clinic EHR database from February 15, 2020 to May 28, 2020. Includes summary characteristics for: (A) all patients with at least one SARS-CoV-2 PCR test, and (B) patients with at least one SARS-CoV-2 PCR test and longitudinal testing data available (i.e. patient received the same lab test on 3 separate days within + / − 30 days of PCR testing date).\n\n(A) Demographics of all patients with PCR testing data\t\n\tCOVIDpos\tCOVIDneg\t\nTotal number of patients\t2232\t72,354\t\nGender:\t\t\t\nMale\t1153 (52%)\t31,613 (44%)\t\nFemale\t1074 (48%)\t40,714 (56%)\t\nRace:\t\t\t\nWhite\t1115 (50%)\t62,605 (87%)\t\nBlack\t420 (19%)\t2792 (3.9%)\t\nAsian\t151 (6.8%)\t1719 (2.4%)\t\nAmerican Indian\t29 (1.3%)\t302 (0.42%)\t\nOther\t517 (23%)\t4936 (6.8%)\t\n(B) Demographics of patients with PCR testing data and longitudinal testing data\t\nTest\tUnits\tPerturbation\tOriginal time window\tCount COVIDpos\tCount COVIDneg\tMean COVIDpos\tMean COVIDneg\tCohen's D\tBH-adjusted M-W p-value\t\nActivated Partial Thrombopl Time, P\tsec\t−1 day\tDays 7–9 Post-Dx\t26\t72\t50.1\t38\t0.57\t0.034\t\nActivated Partial Thrombopl Time, P\tsec\t+1 day\tDays 7–9 Post-Dx\t17\t58\t55\t37.5\t0.81\t0.014\t\nActivated Partial Thrombopl Time, P\tsec\t−1 day\tDays 10–12 Post-Dx\t16\t57\t56.9\t38.4\t0.808\t9.10E-03\t\nActivated Partial Thrombopl Time, P\tsec\t+1 day\tDays 10–12 Post-Dx\t15\t60\t56.9\t38\t1.106\t2.60E-03\t\nActivated Partial Thrombopl Time, P\tsec\t−1 day\tDays 13–15 Post-Dx\t15\t52\t55.5\t37.8\t1.041\t0.014\t\nActivated Partial Thrombopl Time, P\tsec\t+1 day\tDays 13–15 Post-Dx\t14\t48\t51.8\t37.1\t0.962\t0.015\t\nActivated Partial Thrombopl Time, P\tsec\t−1 day\tDays 16–30 Post-Dx\t22\t156\t55.2\t37\t0.913\t5.70E-03\t\nActivated Partial Thrombopl Time, P\tsec\t+1 day\tDays 16–30 Post-Dx\t19\t139\t56\t38.2\t0.725\t3.80E-02\t\nFibrinogen, P\tmg/dL\t−1 day\tClinical presentation\t25\t92\t584.9\t370.7\t1.067\t1.20E-04\t\nFibrinogen, P\tmg/dL\t+1 day\tClinical presentation\t37\t292\t488.2\t326.2\t0.885\t8.80E-06\t\nFibrinogen, P\tmg/dL\t−1 day\tDays 1–3 Post-Dx\t41\t381\t494.5\t318\t1.023\t3.90E-07\t\nFibrinogen, P\tmg/dL\t+1 day\tDays 1–3 Post-Dx\t21\t244\t420.3\t312.2\t0.616\t7.90E-03\t\nFibrinogen, P\tmg/dL\t−1 day\tDays 4–6 Post-Dx\t27\t156\t432.2\t336\t0.495\t0.045\t\nFibrinogen, P\tmg/dL\t+1 day\tDays 4–6 Post-Dx\t24\t105\t472.2\t333.2\t0.712\t0.025\t\nPlatelets\t×10(9)/L\t−1 day\tPre-diagnosis\t34\t575\t187.3\t225.6\t−0.357\t0.057\t\nPlatelets\t×10(9)/L\t+1 day\tPre-diagnosis\t118\t1533\t201.3\t234.4\t−0.328\t7.30E-04\t\nTable 8. Lab test data availability in patients with SARS-CoV-2 PCR testing.\nLab test data availability for all patients who underwent SARS-CoV-2 PCR testing in the Mayo Clinic EHR database from February 15, 2020 to May 28, 2020. Includes counts of lab tests and counts of patients with 1+ and 3+ lab tests both overall and for selected coagulation-related lab tests (activated partial thromboplastin time, D-dimer, fibrinogen, platelets, and prothrombin time).\n\n\tCOVIDpos\tCOVIDneg\t\nTotal number of patients\t2232\t72,354\t\nNumber of patients with 1+ lab test\t566 (25%)\t35,188 (49%)\t\nNumber patents with 1+ test from day −30 to day −1\t299 (13%)\t23,116 (32%)\t\nNumber patents with 1+ test from day 0 to day 30\t452 (20%)\t28,666 (40%)\t\nNumber of patients with 3+ lab tests of the same type\t246 (11%)\t13,666 (19%)\t\nTotal number of lab tests\t98,753\t32,40,491\t\nNumber of lab tests from day −30 to day −1\t12,120\t10,33,762\t\nNumber of lab tests from day 0 to day 30\t86,633\t22,06,729\t\nACTIVATED PTT\t\t\nNumber of lab tests\t362\t6042\t\nNumber of patients with 1+ lab test\t93 (4.0%)\t3544 (4.9%)\t\nNumber of patients with 3+ lab tests\t20 (0.86%)\t406 (0.56%)\t\nD-DIMER, P\t\t\nNumber of lab tests\t911\t2846\t\nNumber of patients with 1+ lab test\t247 (11%)\t2395 (3.3%)\t\nNumber of patients with 3+ lab tests\t99 (4.4%)\t56 (0.077%)\t\nFIBRINOGEN, P\t\t\nNumber of lab tests\t278\t3,017\t\nNumber of patients with 1+ lab test\t84 (3.8%)\t1217 (1.7%)\t\nNumber of patients with 3+ lab tests\t18 (0.81%)\t273 (0.38%)\t\nPLATELETS\t\t\nNumber of lab tests\t2646\t1,08,722\t\nNumber of patients with 1+ lab test\t500 (22%)\t30,732 (42%)\t\nNumber of patients with 3+ lab tests\t231 (10%)\t11544 (16%)\t\nPROTHROMBIN TIME, P\t\t\nNumber of lab tests\t711\t28,007\t\nNumber of patients with 1+ lab test\t197 (8.8%)\t10,446 (14%)\t\nNumber of patients with 3+ lab tests\t46 (2.1%)\t2502 (3.5%)\t\nTable 9. Lab test data availability in patients with SARS-CoV-2 PCR testing and longitudinal lab data.\nLab test data availability for all patients who underwent SARS-CoV-2 PCR testing in the Mayo Clinic EHR database from February 15, 2020 to May 28, 2020 with longitudinal testing data available (i.e. patient received the same lab test on three separate days within + / − 30 days of PCR testing date). Includes counts of lab tests and counts of patients with 1+ and 3+ lab tests both overall and for selected coagulation-related lab tests (activated partial thromboplastin time, D-dimer, fibrinogen, platelets, and prothrombin time).\n\n\tCOVIDpos\tCOVIDneg\t\nTotal number of patients\t246\t13,666\t\nNumber patents with 1+ test from day −30 to day −1\t150 (61%)\t11,567 (85%)\t\nNumber patents with 1+ test from day 0 to day 30\t240 (98%)\t13,501 (99%)\t\nTotal number of lab tests\t89,587\t2,634,070\t\nNumber of lab tests from day −30 to day −1\t8698\t763,808\t\nNumber of lab tests from day 0 to day 30\t80,889\t1,870,262\t\nACTIVATED PTT\t\t\t\nNumber of lab tests\t355\t5186\t\nNumber of patients with 1+ lab test\t86 (35%)\t2722 (20%)\t\nNumber of patients with 3+ lab tests\t20 (8.1%)\t406 (3.0%)\t\nD-DIMER, P\t\t\t\nNumber of lab tests\t855\t1720\t\nNumber of patients with 1+ lab test\t197 (80%)\t1293 (9.5%)\t\nNumber of patients with 3+ lab tests\t99 (40%)\t56 (0.41%)\t\nFIBRINOGEN, P\t\t\t\nNumber of lab tests\t275\t2965\t\nNumber of patients with 1+ lab test\t81 (33%)\t1168 (8.5%)\t\nNumber of patients with 3+ lab tests\t18 (7.3%)\t273 (2%)\t\nPLATELETS\t\t\t\nNumber of lab tests\t2343\t87,517\t\nNumber of patients with 1+ lab test\t245 (100%)\t13,399 (98%)\t\nNumber of patients with 3+ lab tests\t231 (94%)\t11,544 (84%)\t\nPROTHROMBIN TIME, P\t\t\t\nNumber of lab tests\t676\t24,489\t\nNumber of patients with 1+ lab test\t165 (67%)\t7209 (53%)\t\nNumber of patients with 3+ lab tests\t46 (19%)\t2502 (18%)\t\nIt is important to note that while we center the study period around the PCR testing date, this date may not correspond to the same disease state of COVID-19 for each individual in the COVIDpos cohort. To account for the potential variability in disease progression, we have performed a sensitivity analysis on the time intervals (Table 3). Additionally, there are several covariates that may influence these longitudinal trends and should be explored further. For example, we have already considered whether previous or concomitant administration of anticoagulants or antiplatelet agents influences patient lab test results and/or outcomes. Similarly, in the future, we intend to explore whether longitudinal lab measurement trends differ between outpatient, inpatient, and ICU admitted patient cohorts. New datasets can also be utilized; for example, rather than grouping patients by the identified thromboembolic phenotypes extracted from the clinical notes alone, patients could be stratified by those who had imaging studies (duplex ultrasound, CT scan, etc.) performed, and phenotypes could be directly extracted from these procedural reports. As more data accumulates from COVIDpos and COVIDneg patients in the coming months, these analyses need to be expanded to assess similarities and differences in the temporal trends of laboratory test results among a wider range of patient subgroups relevant for COVID-19 outcomes, such as those who have pre-existing conditions (e.g. diabetes, hypertension, obesity, malignancies) or patients who are on specific medication (e.g. ACE inhibitors, statins, immunosuppressants).\n\nIn summary, this work demonstrates significant progress toward enabling scaled and digitized analyses of longitudinal unstructured and structured EHRs to identify variables (e.g. laboratory results) which are associated with relevant clinical phenotypes (e.g. COVID-19 diagnosis and outcomes). In doing so, we identified trends in lab test results which may be relevant to monitor in COVID-19 patients and warrant both clinical and mechanistic follow-up in more targeted and explicitly controlled prospective analyses.\n\nMaterials and methods\nStudy design, setting and patient population\nThis is a retrospective study of patients who underwent polymerase chain reaction (PCR) testing for suspected SARS-CoV-2 infection at the Mayo Clinic and hospitals affiliated to the Mayo health system. This research was conducted under IRB 20–003278, ‘Study of COVID-19 patient characteristics with augmented curation of Electronic Health Records (EHR) to inform strategic and operational decisions’. For further information regarding the Mayo Clinic Institutional Review Board (IRB) policy, and its institutional commitment, membership requirements, review of research, informed consent, recruitment, vulnerable population protection, biologics, and confidentiality policy, please refer to www.mayo.edu/research/institutional-review-board/overview.\n\nLongitudinal lab testing tied to COVID-19 PCR diagnostic testing\nWe analyzed data from 74,586 patients who received PCR tests from the Mayo Clinic between February 15, 2020 to May 28, 2020. Among this population, 2232 patients had at least one positive SARS-CoV-2 PCR test result, and 72,354 patients had all negative PCR test results. In order to align the data for the analysis of aggregate longitudinal trends, we selected a reference date for each patient. For patients in the COVIDpos cohort, we used the date of the first positive PCR test result as the reference date (day = 0). For patients with all negative PCR tests, we used the date of the first PCR test result as the reference date (day = 0). We defined the study period for each patient to be 30 days before and after the PCR testing date. Patients with contradictory PCR test results were excluded for the purpose of this analysis; for example, a positive PCR test result and a negative PCR test result on the same day, or a positive PCR test result followed immediately by several negative PCR test results.\n\nOver 4 million test results from 6298 different types of lab tests were recorded for the patients who received PCR tests in the 60-day window surrounding their PCR testing dates at the Mayo Clinic campuses in Minnesota, Arizona, and Florida. Among these lab tests, we restricted our analysis to 194 tests with at least 1000 observations total and at least 10 observations from the COVIDpos cohort among the patients with PCR testing on or before May 8, 2020. In addition, we considered different subsets of the COVIDpos cohort for the analysis of each of the 194 lab tests, due to differences in availability of testing results. For each lab test, we consider the results from patients with three or more observations during the study period.\n\nIn the end, there are 246 SARS-COV-2 positive and 13,666 SARS-CoV-2 negative patients that had three or more test results during the study period for at least one of the assays among the 194 lab tests considered. We take this set of 246 COVID-19 positive patients to be the COVIDpos cohort. In order to construct the COVIDneg cohort from the 13,666 COVID-19 negative patients, we apply propensity score matching, which is described in the next section.\n\nPropensity score matching to select the final COVIDneg cohort\nTo construct a COVIDneg cohort similar in baseline clinical covariates to the COVIDpos cohort, we employ 1:10 propensity score matching (Austin, 2011). In particular, first we trained a regularized logistic regression model to predict the likelihood that each patient will have a positive or negative COVID-19 test result, using the following covariates: demographics (age, gender, race), anticoagulant/antiplatelet medication use (orders for alteplase, antithrombin III, apixaban, argatroban, aspirin, bivalirudin, clopidogrel, dabigatran, dalteparin, enoxaparin, eptifibatide, heparin, rivaroxaban, warfarin in the past year and in the past 30 days), pre-existing coagulopathies (medical history of thrombotic phenotypes including: deep vein thrombosis, pulmonary embolism, myocardial infarction, venous thromboembolism, thrombotic stroke, cerebral venous thrombosis, and disseminated intravascular coagulation from day −365 to day −31 relative to the PCR testing date), and hospitalization status (i.e. whether or not the patient was hospitalized within the past 30 days of PCR testing).\n\nUsing the predictions from the logistic regression model as propensity scores, we then matched each of the 246 patients in the COVIDpos cohort to 10 patients out of the 13,666 COVID-19 negative patients, using greedy nearest-neighbor matching without replacement (Austin, 2011; Austin, 2014). As a result, we ended up with a final COVIDneg cohort that included 2460 patients with similar baseline characteristics to the COVIDpos cohort. The characteristics of the two cohorts are summarized in Table 1.\n\nFurther, for the analyses conducted on individual lab tests, which include only a subset of patients from the COVIDpos cohort, we use the propensity scores to match each patient from the COVIDpos cohort to 10 patients from the COVIDneg cohort which have the most similar propensity scores and lab tests available. For example, for the fibrinogen lab test, in which we have data on 81 patients from the COVIDpos cohort, we select 810 patients from the COVIDneg cohort and the most similar propensity scores to be the control group. In this way, we ensure that all of the comparisons are done between subsets of the positive and negative cohorts with similar propensity scores, and therefore similar underlying characteristics.\n\nStatistical significance assessments for lab test differences over prognostic time intervals for SARS-CoV-2 infection\nWe conduct a systematic statistical analysis to identify tests that show significant differentiation among the COVIDpos cohort during a set of predetermined prognostic time intervals for SARS-CoV-2 infection. In particular, we group the lab test measurements for each patient into the following nine time intervals relative to their date of PCR testing: pre-infection (days −30 to −11), pre-PCR (days −10 to −2), time of clinical presentation (days −1 to 0), and post-PCR phases 1 (days 1 to 3), 2 (days 4 to 6), 3 (days 7 to 9), 4 (days 10 to 12), 5 (days 13 to 15), and 6 (days 16 to 30).\n\nFor each lab test and for each of each of our nine pre-specified time intervals, we compared the mean lab test value among patients who underwent at least one such lab test in the COVIDpos cohort over that time interval to the mean lab test value in the COVIDneg (matched) cohort over that time window. We only considered (lab test, time interval) pairs in which there were at least three patients contributing to laboratory test results in both groups. Specifically, for each (lab test, time interval) pair, we conducted the following procedure:\n\nCompute (patient, time interval) averages: We compute the average lab test values for each patient in the COVIDpos and COVIDneg (matched) cohorts during the specified time interval.\n\nStatistical hypothesis testing: We conduct a Mann-Whitney U test in order to test the null hypothesis that the average lab test results for each of the (patient, time interval) pairs from the COVIDpos and COVIDneg (matched) cohorts come from the same distribution. In addition, we compute the Cohen’s D statistic as a measure of the effect size.\n\nOnce we have the statistics and p-values for each (test, time window) pair, in order to account for multiple hypotheses, we apply the Benjamini-Hochberg (BH) procedure with FDR controlled at 0.05. The results from the systematic comparisons which met our thresholds for effect size and statistical significance (Cohen’s D > 0.35, BH-adjusted Mann-Whitney p-value <0.05) are shown in Table 2.\n\nSensitivity analysis to assess the impact of perturbed clinical time windows\nWe perform a sensitivity analysis to assess whether or not the key findings from the systematic statistical assessment remain the same if we perturb the considered time intervals. In particular, we repeat the statistical analysis with the time intervals shifted forward or backward 1 day for all patients. For the forward shifted sensitivity analysis, the new time intervals under consideration are: pre-infection (days −30 to −10), pre-PCR (days −9 to −1), time of clinical presentation (days 0 to 1), and post-PCR phases 1 (days 2 to 4), 2 (days 5 to 7), 3 (days 8 to 10), 4 (days 11 to 13), 5 (days 14 to 16), and 6 (days 17 to 30). For the backward shifted sensitivity analysis, the new time intervals under consideration are: pre-infection (days −30 to −12), pre-PCR (days −11 to −3), time of clinical presentation (days −2 to −1), and post-PCR phases 1 (days 0 to 2), 2 (days 3 to 5), 3 (days 6 to 8), 4 (days 9 to 11), 5 (days 12 to 14), and 6 (days 15 to 30). For both the forward and backward sensitivity analyses, we apply the same thresholds of effect size and significance (Cohen’s D > 0.35, BH-adjusted Mann-Whitney p-value <0.05), and we compare the results to the original time intervals.\n\nFrom this analysis, we observe consistent results (i.e. comparisons meeting same criteria of significance and effect) on (i) both perturbations in 83 out of 130 (64%) lab test trends identified in Table 2 and (ii) at least one perturbation in 114 of 130 (87%) lab test trends. In Table 3, we report the specific results of the time shifted windows for five coagulation-related lab tests (fibrinogen, platelets, prothrombin time, activated partial thromboplastin time, and D-dimer).\n\nAugmented curation of anticoagulant administration and the coagulopathy outcomes from the unstructured clinical notes and their triangulation to structured EHR databases\nA state-of-the-art BERT-based neural network (Devlin et al., 2018) was previously developed to classify sentiment regarding a diagnosis in the EHR (Wagner et al., 2020). Sentences containing phenotypes were classified into the following categories: Yes (confirmed diagnosis), No (ruled out diagnosis), Maybe (possibility of disease), and Other (alternate context, e.g. family history of disease). The neural network used to perform this classification was trained using nearly 250 different phenotypes and 18,500 sentences and achieves 93.6% overall accuracy and over 95% precision and recall for Yes/No sentiment classification (Wagner et al., 2020). Here, this model was used to classify the sentiment around coagulopathies in the unstructured text of the 246 COVIDpos and 13,666 COVIDneg patients’ clinical notes, structuring this information so that it could be compiled with longitudinal lab measurement and medication information.\n\nIn particular, we used the BERT model to identify the seven coagulopathy phenotypes mentioned in clinical notes in the Mayo Clinic EHR database, including: deep vein thrombosis, pulmonary embolism, myocardial infarction, venous thromboembolism, thrombotic stroke, cerebral venous thrombosis, and disseminated intravascular coagulation. We validated the performance of this model for these phenotypes on a set of 1000 randomly selected sentences from the clinical notes of the patients in the study population. In Table 6, we report the out-of-sample accuracy metrics for the BERT model on this set of sentences, using manually curated labels provided by one of the study’s authors (CP) to be the ground truth. We demonstrate that the model performs well in the task of identifying thrombotic phenotypes in clinical notes, with an overall accuracy of 94.7%, recall of 97.8%, and precision of 92.8%.\n\nAcknowledgements\nThe authors thank Mathai Mammen, James List, JoAnne Foody, Patrick Lenehan, Murali Aravamudan, Rakesh Barve, Sankar Ardhanari, and Vishy Thiagarajan, for their helpful feedback.\n\nAdditional information\nCompeting interests\nThis author is an employee of nference with financial interests in the company.\n\nThis author is an employee of nference with financial interests in the company.\n\nThis author is an employee of nference with financial interests in the company.\n\nThis author is an employee of nference with financial interests in the company.\n\nThis author is an employee of nference with financial interests in the company.\n\nThis author is an employee of nference with financial interests in the company.\n\nOne or more of the investigators associated with this project and Mayo Clinic have a Financial Conflict of Interest in technology used in the research and that the investigator(s) and Mayo Clinic may stand to gain financially from the successful outcome of the research. Mayo Clinic is an investor in nference. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies.\n\nOne or more of the investigators associated with this project and Mayo Clinic have a Financial Conflict of Interest in technology used in the research and that the investigator(s) and Mayo Clinic may stand to gain financially from the successful outcome of the research. Mayo Clinic is an investor in nference. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies.\n\nOne or more of the investigators associated with this project and Mayo Clinic have a Financial Conflict of Interest in technology used in the research and that the investigator(s) and Mayo Clinic may stand to gain financially from the successful outcome of the research. Mayo Clinic is an investor in nference. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies.\n\nOne or more of the investigators associated with this project and Mayo Clinic have a Financial Conflict of Interest in technology used in the research and that the investigator(s) and Mayo Clinic may stand to gain financially from the successful outcome of the research. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies. The author is also involved in the Mayo Clinic Laboratories.\n\nOne or more of the investigators associated with this project and Mayo Clinic have a Financial Conflict of Interest in technology used in the research and that the investigator(s) and Mayo Clinic may stand to gain financially from the successful outcome of the research. Mayo Clinic is an investor in nference. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies.\n\nOne or more of the investigators associated with this project and Mayo Clinic have a Financial Conflict of Interest in technology used in the research and that the investigator(s) and Mayo Clinic may stand to gain financially from the successful outcome of the research. Mayo Clinic is an investor in nference. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies.\n\nOne or more of the investigators associated with this project and Mayo Clinic have a Financial Conflict of Interest in technology used in the research and that the investigator(s) and Mayo Clinic may stand to gain financially from the successful outcome of the research. Mayo Clinic is an investor in nference. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies.\n\nOne or more of the investigators associated with this project and Mayo Clinic have a Financial Conflict of Interest in technology used in the research and that the investigator(s) and Mayo Clinic may stand to gain financially from the successful outcome of the research. Mayo Clinic is an investor in nference. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies.\n\nThis author is an employee of the Janssen pharmaceutical companies of J&J with financial interests in the company.\n\nThis author is an employee of the Janssen pharmaceutical companies of J&J with financial interests in the company.\n\nThis author is an employee of the Janssen pharmaceutical companies of J&J with financial interests in the company.\n\nThe author is an employee of nference and has financial interests in the company. Outside the submitted work, Venky Soundararajan is listed as inventor of the following patent: \"Systems, methods, and computer readable media for visualization of semantic information and inference of temporal signals indicating salient associations between life science entities\" (US20180082197A1).\n\nAuthor contributions\nFormal analysis, Validation, Investigation, Methodology, Writing - original draft, Writing - review and editing.\n\nFormal analysis, Supervision, Validation, Investigation, Methodology, Writing - original draft, Project administration, Writing - review and editing.\n\nSoftware, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - review and editing.\n\nSoftware, Formal analysis, Validation, Investigation, Methodology, Writing - review and editing.\n\nFormal analysis, Supervision, Investigation, Methodology, Project administration.\n\nFormal analysis, Validation, Investigation, Methodology, Writing - review and editing.\n\nSupervision, Validation, Investigation, Methodology, Writing - original draft, Project administration, Writing - review and editing.\n\nFormal analysis, Supervision, Validation, Investigation, Methodology, Project administration, Writing - review and editing.\n\nSupervision, Investigation, Project administration, Writing - review and editing.\n\nSupervision, Investigation, Methodology, Project administration.\n\nSupervision, Investigation, Project administration, Writing - review and editing.\n\nSupervision, Investigation, Project administration, Writing - review and editing.\n\nSupervision, Project administration.\n\nSupervision, Validation, Project administration, Writing - review and editing.\n\nSupervision, Validation, Investigation, Methodology, Writing - review and editing.\n\nSupervision, Validation, Investigation, Methodology, Writing - review and editing.\n\nConceptualization, Resources, Formal analysis, Supervision, Validation, Investigation, Methodology, Writing - review and editing.\n\nConceptualization, Resources, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Methodology, Writing - original draft, Writing - review and editing.\n\nEthics\nHuman subjects: This research was conducted under IRB 20-003278, \"Study of COVID-19 patient characteristics with augmented curation of Electronic Health Records (EHR) to inform strategic and operational decisions\". All analysis of EHRs was performed in the privacy-preserving environment secured and controlled by the Mayo Clinic. nference, the Mayo Clinic, and the Janssen pharmaceutical companies of Johnson & Johnson (J&J) subscribe to the basic ethical principles underlying the conduct of research involving human subjects as set forth in the Belmont Report and strictly ensure compliance with the Common Rule in the Code of Federal Regulations (45 CFR 46) on the Protection of Human Subjects.\n\nAdditional files\nTransparent reporting form Data availability\nDe-identified data will be made available upon reasonable request to the corresponding author (Venky Soundararajan, venky@nference.net).\n\n10.7554/eLife.59209.sa1\nDecision letter\nvan de Veerdonk Frank L Reviewing EditorRadboud University Medical CenterNetherlands\n Maas Coen ReviewerUniversity Medical Center UtrechtNetherlands\n Chen Jinbo ReviewerUniversity of PennsylvaniaUnited States\n In the interests of transparency, eLife publishes the most substantive revision requests and the accompanying author responses.\n\nAcceptance summary:\n\nThe paper analyzes a large EHR-based dataset of coagulation tests in COVID-19 patients to obtain an understanding of the kinetics of COVID-19 associated coagulopathy. By using machine learning to extract patterns data are provided which support that the majority of thrombotic events in COVID-19 patients are not the result of a DIC-like consumptive coagulopathy, and that this only occurs in a small subset.\n\nDecision letter after peer review:\n\nThank you for submitting your article \"Longitudinal laboratory testing tied to PCR diagnostics in COVID-19 patients reveals temporal evolution of coagulopathy\" for consideration by eLife. Your article has been reviewed by four peer reviewers, and the evaluation has been overseen by a Reviewing Editor and Jos van der Meer as the Senior Editor. The following individuals involved in review of your submission have agreed to reveal their identity: Coen Maas (Reviewer #1); Jinbo Chen (Reviewer #4).\n\nThe reviewers have discussed the reviews with one another and the Reviewing Editor has drafted this decision to help you prepare a revised submission.\n\nWe would like to draw your attention to changes in our revision policy that we have made in response to COVID-19 (https://elifesciences.org/articles/57162). Specifically, when editors judge that a submitted work as a whole belongs in eLife but that some conclusions require a modest amount of additional new data, as they do with your paper, we are asking that the manuscript be revised to either limit claims to those supported by data in hand, or to explicitly state that the relevant conclusions require additional supporting data.\n\nOur expectation is that the authors will eventually carry out the additional experiments and report on how they affect the relevant conclusions either in a preprint on bioRxiv or medRxiv, or if appropriate, as a Research Advance in eLife, either of which would be linked to the original paper.\n\nSummary:\n\nThe authors analyze a large EHR-based dataset of coagulation tests in COVID-19 patients to obtain an understanding of the kinetics of COVID-19 associated coagulopathy. It is a clear approach and the data are important for the clinics. They used machine learning to extract patterns. Overall the conclusions were drawn in many directions. Nonetheless, the paper asks a potentially important question and is adequately written and presented. The data support that the majority of thrombotic events in COVID-19 patients are not the result of a DIC-like consumptive coagulopathy, this only occurs in a small subset. This should also be the focus of the Discussion.\n\nEssential revisions:\n\nPatient characteristics:\n\n– Please clinically define \"pre-existing coagulopathies\".\n\n– It is a unclear what the comparator cohort adds: In part it is not clear who these patients are. Perhaps the controls should be age/sex-matched patients with other causes of hypoxemic respiratory failure/pneumonia? Or different COVID-19 disease severity subgroups? Otherwise what are we inferring from comparing these two groups?\n\n– Ascertained rates of venous thromboembolism are much lower than what others have observed (e.g., Helms ICM 2020, Middeldorp pre-prints, etc.). Could this relate to ascertainment bias in this cohort? Perhaps a push not to perform diagnostic imaging studies lead to lower objective identification of venous thromboembolism than has been generally described in COVID-19?\n\n– Patients are identified as COVID-19 positive or negative based on PCR testing. Actually, using the PCR test a positive/negative infection by SARS-CoV-2 is assessed; COVID-19 is the disease that can follow upon infection. This distinction should be made clear, as not all patients tested positive for SARS-CoV-2 infection necessarily develop COVID-19. What was the guideline followed for PCR-testing: displaying COVID-19 symptoms/ contact with infected persons/ other? This should also be explained and included.\n\n– Introduction: \"… straddling the date of the PCR test.…\" Do the authors refer to the first PCR test here, as it is mentioned that multiple PCR tests may have been performed? Please include a definition.\n\nAnalysis:\n\n– The analysis was restricted to patients who had serial (>/= 3) tests done. This could have led to a survival bias which should be acknowledged.\n\n– This restriction also led to the exclusion of the vast majority of the cohort: 1,192 -> 181 COVID-19pos patients. Why was there such a strong emphasis on longitudinal markers?\n\n– The potential significance of these longitudinal trends are assessed with these tests as far as I can understand, which both only looks to see whether mean/median change was different between the groups, but moreover does not allow for adjustment. Why not use multilevel regression mixture models, longitudinal regression, etc?\n\n– One of the three covariates used in the regularized logistic regression model to predict the likelihood of a positive infection (subsection “Propensity score matching to select the final COVIDneg cohort”) is anticoagulant/antiplatelet medication use. Is this covariate positively or negatively correlated to infection and what is the rationale for this? Table 1 comprises more details; however, these add to further confusion. The Table 1 legend states \"anticoagulant/antiplatelet use within 30 days/1 year of PCR testing date\" i.e. after the PCR test, while the table itself mentions \"medication use in the preceding 30 days/1yr\", so before the PCR test. Please clarify and adapt.\n\nFigures:\n\n– Figure 2A: Why are no data points provided for the -30 to 0 days of the COVID negative patients while these data are shown in Figure 2B and E?\n\n– The same question as above but then for the APTT and D-dimer data in Figure 2 vs. Figure 3 and magnesium in Figure 1 vs. Figure 3. I guess the cohorts are different between the two figures, maybe this should be stated in the figure legends.\n\n– Figure 3: we agree with the authors that the fibrinogen decline and platelet increase in COVID positive patients is re-emphasized in this manner. Also the increase in magnesium and decrease in alkaline phosphatase seem to stand out. Could the authors comment on this?\n\n– Could the authors comment on the number of thrombotic events that were radiographically-confirmed?\n\n– Figure 5: for the individual patients could the authors comment on the heparin therapy with regard to the source of heparin (LMWH vs. UFH) and dosing (prophylactic vs. therapeutic)?\n\n– Figure 6 is very hard to understand; please find another way to graphically display the findings in a clear manner.\n\nSpecific statistical comments:\n\n1) Cohort identification and description. (a) For the 1.3 million lab tests on 194 assays over the 60-day window: provide the mean/range of number of tests separately for positive and negative patients, and also provide the mean/range of the number of tests for pre- vs. post-index \"0\" date; (b) For positive patients, the proportion of those whose PCR positive test is the first test in the 60-day window; (c) If at all possible, COVID-19 related info at the first PCR test for all patients; (4) If possible, reasons for hospitalizations at the day=0;\n\n2) It is not clear why it is important to assess lab tests in relation to diagnosis. For studying association between lab tests with diagnosis, ideally, the positive cases should use the \"time of infection\" as time zero which of course is intractable. But before variation in time from infection to diagnosis by PCR tests, the relevance of test results for diagnosis is unclear. Further, because of the propensity score matching, the cohort may not be suitable for assess the diagnosis: if some matching variables are associated with any of the test results, matching will artificially deflate the association. We therefore suggest the focus of this paper on prognosis only. The Abstract indeed focused on the prognosis, but diagnosis was mentioned multiple times in the manuscript.\n\n3) BERT method: The accuracy of BERT was established in an unpublished manuscript developed by the same research group. What is the proportion of patients who were classified as \"Maybe\", \"Yes\" AND \"No\"? It is helpful if chart review is performed on 100, say, patients, to validate this algorithm in the study context;\n\n4) Tables 3 and 4 indicate that the endpoints were significantly enriched for positive cases who had longitudinal data. But it is possible that patients received more tests because of indications of more negative outcomes. As a result, patients with longitudinal lab tests are representative of all positive patients as indicated by the enrichment. This is an important weakness of the study as this may be a source of bias, making the study results not generalizable. It is important to provide additional information on the comparing characteristics of patients with and without longitudinal tests. It may be worthwhile to provide information on reasons of repeating tests for negative patients.\n\n10.7554/eLife.59209.sa2\nAuthor response\nSummary:\n\nThe authors analyze a large EHR-based dataset of coagulation tests in COVID-19 patients to obtain an understanding of the kinetics of COVID-19 associated coagulopathy. It is a clear approach and the data are important for the clinics. They used machine learning to extract patterns. Overall the conclusions were drawn in many directions. Nonetheless, the paper asks a potentially important question and is adequately written and presented. The data support that the majority of thrombotic events in COVID-19 patients are not the result of a DIC-like consumptive coagulopathy, this only occurs in a small subset. This should also be the focus of the Discussion.\n\nWe thank the editors for their advice to focus the key conclusion of the paper. Accordingly, we have revised the manuscript’s Discussion section to reflect this suggestion. We find that the updated data for this manuscript also support this conclusion that DIC-like consumptive coagulopathy is relatively rare among COVID-19 patients, as shown in updated Table 3.\n\nEssential revisions:\n\nPatient characteristics:\n\n– Please clinically define \"pre-existing coagulopathies\".\n\nWe consider the following phenotypes to be coagulopathies: deep vein thrombosis, pulmonary embolism, myocardial infarction, venous thromboembolism, thrombotic stroke, cerebral venous thrombosis, and disseminated intravascular coagulation. We have added a definition of pre-existing coagulopathies to the Introduction, which includes all patients who have at least one of the phenotypes from days -365 to -31 relative to the PCR testing date. In Table 1 of the revised manuscript, we have now added in the medical history of thrombotic events for the patients in the COVID-19 positive, negative, and negative (matched) cohorts.\n\n– It is a unclear what the comparator cohort adds: In part it is not clear who these patients are. Perhaps the controls should be age/sex-matched patients with other causes of hypoxemic respiratory failure/pneumonia? Or different COVID-19 disease severity subgroups? Otherwise what are we inferring from comparing these two groups?\n\nThe comparator cohort was selected to match the COVIDpos cohort on a variety of clinical characteristics which may be confounding variables for thrombotic events and related lab tests that we observe during the study period. The clinical covariates that we controlled for initially included demographics (age, gender, race), hospitalization status, and anticoagulant/antiplatelet use, which can be viewed as a proxy variable for medical history of thrombotic events. In this revision, we have explicitly added in medical history of thrombotic events as clinical covariates to balance on, as shown in the updated Table 1 of the revised manuscript. We have added a few statements describing the updated COVIDneg (matched) cohort to the last paragraph of the Introduction.\n\n– Ascertained rates of venous thromboembolism are much lower than what others have observed (e.g., Helms ICM 2020, Middeldorp pre-prints, etc.). Could this relate to ascertainment bias in this cohort? Perhaps a push not to perform diagnostic imaging studies lead to lower objective identification of venous thromboembolism than has been generally described in COVID-19?\n\nOur study presents, for the first time, fine grained temporal resolution into lab results change in all COVIDpos patients. In particular, our study is not restricted to severe MODS or ARDS patients, as has been the focus of previous studies such as Helms ICM 2020, Middeldorp preprints, or https://pubmed.ncbi.nlm.nih.gov/32353745/ etc. We expect that this is the reason for the differences in venous thromboembolism rate reported across the different studies.\n\n– Patients are identified as COVID-19 positive or negative based on PCR testing. Actually, using the PCR test a positive/negative infection by SARS-CoV-2 is assessed; COVID-19 is the disease that can follow upon infection. This distinction should be made clear, as not all patients tested positive for SARS-CoV-2 infection necessarily develop COVID-19. What was the guideline followed for PCR-testing: displaying COVID-19 symptoms/ contact with infected persons/ other? This should also be explained and included.\n\nAs recommended by the reviewers, the distinction between SARS-CoV-2 infection and the COVID-19 disease onset and progression has been clarified in the revised paper. The guidelines followed for PCR-testing included all of the following – displaying COVID-19 symptoms, contact with infected persons, and other factors such as potential work-place/community exposure as well as underlying conditions predisposing to SARS-CoV-2 infection. This has been noted in the second paragraph of the Introduction section of the manuscript.\n\n– Introduction: \"… straddling the date of the PCR test.…\" Do the authors refer to the first PCR test here, as it is mentioned that multiple PCR tests may have been performed? Please include a definition.\n\nWe have added a statement to the Introduction, clarifying this point. For the COVIDpos cohort, we center the two month observation period around the date of the first positive PCR test for SARS-CoV-2, and for the COVIDneg cohort, we center the two month observation period around the date of the first PCR test for SARS-CoV-2.\n\nAnalysis:\n\n– The analysis was restricted to patients who had serial (>/= 3) tests done. This could have led to a survival bias which should be acknowledged.\n\nWe thank the reviewers for raising this point. We have added in a statement on potential survival bias to the Discussion section. In particular, we now provide a summary of the clinical characteristics of the study population vs. all patients with PCR tests during the same time period in Table 6. We have also included an additional table characterizing the key lab tests and their availability for the study population vs. all patients (see Tables 7-8).\n\n– This restriction also led to the exclusion of the vast majority of the cohort: 1,192 -> 181 COVID-19pos patients. Why was there such a strong emphasis on longitudinal markers?\n\nThe need for longitudinal data on the testing results, while constraining the study population size greatly, enables us to provide a fine-grained temporal resolution of COVID-associated coagulopathy for the first time. In addition, we consider this study population to be of high clinical interest because these patients are highly enriched for severe thrombotic events during the study period (see Table 4). We have added this in as a point in the seventh paragraph of the Discussion section.\n\n– The potential significance of these longitudinal trends are assessed with these tests as far as I can understand, which both only looks to see whether mean/median change was different between the groups, but moreover does not allow for adjustment. Why not use multilevel regression mixture models, longitudinal regression, etc?\n\nThank you for the suggestion. We considered logistic regression for this analysis, to predict the presence/absence of thrombotic events using the longitudinal lab testing information available for each patient prior to the PCR testing date Day 0. However, due to large heterogeneity in lab tests conducted for the study population, and the relative sparsity of lab testing data available for the COVIDpos population prior to Day 0, we were unable to train an accurate predictive model using the available data. However, we expect that as additional data becomes available this is a promising area for future research, and we have added a note on this in the Discussion section.\n\n– One of the three covariates used in the regularized logistic regression model to predict the likelihood of a positive infection (subsection “Propensity score matching to select the final COVIDneg cohort”) is anticoagulant/antiplatelet medication use. Is this covariate positively or negatively correlated to infection and what is the rationale for this? Table 1 comprises more details; however, these add to further confusion. The Table 1 legend states \"anticoagulant/antiplatelet use within 30 days/1 year of PCR testing date\" i.e. after the PCR test, while the table itself mentions \"medication use in the preceding 30 days/1yr\", so before the PCR test. Please clarify and adapt.\n\nWe observe that anticoagulant/antiplatelet use is negatively correlated with SARS-CoV-2 infection (see Table 1). We hypothesize that the reason for this is that patients who are on anticoagulants/antiplatelets generally have more underlying conditions and thus take more precautionary measures to avoid SARS-CoV-2 infection. In addition, Table 1 shows anticoagulant/antiplatelet use in the 30 days/1 year prior to the PCR testing date. We have revised the name of this covariate in Table 1 for clarification.\n\nFigures:\n\n– Figure 2A: Why are no data points provided for the -30 to 0 days of the COVID negative patients while these data are shown in Figure 2B and E?\n\nIn the revised manuscript, Figure 2A has been renamed to Figure 3A. This plot, which shows the temporal trends of the Fibrinogen lab tests, has no data points between days -30 to 0 because none of the patients in the COVIDpos cohort had Fibrinogen lab test results reported during this time range. For all of the temporal trend plots, we only show data points for which there are at least 3 patients in the COVIDpos and COVIDneg cohorts. We have clarified this in the legends for the updated Figures 1, 2, and 3, and 4.\n\n– The same question as above but then for the APTT and D-dimer data in Figure 2 vs. Figure 3 and magnesium in Figure 1 vs. Figure 3. I guess the cohorts are different between the two figures, maybe this should be stated in the figure legends.\n\nThe cohorts are different because the previous Figure 3 (now Figure 4) is restricted to patients with 3 or more lab tests during the study period, while the previous Figures 1 and 2 (now Figures 1, 2, 3) include patients with 1 or more lab tests during the study period. We have added this statement to the figure legends for clarification.\n\n– Figure 3: we agree with the authors that the fibrinogen decline and platelet increase in COVID positive patients is re-emphasized in this manner. Also the increase in magnesium and decrease in alkaline phosphatase seem to stand out. Could the authors comment on this?\n\nWe agree that the increases in magnesium and alkaline phosphatase do seem significant. We are planning to explore this trend in future analyses.\n\n– Could the authors comment on the number of thrombotic events that were radiographically-confirmed?\n\nWe do not have the radiology reports available in this dataset, so unfortunately we cannot comment on the number of radiographically confirmed events.\n\n– Figure 5: for the individual patients could the authors comment on the heparin therapy with regard to the source of heparin (LMWH vs. UFH) and dosing (prophylactic vs. therapeutic)?\n\nWe have added annotations to Figure 5 indicating which medications were prescribed for prophylaxis. In addition, we have updated the Results section to include a note on these results.\n\n– Figure 6 is very hard to understand; please find another way to graphically display the findings in a clear manner.\n\nIn order to keep the paper focused on clinical data, we have now excluded the previous Figure 6, which was based on single cell data.\n\nSpecific statistical comments:\n\n1) Cohort identification and description. (a) For the 1.3 million lab tests on 194 assays over the 60-day window: provide the mean/range of number of tests separately for positive and negative patients, and also provide the mean/range of the number of tests for pre- vs. post-index \"0\" date; (b) For positive patients, the proportion of those whose PCR positive test is the first test in the 60-day window; (c) If at all possible, COVID-19 related info at the first PCR test for all patients; (4) If possible, reasons for hospitalizations at the day=0;\n\nWe include Tables 7 and 8 which contain the relevant numbers for (1) (a)-(b); this should hopefully provide some further context. For PCR-positive and PCR-negative patient cohorts, we include the overall number of tests and number of patients with tests; we do this for all the tests in aggregate and 5 coagulation-related tests in particular. Table 7 has these numbers for the PCR-tested patient population; Table 8 has them for the study population of PCR-tested patients with longitudinal test data. We included general demographic characteristics as well in Table 6. We were not able to address (c) further or (d) at this time unfortunately.\n\n2) It is not clear why it is important to assess lab tests in relation to diagnosis. For studying association between lab tests with diagnosis, ideally, the positive cases should use the \"time of infection\" as time zero which of course is intractable. But before variation in time from infection to diagnosis by PCR tests, the relevance of test results for diagnosis is unclear. Further, because of the propensity score matching, the cohort may not be suitable for assess the diagnosis: if some matching variables are associated with any of the test results, matching will artificially deflate the association. We therefore suggest the focus of this paper on prognosis only. The Abstract indeed focused on the prognosis, but diagnosis was mentioned multiple times in the manuscript.\n\nWe have clarified that the focus of this paper on prognosis rather than diagnosis. Furthermore, only explicit statements “at the time of diagnosis”, “after diagnosis”, or “following diagnosis” are retained in the Discussion and Results section. This should address the key concern from a statistical analysis standpoint above.\n\n3) BERT method: The accuracy of BERT was established in an unpublished manuscript developed by the same research group. What is the proportion of patients who were classified as \"Maybe\", \"Yes\" AND \"No\"? It is helpful if chart review is performed on 100, say, patients, to validate this algorithm in the study context;\n\nWe have added in validation statistics for the BERT model on a randomly selected set of 1,000 sentences with thrombotic event phenotypes (see Table 5). Overall, we observe that the BERT model has an out-of-sample accuracy of 94.7%, recall of 97.8%, and precision of 92.8%. We have added a paragraph to the Materials and methods section about this validation procedure and the results.\n\n4) Tables 3 and 4 indicate that the endpoints were significantly enriched for positive cases who had longitudinal data. But it is possible that patients received more tests because of indications of more negative outcomes. As a result, patients with longitudinal lab tests are representative of all positive patients as indicated by the enrichment. This is an important weakness of the study as this may be a source of bias, making the study results not generalizable. It is important to provide additional information on the comparing characteristics of patients with and without longitudinal tests. It may be worthwhile to provide information on reasons of repeating tests for negative patients.\n\nWe have added in a table showing the demographics of the patients who received PCR testing and our study population of patients who received PCR testing and took at least one lab test on 3+ separate days (Table 6A and B respectively). In addition, we agree with the reviewer that the study cohort of patients with longitudinal lab tests is enriched for patients with more severe disease outcomes. However, in this revision we have added in medical history clinical covariates to control for in the propensity score matching step of this analysis, so we believe that the COVIDpos and COVIDneg (matched) to be similar in their propensity for more severe disease outcomes.\n==== Refs\nReferences\nAustin PC 2011 An introduction to propensity score methods for reducing the effects of confounding in observational studies Multivariate Behavioral Research 46 399 424 10.1080/00273171.2011.568786 21818162 \nAustin PC 2014 A comparison of 12 algorithms for matching on the propensity score Statistics in Medicine 33 1057 1069 10.1002/sim.6004 24123228 \nCoronavirus disease 2019 (COVID-19) - Symptoms and Causes - Mayo Clinic. (2020) Mayo clinic \nDevlin J Chang MW Lee K Toutanov K 2018 BERT: pre-training of deep bidirectional transformers for language understanding arXiv https://arxiv.org/abs/1810.04805 \nGando S Fujishima S Saitoh D Shiraishi A Yamakawa K Kushimoto S Ogura H Abe T Mayumi T Sasaki J Kotani J Takeyama N Tsuruta R Takuma K Yamashita N Shiraishi SI Ikeda H Shiino Y Tarui T Nakada TA Hifumi T Otomo Y Okamoto K Sakamoto Y Hagiwara A Masuno T Ueyama M Fujimi S Umemura Y Japanese Association for Acute Medicine (JAAM) Focused Outcomes Research in Emergency Care in Acute Respiratory Distress Syndrome, Sepsis and Trauma (FORECAST) Study Group 2020 The significance of disseminated intravascular coagulation on multiple organ dysfunction during the early stage of acute respiratory distress syndrome Thrombosis Research 191 15 21 10.1016/j.thromres.2020.03.023 32353745 \nGao Y Li T Han M Li X Wu D Xu Y Zhu Y Liu Y Wang X Wang L 2020 Diagnostic utility of clinical laboratory data determinations for patients with the severe COVID-19 Journal of Medical Virology 92 791 796 10.1002/jmv.25770 32181911 \nHuang C Wang Y Li X Ren L Zhao J Hu Y Zhang L Fan G Xu J Gu X Cheng Z Yu T Xia J Wei Y Wu W Xie X Yin W Li H Liu M Xiao Y Gao H Guo L Xie J Wang G Jiang R Gao Z Jin Q Wang J Cao B 2020 Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China The Lancet 395 497 506 10.1016/S0140-6736(20)30183-5 \nKlok FA Kruip M van der Meer NJM Arbous MS Gommers D Kant KM Kaptein FHJ van Paassen J Stals MAM Huisman MV Endeman H 2020 Incidence of thrombotic complications in critically ill ICU patients with COVID-19 Thrombosis Research 191 145 147 10.1016/j.thromres.2020.04.013 32291094 \nLevi M Thachil J Iba T Levy JH 2020 Coagulation abnormalities and thrombosis in patients with COVID-19 The Lancet Haematology 7 e438 e440 10.1016/S2352-3026(20)30145-9 32407672 \nPanigada M Bottino N Tagliabue P Grasselli G Novembrino C Chantarangkul V Pesenti A Peyvandi F Tripodi A 2020 Hypercoagulability of COVID-19 patients in intensive care unit: a report of thromboelastography findings and other parameters of hemostasis Journal of Thrombosis and Haemostasis 18 1738 1742 10.1111/jth.14850 32302438 \nTang N Li D Wang X Sun Z 2020 Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia Journal of Thrombosis and Haemostasis 18 844 847 10.1111/jth.14768 32073213 \nWagner T Shweta F Murugadoss K Awasthi S Venkatakrishnan AJ Bade S Puranik A Kang M Pickering BW O'Horo JC Bauer PR Razonable RR Vergidis P Temesgen Z Rizza S Mahmood M Wilson WR Challener D Anand P Liebers M Doctor Z Silvert E Solomon H Anand A Barve R Gores G Williams AW Morice WG Halamka J Badley A Soundararajan V 2020 Augmented curation of clinical notes from a massive EHR system reveals symptoms of impending COVID-19 diagnosis eLife 9 e58227 10.7554/eLife.58227 32633720 \nWebsite 2020 Symptoms of coronavirus https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html May 13, 2020 \nXu P Zhou Q Xu J 2020 Mechanism of thrombocytopenia in COVID-19 patients Annals of Hematology 99 1205 1208 10.1007/s00277-020-04019-0 32296910 \nYang X Yang Q Wang Y Wu Y Xu J Yu Y Shang Y 2020 Thrombocytopenia and its association with mortality in patients with COVID-19 Journal of Thrombosis and Haemostasis 18 1469 1472 10.1111/jth.14848 32302435 \nZhang L Yan X Fan Q Liu H Liu X Liu Z Zhang Z 2020 D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19 Journal of Thrombosis and Haemostasis 18 1324 1329 10.1111/jth.14859 32306492\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-084X",
"issue": "9()",
"journal": "eLife",
"keywords": "COVID-19; SARS-CoV-2; coagulation; electronic health record (EHR); human; laboratory tests; medicine; thrombolytic agents",
"medline_ta": "Elife",
"mesh_terms": "D000368:Aged; D000073640:Betacoronavirus; D015415:Biomarkers; D001777:Blood Coagulation; D001778:Blood Coagulation Disorders; D001780:Blood Coagulation Tests; D000086382:COVID-19; D000086742:COVID-19 Testing; D019411:Clinical Laboratory Techniques; D018352:Coronavirus Infections; D018450:Disease Progression; D005260:Female; D005340:Fibrinogen; D000076662:Host Microbial Interactions; D006801:Humans; D007958:Leukocyte Count; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D058873:Pandemics; D010976:Platelet Count; D011024:Pneumonia, Viral; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D012189:Retrospective Studies; D000086402:SARS-CoV-2; D013997:Time Factors",
"nlm_unique_id": "101579614",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32804081",
"pubdate": "2020-08-17",
"publication_types": "D016428:Journal Article",
"references": "32296910;32633720;32302435;32181911;32353745;21818162;31986264;32291094;32407672;32302438;32306492;24123228;32073213",
"title": "Inference from longitudinal laboratory tests characterizes temporal evolution of COVID-19-associated coagulopathy (CAC).",
"title_normalized": "inference from longitudinal laboratory tests characterizes temporal evolution of covid 19 associated coagulopathy cac"
} | [
{
"companynumb": "US-BAYER-2020-248349",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND\nPrimary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease with a strong association with inflammatory bowel disease (IBD). Medical treatment for PSC is still disappointing, whereas immunomodulators and biologics have been proven to be effective in IBD.\n\n\nOBJECTIVE\nThis study aimed to analyze (i) the natural history of patients with PSC with or without IBD and (ii) the long-term efficacy of biologics in patients with PSC and concomitant IBD or rheumatological disorders.\n\n\nMETHODS\nThis study included 92 consecutive PSC patients, 50 (54.3%) men and 42 (45.7%) women, with a mean age of 32.0±14.3 years at diagnosis and a mean follow-up duration of 103.8±86 months. Forty-nine (53.3%) patients had associated IBD (38 ulcerative colitis, 10 Crohn's disease, one indeterminate colitis).\n\n\nRESULTS\nNo significant differences were found between PSC patients with and without associated IBD in terms of liver transplantation, cancer, and death rates. Cholangiocarcinoma was only identified among patients with PSC alone, whereas other cancers (hepatocellular carcinoma, colorectal, and gallbladder cancer) were found only in the group with associated IBD. Five PSC patients were treated with biologic agents: three with adalimumab and one with infliximab for IBD or for rheumatoid arthritis, and one patient with rituximab for rheumatoid arthritis. Adalimumab decreased alkaline phosphatase in two of three patients after 6 and 12 months, infliximab reduced γ-glutamyltransferase after 6 and 12 months, but liver function tests tended to deteriorate thereafter. Cholangiography changes remained stable in all patients.\n\n\nCONCLUSIONS\nBiologic agents may improve liver function tests in PSC patients, but may be associated with adverse events including deterioration of liver function.",
"affiliations": "aDepartment of Surgery, Oncology and Gastroenterology bDepartment of Medicine cLaboratory of Public Health and Population Studies, Department of Molecular Medicine, University of Padova, Padova, Italy.",
"authors": "Franceschet|Irene|I|;Cazzagon|Nora|N|;Del Ross|Teresa|T|;D'Incà|Renata|R|;Buja|Alessandra|A|;Floreani|Annarosa|A|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D001688:Biological Products; D005765:Gastrointestinal Agents",
"country": "England",
"delete": false,
"doi": "10.1097/MEG.0000000000000596",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-691X",
"issue": "28(5)",
"journal": "European journal of gastroenterology & hepatology",
"keywords": null,
"medline_ta": "Eur J Gastroenterol Hepatol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000893:Anti-Inflammatory Agents; D001650:Bile Duct Neoplasms; D001688:Biological Products; D006528:Carcinoma, Hepatocellular; D018281:Cholangiocarcinoma; D015209:Cholangitis, Sclerosing; D003093:Colitis, Ulcerative; D015179:Colorectal Neoplasms; D003424:Crohn Disease; D018450:Disease Progression; D005060:Europe; D005260:Female; D005706:Gallbladder Neoplasms; D005765:Gastrointestinal Agents; D006801:Humans; D008111:Liver Function Tests; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012042:Registries; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9000874",
"other_id": null,
"pages": "508-13",
"pmc": null,
"pmid": "26872110",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Primary sclerosing cholangitis associated with inflammatory bowel disease: an observational study in a Southern Europe population focusing on new therapeutic options.",
"title_normalized": "primary sclerosing cholangitis associated with inflammatory bowel disease an observational study in a southern europe population focusing on new therapeutic options"
} | [
{
"companynumb": "IT-ROCHE-1906945",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
"druga... |
{
"abstract": "BACKGROUND\nAntisynthetase syndrome is a rare and debilitating multiorgan disease characterized by inflammatory myopathy, interstitial lung disease, cutaneous involvement, and frequent chronic inflammation of the joints. Standard treatments include corticosteroids and immunosuppressants. In some cases, treatment resistance may develop. Administration of immunoglobulins intravenously is recommended in patients with drug-resistant antisynthetase syndrome.\n\n\nMETHODS\nHere, we describe the case of a 56-year-old woman of Algerian origin. She is the first case of a patient with multidrug-resistant antisynthetase syndrome featuring pulmonary involvement and arthropathy, and chronic secondary immune deficiency with recurrent infections, after anti-CD20 treatment, in which her primary antisynthetase syndrome-related symptoms and secondary immune deficiency were treated successfully with subcutaneous administration of immunoglobulin. The administration of immunoglobulin subcutaneously was introduced at a dose of 2 g/kg per month and was well tolerated. Clinical improvement was observed within 3 months of initiation of subcutaneous administration of immunoglobulin. After 22 months of treatment, she showed a significant improvement in terms of muscle strength, pulmonary involvement, arthralgia, and immunodeficiency. Her serum creatine phosphokinase and C-reactive protein levels remained normal. Finally, she was compliant and entirely satisfied with the treatment.\n\n\nCONCLUSIONS\nTaken together, these observations suggest that administration of immunoglobulin subcutaneously may be a useful therapeutic approach to tackle steroid-refractory antisynthetase syndrome while ensuring minimal side effects and improved treatment compliance. This treatment also allowed, in our case, for the regression of the chronic immunodeficiency secondary to rituximab treatment.",
"affiliations": "Department of Internal Medicine, Pitié-Salpetrière Hospital Group, 47-83 Boulevard de l'Hôpital, 75013, Paris, France. patrick.cherin@aphp.fr.;Institut Galliera, 4 rue de Galliera, 75016, Paris, France.;Octapharma France SAS, Boulogne Billancourt, France.;Octapharma France SAS, Boulogne Billancourt, France.;ClinSearch, Malakoff, France.;Department of Internal Medicine, Pitié-Salpetrière Hospital Group, 47-83 Boulevard de l'Hôpital, 75013, Paris, France.",
"authors": "Cherin|Patrick|P|;de Jaeger|Christophe|C|;Crave|Jean-Charles|JC|;Delain|Jean-Christophe|JC|;Tadmouri|Abir|A|;Amoura|Zahir|Z|",
"chemical_list": "D007136:Immunoglobulins; D007166:Immunosuppressive Agents; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-017-1211-9",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 121110.1186/s13256-017-1211-9Case ReportSubcutaneous immunoglobulins for the treatment of a patient with antisynthetase syndrome and secondary chronic immunodeficiency after anti-CD20 treatment: a case report Cherin Patrick +33 (0)1 42 16 57 96patrick.cherin@aphp.fr 1de Jaeger Christophe christophedejaeger@wanadoo.fr 2Crave Jean-Charles jean-charles.crave@octapharma.com 3Delain Jean-Christophe christophe.delain@octapharma.com 3Tadmouri Abir abir.tadmouri@clinsearch.net 4Amoura Zahir zahir.amoura@psl.ap-hop-paris.fr 11 0000 0001 2150 9058grid.411439.aDepartment of Internal Medicine, Pitié-Salpetrière Hospital Group, 47-83 Boulevard de l’Hôpital, 75013 Paris, France 2 Institut Galliera, 4 rue de Galliera, 75016 Paris, France 3 Octapharma France SAS, Boulogne Billancourt, France 4 ClinSearch, Malakoff, France 4 3 2017 4 3 2017 2017 11 5828 10 2016 14 1 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\nAntisynthetase syndrome is a rare and debilitating multiorgan disease characterized by inflammatory myopathy, interstitial lung disease, cutaneous involvement, and frequent chronic inflammation of the joints. Standard treatments include corticosteroids and immunosuppressants. In some cases, treatment resistance may develop. Administration of immunoglobulins intravenously is recommended in patients with drug-resistant antisynthetase syndrome.\n\nCase presentation\nHere, we describe the case of a 56-year-old woman of Algerian origin. She is the first case of a patient with multidrug-resistant antisynthetase syndrome featuring pulmonary involvement and arthropathy, and chronic secondary immune deficiency with recurrent infections, after anti-CD20 treatment, in which her primary antisynthetase syndrome-related symptoms and secondary immune deficiency were treated successfully with subcutaneous administration of immunoglobulin. The administration of immunoglobulin subcutaneously was introduced at a dose of 2 g/kg per month and was well tolerated. Clinical improvement was observed within 3 months of initiation of subcutaneous administration of immunoglobulin. After 22 months of treatment, she showed a significant improvement in terms of muscle strength, pulmonary involvement, arthralgia, and immunodeficiency. Her serum creatine phosphokinase and C-reactive protein levels remained normal. Finally, she was compliant and entirely satisfied with the treatment.\n\nConclusions\nTaken together, these observations suggest that administration of immunoglobulin subcutaneously may be a useful therapeutic approach to tackle steroid-refractory antisynthetase syndrome while ensuring minimal side effects and improved treatment compliance. This treatment also allowed, in our case, for the regression of the chronic immunodeficiency secondary to rituximab treatment.\n\nKeywords\nAntisynthetase syndromeMyositisSubcutaneous human immunoglobulinSecondary immunodeficiencyAnti-Jo-1 antibodyAutoimmune diseaseCase reportissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nAntisynthetase syndrome (aSS) is a rare idiopathic autoimmune condition occurring in a subgroup of patients with polymyositis and dermatomyositis who are positive for one or several of eight anti-aminoacyl transfer ribonucleic acid (RNA) synthetase (ARS) auto-antibodies [1]. Six major clinical hallmarks define the syndrome: fever, myositis, interstitial lung disease, “mechanic’s hands”, Raynaud phenomenon, and inflammatory polyarthritis [2]. Symptoms may occur individually or in a variety of combinations; hence, a straightforward diagnosis is challenging [3, 4]. Of interest, there is evidence that the clinical picture and outcome of aSS are intimately tied to the identity of the ARS antibody being expressed [5, 6]. The most common form of aSS is anti-Jo-1 antibody-associated (anti-histidyl-transfer RNA synthetase) and features polymyositis of proximal muscles alongside interstitial lung disease or, rarely, pulmonary hypertension [7–9].\n\nDue to multiorgan involvement, aSS is a debilitating condition associated with increased morbidity and mortality, especially when pulmonary function is affected [10, 11]. Moreover, myocardial complications and malignancies may also occasionally be observed within this patient population and contribute to poor prognosis [12–14].\n\nCurrently, glucocorticoids are the mainstay of therapy and may be completed by immunosuppressive treatments, typically methotrexate (MTX) or azathioprine, in order to decrease steroid dose and to achieve disease control [15–17]. Cyclophosphamide can be used to control interstitial lung disease. In treatment-refractory patients, rituximab (RTX) may also be considered [18, 19]. Because of the low prevalence of aSS, there is a lack of randomized controlled trials comparing the efficacy and safety of different treatment approaches. However, a few studies supported administration of immunoglobulins intravenously (IVIg) as a promising therapeutic avenue for treatment-refractory patients, or those wishing to avoid the risks associated with chronic corticosteroid exposure [16, 20–23]. More recently, high-dose administration of immunoglobulin subcutaneously (SCIg) has arisen as a less invasive and more economical alternative to IVIg [20, 24, 25].\n\nHere, we report the case of a patient with aSS, refractory to steroid and immunosuppressive treatment, and poorly tolerating both RTX and IVIg. She developed secondary chronic immune deficiency with recurrent infections after anti-CD20 (RTX) treatment. In this patient, a combined SCIg and MTX treatment significantly improved her aSS-specific symptoms and overall health status which, in addition, enabled the disappearance of secondary immune deficiency.\n\nCase presentation\nA 56-year-old woman, 70 kg, of Algerian origin was referred to us in August 2003 presenting with fatigue, proximal and bilateral muscular weakness (muscle testing score of 69 points compared to a score of 88 in healthy individuals), apprehension to grasp, and difficulties in getting dressed. Additional symptoms included effort dyspnea, swollen hands, and purple erythema of her eyelids. Appendicitis, sciatica, tachycardia, hypertension, and asthma were listed in her medical history. Her creatine phosphokinase (CPK, muscle enzymes) levels were six times the normal (N) level. Auto-antibodies measurements were initially not performed.\n\nA muscle biopsy was performed, and showed characteristic patterns of dermatomyositis with perifascicular atrophy, evidence of injury to capillaries and perifascicular myofibers, and inflammatory infiltrates in the perimysial region (predominantly CD4+). She was diagnosed as having dermatomyositis in November 2003 and prednisone treatment (1 mg/kg per day) was initiated. A repeated search for malignancy was negative. A diagnosis of a mild interstitial pneumonitis together with the presence of anti-Jo1 antibodies further confirmed the suspicion of aSS. Her gamma globulin levels were normal.\n\nSince treatment response was incomplete, immunosuppressant therapy with azathioprine (2 mg/kg per day), which was replaced after 9 months by MTX (15 mg per week), was introduced. However, both were poorly tolerated and she developed cytopenia. Therefore, infusions with IVIg (2 g/kg per month) were initiated for six months, in addition to steroids.\n\nIn September 2006, due to lack of response to these different therapies, RTX (2 g every 6 months) was introduced and our patient reported an improvement in her articular and muscular pain. Yet, because of the development of hypogammaglobulinemia, RTX was discontinued in October 2011. Of importance, no immune deficit had been present prior to the introduction of RTX.\n\nShe was readmitted in December 2012 with a muscle weakness score of 75.5 points (over 88 points in healthy individuals) [21]. Her CPK levels were normal, but probing for anti-Jo-1 antibody was positive. In addition, a lung scan revealed the presence of interstitial basal lung infiltrate (Fig. 1). Testing of pulmonary function showed a reduction of single-breath diffusion capacity for carbon monoxide (DLCO; 48%), with a total lung capacity (TLC) of 72%, and forced expiratory volume in 1 second (FEV1)/vital capacity (VC) at 73%. A slight muscle inflammation of her thighs was also evidenced by magnetic resonance imaging (MRI). In terms of treatment strategy, a bolus injection of IVIg (2 g/kg) was administered, but she developed adverse effects, including headache and distal paresthesia, after which she refused to receive another IVIg infusion. Her treatment adherence was poor and in addition to refusing to try a different IVIg formulation, she had also resumed the corticosteroid treatment in November 2012. In fact, she expressed wishes against hospitalizations and stopped all the treatments.Fig. 1 Lung scan showing the presence of interstitial basal lung infiltrate\n\n\n\n\nAn immunologic evaluation showed hypogammaglobulinemia (4.4 g/l), with reduced total immunoglobulin G (IgG) (4.2 g/l), and a reduction in each subclass of IgG: IgG1 2.48 g/l (N >3.82 g/l), IgG2 1.65 g/l (N >2.41), IgG3 0.14 g/l (N >0.2), and IgG4 0.038 g/l (N >0.18 g/l). Her IgA (0.5 g/l, N >0.7) and IgM levels (0.34 g/l, N >0.4) were also decreased. Her IgE levels were normal.\n\nShe was seen again in May 2014, when her general health had deteriorated due to the discontinuation of steroids, RTX, and IgG treatment. In particular, she complained about severe fatigue and presented with swelling of the proximal interphalangeal joints of her right index and middle finger. An MRI scan of her right hand revealed an advanced and destructive arthropathy associated with significant synovitis of the proximal interphalangeal joints of the first, second, and third rays and, to a lesser extent, of the fourth and fifth rays (Fig. 2). Her metacarpal phalangeal joints were not affected, but an erosive synovitis of the dorsal scapholunate articulation and beginning erosion of the lunate were observed. Her radioulnar joint was not affected.Fig. 2 Magnetic resonance imaging scanner of the right hand showing an advanced and destructive arthropathy associated with significant synovitis of the proximal interphalangeal joints of the first, second, and third rays and, to a lesser extent, of the fourth and fifth rays\n\n\n\n\nAt this point, her muscle weakness score was 70/88, with a muscle strength of +3 as measured bilaterally at her middle trapezius, major gluteal, and psoas muscles. Her muscle disability was rated 18/75 (score ranging from 0 no disability to 75 maximum disability) [22]. An MRI of her thighs did not reveal any significant evolution of myopathy since the previous examination in 2012. In particular, there was no important inflammatory signal of the muscle and no sign of amyotrophy.\n\nLikewise, a thorax scan confirmed the stabilization of the abnormalities reported in November 2012, with mostly the basal regions being affected. Pulmonary function testing was also indicative of overall stability compared to 2012: single-breath DLCO was 46%, TLC 70%, and FEV1/VC 73%. Whereas DLCO, TLC (−30%), and functional respiratory deficit (25%) were unchanged, a slight decrease of forced expiratory flow (FEF)25–75 was noted.\n\nOf importance, she complained of frequent infections of the upper airways, including pharyngitis, sinusitis, bronchitis, and otitis for the past 2 years. Consistent with these recurrent infections, an immunologic evaluation confirmed a persistent hypogammaglobulinemia (5.0 g/l), with reduced total IgG (4.1 g/l), and reduction of each subclass of IgG: IgG1 2.3 g/l, IgG2 1.48 g/l, IgG3 0.11 g/l, and IgG4 0.04 g/l. This picture was evocative of a persistent common variable immunodeficiency (CVID) secondary to RTX. Her C-reactive protein (CRP) level was 22.7 mg/l and her CPK level was 489 UI/l.\n\nTreatment with Gammanorm® (SCIg) was initiated in July 2014 (2 g/kg per month divided into two infusions per week). After 3 and 6 months, respectively, of treatment, she reported diffuse pain, which was present since discontinuation of Cortancyl® (prednisone), and general fatigue. Arthritis of her proximal and metacarpal phalangeal joints was still present, but her muscle weakness score had improved to 75/88 and muscle disability was rated 12/75 [22]. Of importance, no novel infectious episode was reported. In fact, Gammanorm® (SCIg) was well tolerated and she confirmed a slight improvement in her general health state.\n\nIn January 2015, MTX (15 mg/week) was reintroduced and a significant clinical improvement was achieved by April. Notably, her serum CRP (3.3 mg/l) and CPK (63 UI/l) returned to normalized levels despite persisting fatigue, along with arthritis of her metacarpal and proximal interphalangeal joints (arthritis confirmed at a consultation in May 2015). Nevertheless, the normalization of her immunodeficiency and the significant improvement in the state of her general health remained stable, as reassessed in November 2015.\n\nFinally, in May 2016, joint manifestations had disappeared and fatigue had regressed significantly. No infection had been observed during the past 18 months. Her muscle weakness score had also improved to 82/88 and muscle disability was rated 9/75. Her CRP and CPK levels were normal. As shown by immunologic evaluation, hypogammaglobulinemia had resolved and all subclasses of IgG were normalized.\n\nMoreover, the results of a thorax scan indicated a slight improvement in basal lung infiltrate, alongside pulmonary function testing: DLCO of 55%, TLC of 75%, and a FEV1/VC 74%.\n\nDiscussion\nTo the best of our knowledge, this is the first report of a case of aSS pathology with concomitant secondary immune deficiency secondary to RTX, successfully treated with SCIg. Of importance, and in addition to a progressive improvement of aSS-related symptoms, our patient fully recovered from RTX-induced immune deficiency, tolerated SCIg treatment very well, and reported a substantial increase in her quality of life. Hence, SCIg emerges as a safe, efficient, and patient-friendly alternative for the treatment of this rare, complex, and burdensome form of polymyositis.\n\nAlthough rare, aSS is a challenging pathology because of the complexity and severity of symptoms [3, 4], some of which are highly debilitating and/or life threatening [10–13]. Unfortunately, the most common therapeutic avenue – corticoid treatment – is jeopardized by side effects and the development of treatment resistance. In the present case, a first-line corticoid therapy did not achieve satisfactory disease control. Conversely, a number of second-line treatments, including immunosuppressant therapy (azathioprine, MTX, RTX) and IVIg, although somewhat efficient in terms of symptomatology were poorly tolerated by the patient. Notably, anti-CD20 immunosuppressant therapy provoked a persistent immunodeficiency, including hypogammaglobulinemia. Due to the recurrence of heavy side effects combined with poor therapeutic efficacy, our patient’s compliance with the treatment degraded and she became reluctant to try alternative approaches (for instance, different IVIg formulations) [26, 27].\n\nUnder the double burden of an untreated aSS and a persistent immune deficiency, our patient’s general health dramatically deteriorated. In this precarious situation, the introduction of SCIg (2 g/kg per month) proved to be efficacious in eradicating the immune deficiency and progressively downscaling aSS-related symptoms. In fact, 6 months into the treatment, her immune function had recovered, as proven by the absence of new infectious episodes and the normalization of her IgG and CRP levels. Her pulmonary and muscle function had also improved and her CPK normalized. In addition, the general improvement in her health enabled resumption of her MTX treatment, and eventually led to full disease control, including alleviation of arthropathy, regression of fatigue, and a substantial increase in quality of life within less than 12 months of SCIg initiation.\n\nWe believe that this double action of SCIg on stabilization of immune function and aSS disease management is of particular interest in the light of several recent reports featuring the prolonged effects of RTX on the immune system. In fact, in their retrospective chart review, Kaplan et al. identified a subset of patients receiving RTX treatment and presenting with prolonged immune suppression, which required immunoglobulin replacement therapy even after discontinuation of anti-CD20 treatment [28].\n\nLikewise, Levy et al. report in their retrospective analysis of 32 studies conducted in France between 2001 and 2014 three cases of prolonged hypogammaglobulinemia in patients who had received RTX as a second-line treatment for immune thrombocytopenia [29]. Of interest, the clinical picture was reminiscent of CVID, including recurrent infections, and lasted up to 2 years after RTX discontinuation. A further analysis of the literature allowed the authors to conclude that severe hypogammaglobulinemia is a rare but severe and long-lasting side effect of RTX treatment. These reports, together with our case, call for caution and the close monitoring of immune function in patients who receive RTX for the treatment of autoimmune disorders.\n\nIn addition to proving efficient at tackling both aSS pathology and secondary immunodeficiency, SCIg was also particularly well tolerated in the present case. Given the poor tolerance of a variety of previous therapies and our patient’s growing opposition to treatment, this represents a chief clinical benefit. Our observations are consistent with previous reports, indicating that the subcutaneous route of Ig administration is generally better tolerated than the systemic one [30]. Another crucial advantage of the SCIg formulation over IVIg is of course the ease of administration, which allows for home-based use and thereby reduces costly hospitalizations, while increasing patient autonomy [31].\n\nConclusions\nIn summary, the case reported here supports SCIg as an efficient and safe alternative, which is more economical than IVIg, for the treatment of complex and/or refractory forms of aSS. Of importance, in this particular case, the clinical benefit of SCIg went beyond the control of primary aSS-related symptoms, since a secondary immune deficiency was also successfully treated. In the light of these promising outcomes, we believe that SCIg should also be considered a valuable tool for the management of other autoimmune conditions.\n\nAcknowledgements\nThe authors would like to thank the IARS (Institut d'Aide à la Recherche Scientifique) Association and Dr Anne Cherin for her help and assistance in preparing this manuscript.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nThe published information is available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nPC, CdJ, and ZA diagnosed, analyzed, and interpreted the patient data regarding the immunodeficiency disease and the treatment. JCC and JCD performed the literature and data collection, and AT was a major contributor in writing the manuscript. 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. Katzap E Barilla-LaBarca ML Marder G Antisynthetase syndrome Curr Rheumatol Rep. 2011 13 175 81 10.1007/s11926-011-0176-8 21455765 \n2. Chatterjee S Prayson R Farver C Antisynthetase syndrome: not just an inflammatory myopathy Cleve Clin J Med. 2013 80 655 66 10.3949/ccjm.80a.12171 24085811 \n3. Dalakas MC Hohlfeld R Polymyositis and dermatomyositis Lancet. 2003 362 971 82 10.1016/S0140-6736(03)14368-1 14511932 \n4. Marie I Hatron PY Cherin P Hachulla E Diot E Vittecoq O Menard JF Jouen F Dominique S Functional outcome and prognostic factors in anti-Jo1 patients with antisynthetase syndrome Arthritis Res Ther. 2013 15 R149 10.1186/ar4332 24286268 \n5. Aggarwal R Cassidy E Fertig N Koontz DC Lucas M Ascherman DP Oddis CV Patients with non-Jo-1 anti-tRNA-synthetase autoantibodies have worse survival than Jo-1 positive patients Ann Rheum Dis. 2014 73 227 32 10.1136/annrheumdis-2012-201800 23422076 \n6. Mahler M Fritzler MJ Epitope specificity and significance in systemic autoimmune diseases Ann N Y Acad Sci. 2010 1183 267 87 10.1111/j.1749-6632.2009.05127.x 20146721 \n7. Ascherman DP The role of Jo-1 in the immunopathogenesis of polymyositis: current hypotheses Curr Rheumatol Rep. 2003 5 425 30 10.1007/s11926-003-0052-2 14609486 \n8. Chatterjee S Farver C Severe pulmonary hypertension in Anti-Jo-1 syndrome Arthritis Care Res (Hoboken) 2010 62 425 9 10.1002/acr.20109 20391490 \n9. Yousem SA Gibson K Kaminski N Oddis CV Ascherman DP The pulmonary histopathologic manifestations of the anti-Jo-1 tRNA synthetase syndrome Mod Pathol. 2010 23 874 80 10.1038/modpathol.2010.65 20228783 \n10. Marie I Hachulla E Hatron PY Hellot MF Levesque H Devulder B Courtois H Polymyositis and dermatomyositis: short term and longterm outcome, and predictive factors of prognosis J Rheumatol. 2001 28 2230 7 11669162 \n11. Marie I Hatron PY Dominique S Cherin P Mouthon L Menard JF Short-term and long-term outcomes of interstitial lung disease in polymyositis and dermatomyositis: a series of 107 patients Arthritis Rheum. 2011 63 3439 47 10.1002/art.30513 21702020 \n12. Dieval C Deligny C Meyer A Cluzel P Champtiaux N Lefevre G Saadoun D Sibilia J Pellegrin JL Hachulla E Myocarditis in Patients With Antisynthetase Syndrome: Prevalence, Presentation, and Outcomes Medicine (Baltimore) 2015 94 e798 10.1097/MD.0000000000000798 26131832 \n13. Legault D McDermott J Crous-Tsanaclis AM Boire G Cancer-associated myositis in the presence of anti-Jo1 autoantibodies and the antisynthetase syndrome J Rheumatol. 2008 35 169 71 18176990 \n14. Rozelle A Trieu S Chung L Malignancy in the setting of the anti-synthetase syndrome J Clin Rheumatol. 2008 14 285 8 10.1097/RHU.0b013e31817d116f 18664993 \n15. Bunch TW Worthington JW Combs JJ Ilstrup DM Engel AG Azathioprine with prednisone for polymyositis. A controlled, clinical trial Ann Intern Med 1980 92 365 9 10.7326/0003-4819-92-3-365 6986827 \n16. Marie I Mouthon L Therapy of polymyositis and dermatomyositis Autoimmun Rev. 2011 11 6 13 10.1016/j.autrev.2011.06.007 21740984 \n17. Metzger AL Bohan A Goldberg LS Bluestone R Pearson CM Polymyositis and dermatomyositis: combined methotrexate and corticosteroid therapy Ann Intern Med. 1974 81 182 9 10.7326/0003-4819-81-2-182 4843574 \n18. Limaye V Hissaria P Liew CL Koszyka B Efficacy of rituximab in refractory antisynthetase syndrome Intern Med J. 2012 42 e4 7 10.1111/j.1445-5994.2011.02702.x 22432998 \n19. Marie I Dominique S Janvresse A Levesque H Menard JF Rituximab therapy for refractory interstitial lung disease related to antisynthetase syndrome Respir Med. 2012 106 581 7 10.1016/j.rmed.2012.01.001 22280877 \n20. Cherin P Belizna C Cartry O Lascu-Dubos G de Jaeger C Delain JC Crave JC Hachulla E Long-term subcutaneous immunoglobulin use in inflammatory myopathies: A retrospective review of 19 cases Autoimmun Rev. 2016 15 281 6 10.1016/j.autrev.2015.12.003 26688441 \n21. Cherin P Herson S Wechsler B Piette JC Bletry O Coutellier A Ziza JM Godeau P Efficacy of intravenous gammaglobulin therapy in chronic refractory polymyositis and dermatomyositis: an open study with 20 adult patients Am J Med. 1991 91 162 8 10.1016/0002-9343(91)90009-M 1714235 \n22. Cherin P Pelletier S Teixeira A Laforet P Genereau T Simon A Maisonobe T Eymard B Herson S Results and long-term followup of intravenous immunoglobulin infusions in chronic, refractory polymyositis: an open study with thirty-five adult patients Arthritis Rheum. 2002 46 467 74 10.1002/art.10053 11840450 \n23. Dalakas MC Controlled studies with high-dose intravenous immunoglobulin in the treatment of dermatomyositis, inclusion body myositis, and polymyositis Neurology. 1998 51 S37 45 10.1212/WNL.51.6_Suppl_5.S37 9851729 \n24. Danieli MG Moretti R Gambini S Paolini L Gabrielli A Open-label study on treatment with 20% subcutaneous IgG administration in polymyositis and dermatomyositis Clin Rheumatol. 2014 33 531 6 10.1007/s10067-013-2478-x 24395197 \n25. Danieli MG Pettinari L Moretti R Logullo F Gabrielli A Subcutaneous immunoglobulin in polymyositis and dermatomyositis: a novel application Autoimmun Rev. 2011 10 144 9 10.1016/j.autrev.2010.09.004 20858553 \n26. Cherin P Cabane J Relevant criteria for selecting an intravenous immunoglobulin preparation for clinical use BioDrugs. 2010 24 211 23 10.2165/11537660-000000000-00000 20623988 \n27. Cherin P Marie I Michallet M Pelus E Dantal J Crave JC Delain JC Viallard JF Management of adverse events in the treatment of patients with immunoglobulin therapy: A review of evidence Autoimmun Rev. 2016 15 71 81 10.1016/j.autrev.2015.09.002 26384525 \n28. Kaplan B Kopyltsova Y Khokhar A Lam F Bonagura V Rituximab and immune deficiency: case series and review of the literature J Allergy Clin Immunol Pract. 2014 2 594 600 10.1016/j.jaip.2014.06.003 25213054 \n29. Levy R Mahevas M Galicier L Boutboul D Moroch J Loustau V Guillaud C Languille L Fain O Bierling P Profound symptomatic hypogammaglobulinemia: a rare late complication after rituximab treatment for immune thrombocytopenia. Report of 3 cases and systematic review of the literature Autoimmun Rev 2014 13 1055 63 10.1016/j.autrev.2014.08.036 25183241 \n30. Quinti I Soresina A Agostini C Spadaro G Matucci A Sfika I Martini H Borghese F Guerra A Alessandra V Prospective study on CVID patients with adverse reactions to intravenous or subcutaneous IgG administration J Clin Immunol. 2008 28 263 7 10.1007/s10875-007-9169-9 18214651 \n31. Lazzaro C Lopiano L Cocito D Subcutaneous vs intravenous administration of immunoglobulin in chronic inflammatory demyelinating polyneuropathy: an Italian cost-minimization analysis Neurol Sci. 2014 35 1023 34 10.1007/s10072-014-1632-9 24469345\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "11(1)",
"journal": "Journal of medical case reports",
"keywords": "Anti-Jo-1 antibody; Antisynthetase syndrome; Autoimmune disease; Case report; Myositis; Secondary immunodeficiency; Subcutaneous human immunoglobulin",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000361:Agammaglobulinemia; D005260:Female; D006801:Humans; D007136:Immunoglobulins; D007153:Immunologic Deficiency Syndromes; D007166:Immunosuppressive Agents; D017563:Lung Diseases, Interstitial; D008279:Magnetic Resonance Imaging; D008727:Methotrexate; D008875:Middle Aged; D009220:Myositis; D065566:Subcutaneous Absorption",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "58",
"pmc": null,
"pmid": "28257650",
"pubdate": "2017-03-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11840450;22280877;24395197;26384525;14609486;11669162;14511932;24286268;24469345;4843574;1714235;18176990;23422076;21455765;20228783;18664993;6986827;24085811;9851729;21702020;25213054;22432998;26688441;20146721;21740984;18214651;20391490;25183241;26131832;20623988;20858553",
"title": "Subcutaneous immunoglobulins for the treatment of a patient with antisynthetase syndrome and secondary chronic immunodeficiency after anti-CD20 treatment: a case report.",
"title_normalized": "subcutaneous immunoglobulins for the treatment of a patient with antisynthetase syndrome and secondary chronic immunodeficiency after anti cd20 treatment a case report"
} | [
{
"companynumb": "PHHY2017FR202439",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": "1",
... |
{
"abstract": "Post transplant Hemophagocytic lymphohistiocytosis (HLH) is a form of secondary HLH, which can be either early onset or late onset and is associated with significant morbidity and mortality. With the increasing popularity of post transplant cyclophosphamide based haploidentical stem cell transplantation (SCT), post transplant HLH is becoming a significant complication especially in benign hematological disorders. Methods: We present 4 cases of post transplant HLH occurring in 2 cases of severe aplastic anemia (post haploidentical SCT) and 2 cases of thalassemia major (post matched sibling SCT). All 4 cases had early onset variety with dismal prognosis. Conclusion: Post-transplant HLH is an important entity in benign hematological disorders, which needs to be identified early and treated promptly with steroids, monoclonal agents or immunosuppressive therapy. Serum ferritin levels are an important biomarker and help in monitoring response.",
"affiliations": "Department of Medical Oncology, Gujarat Cancer and Research Institute, Ahmedabad, Gujarat 380016 India.;Department of Medical Oncology, Gujarat Cancer and Research Institute, Ahmedabad, Gujarat 380016 India.;Department of Medical Oncology, Gujarat Cancer and Research Institute, Ahmedabad, Gujarat 380016 India.;Department of Medical Oncology, Gujarat Cancer and Research Institute, Ahmedabad, Gujarat 380016 India.;Department of Medical Oncology, Gujarat Cancer and Research Institute, Ahmedabad, Gujarat 380016 India.;Department of Medical Oncology, Gujarat Cancer and Research Institute, Ahmedabad, Gujarat 380016 India.;Department of Medical Oncology, Gujarat Cancer and Research Institute, Ahmedabad, Gujarat 380016 India.;Department of Medical Oncology, Gujarat Cancer and Research Institute, Ahmedabad, Gujarat 380016 India.",
"authors": "Garg|Akanksha|A|0000-0002-2020-7928;Shah|Sandip|S|;Patel|Kinnari|K|;Shah|Kamlesh|K|;Anand|Asha|A|;Panchal|Harsha|H|;Patel|Apurva|A|;Parikh|Sonia|S|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1007/s12288-020-01258-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0971-4502",
"issue": "36(4)",
"journal": "Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion",
"keywords": "Allogenic stem cell transplant; Benign hematological disorders; Haploidentical stem cell transplant; Post transplant HLH",
"medline_ta": "Indian J Hematol Blood Transfus",
"mesh_terms": null,
"nlm_unique_id": "9425818",
"other_id": null,
"pages": "674-679",
"pmc": null,
"pmid": "33100709",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article",
"references": "19194205;30617216;25077692;19252966;3139115;26314082;9277044;30814997;29703967;29481673;31455895;24037021;22038983;26619832;17675268;18085676;24782338;11039676;29577525;19709082;27264204;25712613",
"title": "Post-transplant Hemophagocytic Lymphohistiocytosis in Benign Hematological Disorders: Experience of 4 Cases with Review of Literature.",
"title_normalized": "post transplant hemophagocytic lymphohistiocytosis in benign hematological disorders experience of 4 cases with review of literature"
} | [
{
"companynumb": "IN-SA-2021SA002467",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "3",
"d... |
{
"abstract": "Shortness of breath is a common complaint among patients in emergency medicine. While most common causes are usually promptly identified, less frequent aetiologies might be challenging to diagnose, especially in the pre-hospital setting. We report a case of prehospital dyspnoea initially ascribed to pulmonary oedema which turned out to be the result of profound metformin-associated metabolic acidosis. This diagnosis was already made during the prehospital phase by virtue of arterial blood gas measurement. Pre-hospital measurement of arterial blood gases is therefore feasible and can improve diagnostic accuracy in the field, thus avoiding unnecessary delay and potential harm to the patient before initiating the appropriate therapeutic actions.",
"affiliations": "Division of Intensive Care Medicine, Department of Anaesthesiology, Clinical Pharmacology, Intensive Care and Emergency Medicine, Geneva University Hospitals and Faculty of Medicine University of Geneva, CH-1211 Geneva, Switzerland.;Division of Emergency Medicine, Department of Anaesthesiology, Clinical Pharmacology, Intensive Care and Emergency Medicine, Geneva University Hospitals and Faculty of Medicine University of Geneva, CH-1211 Geneva, Switzerland.",
"authors": "Fubini|Pietro Elias|PE|0000-0003-1371-6465;Suppan|Laurent|L|0000-0001-6989-6421",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/healthcare9010074",
"fulltext": "\n==== Front\nHealthcare (Basel)\nHealthcare (Basel)\nhealthcare\nHealthcare\n2227-9032 MDPI \n\n33466796\n10.3390/healthcare9010074\nhealthcare-09-00074\nCase Report\nPrehospital Diagnosis of Shortness of Breath Caused by Profound Metformin-Associated Metabolic Acidosis\nhttps://orcid.org/0000-0003-1371-6465Fubini Pietro Elias 1*† https://orcid.org/0000-0001-6989-6421Suppan Laurent 2† 1 Division of Intensive Care Medicine, Department of Anaesthesiology, Clinical Pharmacology, Intensive Care and Emergency Medicine, Geneva University Hospitals and Faculty of Medicine University of Geneva, CH-1211 Geneva, Switzerland\n2 Division of Emergency Medicine, Department of Anaesthesiology, Clinical Pharmacology, Intensive Care and Emergency Medicine, Geneva University Hospitals and Faculty of Medicine University of Geneva, CH-1211 Geneva, Switzerland; laurent.suppan@hcuge.ch\n* Correspondence: pietroelias.fubini@hcuge.ch† Equal contribution.\n\n\n14 1 2021 \n1 2021 \n9 1 7424 12 2020 12 1 2021 © 2021 by the authors.2021Licensee 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/).Shortness of breath is a common complaint among patients in emergency medicine. While most common causes are usually promptly identified, less frequent aetiologies might be challenging to diagnose, especially in the pre-hospital setting. We report a case of prehospital dyspnoea initially ascribed to pulmonary oedema which turned out to be the result of profound metformin-associated metabolic acidosis. This diagnosis was already made during the prehospital phase by virtue of arterial blood gas measurement. Pre-hospital measurement of arterial blood gases is therefore feasible and can improve diagnostic accuracy in the field, thus avoiding unnecessary delay and potential harm to the patient before initiating the appropriate therapeutic actions.\n\nprehospitalarterial blood gasmetformin poisoningmetabolic acidosisrespiratory distress\n==== Body\n1. Introduction\nShortness of breath (SOB) is one of the most common complaints among patients in prehospital emergency medicine [1]. Most common causes of shortness of breath (pulmonary oedema, pneumonia, chronic obstructive pulmonary disease exacerbation, pulmonary embolism, pneumothorax, etc.) are usually identified rather easily, although less common aetiologies might be overlooked and therefore misdiagnosed if clinicians fail to consider them. Furthermore, even a high clinical suspicion does not equal a definitive diagnosis, which might require para-clinical confirmation through specific investigations such as arterial blood gas (ABG) analysis. We report the case of a patient complaining of SOB that was initially imputed to pulmonary oedema. However, an ABG analysis performed in the field allowed the prehospital emergency physician to identify a profound metformin-associated metabolic acidosis as the actual cause of the patient’s dyspnoea.\n\n2. Case Description\nThe emergency medical call centre (EMCC) dispatched an advanced life support ambulance to take care of a 71-year-old woman who had called complaining about SOB. Upon arrival, prehospital providers noted shallow breathing with a respiratory rate of over 35 breaths per minute. Lung fields were clear to auscultation and the patient showed no sign of cyanosis. There was no haemodynamic compromise. The Glasgow Coma Scale was 15 with no focal deficit and the patient was normothermic. Given the respiratory distress, paramedics initiated oxygen therapy using a high-flow non-rebreather mask. Suspecting acute heart failure (AHF), they asked the EMCC to dispatch a medical mobile unit called ‘Service Mobile d’Urgence et de Réanimation’ (SMUR). These units are staffed by an advanced paramedic and a physician and can be dispatched to assist an ambulance in case of life-threatening emergencies [2]. These SMURs are the only prehospital units equipped with non-invasive ventilation (NIV) devices and portable blood gas analysers (iStat, Abbott Point of Care Inc., Princeton, NJ, USA) and are therefore often called upon to enhance the management of patients in acute respiratory distress or failure. While awaiting the arrival of the SMUR, the paramedics continued their evaluation and discovered that the patient was under metformin for diabetes and diuretics for hypertension, and that she was on day 3 of antibiotic treatment for urinary tract infection. She did not use cigarettes, alcohol, or illicit drugs. The patient was found to be hypoglycaemic at 2.3 mmol/L and received intravenous glucose accordingly. An ABG analysis performed by the SMUR physician shortly after arriving on site showed severe lactic acidosis (FiO2 65%: pH 6.845, PaCO2 1.95 kPa, PaO2 27.7 kPa, HCO3−—2.5 mmol/L, lactate 17.0 mmol/L).\n\nWhile AHF was suspected at first, the profound metabolic acidosis revealed by the ABG analysis was not compatible with the clinical picture. Indeed, the patient was not in cardiogenic shock, and a diagnosis of lactic acidosis secondary to metformin intoxication was thereafter suspected. Intravenous hydration was started and bicarbonates were administered. Since the patient showed signs of respiratory distress and exhaustion, NIV was initiated.\n\nIn-hospital investigations confirmed severe lactic acidosis and acute kidney injury KDIGO stage 3 [3], with a creatinine of 788 µmol/L which yielded an estimated glomerular filtration rate of 5 mL/min/m2 according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. This kidney injury was secondary to the pre-renal disease on severe dehydration (diuretics, decreased drinking inputs, etc.) and sepsis, with consequent acute tubular necrosis. The patient showed no sign of hepatic impairment nor hypoxaemia. There was no hint that the patient’s illness could have been secondary to suicidal or accidental biguanide ingestion. The diagnosis of profound metformin-associated metabolic acidosis secondary to renal failure was definitively established at this stage. Despite aggressive hydration and bicarbonates infusion, the patient remained oligo-anuric with severe metabolic acidosis and showed signs of respiratory exhaustion finally requiring endotracheal intubation. She was admitted to the intensive care unit (ICU) for haemodynamic and respiratory management. The decision to start haemodialysis was finally made basing on the severity of acidosis and lactate level, coexisting renal failure and failure to improve with bicarbonate therapy [4]. The patient improved rapidly under this treatment and was extubated on the next day after pH normalisation and lactate clearance. She was transferred to the internal medicine ward after 48 h and finally discharged from the hospital 10 days later, after full renal recovery.\n\n3. Discussion\nSOB is a major complaint among pre-hospital and ED patients, accounting for over 3.9 million visits in 2017 in the United States [5]. Most of these visits involve patients over 65 years old. Generally, cases of SOB are readily identified and can be ascribed to frequent aetiologies, i.e., heart failure (43%), community-acquired pneumonia (35%), acute exacerbation of chronic respiratory disease (32%), pulmonary embolism (18%), and acute asthma (3%). Two coexisting causes of SOB are found in as many as 47% of patients [6]. Nevertheless, clinicians must be aware that other less frequent aetiologies of SOB should be considered (salicylate intoxication, carbon monoxide poisoning, toxin-related metabolic acidosis, diabetic ketoacidosis, sepsis, anaemia, etc.). They should also acknowledge that diagnosing infrequent causes of SOB might be challenging, especially in the pre-hospital setting, where resources are limited and most investigation tools unavailable. Inappropriate dismissal of infrequent causes of SOB might lead to delayed diagnosis and treatment. Such delays might prove harmful, most particularly in old and frail patients.\n\nOur case exemplifies how pre-hospital ABG measurement can easily improve diagnostic accuracy in such cases. In our prehospital system and in many European countries, trained physicians can be dispatched by EMCCs to provide medical care in the field [7], and can therefore draw and analyze ABG. However, even though recent and compact point-of-care testing devices allow for quick and reliable ABG analysis in the field [8], most emergency medical systems still lack such tools in their standard equipment. Barriers to the implementation of ABG analysis devices in the field have scarcely been described, but might include the absence of prehospital emergency physicians to interpret the results and the fear of unnecessarily delaying transport. Prehospital systems unable to dispatch emergency physicians in the field could however develop specific procedures to allow the use of and interpretation of ABG. Paramedics could be trained to draw arterial blood, protocols could be created to help paramedics determine cases in which ABG analysis could be of use, and distance interpretation by medical supervisors could be considered. Similar procedures have been successfully developed regarding electrocardiographic interpretation [9,10]. In the absence of distance medical supervision, regular algorithms or even electronic apps could be developed to facilitate the interpretation of ABG results [11,12]. Unnecessarily delaying transport could be avoided by limiting and clearly identifying the indications to ABG analysis, and by limiting the number of attempts and the time allowed to draw arterial blood. Moreover, other procedures can be performed while blood is drawn and analyzed, thereby further limiting potential delays. In our system, physicians are allowed only one attempt in a maximum of 60 s.\n\nAbsolute contraindications to ABG sampling can usually be clinically identified easily (local infection, thrombosis or distorted anatomy, severe peripheral vascular disease, abnormal Allen’s test, etc.), and serious complications (infection, arterial occlusion or embolism, nerve injury, pseudo-aneurysm or vessel laceration, etc.) are rare. Minor complications (local pain, minor bleeding or hematoma, vasovagal response, etc.) can be easily managed and anticoagulants or antiplatelet agents do not represent absolute contraindications but often require only increased vascular pressure. Although venous sampling could lead to misdiagnosis, providers can be trained to recognize such samples.\n\nIn this particular case, onsite ABG analysis allowed the physician to suspect metformin-associated metabolic acidosis and start the appropriate treatment even in the pre-hospital setting. While previous studies have failed to show a general positive effect of prehospital ABG on diagnostic accuracy, it can be of significant benefit in specific situations [13]. Moreover, ABG has been shown to improve treatment quality in critically ill patients [13]. In our system, prehospital physicians notify the Emergency Department (ED) team through the EMCC and can activate specific medical support before arrival. Consultants are thus notified before the patient’s arrival in the ED, thereby accelerating the initiation of appropriate and definitive care. In our institution, the decision to initiate haemodialysis is made either by nephrologists or by ICU physicians. In this particular case, the prehospital physician asked for the ICU consultant to be present upon arrival in the ED based on the suspected diagnosis. The patient was therefore quickly assessed by a multidisciplinary team, and therapeutic decisions were rapidly made. All further necessary steps (intubation, ICU admission, dialysis catheter insertion, haemodialysis initiation) were quickly initiated, and the time spent in the ED was therefore limited to a minimum.\n\nMetformin-associated metabolic acidosis is a rare but well-known complication of metformin treatment. Its incidence was calculated to be 4.3 cases per 100,000 patient-years [14]. When it develops, mortality rates as high as 48% have been reported [15,16]. Clinically significant metformin intoxication and lactic acid accumulation almost always occur in the presence of comorbid conditions, such as impaired kidney function. In our case, the patient indeed presented a KDIGO stage 3 acute kidney injury due to pre-renal disease consecutive to severe dehydration and sepsis. Prompt identification and treatment are mandatory in such cases, but diagnosis might be particularly difficult because of aspecific presentation. Moreover, acidaemia can be profound even though the patient does not seem to be critically ill.\n\nAlthough the main cause of the lactic acidosis found on ABG analysis was rapidly identified in this case, other potential aetiologies should be always considered. These include severe sepsis, shock, anemia, seizures, hypoxemia, carbon monoxide or cyanide poisoning, ethylene glycol or salicylates intoxication, alcoholism and liver disease, beta-agonist medication or profound thiamine deficit [17]. In our situation, these aetiologies were rapidly excluded by clinical appreciation and laboratory analysis.\n\nThe role of bicarbonates infusion is still debated in metformin-associated metabolic acidosis as in other causes of anion gap metabolic acidosis [18]. In our case, this treatment was administered given the profound acidaemia and the signs of respiratory exhaustion, with the aim of avoiding endotracheal intubation. As the patient did not improve under supportive care and bicarbonate infusion, the decision to employ extracorporeal removal was swiftly made and, by virtue of a rapid diagnostic path, haemodialysis was started approximately 6 hours after the first medical contact. Haemodialysis has been shown to be effective in cases of metformin-associated metabolic acidoses [19] and is recommended in patients showing signs of severe poisoning. These signs include a lactate concentration higher than 20 mmol/L, a pH ≤ 7.0, or failure to improve with standard treatment within a few hours [4] as in our case.\n\n4. Conclusions\nThis case report shows that prehospital ABG measurement is feasible and can improve diagnostic accuracy in the field. In this particular case, ABG analysis enabled the prehospital physician to make the correct diagnosis in a timely manner, thus allowing the appropriate treatment to be initiated before hospital admission. Unnecessary delay and potential harm to the patient were thereby avoided.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAuthor Contributions\nWriting—original draft preparation, P.E.F. and L.S.; writing—review and editing, P.E.F. and L.S. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research received no external funding.\n\nInstitutional Review Board Statement\nNot applicable.\n\nInformed Consent Statement\nInformed consent was obtained from the patient whose case is reported in this manuscript.\n\nData Availability Statement\nNot applicable.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n==== Refs\nReferences\n1. Lindskou T.A. Weinreich U.M. Lübcke K. Kløjgaard T.A. Lauresen B.S. Mikkelsen S. Christensen E.F. Patient experience of severe acute dyspnoea and relief during treatment in ambulances: A prospective observational study Scand. J. Trauma Resus. 2020 28 10.1186/s13049-020-0715-2 32245510 \n2. Gartner B.A. Fehlmann C. Suppan L. Niquille M. Rutschmann O. Sarasin F. Effect of noninvasive ventilation on intubation risk in prehospital patients with acute cardiogenic pulmonary edema: A retrospective study Eur. J. Emerg. Med. 2020 27 54 58 10.1097/MEJ.0000000000000616 31295150 \n3. Khwaja A. Kidney Disease Improving Global outcomes. KDIGO clinical practice guidelines for acute kidney injury Nephron. Clin. Pract. 2012 120 179 184 \n4. Calello D.P. Liu K.D. Wiegand T.J. Roberts D.M. Lavergne V. Gosselin S. Hoffman R.S. Nolin T.D. Ghannoum M. Extracorporeal Treatment for Metformin Poisoning: Systematic Review and Recommendations From the Extracorporeal Treatments in Poisoning Workgroup Crit. Care Med. 2015 43 1716 1730 10.1097/CCM.0000000000001002 25860205 \n5. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Stat National Hospital Ambulatory Medical Care Survey: 2017 Emergency Department Summary Tables Available online: https://www.cdc.gov/nchs/data/nhamcs/web_tables/2017_ed_web_tables-508.pdf (accessed on 11 September 2020) \n6. Ray P. Birolleau S. Lefort Y. Becquemin M.H. Beigelman C. Isnard R. Teixeira A. Arthaud M. Riou B. Boddaert J. Acute respiratory failure in the elderly: Etiology, emergency diagnosis and prognosis Crit. Care 2006 10 82 10.1186/cc4926 16723034 \n7. Suppan L. Chan M. Gartner B. Regard S. Campana M. Chattelard G. Cottet P. Larribau R. Sarasin F. Niquille M. Evaluation of a Prehospital Rotation by Senior Residents: A Web-Based Survey Healthcare 2021 9 24 10.3390/healthcare9010024 33383633 \n8. Mikkelsen S. Wolsing-Hansen J. Nybo M. Maegaard C.U. Jepsen S. Implementation of the ABL-90 blood gas analyzer in a ground-based mobile emergency care unit Scand. J. Trauma Resusc. Emerg. Med. 2015 23 23 10.1186/s13049-015-0134-y 25888472 \n9. Wermann H.A. Newland R. Cotton B. Transmission of 12-lead electrocardiographic tracings by Emergency Medical Technician-Basics and Emergency Medical Technician-Intermediates: A feasibility study Am. J. Emerg. Med. 2011 29 437 440 10.1016/j.ajem.2010.01.015 20825850 \n10. Brokmann J.C. Conrad C. Rossaint R. Beckers S.K. Uschner D. Brokmann J.C. Treatment of Acute Coronary Syndrome by Telemedically Supported Paramedics Compared With Physician-Based Treatment: A Prospective, Interventional, Multicenter Trial J. Med. Internet Res. 2016 18 10.2196/jmir.6358 27908843 \n11. Segal E. Ross D. Proulx M.H. Xue X. Vacon C. Derivation and validation of the Montreal prehospital ST-elevation myocardial infarction activation rule J. Electrocardiol. 2019 59 10 16 10.1016/j.jelectrocard.2019.12.013 31931466 \n12. Vaid A. Somani S. Russak A.J. Freitas J.K.D. Chaudhry F.F. Paranjpe I. Johnson K.W. Lee S.J. Miotto R. Richter F. Machine Learning to Predict Mortality and Critical Events in a Cohort of Patients With COVID-19 in New York City: Model Development and Validation J. Med. Internet Res. 2020 22 10.2196/24018 33027032 \n13. Zwisler S.T. Zincuk Y. Bering C.B. Zincuk A. Nybo M. Mikkelsen S. Diagnostic value of prehospital arterial blood gas measurements—A randomised controlled trial. Scand J. Trauma Resusc. Emerg. Med. 2019 27 32 10.1186/s13049-019-0612-8 30885262 \n14. Salpeter S.R. Greyber E. Pasternak G.A. Salpeter E.E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus Cochrane Database Syst. Rev. 2010 4 10.1002/14651858.CD002967.pub3 \n15. Lalau J.D. Race J.M. Lactic acidosis in metformin-treated patients. Prognostic value of arterial lactate levels and plasma metformin concentrations Drug. Saf. 1999 20 377 840 10.2165/00002018-199920040-00006 10230584 \n16. Seidowsky A. Nseir S. Houdret N. Fourrier F. Metformin-associated lactic acidosis: A prognostic and therapeutic study Crit. Care Med. 2009 37 2191 2196 10.1097/CCM.0b013e3181a02490 19487945 \n17. Kraut J.A. Madias N.E. Lactic Acidosis N. Engl. J. Med. 2014 371 2309 2319 10.1056/NEJMra1309483 25494270 \n18. Jaber S. Paugam C. Futier E. Lefrant J.Y. Lasocki S. Lescot T. Pottecher J. Demoule A. Ferrandiere M. Asehnoune K. Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): A multicentre, open-label, randomised controlled, phase 3 trial Lancet 2018 392 31 10.1016/S0140-6736(18)31080-8 29910040 \n19. Lalau J.D. Andrejak M. Morinière P. Coevoet B. Debussche X. Westeel P.F. Fournier A. Quichaud J. Hemodialysis in the treatment of lactic acidosis in diabetics treated by metformin: A study of metformin elimination Int. J. Clin. Pharmacol. Ther. Toxicol. 1989 27 285 288 2500402\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2227-9032",
"issue": "9(1)",
"journal": "Healthcare (Basel, Switzerland)",
"keywords": "arterial blood gas; metabolic acidosis; metformin poisoning; prehospital; respiratory distress",
"medline_ta": "Healthcare (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101666525",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33466796",
"pubdate": "2021-01-14",
"publication_types": "D002363:Case Reports",
"references": "2500402;27908843;30885262;26224063;31295150;22890468;33383633;31931466;20091535;25494270;10230584;29910040;33027032;16723034;20825850;19487945;25860205;32245510",
"title": "Prehospital Diagnosis of Shortness of Breath Caused by Profound Metformin-Associated Metabolic Acidosis.",
"title_normalized": "prehospital diagnosis of shortness of breath caused by profound metformin associated metabolic acidosis"
} | [
{
"companynumb": "CH-EMD SERONO-9216400",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional": "3"... |
{
"abstract": "A 76-year-old woman had underwent 5-fluorouracil(5-FU), oxaliplatin(L-OHP)combination therapy(mFOLFOX6)as first-line chemotherapy for peritoneal recurrence after resection of sigmoid colon cancer. She showed severe general fatigue and disturbance of consciousness on the second day of the 12th course of chemotherapy. Computed tomography of the head detected no abnormal findings in the central nervous system. The laboratory results revealed a marked hyperammonemia. She was diagnosed as a disturbance of consciousness due to hyperammonemia and treated her with branched- chain amino acid solution. Then the disturbance of consciousness resolved on the following day. After changing the regimen of chemotherapy, the disturbance of consciousness was not found. Recently, it has been reported that high-dose 5-FU regimen such as mFOLFOX6 causes hyperammonemia as a rare adverse event. We should take hyperammonemia into account when disturbance of consciousness occurs during high-dose 5-FU chemotherapy.",
"affiliations": "Dept. of Surgery, Osaka City Juso Hospital.",
"authors": "Kaizaki|Ryoji|R|;Inoue|Toru|T|;Eguchi|Shinpei|S|;Nishiyama|Tsuyoshi|T|;Nobori|Chihoko|C|;Kunimoto|Tomohiro|T|;Okazaki|Yuki|Y|;Takatsuka|Satoshi|S|;Tsukamoto|Tadashi|T|;Nishiguchi|Yukio|Y|",
"chemical_list": "D002955:Leucovorin; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "47(13)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003243:Consciousness; D005260:Female; D005472:Fluorouracil; D006801:Humans; D022124:Hyperammonemia; D002955:Leucovorin; D009364:Neoplasm Recurrence, Local; D012811:Sigmoid Neoplasms",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1777-1779",
"pmc": null,
"pmid": "33468826",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Disturbance of Consciousness Due to Hyperammonemia during Chemotherapy for Metastasis of Sigmoid Colon Cancer.",
"title_normalized": "a case of disturbance of consciousness due to hyperammonemia during chemotherapy for metastasis of sigmoid colon cancer"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022RR-331860",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"dru... |
{
"abstract": "Wiskott-Aldrich-Syndrome (WAS) is a rare X-linked recessive disease caused by mutations of the WAS gene. It is characterized by immunodeficiency, autoimmunity, low numbers of small platelets (microthrombocytopenia) and a high risk of cancer, especially B cell lymphoma and leukemia.",
"affiliations": "Dr. von Hauner Children's Hospital; Ludwig Maximilians University Munich ; Munich, Germany.;Dr. von Hauner Children's Hospital; Ludwig Maximilians University Munich ; Munich, Germany.;Department of Translational Oncology; National Center for Tumor Diseases and German Cancer Research Center; Heidelberg, Germany; New address: BioNTech AG; Mainz, Germany.;Department of Pediatric Hematology/Oncology; Hannover Medical School; Hannover, Germany; Present address: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences/Department of Pediatrics and Adolescent Medicine, Medical University of Vienna; Vienna, Austria.;Department of Translational Oncology; National Center for Tumor Diseases and German Cancer Research Center ; Heidelberg, Germany.;Department of Translational Oncology; National Center for Tumor Diseases and German Cancer Research Center ; Heidelberg, Germany.;Dr. von Hauner Children's Hospital; Ludwig Maximilians University Munich ; Munich, Germany.",
"authors": "Braun|Christian Joerg|CJ|;Witzel|Maximilian|M|;Paruzynski|Anna|A|;Boztug|Kaan|K|;von Kalle|Christof|C|;Schmidt|Manfred|M|;Klein|Christoph|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4161/21675511.2014.947749",
"fulltext": "\n==== Front\nRare DisRare DisKRADRare Diseases2167-5511Taylor & Francis 94774910.4161/21675511.2014.947749AddendumGene therapy for Wiskott-Aldrich Syndrome—Long-term reconstitution and clinical benefits, but increased risk for leukemogenesis Braun Christian Joerg 1Witzel Maximilian 1Paruzynski Anna 2†Boztug Kaan 3‡von Kalle Christof 2Schmidt Manfred 2Klein Christoph 1*1 Dr. von Hauner Children's Hospital; Ludwig Maximilians University Munich; Munich, Germany2 Department of Translational Oncology; National Center for Tumor Diseases and German Cancer Research Center; Heidelberg, Germany3 Department of Pediatric Hematology/Oncology; Hannover Medical School; Hannover, Germany† New address: BioNTech AG; Mainz, Germany‡ Present address: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences/Department of Pediatrics and Adolescent Medicine, Medical University of Vienna; Vienna, Austria* Correspondence to: Christoph Klein; Email: christoph.klein@med.uni-muenchen.dehttp://dx.doi.org/10.4161/21675511.2014.947749\n\n2014 30 10 2014 30 10 2014 2 1 e9477496 5 2014 6 7 2014 16 7 2014 © 2014 Taylor & Francis, LLC2014Taylor & Francis, LLCThis is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License http://creativecommons.org/licenses/by-nc/3.0/, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.Wiskott-Aldrich-Syndrome (WAS) is a rare X-linked recessive disease caused by mutations of the WAS gene. It is characterized by immunodeficiency, autoimmunity, low numbers of small platelets (microthrombocytopenia) and a high risk of cancer, especially B cell lymphoma and leukemia.\n\nKeywords\nWiskott-Aldrich-Syndromegene therapyinsertional mutagenesisleukemiaimmunodeficiency\n==== Body\nAbbreviations\nWASWiskott-Aldrich-Syndrome\n\nHSCThaematopoietic stem cell transplantation\n\nWASPWAS protein\n\nHLAhuman leukocyte antigen\n\nGTgene therapy, HSC, haematopoietic stem cell\n\nCGDchronic granulomatous disease\n\nADAadenosine deaminase\n\nSCIDsevere combined immunodeficiency\n\nrhG-CSFrecombinant human granulocyte colony-stimulating factor\n\nLTRlong terminal repeat\n\nLAM-PCRlinear amplification-mediated polymerase chain reaction\n\nnrnonrestrictive\n\nISsinsertion sites\n\nTSStranscription start site\n\nT-ALLT-cell acute lymphoblastic leukemia\n\nAMLacute myeloid leukemia\n\nSINself-inativating\n\n\nHaematopoietic stem cell transplantation (HSCT) is considered the standard curative therapy option – but the procedure can have major side effects and is limited by donor availability. Gene therapy with gammaretroviral vectors is able to overcome some of these shortcomings and lead to (at least a partial and temporary) functional immune system reconstitution, but it is associated with the development of leukemia after viral integration and oncogene transactivation. The high rate of integration-associated oncogene activation underlines the necessity for the development and application of safer genome-engineering technologies with similar efficacy and reduced toxicity.\n\nWiskott-Aldrich-Syndrome (WAS) is a rare X-linked recessive disease caused by mutations of the WAS gene1 and characterized by autoimmunity, low numbers of small platelets (microthrombocytopenia), immunodeficiency, and a high risk of cancer, especially B cell lymphoma and leukemia.2 WAS protein (WASP) acts as a key regulator for the polymerization of actin in haematopoietic cells.3 WASP deficiency, therefore, leads to malfunctions of different leukocyte subsets, including defective T and B cell responses, impaired migration, and significant impairment of NK immunological synapse formation.4,5 Severe and generalized infections, bleeding and malignancies lead to an early death in severe WAS.6 The standard therapy is allogeneic HSCT. Although this is usually an effective and curative treatment, it is often associated with significant morbidity and sometimes mortality, especially if no human leukocyte antigen (HLA)-matched HSCT donor is available.7\n\nGene Therapy as an Alternative Treatment for WAS Leads to Molecular Und Functional Correction of Disease\nOver the last decades, gammaretrovirus-based HSC gene therapy (GT) has emerged as an alternative therapeutic strategy for the treatment of hereditary diseases of the immune system (reviewed in8,9). Patients suffering from chronic granulomatous disease (CGD),10 adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID),11,12 and X-linked SCID13-15 experienced clinical improvements and at least partial or temporary correction of immune cell functions. However, severe clinical side-effects, including acute leukemia secondary to insertional mutagenesis and activation of proto-oncogenes, have raised concerns about therapeutic safety.16-22\n\nTen patients suffering from WAS were treated with haematopoietic GT using classical gammaretroviral vectors between 2006 and 2009.23,24 Briefly, after stimulation with recombinant human granulocyte colony-stimulating factor (rhG-CSF) and/or plerixafor, peripheral mononuclear cells were harvested and transduced with a replication-incompetent gammaretroviral vector that expressed a healthy copy of WAS driven by a murine stem cell virus-derived long terminal repeat (LTR) sequence. Patients were conditioned using myeloablative busulfan therapy (8mg/kg) prior to reinfusion of transduced cells. After GT, we were able to observe a strong and sustained expression of WASP in peripheral nuclear blood cells and in platelets, along with an overall reconstitution of lymphocyte function. Patients also showed remarkable clinical improvements with partial to complete resolution of autoimmunity, bleeding diathesis and susceptibility for infections.\n\nA few specific lessons of this study are outlined below:\n\nAge at GT Might Influence Speed of Haematopoietic Reconstitution\nWhile most of our patients were young children at the time of treatment and mostly reconstituted fast after GT, one patient at the age of 14 at the time of GT experienced only a slow reconstitution of his immune system. A similar observation had already been described in a GT trial for X-SCID,25 thus pointing to a potentially slower overall reconstitution in older patients.\n\nGammaretroviral Gene Therapy Vector Integration Favors Certain Genomic Regions\nRetroviral insertion site (IS) analysis using standard and nonrestrictive (nr) linear amplification-mediated polymerase chain reaction (LAM-PCR)26 revealed more than 140,000 unambiguous ISs with an initially highly polyclonal repopulation of the haematopoietic system. A comprehensive analysis of IS patterns demonstrated a typical gammaretroviral insertion pattern with integrations accumulating at transcription start sites (TSS) of gene-coding regions. The majority of most frequently affected genes had previously been described as proto-oncogenes (including MECOM27 and LMO228).\n\nInsertional Mutagenesis Leads to Gene Activation and the Development of Haematopoietic Malignancies\nSix patients developed T-cell acute lymphoblastic leukemia (T-ALL) between 16 months and 5 y after GT, all of whom carried gammaretroviral insertion within or close to the LMO2 gene locus. One patient developed acute myeloid leukemia (AML) and LAM-PCR identified an insertion within the MSD1 gene locus. Insertion site kinetics prior to onset of leukemia were markedly diverse. Whereas all T-ALL patients had a polyclonal IS pattern without indications for a clonal outgrowth, the patient developing AML showed a slow increase of a MDS1 clone contribution over time. Of note, 2 patients with T-ALL developed AML shortly after or during maintenance therapy, with dominant clones harboring vector ISs close to either MDS1 or MN1 gene loci, respectively. In summary, we were able to demonstrate the feasibility of GT for WAS and the sustainability of WAS gene expression and functional correction over years, but also that classical gammaretroviral gene therapy is associated with an unacceptably high rate of secondary malignancies in WAS, raising considerable safety concerns.\n\nTreatment Strategy for Leukemic Patients after GT\nPatients WAS6, WAS7, WAS9 and WAS10 underwent allogeneic HSCT between 4 and 12 months after their initial diagnosis of T-ALL. Up to date (June 2014) they are in complete remission. Patients WAS1 and WAS8 reached a state of complete clinical, morphological and molecular remission using chemotherapy, but developed AML more than a year after their initial T-ALL diagnosis. They received induction chemotherapy and were treated with allogeneic HSCT. Patient WAS1 is in complete remission (June 2014) whereas patient WAS8 succumbed to transplant-related toxicities. Patient WAS5 had an early leukemia relapse while on consolidation chemotherapy. He has achieved a second state of remission using chemotherapy and was treated by allogeneic HSCT. However, leukemia relapsed and he subsequently succumbed to progressive leukemia.\n\n“Self-inactivating” Vectors as a Novel Tool for Gene Therapy\nOver the last years, significant improvements to viral vectors have been proposed and tested experimentally. One of the major advancements is probably the creation of so-called “self-inactivating” (SIN) viruses. By deleting enhancer elements in the LTR region and using internal mammalian promoters, the ability of SIN viruses to transactivate genomic loci in the proximity of the viral IS is dramatically reduced.29 In contrast to gammaretroviral vectors, lentiviral vectors are characterized by their ability to transduce non-dividing (stem) cells and a genomic integration pattern that does not favor the promoter-region of genes as much as gammaretroviruses do.30 However, choosing the right internal promoter can be difficult. While strong and ubiquitously active promoters may offer strong expression of the respective gene of interest, concerns have arisen about pathological effects of non-physiological gene expression in defined cellular lineages.31,32 This may not be a concern in WAS (WAS-protein is physiologically expressed in all nucleated haematopoietic cells and in platelets), yet tissue-specific promoters, like the reconstituted physiological WAS promoter for the first SIN-lenti gene therapy trial for WAS,33 may promise more physiological lineage-specific gene expression. However, intrinsic promoters are not yet readily available for every gene of interest. In addition to using endogenous promoters, replacing VSV-G pseudotyping with a target-cell-specific envelope might help to increase specificity and limit potential-side effects.34,35\n\nValue of Insertion Site Monitoring to Predict Onset of Leukemia and for Treatment Decisions\nIn contrast to the first 2 patients enrolled in the Paris trial for γc-SCID,18,19 whose clones harboring LMO2 gene insertions increased slowly and steadily, IS monitoring could not predict the onset of the fast progressing T-ALL in our patients (regular follow-up analysis was undertaken at intervals of 3 to 6 months). A possible reason for the fast T-ALL progression may be a pre-leukemic clone expansion in a poorly accessible niche like the thymus or lymph nodes, and the acute release of those clones at the onset of leukemia. In contrast, for 2 of the AML patients, an increase of contribution of clones with insertions in close proximity to the MECOM gene locus had been detected months prior to onset of leukemia, suggesting a slow expansion of a (pre-)malignant clone. In general, integration site analysis is useful to identify integration clusters in certain gene loci, i.e. LMO2 and MECOM, to reveal whether in vivo clonal selection occurs, and whether proto-oncogenes or cell proliferating genes are involved. IS monitoring can help to predict the onset of AML and, depending on donor availability, an early bone marrow transplant can be considered. Even though monitoring clearly did not help to predict the onset of T-ALL by particular clones, the degree of polyclonality reconstitution during treatment can be helpful for the assessment of the risk probability of future malignant transformation and facilitate the decision on the need for an eventual stem cell transplantation (again depending on donor availability).\n\nPopulation Dynamics and Homeostatic Control–how Human Gene Therapy Trials Significantly Differ from Insertional Mutagenesis Observed in vitro\nBoth the activation of oncogenes and the functional inactivation of tumor-suppressors after viral insertion into the genome are known risk factors for tumor development, and, therefore, have always been a major concern and point of discussion during the development of human gene therapy trials.36,37 While one single insertional transactivation of an oncogene can, theoretically, be enough to facilitate cellular expansion, malignant transformation typically requires the occurrence of at least a second hit. Furthermore, biological filters may prevent a dominant clonal outgrowth – for example, the activation of strong oncogenes in otherwise normal cells can lead to oncogenic stress and the subsequent activation of tumor-suppressor pathways and cell cycle arrest or cell death.38 Noteworthy, natural killer (NK) cells, monocytes and certain subsets of T cells (all of which are less functional in severe WAS) have important roles in the physiological anti-tumor immune response.39 It has been shown that expression of functional WAS protein in a WASP-negative cell can reconstitute the proliferative defects.40 It is unclear, however, if unphysiologically high levels of transgene expression may render haematopoietic cells more prone to expansion, possibly without dominant mutagenesis, after vector insertion. The use of SIN retroviral vectors with weaker and physiologically active endogenous promoters may prevent this “overcorrection” and make cells less susceptible to undergo clonal dominance.\n\nThe first HSCT studies using gammaretroviral vectors have yielded ambiguous results. Ectopic expression of the common gamma chain in γc-SCID patients resulted in T-cell ALL in 5 out of 20 patients, whereas expression of adenosine deaminase in ADA-SCID patients has not led to leukemogenesis. All patients and parents were informed about a risk of leukemogenesis prior to accrual.\n\nConclusions\nWe have demonstrated that gene therapy for WAS using classical gammaretroviral vectors is feasible and can lead to long-term correction of the disease, but the rate of leukemogenesis associated with integrational gene activation is very high. New vector designs incorporating self-inactivating LTR configurations and mammalian promoters may improve safety.33 Even though long-term observations on efficacy and safety are still pending, there is hope that the introduction of these features will reduce side effects while preserving therapeutic efficacy over many years. The development of novel genome-engineering tools may offer new therapeutic strategies for patients with WAS and other primary immunodeficiency disorders.\n\nDisclosure of Potential Conflicts of Interest\nNo potential conflict of interest was disclosed.\n==== Refs\nReferences\n1. \nDerry JM , Ochs HD , Francke U . Isolation of a novel gene mutated in wiskott-aldrich syndrome . Cell \n1994 ; 78 :635 -44 ; PMID:8069912; http://dx.doi.org/10.1016/0092-8674(94)90528-28069912 \n2. \nOchs HD , Filipovich AH , Veys P , Cowan MJ , Kapoor N . Wiskott-aldrich syndrome: diagnosis, clinical and laboratory manifestations, and treatment . Biol. Blood Marrow Transpl \n2009 ; 15 :84 -90 ; PMID:19147084; http://dx.doi.org/10.1016/j.bbmt.2008.10.00719147084 \n3. \nThrasher AJ . Wasp in immune-system organization and function . Nat Rev Immunol \n2002 ; 2 :635 -46 ; PMID:12209132; http://dx.doi.org/10.1038/nri88412209132 \n4. \nBouma G , Burns SO , Thrasher AJ \nWiskott–aldrich syndrome: immunodeficiency resulting from defective cell migration and impaired immunostimulatory activation . Immunobiology \n2009 ; 214 :778 -90 .19628299 \n5. \nBanerjee PP , Pandey R , Zheng R , Suhoski MM , Monaco-Shawver L , Orange JS . Cdc42-interacting protein-4 functionally links actin and microtubule networks at the cytolytic NK cell immunological synapse . J Exp Med \n2007 ; 204 :2305 -20 ; PMID: 17785506; http://dx.doi.org/10.1084/jem.2006189317785506 \n6. \nImai K , Morio T , Zhu Y , Jin Y , Itoh S , Kajiwara M , Yata J-I , Mizutani S , Ochs HD , Nonoyama S , Clinical course of patients with WASP gene mutations . Blood \n2004 ; 103 :456 -64 ; PMID:12969986; http://dx.doi.org/10.1182/blood-2003-05-148012969986 \n7. \nMoratto D , Giliani S , Bonfim C , Mazzolari E , Fischer A , Ochs HD , Cant AJ , Thrasher AJ , Cowan MJ , Albert MH , et al. \nLong-term outcome and lineage-specific chimerism in 194 patients with wiskott-aldrich syndrome treated by hematopoietic cell transplantation in the period 1980-2009: an international collaborative study . Blood \n2011 ; 118 :1675 -84 ; PMID:21659547; http://dx.doi.org/10.1182/blood-2010-11-31937621659547 \n8. \nKay MA . State-of-the-art gene-based therapies: the road ahead . Nat Rev Genet \n2011 ; 12 :316 -28 ; PMID:21468099; http://dx.doi.org/10.1038/nrg297121468099 \n9. \nFischer A , Hacein-Bey Abina S , Cavazzana-Calvo M . 20 years of gene therapy for SCID . Nat Immunol \n2010 ; 11 :457 -60 ; PMID:20485269; http://dx.doi.org/10.1038/ni0610-45720485269 \n10. \nOtt MG , Schmidt M , Schwarzwaelder K , Stein S , Siler U , Koehl U , Glimm H , Kühlcke K , Schilz A , Kunkel H , et al. \nCorrection of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1 . Nat Med \n2006 ; 12 :401 -9 ; PMID: 16582916; http://dx.doi.org/10.1038/nm139316582916 \n11. \nAiuti A . Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning . Science \n2002 ; 296 :2410 -3 ; PMID:12089448; http://dx.doi.org/10.1126/science.107010412089448 \n12. \nAiuti A , Cattaneo F , Galimberti S \nGene therapy for immunodeficiency due to adenosine deaminase deficiency – NEJM, … \nEngl J \n2009 ; 360 :447 -58 .\n13. \nCavazzana-Calvo M , Hacein-Bey S , de Saint Basile G , Gross F , Yvon E , Nusbaum P , Selz F , Hue C , Certain S , Casanova JL , et al. \nGene therapy of human severe combined immunodeficiency (SCID)-X1 disease . Science \n2000 ; 288 :669 -72 ; PMID:10784449; http://dx.doi.org/10.1126/science.288.5466.66910784449 \n14. \nHacein-Bey Abina S , Le Deist F , Carlier F , Bouneaud C , Hue C , De Villartay J-P , Thrasher AJ , Wulffraat N , Sorensen R , Dupuis-Girod S , et al. \nSustained correction of X-Linked severe combined immunodeficiency by ex vivo gene therapy . N Engl J Med \n2002 ; 346 :1185 -93 ; PMID:11961146; http://dx.doi.org/10.1056/NEJMoa01261611961146 \n15. \nHacein-Bey Abina S , Hauer J , Lim A , Picard C. , Wang GP , Berry CC , Martinache C , Rieux-Laucat F , Latour S , Belohradsky BH , et al. \nEfficacy of gene therapy for X-Linked severe combined immunodeficiency . N Engl J Med \n2010 ; 363 :355 -64 ; PMID: 20660403; http://dx.doi.org/10.1056/NEJMoa100016420660403 \n16. \nDave UP . Gene therapy insertional mutagenesis insights . Science \n2004 ; 303 :333 ; PMID:14726584; http://dx.doi.org/10.1126/science.109166714726584 \n17. \nHacein-Bey Abina S , Garrigue A , Wang G P , Soulier J , Lim A , Morillon E , Clappier E , Caccavelli L , Delabesse E , Beldjord K , et al. \nInsertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. \nJ Clin Invest \n2008 ; 118 :3132 -42 ; PMID:18688285; http://dx.doi.org/10.1172/JCI3570018688285 \n18. \nHacein-Bey Abina S , von Kalle C , Schmidt M , Le Deist F , Wulffraat N , McIntyre E , Radford I , Villeval J-L , Fraser CC , Cavazzana-Calvo M , et al. \nAdverse event after successful gene therapy for X-linked severe combined immunodeficiency . N Engl J Med \n2003 ; 348 :255 -6 ; PMID:12529469; http://dx.doi.org/10.1056/NEJM20030116348031412529469 \n19. \nHacein-Bey Abina S , Von Kalle C , Schmidt M , McCormack M P , Wulffraat N , Leboulch P , Lim A , Osborne CS , Pawliuk R , Morillon E , et al. \nLMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1 . Science \n2003 ; 302 :415 -9 ; PMID:14564000; http://dx.doi.org/10.1126/science.108854714564000 \n20. \nHowe SJ , Mansour MR , Schwarzwaelder K , Bartholomae C , Hubank M , Kempski H , Brugman MH , Pike-Overzet K , Chatters SJ , de Ridder D , et al. \nInsertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients . J Clin Invest \n2008 ; 118 :3143 -50 ; PMID:18688286; http://dx.doi.org/10.1172/JCI3579818688286 \n21. \nOtt MG , Schmidt M , Schwarzwaelder K , Stein S , Siler U , Koehl U , Glimm H , Kühlcke K , Schilz A , Kunkel H , et al. \nCorrection of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1 . Nat Med \n2006 ; 12 :401 -9 ; PMID: 16582916; http://dx.doi.org/10.1038/nm139316582916 \n22. \nStein S , Ott MG , Schultze-Strasser S , Jauch A , Burwinkel B , Kinner A , Schmidt M , Krämer A , Schwäble J , Glimm H , et al. \nGenomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease . Nat Med \n2010 ; 16 :198 -204 ; 1 -8 ; PMID:2005738820098431 \n23. \nBoztug K , Schmidt M , Schwarzer A , Banerjee PP , Díez IA , Dewey RA , Böhm M , Nowrouzi A , Ball CR , Glimm H , et al. \nStem-cell gene therapy for the Wiskott-Aldrich syndrome . N Engl J Med \n2010 ; 363 :1918 -27 ; PMID:21067383; http://dx.doi.org/10.1056/NEJMoa100354821067383 \n24. \nBraun CJ , Boztug K , Paruzynski A , Witzel M , Schwarzer A , Rothe M , Modlich U , Beier R , Göhring G , Steinemann D , et al. \nGene therapy for wiskott-aldrich syndrome–long-term efficacy and genotoxicity . Sci Transl Med \n2014 ; 6 :227ra33 ; PMID: 24622513; http://dx.doi.org/10.1126/scitranslmed.300728024622513 \n25. \nThrasher AJ , Hacein-Bey Abina S , Gaspar HB , Blanche S , Davies EG , Parsley K , Gilmour K , King D , Howe S , Sinclair J , et al. \nFailure of SCID-X1 gene therapy in older patients . Blood \n2005 ; 105 :4255 -7 ; PMID:15687233; http://dx.doi.org/10.1182/blood-2004-12-483715687233 \n26. \nSchmidt M , Schwarzwaelder K , Bartholomae C , Zaoui K , Ball C , Pilz I , Braun S , Glimm H , von Kalle C . High-resolution insertion-site analysis by linear amplification-mediated PCR (LAM-PCR) . Nat Methods \n2007 ; 4 :1051 -7 ; PMID:18049469; http://dx.doi.org/10.1038/nmeth110318049469 \n27. \nHo PA , Alonzo TA , Gerbing RB , Pollard J A , Hirsch B , Raimondi SC , Cooper T , Gamis AS , Meshinchi S . High EVI1 expression is associated with MLL rearrangements and predicts decreased survival in paediatric acute myeloid leukaemia: a report from the children's oncology group . Br J Haematol \n2013 ; 162 :670 -7 ; PMID:23826732; http://dx.doi.org/10.1111/bjh.1244423826732 \n28. \nNam C-H , Rabbitts TH . The Role of LMO2 in development and in T cell leukemia after chromosomal translocation or retroviral insertion . Mol Ther \n2006 ; 13 :15 -25 ; PMID:16260184; http://dx.doi.org/10.1016/j.ymthe.2005.09.01016260184 \n29. \nModlich U , Navarro S , Zychlinski D , Maetzig T , Knoess S , Brugman MH , Schambach A , Charrier S , Galy A , Thrasher AJ, et al. \nInsertional transformation of hematopoietic cells by self-inactivating lentiviral and gammaretroviral vectors . Mol Ther \n2009 ; 17 :1919 -28 ; PMID:19672245; http://dx.doi.org/10.1038/mt.2009.17919672245 \n30. \nWu XL , Li Y , Crise B , Burgess SM . Transcription start regions in the human genome are favored targets for MLV integration . Science \n2003 ; 300 :1749 -51 ; PMID:12805549; http://dx.doi.org/10.1126/science.108341312805549 \n31. \nMuñoz P , Toscano MG , Real PJ , Benabdellah K , Cobo M , Bueno C , Ramos-Mejı´a V , Menendez P , Anderson P , Martı´n F , Specific marking of hESCs-derived hematopoietic lineage by WAS-Promoter driven lentiviral vectors . PLoS ONE \n2012 ; 7 :e39091 ; PMID: 22720040; http://dx.doi.org/10.1371/journal.pone.003909122720040 \n32. \nToscano MG , Romero Z , Muñoz P , Cobo M , Benabdellah K , Martin F \nPhysiological and tissue-specific vectors for treatment of inherited diseases . Gene Ther \n2011 ; 18 :117 -27 .\n33. \nAiuti A , Biasco L , Scaramuzza S , Ferrua F , Cicalese MP , Baricordi C , Dionisio F , Calabria A , Giannelli S , Castiello MC , et al. \nLentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome . Science \n2013 ; 341 :1233151 .\n34. \nEngelstädter M , Buchholz CJ , Bobkova M , Steidl S , Merget-Millitzer H , Willemsen RA , Stitz J , Cichutek K \nTargeted gene transfer to lymphocytes using murine leukaemia virus vectors pseudotyped with spleen necrosis virus envelope proteins . Gene Ther \n2001 ; 8 :1202 -6 ; http://dx.doi.org/10.1038/sj.gt.330150011509952 \n35. \nFunke S , Maisner A , hlebach MDMU , Koehl U , Grez M , Cattaneo R , Cichutek K , Buchholz CJ . Targeted cell entry of lentiviral vectors . Mol Ther \n2008 ; 16 :1427 -36 ; PMID:18578012; http://dx.doi.org/10.1038/mt.2008.12818578012 \n36. \nBaum C , von Kalle C , Staal FJT , Li Z , Fehse B , Schmidt M , Weerkamp F , Karlsson S , Wagemaker G , Williams DA . Chance or necessity? insertional mutagenesis in gene therapy and its consequences . Mol Ther \n2004 ; 9 :5 -13 ; PMID:14741772; http://dx.doi.org/10.1016/j.ymthe.2003.10.01314741772 \n37. \nAnderson WF . The best of times, the worst of times . Science \n2000 ; 288 :627 -9 ; PMID:10799000; http://dx.doi.org/10.1126/science.288.5466.62710799000 \n38. \nHaigis KM . A. sweet-cordero, new insights into oncogenic stress . Nat Genet \n2011 ; 43 :177 -8 ; PMID: 21350495; http://dx.doi.org/10.1038/ng0311-17721350495 \n39. Vivier E, Ugolini S, Blaise D, Chabannon C, Brossay, L. Targeting natural killer cells and natural killer T cells in cancer . Nat Rev \n2012 ; 12 .\n40. \nDewey RA , Avedillo Dı´ez I , Ballmaier M , Filipovich A , Greil J , Güngör T , Happel C , Maschan A , Noyan F , Pannicke U , et al. \nRetroviral WASP gene transfer into human hematopoietic stem cells reconstitutes the actin cytoskeleton in myeloid progeny cells differentiated in vitro . Exp Hematol \n2006 ; 34 :1161 -9 ; PMID: 16939809; http://dx.doi.org/10.1016/j.exphem.2006.04.02116939809\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2167-5511",
"issue": "2(1)",
"journal": "Rare diseases (Austin, Tex.)",
"keywords": "Wiskott-Aldrich-Syndrome; gene therapy; immunodeficiency; insertional mutagenesis; leukemia",
"medline_ta": "Rare Dis",
"mesh_terms": null,
"nlm_unique_id": "101603407",
"other_id": null,
"pages": "e947749",
"pmc": null,
"pmid": "26942098",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": "16582916;12805549;19672245;11509952;15687233;12209132;17785506;16939809;19179314;12089448;22437937;10784449;14741772;18688285;12969986;22720040;20962871;20485269;18578012;24622513;23826732;18049469;21067383;12529469;11961146;8069912;14564000;21468099;21659547;23845947;19628299;18688286;20098431;21350495;19147084;16260184;10799000;14726584;20660403",
"title": "Gene therapy for Wiskott-Aldrich Syndrome-Long-term reconstitution and clinical benefits, but increased risk for leukemogenesis.",
"title_normalized": "gene therapy for wiskott aldrich syndrome long term reconstitution and clinical benefits but increased risk for leukemogenesis"
} | [
{
"companynumb": "DE-OTSUKA-2015_015973",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUSULFAN"
},
"drugadditional": null,
"d... |
{
"abstract": "BACKGROUND\nOn 3 September 2012, the licensed indication for acetylcysteine was changed in the United Kingdom (UK) so that all patients with a plasma paracetamol concentration above a \"100 mg/L\" (4 h post ingestion) nomogram treatment line after an acute paracetamol (acetaminophen) overdose should be treated. This is a lower threshold than that used in the United States, Canada, Australia, and New Zealand. Here we report the impact of this change in the UK on the management of patients with acute overdose in different paracetamol concentration ranges.\n\n\nMETHODS\nThis is a cohort study, consisting of a retrospective analysis conducted on prospectively collected audit data in three UK hospitals. Following appropriate ethical and data protection authority approval, data for patients presenting within 24 h of an acute timed single paracetamol overdose were extracted. Numbers of admissions and use of antidote in relation to different paracetamol concentration bands (< 100 mg/L; 100-149 mg/L; 150-199 mg/L; and ≥ 200 mg/L at 4 h) were analyzed for one-year periods before and after the change.\n\n\nRESULTS\nComparing the year before with the year after the change, there was no change in the numbers of patients presenting to hospital within 24 h of acute timed paracetamol overdose (1246 before and 1251 after), but more patients were admitted (759 before and 849 after) and treated with acetylcysteine (389 before and 539 after). Of the 150 additional patients treated with acetylcysteine in the year following the change, 114 (76%, 95% CI: 68.4-82.6) were in the 100-149 group and 9 (6.0%, 95% CI: 2.8-11.1) in the 150-199 group.\n\n\nCONCLUSIONS\nChanges to national guidelines for managing paracetamol poisoning in the UK have increased the numbers of patients with acute overdose treated with acetylcysteine, with most additional treatments occurring in patients in the 100-149 mg/L dose range, a group at low risk of hepatotoxicity and higher risk of adverse reactions.",
"affiliations": "National Poisons Information Service (Edinburgh) & Royal Infirmary of Edinburgh , Edinburgh , UK.",
"authors": "Bateman|D N|DN|;Dear|J W|JW|;Carroll|R|R|;Pettie|J|J|;Yamamoto|T|T|;Elamin|M E M O|ME|;Peart|L|L|;Dow|M|M|;Coyle|J|J|;Gray|A|A|;Dargan|P I|PI|;Wood|D M|DM|;Eddleston|M|M|;Thomas|S H L|SH|",
"chemical_list": "D000931:Antidotes; D000082:Acetaminophen; D000111:Acetylcysteine",
"country": "England",
"delete": false,
"doi": "10.3109/15563650.2014.954125",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "52(8)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "Acetylcysteine; Antidote; Paracetamol; Poisoning; Regulation",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000082:Acetaminophen; D000111:Acetylcysteine; D000931:Antidotes; D056486:Chemical and Drug Induced Liver Injury; D062787:Drug Overdose; D006760:Hospitalization; D006801:Humans; D008099:Liver; D049451:Nomograms; D017410:Practice Guidelines as Topic; D012189:Retrospective Studies; D012307:Risk Factors; D006113:United Kingdom",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "868-72",
"pmc": null,
"pmid": "25200454",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Impact of reducing the threshold for acetylcysteine treatment in acute paracetamol poisoning: the recent United Kingdom experience.",
"title_normalized": "impact of reducing the threshold for acetylcysteine treatment in acute paracetamol poisoning the recent united kingdom experience"
} | [
{
"companynumb": "GB-JNJFOC-20140915272",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "To report a case of severe multisystem illness, near death and permanent kidney failure in a woman with a history of anorexia nervosa-binge purge type due to abuse of prescription metformin, an approved oral diabetes medication obtained surreptitiously via the internet.\n\n\n\nPsychiatric and medical records were reviewed from the medical care of this patient. A literature search was also performed on prescription medication abuse as a mode of purging.\n\n\n\nMetformin abuse in a patient with an eating disorder as a purging behavior is a rarely reported, albeit very dangerous entity. Clinicians treating eating disorders should increasingly be aware of the potential abuse of prescription medications, unapproved for weight loss but which have weight loss, as a reported side effect. This is particularly important as the ability to obtain prescription medications via the internet, without a prescription, becomes more ubiquitous.",
"affiliations": "Department of Medicine, ACUTE, Denver Health, Denver, Colorado.;Department of Medicine, ACUTE, Denver Health, Denver, Colorado.;Department of Medicine, ACUTE, Denver Health, Denver, Colorado.;Department of Medicine, ACUTE, Denver Health, Denver, Colorado.;Department of Medicine, ACUTE, Denver Health, Denver, Colorado.;Columbia University, New York, New York.;Department of Medicine, ACUTE, Denver Health, Denver, Colorado.",
"authors": "Geer|Bashir|B|;Gibson|Dennis|D|;Grayeb|Daniela|D|;Benabe|Jodie|J|;Victory|Shelby|S|;Mehler|Shoshanah|S|;Mehler|Philip|P|0000-0002-9598-6428",
"chemical_list": "D008687:Metformin",
"country": "United States",
"delete": false,
"doi": "10.1002/eat.23010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0276-3478",
"issue": "52(3)",
"journal": "The International journal of eating disorders",
"keywords": "anorexia nervosa; internet; kidney failure; lactic acidosis; metformin; prescription medications; purging",
"medline_ta": "Int J Eat Disord",
"mesh_terms": "D000856:Anorexia Nervosa; D056912:Binge-Eating Disorder; D005260:Female; D006801:Humans; D008687:Metformin; D008875:Middle Aged; D019966:Substance-Related Disorders",
"nlm_unique_id": "8111226",
"other_id": null,
"pages": "319-321",
"pmc": null,
"pmid": "30629296",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Metformin abuse: A novel and dangerous purging behavior in anorexia nervosa.",
"title_normalized": "metformin abuse a novel and dangerous purging behavior in anorexia nervosa"
} | [
{
"companynumb": "US-INVENTIA-000270",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "Interstitial granulomatous dermatitis (IGD) is a rare dermatosis generally seen in the setting of rheumatic diseases, but also hematological disorders, internal malignances, infections, or drug induced. Herein, we report an exceptional case of an IGD with a clear chronological association with tocilizumab onset and cessation in a patient with adult-onset Still's disease. We review the granulomatous cutaneous reactions so far reported with this novel therapy: sarcoidosis, granuloma annulare, and IGD. Tocilizumab is a humanized anti-interleukin 6 receptor monoclonal antibody useful for the treatment of various systemic inflammatory disorders. Lately, it has found useful also for granulomatous diseases such as giant cell arteritis and even a promising response in IGD. Therefore, we believe our case adds the possibility of an IGD presenting as a paradoxical reaction.",
"affiliations": "Department of Dermatology, Hospital Universitari Sagrat Cor, Grupo Quirónsalud, Barcelona, Spain.;Department of Dermatology, Hospital Universitari Sagrat Cor, Grupo Quirónsalud, Barcelona, Spain.;Department of Dermatology, Hospital Universitari Sagrat Cor, Grupo Quirónsalud, Barcelona, Spain.;Department of Dermatology, Hospital Universitari Sagrat Cor, Grupo Quirónsalud, Barcelona, Spain.;Department of Pathology, Hospital Universitari General de Catalunya, Grupo Quirónsalud, Universitat internacional de Catalunya, Sant Cugat del Vallès, Barcelona, Spain.;Department of Dermatology, Hospital Universitari Sagrat Cor, Grupo Quirónsalud, Barcelona, Spain.",
"authors": "Altemir|Arcadi|A|0000-0003-3916-9105;Iglesias-Sancho|Maribel|M|;Sola-Casas|María de Los Ángeles|MLÁ|;Novoa-Lamazares|Luis|L|;Fernández-Figueras|Maite|M|;Salleras-Redonnet|Montse|M|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C502936:tocilizumab",
"country": "United States",
"delete": false,
"doi": "10.1111/dth.14207",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1396-0296",
"issue": "33(6)",
"journal": "Dermatologic therapy",
"keywords": "granulomatous drug reaction; interleukin-6 inhibitors; interstitial granulomatous dermatitis; paradoxical reaction; tocilizumab",
"medline_ta": "Dermatol Ther",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D003872:Dermatitis; D006099:Granuloma; D016460:Granuloma Annulare; D006801:Humans",
"nlm_unique_id": "9700070",
"other_id": null,
"pages": "e14207",
"pmc": null,
"pmid": "32816393",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Interstitial granulomatous dermatitis following tocilizumab, a paradoxical reaction?",
"title_normalized": "interstitial granulomatous dermatitis following tocilizumab a paradoxical reaction"
} | [
{
"companynumb": "ES-MYLANLABS-2021M1007470",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
... |
{
"abstract": "Severe asthma is very difficult to manage in many individuals, and systemic corticosteroids are often used to prevent or manage acute exacerbations. Furthermore, comorbid allergic conditions may render standard therapies inadequate. A 51-year-old man presented with severe eosinophilic asthma requiring nearly constant oral corticosteroid usage despite using high-dose inhaled corticosteroids and secondary asthma controllers. His condition was complicated by aspirin-exacerbated respiratory disease, including severe nasal polyposis, chronic rhinosinusitis, as well as chronic idiopathic urticaria. Mepolizumab was initiated and led to dramatic improvement of asthma over 6 months. However, he continued to experience exacerbations of chronic idiopathic urticaria not responsive to H1-antihistamines. Omalizumab was added, and the patient's urticaria attained marked improvement with only an occasional breakthrough rash. Dual biologic therapies can be a unique and useful steroid-sparing treatment option for patients with uncontrolled severe asthma and chronic idiopathic urticaria.",
"affiliations": "Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana, USA.;Section of Allergy/Immunology, Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana, USA dkauf1@lsuhsc.edu.",
"authors": "Caskey|Joshua Ray|JR|;Kaufman|David|D|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D018927:Anti-Asthmatic Agents; D000069444:Omalizumab",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-242211",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(5)",
"journal": "BMJ case reports",
"keywords": "asthma; dermatology; drugs: respiratory system; immunology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D018927:Anti-Asthmatic Agents; D001249:Asthma; D001691:Biological Therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D000069444:Omalizumab",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34016636",
"pubdate": "2021-05-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Dual biologic therapy in a patient with severe asthma and other allergic disorders.",
"title_normalized": "dual biologic therapy in a patient with severe asthma and other allergic disorders"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2021-11462",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CETIRIZINE HYDROCHLORIDE"
},
"... |
{
"abstract": "Objective To investigate whether symptomatic treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is non-inferior to antibiotics in the treatment of uncomplicated lower urinary tract infection (UTI) in women, thus offering an opportunity to reduce antibiotic use in ambulatory care.Design Randomised, double blind, non-inferiority trial.Setting 17 general practices in Switzerland.Participants 253 women with uncomplicated lower UTI were randomly assigned 1:1 to symptomatic treatment with the NSAID diclofenac (n=133) or antibiotic treatment with norfloxacin (n=120). The randomisation sequence was computer generated, stratified by practice, blocked, and concealed using sealed, sequentially numbered drug containers.Main outcome measures The primary outcome was resolution of symptoms at day 3 (72 hours after randomisation and 12 hours after intake of the last study drug). The prespecified principal secondary outcome was the use of any antibiotic (including norfloxacin and fosfomycin as trial drugs) up to day 30. Analysis was by intention to treat.Results 72/133 (54%) women assigned to diclofenac and 96/120 (80%) assigned to norfloxacin experienced symptom resolution at day 3 (risk difference 27%, 95% confidence interval 15% to 38%, P=0.98 for non-inferiority, P<0.001 for superiority). The median time until resolution of symptoms was four days in the diclofenac group and two days in the norfloxacin group. A total of 82 (62%) women in the diclofenac group and 118 (98%) in the norfloxacin group used antibiotics up to day 30 (risk difference 37%, 28% to 46%, P<0.001 for superiority). Six women in the diclofenac group (5%) but none in the norfloxacin group received a clinical diagnosis of pyelonephritis (P=0.03).Conclusion Diclofenac is inferior to norfloxacin for symptom relief of UTI and is likely to be associated with an increased risk of pyelonephritis, even though it reduces antibiotic use in women with uncomplicated lower UTI.Trial registration ClinicalTrials.gov NCT01039545.",
"affiliations": "Institute for Infectious Diseases, University of Bern, Bern, Switzerland andreas.kronenberg@ifik.unibe.ch.;CTU Bern, University of Bern, Bern, Switzerland.;Applied Health Research Centre, Li Ka Shing Knowledge Institute of St Michael's Hospital, Department of Medicine and Institute of Health Policy, Management and Evaluation, University of Toronto, Canada.;Institute for Infectious Diseases, University of Bern, Bern, Switzerland.;Applied Health Research Centre, Li Ka Shing Knowledge Institute of St Michael's Hospital, Department of Medicine and Institute of Health Policy, Management and Evaluation, University of Toronto, Canada.;Medix General Practice Network, Bern, Switzerland.;Medix General Practice Network, Bern, Switzerland.;Institute of Primary Health Care, University of Bern, Bern, Switzerland.;CTU Bern, University of Bern, Bern, Switzerland.;Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.;Applied Health Research Centre, Li Ka Shing Knowledge Institute of St Michael's Hospital, Department of Medicine and Institute of Health Policy, Management and Evaluation, University of Toronto, Canada.",
"authors": "Kronenberg|Andreas|A|;Bütikofer|Lukas|L|;Odutayo|Ayodele|A|;Mühlemann|Kathrin|K|;da Costa|Bruno R|BR|;Battaglia|Markus|M|;Meli|Damian N|DN|;Frey|Peter|P|;Limacher|Andreas|A|;Reichenbach|Stephan|S|;Jüni|Peter|P|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D009643:Norfloxacin",
"country": "England",
"delete": false,
"doi": "10.1136/bmj.j4784",
"fulltext": "\n==== Front\nBMJBMJbmjThe BMJ0959-81381756-1833BMJ Publishing Group Ltd. 29113968krona03931710.1136/bmj.j4784ResearchSymptomatic treatment of uncomplicated lower urinary tract infections in the ambulatory setting: randomised, double blind trial Kronenberg Andreas senior lecturer1 2 3Bütikofer Lukas senior statistician4 5Odutayo Ayodele postdoctoral fellow6Mühlemann Kathrin professor1 2da Costa Bruno R assistant professor and associate director6 7Battaglia Markus primary care physician3Meli Damian N primary care physician3 7Frey Peter consultant7Limacher Andreas consultant4 5Reichenbach Stephan associate professor and attending physician5 8Jüni Peter professor and director6 7\n1 Institute for Infectious Diseases, University of Bern, Bern, Switzerland\n2 Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland\n3 Medix General Practice Network, Bern, Switzerland\n4 CTU Bern, University of Bern, Bern, Switzerland\n5 Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland\n6 Applied Health Research Centre, Li Ka Shing Knowledge Institute of St Michael’s Hospital, Department of Medicine and Institute of Health Policy, Management and Evaluation, University of Toronto, Canada\n7 Institute of Primary Health Care, University of Bern, Bern, Switzerland\n8 Department of Rheumatology, Immunology and Allergology, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandCorrespondence to: A Kronenberg andreas.kronenberg@ifik.unibe.ch2017 08 11 2017 359 j478409 10 2017 Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions2017BMJThis is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.\nObjective To investigate whether symptomatic treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is non-inferior to antibiotics in the treatment of uncomplicated lower urinary tract infection (UTI) in women, thus offering an opportunity to reduce antibiotic use in ambulatory care.\n\n\nDesign Randomised, double blind, non-inferiority trial.\n\n\nSetting 17 general practices in Switzerland.\n\n\nParticipants 253 women with uncomplicated lower UTI were randomly assigned 1:1 to symptomatic treatment with the NSAID diclofenac (n=133) or antibiotic treatment with norfloxacin (n=120). The randomisation sequence was computer generated, stratified by practice, blocked, and concealed using sealed, sequentially numbered drug containers.\n\n\nMain outcome measures The primary outcome was resolution of symptoms at day 3 (72 hours after randomisation and 12 hours after intake of the last study drug). The prespecified principal secondary outcome was the use of any antibiotic (including norfloxacin and fosfomycin as trial drugs) up to day 30. Analysis was by intention to treat.\n\n\nResults 72/133 (54%) women assigned to diclofenac and 96/120 (80%) assigned to norfloxacin experienced symptom resolution at day 3 (risk difference 27%, 95% confidence interval 15% to 38%, P=0.98 for non-inferiority, P<0.001 for superiority). The median time until resolution of symptoms was four days in the diclofenac group and two days in the norfloxacin group. A total of 82 (62%) women in the diclofenac group and 118 (98%) in the norfloxacin group used antibiotics up to day 30 (risk difference 37%, 28% to 46%, P<0.001 for superiority). Six women in the diclofenac group (5%) but none in the norfloxacin group received a clinical diagnosis of pyelonephritis (P=0.03).\n\n\nConclusion Diclofenac is inferior to norfloxacin for symptom relief of UTI and is likely to be associated with an increased risk of pyelonephritis, even though it reduces antibiotic use in women with uncomplicated lower UTI.\n\n\nTrial registration ClinicalTrials.gov NCT01039545.\n==== Body\nIntroduction\nAntimicrobial stewardship aims at reducing antibiotic resistance by optimising or decreasing antibiotic use,1 which includes the prevention of antibiotic treatment in cases of viral infections, tailored prescription of narrow spectrum antibiotics, shortening the course of treatment, and deferring treatment for low risk bacterial infections. Urinary tract infection (UTI) is one of the most common bacterial infections in adults, affecting considerably more women than men.2 Approximately half of women have at least one UTI in their lifetime, and 20-30% have two or more.3 Antibiotic prescriptions for UTI account for 10-20% of all antibiotic prescriptions in ambulatory care and are second only to antibiotic prescriptions for respiratory tract infections.4\n5 Reducing antibiotic prescriptions for UTI could potentially decrease the risk of antibiotic resistance. Therefore, the benefit of antibiotic treatment needs to be weighed against the potential for adverse effects, at both the individual level (adverse drug reactions) and the population level (as a driver of antibiotic resistance).\n\nSymptoms of UTI may arise from local increases in pro-inflammatory factors such as prostaglandins, and non-steroidal anti-inflammatory drugs (NSAIDs) may be useful in alleviating symptoms.6\n7\n8 A small randomised pilot trial, which compared the NSAID ibuprofen with the antibiotic ciprofloxacin in 80 women with uncomplicated lower UTI, concluded that symptomatic treatment with NSAIDs may be non-inferior to antibiotics, but suggested confirmation in a larger trial.9 Two adequately powered randomised double blind trials were therefore initiated simultaneously in February 2012 in Germany and Switzerland. Results of the German trial, which compared ibuprofen with fosfomycin in 494 women, were recently published.10 Here we report results of the Swiss trial, which compared diclofenac with norfloxacin in women with uncomplicated lower UTI.\n\nMethods\nStudy design\nThis randomised controlled trial with blinding of patients and assessors was conducted in 17 general practices in the German speaking part of Switzerland. All women provided written informed consent.\n\nPatients, randomisation, and treatment\nWomen aged 18 to 70 years, who visited their general practitioner because of one or more symptoms or signs typical of acute lower UTI (dysuria, frequency, macrohaematuria, cloudy or smelly urine) or self diagnosed symptomatic cystitis were eligible if their urine dipstick was positive for nitrite or leucocytes, or both. We excluded pregnant women and women with clinical signs of upper UTI such as fever (axillary body temperature >38°C), costovertebral pain or tenderness, rigors, and nausea or vomiting. We also excluded women with known or suspected anatomical or functional abnormality of the urinary tract and comorbidities such as diabetes mellitus, active gastric or duodenal ulcer disease or gastrointestinal bleeding, inflammatory bowel disease, severe liver dysfunction (liver cirrhosis and ascites), coagulopathy (including treatment with coumarine derivates), renal insufficiency grade 3 or higher (calculated glomerular filtration rate <60 mL/min), known congestive heart failure (New York Heart Association (NYHA) III or higher), psychiatric illness or dementia, inability to communicate in German or French, and any other serious comorbidity as judged by the treating doctor. In addition we excluded women with documented immunosuppression (eg, prednisone equivalent >10 mg/day for >14 days, chemotherapy, radiotherapy, immunomodulators, HIV infection, neutropenia) or hypersensitivity to one of the study drugs or a history of asthma, urticaria, or hypersensitivity-like reactions after consumption of salicylic acid or other non-steroidal anti-inflammatory drugs, as well as women with vaginal symptoms (discharge, irritation), bladder catheter in situ or during the past 30 days, recurrent UTI (more than three infections during the past 12 months), antibiotic treatment during the past four weeks, or UTI symptoms present for more than seven days before visiting the doctor.\n\nWomen were randomly allocated in a 1:1 ratio to diclofenac or norfloxacin treatment. The randomisation sequence was computer generated, stratified by practice, and blocked with randomly varying block sizes of 4 and 6. Allocation was concealed with sealed, sequentially numbered opaque drug containers of identical appearance that contained opaque hard gelatine capsules of identical size and colour. Women allocated to diclofenac received capsules containing 75 mg diclofenac retard for three days (Olfen-75 duo release; Mepha Pharma, Basel, Switzerland) and women allocated to norfloxacin received capsules containing 400 mg norfloxacin for three days (Norfloxacin-Teva; Teva Pharma, Tel Aviv, Israel; or Norflocin-Mepha; Lactab, Mepha Pharma, Basel, Switzerland from October 2013 onwards owing to delivery restrictions). We chose norfloxacin because of the high susceptibility rates in Switzerland and diclofenac because of its identical frequency of being administered, which facilitated patient blinding. Women started treatment immediately after randomisation on day 0 and were advised to take two capsules each day: one in the morning and one in the evening. All women were given a single open label package of fosfomycin (Monuril; Zambon, Cadempino, Switzerland) to be taken as rescue antibiotic (3 g dose) after completion of the study drug on day 3 at their discretion, if symptoms persisted.\n\nProcedures and outcomes\nThe prespecified primary outcome was symptom resolution on day 3 (72 hours after randomisation and 12 hours after intake of the last study drug). In the absence of antimicrobial resistance, the mean duration of symptoms in women with uncomplicated UTIs treated with antibiotics is three days.11 The self report questionnaire used to ascertain severity of symptoms was developed based on questionnaires described by Clayson et al12 and Little et al.13 Women rated the severity of five UTI symptoms (dysuria, frequency, urgency, abdominal pain when passing urine, pain or tenderness in the lower back or loin) daily from days 0 (randomisation) to 10 in a diary and on day 30 by telephone interview on a Likert scale from 0 to 6, with their composite score ranging from 0 to 30. Symptom resolution was defined as 2 or less points (slight, very slight, or no problems) on all five components.12\n14\n15 Complete absence of symptoms was defined as 0 points on all components. When the trial was registered on ClinicalTrials.gov (NCT01039545), the day of randomisation was defined as day 1, but for the purposes of this report it was defined as day 0. Therefore day 4, described as the time point of the primary outcome on ClinicalTrials.gov, corresponds to day 3 in this report. The prespecified principal secondary outcome was the use of any antibiotic (including norfloxacin and fosfomycin as trial drugs) up to day 30. The remaining prespecified outcomes were resolution of symptoms on day 7; complete absence of symptoms on days 3 and 7; use of rescue antibiotic (fosfomycin) up to day 3; negative urinary culture result on day 10; reconsultations because of UTI up to day 30; mean composite symptom score on days 3, 7, and 30; time until resolution of symptoms; adverse events; serious adverse events; European quality of life (EQ-5D) health state and visual analogue scale on day 3; working days lost; and overall satisfaction with management of the UTI. Additional time points analysed, which were not prespecified in the protocol but specified before statistical analysis, included days 10 and 30 for resolution and complete absence of symptoms, day 10 for symptom scores, day 3 for use of any antibiotic, and day 30 for use of rescue antibiotics. \n\nThe treating doctor and an independent, blinded interviewer carried out telephone interviews on days 10 and 30, respectively, to assess serious adverse events, adverse events of grade 3 or more severity, any additional unplanned medical visits, including telephone contacts, and co-medications. The clinical diagnosis of pyelonephritis required the occurrence of loin pain and fever, leading to an unplanned outpatient visit. Mid-stream urinary samples obtained on days 0 and 10 were processed according to standard laboratory procedures, using a cut-off of ≥103 colony forming units per millilitre for a urinary culture to be considered positive16; mixed flora with no predominant microorganism, Lactobacilli or Streptococcus viridans group were considered a negative result. The supplementary appendix provides details of the baseline assessments, diaries, and scores used.\n\nStatistical analysis\nWe originally planned to recruit 400 women, but recruitment was slow and financial constraints led us to decide in June 2014 to stop patient recruitment by December 2014, when an expected 260 women would be included. The decision was made without inspecting the data and after repeating the power analysis based on a normal approximation test of proportions,17 which was less conservative than the simulation based approach originally used. With the original assumption of 70% of women reaching symptom resolution up to day 3 in both groups and the original, prespecified non-inferiority margin of 15% on a risk difference scale, the projected sample size of 260 women would yield a power of 84% to detect non-inferiority at a one sided type I error of 5%. A systematic review and meta-analysis by Falagas et al18 suggested symptom resolution in approximately 25% of women with UTI receiving placebo and in approximately 60% of women receiving antibiotics. The selected non-inferiority margin of 15% was less than half of the pooled risk difference between antibiotics and placebo of 35%.\n\nThe primary outcome was evaluated using a risk difference with a corresponding two sided 95% confidence interval, a one sided normal approximation test for non-inferiority, and a two sided χ2 test for superiority. We compared secondary outcomes using conventional two sided P values for superiority and corresponding two sided 95% confidence intervals. We used risk differences with χ2 tests for binary data, Poisson regression with robust standard errors for counts, and linear regression with robust standard errors for continuous data. Kaplan-Meier curves accompanied by hazard ratios from Cox models were used to analyse time to definite symptom resolution and time to antibiotic use. Women were considered to have reached definite symptom resolution in the time-to-event analysis if they reached ≤2 points (slight, very slight, or no problems) on all five components of the symptom severity score and did not report a subsequent flare-up. All women were included in the analysis in the groups to which they were originally allocated (intention to treat analysis), with missing values accounted for by multiple imputation (see supplementary appendix and supplementary table 1).\n\nWe performed prespecified subgroup analyses of the primary outcome accompanied by Mantel-Haenszel tests for interaction by age (<45 v ≥45 years), symptom severity at baseline (≤20 v >20), symptom duration (≤3 v >3 days), and presence of a positive urinary culture result at baseline; post hoc subgroup analyses were performed for urine leucocytes (≤++ v >++) and the presence of norfloxacin resistant Enterbacteriaceae. In per protocol analyses, we excluded women with protocol deviations, defined as women with no documented intake of at least one dose of study drug, crossovers, and women who used rescue antibiotics before day 3. These analyses were prespecified in a statistical analysis plan before the end of recruitment and inspection of the data.\n\nIn sensitivity analyses specified post hoc, we fitted mixed effects models with a random intercept for trial site and multivariable Poisson and linear regression models adjusted for baseline characteristics to estimate treatment effects. For the Poisson regression models we used robust sandwich estimators of standard errors.19 We then transformed the resulting relative risks to risk differences by combining them with the control group risk in patients allocated to norfloxacin to ensure direct comparability with primary analyses. In further post hoc analyses of women allocated to diclofenac, we compared baseline characteristics and outcomes between those who used antibiotics until day 30 and those who never used antibiotics, determined the time between symptom onset and diagnosis in those with a clinical diagnosis of pyelonephritis, and explored whether blood or urine findings at baseline were associated with pyelonephritis with clinically relevant positive or negative likelihood ratios above 5 or below 0.2, respectively, which could be used to rule in or rule out a future clinical diagnosis of pyelonephritis. All analyses were done in RStudio version 1.0.143 (RStudio: Integrated Development for R. RStudio, Boston, MA www.rstudio.com/).\n\nPatient involvement\nNo patients were involved in setting the research question or the outcome measures, nor were they involved in developing plans for recruitment, design, or implementation of the study. No patients were asked to advise on interpretation or writing up of results. We plan to disseminate the results of the research to all the scientific community, including trial participants.\n\nResults\nBetween 7 February 2012 and 3 December 2014, 253 women were included in the trial. Thirty six patients were recruited in seven single practices, 108 in nine group practices, and 109 in one big medical centre with 17 doctors in the centre of Bern, Switzerland. One hundred and thirty three patients were randomly allocated to diclofenac and 120 to norfloxacin. A total of 125 women (94%) in the diclofenac group and 118 women (98%) in the norfloxacin group. received treatment as allocated. Follow-up until day 30 was complete for 119 (89%) and 112 women (93%), respectively (fig 1). Groups were similar (table 1), with a mean age of 36.8 years (SD 14.1), a mean duration of symptoms of 3.4 days (SD 2.7), and a mean composite symptom score of 13.7 points out of 30 (SD 4.0), and urgency, frequency, and dysuria as the most prevalent symptoms. Thirty five urine samples were positive for nitrite (14%) and 191 had more than ++ leucocytes (75%). Urinary cultures gave positive results for 185 urine samples (73%), resulting in a total of 193 isolates, of which 187 (97%) had documented norfloxacin susceptibility. In total, 173 isolates contained Enterobacteriaceae, 160 of which were tested for fosfomycin susceptibility and 158 were found to be susceptible (99%).\n\n\nFig 1 Participant flow through study. NSAID=non-steroidal anti-inflammatory drug\n\nTable 1 Baseline characteristics of participants. Values are means (standard deviations) unless stated otherwise\n\nCharacteristics\tDiclofenac group (n=133)\tNorfloxacin group (n=120)\t\nAge (years)\t37.8 (14.2)\t35.6 (14.0)\t\n No (%) aged <45 years\t94 (71)\t89 (74)\t\nSymptom duration: days since UTI onset\t3.6 (3.1)\t3.2 (2.0)\t\n No (%) with symptom duration ≤3 days\t80 (60)\t83 (69)\t\nNo of UTIs in past 12 months\t0.6 (1.1)\t0.6 (0.9)\t\nBaseline UTI symptoms (score 0-6):\t\t\t\n Dysuria\t3.3 (1.3)\t3.3 (1.2)\t\n Urgency\t3.7 (1.0)\t3.6 (0.9)\t\n Night frequency\t2.6 (1.5)\t2.6 (1.4)\t\n Day frequency\t3.5 (0.9)\t3.5 (0.9)\t\n Lower abdominal pain while urinating\t2.6 (1.5)\t2.6 (1.6)\t\n Back or loin pain\t1.1 (1.4)\t1.2 (1.5)\t\n Total symptom score\t13.7 (3.9)\t13.8 (3.8)\t\n No (%) with symptom score ≤20\t127 (95)\t115 (96)\t\nBlood tests:\t\t\t\n C reactive protein (mg/L)\t6.7 (10.5)\t8.5 (13.7)\t\n No (%) with C reactive protein >10 mg/L\t24 (18)\t29 (24)\t\n Leucocytes (109/L)\t8.5 (2.4)\t8.7 (2.2)\t\nUrinary dipstick:\t\t\t\n No (%) positive for nitrites\t17 (13)\t18 (15)\t\n Median (interquartile range) erythrocytes (+ to ++++)\t+++ (++ to ++++)\t+++ (++ to ++++)\t\n Median (interquartile range) leucocytes (+ to ++++)\t+++ (+++ to ++++)\t+++ (+++ to ++++)\t\n No (%) with leucocyte result >++\t101 (76)\t90 (75)\t\nUrinary culture (No (%))*:\t\t\t\n Negative\t36 (27)\t31 (26)\t\n Positive†\t96 (72)\t89 (74)\t\n \nEscherichia coli\n\t82 (62)\t75 (63)\t\n Other Enterobacteriaceae\t10 (8)\t6 (5)\t\n \nStaphylococcus saprophyticus\n\t4 (3)\t7 (6)\t\n \nEnterococcus faecalis\n\t1 (1)\t6 (5)\t\n βhaemolytic streptococcus group B\t1 (1)\t1 (1)\t\n Susceptibility to norfloxacin\t92 (69)\t87 (73)\t\n Enterobacteriaceae\t88 (66)\t79 (66)\t\n Susceptibility to fosfomycin‡\t84 (63)\t71 (59)\t\nUTI=urinary tract infection.\n\n*Results missing in one patient in diclofenac group.\n\n†Do not sum up owing to two double mixed infections in the diclofenac group and four double and one triple mixed infection in the norfloxacin group.\n\n‡Relates to Enterobacteriaceae only. Two isolates from the diclofenac group (n=1 Proteus mirabilis, n=1 Enterobacter cloacae) were not susceptible to fosfomycin.\n\nTable 2 presents the clinical outcomes. The primary outcome, resolution of symptoms at day 3, was observed in 72 (54%) women in the diclofenac group and 96 (80%) in the norfloxacin group (risk difference 27%, 95% confidence interval 15% to 38%, one sided P=0.98 for non-inferiority, two sided P<0.001 for superiority in favour of norfloxacin group). The principal secondary outcome, use of any antibiotic up to day 30, was observed in 82 (62%) women in the diclofenac group and 118 (98%) in the norfloxacin group (risk difference 37%, 28% to 46%, P<0.001 for superiority in favour of diclofenac group). Among the 82 women in the diclofenac group who used antibiotics, 58 (71%) decided to take antibiotics during the first three days; 55 of these 58 (95%) women took the rescue antibiotic fosfomycin. Supplementary table 13 presents antibiotics taken in addition to the study drugs for any indication and for recurrent UTI. Five (4%) women in the diclofenac group and 13 (11%) in the norfloxacin group took additional analgesics up to day 3.\n\nTable 2 Primary and secondary outcomes. Values are numbers (percentages) unless stated otherwise\n\nOutcomes\tDiclofenac group (n=133)\tNorfloxacin group (n=120)\tRisk or mean difference (95% CI)\tP value\t\nResolution of symptoms:\t\t\t\t\t\n Day 3 (primary outcome)\t72 (54)\t96 (80)\t27 (15 to 38)\t<0.001\t\n Day 7\t111 (83)\t115 (96)\t12 (4 to 19)\t0.003\t\n Day 10*\t126 (95)\t116 (97)\t2 (−3 to 7)\t0.45\t\n Day 30*\t127 (95)\t111 (93)\t−3 (−9 to 3)\t0.32\t\nComplete absence of symptoms:\t\t\t\t\t\n Day 3\t10 (8)\t20 (17)\t9 (0 to 17)\t0.038\t\n Day 7\t44 (33)\t65 (54)\t21 (9 to 34)\t0.001\t\n Day 10*\t70 (53)\t\n77 (64)\t12 (−1 to 24)\t0.07\t\n Day 30*\t101 (76)\t99 (83)\t6 (−4 to 17)\t0.22\t\nMean (SD) change of symptom score:\t\t\t\t\t\n Day 3\t−7.3 (4.7)\t−10.3 (4.1)\t3.0 (1.9 to 4.1)\t<0.001\t\n Day 7\t−11.0 (4.8)\t−12.6 (4.2)\t1.6 (0.5 to 2.7)\t0.005\t\n Day 10*\t−12.2 (4.3)\t−12.9 (4.1)\t0.7 (−0.4 to 1.7)\t0.20\t\n Day 30\t−13.0 (4.4)\t−13.1 (4.3)\t0.1 (−1.0 to 1.1)\t0.88\t\nUse of any antibiotic:\t\t\t\t\t\n ≤day 3*\t58 (44)\t116 (97)\t−54 (−63 to −44)\t<0.001\t\n <day 30 (principal secondary outcome)\t82 (62)\t118 (98)\t−37 (−46 to −28)\t<0.001\t\nUse of rescue antibiotic:\t\t\t\t\t\n ≤day 3\t55 (41)\t9 (8)\t34 (24 to 43)\t<0.001\t\n <day 30*\t73 (55)\t18 (15)\t40 (29 to 51)\t<0.001\t\nNegative urinary culture at day 10\t96 (72)\t112 (93)\t21 (11 to 30)\t<0.001\t\nReconsultations because of UTI (<day 30)\t27 (20)\t10 (8)\t12 (3 to 20)\t0.010\t\nMean (SD) quality of life (range 0-10):\t\t\t\t\t\n EuroQol health state (day 3)\t8.8 (2.2)\t9.4 (1.5)\t0.6 (0.2 to 1.0)\t0.005\t\n EuroQol visual analogue scale (day 3)\t7.4 (1.9)\t8.3 (1.5)\t1.0 (0.5 to 1.4)\t<0.001\t\n Patient satisfaction with UTI management\t5.7 (3.0)\t8.2 (2.1)\t2.5 (1.9 to 3.2)\t<0.001\t\n No of working days lost due to UTI\t0.6 (0.8)\t0.5 (0.8)\t0.2 (−0.1 to 0.5)†\t0.18\t\nUTI=urinary tract infection; EuroQol=European quality of life instrument.\n\nPositive differences favour norfloxacin, negative differences favour diclofenac.\n\n*Analysis of additional time points, not prespecified in protocol.\n\n†Relative rate increase calculated from Poisson regression.\n\nFigure 2 presents time to event curves for definite resolution of symptoms (top panel) and use of antibiotics (bottom panel) until day 10 (fig 2 and supplementary table 2). Supplementary figure 1 shows the course of symptom scores. The median time until resolution of symptoms was four days in the diclofenac group compared with two days in the norfloxacin group (hazard ratio 1.64, 95% confidence interval 1.26 to 2.14, P<0.001). The median time until antibiotic use was five and zero days, respectively (10.06, 6.67 to 15.17, P<0.001). Figure 3 shows subgroup analyses for the primary and main secondary outcome. Results appeared consistent across all subgroups. Sensitivity analyses revealed consistent results for the primary and main secondary outcome (see supplementary tables 3-6).\n\n\nFig 2 Kaplan-Meier plot for (top panel) time until definite resolution of symptoms and (bottom panel) time until antibiotic use up to day 10. Nineteen women in the diclofenac group and nine in the norfloxacin group who reached the primary outcome definition of symptom resolution on day 3 subsequently reported a slight flare-up; they were considered to have experienced symptom resolution on day 3 (table 2), but reached definite symptoms later than day 3 (fig 2); six women in the diclofenac group and six in the norfloxacin group who reached the primary outcome definition of symptom resolution on day 3 did not provide enough information to derive the time point of definite resolution and were censored at day 0 (five in each group) or day 10 (one in each group)\n\n\nFig 3 Subgroup analyses of primary outcome (resolution of symptoms at day 3) and main secondary outcome. Positive differences favour norfloxacin, negative differences favour diclofenac\n\nThe remaining prespecified outcomes favoured norfloxacin except for change in symptom score on day 30 (P=0.88) and working days lost (P=0.18, table 2). Post hoc analyses of additional time points revealed little evidence of a difference between groups for resolution or complete absence of symptoms on days 10 and 30 or change of symptom score on day 10 (P≥0.07) and strong evidence for a difference in favour of the diclofenac group for antibiotic use up to day 3 (P<0.001, table 2).\n\nSupplementary table 7 shows a post hoc comparison of baseline characteristics of women who had never used antibiotics (n=51) with women who had used any antibiotics until day 30 (n=82) among those randomly allocated to diclofenac. We found little evidence for a difference between groups, except for one component of the symptom composite score. Supplementary table 8 presents a comparison of outcomes. Resolution and complete absence of symptoms at day 3 were more common among women who never used antibiotics (P<0.01), changes of symptom scores were more pronounced at day 3 (P<0.01), reconsultations were less frequent (P<0.01), and scores on quality of life and satisfaction with care were higher (P<0.02). The median time to symptom resolution was three days in women who never used antibiotics and five days in women who used antibiotics (hazard ratio 0.61, 95% confidence interval 0.42 to 0.88, P<0.01, see supplementary figure 2 and supplementary table 9). Thirty four urinary cultures had been positive at baseline among women who never used antibiotics, and the results for 16 of these spontaneously became negative on day 10 (47%).\n\nTable 3 presents adverse events that resulted in reconsultations: 43 events in 41 women in the diclofenac group (31%) and 22 events in 21 women in the norfloxacin group (18%). Adverse events related to UTI were more common in the diclofenac group (P=0.01), with six cases of clinically diagnosed pyelonephritis in the diclofenac group (5%) and none in the norfloxacin group (P=0.03); one woman with clinically diagnosed pyelonephritis in the diclofenac group was classified to have experienced a serious adverse event as she was admitted to hospital to receive intravenous antibiotic treatment. Supplementary table 10 shows a comparison of baseline characteristics of women with and without pyelonephritis in the diclofenac group. Supplementary table 11 presents the timing of administered antibiotics since symptom onset and randomisation, and the type of antibiotic used in the six women with pyelonephritis. The median time from symptom onset to clinical diagnosis of pyelonephritis was 5.5 days (range 5.0-8.0 days). A post-hoc analysis revealed that C reactive protein levels >10 mg/L at baseline were observed in 21 women in the diclofenac group without pyelonephritis (17%) and in three women with pyelonephritis (50%, see supplementary table 10). This resulted in a positive likelihood ratio of 3.02 (95% confidence interval 1.07 to 5.98) for C reactive protein levels >10 mg/L. None of the remaining analysed characteristics was associated with statistically significant and clinically relevant positive or negative likelihood ratios suitable to rule in or rule out a future diagnosis of a pyelonephritis (see supplementary table 12). Supplementary table 14 shows that mean symptom scores for women who developed pyelonephritis were higher at baseline and day 3 compared with women who did not develop pyelonephritis, but differences subsequently diminished. Supplementary figure 3 graphically shows the course of symptom scores in patients with and without pyelonephritis in the diclofenac group.\n\nTable 3 Adverse events resulting in reconsultations up to 30 days\n\nAdverse events\tNo (%) in diclofenac group (n=133)\tNo (%) in norfloxacin group (n=120)\tRisk difference (95% CI)\tP value*\t\nRelated to UTI\t26 (20)\t10 (8)\t11 (3 to 20)\t0.012\t\n Persistent symptoms\t16 (12)\t4 (3)\t9 (2 to 15)\t0.011\t\n Additional symptoms\t6 (5)\t2 (2)\t3 (−1 to 7)\t0.29\t\n Recurrent UTI†\t5 (4)\t4 (3)\t0 (−4 to 5)\t1.00\t\n Pyelonephritis‡\t6 (5)\t0 (0)\t5 (1 to 8)\t0.031\t\nOther adverse event\t17 (13)\t12 (10)\t3 (−5 to 11)\t0.56\t\n Exanthema\t1 (1)\t2 (2)\t−1 (−4 to 2)\t0.61\t\n Vaginitis\t3 (2)\t0 (0)\t2 (0 to 5)\t0.25\t\n Gastrointestinal symptoms§ \t3 (2)\t3 (3)\t−0 (−4 to 4)\t1.00\t\nLow back pain¶\t5 (4)\t2 (2)\t2 (−2 to 6)\t0.45\t\nViral infection\t1 (1)\t3 (3)\t−2 (−5 to 1)\t0.35\t\nTrauma\t3 (2)\t1 (1)\t1 (−2 to 4)\t0.62\t\nMiscellaneous**\t3 (2)\t1 (1)\t1 (−2 to 4)\t0.62\t\nUTI=urinary tract infection.\n\nNumbers do not add up as patients experienced at least one adverse event for each category.\n\n*Two sided Fisher’s exact test.\n\n†Recurrent UTI was defined as additional visits after day 14 because of recurrent UTI symptoms after symptoms had resolved by day 10, and the physician decided to treat with antibiotics.\n\n‡One patient in the diclofenac group was admitted to hospital on day 4 because of pyelonephritis.\n\n§Includes one case of diverticulitis in the norfloxacin group.\n\n¶Considered to be of musculoskeletal origin by treating doctor.\n\n**Includes one case of external otitis and two cases of tonsillitis in the diclofenac group and one case of hair loss in the norfloxacin group.\n\nDiscussion\nIn this randomised, double blind trial in women with uncomplicated lower urinary tract infection (UTI), symptomatic treatment with the non-steroidal anti-inflammatory drug (NSAID) diclofenac was inferior to antibiotic treatment with norfloxacin in controlling symptoms. Those treated with diclofenac were 27% less likely to have symptom resolution at day 3 after randomisation and 12% less likely to have symptom resolution at day 7 after randomisation, with higher mean symptom scores, more frequent reconsultations, a higher incidence of clinically diagnosed pyelonephritis, and lower patient satisfaction than those in the norfloxacin group. Conversely, women who received diclofenac were 37% less likely to receive antibiotics until day 30 after randomisation.\n\nA meta-analysis of five trials concluded that antibiotics are clinically superior to placebo in women with uncomplicated lower UTI.18 Our trial, in conjunction with the recently published trial by Gágyor et al,10 suggests that antibiotics are also clinically superior to symptomatic treatment with NSAIDs. This contrasts with the findings of a small pilot trial by Bleidorn et al,9 where clinical outcomes of treatment with ibuprofen were similar to those of antibiotic treatment with ciprofloxacin. The pilot trial triggered both our trial and that by Gágyor et al.10 Both pivotal trials were adequately powered but failed to detect non-inferiority of NSAIDs compared with antibiotics for symptom control. Importantly, both trials suggest that symptomatic treatment with NSAIDs is associated with an increase in the risk of clinically diagnosed pyelonephritis, which translates into a number needed to harm of 23 compared with antibiotic treatment in our trial. The risk of clinically diagnosed pyelonephritis in patients allocated to NSAIDs appeared higher than the risk observed in patients allocated to placebo in antibiotic trials by Christiaens et al and Ferry et al.20\n21 Although indirect comparisons like these should be interpreted with caution,22 they would be in line with recent evidence suggesting that NSAIDs may actually be harmful in patients with infectious diseases,23\n24\n25 despite potential antibacterial activities of diclofenac26 and ibuprofen.27 On the beneficial side, both pivotal trials suggest that antibiotic use can be halved on average by initial symptomatic treatment with NSAIDs, with a corresponding number needed to treat of 2 to prevent one instance of antibiotic use. We provided women with a rescue antibiotic for discretionary use after completion of the study drug and reaching the primary endpoint. This may have facilitated antibiotic use in the NSAID treatment arm of our trial. None the less, given the high global incidence of UTIs, the observed reduction in antibiotic use is highly relevant and is likely to immediately decrease resistance rates for Escherichia coli and even other microorganisms in the affected population.28\n\n\nThe increasing antibiotic resistance among uropathogens in general and E coli (the most common uropathogen) in particular is a global concern. Many studies show a clear correlation between antibiotic consumption and rising resistance rates. Accordingly, antibiotics are often withheld in cases of self limited, benign bacterial diseases such as acute otitis media, sinusitis, and traveller’s diarrhoea at the cost of a prolongation of symptoms by typically 1-3 days.29\n30\n31\n32\n33\n34\n35\n36 Our results in women with uncomplicated lower UTI are well in line with the prolongation of symptoms observed with symptomatic treatment of these conditions. As many women in the diclofenac group resorted to antibiotic treatment in our trial, a strategy of selectively deferring rather than completely withholding antibiotic treatment may be preferable for uncomplicated lower UTI.37 This can be achieved through a shared decision making process, during which clinicians inquire about their patients’ ideas and expectations about antibiotic treatment for uncomplicated UTI and also explore the option of delaying antibiotic use as a treatment strategy.\n\nSubgroup analyses did not provide evidence for any clinically relevant treatment by subgroup interactions. In particular, in contrast with the study by Gágyor et al,10 reduction in antibiotic prescription was comparable in women with and without positive urinary culture results. Testing initial urine samples for other biomarkers associated with UTI, such as heparin binding protein, interleukin 6, acetic acid, trimethylamine, xanthine oxidase, myeloperoxidase, or others,38\n39\n40 might have resulted in promising treatment by subgroup interactions, but these tests are not yet established in clinical practice, and we are unaware of any evidence to suggest that such interactions would be likely. In subgroup analyses, there were no relevant differences in baseline characteristics that would allow an early identification of women likely to benefit from diclofenac alone. However, in additional post hoc analyses, which were purely hypothesis generating, we found that the clinical diagnosis of pyelonephritis was established not earlier than five days after symptom onset, and that C reactive protein values >10 mg/L were more common at baseline in women who subsequently had a diagnosis of pyelonephritis. Taken together, these exploratory findings could support a tailored strategy of immediate antibiotic use in women with C reactive protein levels >10 mg/L and symptomatic treatment in remaining women for up to three or four days after symptom onset, followed by deferred, selective antibiotic use in those women who did not show a clear improvement by then. Naturally, such a tailored strategy would need to be evaluated in an appropriately powered randomised trial.\n\nStrengths and limitations of this study\nOur trial should be interpreted in view of its strengths and limitations. Strengths are its randomised double blind design with appropriate concealment of allocation; blinding of patients, therapists, and outcome assessors; the low loss to follow-up; the robustness of results in a series of sensitivity analyses; and the multicentre primary care setting. The premature termination of patient recruitment before reaching the initially planned sample size is an obvious limitation. However, the decision to stop recruitment was made without inspecting the data and is therefore unlikely to have biased our findings.41 Despite the smaller than originally planned sample size, our results are completely unequivocal. The self report questionnaire used to ascertain severity of symptoms was developed based on questionnaires described by Clayson et al12 and Little et al,13 which were available at the time of designing our trial. Women had to rate the severity of dysuria, frequency, urgency, and abdominal pain when passing urine and pain or tenderness in the lower back or loin on Likert scales from 0 to 6. The resulting summary score from 0 to 30 used to assess symptom severity as one of the secondary outcomes was not psychometrically validated and should therefore be considered exploratory. The primary outcome of symptom resolution at day 3 was defined as slight, very slight, or no problems reported for all five components.12\n14\n15 As these components assessed well established concepts and the calculation of a summary score was not necessary, we consider our primary outcome to be valid. A final limitation is that our results are not generalisable to countries and clinical settings with lower rates of susceptibility, which could decrease the effectiveness of antibiotics and render symptomatic treatment with NSAIDs less inferior.\n\nConclusions\nSymptomatic treatment is inferior to antibiotic treatment for women with uncomplicated lower UTI in an ambulatory setting, as it increases median symptom duration by two days and is likely to be associated with an increased risk of clinically diagnosed pyelonephritis. The observed clinically relevant reduction in antibiotic use, which would likely contribute directly to decreasing resistance rates in the affected population, suggests that alternative approaches of combining symptomatic treatment with deferred, selective antibiotic use should be developed and tested in future trials.\n\nWhat is already known on this topic\nUncomplicated urinary tract infection is a common reason for antibiotic prescription in ambulatory care even though it is often benign and self limiting\n\nReducing antibiotic usage is important to combat increasing rates of antibiotic resistance\n\nWhat this study adds\nSymptomatic treatment of lower urinary tract infections prolongs symptom duration and is likely to be associated with an increased risk of pyelonephritis\n\nWeb extra Extra material supplied by authors\n\n\nSupplementary information: Investigator and committee members, collaborators, additional methods, tables, and figures\n\n We thank the patient participants; the doctor participants for their meticulous data collection; CTU Bern, the clinical trials unit of the University of Bern for the development of the database (Malcolm Sturdy), monitoring (Lucia Kacina), and telephone interview and data clearance (Madeleine Dähler); the Institute of Primary Health Care BIHAM (Berner Institut für Hausarztmedizin), for its organisational support; and the hospital pharmacy of Inselspital for the production and blinding of the study drugs (Marco Eschenmoser).\n\nParticipating doctors: Peter Duner, Eggiwil; Christoph Fry, Belp; Ursula Grob, Herzogenbuchsee; Felix Huber, Zürich; Beat Köstner-Mösching, Neuenegg; Andreas Kronenberg, Bern; Corinna Kronenberg, Stettlen; Danielle Lemann, Langnau; Damian Meli, Huttwil; Gabriele Reinheimer, Worb; Véronique Rigamonti Wermelinger, Bern; Ralf Schäfer, Bern; Urs Schneeberger, Niederönz; Christian Studer, Luzern; Fritz Weber, Buchs; Doris Zundel, Bätterkinden; and Anne-Marie Zundel Funk, Zollikofen.\n\nContributors: AK, KM, and PJ conceived and designed the study and obtained funding. AK, MB, DM, and PF acquired the data. LB, BRdC, AL, SR, and PJ did the analysis and interpreted it in collaboration with the remaining authors. AK and PJ are the guarantors of the study results, had full access to the final data, cowrote the manuscript, and had final responsibility for content and the decision to submit for publication. All authors critically revised the paper for important intellectual content and approved the final version.\n\nFunding: This study was supported by the Swiss National Foundation (project 32003B_130867), Swiss Academy of Medical Sciences, SwissLife foundation, and Else Kroener-Fresenius foundation. PJ is a tier 1 Canada research chair in clinical epidemiology of chronic diseases. This research was completed, in part, with funding from the Canada research chairs programme. The funding bodies were not involved in the design or the conduct of the trial, nor in the writing of the manuscript or the decision to submit the manuscript for publication. The funding bodies only had access to the data after finalisation of the statistical analysis plan and completion of all analyses.\n\nCompeting interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work besides the acknowledged financial support. AK has received travel grant and meeting expenses from Gilead, Viofor, and the World Health Organization, is advisor of the Swiss Federal Office of Public Health concerning antibiotic resistance epidemiology in Switzerland, and provides non-interpreted annual resistance data to LEO Pharma and the Swiss government. PJ has received research grants to the institution from Astra Zeneca, Biotronik, Biosensors International, Eli Lilly, and The Medicines Company for cardiovascular trials, and serves as unpaid member of the steering group of cardiovascular trials funded by Astra Zeneca, Biotronik, Biosensors, St Jude Medical, and The Medicines Company. The remaining authors declare no financial relationships with any organisations that might have an interest in the submitted work in the previous three years and no other relationships or activities that could appear to have influenced the submitted work.\n\nEthical approval: This study was conducted in accordance with the Declaration of Helsinki and was approved by the local research ethics committee and the Swiss Agency for Therapeutic Products, swissmedic.\n\nData sharing: The statistical analysis plan and the final version of the study protocol are available from the corresponding author. Anonymised patient level data will be made available from the corresponding author at the Institute for Infectious Diseases, University Bern on reasonable request. Consent was not obtained for data sharing but the presented data are anonymised and risk of identification is low. No additional data are available.\n\nTransparency: The lead authors (AK and PJ) affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.\n==== Refs\n1 Organization WH. Global Action Plan on Antimicrobial Resistance. WHO Library Cataloguing-in-Publication Data, 2015 .\n2 Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Am J Med \n2002 ;113 (Suppl 1A ):5 -13 . 10.1016/S0002-9343(02)01054-9 pmid:12113866.\n3 Foxman B, Brown P. Epidemiology of urinary tract infections: transmission and risk factors, incidence, and costs. Infect Dis Clin North Am \n2003 ;17 :227 -41 . 10.1016/S0891-5520(03)00005-9 pmid:12848468.12848468 \n4 Mühlemann K. Surveillance of antibiotic prescription in the outpatient setting using the national Sentinel network (OP-159, http://www.smw.ch/docs/PdfContent/smw-12931.pdf\n). WONCA World Organization of National Colleges, Academies and Academic Associations of General Practitioners/Family Physicians; 2009; Basel. Switzerland; 2009.\n5 Lundborg CS, Olsson E, Mölstad S. Swedish Study Group on Antibiotic Use. Antibiotic prescribing in outpatients: a 1-week diagnosis-prescribing study in 5 counties in Sweden. Scand J Infect Dis \n2002 ;34 :442 -8 . 10.1080/00365540110080647 pmid:12160172.12160172 \n6 Farkas A, Alajem D, Dekel S, Binderman I. Urinary prostaglandin E2 in acute bacterial cystitis. J Urol \n1980 ;124 :455 -7 . 10.1016/S0022-5347(17)55493-2 pmid:6999176.6999176 \n7 Schwarz NT, Jung SY, Kalff JC, Chancellor M, Bauer AJ. Bacterial toxin N-formyl-methionyl-leucyl-phenylalanine acutely contracts human and rabbit detrusor through the release of eicosanoids. J Urol \n2002 ;167 :2603 -12 . 10.1016/S0022-5347(05)65045-8 pmid:11992095.11992095 \n8 Poljakovic M, Svensson ML, Svanborg C, Johansson K, Larsson B, Persson K. Escherichia coli-induced inducible nitric oxide synthase and cyclooxygenase expression in the mouse bladder and kidney. Kidney Int \n2001 ;59 :893 -904 . 10.1046/j.1523-1755.2001.059003893.x pmid:11231344.11231344 \n9 Bleidorn J, Gágyor I, Kochen MM, Wegscheider K, Hummers-Pradier E. Symptomatic treatment (ibuprofen) or antibiotics (ciprofloxacin) for uncomplicated urinary tract infection?--results of a randomized controlled pilot trial. BMC Med \n2010 ;8 :30 \n10.1186/1741-7015-8-30 pmid:20504298.20504298 \n10 Gágyor I, Bleidorn J, Kochen MM, Schmiemann G, Wegscheider K, Hummers-Pradier E. Ibuprofen versus fosfomycin for uncomplicated urinary tract infection in women: randomised controlled trial. BMJ \n2015 ;351 :h6544 \n10.1136/bmj.h6544 pmid:26698878.26698878 \n11 Little P, Merriman R, Turner S, et al. Presentation, pattern, and natural course of severe symptoms, and role of antibiotics and antibiotic resistance among patients presenting with suspected uncomplicated urinary tract infection in primary care: observational study. BMJ \n2010 ;340 :b5633 \n10.1136/bmj.b5633 pmid:20139213.20139213 \n12 Clayson D, Wild D, Doll H, Keating K, Gondek K. Validation of a patient-administered questionnaire to measure the severity and bothersomeness of lower urinary tract symptoms in uncomplicated urinary tract infection (UTI): the UTI Symptom Assessment questionnaire. BJU Int \n2005 ;96 :350 -9 . 10.1111/j.1464-410X.2005.05630.x pmid:16042729.16042729 \n13 Little P, Turner S, Rumsby K, et al. Dipsticks and diagnostic algorithms in urinary tract infection: development and validation, randomised trial, economic analysis, observational cohort and qualitative study. Health Technol Assess \n2009 ;13 :iii -iv, ix-xi, 1-73 . 10.3310/hta13190 pmid:19364448.\n14 Gupta K, Hooton TM, Roberts PL, Stamm WE. Short-course nitrofurantoin for the treatment of acute uncomplicated cystitis in women. Arch Intern Med \n2007 ;167 :2207 -12 . 10.1001/archinte.167.20.2207 pmid:17998493.17998493 \n15 McNulty CA, Richards J, Livermore DM, et al. Clinical relevance of laboratory-reported antibiotic resistance in acute uncomplicated urinary tract infection in primary care. J Antimicrob Chemother \n2006 ;58 :1000 -8 . 10.1093/jac/dkl368 pmid:16998209.16998209 \n16 Grabe M. (chairman) B-JT, Botto H, Çek M, Naber KG, Pickard RS, Tenke P, Wagenlehner F, Wullt B. Guidelines on Urological Infections. 2013 [cited 2015 9.7.2015]; Available from: http://uroweb.org/wp-content/uploads/18_Urological-infections_LR.pdf\n\n17 Chow S-C, Shao J, Wang H. Sample Size Calculations in Clinical Research . 2nd edn Chapman & Hall/CRC; 2008 .\n18 Falagas ME, Kotsantis IK, Vouloumanou EK, Rafailidis PI. Antibiotics versus placebo in the treatment of women with uncomplicated cystitis: a meta-analysis of randomized controlled trials. J Infect \n2009 ;58 :91 -102 . 10.1016/j.jinf.2008.12.009 pmid:19195714.19195714 \n19 Zou G. A modified poisson regression approach to prospective studies with binary data. Am J Epidemiol \n2004 ;159 :702 -6 . 10.1093/aje/kwh090 pmid:15033648.15033648 \n20 Christiaens TC, De Meyere M, Verschraegen G, Peersman W, Heytens S, De Maeseneer JM. Randomised controlled trial of nitrofurantoin versus placebo in the treatment of uncomplicated urinary tract infection in adult women. Br J Gen Pract \n2002 ;52 :729 -34 .pmid:12236276.12236276 \n21 Ferry SA, Holm SE, Stenlund H, Lundholm R, Monsen TJ. Clinical and bacteriological outcome of different doses and duration of pivmecillinam compared with placebo therapy of uncomplicated lower urinary tract infection in women: the LUTIW project. Scand J Prim Health Care \n2007 ;25 :49 -57 . 10.1080/02813430601183074 pmid:17354160.17354160 \n22 Bucher HC, Guyatt GH, Griffith LE, Walter SD. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol \n1997 ;50 :683 -91 . 10.1016/S0895-4356(97)00049-8 pmid:9250266.9250266 \n23 Little P, Moore M, Kelly J, et al. PIPS Investigators. Ibuprofen, paracetamol, and steam for patients with respiratory tract infections in primary care: pragmatic randomised factorial trial. BMJ \n2013 ;347 :f6041 \n10.1136/bmj.f6041 pmid:24162940.24162940 \n24 Basille D, Plouvier N, Trouve C, Duhaut P, Andrejak C, Jounieaux V. Non-steroidal Anti-inflammatory Drugs may Worsen the Course of Community-Acquired Pneumonia: A Cohort Study. Lung \n2017 ;195 :201 -8 . 10.1007/s00408-016-9973-1 pmid:28005149.28005149 \n25 Le Bourgeois M, Ferroni A, Leruez-Ville M, et al. Children, Antibiotics, Nonsteroidal Anti-inflammatory Drugs and Childhood Empyema (ChANCE) Study Group. Nonsteroidal Anti-Inflammatory Drug without Antibiotics for Acute Viral Infection Increases the Empyema Risk in Children: A Matched Case-Control Study. J Pediatr \n2016 ;175 :47 -53.e3 .pmid:27339249.27339249 \n26 Mazumdar K, Dutta NK, Dastidar SG, Motohashi N, Shirataki Y. Diclofenac in the management of E. coli urinary tract infections. In Vivo \n2006 ;20 :613 -9 .pmid:17091768.17091768 \n27 Obad J, Šušković J, Kos B. Antimicrobial activity of ibuprofen: new perspectives on an “Old” non-antibiotic drug. Eur J Pharm Sci \n2015 ;71 :93 -8 . 10.1016/j.ejps.2015.02.011 pmid:25708941.25708941 \n28 Gottesman BS, Carmeli Y, Shitrit P, Chowers M. Impact of quinolone restriction on resistance patterns of Escherichia coli isolated from urine by culture in a community setting. Clin Infect Dis \n2009 ;49 :869 -75 . 10.1086/605530 pmid:19686074.19686074 \n29 Glasziou PP, Del Mar CB, Sanders SL, Hayem M. Antibiotics for acute otitis media in children. Cochrane Database Syst Rev \n2004 ;(1 ):CD000219 pmid:14973951.14973951 \n30 Falagas ME, Giannopoulou KP, Vardakas KZ, Dimopoulos G, Karageorgopoulos DE. Comparison of antibiotics with placebo for treatment of acute sinusitis: a meta-analysis of randomised controlled trials. Lancet Infect Dis \n2008 ;8 :543 -52 . 10.1016/S1473-3099(08)70202-0 pmid:18718440.18718440 \n31 Ahovuo-Saloranta A, Borisenko OV, Kovanen N, et al. Antibiotics for acute maxillary sinusitis. Cochrane Database Syst Rev \n2008 ;(2 ):CD000243 pmid:18425861.18425861 \n32 Del Mar CB, Glasziou PP, Spinks AB. Antibiotics for sore throat. Cochrane Database Syst Rev \n2006 ;(4 ):CD000023 pmid:17054126.17054126 \n33 de Bruyn G, Hahn S, Borwick A. Antibiotic treatment for travellers’ diarrhoea. Cochrane Database Syst Rev \n2000 ;(3 ):CD002242 pmid:10908534.10908534 \n34 Genton B, D’Acremont V. Evidence of efficacy is not enough to develop recommendations: antibiotics for treatment of traveler’s diarrhea. Clin Infect Dis \n2007 ;44 :1520 \n, author reply 1521-2. 10.1086/517837 pmid:17479953.17479953 \n35 Tan T, Little P, Stokes T. Guideline Development Group. Antibiotic prescribing for self limiting respiratory tract infections in primary care: summary of NICE guidance. BMJ \n2008 ;337 :a437 \n10.1136/bmj.a437 pmid:18650239.18650239 \n36 Rovers MM, Glasziou P, Appelman CL, et al. Antibiotics for acute otitis media: a meta-analysis with individual patient data. Lancet \n2006 ;368 :1429 -35 . 10.1016/S0140-6736(06)69606-2 pmid:17055944.17055944 \n37 Little P, Moore MV, Turner S, et al. Effectiveness of five different approaches in management of urinary tract infection: randomised controlled trial. BMJ \n2010 ;340 :c199 \n10.1136/bmj.c199 pmid:20139214.20139214 \n38 Kjölvmark C, Påhlman LI, Åkesson P, Linder A. Heparin-binding protein: a diagnostic biomarker of urinary tract infection in adults. Open Forum Infect Dis \n2014 ;1 :ofu004 \n10.1093/ofid/ofu004 pmid:25734078.25734078 \n39 Lam CW, Law CY, To KK, et al. NMR-based metabolomic urinalysis: a rapid screening test for urinary tract infection. Clin Chim Acta \n2014 ;436 :217 -23 . 10.1016/j.cca.2014.05.014 pmid:24909875.24909875 \n40 Ciragil P, Kurutas EB, Miraloglu M. New markers: urine xanthine oxidase and myeloperoxidase in the early detection of urinary tract infection. Dis Markers \n2014 ;2014 :1 -5 . 10.1155/2014/269362 pmid:24591758.\n41 Bassler D, Briel M, Montori VM, et al. STOPIT-2 Study Group. Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis. JAMA \n2010 ;303 :1180 -7 .pmid:20332404.20332404\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0959-8138",
"issue": "359()",
"journal": "BMJ (Clinical research ed.)",
"keywords": null,
"medline_ta": "BMJ",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000553:Ambulatory Care; D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004311:Double-Blind Method; D005260:Female; D058006:General Practice; D006801:Humans; D008875:Middle Aged; D009643:Norfloxacin; D013557:Switzerland; D016896:Treatment Outcome; D014552:Urinary Tract Infections",
"nlm_unique_id": "8900488",
"other_id": null,
"pages": "j4784",
"pmc": null,
"pmid": "29113968",
"pubdate": "2017-11-07",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "12160172;12113866;18650239;24591758;12848468;26698878;12236276;20504298;17998493;20332404;17091768;28005149;15033648;24909875;10908534;18718440;19364448;25708941;16998209;17354160;6999176;20139213;19195714;16042729;25734078;11992095;14973951;17479953;9250266;17055944;17054126;19686074;18425861;24162940;27339249;20139214;11231344",
"title": "Symptomatic treatment of uncomplicated lower urinary tract infections in the ambulatory setting: randomised, double blind trial.",
"title_normalized": "symptomatic treatment of uncomplicated lower urinary tract infections in the ambulatory setting randomised double blind trial"
} | [
{
"companynumb": "PHHY2019CH066074",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DICLOFENAC"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Delayed suprachoroidal hemorrhage (DSCH) is a rare but devastating complication of trabeculectomy, usually resulting in a poor visual prognosis. The typical presentation of DSCH includes acute visual loss, high intraocular pressure, a shallow anterior chamber, and choroidal elevation. We report a patient with hypertension who had DSCH following trabeculectomy, with an unusual presenting picture of a large blood clot hanging in a deep anterior chamber. Anterior chamber irrigation and choroidal taps were performed immediately. The intraocular pressure was soon controlled, and the visual acuity returned to 20/25 in 6 months.",
"affiliations": "Department of Ophthalmology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan.;Department of Ophthalmology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan.;Department of Ophthalmology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan.",
"authors": "Lin|Hong-Zin|HZ|;Huang|Chin-Te|CT|;Lee|Yuan-Chieh|YC|",
"chemical_list": null,
"country": "China (Republic : 1949- )",
"delete": false,
"doi": "10.1016/j.tcmj.2015.06.003",
"fulltext": "\n==== Front\nTzu Chi Med J\nCi Ji Yi Xue Za Zhi\nTCMJ\nTzu-Chi Medical Journal\n1016-3190 2223-8956 Medknow Publications & Media Pvt Ltd India \n\nTCMJ-28-73\n10.1016/j.tcmj.2015.06.003\nCase Report\nA blood clot hanging in the anterior chamber due to delayed suprachoroidal hemorrhage after trabeculectomy\nLin Hong-Zin a Huang Chin-Te a Lee Yuan-Chieh abcd* a Department of Ophthalmology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan\nb Department of Ophthalmology and Visual Science, Tzu Chi University, Hualien, Taiwan\nc Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan\nd Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan\n* Corresponding author. Department of Ophthalmology, Buddhist Tzu Chi General Hospital, 707, Section 3, Chung-Yang Road, Hualien, Taiwan. Tel.: +886 3 8561825; fax: +886 3 8577161. E-mail address: yuanchieh.lee@gmail.com (Y.-C. Lee).\n\nApr-Jun 2016 \n03 8 2015 \n28 2 73 75\n03 6 2015 08 6 2015 13 6 2015 Copyright: © 2016, Buddhist Compassion Relief Tzu Chi Foundation2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Delayed suprachoroidal hemorrhage (DSCH) is a rare but devastating complication of trabeculectomy, usually resulting in a poor visual prognosis. The typical presentation of DSCH includes acute visual loss, high intraocular pressure, a shallow anterior chamber, and choroidal elevation. We report a patient with hypertension who had DSCH following trabeculectomy, with an unusual presenting picture of a large blood clot hanging in a deep anterior chamber. Anterior chamber irrigation and choroidal taps were performed immediately. The intraocular pressure was soon controlled, and the visual acuity returned to 20/25 in 6 months.\n\nDelayed suprachoroidal hemorrhageHyphemaIntraocular pressureTrabeculectomy\n==== Body\n1. Introduction\nSuprachoroidal hemorrhage is a rare but devastating complication which may occur in any type of intraocular surgery, especially when accompanied by a fluctuation in intraocular pressure (IOP). A suprachoroidal hemorrhage is called an expulsive hemorrhage when it occurs intraoperatively and the ocular contents prolapse through the wound. If it occurs postoperatively, it is called a delayed suprachoroidal hemorrhage (DSCH). Suprachoroidal hemorrhage usually presents with visual loss, a high IOP, shallow anterior chamber, and dark red dome-shaped or even appositional “kissing” choroidal elevation. Here we report a case of DSCH following trabeculectomy, with a presenting picture of a large blood clot hanging in the anterior chamber. Our management led to satisfactory results.\n\n2. Case report\nA 72-year-old man received a trabeculectomy in the right eye at another hospital. On the 1st postoperative day, a subtotal hyphema was noted, which was refractory to anterior chamber irrigation, and led to a refractory high IOP (up to 60 mm Hg under topical travoprost, timolol, and brimonidine, and oral acetazolamide). He was referred to our hospital on the 5th postoperative day. Syncope with temporary cardiac arrest occurred that night, and an electrocardiogram showed right branch bundle block with multiple premature ventricular complexes. Hypertension up to 153/96 mm Hg was noted and nifedipine was prescribed. Timolol was then discontinued. An anterior chamber paracentesis was performed daily to lower the IOP and to remove part of the hyphema. On the 13th postoperative day, anterior chamber irrigation and a pars plana vitrectomy were performed to remove the hyphema and the very dense vitreous hemorrhage. Abundant pigment on the posterior capsule and anterior hyaloid face was noted intraoperatively. On the 18th postoperative day, the patient underwent a trabeculectomy with mitomycin-C. No hyphema occurred this time and the IOP was 13 mm Hg postoperatively. The visual acuity returned to 20/25 in 3 months.\n\nTwo years later, a fornix-based trabeculectomy with mitomycin-C was performed smoothly in the left eye due to progressive visual field loss. On the 1st postoperative day, the patient had an IOP of 12 mm Hg with a diffuse bleb, a deep anterior chamber with no hyphema, and a patent peripheral iridectomy. However, he came to our emergency room with sudden painful loss of vision on the 3rd postoperative day. On examination, his visual acuity was limited to light perception, and the IOP was 49 mm Hg in his left eye. Slitlamp examination showed a round blood clot with an appearance like a nested cocoon hanging in the anterior chamber and obscuring the pupil (Fig. 1). The patient was not taking anticoagulants or antiplatelet medications. Immediate aspiration of the blood clot and irrigation of the anterior chamber were performed. The blood clot in the anterior chamber was found connected to a suprachoroidal hemorrhage. Two circumferential sclerotomies 4 mm from the limbus and 3 mm in length were performed in the superior nasal and superior temporal quadrants. The suprachoroidal hemorrhage was then drained from the two sclerotomies with constant irrigation pressure from the anterior chamber. His ocular pain subsided the next day. The IOP was 20 mm Hg. A B-scan showed mild residual suprachoroidal hemorrhage at the very peripheral area (Fig. 2). After 6 months, his visual acuity returned to 20/25. The IOP was 16 mm Hg.\n\nFig. 1 Three days after trabeculectomy, this patient had a sudden painful loss of vision. A slit lamp examination reveals a large blood clot with an appearance like a nested cocoon hanging in the anterior chamber and obscuring the pupil.\n\nFig. 2 On the day after choroidal tap and anterior chamber irrigation, a B-scan image shows residual hemorrhage in the superior-peripheral area (arrows).\n\n3. Discussion\nDSCH typically occurs after uncomplicated glaucoma filtration surgery. The incidence of DSCH after glaucoma filtration procedures varies from 1.6% to 6.2% [12]. The risk factors include systemic conditions such as advanced age, atherosclerosis, hypertension, ischemic heart disease, and anticoagulant usage, and ocular conditions including myopia, aphakia, a high preoperative IOP, a drop in IOP, postoperative hypotony, and tube shunt implantation [345]. Our patient was 72 years old and was taking clopidogrel for ischemic heart disease before the second operation. Hyphema and vitreous hemorrhage occurred after a trabeculectomy in the right eye, and DSCH occurred after a trabeculectomy in the left eye. He had pseudophakia in both eyes, and there was no postoperative hypotony. His systemic risk factors might have played a major role in the development of DSCH.\n\nDSCH usually presents with a sudden onset of painful visual loss, an elevated IOP, a shallow anterior chamber, and peripheral large choroidal elevations with dark coloration. However, instead of a shallow anterior chamber, our patient had a deep anterior chamber with an overhanging cocoon-like blood clot, which has never been described before in literature. Our initial impression was ordinary bleeding from the peripheral iridectomy. After the blood clot was found connected to the suprachoroidal hemorrhage, DSCH was diagnosed as the underlying etiology. A suprachoroidal hemorrhage through the angle to the anterior chamber transferred the pressure to the anterior chamber. The iris-lens diaphragm was therefore not pushed forward, and the anterior chamber depth was maintained. The overall IOP was still high. The connection to the suprachoroidal hemorrhage also explained why and how the large blood clot was hanging from the superior angle.\n\nThe timing of surgical intervention and the optimal procedure remain unclear. A wait of 7 days to 14 days to allow liquefaction of the blood clot is usually recommended [67]. But this delay in intervention may increase inflammation, leading to irreversible damage such as retinal adhesions or cyclitic membrane formation. This would require complex vitreoretinal surgery, and thus a poor final prognosis [8]. Early surgical intervention after the diagnosis of DSCH has been suggested [910]. Pakravan et al [9] recommended an immediate choroidal tap and anterior chamber reformation after diagnosis of DSCH. They suggested two scleral incisions 4 mm in length and a 1 mm sclerectomy in both inferior quadrants. After massage to remove the serosanguinous fluid, they created a para-centesis to reform the anterior chamber with a balanced salt solution. We also performed surgical drainage in our patient immediately after the diagnosis of DSCH. However, we performed scleral incisions in two superior quadrants, instead of inferior quadrants. We believed that the DSCH would be located more superiorly in this patient because the large blood clot in the anterior chamber was connected to the DSCH at the 12 o’clock area. We also did not massage the fluid in our patient so as not to stretch or distort the weakened, previously ruptured vessels and induce secondary hemorrhage. Fortunately, the blood was evacuated smoothly. The IOP returned to normal limits the next day and the visual acuity returned to 20/25 in 6 months.\n\nIn conclusion, we report a blood clot hanging in a deep anterior chamber as an unusual presentation of DSCH after trabeculectomy. Immediate choroidal tap and anterior chamber irrigation without massage led to a satisfactory visual result.\n\nConflict of interest: none.\n==== Refs\n[1] Givens K Shields MB Suprachoroidal hemorrhage after glaucoma filtering surgery Am J Ophthalmol 1987 15 689 94 \n[2] Paysse E Lee PP Lloyd MA Sidoti PA Fellenbaum PS Baerveldt G Suprachoroidal hemorrhage after Molteno implantation J Glaucoma 1996 5 170 5 8795754 \n[3] Chu TG Green RL Suprachoroidal hemorrhage SurvOphthalmol 1999 43 471 86 \n[4] Tuli SS WuDunn D Ciulla TA Cantor LB Delayed suprachoroidal hemorrhage after glaucoma filtration procedures Ophthalmology 2001 108 1808 11 11581053 \n[5] Jeganathan VS Ghosh S Ruddle JB Gupta V Coote MA Crowston JG Risk factors for delayed suprachoroidal hemorrhage following glaucoma surgery Br J Ophthalmol 2008 92 1393 6 18684750 \n[6] Stamper RL Lieberman MF Drake MV Becker-Shaffer's diagnosis and therapy of the glaucomas 2009 USA Mosby 514 5 \n[7] Allingham RR Damji KF Freedman SF Shield textbook of glaucoma 2011 Philadelphia Lippincott Williams & Wilkins 504 5 \n[8] Weinberg DV Rosenberg LI Retina to retina adhesions following suprachoroidal hemorrhage Br J Ophthalmol 1996 80 674 \n[9] Pakravan M Yazdani S Afroozifar M Kouhestani N Ghassami M Shahshahan M An alternative approach for management of delayed suprachoroidal hemorrhage after glaucoma procedures J Glaucoma 2014 23 37 40 22668976 \n[10] Jin W Xing Y Xu Y Wang W Yang A Management of delayed suprachoriodal haemorrhage after intraocular surgery and trauma Graefes Arch Clin Exp Ophthalmol 2014 252 1189 93 24473672\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": null,
"issue": "28(2)",
"journal": "Ci ji yi xue za zhi = Tzu-chi medical journal",
"keywords": "Delayed suprachoroidal hemorrhage; Hyphema; Intraocular pressure; Trabeculectomy",
"medline_ta": "Ci Ji Yi Xue Za Zhi",
"mesh_terms": null,
"nlm_unique_id": "9514171",
"other_id": null,
"pages": "73-75",
"pmc": null,
"pmid": "28757726",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "8795754;8795385;22668976;18684750;24473672;11581053;3578467;10416790",
"title": "A blood clot hanging in the anterior chamber due to delayed suprachoroidal hemorrhage after trabeculectomy.",
"title_normalized": "a blood clot hanging in the anterior chamber due to delayed suprachoroidal hemorrhage after trabeculectomy"
} | [
{
"companynumb": "ALCN2016TW005189",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAZOLAMIDE"
},
"drugadditional": "3",
"dr... |
{
"abstract": "We performed a study to identify potential causes and risk factors of vertebral fracture cascade. Vertebral fracture cascade is a severe clinical event in patients with bone fragility. Only half of patients have an identified cause of secondary osteoporosis.\n\n\nBACKGROUND\nVertebral fracture (VF) is the most common osteoporotic fracture, and a strong risk factor of subsequent VFs leading to VF cascade (VFC). We prompted a study to identify potential causes and risk factors of VFC.\n\n\nMETHODS\nVFC observations were collected retrospectively between January 2016 and April 2017. VFC was defined as an occurrence of at least three VFs within 1 year.\n\n\nRESULTS\nWe included in 10 centers a total of 113 patients with VFC (79.6% of women, median age 73, median number of VFs in the cascade, 5). We observed 40.5% and 30.9% of patients with previous major fractures and a previous VF, respectively, and 68.6% with densitometric osteoporosis; 18.9% of patients were currently receiving oral glucocorticoids and 37.1% in the past. VFC was attributed by the physician to postmenopausal osteoporosis in 54% of patients. A secondary osteoporosis associated with the VFC was diagnosed in 52 patients: glucocorticoid-induced osteoporosis (25.7%), non-malignant hemopathies (6.2%), alcoholism (4.4%), use of aromatase inhibitors (3.6%), primary hyperparathyroidism (2.7%), hypercorticism (2.7%), anorexia nervosa (2.7%), and pregnancy and lactation-associated osteoporosis (1.8%). A total of 11.8% of cases were reported following a vertebroplasty procedure. A total of 31.5% patients previously received an anti-osteoporotic treatment. In six patients, VFC occurred early after discontinuation of an anti-osteoporotic treatment, in the year after the last dose effect was depleted: five after denosumab and one after odanacatib.\n\n\nCONCLUSIONS\nThe results of this retrospective study showed that only half of VFC occurred in patients with a secondary cause of osteoporosis. Prospective studies are needed to further explore the determinants of this severe complication of osteoporosis.",
"affiliations": "Rheumatology Department, CHU Lapeyronie Montpellier, 371 avenue du Gaston Giraud, 34090, Montpellier, France. che.helene@yahoo.fr.;Department of Rheumatology, BIAM - UMR E 4320 TIRO-MATOs CEA/UNS, Université Côte D'Azur, Centre Hospitalier Universitaire Nice, Nice, France.;Service de rhumatologie, CHRU France et Université de Lille, Université Littoral Côte d'Opale, 59000 Lille, PMOI EA 4490 faculté de chirurgie dentaire, place de Verdun, 59000, Lille, France.;Service de rhumatologie, CHRU France et Université de Lille, Université Littoral Côte d'Opale, 59000 Lille, PMOI EA 4490 faculté de chirurgie dentaire, place de Verdun, 59000, Lille, France.;Rheumatology Department, CHU de Saint Etienne, INSERM U1059, Lab Biologie Intégrée du Tissu Osseux, Université de Lyon, 42055, Saint-Etienne Cedex 2, France.;Rheumatology Department, CH Simone Veil du Vitre, 30 route de Rennes, 35500, Vitre, France.;Rheumatology Department, CHU La Miletrie Poitiers, 2 rue de la Miletrie, 86021, Poitiers Cedex, France.;Rheumatology Department, CHU Pellegrin Bordeaux, Rue de la pelouse de Douet, 33000, Bordeaux, France.;Rheumatology Department, Hôpitaux Universitaires de Strasbourg, 1 avenue Moliere, 67098, Strasbourg, France.;Rheumatology Department, CHR Orléans, 14 avenue de l'Hopital, 45000, Orleans, France.;Rheumatology Department, INSERM 1153, CHU Paris Cochin, Paris Descartes University, 27 rue du Faubourg Saint-Jacques, 75014, Paris, France.;Rheumatology Department, INSERM 1153, CHU Paris Cochin, Paris Descartes University, 27 rue du Faubourg Saint-Jacques, 75014, Paris, France.",
"authors": "Che|H|H|;Breuil|V|V|;Cortet|B|B|;Paccou|J|J|;Thomas|T|T|;Chapuis|L|L|;Debiais|F|F|;Mehsen-Cetre|N|N|;Javier|R M|RM|;Loiseau Peres|S|S|;Roux|C|C|;Briot|K|K|",
"chemical_list": "D050071:Bone Density Conservation Agents; D005938:Glucocorticoids",
"country": "England",
"delete": false,
"doi": "10.1007/s00198-018-4793-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0937-941X",
"issue": "30(3)",
"journal": "Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA",
"keywords": "Cascade; Osteoporosis; Risks factors; Vertebral fractures",
"medline_ta": "Osteoporos Int",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D050071:Bone Density Conservation Agents; D005260:Female; D005602:France; D005938:Glucocorticoids; D006801:Humans; D008297:Male; D008875:Middle Aged; D010024:Osteoporosis; D015663:Osteoporosis, Postmenopausal; D058866:Osteoporotic Fractures; D012008:Recurrence; D012189:Retrospective Studies; D012307:Risk Factors; D016103:Spinal Fractures",
"nlm_unique_id": "9100105",
"other_id": null,
"pages": "555-563",
"pmc": null,
"pmid": "30519756",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": "10320531;10371229;10733048;10841167;11176842;17206492;17473494;17611706;1780656;19657121;19657122;2035348;20570833;21130353;22222166;22229787;22513649;23246689;23427068;25138263;25645589;26314987;26363627;26376401;26510845;26541263;26694595;26694598;26892042;27083866;27732330;28104509;28240371;28243796;28283537;28789921;28882718;29105841;29230512;29393984;29396698;29455249;29492590;8254091;8481587",
"title": "Vertebral fractures cascade: potential causes and risk factors.",
"title_normalized": "vertebral fractures cascade potential causes and risk factors"
} | [
{
"companynumb": "FR-TEVA-2019-FR-1043598",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ALENDRONATE SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "Rationale/Objectives: A human coronavirus (HCoV-19) has caused the novel coronavirus disease (COVID-19) outbreak worldwide. There is an urgent need to develop new interventions to suppress the excessive immune response, protect alveolar function, and repair lung and systemic organ damage. Zofin (previously known as Organicell Flow) is a novel therapeutic that is derived from the soluble and nanoparticle fraction (extracellular vesicles and exosomes) of human amniotic fluid. Here within, we present the clinical outcomes after Zofin treatment in three critically ill patients suffering from severe, multi-organ complications induced by COVID-19 infection. All patients were diagnosed with COVID-19, developed respiratory failure, and were hospitalized for more than 40 days. Methods: Zofin was administered to patients concurrently with ongoing medical care who were monitored for 28-days post-therapy. SOFA score assessment, chest X-rays, and inflammatory biomarker testing was performed. Main Results: There were no adverse events associated with the therapy. The patients showed improvements in ICU clinical status and experienced respiratory improvements. Acute delirium experienced by patients completely resolved and inflammatory biomarkers improved. Conclusions: Primary outcomes demonstrate the therapy was safe, accessible, and feasible. This is the first demonstration of human amniotic fluid-derived nanoparticles as a safe and potentially efficacious therapeutic treatment for respiratory failure induced by COVID-19 infection.",
"affiliations": "Organicell Regenerative Medicine, Inc., Miami, FL, United States.;Organicell Regenerative Medicine, Inc., Miami, FL, United States.;Landmark Hospital Athens, Athens, GA, United States.;Landmark Hospital Athens, Athens, GA, United States.;Landmark Hospital Naples, Naples, FL, United States.;Technomad, Bonita Springs, FL, United States.;Organicell Regenerative Medicine, Inc., Miami, FL, United States.;Organicell Regenerative Medicine, Inc., Miami, FL, United States.;Organicell Regenerative Medicine, Inc., Miami, FL, United States.;Organicell Regenerative Medicine, Inc., Miami, FL, United States.;Organicell Regenerative Medicine, Inc., Miami, FL, United States.;Organicell Regenerative Medicine, Inc., Miami, FL, United States.;Organicell Regenerative Medicine, Inc., Miami, FL, United States.;Organicell Regenerative Medicine, Inc., Miami, FL, United States.",
"authors": "Mitrani|Maria Ines|MI|;Bellio|Michael A|MA|;Sagel|Anthony|A|;Saylor|Marie|M|;Kapp|William|W|;VanOsdol|Kathryn|K|;Haskell|Gwendolyn|G|;Stewart|Danique|D|;Abdullah|Zanub|Z|;Santos|Ivan|I|;Milberg|Julian|J|;Arango|Alissa|A|;Mitrani|Albert|A|;Shapiro|George C|GC|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fmed.2021.583842",
"fulltext": "\n==== Front\nFront Med (Lausanne)\nFront Med (Lausanne)\nFront. Med.\nFrontiers in Medicine\n2296-858X\nFrontiers Media S.A.\n\n10.3389/fmed.2021.583842\nMedicine\nCase Report\nCase Report: Administration of Amniotic Fluid-Derived Nanoparticles in Three Severely Ill COVID-19 Patients\nMitrani Maria Ines 1*\n\nBellio Michael A. 1\n\nSagel Anthony 2\nSaylor Marie 2\n\nKapp William 3\nVanOsdol Kathryn 4\nHaskell Gwendolyn 1\n\nStewart Danique 1\nAbdullah Zanub 1\nSantos Ivan 1\n\nMilberg Julian 1\nArango Alissa 1\nMitrani Albert 1\n\nShapiro George C. 1\n1Organicell Regenerative Medicine, Inc., Miami, FL, United States\n2Landmark Hospital Athens, Athens, GA, United States\n3Landmark Hospital Naples, Naples, FL, United States\n4Technomad, Bonita Springs, FL, United States\nEdited by: Jiapeng Huang, University of Louisville, United States\n\nReviewed by: Paolo De Coppi, University College London, United Kingdom; William Rawlinson, New South Wales Health Pathology, Australia\n\n*Correspondence: Maria Ines Mitrani mari@organicell.com\nThis article was submitted to Intensive Care Medicine and Anesthesiology, a section of the journal Frontiers in Medicine\n\n17 3 2021\n2021\n17 3 2021\n8 58384213 8 2020\n16 2 2021\nCopyright © 2021 Mitrani, Bellio, Sagel, Saylor, Kapp, VanOsdol, Haskell, Stewart, Abdullah, Santos, Milberg, Arango, Mitrani and Shapiro.\n2021\nMitrani, Bellio, Sagel, Saylor, Kapp, VanOsdol, Haskell, Stewart, Abdullah, Santos, Milberg, Arango, Mitrani and Shapiro\nThis 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.\nRationale/Objectives: A human coronavirus (HCoV-19) has caused the novel coronavirus disease (COVID-19) outbreak worldwide. There is an urgent need to develop new interventions to suppress the excessive immune response, protect alveolar function, and repair lung and systemic organ damage. Zofin (previously known as Organicell Flow) is a novel therapeutic that is derived from the soluble and nanoparticle fraction (extracellular vesicles and exosomes) of human amniotic fluid. Here within, we present the clinical outcomes after Zofin treatment in three critically ill patients suffering from severe, multi-organ complications induced by COVID-19 infection. All patients were diagnosed with COVID-19, developed respiratory failure, and were hospitalized for more than 40 days.\n\nMethods: Zofin was administered to patients concurrently with ongoing medical care who were monitored for 28-days post-therapy. SOFA score assessment, chest X-rays, and inflammatory biomarker testing was performed.\n\nMain Results: There were no adverse events associated with the therapy. The patients showed improvements in ICU clinical status and experienced respiratory improvements. Acute delirium experienced by patients completely resolved and inflammatory biomarkers improved.\n\nConclusions: Primary outcomes demonstrate the therapy was safe, accessible, and feasible. This is the first demonstration of human amniotic fluid-derived nanoparticles as a safe and potentially efficacious therapeutic treatment for respiratory failure induced by COVID-19 infection.\n\nCOVID-19\ncritical care\nARDS (acute respiratory distress syndrome)\nexosomes\namniotic fluid (AF)\nextracellular vesicles\n==== Body\nBackground\n\nA human coronavirus (HCoV-19) has caused the novel coronavirus disease (COVID-19) outbreak worldwide. The main symptoms of COVID-19 include fever, fatigue, and cough that can progress rapidly to severe and critical conditions resulting in pulmonary edema leading to the most common complications: acute lung injury (ALI) and acute respiratory distress syndromes (ARDS) (1–5). The majority of cases result in mild symptoms, but some can progress into pneumonia and multi-organ failure. According to severity, it is divided into mild, normal, severe, and critically ill, the last of which is associated with ICU admission and mortality (6). Immune activation in some patients and the appearance of cytokine storm syndrome is one of the most potent causes of severe damage to lungs and other organs, which may lead to death.\n\nIn the early stages of the COVID-19 pandemic, treatment for COVID-19 patients included non-specific anti-viral, anti-inflammatory medication, oxygen therapy, mechanical ventilation, and blood pressure medications. A definitive antiviral therapy or ALI treatment for patients with or recovering from COVID-19 infections continues to be in development. Furthermore, as the number of COVID-19 infections continues to rise, severe cases continue to result in organ failure and long-term impairments. As a result, there remains an urgent need to develop new interventions to suppress the excessive immune response in a timely manner during the course of disease, protect alveolar function, and repair the pulmonary and systemic organ damage caused after the infection (7).\n\nOne hallmark feature of critical COVID-19 patients is the extremely high expression of pro-inflammatory markers, including C Reactive protein (CRP) and cytokines IL-6, TNFα, and IL8 (8). Anti-inflammatory and immune modulatory therapies have risen as strong therapeutic candidates because inflammatory cytokine storm is common in severe cases and is the highest amongst non-survival patients (8). Exaggerated immune response, the secretion of pro-inflammatory cytokines, and marked pulmonary infiltration are lethal components of viral infections (9). Therefore, traditional anti-inflammatory treatments, such as the anti-interlukin-6 receptor monoclonal antibody Tocilizumab and corticosteroids, are actively being used to suppress cytokine storms and prevent further injury. However, current standard of care anti-inflammatory medications are not optimal due to the concern that they may delay the elimination of the virus and risk secondary infection (8). Furthermore, severe COVID-19 cases continue to persist despite the incorporation of these current treatment options. Cell-based therapies are actively being tested for COVID-19 infections due to the observed immunomodulatory and anti-inflammatory effects (10). However, cell therapies are often limited due to cell delivery challenges and inadequate cell survival post-infusion (11). Furthermore, research has uncovered that cell-beneficial effects are mainly paracrine-mediated via the release of growth factors, cytokines, and extracellular vesicles such as exosomes rather than engraftment and differentiation (12, 13). Therefore, our proposed therapeutic intervention utilizes cell- and tissue-secreted paracrine factors, rather than the cells themselves, as the active drug components.\n\nZofin (previously known as Organicell Flow) is a novel biologic that is derived from the soluble and nanoparticle fraction of human amniotic fluid. The manufactured Zofin therapeutic is an acellular product characterized to contain over 300 growth factors, cytokines, and chemokines as well as other extracellular vesicles and exosomes secreted from perinatal tissues. Amniotic fluid sourced biologics have been studied for the therapeutic use of orthopedic repair due to the abundance of anti-inflammatory and tissue healing components (14–16). However, the use of amniotic fluid-derived paracrine factors, including proteins and nanoparticles, have not been tested for the treatment of COVID-19-induced systemic organ damage and respiratory failure.\n\nHere within, we present three case reports of critically ill patients suffering from severe, multi-organ complications induced by COVID-19 infection who were treated with Zofin in addition to the authorized standard of care available at that time. These patients represent the subset of COVID-19 patients most effected by the virus. These three patients tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using a real-time reverse transcriptase polymerase chain reaction assay, were diagnosed with ARDS, and suffered from severe organ damage and respiratory failure. At the time of hospital admission there was no emergency authorized standard of care for COVID-19 infection. These patients were treated with supplemental oxygen, anti-inflammatories, antibiotics, antiviral medication, and other medications required to manage their multiorgan failure symptoms. Prior to enrollment for investigational treatment at the study site ICU (Landmark Hospital of Athens), these patients had been hospitalized for over 40 days and were transferred from the initial hospital sites to appropriately manage multiple comorbidities. The physicians explored all authorized pharmacological options available to them at that time. Due to the concern for declining and irreversible injury, the treating physician requested single patient emergency, compassionate use IND (eIND) to administer Zofin.\n\nThe first patient (de-identified subject CU#1) approved for Zofin was a 74-year-old Caucasian female with multiple comorbidities including obesity, hypertension (HTN), type 2 diabetes, depression, hyperlipidemia (HLD), and vitamin D deficiency. This patient was initially admitted to the hospital 44 days prior to treatment at the study site. Initial diagnosis was acute hypoxemic respiratory failure with positive COVID-19 infection. The patient was orally intubated after 6 days in the hospital and treated for COVID-19 with pneumonia. COVID-19+ tests were reported for 20 days post-admission. Tracheostomy placement was performed prior to transfer to the study site. Patient CU#1 continued to require mechanical ventilation prior to treatment and developed acute metabolic encephalopathy with ICU delirium along with acute kidney injury and anemia. The initial COVID-19 treatment upon admission included a 10-day course of Hydroxychloroquine, three doses of Ribavarin, and Kaletra. Inclusion of additional medication was ongoing to manage complications induced by the multiple comorbidities. Ten days after transfer to the study site, Zofin infusion was initiated in addition to ongoing medical treatment. Due to the patient's high BMI, it was decided to administer a total of four doses instead of the originally planned three. FDA approval was obtained prior to this protocol change.\n\nThe second patient (de-identified subject CU#2) was a 79-year-old Caucasian female with multiple chronic comorbidities including obesity, HTN, HLD, Hodgkin's disease, hypothyroidism (HYT), and status post-left carotid endarterectomy. This patient was admitted to the hospital 47 days prior to treatment at the study site. Her initial diagnosis included septic syndrome and hypoxemic respiratory failure with positive COVID-19 infection. The initial treatment reports did not indicate if this patient received any anti-viral medication to target the COVID-19 infection; instead, the treatment included a wide range of medications to manage the severe symptoms associated with comorbidities, antibiotics (Cefepime and Vancomycin), and hemodialysis. Due to the severity of the patient upon admission, mechanical ventilation was immediately required after 2 days. The patient was extubated and then reintubated, followed by tracheostomy placement. COVID-19+ tests were reported for 16 days post-admission. Hospital course was complicated by acute kidney injury, anemia requiring blood transfusion, encephalopathy, and septic shock. The patient underwent PEG placement a few days prior to transfer to the study site. Transfer of the patient to the study site was completed for ventilator liberation and management of other comorbidities. Like the previous patient, the high BMI of CU#2 qualified this patient for four doses of Zofin, as approved by the FDA.\n\nThe third patient (de-identified subject CU#3) was a 66-year-old Hispanic male with comorbidities that included type 2 diabetes and HTN. This patient was admitted to the hospital 42 days prior to treatment at the study site. Initial diagnosis was hypoxemic respiratory failure secondary to COVID-19 pneumonia. Initial COVID-19 treatments included Hydroxychloroquine as an outpatient, followed by Tocilizumab on admission. Patient CU#3 required intubation that was followed by extubation and reintubation. Hospital course was complicated by hypoxemic cardiac arrest, acute kidney injury that required renal replacement therapy, acute DVT, and encephalopathy. The patient underwent tracheostomy prior to transfer to the study site. Transfer to the study site was completed for ventilator liberation, management of hemodialysis, continuation of nutritional support, and management of other comorbidities. COVID-19+ tests were reported for 8 days post-admission. Additional medication and antibiotics were incorporated throughout treatment as the patient's condition evolved. The patient received three doses of Zofin beginning 9 days after transfer to the study site.\n\nThe primary objective of these three eINDs was to demonstrate safety, feasibility, and accessibility of Zofin for the treatment of these severely ill patients. Secondarily, we aimed to observe post-treatment changes in clinical status improvement and inflammatory biomarker improvement that may suggest potential therapeutic efficacy. Our underlying hypothesis suspected that Zofin treatment would improve patient outcomes and promote lung and organ failure assessment recovery. This report demonstrates the first use of an amniotic fluid-derived product in humans as a potential therapeutic to aid in the recovery from severe organ injuries induced by COVID-19 infection.\n\nMethods\n\nEthics\n\nThis study involving human participants was reviewed and approved by the FDA and the Independent Review Board Western Institutional Review Board. The patient's consent to participate in the study and for data publication was obtained at the treatment site by the patient's proxy using an IRB approved informed consent form. These single patient INDs were submitted under the approved parent IND #19881 and FDA approval was issued with the following IND numbers: CU#1 IND#22370, CU#2 IND#22371, and CU#3 IND#22897. IRB approval was issued by letters of acknowledgment from the Western Institutional Review Board.\n\nTherapeutic Intervention\n\nThe therapeutic intervention studied in these case reports was an acellular biologic called Zofin. Zofin was manufactured by Organicell Regenerative Medicine, Inc. in Miami, FL. The Zofin product was derived from human amniotic fluid donated from consenting adults during routine, planned cesarean sections under IRB approved donor screening (IRB approval agency: IRCM). Donor qualification was performed under FDA CFR 1271. Donor qualification was certified following the review of the mother's medical history, social history, physical examination, and raw product recovery information. Relevant communicable disease testing was completed, and the mother was reported to have negative/non-reactive results for CMV total Ab, Hepatitis B core total Ab, Hepatitis B surface Ag, Hepatitis C virus Ab, HIV-1/HIV-2 Plus O, HTLV I/II Ab, Syphilis screening—non-treponemal, Ultrio Elite HBV, Ultrio Elite HCV, Ultrio Eliter HIV-1/2, and WNV. Upon receipt, the collected amniotic fluid was subjected to centrifugation and proprietary filtration to remove large particle debris and preserve the natural protein, nanoparticle, and exosome composition of amniotic fluid. The final Zofin product was released by Organicell Regenerative Medicine, Inc. after meeting the release criteria requirements. The specific release criteria parameters for the product administered in these treatments were: sterility (14-day cultures: no growth for aerobic, anaerobic, and fungal contamination), endotoxin (<0.05 EU/mL), nanoparticle composition (concentration = 3.26 × 1011/mL, mode particle size = 90.2 nm), protein concentration (2.83 mg/mL), and hyaluronic acid concentration (261 ng/mL). Zofin was stored frozen and shipped on dry ice to the treatment location following validated storage and shipping methods.\n\nPatient Standard Care and Administration of Therapeutic Intervention\n\nPatient care and product infusion throughout the study period was performed at Landmark Hospital Athens, in Athens, GA. Standard care was followed along with Zofin administration under approved single patient eIND by the FDA and under IRB oversight. The patient care was defined by the treating physician in accordance with the authorized standard of care practices ongoing at the study site at the time of patient enrollment. The care was focused on treating the multiple ongoing organ failure issues induced by the COVID-19 infection. At the time of hospital admission, there was no standardized or authorized therapy for COVID-19 infection. These patients were treated with available anti-viral, anti-inflammatory, antibiotics, and other medication required to manage their occurring symptoms. Supplemental oxygen therapy and ventilation was provided as determined by the physicians. Zofin was administered intravenously at a dose of 1 mL diluted in 100 mL of normal saline. Intravenous infusion was performed at a rate of 2 mL/min. Product thawing and dilution occurred immediately before administration. Patients CU#1 and CU#2 received a total of four doses administered on day 0, day 4, day 6, and day 8. Patient CU#3 received a total of three doses administered on day 0, day 4, and day 8.\n\nSOFA Score Assessment\n\nChartPad Software (Technomad), a cloud-based electronic data capture platform, was used to collect patient data. SOFA score was calculated as reported in the literature (17) and was assessed on 0, 4, 6, 8, 14, 21, and 28 days after the initiation of Zofin therapy. The SOFA score was derived from clinical and laboratory results obtained for respiration (PaO2/FiO2, mmHg), coagulation (platelets, × 103/μL), liver (bilirubin, mg/dL), cardiovascular (mean arterial pressure), neurologic (Glasgow coma score), and renal (creatinine, mg/dL).\n\nChest X-Ray\n\nA portable chest x-ray (CXR) was used to acquire imaging at baseline and throughout treatment to evaluate, identify, and monitor lung abnormalities (18). After images were acquired, analysis was performed by the radiologist at Landmark Hospital and CXR reports were generated to outline the clinical findings.\n\nBiomarker Testing\n\nBiomarker collection occurred at 0, 4, 6, 8, 14, 21, and 28 days after initiation of Zofin therapy to assess for concentration of D-Dimer, CRP, IL2, IL6, and TNFα. D-Dimer and CRP measurements were performed at the Athens Regional Labs, while IL2, IL6, and TNFα were measured by Quest Diagnostics.\n\nResults\n\nFollow up of ICU Clinical Status\n\nThe clinical status of the patients was monitored for 28 days post-initiation of Zofin therapy. After treatment, the respiratory status of the patients improved and stabilized. CU#1 respiratory status improved throughout the 28 days, changing from a 21% oxygen T-collar to room air with no oxygen therapy requirement, CU#2 respiratory status improved during the 28 days with a transition from mechanical ventilation to non-mechanical ventilation, and the respiratory status of CU#3 improved 4 days post-treatment with decannulation and subsequent removal from oxygen therapy by day 14. Furthermore, all patients were transferred out of ICU status to the step-down unit within the 28-day period (Table 1). Patient CU#1 was discharged from the hospital 29 days post-treatment initiation and patient CU#3 was discharged from the hospital 26 days post-treatment initiation. Patient CU#2 remained in the hospital as she had experienced setbacks due to aspiration but was controlled and stable in the step-down unit with ventilation and hemodialysis.\n\nTable 1 Clinical status of compassionate use patients.\n\nPatient ID\tCU#1\tCU#2\tCU#3\t\nAge\t74\t79\t66\t\nGender\tF\tF\tM\t\nWeight (kg)\t118.75\t100.24\t60.36\t\nBMI (kg/m2)\t38.43\t40.18\t22.14\t\nPrior comorbidities\tObesity, HTN, T2DM, depression, HLD, Vit. D deficiency\tObesity, HTN, HLD, Hodgkin's disease, HYT, status post left carotid endarterectomy\tT2DM, HTN\t\nPre-treatment complications\tHyperglycemia Acute lung injury (ARDS) Anemia with normocytic indices\tHyperglycemiaAcute renal failureAnemia requiring blood transfusionAcute lung injury (ARDS)\tAcute renal injury Acute renal failure Acute lung injury (ARDS) Hyperglycemia\t\nDays hospitalized\nPrior to treatment\t44\t48\t42\t\nRespiratory status\tBase: 21% T-Collar\nDay 4: 21% T-Collar\nDay 6: 21% T-Collar\nDay 8: 21% T-Collar\nDay 14: 21% T-Collar\nDay 21: PMV room air\nDay 28: room air\tBase: CPAP 5 PS 10 30%\nDay 4: CPAP 5 PS 10 35%. Weaned PS to 8 and FiO2 to 30%\nDay 6: CPAP PS 40 %\nDay 8: Patient placed on 40% ATC at 0811 and the PMV at 1531\nDay 14: Patient placed on 40% ATC at 0811 and the PMV at 1531\nDay 21: 40% T-Collar\nDay 28: 30% T-Collar\tBase: PS/CPAP 8/5 24%\nDay 4: Patient tolerates trial cap and is successfully decannulated\nDay 8: Placed on 2L of O2\nDay14: Weaned down to room air\nDay 21: Remains in room air\nDay 28: Discharged 26 days after baseline\t\nStatus after 28-day follow up period\tDecannulated, discharged\tStep-down unit, remained in ventilation and hemodialysis\tDecannulated, not in hemodialysis, discharged\t\nHTN, hypertension; T2DM, type-2 diabetes; HLD, hyperlipidemia; HYT, hypothyroidism.\n\nEffect of Zofin on SOFA Score\n\nImprovement in SOFA score was found in all patients. SOFA score calculations decreased from 3 to 0 in CU#1 within 28 days, from 7 to 4 in CU#2 within 28 days, and from 4 to 0 in CU#3 within 21 days (Table 2). Assessment of the individual parameters used to calculate SOFA score showed improvements in PaO2/FiO2 and Glasgow score for CU#1, improvements in Glasgow score and creatinine levels for CU#2, and improvements in PaO2/FiO2 and creatinine levels for CU#3 (Table 2). Platelet count, bilirubin, and MAP measurements remained stable throughout the treatment course.\n\nTable 2 SOFA score parameters.\n\nPatient\tSOFA Score\tPaO2/FiO2\tPlatelet Count (× 103)\tBilirubin (mg/dL)\tGlasgow score\tMAP(mmHg)\tCreatinine (mg/dL)\t\nCU#1\tDay 0: 3\tDay 0: 342\tDay 0: 310\tDay 0: 0.5\tDay 0: 10–12\tDay 0: 77–103\tDay 0: 0.78\t\n\tDay 4: 2\tDay 4: 457\tDay 4: 364\tDay 4: 0.7\tDay 4: 10–12\tDay 4: 65–86\tDay 4: 1.10\t\n\tDay 6: 1\tDay 6: 466\tDay 6: 340\tDay 6: 0.6\tDay 6: 13–14\tDay 6: 92–96\tDay 6: 0.89\t\n\tDay 8: 1\tDay 8: 476\tDay 8: 329\tDay 8: 0.6\tDay 8: 13–14\tDay 8: 74–94\tDay 8: 0.98\t\n\tDay 14: 0\tDay 14: 462\tDay 14: 405\tDay 14: 0.6\tDay 14: 15\tDay 14: 79\tDay 14: 0.89\t\n\tDay 21: 0\tDay 21: 471\tDay 21: 423\tDay 21: 0.7\tDay 21: 15\tDay 21: 75\tDay 21: 0.94\t\n\tDay 28: 0\tDay 28: 471\tDay 28: 342\tDay 28: 0.6\tDay 28: 15\tDay 28: 95\tDay 28: 0.97\t\nCU#2\tDay 0: 7\tDay 0: 242\tDay 0: 183\tDay 0: 0.4\tDay 0: 10–12\tDay 0: 62–94\tDay 0: 3.55\t\n\tDay 4: 7\tDay 4: 268\tDay 4: 204\tDay 4: 0.3\tDay 4: 10–12\tDay 4: 76–92\tDay 4: 3.74\t\n\tDay 6: 4\tDay 6: 280\tDay 6: 190\tDay 6: 0.5\tDay 6: 15\tDay 6: 85–95\tDay 6: 1.98\t\n\tDay 8: 3\tDay 8: 232\tDay 8: 201\tDay 8: 0.4\tDay 8: 15\tDay 8: 73–96\tDay 8: 1.79\t\n\tDay 14: 4\tDay 14: 245\tDay 14: 214\tDay 14: 0.3\tDay 14: 15\tDay 14: 93\tDay 14: 3.28\t\n\tDay 21: 4\tDay 21: 240\tDay 21: 201\tDay 21: 0.3\tDay 21: 15\tDay 21: 82\tDay 21: 2.29\t\n\tDay 28: 4\tDay 28: 271\tDay 28: 269\tDay 28: 0.3\tDay 28: 15\tDay 28: >70\tDay 28: 2.27\t\nCU#3\tDay 0: 4\tDay 0: 350\tDay 0: 428\tDay 0: 0.3\tDay 0: 15\tDay 0: 90\tDay 0: 3.96\t\n\tDay 4: 3\tDay 4: 466\tDay 4: 540\tDay 4: 0.3\tDay 4: 15\tDay 4: 89\tDay 4: 4.16\t\n\tDay 6: –\tDay 6: –\tDay 6: –\tDay 6: –\tDay 6: –\tDay 6: –\tDay 6: –\t\n\tDay 8: 3\tDay 8: 471\tDay 8: 723\tDay 8: 0.6\tDay 8: 15\tDay 8: 99\tDay 8: 5.2\t\n\tDay 14: 2\tDay 14: 471\tDay 14: 507\tDay 14: 0.3\tDay 14: 15\tDay 14: 85\tDay 14: 2.73\t\n\tDay 21: 0\tDay 21: 467\tDay 21: 294\tDay 21: 0.3\tDay 21: 15\tDay 21: 84\tDay 21: 1.24\t\n\tDay 28: –\tDay 28: –\tDay 28: –\tDay 28: –\tDay 28: –\tDay 28: –\tDay 28: –\t\n–, sample not taken.\n\nEffect of Zofin on Lung Imaging\n\nCXR images were collected throughout the treatment and the changes from baseline to day 21 and 28 were observed and reported (Figure 1). CXR analysis of patient CU#1 displayed at baseline show an infiltrate present in the left lower lobe with no defined pleural fluid. After 28 days, CXR showed basilar, infrahilar air space opacity present bilaterally in the base of the lungs. CXR analysis of patient CU#2 displayed bilateral pulmonary disease at baseline. At day 28, CXR analysis showed small pleural effusions. CXR analysis of patient CU#3 displayed bilateral upper lobe infiltrate at baseline. At day 21, CXR analysis showed residual consolidation present in the left perihilar region. There was partial interval resolution of right upper lobe pneumonic consolidation.\n\nFigure 1 Chest-X ray images. Chest-X ray images of patient CU#1 at day 0 and day 28 (Left). Chest-X ray images of patient CU#2 at day 0 and day 28 (Middle). Chest-X ray images of patient CU#3 at day 0 and day 21 (Right).\n\nInflammatory Biomarker Assessment\n\nQuantification of inflammatory biomarkers was completed at each testing time point (Table 3). There was a slight increase in TNFα for CU#1 within 28 days. CU#1 had an elevation in CRP and IL-6 that was attributed to bacteremia from an infected vein port at day 4, 6, and 8. However, levels of CRP and IL-6 began to drop below baseline by day 14 through day 28. Additionally, D-Dimer concentration decreased in this patient on day 28. CU#2 also showed a decrease in CRP and IL-6 levels by day 14 through day 28, however, TNFα and D-Dimer remained elevated. CU#3 showed high levels of inflammatory markers TNFα, IL-6, and D-Dimer up to day 8, however, declines in all markers were reported by day 21. Furthermore, CRP levels in CU#3 declined dramatically by day 21. IL-2 levels were below the detection level in all patients at all-time points.\n\nTable 3 Inflammatory biomarkers.\n\nPatient\tD-Dimer (ng/mL)\tCRP(mg/dL)\tIL6 (pg/mL)\tIL2(pg/mL)\tTNFα (pg/mL)\t\nCU#1\tDay 0: 1,033\tDay 0: 2.66\tDay 0: 19.39\tDay 0: <38.0\tDay 0: 0.95\t\n\tDay 4: 1,113\tDay 4: >8.00\tDay 4: 50.83\tDay 4: <38.0\tDay 4: 2.06\t\n\tDay 6: 1,069\tDay 6: >8.00\tDay 6: 51.95\tDay 6: <38.0\tDay 6: 2.08\t\n\tDay 8: 1,165\tDay 8: >8.00\tDay 8: 40.29\tDay 8: <38.0\tDay 8: 2.29\t\n\tDay 14: 1,122\tDay 14: 1.28\tDay 14: 8.23\tDay 14: <38.0\tDay 14: 2.58\t\n\tDay 21: 963\tDay 21: 0.93\tDay 21: 7.70\tDay 21: <38.0\tDay 21: 2.97\t\n\tDay 28: 599\tDay 28: 0.70\tDay 28: 6.43\tDay 28: <38.0\tDay 28: 1.36\t\nCU#2\tDay 0: 5,871\tDay 0: 1.74\tDay 0: 23.62\tDay 0: <38.0\tDay 0: 1.77\t\n\tDay 4: 4,305\tDay 4: 1.79\tDay 4: 22.17\tDay 4: <38.0\tDay 4: 1.99\t\n\tDay 6: 2,377\tDay 6: 2.49\tDay 6: –\tDay 6: –\tDay 6: –\t\n\tDay 8: 1,980\tDay 8: 4.19\tDay 8: 32.82\tDay 8: <38.0\tDay 8: 1.69\t\n\tDay 14: 3,444\tDay 14: 1.04\tDay 14: 17.79\tDay 14: <38.0\tDay 14: 2.13\t\n\tDay 21: 3,627\tDay 21: 0.59\tDay 21: 16.57\tDay 21: <38.0\tDay 21: 1.90\t\n\tDay 28: 4,468\tDay 28: 0.35\tDay 28: 13.58\tDay 28: <38.0\tDay 28: 2.21\t\nCU#3\tDay 0: 1,098\tDay 0: 6.48\tDay 0: 29.78\tDay 0: <38.0\tDay 0: 7.85\t\n\tDay 4: 1,130\tDay 4: 2.15\tDay 4: 28.71\tDay 4: <38.0\tDay 4: 6.51\t\n\tDay 6: –\tDay 6: –\tDay 6: –\tDay 6: –\tDay 6: –\t\n\tDay 8: 1,082\tDay 8: 1.98\tDay 8: 1,259\tDay 8: <38.0\tDay 8: >10\t\n\tDay 14: 1,647\tDay 14: 2.79\tDay 14: 7.9\tDay 14: <38.0\tDay 14: 6.53\t\n\tDay 21: 828\tDay 21: 0.18\tDay 21: 7.12\tDay 21: <38.0\tDay 21: 4.67\t\n\tDay 28: –\tDay 28: –\tDay 28: –\tDay 28: –\tDay 28: –\t\n–, sample not taken.\n\nDiscussion\n\nThese completed case studies are the first demonstrations of human amniotic fluid-derived nanoparticles as a safe and potentially efficacious therapeutic treatment to recover from complications induced by COVID-19 infection. The multi-dose administration of Zofin as a therapeutic approach for patients severely ill from COVID-19 was safe and well-tolerated, without the report of any serious adverse events. The molecular composition of Zofin, particularly the nanoparticle population that includes perinatal secreted extracellular vesicles and exosomes, has strong potential as a COVID-19 therapeutic (19). Extracellular and exosome-based therapeutics are beginning to be explored in the clinic and have quickly emerged as a promising therapeutic candidate due to the anti-inflammatory and tissue regenerative effects shown across various pre-clinical models (20–22). For example, the delivery of exosomal cargo to recipient macrophages stimulates M2 polarization that leads to the reduction of pro-inflammatory cytokine secretion (23). Similarly, exosome-mediated transfer of miRNA between immune cells may contribute to immune response at various cellular pathway levels, such as the suppression of pro-inflammatory response initiated in the presence of endotoxins (24). Based on this pre-clinical data, it is hypothesized that the immune modulatory effect of exosomes is particularly useful in mitigating symptoms associated with COVID-19 infection, and to promote the induction of endogenous tissue repair (25).\n\nIn these three cases, we are limited by the absence of experimental controls. First, the absence of a placebo control group and administration of the therapy as open label does not allow for scientific proof of efficacy. Similarly, the combination of ongoing care with Zofin treatment makes it difficult to determine the extent of therapeutic efficacy derived solely from the therapeutic. Therefore, the precise therapeutic value of Zofin can only be speculated based on the collected data post-treatment. With these limitations in mind, the primary take-away from these single patient cases is focused on safety, accessibility, and feasibility. As a new biologic, the primary objective of small, single patient studies is to demonstrate therapeutic safety. Safety was strictly monitored during product infusion and throughout the following days by the treating physician and onsite nurses. There was no reported appearance of any adverse reactions or adverse events. Therefore, Zofin was determined to be safe for the treated patients. Furthermore, these first completed studies support the accessibility and feasibility of the therapeutic. Zofin is an acellular biologic that requires minimal training and specialized equipment to ship, prepare for infusion, and administration. The product can be stored in standard medical freezers (below −20°C) and can be prepared for infusion by the onsite hospital pharmacist. There were no issues with drug handling and preparation at the hospital site. This experience is an important step toward the development of a therapy with wide-spread distribution potential and rapid incorporation into clinics.\n\nDespite the experimental limitations, analysis of the collective data in all patients showed a reduction of SOFA score, improvement in ICU clinical status, and respiratory improvements. To date, the patient's laboratory results have shown improvements with decreased inflammatory biomarkers. Because of the small patient population and the lack of a placebo control, it is premature to determine the potential mechanism of action for the observed clinical effects. However, inflammatory biomarkers CRP and IL-6 decreased in all patients, similarly to other reported cases utilizing cell therapies, thus allowing for the further investigation of an anti-inflammatory effect (26, 27). All data was reported by the treating physician and nursing staff. Patients were not asked to share their perspective of the treatment outcome.\n\nThe clinical features of patient CU#1 improved considerably with lungs improving on CXR and both mental status and kidney function returning to normal. Respiratory function of this patient improved 21 days post-treatment, transitioning from a 21% T-collar to room air PMV and decannulation on day 26, representing a considerable achievement for this patient demographic. Inflammatory marker status of this patient, IL6 and CRP, improved after the 14-day time point. The patient further improved to hospital discharge after 29 days post-treatment initiation.\n\nThe clinical features of patient CU#2 systemically improved, including respiratory function, during the treatment time course. The patient transitioned from CPAP 5 PS 10 30% ventilation to 30% T-Collar ventilation by day 28 and the acute delirium improved. This patient sustained acute kidney injury and required regular hemodialysis during the study period.\n\nAfter receiving Zofin, patient CU#3 displayed rapid improvement in respiratory function, with a complete decannulation from oxygen therapy by day 4. The patient had a complete recovery of renal function, had decreased creatinine concentration levels, and was removed from hemodialysis by day 17. CU#3 was discharged 26 days post-treatment initiation.\n\nOur positive experience with these three patients further warrants placebo-controlled testing to determine the therapeutic effects of Zofin in this patient population. Organicell Regenerative Medicine is currently conducting the first multicenter, randomized, double-blinded, placebo-controlled phase I/II clinical trial to test Zofin in COVID-19 patients with moderate to severe Acute Respiratory Distress Syndrome.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary materials, further inquiries can be directed to the corresponding author/s.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by letters of acknowledgment by Independent Review Board-Western Institutional Review Board. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nMM: study design, data interpretation, writing, figures. MB: study design, data interpretation, writing, data analysis, literature search, figures. AS and MS: patient care, data collection, data interpretation. WK and AM: study design. KV: data collection. GH: data collection, data analysis, figures, writing. DS: study design, writing, product manufacturing. ZA, IS, and JM: study design, product manufacturing. GS: study design, data analysis, data interpretation, writing. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\n\nMM, AM, and GS reports personal fees and other from Organicell Regenerative Medicine, Inc., outside the submitted work. In addition, MM has a patent COMPOSITIONS COMPRISING NANOPARTICLES, METHOD OF MAKING AND USES THEREOF pending. MB, GH, DS, ZA, IS, and JM report personal fees from Organicell Regenerative Medicine, Inc., outside the submitted work. WK is a medical advisor to Organicell Regenerative Medicine. The remaining 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. Ai T Yang Z Hou H Zhan C Chen C Lv W . Correlation of chest CT and RT-PCR testing in coronavirus disease 2019 (COVID-19) in China: a report of 1014 cases. Radiology. (2020):200642. 10.1148/radiol.2020200642 32101510\n2. Pan F Ye T Sun P Gui S Liang B Li L . Time course of lung changes on chest CT during recovery from 2019 novel coronavirus (COVID-19) pneumonia. Radiology. (2020) 295 :715–21. 10.1148/radiol.2020200370 32053470\n3. Pan Y Guan H Zhou S Wang Y Li Q Zhu T . Initial CT findings and temporal changes in patients with the novel coronavirus pneumonia (2019-nCoV): a study of 63 patients in Wuhan, China. Eur Radiol. (2020) 30 :3306–9. 10.1007/s00330-020-06731-x 32055945\n4. Shi H Han X Jiang N Cao Y Alwalid O Gu J . Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis. (2020) 20 :425–34. 10.1016/S1473-3099(20)30086-4 32105637\n5. Cascella M Rajnik M Cuomo A Dulebohn SC Di Napoli R . Features, Evaluation and Treatment Coronavirus (COVID-19). Treasure Island, FL: StatPearls (2020).\n6. Wu Z McGoogan JM . Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA. (2020) 323 :1239–42. 10.1001/jama.2020.2648 32091533\n7. Shi Y Wang Y Shao C Huang J Gan J Huang X . COVID-19 infection: the perspectives on immune responses. Cell Death Differ. (2020) 27 :1451–4. 10.1038/s41418-020-0530-3 32205856\n8. Zhang W Zhao Y Zhang F Wang Q Li T Liu Z . The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): the perspectives of clinical immunologists from China. Clin Immunol. (2020) 214 :108393. 10.1016/j.clim.2020.108393 32222466\n9. Fajgenbaum DC June CH . Cytokine storm. N Engl J Med. (2020) 383 :2255–73. 10.1056/NEJMra2026131 33264547\n10. Khoury M Cuenca J Cruz FF Figueroa FE Rocco PRM Weiss DJ . Current status of cell-based therapies for respiratory virus infections: applicability to COVID-19. Eur Respir J. (2020) 55 :2000858. 10.1183/13993003.00858-2020 32265310\n11. Hong KU Guo Y Li QH Cao P Al-Maqtari T Vajravelu BN . c-kit+ Cardiac stem cells alleviate post-myocardial infarction left ventricular dysfunction despite poor engraftment and negligible retention in the recipient heart. PLoS ONE. (2014) 9 :e96725. 10.1371/journal.pone.0096725 24806457\n12. Mendt M Rezvani K Shpall E . Mesenchymal stem cell-derived exosomes for clinical use. Bone Marrow Transplant. (2019) 54 (Suppl. 2 ):789–92. 10.1038/s41409-019-0616-z 31431712\n13. Harrell CR Jovicic N Djonov V Arsenijevic N Volarevic V . Mesenchymal stem cell-derived exosomes and other extracellular vesicles as new remedies in the therapy of inflammatory diseases. Cells. (2019) 8 :1605. 10.3390/cells8121605 31835680\n14. Karacal N Kosucu P Cobanglu U Kutlu N . Effect of human amniotic fluid on bone healing. J Surg Res. (2005) 129 :283–7. 10.1016/j.jss.2005.03.026 15916770\n15. Ozgenel GY Filiz G Ozcan M . Effects of human amniotic fluid on cartilage regeneration from free perichondrial grafts in rabbits. Br J Plast Surg. (2004) 57 :423–8. 10.1016/j.bjps.2003.12.021 15191823\n16. Pierce J Jacobson P Benedetti E Peterson E Phibbs J Preslar A . Collection and characterization of amniotic fluid from scheduled C-section deliveries. Cell Tissue Bank. (2016) 17 :413–25. 10.1007/s10561-016-9572-7 27460879\n17. Lambden S Laterre PF Levy MM Francois B . The SOFA score-development, utility and challenges of accurate assessment in clinical trials. Crit Care. (2019) 23 :374. 10.1186/s13054-019-2663-7 31775846\n18. Jacobi A Chung M Bernheim A Eber C . Portable chest X-ray in coronavirus disease-19 (COVID-19): a pictorial review. Clin Imaging. (2020) 64 :35–42. 10.1016/j.clinimag.2020.04.001 32302927\n19. Tsuchiya A Takeuchi S Iwasawa T Kumagai M Sato T Motegi S . Therapeutic potential of mesenchymal stem cells and their exosomes in severe novel coronavirus disease 2019 (COVID-19) cases. Inflamm Regen. (2020) 40 :14. 10.1186/s41232-020-00121-y 32582401\n20. Barile L Moccetti T Marban E Vassalli G . Roles of exosomes in cardioprotection. Eur Heart J. (2017) 38 :1372–9. 10.1093/eurheartj/ehw304 27443883\n21. Williams AM Bhatti UF Brown JF Biesterveld BE Kathawate RG Graham NJ . Early single-dose treatment with exosomes provides neuroprotection and improves blood–brain barrier integrity in swine model of traumatic brain injury and hemorrhagic shock. J Trauma Acute Care Surg. (2020) 88 :207–18. 10.1097/TA.0000000000002563 31804413\n22. Ha DH Kim HK Lee J Kwon HH Park GH Yang SH . Mesenchymal stem/stromal cell-derived exosomes for immunomodulatory therapeutics and skin regeneration. Cells. (2020) 9 :1157. 10.3390/cells9051157 32392899\n23. Bouchareychas L Duong P Covarrubias S Alsop E Phu TA Chung A . Macrophage exosomes resolve atherosclerosis by regulating hematopoiesis and inflammation via MicroRNA Cargo. Cell Rep. (2020) 32 :107881. 10.1016/j.celrep.2020.107881 32668250\n24. Alexander M Hu R Runtsch MC Kagele DA Mosbruger TL Tolmachova T . Exosome-delivered microRNAs modulate the inflammatory response to endotoxin. Nat Commun. (2015) 6 :7321. 10.1038/ncomms8321 26084661\n25. Pinky Gupta S Krishnakumar V Sharma Y Dinda AK Mohanty S . Mesenchymal stem cell derived exosomes: a nano platform for therapeutics and drug delivery in combating COVID-19. Stem Cell Rev Rep. (2020) 17 :33–43. 10.1007/s12015-020-10002-z 32661867\n26. Raza SS Seth P Khan MA . “Primed” mesenchymal stem cells: a potential novel therapeutic for COVID-19 patients. Stem Cell Rev Rep. (2020) 1–10. 10.1007/s12015-020-09999-0 31907765\n27. Tang L Jiang Y Zhu M Chen L Zhou X Zhou C . Clinical study using mesenchymal stem cells for the treatment of patients with severe COVID-19. Front Med. (2020) 14 :664–73. 10.1007/s11684-020-0810-9 32761491\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2296-858X",
"issue": "8()",
"journal": "Frontiers in medicine",
"keywords": "ARDS (acute respiratory distress syndrome); COVID-19; amniotic fluid (AF); critical care; exosomes; extracellular vesicles",
"medline_ta": "Front Med (Lausanne)",
"mesh_terms": null,
"nlm_unique_id": "101648047",
"other_id": null,
"pages": "583842",
"pmc": null,
"pmid": "33816515",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "32091533;31835680;31775846;32761491;24806457;32392899;32265310;32302927;32582401;27460879;31804413;32222466;26084661;33264547;15916770;32105637;32668250;32592163;31431712;15191823;32101510;32661867;32055945;27443883;32053470;32205856",
"title": "Case Report: Administration of Amniotic Fluid-Derived Nanoparticles in Three Severely Ill COVID-19 Patients.",
"title_normalized": "case report administration of amniotic fluid derived nanoparticles in three severely ill covid 19 patients"
} | [
{
"companynumb": "US-009507513-2107USA000150",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LOPINAVIR\\RITONAVIR"
},
"drugadditional": ... |
{
"abstract": "Kikuchi-Fujimoto disease (KFD), or histiocytic necrotizing lymphadenitis, is a rare, benign, and self-limited disease that causes lymphadenopathy and has a characteristic histological appearance. The etiology of this disease is unknown, but a possible infectious trigger has been hypothesized. In the adult population this disease is more common in females; however, in the pediatric population it is more common in males. Descriptions in the pediatric literature are lacking, particularly in the United States. The authors report three cases of pediatric KFD that presented at the same institution in a 9-month time period. All three patients were male and of non-Asian descent who were diagnosed with KFD by histopathologic specimen after presenting with unilateral cervical lymphadenitis. Each patient had additional laboratory evidence of a possible bacterial infection at the time of diagnosis. These three cases highlight the importance of considering KFD early when a pediatric patient presents with unilateral cervical lymphadenitis. The authors discuss the epidemiology, etiology, clinical manifestations, diagnostic approaches, and treatment of KFD. [Pediatr Ann. 2019;48(10):e406-e411.].",
"affiliations": null,
"authors": "Batton|Emily|E|;Alali|Muayad|M|;Hageman|Joseph R|JR|;Parilla|Megan|M|;Yu|Karl O A|KOA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.3928/19382359-20190920-01",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-4481",
"issue": "48(10)",
"journal": "Pediatric annals",
"keywords": null,
"medline_ta": "Pediatr Ann",
"mesh_terms": "D000293:Adolescent; D002648:Child; D003937:Diagnosis, Differential; D020042:Histiocytic Necrotizing Lymphadenitis; D006801:Humans; D008297:Male",
"nlm_unique_id": "0356657",
"other_id": null,
"pages": "e406-e411",
"pmc": null,
"pmid": "31610000",
"pubdate": "2019-10-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Kikuchi-Fujimoto Disease in Children: An Important Diagnostic Consideration for Cervical Lymphadenitis.",
"title_normalized": "kikuchi fujimoto disease in children an important diagnostic consideration for cervical lymphadenitis"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2019-10445",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RIFAMPIN"
},
"drugadd... |
{
"abstract": "OBJECTIVE\nThe purpose of this study is to determine the frequency of adverse perinatal outcome in women with hyperemesis gravidarum and identify prognostic factors.\n\n\nMETHODS\nThis is a case-control study in which outcomes of first pregnancies were compared between 254 women with hyperemesis gravidarum treated with intravenous fluids and 308 controls. Prognostic factors were identified by comparing the clinical profile of patients with hyperemesis gravidarum with a normal and an adverse pregnancy outcome. Binary responses were analyzed using either a Chi-square or Fisher exact test and continuous responses were analyzed using a t-test.\n\n\nRESULTS\nWomen with hyperemesis gravidarum have over a 4-fold increased risk of poor outcome including preterm birth and lower birth weight (p<0.0001). Among maternal characteristics, only gestational hypertension had an influence on outcome (p<0.0001). Treatment as an outpatient and/or by alternative medicine (acupuncture/acupressure/Bowen massage) was associated with a positive outcome (p<0.0089). Poor outcomes were associated with early start of symptoms (p<0.019), and treatment with methylprednisolone (p<0.0217), promethazine (p<0.0386), and other antihistamines [diphenhydramine (Benadryl), dimenhydrinate (Gravol), doxylamine (Unisom), hydroxyzine (Vistaril/Atarax), doxylamine and pyridoxine (Diclectin/Bendectin)] (p<0.0151) independent of effectiveness. Among these medications, only the other antihistamines were prescribed independent of severity: they were effective in less than 20% of cases and were taken by almost 50% of patients with an adverse outcome.\n\n\nCONCLUSIONS\nPoor outcomes are significantly greater in women with HG and are associated with gestational hypertension, early symptoms, and antihistamine use. Given these results, there is an urgent need to address the safety and effectiveness of medications containing antihistamines in women with severe nausea of pregnancy.",
"affiliations": "University of California, Los Angeles, Department of Obstetrics and Gynecology, Los Angeles, CA, USA. Electronic address: mfejzo@mednet.ucla.edu.",
"authors": "Fejzo|Marlena S|MS|;Magtira|Aromalyn|A|;Schoenberg|Frederic Paik|FP|;MacGibbon|Kimber|K|;Mullin|Patrick|P|;Romero|Roberto|R|;Tabsh|Khalil|K|",
"chemical_list": "D006633:Histamine Antagonists",
"country": "Ireland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-2115",
"issue": "170(1)",
"journal": "European journal of obstetrics, gynecology, and reproductive biology",
"keywords": "Antihistamines; Fetal outcome; Hyperemesis gravidarum; Nausea; Pregnancy",
"medline_ta": "Eur J Obstet Gynecol Reprod Biol",
"mesh_terms": "D000328:Adult; D016022:Case-Control Studies; D005260:Female; D006633:Histamine Antagonists; D006801:Humans; D006939:Hyperemesis Gravidarum; D011247:Pregnancy; D011256:Pregnancy Outcome; D011379:Prognosis; D016896:Treatment Outcome; D014481:United States",
"nlm_unique_id": "0375672",
"other_id": null,
"pages": "71-6",
"pmc": null,
"pmid": "23751910",
"pubdate": "2013-09",
"publication_types": "D016428:Journal Article",
"references": "1790200;16449178;16551377;12380668;18260047;15305820;9742356;22901019;4877794;21288626;23400353;18272326;15255878;10804035;3691940;19270317;21749625;20044860;16150279;16006438",
"title": "Antihistamines and other prognostic factors for adverse outcome in hyperemesis gravidarum.",
"title_normalized": "antihistamines and other prognostic factors for adverse outcome in hyperemesis gravidarum"
} | [
{
"companynumb": "US-JNJFOC-20130902692",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FAMOTIDINE"
},
"drugadditional": null,
... |
{
"abstract": "The purpose of this case report is to present a rare case of amlodipine-induced gingival overgrowth with a secondary formation of necrotizing ulcerative gingivitis involving the upper and lower arches of a 68-year-old female patient with a chief complaint of \"swollen gums and pain on mastication which has been recurring for the past 5 years.\"\nThe treatment plan of this case was divided according to quadrants of the mouth. Each week, one quadrant was surgically excised, and the remaining quadrants were observed for any changes. The gingival overgrowths were excised using a 15 blade, and debris/plaque was removed with Gracey curettes.\nAlthough full-mouth exodontia was performed, the patient unfortunately suffered with recurrences in GO. These results are suggestive of idiopathic causes of GO.\nCareful examination, physician referrals, and biopsy to rule out any specific anomalies and to assist in proper diagnosis are followed by sequential management of the case results in productive outcomes.",
"affiliations": "Department of Clinical Sciences, College of Dentistry, Ajman University, Ajman, UAE.;Department of Clinical Sciences, College of Dentistry, Ajman University, Ajman, UAE.;Department of Clinical Sciences, College of Dentistry, Ajman University, Ajman, UAE.;Department of Periodontics, Sri Rajiv Gandhi College of Dental Sciences and Hospital, Banguluru, Karnataka State 560032, India.",
"authors": "Damdoum|Marah|M|https://orcid.org/0000-0002-4423-1674;Varma|Sudhir Rama|SR|https://orcid.org/0000-0001-6793-9344;Jaber|Mohamed A|MA|https://orcid.org/0000-0002-5524-5131;Nambiar|Manjusha|M|https://orcid.org/0000-0002-9791-0558",
"chemical_list": null,
"country": "Egypt",
"delete": false,
"doi": "10.1155/2021/4120148",
"fulltext": "\n==== Front\nCase Rep Dent\nCase Rep Dent\nCRID\nCase Reports in Dentistry\n2090-6447\n2090-6455\nHindawi\n\n10.1155/2021/4120148\nCase Report\nNecrotizing Ulcerative Gingivitis, a Rare Manifestation as a Sequel of Drug-Induced Gingival Overgrowth: A Case Report\nhttps://orcid.org/0000-0002-4423-1674\nDamdoum Marah marahdamdoum@gmail.com\n1\nhttps://orcid.org/0000-0001-6793-9344\nVarma Sudhir Rama s.varma@ajman.ac.ae\n1 2\nhttps://orcid.org/0000-0002-5524-5131\nJaber Mohamed A. 1 2\nhttps://orcid.org/0000-0002-9791-0558\nNambiar Manjusha 3\n1Department of Clinical Sciences, College of Dentistry, Ajman University, Ajman, UAE\n2Centre of Medical and Biomedical Allied Health Sciences Research, Ajman University, Ajman, UAE\n3Department of Periodontics, Sri Rajiv Gandhi College of Dental Sciences and Hospital, Banguluru, Karnataka State 560032, India\nAcademic Editor: Ronald S. Brown\n\n2021\n21 9 2021\n2021 412014826 6 2021\n7 8 2021\n2 9 2021\nCopyright © 2021 Marah Damdoum 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.\nPurpose\n\nThe purpose of this case report is to present a rare case of amlodipine-induced gingival overgrowth with a secondary formation of necrotizing ulcerative gingivitis involving the upper and lower arches of a 68-year-old female patient with a chief complaint of “swollen gums and pain on mastication which has been recurring for the past 5 years.”\n\nMaterials and Methods\n\nThe treatment plan of this case was divided according to quadrants of the mouth. Each week, one quadrant was surgically excised, and the remaining quadrants were observed for any changes. The gingival overgrowths were excised using a 15 blade, and debris/plaque was removed with Gracey curettes.\n\nResults\n\nAlthough full-mouth exodontia was performed, the patient unfortunately suffered with recurrences in GO. These results are suggestive of idiopathic causes of GO.\n\nConclusion\n\nCareful examination, physician referrals, and biopsy to rule out any specific anomalies and to assist in proper diagnosis are followed by sequential management of the case results in productive outcomes.\n==== Body\npmc1. Introduction\n\nDrug-induced gingival overgrowth (DIGO) manifests as a result of drug interactions mainly produced by anticonvulsants [1], immunosuppressants [2], and calcium channel blockers [3]. Several factors including age, sex, genetic predisposition, systemic diseases, hormonal imbalances, congenital disorders, poor oral hygiene, and local plaque/debris may influence the relationship of these drugs to gingival overgrowth [4]. Gingival overgrowths can affect speech, mastication, and esthetics, and there are various methods of treatment for excising the excess tissue [5]. These overgrowths can be classified according to their size and location and graded between grade 0 and grade III [6] (Table 1). The pharmacological action of each drug is different; however, they all act similarly to secondary tissue receptors by creating enlargements in the gingival tissue. The exact mechanism of these gingival overgrowths in association to drugs is not fully understood, and there are many hypotheses and theories related to DIGO [7–11]. Drug-induced gingival overgrowth is typically detected after 3 months of drug consumption [12]. Clinical features of DIGO could be localized or generalized and may range from mild to severe enlargements of the marginal and papillary gingiva [13]. The anterior region of the mouth is more affected than the posterior region and is more pronounced on the facial surfaces than the palatal/lingual surfaces [14]. DIGO cannot be prevented in susceptible patients but it can be tolerated by regular periodontal therapy and plaque control [15]. The current case report presents a rare case of necrotizing ulcerative gingivitis as a secondary reaction to amlodipine-induced gingival overgrowth.\n\n2. Pathophysiology\n\nThe mechanism of gingival overgrowth and its contributory mechanism with relation to fibroblastic proliferation are varied. A theory of genetic predisposition was earlier postulated by Seymour et al. in 1996 [3]. The inflammatory changes and responses of gingival fibroblasts coupled with connective tissue matrix proliferation exemplify the fibroblastic characterization with relation to the various drugs responsible for this change [16]. Another theory postulated that bacterial plaque was responsible for gingival inflammation. The drugs responsible for gingival overgrowth causes an increased production of glycosaminoglycans. The drugs further reduce folate uptake in the cellular matrix. Reduced folate uptake results in decreased synthesis of matrix metalloproteinases which is responsible for conversion of collagenase precursor into mature collagenase, resulting in a matrix and connective tissue build up. The bacterial plaque when present causes the inflammatory component, thus completing the cycle [17].\n\n3. Case Report\n\nThis case presents a 68-year-old female patient with a chief complaint of swollen gums and pain on mastication which has been recurring for the past 5 years. According to the patient, she started taking amlodipine 5 mg/day 7 years ago and started experiencing enlargements of the gingiva 5 years ago. She stopped taking amlodipine for 6 months and claims the enlargements improved. However, her physician recommended that she continue taking amlodipine 10 mg/day due to her uncontrolled hypertension. Medical history was taken in which the patient reported having diabetes mellitus type II and hypercholesterolemia for the past 8 years. She takes a series of drugs for her medical conditions (Table 2). She has been hypertensive for the past 7 years and has been taking amlodipine since then. She stopped amlodipine 2 years ago for 6 months due to gingival overgrowths; however, amlodipine had to be continued due to her uncontrolled hypertension.\n\nOn taking dental history, it was found that she underwent multiple gingivectomies in the past with recurrence every few months. During previous episodes, the patient had described the condition as similar to the one presented currently with excruciating pain and pus discharge. Furthermore, the patient described the treatment advised as “gum shaping by the doctor”. From patient's explanations, it was assumed that the clinical picture matched the current situation, and a history of NUG could have been prevalent at that time period.\n\nThe patient presented with a dental history that includes thick deposits of calculus and plaque on all remaining teeth with fibrous, nodular, hard gingival overgrowths extending to most of the clinical crown in the anterior and posterior parts of the maxillary and mandibular arches (Figure 1). The overgrowths can be classified as grade III according to Bokenkamp's 1994 classification for gingival overgrowth [6] (Table 1). Additionally, a yellowish-white pseudomembranous slough was found covering the interdental papilla in the mandibular left area (Figure 2). Radiographically, bone loss can be observed around the teeth and implants; however, clinically, the implants are not mobile as submerged (Figure 3). Abrasion of the teeth can be observed indicating parafunctional habits, as the patient had given a history of clenching which was consciously done and also from her family member, that patient was a bruxer and exhibited grinding at night. This also confirmed our diagnosis as stage 4, grade C periodontitis, currently unstable.\n\n3.1. Sequence of Treatment\n\nThe treatment plan of this case was divided according to quadrants of the mouth. Each week, one quadrant was surgically treated with the overgrown gingival tissue being excised, and the mobile teeth were extracted. The decision to extract her teeth was from a multidisciplinary point of view involving a periodontist and prosthodontist, as salvaging the remaining teeth was challenging and time consuming with hopeless prognosis. Since the overgrowths affected mastication, speech, and esthetics, a surgical approach (i.e., gingivectomy) was utilized with local anesthesia being administered. The gingival overgrowths were excised using a 15 blade; plaque and calculus were removed with Gracey curettes (Dentsply, USA). After every gingivectomy, azithromycin-xithrone (Amoun Egypt) 500 mg, diclofenac-rofenac (Bin Sina, UAE) 50 g sachet, along with chlorhexidine mouthwash (Curasept, UK), were prescribed. Surgical excision began in quadrant 4, which was the least affected quadrant. An external bevel incision gingivectomy was performed along with scaling and root surface debridement. The gingiva was sutured with silk (Black Braided, size 4-0, 19 cm, Teleflex, USA). At one-week surgical postop, the following was noted: the gingiva in the mandibular right quadrant was healing within normal limits. The gingiva in the mandibular left quadrant was edematous, fibrous, hemorrhagic, and painful swellings which had purulent exudate (Figure 2). An external bevel incision gingivectomy was done along with extraction of #33, #34, #35, and 45 due to extensive grade III mobility (Figures 4 and 5). The mobile teeth were diagnosed as stage 4 grade C periodontitis, currently unstable (AAP Classification, 2017). Apical curettage was performed, and copious irrigation with saline was done. Simple interrupted sutures were placed with silk. Placement of a periodontal pack along with oral hygiene reinforcement instructions was given. During the follow-up visit the following week, healing was uneventful for the most part with slight regression of gingival overgrowth. Poor oral hygiene can be observed along the sutures which were surrounded by plaque and debris (Figure 6). For the maxillary arch, an external bevel incision gingivectomy was done, and extraction of #11, #21, and #12 was done due to grade III mobility (Figures 7–9).\n\nDuring the follow-up visits, the maxillary arch presented with signs of inflammation, pus, and exudates around the teeth and sutures (Figure 10). There also seemed to be recurrence of gingival overgrowth around the implant-retained 4 unit bridge in the anterior mandible (Figure 11). The bridge was removed, and implants remained submerged in the alveolar bone. After bridge removal, azithromycin was prescribed as reported in earlier literature about its efficiency in treating DIGO [18]. During a 2-week follow-up, recurrence of GO was identified in all quadrants. The patient was referred to a cardiologist for a follow-up and possible substitution of amlodipine. Perindopril indapamide (a thiazide-like diuretic) was recommended by the cardiologist as an alternative. The remaining drugs consumed by the patient continued normally. During the first recall visit after complete exodontia and drug substitution, the patient presented with recurrence in the upper and lower arches. Since gingival overgrowth did not subside after complete exodontia and drug substitution, it can be assumed that the submerged implants in the lower anterior region and upper right posterior region could be the cause for this recurrence. Treatment modalities were further contemplated with regard to removal of the submerged implants; however, after clinical and radiographic assessment, it was further decided to retain the implants and to put the patient on follow-up to see if there was a possibility of recurrence. The patient was put on a strict oral hygiene plan and maintenance recall phase every 2 months.\n\n4. Results\n\nThis case report presents a rare case of nonhealing AIGO with a secondary NUG reaction. Two biopsies were taken to confirm the diagnosis in which both biopsies revealed chronic inflammatory processes. For AIGO-associated conditions, there are a range of treatment modalities that clinicians can explore. The proposed modes of treatment in the literature include nonsurgical and surgical drug modification and periodontal therapies. For the current case, all of these modalities were performed, and biopsies were done to confirm NUG as a manifestation of DIGO. Although full-mouth exodontia was performed, the patient unfortunately suffered with recurrences in GO. These results are suggestive of idiopathic causes of GO.\n\n5. Discussion\n\n5.1. Oral Hygiene\n\nSome studies say oral hygiene and local factors like plaque and calculus can affect the severity of gingival overgrowth; however, it is not a requirement for DIGO [4, 19]. A crosssectional study done in 1973 tested the association between dilantin-induced gingival overgrowth and oral hygiene. The study did not show that oral hygiene was statistically significant in the formation of gingival hyperplasia [4]. Seymour et al. reported in 2000 that most of the evidence to support a relationship between bacterial plaque and gingival overgrowth has been derived from crosssectional studies, and it is not clear whether plaque is a contributory factor or a consequence of the gingival changes [4]. A 2015 case report by Mathur et al. took a nonsurgical approach to their DIGO case. They reported that “there appears to be three significant factors which are important for the expression of these gingival changes, notably drug variables, plaque-induced inflammatory changes in gingival tissue, and genetic factors which determine the heterogeneity of the fibroblasts” [19]. The gingival overgrowths subsided after periodontal therapy, and no surgical intervention was needed. In a 2020 case report by Uppal et al., they report a case of DIGO that was treated nonsurgically through a periodontal approach first and report that “as the enlargement did not subside after drug substitution and phase 1 therapy, surgical phase was planned further” [20]. There is definitely an unclear definition as to whether oral hygiene plays a role in DIGO, but regardless, patient education on oral hygiene and maintenance is crucial in every treatment plan.\n\n5.2. Histopathology\n\nFor this case, a biopsy was sent with a gross description of the tissue sample; it consisted of two pieces of gray white to brown tissue measuring 2.0 × 0.8 × 0.5 cm and 1.5 × 1.4 × 0.8 cm.\n\nMicroscopically, the histopathological sections show mucosa covered soft tissue with an area of ulceration along with granulation tissue. Subepithelial soft tissue is hyalinized and shows a dense infiltrate composed predominantly of plasma cells merged with a few lymphocytes, eosinophils, and neutrophils. These features are consistent with acute on chronic inflammatory processes. The predominance of inflammatory cells indicates that the gingival overgrowth was not only caused by a drug induction but rather by presence of a secondary condition as well. This secondary condition can be identified as necrotizing ulcerative gingivitis. In the literature, the histopathology of NUG has been identified as ulcerations with dense infiltrations of PMNs and plasma cells which is interpreted as an area of established chronic gingivitis on which the acute lesion became superimposed [2].\n\nOur biopsy showed areas of ulcerations, predominance of plasma cells (indicating a chronic lesion), along with some PMNs. The signs and symptoms along with the histopathological review were suggestive of NUG as a secondary reaction to AIGO. A second biopsy was taken of healthy gingival tissue, to confirm our diagnosis of AIGO. The biopsy was received in a labelled container with patient identification and fixed in formalin, where multiple pieces are gray brown in color, irregular soft tissue, and measured in aggregate 1.5 × 1 × 0.2 cm. All submitted in one cassette. The gingival biopsy revealed squamous epithelium hyperplasia with underlying chronic inflammation (Figures 12 and 13), consistent with a reactive process, and negative for hyperkeratosis and atypia. These reports are consistent with a secondary inflammatory reaction (NUG) as a manifestation of amlodipine-induced gingival overgrowth [21]. The current case is similar to a case report where DM type 2, hypercholesterolemia, and amlodipine for hypertension were of similar findings. The difference being the time frame for the presentation, in the current case, was nine months ago, while in the earlier reported literature, it had presented after three years of intake of the medication (amlodipine) [22]. Meanwhile, our patient has had GO for the past 5 years and experienced the changes in her gingiva almost instantly after switching back to amlodipine the second time. Interestingly, in the current case, a possible role of statins in the progression of GO could be attributed as seen from a previous study where statins and calcium channel blockers when prescribed together resulted in adverse effects, a predominant feature being GO [23].\n\n5.3. Secondary Reactions\n\nIn our case, we reported necrotizing ulcerative gingivitis (NUG) as a secondary reaction to amlodipine-induced gingival overgrowth. In an earlier study by Vishnusdas et al., they reported a case involving amlodipine-induced gingival plasma cell granuloma, and the etiology is multifactorial, with a possible role of drug/cellular interaction playing a contributory role in the pathogenesis of this entity [24]. Another case report done in 2019 by Gulati et. al found an unusual plasma cell granuloma formation secondary to GO. This case report states that biopsies for unusual lesions should be comprehensively examined regardless of clinical appearance or treatment success rate in order to rule out neoplasms and plan for treatment accordingly [21]. For this case, a biopsy was sent with a gross description of the tissue sample, it consisted of two pieces of gray white to brown tissue measuring 2.0 × 0.8 × 0.5 cm and 1.5 × 1.4 × 0.8 cm. Microscopically, the histopathological sections show mucosa covered soft tissue with an area of ulceration along with granulation tissue. Subepithelial soft tissue is hyalinized and shows a dense infiltrate composed predominantly of plasma cells merged with a few lymphocytes, eosinophils, and neutrophils. These features are consistent with acute on chronic inflammatory processes. The predominance of inflammatory cells indicates that the gingival overgrowth was not only caused by a drug induction, but rather by presence of a secondary condition as well. This secondary condition can be identified as necrotizing ulcerative gingivitis. In the literature, the histopathology of NUG has been identified as ulcerations with dense infiltrations of PMNs and plasma cells which is interpreted as an area of established chronic gingivitis on which the acute lesion became superimposed [2]. Our biopsy showed areas of ulcerations, predominance of plasma cells (indicating a chronic lesion), along with some PMNs. The signs and symptoms along with the histopathological review were suggestive of NUG as a secondary reaction to AIGO. A second biopsy was taken of healthy gingival tissue, to confirm our diagnosis of AIGO. The biopsy was received in a labelled container with patient identification and fixed in formalin, where multiple pieces are gray brown in color, irregular soft tissue, and measured in aggregate 1.5 × 1 × 0.2 cm. All submitted in one cassette. The gingival biopsy revealed squamous epithelium hyperplasia with underlying chronic inflammation (Figures 12 and 13). Consistent with a reactive process. Negative for hyperkeratosis and atypia. These reports are consistent with a secondary inflammatory reaction (NUG) as a manifestation of amlodipine-induced gingival overgrowth.\n\nThe current case is similar to a case report where DM type 2, hypercholesterolemia, and amlodipine for hypertension were of similar findings. The difference being the time frame for the presentation, in the current case, was nine months ago, while in the earlier reported literature, it had presented after three years of intake of the medication (amlodipine) [22]. Meanwhile, our patient has had GO for the past 5 years and experienced the changes in her gingiva almost instantly after switching back to amlodipine the second time. Interestingly, in the current case, a possible role of statins in the progression of GO could be attributed as seen from a previous study where statins and calcium channel blockers when prescribed together resulted in adverse effects, a predominant feature being GO [23].\n\n6. Conclusion\n\nDIGO related to calcium channel blockers, immunosuppressants, and anticonvulsants in the past reported clinical presentations concluded by clinicians as rare entities. The case presented in our study shows the possible effects of amlodipine-induced GO and the challenges dentists can face in the management of this condition. Careful examination, physician referrals, and biopsy to rule out any specific anomalies and to assist in proper diagnosis are followed by sequential management of the case results in productive outcomes.\n\nAbbreviations\n\nDIGO: Drug-induced gingival overgrowth\n\nAIGO: Amlodipine-induced gingival overgrowth\n\nGO: Gingival overgrowth\n\nNUG: Necrotizing ulcerative gingivitis\n\nPMN: Polymorphonuclear cells.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 Fibrous, nodular, hard gingival overgrowths extending to most of the clinical crown in the anterior and posterior parts of the mandibular arch.\n\nFigure 2 Yellowish-white pseudomembranous slough was found covering the interdental papilla in the mandibular left area.\n\nFigure 3 Panoramic radiograph presenting bone loss around teeth and lower 4-unit implant-retained bridge.\n\nFigure 4 External bevel incision gingivectomy of the lower left quadrant and exodontia of #33, #34, and #35.\n\nFigure 5 Gingiva removed from the lower left quadrant and extracted teeth (#33, #34, and #35).\n\nFigure 6 1 week after surgical excision of the lower left quadrant.\n\nFigure 7 External bevel gingivectomy of the upper right quadrant.\n\nFigure 8 Gingiva removed from the upper left quadrant and extracted teeth (#11 and #21).\n\nFigure 9 External bevel gingivectomy of the upper left quadrant.\n\nFigure 10 Recall after 2 weeks of surgical intervention of maxillary arch. Pus and exudates were observed around teeth and sutures. Full exodontia was done for the remaining teeth in the upper arch.\n\nFigure 11 1 month recall after surgical intervention of the mandibular arch. Recurrence was presented, and full-mouth exodontia was done for the lower arch.\n\nFigure 12 Histopathological slide of gingival biopsy revealed squamous epithelium hyperplasia with underlying chronic inflammation.\n\nFigure 13 Histopathological slide of gingival biopsy revealed squamous epithelium hyperplasia with underlying chronic inflammation.\n\nTable 1 Bokenkamp and Bohnhorst, 1994 classification.\n\nGrade\tClinical findings\t\nGrade 0\tNo signs of gingival overgrowth\t\nGrade I\tGingival hyperplasia confined to interdental papilla\t\nGrade II\tHyperplasia of interdental papilla and marginal gingiva\t\nGrade III\tGingival hyperplasia covering at least three quarters of tooth crowns\t\n\nTable 2 Drugs taken by the patient.\n\nName of the drug\tDosage\tDuration\tPharmacological action\tMedical condition\t\nGliclazide\t60 mg\t8 years\tSulfonylureas\tDiabetes mellitus type II\t\nBisoprolol hemifumarate\t2.5 mg\t1 year\tNonselective beta blocker\tHeart murmurs\t\nPerindopril arginine\t5 mg\t1 year\tACE inhibitor\tHypertension\t\nAmlodipine besylate\t10 mg\t7 years\tCalcium channel blocker\tHypertension\t\nRosuvastatin\t10 mg\t8 years\tHMG-CoA reductase inhibitor\tHypercholesterolemia\n==== Refs\n1 Cebrian J. L. Chamorro M. Arias J. Gomez E. Extreme phenytoin-induced gingival hyperplasia. Presentation of two cases Medicina oral, Patología Oral y Cirugía Bucal 1998 3 4 237 240 11507500\n2 Eggerath J. English H. Leichter J. W. Drug-associated gingival enlargement: case report and review of aetiology, management and evidence-based outcomes of treatment Journal of the New Zealand Society of Periodontology 2005 88 7 14 16237888\n3 Seymour R. A. Ellis J. S. Thomason J. M. Monkman S. Idle J. R. Amlodipine-induced gingival overgrowth Journal of Clinical Periodontology 1994 21 4 281 283 10.1111/j.1600-051X.1994.tb00318.x 2-s2.0-0028411662 8195445\n4 Seymour R. A. Ellis J. S. Thomason J. M. Risk factors for drug-induced gingival overgrowth Journal of Clinical Periodontology: Review article 2000 27 4 217 223 10.1034/j.1600-051x.2000.027004217.x 2-s2.0-0034169030 10783833\n5 Mavrogiannis M. Ellis J. S. Thomason J. M. Seymour R. A. The management of drug-induced gingival overgrowth Journal of Clinical Periodontology 2006 33 6 434 439 10.1111/j.1600-051X.2006.00930.x 2-s2.0-33646674663 16677333\n6 Bökenkamp A. Bohnhorst B. Beier C. Albers N. Offner G. Brodehl J. Nifedipine aggravates cyclosporine A-induced gingival hyperplasia Pediatric Nephrology 1994 8 2 181 185 10.1007/BF00865474 2-s2.0-0028209890 8018496\n7 Border W. A. Noble N. A. Transforming growth factor beta in tissue fibrosis The New England Journal of Medicine 1994 331 1286 1292 7935686\n8 Brown R. S. Sein P. Corio R. Bottomley W. K. Nitrendipine-induced gingival hyperplasia: First case report Oral Surgery, Oral Medicine, and Oral Pathology 1990 70 5 593 596 10.1016/0030-4220(90)90406-I 2-s2.0-0025175930\n9 Das S. J. Olsen I. KeratinocytE growth factor is upregulated by the hyperplasia-inducing drug nifedipine Cytokine 2000 12 10 1566 1569 10.1006/cyto.2000.0756 2-s2.0-0033786335 11023675\n10 Nyska A. Shemesh M. Tal H. Dayan D. Gingival hyperplasia induced by calcium channel blockers: Mode of action Medical Hypotheses 1994 43 2 115 118 10.1016/0306-9877(94)90061-2 2-s2.0-0028141631 7990738\n11 van der Vleuten C. J. Trijbels-Smeulders M. A. van de Kerkhof P. C. Telan-giectasia and gingival hyperplasia as side-effects of amlodipine (Norvasc) in a 3-year-old girl Acta Dermato-Venereologica 1999 79 4 323 324 10.1080/000155599750010779 2-s2.0-0032968212 10429995\n12 Livada R. Shiloah J. Calcium channel blocker-induced gingival enlargement Journal of Human Hypertension 2014 28 1 10 14 10.1038/jhh.2013.47 2-s2.0-84889671323 23739159\n13 Marshall R. I. Bartold P. M. Medication induced gingival overgrowth Oral Diseases 1998 4 2 130 151 10.1111/j.1601-0825.1998.tb00269.x 9680902\n14 Newman M. G. Takei H. Klokkevold P. R. Carranza F. A. Carranza's Clinical Periodontology 2011 Elsevier Health Sciences\n15 Kim J. Y. Park S. H. Cho K. S. Mechanism of azithromycin treatment on gingival overgrowth Journal of Dental Research 2008 87 11 1075 1079 10.1177/154405910808701110 2-s2.0-58149229712 18946018\n16 Agrawal A. A. Gingival enlargements: differential diagnosis and review of literature World Journal of Clinical Cases 2015 3 9 779 788 10.12998/wjcc.v3.i9.779 26380825\n17 Dongari-Bagtzoglou A. Research, Science and Therapy Committee, American Academy of Periodontology Drug-associated gingival enlargement Journal of Periodontology-Periodontics 2004 75 10 1424 1431 10.1902/jop.2004.75.10.1424 2-s2.0-8744279143 15562922\n18 Klar L. A. Gingival hyperplasia during dilantin-therapy; a survey of 312 patients Journal of Public Health Dentistry 1973 33 3 180 185 10.1111/j.1752-7325.1973.tb00658.x 2-s2.0-0015633729 4516327\n19 Mathur S. Khatri R. K. Mathur R. Srivastava R. Nag B. P. Drug induced gingival overgrowth: a rare case report Journal of Clinical and Diagnostic Research: JCDR 2015 9 1 ZD31 ZD33 10.7860/JCDR/2015/11384.5500 2-s2.0-84924859965 25738096\n20 Uppal J. Trivedi H. Gupta N. D. Bey A. Periodontal management of severe periodontitis and generalized gingival enlargement in a patient with chronic renal failure Journal of Indian Society of Periodontology 2020 24 3 284 288 10.4103/jisp.jisp_194_19 32773982\n21 Gulati R. Ratre M. S. Khetarpal S. Varma M. A case report of a gingival plasma cell granuloma in a patient on antihypertensive therapy: diagnostic enigma Frontiers in Dentistry 2019 16 2 144 148 10.18502/fid.v16i2.1366 31777856\n22 Smitha K. Amlodipine-induced gingival overgrowth in a patient with uncontrolled type 2 diabetes mellitus with hypercholesterolemia: a case report Clinical Advances in Periodontics 2012 2 2 115 122 10.1902/cap.2012.110026 32781818\n23 Missouris G. G. Kalaitzidis R. G. Cappuccio F. P. MacGregor G. A. Gingival hyperplasia caused by calcium channel blockers Journal of Human Hypertension 2000 14 2 155 156 10.1038/sj.jhh.1000954 2-s2.0-0033954951 10723125\n24 Sameer Z. Shriram B. Rekha K. Vishnudas B. Amlodipine induced plasma cell granuloma of the gingiva: a novel case report Journal of Natural Science, Biology, and Medicine 2014 5 2 p. 472 10.4103/0976-9668.136267 2-s2.0-84904154062\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2021()",
"journal": "Case reports in dentistry",
"keywords": null,
"medline_ta": "Case Rep Dent",
"mesh_terms": null,
"nlm_unique_id": "101573242",
"other_id": null,
"pages": "4120148",
"pmc": null,
"pmid": "34603800",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "32773982;11507500;15562922;10723125;32781818;16237888;7935686;26380825;18946018;25097440;16677333;10783833;31777856;23739159;10429995;8195445;2234880;11023675;25738096;9680902;4516327;7990738;8018496",
"title": "Necrotizing Ulcerative Gingivitis, a Rare Manifestation as a Sequel of Drug-Induced Gingival Overgrowth: A Case Report.",
"title_normalized": "necrotizing ulcerative gingivitis a rare manifestation as a sequel of drug induced gingival overgrowth a case report"
} | [
{
"companynumb": "AE-ACCORD-243169",
"fulfillexpeditecriteria": "1",
"occurcountry": "AE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
"drugadditional": "2",
... |
{
"abstract": "Delayed post-hypoxic encephalopathy is an uncommon but potentially debilitating consequence of hypoxic-ischemic brain injury. This condition is characterized by delayed neurological deterioration days-to-weeks after an initial partial or complete recovery from hypoxic-ischemic brain injury. The course of recovery from this condition is highly variable, ranging from rapid and fatal progression over several weeks to delayed but occasionally complete recovery. There are no reports describing neurorehabilitative, including neuropharmacologic, interventions for persons with persistent neurological and/or neurobehavioural deficits following delayed post-hypoxic encephalopathy. This study describes the case of a 24-year old male who developed delayed post-hypoxic encephalopathy following an unintentional methadone and diazepam overdose and who demonstrated cognitive and neurobehavioural improvements during treatment with amantadine HCl hydrochloride in a single-case, open-label design. A brief review of the literature regarding this condition, its treatment and suggestions for further study are presented.",
"affiliations": "Brain Injury Rehabilitation Unit, Spalding Rehabilitation Hospital, Aurora, CO, USA. david.arciniegas@uchsu.edu",
"authors": "Arciniegas|David B|DB|;Frey|Kimberly L|KL|;Anderson|C Alan|CA|;Brousseau|Kristin M|KM|;Harris|Susie N|SN|",
"chemical_list": "D015259:Dopamine Agents; D006993:Hypnotics and Sedatives; D009294:Narcotics; D000547:Amantadine; D003975:Diazepam; D008691:Methadone",
"country": "England",
"delete": false,
"doi": "10.1080/02699050410001720130",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-9052",
"issue": "18(12)",
"journal": "Brain injury",
"keywords": null,
"medline_ta": "Brain Inj",
"mesh_terms": "D000328:Adult; D000547:Amantadine; D001921:Brain; D001930:Brain Injuries; D003072:Cognition Disorders; D003711:Demyelinating Diseases; D003975:Diazepam; D015259:Dopamine Agents; D006801:Humans; D006993:Hypnotics and Sedatives; D020925:Hypoxia-Ischemia, Brain; D008279:Magnetic Resonance Imaging; D008297:Male; D001523:Mental Disorders; D008691:Methadone; D009294:Narcotics",
"nlm_unique_id": "8710358",
"other_id": null,
"pages": "1309-18",
"pmc": null,
"pmid": "15666573",
"pubdate": "2004-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Amantadine for neurobehavioural deficits following delayed post-hypoxic encephalopathy.",
"title_normalized": "amantadine for neurobehavioural deficits following delayed post hypoxic encephalopathy"
} | [
{
"companynumb": "GXKR2005US00953",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "TRAMADOL"
},
"drugadditional": null,
"drugadm... |
{
"abstract": "Gadolinium is highly toxic. Gadolinium-based contrast agents (GBCAs) consist of gadolinium ions and a chelating agent that binds the gadolinium ion tightly in order not to manifest its toxicity. Knowledge regarding gadolinium deposition in patients with normal renal function has advanced dramatically. Since 2014, increasing attention has been given to residual gadolinium known to accumulate in the tissues of patients with normal renal function. High signal intensity on T1-weighted images (T1WI) in the dentate nucleus, globus pallidus, and pulvinar region of the thalamus correlate roughly with the number of previous GBCA administrations. Pathological analyses have revealed that residual gadolinium is deposited not only in these brain regions, but also in extracranial tissues such as liver, skin and bone. The risks attendant with these deposits are unknown. Common sense dictates that gadolinium deposition be kept as low as possible, and that gadolinium contrast agents be used only when absolutely necessary, with preferential use of macrocyclic chelates, which seem to be deposited at lower concentrations.",
"affiliations": "Department of Radiology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan. Electronic address: k_a@hotmail.co.jp.;Department of Radiology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.;Department of Radiology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.;Department of Radiology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.;Department of Radiology, Hyogo College of Medicine, Hyogo 663-8501, Japan.;Department of Radiology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.",
"authors": "Kanda|Tomonori|T|;Nakai|Yudai|Y|;Oba|Hiroshi|H|;Toyoda|Keiko|K|;Kitajima|Kazuhiro|K|;Furui|Shigeru|S|",
"chemical_list": "D003287:Contrast Media; D005682:Gadolinium",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.mri.2016.08.024",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0730-725X",
"issue": "34(10)",
"journal": "Magnetic resonance imaging",
"keywords": "Dentate nucleus; Gadolinium; Gadolinium based contrast agent (GBCA); Magnetic resonance image (MRI)",
"medline_ta": "Magn Reson Imaging",
"mesh_terms": "D001921:Brain; D003287:Contrast Media; D005682:Gadolinium; D006801:Humans; D007089:Image Enhancement; D008279:Magnetic Resonance Imaging; D012189:Retrospective Studies",
"nlm_unique_id": "8214883",
"other_id": null,
"pages": "1346-1350",
"pmc": null,
"pmid": "27613998",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Gadolinium deposition in the brain.",
"title_normalized": "gadolinium deposition in the brain"
} | [
{
"companynumb": "JP-GE HEALTHCARE MEDICAL DIAGNOSTICS-OSCN-PR-1609L-0132",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GADOLINIUM"
},
... |
{
"abstract": "BACKGROUND\nPsychosis in Parkinson disease is a therapeutic challenge. Regular strategies of treatment are aimed at reducing dopamine medication, and if necessary addition of clozapine.\n\n\nMETHODS\nWe describe the case of a patient with persistent psychosis. Nocturnal visual hallucinations persisted in spite of reduced dopaminergic medication and sequential treatment with atypical antipsychotic medication (quetiapine and clozapine) in combination with an acetylcholinesterase inhibitor (rivastigmine). After dispensing a dopamine enhancing antidepressant (mirtazapine), prescribed to improve sleeping, the psychotic symptoms almost immediately disappeared while Parkinson's symptoms declined.\n\n\nRESULTS\nOne other case about a positive effect of mirtazapine on (auditory) hallucinations in Parkinson has been published. The reason for the reduction of psychosis in Parkinson-related disease could have been the effect of antagonism of serotonin (5HT)-2 A and/or antagonism of 5HT-2C leading to dopamine release.\n\n\nCONCLUSIONS\nTherapeutic effects of medication with strong antagonism for 5HT-2 A and 5HT-2C, like mirtazapine, mianserine, trazodone and nefazodone, in Parkinson-related diseases should be subject for further research. Serotonin might be associated with psychosis in Parkinson-related disease.",
"affiliations": "Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands.;Department of Neurology, St. Antonius Hospital, Nieuwegein, The Netherlands.",
"authors": "Godschalx-Dekker|J A|JA|;Siegers|H P|HP|",
"chemical_list": "D006634:Histamine H1 Antagonists; D008803:Mianserin; D000078785:Mirtazapine",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0034-1367014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0176-3679",
"issue": "47(3)",
"journal": "Pharmacopsychiatry",
"keywords": null,
"medline_ta": "Pharmacopsychiatry",
"mesh_terms": "D000368:Aged; D006634:Histamine H1 Antagonists; D006801:Humans; D008297:Male; D008803:Mianserin; D000078785:Mirtazapine; D020734:Parkinsonian Disorders; D011618:Psychotic Disorders",
"nlm_unique_id": "8402938",
"other_id": null,
"pages": "81-3",
"pmc": null,
"pmid": "24504487",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Reduction of parkinsonism and psychosis with mirtazapine: a case report.",
"title_normalized": "reduction of parkinsonism and psychosis with mirtazapine a case report"
} | [
{
"companynumb": "NL-MYLANLABS-2017M1083897",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLONAZEPAM"
},
"drugadditional": "3",
... |
{
"abstract": "Anaesthetic hypersensitivity reactions can be IgE- or not IgE-mediated and are a challenge to find the causal agent. Histamine and tryptase determination are classically considered useful in the diagnosis of these reactions. The aim of our study was to assess the diagnostic usefulness of plasma histamine and different cut-off points of serum tryptase.\n\n\nMETHODS\nPatients suffering a reaction suggestive of hypersensitivity during general anaesthesia in Clínica Universidad de Navarra (2008-2012) were included. Serum tryptase and plasma histamine were measured at the time of the reaction and 2 h later. Baseline tryptase was also determined. Four to eight weeks after the reaction an allergological study was performed to all the drugs or products involved in the reaction.\n\n\nRESULTS\nSixty-five patients suffered an immediate hypersensitivity reaction during the period of the study. Thirty-seven patients (20 male) with median age 48 years (12-79) were included because they completed allergological study, and histamine and tryptase were correctly obtained. Elevated plasma histamine was observed in 34 cases (92%). Tryptase exceeded twice the basal values in 10 patients (31%). Using different cut-off points of tryptase, the number of patients with elevated tryptase would be 15 patients (41%) for a cut-off point of 5 μg/L; 12 patients (32%) for a cut-off point of 8.23 μg/L; nine patients (24%) for 10.5 μg/L; and eight patients (22%) for 11.4 μg/L. The median tryptase level for the IgE-mediated reactions was 9.0 μg/L (2-70 μg/L) and 4.0 μg/L (3-13 μg/L) in non-IgE-mediated reactions (P < 0.01). Median tryptase levels were higher in more severe reactions (grade 2 or 3) in comparison with grade 1. The best ratio for serum-tryptase-during-reaction/basal-serum-tryptase to discriminate between IgE and non-IgE reactions was 2.0.\n\n\nCONCLUSIONS\nThe best criterion for discriminating IgE- and non IgE-mediated hypersensitivity reactions in anaesthesia was a tryptase value exceeding twice the basal one.",
"affiliations": "Departamento de Alergología e Inmunología Clínica, Clínica Universidad de Navarra, Pamplona, Spain.",
"authors": "Berroa|F|F|;Lafuente|A|A|;Javaloyes|G|G|;Ferrer|M|M|;Moncada|R|R|;Goikoetxea|M J|MJ|;Urbain|C M|CM|;Sanz|M L|ML|;Gastaminza|G|G|",
"chemical_list": "D000777:Anesthetics; D006632:Histamine; D053802:Tryptases",
"country": "England",
"delete": false,
"doi": "10.1111/cea.12237",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-7894",
"issue": "44(2)",
"journal": "Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology",
"keywords": "anaesthesia; anaphylaxis; histamine; hypersensitivity; tryptase",
"medline_ta": "Clin Exp Allergy",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000777:Anesthetics; D002648:Child; D004342:Drug Hypersensitivity; D005260:Female; D006632:Histamine; D006801:Humans; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011446:Prospective Studies; D053802:Tryptases",
"nlm_unique_id": "8906443",
"other_id": null,
"pages": "270-7",
"pmc": null,
"pmid": "24237068",
"pubdate": "2014-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The usefulness of plasma histamine and different tryptase cut-off points in the diagnosis of peranaesthetic hypersensitivity reactions.",
"title_normalized": "the usefulness of plasma histamine and different tryptase cut off points in the diagnosis of peranaesthetic hypersensitivity reactions"
} | [
{
"companynumb": "ES-APOTEX-2015AP008195",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"drugadditional": null,
... |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.