article dict | reports listlengths 1 3.97k |
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{
"abstract": "Drug-assisted interviews are an effective tool in the management of various psychiatric illnesses where psychopharmacological, as well as routine psychological interventions, do not prove beneficial. These have most commonly been done by using barbiturates and benzodiazepines that have given favourable results for a long time. However, they carry the risk of respiratory depression and difficulty in maintaining the plane of sedation where the patient is amenable to interviewing. In our experience of drug-assisted interviews with two patients we used intravenous dexmedetomidine, which is being used in anaesthesia practice for conscious sedation or sedation in the intensive care unit. We found dexmedetomidine to be superior to thiopentone in achieving a level of conscious sedation where the patients were amenable for an interview, with no significant adverse events and faster post-anaesthetic recovery.",
"affiliations": "Anesthesiology, Pain Medicine and Critical Care, All India Institute of Medical Sciences, New Delhi, India, New Delhi, Delhi, India.;Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India.;Anesthesiology, Pain Medicine and Critical Care, All India Institute of Medical Sciences, New Delhi, India, New Delhi, Delhi, India.;Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India.",
"authors": "Goswami|Devalina|D|;Garg|Harshit|H|http://orcid.org/0000-0002-9720-627X;Carounagarane|Hamsenandinie|H|;Deb|Koushik Sinha|KS|",
"chemical_list": "D006993:Hypnotics and Sedatives; D020927:Dexmedetomidine; D013874:Thiopental",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-227195",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "11(1)",
"journal": "BMJ case reports",
"keywords": "anaesthesia; anxiety disorders (including ocd and ptsd); drugs: psychiatry",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000293:Adolescent; D001044:Aphonia; D001766:Blindness; D016292:Conscious Sedation; D020927:Dexmedetomidine; D004213:Dissociative Disorders; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives; D007407:Interviews as Topic; D012121:Respiration, Artificial; D013874:Thiopental; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30567267",
"pubdate": "2018-12-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "4835444;25206490;25478365;22951703;25885374;25161793;20785535;28105598;628696;21391103;2372182;18495053;22651673;29464690;22216050",
"title": "Dexmedetomidine-assisted drug interviews: an observation in psychiatric setting.",
"title_normalized": "dexmedetomidine assisted drug interviews an observation in psychiatric setting"
} | [
{
"companynumb": "IN-MYLANLABS-2019M1008365",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ESCITALOPRAM OXALATE"
},
"drugadditional": nu... |
{
"abstract": "Deregulated Notch signaling is implicated in T-cell acute lymphoblastic leukemia (T-ALL)/T-cell lymphoblastic lymphoma (T-LBL). Crenigacestat (LY3039478) prevents cleavage of Notch proteins and may benefit patients with relapsed/refractory T-ALL/T-LBL.\n\n\n\nJJCB was a multicenter, nonrandomized, open-label, dose-escalation, phase 1 study in adult patients with relapsed/refractory T-ALL/T-LBL. Eligible patients received Crenigacestat orally 3 times per week plus dexamethasone at 24 mg twice daily on days 1 to 5 every other week in a 28-day cycle. The starting level of Crenigacestat was 50 mg, and dose escalation was performed with a modified 3+3 scheme for the estimation of dose-limiting toxicity (DLT) at the recommended dose level.\n\n\n\nIn total, 36 patients with T-ALL (n = 31 [86.1%]) or T-LBL (n = 5 [13.9%]) were treated with Crenigacestat and dexamethasone. Six patients (16.7%) experienced DLTs: 2 of 12 (16.7%) in the 75-mg cohort (grade 4 gastrointestinal hemorrhage and grade 3 nausea, vomiting, and diarrhea), 1 of 15 (6.7%) in the 100-mg cohort (grade 3 diarrhea), and 3 of 3 (100%) in the 125-mg cohort (grade 3 diarrhea, nausea, and vomiting). The maximum tolerated dosewas 75 mg plus 24 mg of dexamethasone daily on days 1 to 5. Twenty-eight patients (77.8%) experienced 1 or more treatment-emergent adverse events related to the study treatment. The best overall response was a confirmed response, with 1 patient (2.8%) having a duration of response of 10.51 months. Six patients (16.7%) achieved stable disease, and 12 patients (33.3%) experienced progressive disease. The remaining 17 patients (47.2%) were not evaluable. The median event-free survival was 1.18 months (95% confidence interval, 0.76-2.14 months) among all groups. A pharmacodynamic analysis showed decreased plasma amyloid β levels.\n\n\n\nCrenigacestat demonstrated limited clinical activity at the recommended dose in adult patients with relapsed/refractory T-ALL/T-LBL.",
"affiliations": "The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Specialized, Diagnostic, and Experimental Medicine, University of Bologna, Bologna, Italy.;Saint Louis Hospital, Paris, France.;Central University Research Hospital (CHRU) De Nantes, Hotel-Dieu, Nantes, France.;University Hospital Frankfurt, Frankfurt am Main, Germany.;Eli Lilly and Company, Indianapolis, Indiana.;Eli Lilly and Company, Surrey, United Kingdom.;Eli Lilly and Company, Surrey, United Kingdom.;Eli Lilly and Company, Indianapolis, Indiana.;Eli Lilly and Company, Indianapolis, Indiana.;Dana-Farber Cancer Institute, Boston, Massachusetts.",
"authors": "Borthakur|Gautam|G|;Martinelli|Giovanni|G|;Raffoux|Emmanuel|E|;Chevallier|Patrice|P|0000-0003-3142-5581;Chromik|Jörg|J|;Lithio|Andrew|A|;Smith|Claire L|CL|;Yuen|Eunice|E|;Oakley|Gerard Joseph|GJ|;Benhadji|Karim A|KA|;DeAngelo|Daniel J|DJ|",
"chemical_list": "D001552:Benzazepines; D003907:Dexamethasone; C000654634:crenigacestat",
"country": "United States",
"delete": false,
"doi": "10.1002/cncr.33188",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-543X",
"issue": "127(3)",
"journal": "Cancer",
"keywords": "Crenigacestat; LY3039478; Notch; T-cell acute lymphoblastic leukemia (T-ALL); T-cell lymphoblastic lymphoma (T-LBL)",
"medline_ta": "Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001552:Benzazepines; D003907:Dexamethasone; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; D055815:Young Adult",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "372-380",
"pmc": null,
"pmid": "33107983",
"pubdate": "2021-02-01",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Phase 1 study to evaluate Crenigacestat (LY3039478) in combination with dexamethasone in patients with T-cell acute lymphoblastic leukemia and lymphoma.",
"title_normalized": "phase 1 study to evaluate crenigacestat ly3039478 in combination with dexamethasone in patients with t cell acute lymphoblastic leukemia and lymphoma"
} | [
{
"companynumb": "US-MYLANLABS-2021M1035343",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE SODIUM PHOSPHATE"
},
"drugaddit... |
{
"abstract": "Phenytoin has a narrow therapeutic window, and when managing cases of toxicity, clinicians are very wary of this fact. Typically, if patient presents with symptoms suggestive of phenytoin toxicity, total serum phenytoin is promptly ordered. That could be falsely low especially in elderly or critically ill patients, which may lead to a low albumin level resulting in this discrepancy. The free phenytoin can be best estimated using the Sheiner-Tozer equation. Herein, we describe a case of an elderly male patient who presented with drowsiness, gait changes, and elevated liver enzymes and a normal total serum phenytoin level of 18 ng/dL (normal, 10-20 ng/dL).After taking his albumin level into account, his free phenytoin level was calculated to be 27 ng/dL, and the phenytoin was discontinued leading to resolution of his symptoms as well as a return of his liver function panel values to baseline.",
"affiliations": "Department of Internal Medicine, SUNY Upstate, Syracuse, NY, USA. Electronic address: imams@upstate.edu.;Department of Internal Medicine, SUNY Upstate, Syracuse, NY, USA.;Department of Internal Medicine, SUNY Upstate, Syracuse, NY, USA.;Department of Internal Medicine, SUNY Upstate, Syracuse, NY, USA.;Department of Internal Medicine, Syracuse Veterans Affairs Medical Center, Syracuse, NY, USA.;Department of Internal Medicine, Syracuse Veterans Affairs Medical Center, Syracuse, NY, USA.",
"authors": "Imam|Syed Haider|SH|;Landry|Kristen|K|;Kaul|Viren|V|;Gambhir|Harvir|H|;John|Dinesh|D|;Kloss|Brian|B|",
"chemical_list": "D000927:Anticonvulsants; D010672:Phenytoin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "32(10)",
"journal": "The American journal of emergency medicine",
"keywords": null,
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000368:Aged; D000927:Anticonvulsants; D056486:Chemical and Drug Induced Liver Injury; D020233:Gait Disorders, Neurologic; D006801:Humans; D034141:Hypoalbuminemia; D008297:Male; D010672:Phenytoin; D012894:Sleep Stages",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "1301.e3-4",
"pmc": null,
"pmid": "24768668",
"pubdate": "2014-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Free phenytoin toxicity.",
"title_normalized": "free phenytoin toxicity"
} | [
{
"companynumb": "US-PFIZER INC-2014277590",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PHENYTOIN"
},
"drugadditional": null,
... |
{
"abstract": "No proven treatments exist for bronchiolitis obliterans syndrome (BOS) following lung transplantation. Inhaled liposomal cyclosporine (L-CsA) may prevent BOS progression.\nA 48-week phase IIb randomised clinical trial was conducted in 21 lung transplant patients with BOS assigned to either L-CsA with standard-of-care (SOC) oral immunosuppression (L-CsA group) or SOC (SOC-alone group). Efficacy end-points were BOS progression-free survival (defined as absence of ≥20% decline in forced expiratory volume in 1 s (FEV1) from randomisation, re-transplantation or death) and BOS grade change.\nBOS progression-free survival was 82% for L-CsA versus 50% for SOC-alone (p=0.1) and BOS grade worsened in 18% for L-CsA versus 60% for SOC-alone (p=0.05). Mean changes in ΔFEV1 and forced vital capacity, respectively, stabilised with L-CsA: +0.005 (95% CI -0.004- +0.013) and -0.005 (95% CI -0.015- +0.006) L·month-1, but worsened with SOC-alone: -0.023 (95% CI -0.033- -0.013) and -0.026 (95% CI -0.039- -0.014) L·month-1 (p<0.0001 and p=0.009). Median survival (4.1 versus 2.9 years; p=0.03) and infection rate (45% versus 60%; p=0.7) improved with L-CsA versus SOC-alone; creatinine and tacrolimus levels were similar.\nL-CsA was well tolerated and stabilised lung function in lung transplant recipients affected by BOS without systemic toxicity, providing a basis for a global phase III trial using L-CsA.",
"affiliations": "Shock, Trauma and Transplantation and Dept of Medicine, University of Maryland, Baltimore, MD, USA.;Dept of Epidemiology, University of Maryland, Baltimore, MD, USA.;Cardiac Surgery, Memorial Hermann Hospital Texas Medical Center, Houston, TX, USA.;Shock, Trauma and Transplantation and Dept of Medicine, University of Maryland, Baltimore, MD, USA.;Shock, Trauma and Transplantation and Dept of Medicine, University of Maryland, Baltimore, MD, USA.;Dept of Cardiothoracic Surgery, University of Maryland, Baltimore, MD, USA.;Dept of Epidemiology, University of Maryland, Baltimore, MD, USA.",
"authors": "Iacono|Aldo|A|;Wijesinha|Marniker|M|;Rajagopal|Keshava|K|;Murdock|Natalia|N|;Timofte|Irina|I|;Griffith|Bartley|B|;Terrin|Michael|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1183/23120541.00167-2019",
"fulltext": "\n==== Front\nERJ Open ResERJ Open ResERJORerjorERJ Open Research2312-0541European Respiratory Society 3097235110.1183/23120541.00167-201900167-2019Original ArticlesBronchiolitis Obliterans Syndrome14A randomised single-centre trial of inhaled liposomal cyclosporine for bronchiolitis obliterans syndrome post-lung transplantation A trial of inhaled L-CsA for BOS post-lung transplantationIacono Aldo 1Wijesinha Marniker 2Rajagopal Keshava 3Murdock Natalia 1Timofte Irina 1Griffith Bartley 4Terrin Michael 21 Shock, Trauma and Transplantation and Dept of Medicine, University of Maryland, Baltimore, MD, USA2 Dept of Epidemiology, University of Maryland, Baltimore, MD, USA3 Cardiac Surgery, Memorial Hermann Hospital Texas Medical Center, Houston, TX, USA4 Dept of Cardiothoracic Surgery, University of Maryland, Baltimore, MD, USAAldo Iacono, Shock, Trauma and Transplantation and Dept of Medicine, University of Maryland School of Medicine, 22 S. Greene Street, Baltimore, MD 21201, USA. E-mail: aiacono@umm.edu10 2019 30 10 2019 5 4 00167-201902 7 2019 25 8 2019 Copyright ©ERS 20192019http://creativecommons.org/licenses/by-nc/4.0/This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.Introduction\nNo proven treatments exist for bronchiolitis obliterans syndrome (BOS) following lung transplantation. Inhaled liposomal cyclosporine (L-CsA) may prevent BOS progression.\n\nMethods\nA 48-week phase IIb randomised clinical trial was conducted in 21 lung transplant patients with BOS assigned to either L-CsA with standard-of-care (SOC) oral immunosuppression (L-CsA group) or SOC (SOC-alone group). Efficacy end-points were BOS progression-free survival (defined as absence of ≥20% decline in forced expiratory volume in 1 s (FEV1) from randomisation, re-transplantation or death) and BOS grade change.\n\nResults\nBOS progression-free survival was 82% for L-CsA versus 50% for SOC-alone (p=0.1) and BOS grade worsened in 18% for L-CsA versus 60% for SOC-alone (p=0.05). Mean changes in ΔFEV1 and forced vital capacity, respectively, stabilised with L-CsA: +0.005 (95% CI −0.004– +0.013) and −0.005 (95% CI −0.015– +0.006) L·month−1, but worsened with SOC-alone: −0.023 (95% CI −0.033– −0.013) and −0.026 (95% CI −0.039– −0.014) L·month−1 (p<0.0001 and p=0.009). Median survival (4.1 versus 2.9 years; p=0.03) and infection rate (45% versus 60%; p=0.7) improved with L-CsA versus SOC-alone; creatinine and tacrolimus levels were similar.\n\nConclusions\nL-CsA was well tolerated and stabilised lung function in lung transplant recipients affected by BOS without systemic toxicity, providing a basis for a global phase III trial using L-CsA.\n\nLiposomal aerosol cyclosporine (L-CsA) was well tolerated and stabilised lung function in lung transplant recipients affected by BOS. The data provide evidence for an ongoing global phase III trial using L-CsA for BOS.\nhttp://bit.ly/2HB8w5j\n\nPlylar Grantpari pharma\n==== Body\nIntroduction\nOutcomes after lung transplantation are poor due to bronchiolitis obliterans [1]. Since bronchiolitis obliterans is not readily demonstrated by lung biopsies, the term bronchiolitis obliterans syndrome (BOS) is applied, defined as a sustained forced expiratory volume in 1 s (FEV1) decline [2]. Treatments for bronchiolitis obliterans are poorly efficacious [3–6]. When higher dosages of calcineurin inhibitors are given for improved immunosuppression, nephrotoxicity and opportunistic infections are limiting [7].\n\nBronchiolitis obliterans is a complex immunological process triggered by a pathogenetic alloresponse leading to epithelial injury, bronchiolar fibro-obliteration and FEV1 decline [8–10], making the bronchiolar epithelium an interventional target. It has been established that inhalational cyclosporine is deposited in peripheral bronchioles in elevated concentrations [11–13].\n\nIn rodent and canine orthotopic lung transplant models, inhaled cyclosporine as single-agent therapy prevents histological rejection in a manner comparable to systemic immunosuppression, with higher intragraft cyclosporine concentrations [14–17]. In humans, numerous clinical trials have shown that inhaled cyclosporine can prevent or ameliorate histological rejection and improve lung function [18–28]. FEV1 improvement has been shown to be dependent on the cyclosporine allograft concentration [21, 27, 28]. Previous studies of inhaled cyclosporine relied on propylene glycol to solubilise cyclosporine with a jet nebuliser, which resulted in adverse respiratory symptoms in up to 50% of patients [25]. Better tolerated aerosol formulations with quicker delivery and enhanced bioavailability are needed.\n\nThis trial, which used a liposomal formulation of aerosolised cyclosporine A (L-CsA), tailored for fast and targeted drug aerosol delivery with a high-performance nebuliser (eFlow), given in addition to standard-of-care (SOC) oral immunosuppression for the treatment of BOS following lung transplantation, is the first randomised controlled study using L-CsA for BOS treatment.\n\nMethods\nPatient characteristics\nThis open-label randomised trial was conducted at the University of Maryland (Baltimore, MD, USA) with Institutional Review Board approval. This study is registered at ClinicalTrials.gov with identifier number NCT01650545. The trial was conducted by way of the primary author's (A.I.) Investigational New Drug (IND) application. Enrolment was from September 2012 to January 2015. Follow-up for lung function was for 1 year and survival until September 2017.\n\nPatients ≥18 years of age were eligible if recipients of a single or bilateral pulmonary allograft, had clinically diagnosed BOS grade 1 or 2 [2] within 4 weeks of study entry and were receiving tacrolimus-based immunosuppression. Exclusion criteria are listed in the supplementary material. No patient had restrictive chronic lung allograft dysfunction or antibody-mediated rejection prior to or at randomisation, or thereafter [29, 30].\n\nInvestigational medicinal product\nThe product is a drug–device combination: L-CsA and an investigational eFlow nebuliser system (PARI Pharma, Gräfelfing, Germany). L-CsA was supplied in vials of 5 mg/1.25 mL and 10 mg/2.5 mL containing liposomes ∼50 nm diameter (polydispersity index <0.4) after reconstitution. The eFlow nebuliser produces an aerosol in the respirable range (2.8−5 µm). Average inhalation time was 10–15 min.\n\nTreatment regimens\nConventional oral immunosuppression (SOC) included: tacrolimus (0.06 mg·kg−1·day−1), mycophenolate mofetil (2000 mg·day−1) and prednisone (10–20 mg·day−1). Immunosuppression was adjusted per the University of Maryland protocol (supplementary material). Augmented immunosuppression was given for treatment of histological or clinical rejection consisting of corticosteroids (intravenous methylprednisolone 1 g·day−1 (3 days) or oral prednisone at a dose of 100 mg tapered to 10 mg over 14 days) or antithymocyte globulin (ATG) 1.5 mg·kg−1·day−1 (3–5 days).\n\nPatients randomised to the L-CsA arm were scheduled to receive L-CsA twice daily for 24 weeks at doses of 5 mg (single allograft) or 10 mg (double allograft), in addition to SOC. After the initial 24-week treatment period, patients in the L-CsA arm continued on SOC during a subsequent 24-week follow-up. Patients randomised to the SOC-alone arm received standard immunosuppression only.\n\nTrial design and evaluations\nThe objective of the study was to evaluate safety and efficacy of L-CsA for grade 1 and 2 BOS. Because single lung recipients have a worse outcome, randomisation was stratified according to single and bilateral status. Patients were then randomly assigned to groups according to block randomisation in a 1:1 ratio to receive either L-CsA or SOC-alone. Study treatment began as soon as possible after randomisation, typically within 7 days. If SOC-alone patients met a primary end-point of ≥20% decline in FEV1 from randomisation and still met initial study entry criteria, L-CsA was permitted as “rescue” crossover. Additionally, if this efficacy end-point occurred during the second 24-week follow-up period after L-CsA administration in that arm, L-CsA could then be re-initiated for a second 24-week period. Crossover patients in both arms were followed clinically, but their data were included in the study analyses end-points up until they met a primary study end-point.\n\nEnd-points\nThere were two primary end-points: 1) a composite of BOS progression-free survival, defined as time from randomisation to ≥20% decline in FEV1, re-transplantation or death, whichever occurred first (prolonged mechanical ventilation and irreversible respiratory failure equivalent to ≥20% decline of FEV1), and 2) BOS grade progression by grade changes from randomisation to study completion. A decline in FEV1 was validated for absence of concurrent illness measured at intervals ≥3 weeks apart.\n\nOther exploratory end-points included change in lung function, quantitation of histological bronchiolitis obliterans and bronchoalveolar lavage (BAL) cytokine measurements (interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-10, IL-17, interferon (IFN)-γ and tumour necrosis factor (TNF)-α)) by multiplex assay (Luminex 100 system; Luminex, Austin, TX, USA) analysed using Bio-Plex Manager (Bio-Rad, Hercules, CA, USA). BAL was performed before randomisation, at week 24, and when indicated clinically [2].\n\nSafety\nPatient and graft survival and adverse events including infections and symptoms related to L-CsA were quantified as an index of safety and compared between study arms. An Outcomes and Safety Committee adjudicated events.\n\nStatistical analysis\nAs the first phase IIb trial using L-CsA for BOS treatment, the number of patients to be randomised was determined by the availability of L-CsA and other resources. The IND study specified the end-points, safety measures and a 3-year enrolment period of 30 patients. No modifications were made after trial initiation. 15 patients per group was deemed appropriate, as absence of the desired outcomes for L-CsA would discourage future drug development. Enrolment of qualifying recipients was discontinued after 3 years after accrual of 21 subjects. The target enrolment goal was not met due to lower than anticipated enrolment rates. Outcome data collection continued until either a primary outcome event occurred or patients without events completed the study at 48 weeks. Patient and graft survival were monitored until September 2017 as an assessment of safety independent of continuation or discontinuation of L-CsA. Patients were analysed according to the intention-to-treat principle. No patient was lost to follow-up.\n\nEnd-point events were compared by Kaplan–Meier survival analyses and log-rank testing as specified a priori by our protocol. A p-value of <0.05 indicated statistical significance. Since the patient survival analysis showed nonproportionality, the Renyi statistic was also used. Data are presented with hazard ratios and 95% confidence intervals. For lung function analyses, multivariate linear mixed effects statistical models (PROC MIXED in SAS version 9.1.3; SAS Institute, Cary, NC, USA) were utilised [31]. Secondary end-points included lung function changes, infection rates and survival. For lung function, as pre-specified for single and bilateral lungs, one mixed model was based only on post-randomisation lung function data using a longitudinal regression model, while a second model accounted for intragroup values pre-randomisation adjusting for within-patient trends that could potentially influence post-randomisation function. Changes in cytokine measurements from pre- to post-randomisation were compared using two-way ANOVA from 42 BAL collections (21 in each group). Sirolimus and tacrolimus levels and routine laboratory values were compared using a mixed effects model. A total of 243 pulmonary function tests (122 L-CsA and 121 SOC-alone) and 603 blood samples were analysed.\n\nResults\nPatient characteristics\nOf 43 patients screened, 17 failed to meet BOS grade criteria and 21 were randomised (11 to L-CsA and 10 to SOC-alone) (figure 1). Baseline characteristics and clinical management of the two groups were similar, although more cytomegalovirus mismatches were randomised to L-CsA (table 1). Mean±sd time to BOS confirmation for L-CsA was comparable to SOC-alone (1391±859 versus 1061±796 days; p=0.41). Forced vital capacity (FVC) decline prior to randomisation for both L-CsA and SOC-alone was similar (−0.025 (95% CI −0.034– −0.015) versus −0.021 (95% CI −0.030– −0.012) L; p=0.69). Azithromycin use, induction cycles, BOS grades and absolute FEV1 decline rates prior to randomisation were all similar (supplementary material). All randomised patients reached the efficacy end-point or completed 48 weeks of follow-up. Both the L-CsA and SOC-alone groups received similar cycles of augmentation of immune suppression after randomisation (three steroid pulses and one ATG cycle). Five patients has positive donor-specific antibody results post-transplantation: two patients in L-CsA and three in SOC-alone (three with human leukocyte antigen class 2 reactivity).\n\nFIGURE 1 Study enrolment. L-CsA: liposomal cyclosporine; SOC: standard of care; FEV1: forced expiratory volume in 1 s; BOS: bronchiolitis obliterans syndrome. 43 patients were assessed for eligibility for this study. 17 screened patients did not meet BOS grade 1 or 2 criteria and three patients met exclusion criteria. 23 patients met eligibility criteria. One patient died and one patient withdrew prior to randomisation. 21 patients were randomised: 11 patients to the inhaled L-CsA treatment arm given in addition to conventional oral immunosuppression (SOC) and 10 patients to the SOC-alone arm. Patients were followed until an efficacy end-point occurred (a ≥20% FEV1 decline or re-transplantation or death) or until week 48. If the efficacy end-point event occurred before week 48 in the SOC-alone arm, crossover to L-CsA was permitted. If the efficacy end-point occurred in the L-CsA group during the 24-week observation interval only, re-treatment with L-CsA was possible if patients still fulfilled eligibility criteria. One SOC-alone patient developed protracted respiratory failure (>3 weeks duration) due to progressive BOS. #: the mean duration of L-CsA crossover or re-therapy was 156 days (a successful L-CsA “crossover” or “re-therapy” was defined as absence of ≥20% FEV1 decline relative to the time of initiation, according to the end-point definition).\n\nTABLE 1 Baseline (pre-randomisation) characteristics of patients assigned to either inhaled liposomal cyclosporine (L-CsA) with standard-of-care (SOC) oral immunosuppression (L-CsA group) or SOC (SOC-alone group)\n\n\tL-CsA\tSOC-alone\tp-value\t\nSubjects\t11\t10\t\t\nAge years\t59.1±13.7\t63.8±13.1\t0.4\t\nSex\t\t\t0.4\t\n Female\t5 (45)\t2 (20)\t\t\n Male\t6 (55)\t8 (80)\t\t\nRace\t\t\t>0.9\t\n African-American\t3 (27)\t2 (20)\t\t\n Caucasian\t8 (73)\t8 (80)\t\t\nLung disease\t\t\t>0.9\t\n COPD\t3 (27)\t3 (30)\t\t\n Pulmonary fibrosis\t7 (64)\t6 (60)\t\t\n Pulmonary hypertension\t0 (0)\t1 (10)\t\t\n Sarcoidosis\t1 (9)\t0 (0)\t\t\nTransplant type\t\t\t0.7\t\n Single\t5 (45)\t6 (60)\t\t\n Double\t6 (55)\t4 (40)\t\t\nImmunosuppression\t\t\t\t\n Tacrolimus\t\t\t\t\n Patients\t8\t10\t\t\n Level ng·mL−1\t9.9±3.1\t7.7±3.7\t0.2\t\n Sirolimus\t\t\t\t\n Patients\t3\t4\t\t\n Level ng·mL−1\t7.2±3.8\t7.1±4.9\t>0.9\t\n Azithromycin\t6\t7\t0.7\t\nLaboratory results\t\t\t\t\n Creatinine mg·dL−1\t1.6±0.5\t1.4±0.4\t0.3\t\n White blood cell count × 109 L−1\t7.2±2.3\t7.9±2.9\t0.6\t\n Platelet count × 109 L−1\t238.2±92.8\t214.0±64.9\t0.5\t\n Alanine transaminase U·L−1\t26.6±14.4\t30.6±15.4\t0.6\t\n Aspartate transaminase U·L−1\t32.2±14.4\t29.4±12.0\t0.7\t\n Bilirubin mg·dL−1\t0.4±0.1\t0.4±0.2\t0.5\t\n Haemoglobin g·dL−1\t11.8±2.0\t11.5±1.6\t0.7\t\n Haematocrit %\t36.8±6.1\t35.1±4.5\t0.5\t\nDonor (D)–recipient (R) matching\t\t\t\t\n HLA mismatches\t4.3±1.2\t4.6±1.2\t0.6\t\n Cytomegalovirus\t\t\t0.4\t\n R+/D+\t3\t2\t\t\n R+/D−\t4\t4\t\t\n R−/D+\t3\t0\t\t\n R−/D−\t1\t4\t\t\nDonor characteristics\t\t\t\t\n Age years\t32.4±11.8\t32.8±11.3\t>0.9\t\n Sex\t\t\t0.6\t\n Female\t4 (36)\t2 (20)\t\t\n Male\t7 (64)\t8 (80)\t\t\n Race\t\t\t0.4\t\n African-American\t5 (45)\t2 (20)\t\t\n Caucasian\t6 (55)\t8 (80)\t\t\n Smoking history ≥20 pack-years\t\t\t0.5\t\n Yes\t2\t0\t\t\n No\t8\t10\t\t\n Unknown\t1\t0\t\t\n Ischaemic time h\t4.69±2.02\t5.53±3.00\t0.5\t\nPulmonary function\t\t\t\t\n FEV1 at randomisation L\t1.66±0.56\t1.78±0.60\t0.7\t\n BOS grade at randomisation\t\t\t>0.9\t\n 1\t7 (64)\t7 (70)\t\t\n 2\t4 (36)\t3 (30)\t\t\n Time from transplantation to diagnosis of BOS days\t1391±859\t1061±796\t0.4\t\n Time from transplantation to randomisation days\t1417.7±852.4\t1097.0±788.0\t0.4\t\n ΔFEV1 from transplantation to randomisation L·month−1\t−0.003±0.004\t−0.008±0.002\t0.2\t\nData are presented as n, mean±sd or n (%), unless otherwise stated. COPD: chronic obstructive pulmonary disease; HLA: human leukocyte antigen; FEV1: forced expiratory volume in 1 s; BOS: bronchiolitis obliterans syndrome.\n\nBOS progression\nMean±sd FEV1 changes from baseline maximal values were similar at randomisation for L-CsA versus SOC-alone (−31.2±9% and −31.8±6.8%; p=0.8). BOS progression-free survival was observed in nine out of 11 (82%) patients treated with L-CsA versus five out of 10 (50%) SOC-alone patients (hazard ratio 3.19 (95% CI 0.62–16.50); p=0.1) (figure 2a). Only one L-CsA patient met this primary end-point while receiving L-CsA; the second met the end-point while off L-CsA (following the initial 24-week on-treatment period) and stabilised after L-CsA was resumed (a “rescue” crossover). Of the five end-point occurrences in the SOC-alone group, two patients were re-transplanted, one developed respiratory failure and one out of two patients who crossed over from SOC-alone responded to L-CsA without further interventions. BOS grade progression from randomisation occurred three-fold less commonly in patients receiving L-CsA versus SOC-alone (p=0.05) (figure 2b).\n\nFIGURE 2 a) One efficacy end-point of the study was bronchiolitis obliterans syndrome (BOS) progression-free survival, defined as time after randomisation to a ≥20% forced expiratory volume in 1 s (FEV1) decline, re-transplantation or death, whichever occurred first. (Prolonged mechanical ventilation due to respiratory failure was considered equivalent to a ≥20% decline in FEV1.) Five out of 10 patients (50%) in the standard of care (SOC)-alone arm experienced treatment failure compared with two out of 11 (18%) patients randomised to L-CsA (SOC versus L-CsA hazard ratio 3.19 (95% CI 0.62–16.50); p=0.1). A decline in FEV1 was validated for concurrent lung or other illnesses other than BOS, and measured and confirmed at intervals of ≥3 weeks apart. The baseline study FEV1 used was the value obtained from randomisation. b) Number of patients alive as of September 12, 2017: five out of 11 (45%) in the L-CsA arm versus none out of 10 (0%) in the SOC-alone arm (p=0.03). The other efficacy end-point was change in BOS grades from randomisation to study completion at 48 weeks. Patient changes in BOS grade during the 48-week study period, from baseline grade at randomisation, in the L-CsA and SOC-alone arms. A three-fold reduction in the grade of BOS progression, indicating functional BOS disease stability by L-CsA, was demonstrated in patients treated with L-CsA compared with those who received SOC-alone (p=0.05).\n\nLung function changes prior to randomisation and after L-CsA\nΔFEV1 post-randomisation demonstrated stability with L-CsA (+0.005 (95% CI −0.004– +0.013) L·month−1) compared with SOC-alone (−0.023 (95% CI −0.033– −0.013) L·month−1; p<0.0001) (figure 3a). Additionally, within randomised groups, ΔFEV1 showed improvement after randomisation to L-CsA compared with deterioration prior to study treatment (ΔFEV1 pre-randomisation −0.021 (95% CI −0.032– −0.011) L·month−1\nversus post-randomisation +0.005 (95% CI −0.004– +0.013) L·month−1; p=0.0002). In contrast, patients in the SOC-alone group had continued FEV1 decline post-randomisation comparable to pre-randomisation (ΔFEV1 pre-randomisation −0.028 (95% CI −0.039– −0.018) L·month−1\nversus post-randomisation −0.025 (95% CI −0.035– −0.015) L·month−1; p=0.3) (figure 3b).\n\nFIGURE 3 a, b) Comparisons of forced expiratory volume in 1 s (FEV1) over time, analysed by multivariate linear mixed effects in the liposomal cyclosporine (L-CsA) and standard of care (SOC)-alone arms, analysed a) before and b) after randomisation to the respective arms of the trial. In the year prior to randomisation, FEV1 slopes were similar between the L-CsA and SOC-alone groups (pre-randomisation ΔFEV1 −0.021 (95% CI −0.032– −0.011) versus −0.028 (95% CI −0.039– −0.018) L·month−1; p=0.3). The post-randomisation ΔFEV1 demonstrated stability for the L-CsA arm (+0.005 (95% CI −0.004– +0.013) L·month−1) compared with significant deterioration in the SOC-alone arm (−0.025 (95% CI −0.035– −0.015) L·month−1) (p<0.0001). Within-group pre- and post-randomisation FEV1 analyses (L-CsA and SOC-alone, analysed distinctly) demonstrated improvement in patients after randomisation to L-CsA compared with ΔFEV1 decline prior to randomisation while receiving SOC-alone (pre-randomisation ΔFEV1 −0.021 (95% CI −0.032– −0.011) L·month−1\nversus post-randomisation +0.005 (95% CI −0.004– +0.013) L·month−1; p=0.0002). In contrast, patients in the SOC-alone arm demonstrated continued FEV1 decline after randomisation similar to pre-randomisation values (pre-randomisation ΔFEV1 −0.028 (95% CI −0.039– −0.018) L·month−1\nversus post-randomisation −0.025 (95% CI −0.035– −0.015) L·month−1; p=0.3). c, d) Comparisons of c) forced vital capacity (FVC) and d) forced expiratory flow at 25–75% of FVC (FEF25–50%) over the 48-week post-randomisation period in the L-CsA and SOC-alone arms, analysed after randomisation and compared between patient groups with their respective arms of the trial. For ΔFVC, L-CsA versus SOC-alone: −0.005 (95% CI −0.015– +0.006) and −0.026 (95% CI −0.039– −0.014) L·month−1) (p=0.009). For ΔFEF25–75%, L-CsA versus SOC-alone: +0.008 (95% CI −0.015– +0.031) and −0.015 (95% CI −0.042– +0.011) L·month−1 (p=0.1).\n\nΔFVC similarly showed improvement post-randomisation for L-CsA and decline for SOC-alone (L-CsA −0.005 (95% CI −0.015– +0.006) L·month−1\nversus SOC-alone −0.026 (95% CI −0.039– −0.014) L·month−1; p=0.009) (figure 3c). For the change in forced expiratory flow at 25–75% of FVC (ΔFEF25–75%), a similar pattern was shown post-randomisation for L-CsA (+0.008 (95% CI −0.015– +0.031) L·month−1) versus SOC-alone (−0.015 (95% CI −0.042– +0.011) L·month−1) (p=0.1) (figure 3d). Of the three subjects for whom L-CsA was administered as a rescue therapy (re-initiated for L-CsA or crossover from SOC-alone), the ΔFEV1 slope after L-CsA rescue at 24 weeks was +0.01 (95% CI 0.003–0.018) L·month−1.\n\nBAL cytokines\nCytokines measured were similar before randomisation between the L-CsA and SOC-alone groups. The following cytokines were significantly different after randomisation in L-CsA versus SOC-alone (median (interquartile range)): IL-2 7.1 (0.5–7.1) versus 48.4 (11.3–55.2) pg·mL−1 (p=0.04), IL-10 3.3 (0–13.0) versus 0 (0–2.5) pg·mL−1 (p=0.04) and IFN-γ 3.8 (0.2–37.6) versus 0.8 (0.7–4.4) pg·mL−1 (p=0.05) (figure 4). IL-1β, IL-6, IL-8, IL-17 and TNF-α showed no significant differences before or during the study.\n\nFIGURE 4 A comparison of a) interleukin (IL)-2, b) IL-10 and c) interferon (IFN)-γ cytokines between the liposomal cyclosporine (L-CsA) and standard of care (SOC)-alone arms, pre- and post-randomisation during the 48-week follow-up. Data are presented as median with interquartile range (IQR) (boxes), together with minimum and maximum values (whiskers); the circle within a box represents the mean, while circles outside of a box represent outliers. Compared with SOC-alone, the post-randomisation changes in IL-2, IL-10 and IFN-γ (analysed by two-way ANOVA) were significantly different in the L-CsA group, with post-randomisation values (median (interquartile range)): IL-2 7.1 (0.5–17.1) pg·mL−1 in L-CsA versus 48.4 (11.3–55.2) pg·mL−1 in SOC-alone (p=0.04), IL-10 3.3 (0–13.0) pg·mL−1 in L-CsA versus 0 (0–2.5) pg·mL−1 in SOC-alone (p=0.04) and IFN-γ 3.8 (0.2–37.6) pg·mL−1 in L-CsA versus 0.8 (0.7–4.4) pg·mL−1 in SOC-alone (p=0.05). All other cytokines measured, including IL-1β, IL-6, IL-8, IL-17 and tumour necrosis factor-α, showed no significant differences post-randomisation between patients randomised to L-CsA versus SOC-alone.\n\nSystemic immune suppression\nMaintenance tacrolimus blood levels and doses and prednisone doses were similar at baseline (table 1) and at study completion for L-CsA and SOC-alone: tacrolimus levels 6.32 (95% CI 4.57–8.07) versus 5.19 (95% CI 3.08–7.30) ng·mL−1 (p=0.4), tacrolimus doses 2.0 (95% CI 1.4–2.7) versus 2.5 (95% CI 1.8–3.1) mg·day−1 (p=0.1) and prednisone doses 11.6 (95% CI 9.0–14.0) versus 9.9 (95% CI 7.0–12.7) mg·day−1 (p=0.3). Augmentation cycles did not differ between the treatment arms before or after randomisation. Sirolimus blood levels were lower in L-CsA compared with SOC-alone at study completion (2.65 (95% CI 0.00–5.73) versus 9.29 (95% CI 7.06–11.51) ng·mL−1; p=0.0007), but were similar at randomisation (table 1).\n\nHistopathology before and after randomisation to L-CsA\nTransbronchial biopsies were performed when indicated by the University of Maryland protocol. Prior to randomisation, histology demonstrated four cases with airway rejection in L-CsA cases (two patients B1 and two patients with histological changes suggestive of bronchiolitis obliterans) and only one receiving SOC-alone (one patient with changes suggestive of bronchiolitis obliterans). Post-randomisation, four patients receiving SOC-alone had airway rejection (two patients B2 and two patients B1), whereas two patients receiving L-CsA had B1 airway rejection. One patient receiving L-CsA and two patients receiving SOC-alone experienced grade 1 acute rejection. No patient had histopathological changes consistent with antibody-mediated rejection or positive C4d staining prior to or after randomisation.\n\nPharmacokinetics\nCyclosporine blood sampling was done for all patients randomised to L-CsA and one crossover patient. Mean±sd maximum cyclosporine blood concentration (Cmax) was 57.42±34.26 ng·mL−1 achieved after 15−30 min (tmax) and the half-life (t1/2) was ∼2 h. At 24 h, mean±sd cyclosporine blood concentration was 1.42±4.91 ng·mL−1.\n\nAdverse events\nNo adverse event required withdrawal from L-CsA or permanent drug discontinuation. No patient was lost to follow-up. Peak expiratory flow (PEF) at the first dosing was 367.7 L·min−1 prior to inhalation and 327.7 L·min−1 after inhalation (−10.9% decrease). No patients met the pre-specified PEF 20% decline criterion to discontinue L-CsA. Three adverse events were related to L-CsA: conjunctivitis, pharyngitis and productive cough.\n\nMean creatinine at end of follow-up (week 48) for L-CsA and SOC-alone was 1.52 (95% CI 1.31–1.73) versus 1.65 (95% CI 1.41–1.89) mg·dL−1 (p=0.3). Aspartate transaminase (AST), alanine transaminase (ALT) and bilirubin remained within reference ranges (AST 14–36 U·L−1, ALT 9–52 U·L−1 and bilirubin 0.3–1.2 mg·dL−1) in both arms. Serious adverse events occurred with nearly equal frequency for L-CsA and SOC-alone (22 versus 24 events). Four pneumonia events occurred, all in the SOC-alone group. There was no difference in infection rates: five out of 11 (45%) and six out of 10 (60%) patients in the L-CsA and SOC-alone groups, respectively (p=0.7). No adverse events had a fatal outcome.\n\nSurvival for L-CsA patients improved compared with SOC-alone (45% (five out of 11) alive compared with 0% (none out of 10) alive; median 4.1 versus 2.9 years; p=0.03 (Renyi test p=0.07)) (figure 5a). Graft survival (death and re-transplant) was similarly improved: 4.1 years L-CsA versus 2.7 years SOC-alone; six out of 11 treatment failures, one re-transplant; 10 out of 10 treatment failures, three re-transplants (p=0.01) (figure 5b). Causes of death were all chronic allograft rejection with the exception of disseminated skin cancer (L-CsA) and renal failure (SOC-alone).\n\nFIGURE 5 a) A comparison of long-term patient survival between the treatment groups. L-CsA: liposomal cyclosporine; SOC: standard of care. As of September 2017, 45% of patients (five out of 11) randomised to the inhaled L-CsA arm were alive, while 0% of patients (none out of 10) randomised to the SOC-alone arm were alive (p=0.03). Median patient survival was 4.1 years for L-CsA compared with 2.9 years for SOC-alone. b) A comparison of long-term graft survival between the treatment groups. As of September 2017, 45% of patients (five out of 11) randomised to the L-CsA arm were alive and free of re-transplantation (one re-transplantation occurred) compared with 0% of patients (none out of 10) randomised to the SOC-alone arm (three re-transplantations occurred) (p=0.01). Median graft survival was 4.1 years for L-CsA compared with 2.7 years for SOC-alone.\n\nDiscussion\nLung transplant survival is limited and has failed to improve substantially during the past two decades. Bronchiolitis obliterans is a leading cause of death [3]. Inhalation of cyclosporine provides high bronchiolar concentrations and may arrest BOS progression [21]. This initial exploratory randomised controlled open-label trial of L-CsA provides evidence for improvement of BOS defined by the composite end-point, i.e. BOS progression-free survival, with a clinically meaningful improvement at 48 weeks (82% L-CsA versus 50% SOC-alone; p=0.1) and a three-fold arrest of BOS grade progression (p=0.05). Although the difference in BOS progression-free survival was not significant statistically in 21 cases, the clinical magnitude of the benefit, i.e. an absolute difference of 32%, was large. Moreover, comparison of change in BOS grade from randomisation was also impressive, with a two-thirds reduction in L-CsA patients.\n\nL-CsA significantly stabilised FEV1 and FVC compared with SOC-alone. In addition to the intergroup differences in FEV1 decline, the intragroup change in FEV1 slopes differed before and after randomisation in L-CsA, converting from a negative to positive slope; in contrast, SOC-alone controls declined functionally post-randomisation at rates similar to pre-randomisation, demonstrating the characteristic inexorable decline of FEV1 from BOS despite current SOC management without L-CsA [32, 33]. Crossover patients who were off L-CsA but started L-CsA because of ongoing deterioration showed similar FEV1 improvements. Prior investigations of bronchiolitis obliterans using aerosol cyclosporine in propylene glycol, as well as a recent study using inhaled cyclosporine for BOS following haematopoietic stem cell transplantation, have shown similar pulmonary function benefits [20, 26, 34], as have other nonrandomised studies using immunosuppressive therapies for bronchiolitis obliterans [35].\n\nL-CsA resulted in the improvement of long-term survival and graft survival (4.1 versus 2.9 years with SOC-alone), a finding nearly matching an observational cohort study performed at the University of Pittsburgh in the USA in 2005 comparing histological bronchiolitis obliterans patients treated with inhaled cyclosporine to SOC-alone controls (median survival 4.5 versus 2.4 years) [18]. An L-CsA survival benefit was also noted in a randomised double-blind placebo-controlled trial showing bronchiolitis obliterans could be prevented by the addition of aerosolised cyclosporine–propylene glycol [25].\n\nAllograft histology demonstrated reduced severity and frequency of bronchiolar inflammation after L-CsA randomisation but not before randomisation and synchronous levels of IL-2 in BAL were lower in L-CsA cases after but not prior to randomisation [36]. Elevated cyclosporine concentrations in the rejecting lung would explain these findings [21, 28]. Increases in BAL cytokines IFN-γ and IL-10 were also observed in L-CsA patients; IFN-γ regulates cellular proliferation and collagen synthesis, while IL-10 can induce immune tolerance [37, 38].\n\nAlthough the L-CsA and SOC-alone groups were similar with reference to baseline and subsequent BOS treatments, including tacrolimus exposure, immunosuppressive augmentation cycles and azithromycin use [39], the SOC-alone cohort did have significantly higher sirolimus blood levels consistent with physician-directed attempts to control progressing BOS and lung failure. The drug dose of L-CsA was given twice a day to ensure that the beneficial dose of 5 mg would be deposited in the lung allograft. Pharmacokinetics studies demonstrated a low vascular concentration of cyclosporine. Infections and respiratory infections were similar between groups, and L-CsA offered greatly improved tolerability and reduced treatment time with the eFlow nebuliser (10–15 min) compared with cyclosporine–propylene glycol formulations [25]. With increased experience using L-CsA in larger scale trials, systemic immunosuppressive requirements could lessen, as witnessed by reduced sirolimus exposure in L-CsA patients.\n\nIn this small, single-centre trial, the addition of inhaled L-CsA offered a substantial functional benefit without additional toxicity. Due to the exploratory nature of this study, further experience is needed to confirm the magnitude and duration of the observed effects. Patient enrolment for a phase III international multicentre trial using L-CsA for BOS has begun (CliniclaTrials.gov identifiers NCT03657342 and NCT03656926).\n\nSupplementary material\n10.1183/23120541.00167-2019.Supp1Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.\n\nSupplementary material 00167-2019.SUPPLEMENT\n\n Acknowledgements\nJennifer McGrain and Joseph Rinaldi Jr (Dept of Medicine, University of Maryland, Baltimore, MD, USA) provided excellent research coordination and data management support, respectively. The comments of Anthony F. Suffredini (NIH Clinical Center, National Institutes of Health, Bethesda, MD, USA) are gratefully acknowledged, and we thank Si Pham (Mayo Clinic Jacksonville, Jacksonville, FL, USA) for leading the Safety and Monitoring Committee (together with Keshava Rajagopal), and Michelle Ruff (Dept of Medicine, University of Maryland) for excellent administrative assistance.\n\nThis article has supplementary material available from openres.ersjournals.com\n\nThis study is registered at ClinicalTrials.gov with identifier number NCT01650545. Individual participant data will be available after de-identification, including the study protocol, within the first year after article publication. Investigators who propose to use the data will need to be approved by an independent review committee identified for this purpose, for individual participant data for meta-analyses. Proposals may be submitted up to 24 months following article publication.\n\nAuthor contributions: A. Iacono, B Griffith and M. Terrin contributed to the conception and design of this study, interpreted results, and performed or assisted with the writing and the final proofing of the article to completion. I. Timofte, K. Rajagopal, M. Wijesinha and N. Murdock formulated specific databases for data interpretation, performed the final statistical analyses and commented on all study results formally, and also revised the manuscript critically for essential intellectual content. All authors gave final approval of the manuscript to be published, and agree to be accountable for data integrity and all other essential aspects.\n\nSupport statement: We are grateful to PARI Pharma GmbH for drug and device supply for this investigation, and a research grant to the University of Maryland School of Medicine; the IPF Foundation for nursing support; and the Plylar and Riehl Foundations for generously supporting the Lung Healing Center for overall study support. Funding information for this article has been deposited with the Crossref Funder Registry.\n\nConflict of interest: A. Iacono reports grants from PARI Pharmaceutical outside the submitted work. In addition, he has a patent for the “Use of Aerosolized Cyclosporine for Prevention and Treatment of Pulmonary Disease” issued and is Chairman for an upcoming phase III trial “Inhaled Liposomal Cyclosporine A (L-CsA) for the treatment of Bronchiolitis Obliterans (BO)”.\n\nConflict of interest: M. Wijesinha has nothing to disclose.\n\nConflict of interest: K. Rajagopal has nothing to disclose.\n\nConflict of interest: N. Murdock has nothing to disclose.\n\nConflict of interest: I. Timofte has nothing to disclose.\n\nConflict of interest: B. Griffith has nothing to disclose.\n\nConflict of interest: M. 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Semin Thorac Cardiovasc Surg \n2004 ; 16 : 350 –355 .15635539 \n5 Knoop C , Haverich A , Fischer S \nImmunosuppressive therapy after human lung transplantation . Eur Respir J \n2004 ; 23 : 159 –171 .14738248 \n6 Snyder LD , Hartwig MG , Ganous T , et al. \nCytokine gene polymorphisms are not associated with bronchiolitis obliterans syndrome or survival after lung transplant . J Heart Lung Transplant \n2006 ; 25 : 1330 –1335 .17097497 \n7 Kahan BD \nCyclosporine . N Engl J Med \n1989 ; 321 : 1725 –1738 .2687689 \n8 Belperio JA , Weigt SS , Fishbein MC , et al. \nChronic lung allograft rejection: mechanisms and therapy . Proc Am Thorac Soc \n2009 ; 6 : 108 –121 .19131536 \n9 Duncan SR , Leonard C , Theodore J , et al. \nOligoclonal CD4+ T cell expansions in lung transplant recipients with obliterative bronchiolitis . Am J Respir Crit Care Med \n2002 ; 165 : 1439 –1444 .12016109 \n10 Duncan SR , Valentine V , Roglic M , et al. \nT cell receptor biases and clonal proliferations among lung transplant recipients with obliterative bronchiolitis . J Clin Invest \n1996 ; 97 : 2642 –2650 .8647959 \n11 O'Riordan TG , Duncan SR , Burckart GJ , et al. \nProduction of an aerosol of cyclosporine as a prelude to clinical studies . J Aerosol Med \n1992 ; 5 : 171 –177 .\n12 O'Riordan TG , Iacono A , Keenan RJ , et al. \nDelivery and distribution of aerosolized cyclosporine in lung allograft recipients . Am J Respir Crit Care Med \n1995 ; 151 : 516 –521 .7842214 \n13 Behr J , Zimmermann G , Baumgartner R , et al. \nLung deposition of a liposomal cyclosporine A inhalation solution in patients after lung transplantation . J Aerosol Med Pulm Drug Deliv \n2009 ; 22 : 121 –130 .19422312 \n14 Muggenburg BA , Hoover MD , Griffith BP , et al. \nAdministration of cyclosporine by inhalation: a feasibility study in beagle dogs . J Aerosol Med \n1990 ; 3 : 1 –13 .\n15 Mitruka SN , Won A , McCurry KR , et al. \nIn the lung aerosol cyclosporine provides a regional concentration advantage over intramuscular cyclosporine . J Heart Lung Transplant \n2000 ; 19 : 969 –975 .11044692 \n16 Dowling RD , Zenati M , Burckart GJ , et al. \nAerosolized cyclosporine as single-agent immunotherapy in canine lung allografts . Surgery \n1990 ; 108 : 198 –204 .2382220 \n17 Keenan RJ , Duncan AJ , Yousem SA , et al. \nImproved immunosuppression with aerosolized cyclosporine in experimental pulmonary transplantation . Transplantation \n1992 ; 53 : 20 –25 .1733067 \n18 Iacono AT , Corcoran TE , Griffith BP , et al. \nAerosol cyclosporin therapy in lung transplant recipients with bronchiolitis obliterans . Eur Respir J \n2004 ; 23 : 384 –390 .15065826 \n19 Iacono AT , McCurry KR , Corcoran TE \nInhalation cyclosporine: a new use in lung transplantation? \nCurr Opin Organ Transplant \n2003 ; 8 : 327 –333 .\n20 Iacono AT , Keenan RJ , Duncan SR , et al. \nAerosolized cyclosporine in lung recipients with refractory chronic rejection . Am J Respir Crit Care Med \n1996 ; 153 : 1451 –1455 .8616581 \n21 Corcoran TE , Smaldone GC , Dauber JH , et al. \nPreservation of post-transplant lung function with aerosol cyclosporin . Eur Respir J \n2004 ; 23 : 378 –383 .15065825 \n22 Keenan RJ , Zeevi A , Iacono AT , et al. \nEfficacy of inhaled cyclosporine in lung transplant recipients with refractory rejection: correlation of intragraft cytokine gene expression with pulmonary function and histologic characteristics . Surgery \n1995 ; 118 : 385 –391 .7638755 \n23 Keenan RJ , Iacono A , Dauber JH , et al. \nTreatment of refractory acute allograft rejection with aerosolized cyclosporine in lung transplant recipients . J Thorac Cardiovasc Surg \n1997 ; 113 : 335 –340 .9040628 \n24 Iacono A , Dauber J , Keenan R , et al. \nInterleukin 6 and interferon-gamma gene expression in lung transplant recipients with refractory acute cellular rejection: implications for monitoring and inhibition by treatment with aerosolized cyclosporine . Transplantation \n1997 ; 64 : 263 –269 .9256185 \n25 Iacono AT , Johnson BA , Grgurich WF , et al. \nA randomized trial of inhaled cyclosporine in lung-transplant recipients . N Engl J Med \n2006 ; 354 : 141 –150 .16407509 \n26 Groves S , Galazka M , Johnson B , et al. \nInhaled cyclosporine and pulmonary function in lung transplant recipients . J Aerosol Med Pulm Drug Deliv \n2010 ; 23 : 31 –39 .19580368 \n27 Iacono AT , Smaldone GC , Keenan RJ , et al. \nDose-related reversal of acute lung rejection by aerosolized cyclosporine . Am J Respir Crit Care Med \n1997 ; 155 : 1690 –1698 .9154878 \n28 Corcoran TE , Niven R , Verret W , et al. \nLung deposition and pharmacokinetics of nebulized cyclosporine in lung transplant patients . J Aerosol Med Pulm Drug Deliv \n2014 ; 27 : 178 –184 .23668548 \n29 Verleden GM , Raghu G , Meyer K , et al. \nA new classification system for chronic lung allograft dysfunction . J Heart Lung Transplant \n2014 ; 33 : 127 –133 .24374027 \n30 Glanville A , Verleden GM , Todd J , et al. \nChronic lung allograft dysfunction: definition and update of restrictive allograft syndrome – a consensus report from the Pulmonary Council of the ISHLT . J Heart Lung Transplant \n2019 ; 38 : 483 –492 .31027539 \n31 Laird NM , Ware JH \nRandom-effects models for longitudinal data . Biometrics \n1982 ; 38 : 963 –974 .7168798 \n32 Song MK , De Vito Dabbs A , Studer SM , et al. \nCourse of illness after the onset of chronic rejection in lung transplant recipients . Am J Crit Care \n2008 ; 17 : 246 –253 .18450681 \n33 Lama VN , Murray S , Lonigro RJ , et al. \nCourse of FEV1 after onset of bronchiolitis obliterans syndrome in lung transplant recipients . Am J Respir Crit Care Med \n2007 ; 175 : 1192 –1198 .17347496 \n34 Gormley N , Ramos C , Reger R , et al. \nInhaled cyclosporine for the treatment of bronchiolitis obliterans following hematopoietic stem cell transplantation (HSCT) or lung transplantation . Blood \n2013 ; 122 : 2057 .\n35 Moniodis A , Townsend K , Rabin A , et al. \nComparison of extracorporeal photopheresis and alemtuzumab for the treatment of chronic lung allograft dysfunction . J Heart Lung Transplant \n2018 ; 37 : 340 –348 .28431983 \n36 Albring A , Wendt L , Harz N , et al. \nRelationship between pharmacokinetics and pharmacodynamics of calcineurin inhibitors in renal transplant patients . Clin Transplant \n2015 ; 29 : 294 –300 .25557538 \n37 Antoniou KM , Nicholson AG , Dimadi M , et al. \nLong-term clinical effects of interferon gamma-1b and colchicine in idiopathic pulmonary fibrosis . Eur Respir J \n2006 ; 28 : 496 –504 .16611657 \n38 Moore KW , de Waal Malefyt R , Coffman RL , et al. \nInterleukin-10 and the interleukin-10 receptor . Annu Rev Immunol \n2001 ; 19 : 683 –765 .11244051 \n39 Brenden C , Haughton M , Leonard S , et al. \nTherapy options for chronic lung allograft dysfunction–bronchiolitis obliterans syndrome following first-line immunosuppressive strategies: a systematic review . J Heart Lung Transplant \n2017 ; 36 : 921 –933 .28662986\n\n",
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"title": "A randomised single-centre trial of inhaled liposomal cyclosporine for bronchiolitis obliterans syndrome post-lung transplantation.",
"title_normalized": "a randomised single centre trial of inhaled liposomal cyclosporine for bronchiolitis obliterans syndrome post lung transplantation"
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"abstract": "Gigantomastia is an abnormal and rare breast condition characterized by excessive breast tissue growth that can result in physical and psychosocial debilitation. While the etiology is not fully understood, it is postulated that abnormal endogenous hormone stimulation plays a contributory role and often requires mastectomy for definitive treatment. Proliferation of all elements is commonly observed, including glands, ducts, stroma, fat, vessels and skin. Pseudoangiomatous stromal hyperplasia (PASH) is an additional benign breast disease defined microscopically by proliferation of mammary stroma. PASH often clinically presents as an incidental finding while evaluating other benign or malignant lesions, or less commonly as a palpable, well-circumscribed breast mass. Uncommon cases have been reported in which PASH presents as a bilateral, diffuse process. In this case presentation, we report a rare case of a 20-year-old woman presenting with acute onset gigantomastia most likely due to diffuse PASH.",
"affiliations": "University of California San Francisco, Department of Radiology and Biomedical Imaging, 1825 4th St, San Francisco, CA 94158, USA. Electronic address: Shrilakshmi.vyas@ucsf.edu.;University of California San Francisco, Department of Radiology and Biomedical Imaging, 1825 4th St, San Francisco, CA 94158, USA. Electronic address: Heather.greenwood@ucsf.edu.;University of California San Francisco, UCSF, Department of Pathology, 505 Parnassus Avenue, San Francisco, CA 94143, USA. Electronic address: Tyler.jankowski@ucsf.edu.;University of California San Francisco, Department of Radiology and Biomedical Imaging, 1825 4th St, San Francisco, CA 94158, USA. Electronic address: Rita.freimanis@ucsf.edu.;University of California San Francisco, Department of Radiology and Biomedical Imaging, 1825 4th St, San Francisco, CA 94158, USA. Electronic address: Kimberly.kallianos@ucsf.edu.;University of California San Francisco, Department of Radiology and Biomedical Imaging, 1825 4th St, San Francisco, CA 94158, USA. Electronic address: Travis.henry@ucsf.edu.;University of California San Francisco, Department of Radiology and Biomedical Imaging, 1825 4th St, San Francisco, CA 94158, USA. Electronic address: Loretta.strachowski@ucsf.edu.",
"authors": "Vyas|Shrilakshmi|S|;Greenwood|Heather I|HI|;Jankowski|Tyler|T|;Freimanis|Rita I|RI|;Kallianos|Kimberly G|KG|;Henry|Travis S|TS|;Strachowski|Loretta M|LM|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1016/j.clinimag.2020.06.020",
"fulltext": null,
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"issn_linking": "0899-7071",
"issue": "68()",
"journal": "Clinical imaging",
"keywords": "Benign breast disease; Gigantomastia; Pseudoangiomatous stromal hyperplasia (PASH)",
"medline_ta": "Clin Imaging",
"mesh_terms": "D000328:Adult; D000798:Angiomatosis; D001940:Breast; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D006965:Hyperplasia; D006984:Hypertrophy; D008408:Mastectomy; D055815:Young Adult",
"nlm_unique_id": "8911831",
"other_id": null,
"pages": "57-60",
"pmc": null,
"pmid": "32570010",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of acute onset gigantomastia in a 20-year-old woman.",
"title_normalized": "a case of acute onset gigantomastia in a 20 year old woman"
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"abstract": "and importance: WAGR syndrome is a rare genetic disorder consist of Wilms tumor, Aniridia, Genitourinary abnormalities, and Intellectual disability. During the enduring COVID-19 pandemic, it has become extremely important to document the properties of SARS-CoV-2 and its interactions with other diseases. Herein, we present the first case of Syrian child with WAGR syndrome that has been affected by COVID-19.\na 17-month-old boy was diagnosed with WAGR syndrome. During the follow-up, he developed rhinorrhea, cough, and moderate dyspnea with no fever. Computed tomography scan was normal and polymerase chain reaction test was positive. The child started an oxygen therapy with broad-spectrum antibiotics based on laboratory findings. His vital signs and laboratory values improved gradually without any further complications.\nCOVID-19 has a special interest regarding its course in children. Although the clinical presentation varies, the current data reveal a better prognosis in children.\nSARS-CoV-2 infection may result in non-specific symptoms and normal CT scan findings in children with WAGR syndrome. The accurate diagnosis, effective isolation and monitoring of the child, and successful management can improve the prognosis and shorten the infection period.",
"affiliations": "Faculty of Medicine, Damascus University, Damascus, Syria.;Faculty of Medicine, Damascus University, Damascus, Syria.;Faculty of Medicine, Damascus University, Damascus, Syria.;Bachelor of Pharmacy, Damascus University, Damascus, Syria.;Department of Pathology, Faculty of Medicine, Tishreen University, Lattakia, Syria.;Faculty of Medicine, Damascus University, Damascus, Syria.",
"authors": "Jomaa|Sami|S|;Shubat|Dana|D|;AlTabban|Mamdoh|M|;Abdullah|Ibrahim|I|;Ismail|Sawsan|S|;Khouri|Lina|L|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.amsu.2021.102732",
"fulltext": "\n==== Front\nAnn Med Surg (Lond)\nAnn Med Surg (Lond)\nAnnals of Medicine and Surgery\n2049-0801\nElsevier\n\nS2049-0801(21)00682-8\n10.1016/j.amsu.2021.102732\n102732\nCase Report\nSequences of COVID-19 in a child with WAGR syndrome: A case report\nJomaa Sami sami.jomaa1997@gmail.com\na∗\nShubat Dana shubatdana@gmail.com\na\nAlTabban Mamdoh Mamdoh962011@gmail.com\na\nAbdullah Ibrahim Ibrahim.Ay.Abdullah@gmail.com\nbc\nIsmail Sawsan sawsanismail8@gmail.com\nd\nKhouri Lina linakhouri60@yahoo.com\nae\na Faculty of Medicine, Damascus University, Damascus, Syria\nb Bachelor of Pharmacy, Damascus University, Damascus, Syria\nc Genetics and Bioinformatics Association, Syria\nd Department of Pathology, Faculty of Medicine, Tishreen University, Lattakia, Syria\ne Program Director of Children University Hospital, Damascus University, Children University Hospital, Damascus, Syria\n∗ Corresponding author. sami.jomaa1997@gmail.com\n17 8 2021\n9 2021\n17 8 2021\n69 1027324 7 2021\n14 8 2021\n15 8 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nIntroduction\n\nand importance: WAGR syndrome is a rare genetic disorder consist of Wilms tumor, Aniridia, Genitourinary abnormalities, and Intellectual disability. During the enduring COVID-19 pandemic, it has become extremely important to document the properties of SARS-CoV-2 and its interactions with other diseases. Herein, we present the first case of Syrian child with WAGR syndrome that has been affected by COVID-19.\n\nCase presentation\n\na 17-month-old boy was diagnosed with WAGR syndrome. During the follow-up, he developed rhinorrhea, cough, and moderate dyspnea with no fever. Computed tomography scan was normal and polymerase chain reaction test was positive. The child started an oxygen therapy with broad-spectrum antibiotics based on laboratory findings. His vital signs and laboratory values improved gradually without any further complications.\n\nDiscussion\n\nCOVID-19 has a special interest regarding its course in children. Although the clinical presentation varies, the current data reveal a better prognosis in children.\n\nConclusion\n\nSARS-CoV-2 infection may result in non-specific symptoms and normal CT scan findings in children with WAGR syndrome. The accurate diagnosis, effective isolation and monitoring of the child, and successful management can improve the prognosis and shorten the infection period.\n\nHighlights\n\n• WAGR syndrome is a rare genetic disorder that consists of Wilms tumor, aniridia, genitourinary anomalies, and mental retardation.\n\n• COVID-19 may manifest with non-specific symptoms with unremarkable CT scan findings in children with WAGR syndrome.\n\n• COVID-19 accurate diagnosis, effective isolation and monitoring, and proper management can improve the prognosis and shorten the infection period.\n\n• COVID-19 may have no effects on renal function in patients with WAGR syndrome.\n\nKeywords\n\nCOVID-19\n2019-nCoV disease\nWAGR syndrome\nChildren\nCase report\n==== Body\nGrantor\n\nSami Jomaa.\n\n1 Introduction\n\nIn December 2019, an outbreak of unexplained pneumonia emerged in China. Studies have exposed that it was first recorded in a local seafood market in Wuhan, China [1]. Later, the World Health Organization (WHO) stated the burst of a rapidly expanding pandemic termed coronavirus disease (COVID-19) caused by a novel virus named the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) [2].\n\nThe limited data about its impact on children, especially those with underlying diseases, has raised concerns [3]. Studies have revealed that children have a more desirable SARS-CoV-2 infection pattern and a better prognosis than adults [[4], [5], [6]]. However, a rigorous course of COVID-19 may develop in children with underlying chronic diseases such as immune deficiencies, malignancies, and asthma due to the continued systemic inflammation [6]. Moreover, the literature reported variant outcomes of children who were infected with SARS-CoV-2 and had a previous underlying disease, including congenital heart disease, prematurity, hydronephrosis, Down syndrome, and 18q deletion syndrome [3].\n\nTo provide more data about COVID-19 and whether it is associated with a more severe course in children with relatively rare diseases or not, we present the first case of a child with WAGR syndrome who was infected with SARS-CoV-2 during the period he was being prepared for the surgery and adjuvant chemotherapy.\n\nThis case report has been reported in line with the SCARE 2020 criteria [7].\n\n2 Presentation of case\n\nA 17-month-old male is brought to our department due to abdominal distension for the last three months. His parents said that “he failed to gain weight gain despite his normal appetite”. The child was born at term without any pregnancy-related complications. His weight at birth was 2.5 kg. He has been receiving his vaccines according to the National Vaccination Program. He looked very stiff, with tight muscles. He cannot walk nor respond to sounds around him. He cannot say a single word (e.g., mama or dada) or gain new ones. He shows no affection for his parents. He does not point to show things to others and does not copy others. His medical, surgical, and familial history was unremarkable. The parents mentioned being third-degree blood relatives. On admission, the child's weight and height were 7.3 kg and 70 cm, respectively. He was afebrile and had no signs of fatigue. He had a mild pallor with no history of vomiting or diarrhea. His blood pressure was 140/80 mmHg. A complete absence of bilateral iris with severe horizontal nystagmus and medial strabismus in the right eye was observed (Fig. 1). Fundal microscopy revealed typical findings without any abnormalities.Fig. 1 Shows a complete bilateral absence of iris.\n\nFig. 1\n\nClinical examination revealed a firm mass in the upper right quadrant, a right inguinal hernia, a subcoronal hypospadias, a small penis circumcised, and an absent right testicle (Fig. 4). No lymphadenopathy was determined. We also detected a right-sided flat foot (Fig. 2) with overlapped toes (Fig. 3). Laboratory tests revealed mild microcytic anemia (RBCs: 5.03 × 106/μl; Hemoglobin: 10.3 g/dl; MCV: 69 fl), a decreased platelet count (175 × 103/μl), a normal WBC count (11000 × 103/μl; Neutrophils: 49%; Lymphocytes: 44%), and normal kidney functional tests (creatinine: 0.4 mg/dL, urea: 18 mg/dL). Lab results also revealed elevated levels of FHS (0.41 mIU/ml: normal up to 0.20 mIU/ml) and decreased 17-hydroxyprogesterone levels (0.356 ng/ml: normal 0.50–2.4 ng/ml). LH and testosterone levels were within the reference range, 0.518 mIU/ml and 13.60 ng/dL, respectively. Pelvic ultrasound showed a mass measures 9.9 × 7.5 cm with clear borders and regular edges embracing most of the right kidney, pushing the inferior surface of the liver superiorly, and comply with Wilms tumor. A right migratory testicle in the right inguinal canal measuring 0.45 × 1.95 cm was observed. A normal shaped and positioned right kidney without hydronephrosis, calcifications, or stones was observed. Furthermore, a right inguinal hernia was detected. Computed tomography (CT) scan revealed a mass on the right kidney measures 9.9 × 7.5 cm (Fig. 5), with no other lesions.Fig. 2 Shows a right-sided flat foot.\n\nFig. 2\n\nFig. 3 Exposes a right-sided overlapped toes.\n\nFig. 3\n\nFig. 4 Shows a small penis and an absent right testicle.\n\nFig. 4\n\nFig. 5 Exhibits a mass on the right kidney measures 9.9 × 7.5 cm.\n\nFig. 5\n\nWe established our diagnosis with WAGR syndrome based on the clinical findings (Wilms tumor; Aniridia; Genitourinary anomalies; Mental Retardation) rather than the genetic testing; it was unavailable in our hospital, and the child parents cannot afford its expensive cost in a private center. However, aniridia and one or more other anomalies can confirm the diagnosis if genetic confirmation was unavailable.\n\nDuring his follow-up and tuition for surgery, the child developed rhinorrhea, cough, and moderate dyspnea with substernal and subcostal retractions. The child was afebrile with no signs of cyanosis. Lung auscultation exposed fine bilateral crackles. A new chest CT scan was obtained, and the findings were unremarkable (Fig. 6). Based on the clinical features, we isolated the child, initiated oxygen therapy, and took a nasal swab to test for SARA-CoV-2 infection, which reported a positive result. Laboratory examinations at the isolation ward revealed elevated white blood cells (WBC) (16.4 × 103/μl; Neutrophils: 60%; Lymphocytes: 31%), platelets (484 × 103/μl), C-reactive protein (CRP) (9.66 mg/dL), fibrinogen (978 mg/dL), and D-dimer levels (203 ng/ml), with mild anemia (RBC: 4.40 × 106/μl; Hemoglobin 9.7 g/dl; MCV: 69 fl). His room-air oxygen saturation ranged between 84 and 86% and increased to 96–97% with an oxygen face mask. Due to the high procalcitonin levels (0.32 ng/ml) – which suggest a superimposed infection – we initiated therapy with broad-spectrum antibiotics, Vancomycin and Ceftriaxone; prednisolone was given as needed.Fig. 6 Reveals a normal CT scan in a positive SARS-CoV-2 child.\n\nFig. 6\n\nDuring the isolation, the child was in hemodynamic stability and has experienced neither a cardiovascular collapse nor thromboembolic events. His lungs auscultation, laboratory values, and oxygen saturation were improving gradually. Eight days after the isolation, his symptoms receded, lungs were clear to auscultation, CRP (0.4 mg/dL), Procalcitonin (0.14 ng/ml), D-dimer (136 ng/dL), Fibrinogen (246 mg/dL), and platelets (380 × 103/μl) levels return to normal levels, WBC count declined (11.7 × 103/μl; Neutrophils: 52.9%; Lymphocytes: 38.3%), anemia was improved (RBC: 5.20 × 103/μl; Hb: 12 g/dl; MCV: 73.4 fl), and oxygen saturation levels were stable. Based on the clinical and laboratory findings, we discharged the child and asked his parents to continue a 14-day quarantine at home. It is worth noting that the child was infected with coronavirus early in 2021, before the emergent of the Delta variant.\n\nAfter two weeks, his parents brought him to resume his treatment plan. He appeared to be in a stable condition, with regular vital signs. He received neoadjuvant chemotherapy for four weeks – then underwent a laparotomy under general anesthesia. We observed a large mass at the expense of the right kidney and spread outside the kidney into nearby tissue. We performed a right nephrectomy with periaortic lymph node dissection while preserving the right adrenal gland. Gross examination of the excised mass revealed a necrotic mass measuring 14 × 10 × 9 cm. Histologic exam (Fig. 7) demonstrated a neoplastic proliferation consisting of three components, blastemal, epithelial, and stromal elements. The blastemal component is demarcated by the overgrowth of undifferentiated small to intermediate-sized cells with relatively small regular nuclei and small nucleoli. The epithelium consists of well-differentiated glomerular-like structures and trivial, mature tubules. Finally, the stroma is defined by spindle cells with oval to spindle-shaped nuclei and bland nucleoli, in addition to areas of necrosis. No residual tumor is apparent at or beyond the margins of excision, which results in a stage 2b tumor according to the NWTS grading system which used in our hospital.Fig. 7 A histologic images reveal the three components of Wilms' tumor. A: blastema consists of small to small-to medium-sized, round, blue, undifferentiated cells with relatively small regular nuclei and nucleoli cell. B: well-differentiated epithelial cells consist of glomerular-like structures and small, mature tubules. C: stromal cells showing no clear cell borders, oval to spindle-shaped nuclei with bland nucleoli. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 7\n\nThe child received adjuvant chemotherapy consists of actinomycin D and vincristine for 28 weeks to eliminate any possible remaining cancer cells. CT scan was conducted six months later and revealed no signs of tumor relapse or metastasis. The right kidney did not show cortical thinning or other abnormalities. The patient suffered from vomiting, diarrhea, and hair loss, with a mild decrease in total blood count elements due to the adverse effects of chemotherapy. Kidney function tests were unremarkable, and the child has not experienced oliguria or hematuria. That implies COVID-19 may have no impact on the conventional prognosis of the underlying disease. However, long-term follow-up of renal function is mandatory.\n\n3 Discussion\n\nOur case presents the first case of WAGR syndrome accompanied by SARS-CoV-2 infection. WAGR syndrome (Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation) is a rare genetic disorder marked by a predisposition to several conditions, including malignancies, eye abnormalities, and intellectual disability [8]. WAGR syndrome presents in various clinical pictures based on genes involvement, BDNF, WT1, and PAX6 mutations [9].\n\nWilms tumor is the most common renal tumor in children accounts for 6% of all childhood malignancies. It manifests with an abdominal mass, fatigue, anorexia, and weight loss. It is usually managed by transabdominal radical nephrectomy followed by chemotherapy consisting of actinomycin D and vincristine [10,11]. Studies have revealed that patients with unilateral Wilms tumor are less likely to develop a contralateral renal failure. Nevertheless, hyperfiltration injury and subsequent microalbuminuria are relatively common [10].\n\nAniridia is a rare condition with incidence ranges between 1:47,000 and 1:100,000 [12]. Due to the pan ocular effects of deletion of the PAX6 gene, most individuals with WAGR syndrome will suffer from moderate to severe visual impairment secondary to aniridia such as cataracts, glaucoma, nystagmus, or strabismus [8].\n\nGenitourinary anomalies are more frequent in males, cryptorchidism being the most common anomaly [13]. Hypospadias and inguinal hernia also have been reported [8]. Interestingly, the previous three abnormalities were found together in our case.\n\nFurthermore, musculoskeletal deformities have also been reported in patients with WAGR syndrome and presented with hypertense Achilles, scoliosis, kyphosis, metatarsal adductus, and talipes [8]. To our knowledge, this is the first report of a child with WAGR syndrome presenting with unilateral, right-sided overlapping toes and a flat foot. Genetic confirmation embraces WT1 and PAX6 gene involvement [9], whereas the clinical picture requires aniridia and one or more of the other anomalies [8].\n\nDuring the COVID-19 pandemic, cases have been reported about children with SARS-CoV-2 infection and genetic syndromes, including Down syndrome, 18q deletion syndrome, and several unspecified genetic syndromes [3]. To the best of our knowledge, this is the first case in which SARS-CoV-2 infects a child who was diagnosed with WAGR syndrome during his follow-up and preparing for the management period.\n\nStudies have shown that children have a more favorable prognosis compared to adults [4,5]. According to research data, children have an increased activity of the angiotensin-converting enzyme (ACE2); that may protect them against severe SARS-CoV-2 infection [6].\n\nSince children often have frequent viral respiratory tract infections, it is possible that they were infected with one of the other common coronavirus strains when they have been recently vaccinated with live vaccines in their community, including Bacillus Calmette-Guerin, which can protect them from infection [6,14]. Because the immune system in children is not mature enough to trigger the cytokines storm, the symptoms tend to be less in severity [15]. Children tend to be less infectious as they have a lower viral load [6]. We believe that our patient got the virus from his community during the follow-up, as more than 95% of SARS-CoV-2 infections in infants had a community source [14].\n\nChildren exhibit a discrepancy in their presentation. Nonspecific symptoms of upper respiratory tract infection being the most frequent [6]. A systematic review of 38 studies reported that a total of 1117 infected children, 14.2% were asymptomatic, and about half of the patients experienced fever or cough [5]. Alternatively, rhinorrhea, nasal congestion, and respiratory distress are less frequent [5]. Another systematic review and meta-analysis of 65 studies have described the clinical symptoms of 1214 children; fever and upper respiratory symptoms were the most common, and their incidence rates were 38% and 35%, respectively [14]. According to a review, children's loss of scent is an uncommon symptom [5]. Although fever is the most common symptom, it can be within the normal range in some infected children as our patient. These findings suggest that COVID-19 symptoms are nonspecific and span from asymptomatic to extreme conditions.\n\nPolymerase Chain Reaction (PCR) testing of the nasopharyngeal swab constitutes the gold standard diagnostic method for COVID-19 [15]. Furthermore, positive PCR children may reveal normal findings on CT scan [16].\n\nWhile the decrease in WBC count is common [15], a systematic review of 174 cases has reported that it can be elevated, decreased, or within the normal range [5]. Tow systematic reviews have shown that CRP and procalcitonin levels were increased in 13.6% and 10.6% of cases [17], and 19.3% and 49.8% of cases, respectively [5]. Contrary, another review has reported that CRP and procalcitonin levels are usually normal [15].\n\nA systematic review and meta-analysis of 1214 infected children reported that many children admitted to the hospitals had a mild progression of symptoms [14]. The primary reason for admission was for isolation commitments rather than consequences of the intensity of their medical situation [14]. Monitoring vital signs and providing oxygen through a high-flow nasal cannula, noninvasive ventilation, or ventilators are part of the management protocol [15,17]. A systematic review and meta-analysis have revealed that 22 of 354 patients received oxygen therapy, while only four required invasive ventilator support [14]. Blood tests and chest X-rays are necessary for follow-up [15,17]. Antibiotics can only be used for superimposed infections, not for empirical management. In severe cases, antiviral drugs are recommended [15,17].\n\nTo date, this is the first case report that describes the aligning of COVID-19 with a child diagnosed with WAGR syndrome. A unique systematic review has delineated the features of children with comorbidities and who were diagnosed with COVID-19 [3]. The outcomes have revealed that a small proportion of infected children with comorbidities face a higher risk of severe disease [3]. The most common comorbidities observed were chronic cardiac disease, diabetes mellitus, non-asthmatic chronic lung disease, asthma, and obesity [3].\n\n4 Conclusion\n\nCOVID-19 still has concerns regarding its symptoms, prognosis, and outcomes in children, especially those with underlying chronic or rare diseases, such as WAGR syndrome. SARS-CoV-2 infection may result in non-specific symptoms (e.g., rhinorrhea, cough, and dyspnea) and normal CT scan findings in children with rare diseases. Moreover, the presence of fever is not predominant. However, the accurate diagnosis with PCR, effective isolation and monitoring of the child, and appropriate management can improve the prognosis and shorten the infection period.\n\nDeclarations\n\nConflicts of interest\n\nThe authors declared that they have no conflict of interest.\n\nEthical approval\n\nEthical approval was not required.\n\nSources of funding\n\nNo funding is required.\n\nAuthor contribution\n\nSJ obtained the information of this case. SJ, DS, MA, and IA drafted the manuscript. LK and SI revised the final draft. LK was the supervisor of this work. Registration of Research Studies: This is not an original research project involving human participants in an interventional or an observational study but a case report. This registration was not required.\n\nConsent of patient\n\nWritten informed consent was obtained from the child's parents for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nProvenance and peer review\n\nNot commissioned, externally peer-reviewed.\n\nAcknowledgment\n\nWe are grateful for Dr. Najdat Nameh and Dr. Shaimaa Khallouf as they facilitate and provide important information during the revision process.\n==== Refs\nReferences\n\n1 Li X. Song Y. Wong G. Cui J. Bat origin of a new human coronavirus: there and back again Sci. China Life Sci. 63 3 2020 461 462 32048160\n2 Li M. Chen L. Zhang J. Xiong C. Li X. The SARS-CoV-2 receptor ACE2 expression of maternal-fetal interface and fetal organs by single-cell transcriptome study PloS One 15 4 2020 e0230295\n3 Williams N. Radia T. Harman K. Agrawal P. Cook J. Gupta A. COVID-19 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children and adolescents: a systematic review of critically unwell children and the association with underlying comorbidities Eur. J. Pediatr. 180 3 2021 689 697 32914200\n4 Mehta N.S. Mytton O.T. Mullins E.W.S. Fowler T.A. Falconer C.L. Murphy O.B. Langenberg C. Jayatunga W.J.P. Eddy D.H. Nguyen-Van-Tam J.S. SARS-CoV-2 (COVID-19): what do we know about children? A systematic review Clin. Infect. Dis. 71 9 2020 2469 2479 32392337\n5 de Souza T.H. Nadal J.A. Nogueira R.J.N. Pereira R.M. Brandão M.B. Clinical manifestations of children with COVID-19: a systematic review Pediatr. Pulmonol. 55 8 2020 1892 1899 32492251\n6 Aygün D. Önal P. Apaydın G. Çokuğraş H. Coronavirus infections in childhood and vaccine studies Turk Arch Pediatr 56 1 2021 10 14 34013223\n7 Agha R.A. Franchi T. Sohrabi C. Mathew G. Kerwan A. Thoma A. Beamish A.J. Noureldin A. Rao A. Vasudevan B. Challacombe B. Perakath B. Kirshtein B. Ekser B. Pramesh C.S. Laskin D.M. Machado-Aranda D. Miguel D. Pagano D. Millham F.H. Roy G. Kadioglu H. Nixon I.J. Mukhejree I. McCaul J.A. Chi-Yong Ngu J. Albrecht J. Rivas J.G. Raveendran K. Derbyshire L. Ather M.H. Thorat M.A. Valmasoni M. Bashashati M. Chalkoo M. Teo N.Z. Raison N. Muensterer O.J. Bradley P.J. Goel P. Pai P.S. Afifi R.Y. Rosin R.D. Coppola R. Klappenbach R. Wynn R. De Wilde R.L. Surani S. Giordano S. Massarut S. Raja S.G. Basu S. Enam S.A. Manning T.G. Cross T. Karanth V.K.L. Kasivisvanathan V. Mei Z. The SCARE 2020 guideline: updating consensus surgical CAse REport (SCARE) guidelines Int. J. Surg. 84 2020 226 230 33181358\n8 Fischbach B.V. Trout K.L. Lewis J. Luis C.A. Sika M. WAGR syndrome: a clinical review of 54 cases Pediatrics 116 4 2005 984 988 16199712\n9 Hol J.A. Jongmans M.C.J. Sudour-Bonnange H. Ramírez-Villar G.L. Chowdhury T. Rechnitzer C. Pal N. Schleiermacher G. Karow A. Kuiper R.P. de Camargo B. Avcin S. Redzic D. Wachtel A. Segers H. Vujanic G.M. van Tinteren H. Bergeron C. Pritchard-Jones K. Graf N. van den Heuvel-Eibrink M.M. Clinical characteristics and outcomes of children with WAGR syndrome and Wilms tumor and/or nephroblastomatosis: the 30-year SIOP-RTSG experience Cancer 127 4 2021 628 638 33146894\n10 Bhutani N. Kajal P. Sharma U. Many faces of Wilms Tumor: recent advances and future directions Ann Med Surg (Lond) 64 2021 102202 33747498\n11 Green D.M. Breslow N.E. Beckwith J.B. Ritchey M.L. Shamberger R.C. Haase G.M. D'Angio G.J. Perlman E. Donaldson M. Grundy P.E. Weetman R. Coppes M.J. Malogolowkin M. Shearer P. Coccia P. Kletzel M. Thomas P.R. Macklis R. Tomlinson G. Huff V. Newbury R. Weeks D. Treatment with nephrectomy only for small, stage I/favorable histology Wilms' tumor: a report from the National Wilms' Tumor Study Group J. Clin. Oncol. 19 17 2001 3719 3724 11533093\n12 Netland P.A. Scott M.L. Boyle J.W.t. Lauderdale J.D. Ocular and systemic findings in a survey of aniridia subjects J aapos 15 6 2011 562 566 22153401\n13 Shimamura Y. Okamoto T. Abe K. Takuto M. Ogawa Y. Takizawa H. WAGR syndrome Kidney Int. 99 1 2021 271 33390234\n14 Bhuiyan M.U. Stiboy E. Hassan M.Z. Chan M. Islam M.S. Haider N. Jaffe A. Homaira N. Epidemiology of COVID-19 infection in young children under five years: a systematic review and meta-analysis Vaccine 39 4 2021 667 677 33342635\n15 De Rose D.U. Piersigilli F. Ronchetti M.P. Santisi A. Bersani I. Dotta A. Danhaive O. Auriti C. Novel Coronavirus disease (COVID-19) in newborns and infants: what we know so far Ital. J. Pediatr. 46 1 2020 56 32349772\n16 Duan Y.N. Zhu Y.Q. Tang L.L. Qin J. CT features of novel coronavirus pneumonia (COVID-19) in children Eur. Radiol. 30 8 2020 4427 4433 32291501\n17 Ludvigsson J.F. Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults Acta Paediatr. 109 6 2020 1088 1095 32202343\n\n",
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"keywords": "2019-nCoV disease; COVID-19; Case report; Children; WAGR syndrome",
"medline_ta": "Ann Med Surg (Lond)",
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"title": "Sequences of COVID-19 in a child with WAGR syndrome: A case report.",
"title_normalized": "sequences of covid 19 in a child with wagr syndrome a case report"
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"abstract": "Perampanel is a selective, noncompetitive amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptor antagonist indicated for management of partial-onset and primary generalized seizures in epilepsy patients aged ≥12 years.\nA 29-year-old, white female with significant history of medically refractory frontal lobe epilepsy, status post right frontal and temporal resections, was initiated on perampanel as an add-on therapy to phenytoin extended-release (330 mg/d) and clonazepam (2.5 mg/d). She previously failed several antiepileptic drugs because of inefficacy and/or intolerance. Perampanel was initiated at 2 mg/d and the dose was increased by 2 mg/d increments every 2 to 3 weeks. Following the first dose, nausea and drowsiness were reported but resolved the following day. Three days after titration to 6 mg/d, the patient developed complete food aversion and became more irritable and anxious while no seizure frequency improvement was noted. No change of sense of taste was reported. After reduction to 4 mg/d, adverse effects improved but did not completely resolve until 2 months following perampanel discontinuation.\nA PubMed search revealed no published literature or case reports of perampanel-induced food aversion or anorexia in a presence or absence of phenytoin and clonazepam.\nIn this report, a temporal relationship was observed between perampanel dose-increase and the development of food aversion. Return to baseline appetite and eating habits following perampanel discontinuation strongly suggest perampanel involvement. At this time, the exact mechanism(s) behind food aversion associated with perampanel is/are unknown.",
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"authors": "Marvanova|Marketa|M|https://orcid.org/0000-0003-4998-8921",
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"doi": "10.9740/mhc.2019.03.100",
"fulltext": "\n==== Front\nMent Health ClinMent Health ClinmhclThe Mental Health Clinician2168-9709College of Psychiatric & Neurologic Pharmacists 10.9740/mhc.2019.03.100mhcl-09-03-01Case ReportPerampanel-induced, new-onset food aversion in a 29-year-old female with medically refractory frontal lobe epilepsy Marvanova Marketa https://orcid.org/0000-0003-4998-8921PharmD, PhD, BCGP, BCPP1 (Corresponding author) Chair and Associate Professor, Department of Pharmacy Practice, School of Pharmacy, College of Health Professions, North Dakota State University, Fargo, North Dakota, marketa.marvanova@ndsu.eduDisclosures: M.M. serves as a clinical specialist consultant in neurology and psychiatry for Lexicomp, Wolters Kluwer.\n\n3 2019 1 3 2019 9 2 100 104 © 2019 CPNP. The Mental Health Clinician is a publication of the College of Psychiatric and Neurologic Pharmacists.2019This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nPerampanel is a selective, noncompetitive amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptor antagonist indicated for management of partial-onset and primary generalized seizures in epilepsy patients aged ≥12 years.\n\nPatient History\nA 29-year-old, white female with significant history of medically refractory frontal lobe epilepsy, status post right frontal and temporal resections, was initiated on perampanel as an add-on therapy to phenytoin extended-release (330 mg/d) and clonazepam (2.5 mg/d). She previously failed several antiepileptic drugs because of inefficacy and/or intolerance. Perampanel was initiated at 2 mg/d and the dose was increased by 2 mg/d increments every 2 to 3 weeks. Following the first dose, nausea and drowsiness were reported but resolved the following day. Three days after titration to 6 mg/d, the patient developed complete food aversion and became more irritable and anxious while no seizure frequency improvement was noted. No change of sense of taste was reported. After reduction to 4 mg/d, adverse effects improved but did not completely resolve until 2 months following perampanel discontinuation.\n\nReview of Literature\nA PubMed search revealed no published literature or case reports of perampanel-induced food aversion or anorexia in a presence or absence of phenytoin and clonazepam.\n\nConclusion\nIn this report, a temporal relationship was observed between perampanel dose-increase and the development of food aversion. Return to baseline appetite and eating habits following perampanel discontinuation strongly suggest perampanel involvement. At this time, the exact mechanism(s) behind food aversion associated with perampanel is/are unknown.\n\nfrontal lobe epilepsyperampanelfood aversionphenytoinCYP3A4AMPA receptormedically refractory epilepsyCitationHow to cite: Marvanova M. Perampanel-induced, new-onset food aversion in a 29-year-old female with medically refractory frontal lobe epilepsy. Ment Health Clin [Internet].\n==== Body\nBackground\nPerampanel (PER) is a selective, noncompetitive amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist; and is the first-in-class antiepileptic drug (AED) with this mechanism of action.1,2 It is currently approved as a monotherapy for partial-onset seizures with or without secondary generalization, and as an add-on therapy for primary generalized seizures in patients with epilepsy aged ≥12 years.1,3 It displays linear pharmacokinetics at clinically-relevant doses of 2 to 12 mg/d and is administered once daily at bedtime because of its long half-life (approximately 105 hours).1 Perampanel is a primary substrate for liver cytochrome P450 (CYP) 3A4 isoenzymes and undergoes extensive liver metabolism via oxidation and subsequent glucuronidation to inactive metabolites.1 It is, therefore, a target for drug interactions with medications with strong-inducing or inhibiting CYP3A4 effects.1 Administration of phenytoin or carbamazepine, both strong inducers of CYP3A4, are reported to be associated with significantly decreased PER plasma concentrations, 50% and 67%, respectively.1\n\nInitial PER dose is 2 mg/d when administered in the absence of a medication inducing its metabolism or 4 mg/d if administered with a strong CYP3A4 inducer. Based on therapeutic response and tolerance, the dose can be increased weekly by 2 mg/d to a maximum of 12 mg/d.1 The most commonly-reported treatment-emergent adverse effects (AEs) of PER in adults were dizziness, somnolence, irritability, nervousness, vertigo, ataxia, headache, and nausea.1,4-7 In agreement, PER use in 39 treatment-resistant patients with frontal lobe epilepsy as an add-on therapy to other 3 to 4 AEDs was associated with dizziness, somnolence, irritability, malaise, and headache.8\n\nDespite nausea as a common AE, randomized, double-blind placebo-controlled Phase III registration studies4-7,9,10 of PER in patients with refractory partial-onset seizures reported weight increase. Weight increase above 7% of baseline weight was reported in 11.6% to 19.2% of PER-treated adults versus 4.4% to 8.3% in placebo-treated groups. On average, PER-associated weight increase was 1.2 kg compared to 0.4 kg with placebo.4-7,9 In addition, Youn et al10 reported appetite and weight changes, reflecting either increase or decrease, however no report of food aversion.\n\nIn this report, I describe what I believe is the first report of PER-induced total food aversion in an individual with medically refractory epilepsy. Food aversion is characterized by alteration of eating or feeding behavior manifesting as select food intolerance, repulsion and avoidance associated with adverse physical reaction such as nausea and/or vomiting. It is a very diverse condition with different severity levels and can be associated with psychological or emotional state, environment or exposure to aversive stimulus, medications, or a physiological state such as pregnancy.11-13\n\nCase Report\nA 29-year-old, right-handed white female was admitted to the epilepsy monitoring unit for video electroencephalography monitoring and medication adjustment in a large urban academic medical center. Her medical history was significant for medically refractory frontal lobe epilepsy with complex focal seizures with or without secondary generalization status post partial right frontal (2001) and right temporal resection (2008). Medication adjustment was warranted because of frequent daily seizures including clusters of 2 to 3 seizures despite adherence to phenytoin and clonazepam (CLZ). A complete list of home medications, social history, and admission vital signs and labs, are included in Table 1. Several AEDs and a modified Atkin's diet were previously discontinued because of inefficacy and/or intolerance (Table 2).\n\nTABLE 1 Social history and home medication regimen, vital signs, and laboratory results at admission\n\nAdmission Information\t\nSocial history\t\n Smoking: negative\t\n Alcohol: negative\t\n Illicit drug use: negative\t\n Living situation: lives with her parents, who are her primary caregivers\t\n Sexually active: negative\t\nHome medications\t\n Phenytoin ER, 30 mg in the morning and 300 mg in the evening\t\n Clonazepam, 1 mg in the morning and 1.5 mg in the evening\t\n Folic acid, 1 mg daily\t\n Calcium carbonate, 500 mg daily\t\n Cholecalciferol, 3000 IU daily\t\nVital signs\t\n Blood pressure: 114/60 mm Hg\t\n Heart rate: 76 bpm\t\n Body mass index: 19.9 kg/m2 (normal range: 18.5 to 24.9 kg/m2)\t\nLaboratory\t\n Complete blood count: WNL\t\n Comprehensive metabolic panel: WNL\t\n Free phenytoin level: 2.1 mg/dL\t\nER = extended-release; WNL = within the normal limit.\n\nTABLE 2 Tolerability and efficacy of previous trials of pharmacologic and nonpharmacologic modalities\n\nTreatment Modality\tAdverse Event/Paradoxical Reaction\tEfficacy\t\nPharmacologic\t\n Carbamazepine\tSuicidal ideation and depression\t\t\n Lamotrigine\tIncreased anxiety\tLack of efficacy\t\n Levetiracetam\tIncreased seizure frequency\t\t\n Phenobarbital\tStatus epilepticus\t\t\n Valproic acid and its derivatives\tIncreased anxiety\tLack of efficacy\t\n Zonisamide\tIncreased anxiety\tLack of efficacy\t\nNonpharmacologic\t\n Modified Atkin's diet\tWeight loss (22 lb)a\tLack of efficacy\t\na Modified Atkin's diet was discontinued 4 months prior to the trial with perampanel. With the diet, the patient experienced a 22-lb weight loss in the absence of decreased appetite or food aversion.\n\nPerampanel was added to her current home AED regimen of phenytoin and CLZ and, because of her prior history of paradoxical reactions, patient was initiated at 2 mg/d, a lower dose than recommended for an individual on concomitant strong CYP3A4 inducers.1,14 She denied all commonly reported AEs following initial administration other than nausea and drowsiness which resolved the next day. Her electroencephalogram remained unchanged. The day after initiation of PER 2 mg/d, she was discharged with instructions to increase by 2 mg/d every 2 weeks up to 6 mg/d until follow-up with her epileptologist (sooner for AEs or increased seizure frequency). Previous home doses of phenytoin and CLZ were continued. Upon admission and discharge (hospital day 2) complete blood count and complete metabolic panel were unremarkable and free phenytoin level was unchanged (2.1 mg/dL).\n\nShe tolerated the initial PER dose titration well. Three days after the dose increase to 6 mg/d, she experienced new-onset food aversion. Over the phone, the food aversion was described by her mother (primary caregiver) as the smell or sight of any food including fruits or vegetables resulting in nausea despite absence of any physical problem. No change in sense of taste was reported. This was a new presentation for her, not previously experienced. In addition, the patient became more irritable and anxious after the dose increase. No seizure frequency improvement was reported. The patient and her mother expressed interest in PER discontinuation. Two days after dose reduction to 4 mg/d, she was able to sit by the kitchen table during meal times but had some residual effect and was unable to eat a large amount of food, and this further improved when dose was decreased to 2 mg/d. When PER was discontinued, it took about 2 months before return to baseline appetite. During PER trial, the patient lost a total of 8.4 lb (body mass index = 18.5 kg/m2). Body mass index increased to 19.3 kg/m2 within approximately 2 months after PER discontinuation.\n\nLiterature Search\nA PubMed search in May 2018 revealed no published case report or information on PER-induced food aversion or anorexia associated with monotherapy or combinational therapy with another AED in adults with epilepsy. Key words used were: perampanel, food aversion, decreased appetite, nausea, and anorexia.\n\nDiscussion\nThis report describes new-onset total food aversion 3 days after PER dose increase from 4 mg/d to 6 mg/d in a young adult female with medically refractory frontal lobe epilepsy, partial right frontal and temporal resections, and a variety of paradoxical AED reactions. The Naranjo total score was 6, estimating that this was a probable adverse drug reaction associated with PER. A temporal relationship was observed between PER dose of 6 mg/d and development of food aversion. Perampanel dose decrease was associated with improvement and PER discontinuation followed by washout period was associated with return to baseline appetite and eating, strongly suggesting PER-contribution.\n\nAs about 50% of PER plasma concentration would be decreased by concomitantly administered phenytoin due to CYP3A4 induction, it can be postulated that food aversion was induced by lower PER serum concentration that would correspond to an oral PER dose of 3 mg/d in an individual with PER monotherapy.1 However, it is difficult to pinpoint association with specific PER serum level as the patient's pharmacogenomic profile was unknown (to identify CYP3A4 phenotype) and no PER serum levels were obtained.\n\nBecause of general lack of understanding of etiology, mechanisms, and involved neurocircuit(s) behind food aversion, at this time the precise mechanism(s) of observed total food aversion are unknown. However, as PER acts as a selective glutamate AMPA receptor antagonist and onset of food aversion was associated with PER dose increase, AMPA receptors involvement is suggested.1 In support of this, the patient experienced increased anxiety and irritability following dose increase which are known PER AEs linked to AMPA-receptor antagonism.1,2 AMPA receptors are widely expressed in the brain, and PER-antagonism is associated with antiepileptic activity due to antagonism in the cerebral cortex and hippocampus, while AEs are associated with receptor antagonism in similar or other brain regions.1,2,15 Brain regions associated with feeding and aversive motivational control, such as the ventromedial prefrontal cortex, lateral hypothalamus, lateral habenula, and ventral tegmental, may play a role in food aversion.16-22\n\nI cannot rule out pharmacodynamic interaction(s) between PER and phenytoin, however no food aversion was previously reported.10,23,24 It is highly unlikely that aversion was caused by PER-induced pharmacokinetic changes of phenytoin or CLZ as PER at this dose is neither a potent inhibitor nor inducer of liver enzymes.1 Clonazepam and PER are primarily eliminated via CYP3A4 metabolism, therefore, CLZ serum concentration could be increased due to competition for CYP3A4-iduced metabolism and thus possibly potentiate the anorectic effect of CLZ.1 Without serum concentration data for CLZ, I cannot definitively rule this out; however, a recent study25 demonstrated that PER administration had no significant impact on clonazepam clearance. As PER has a low hepatic extraction ratio (<0.3), and free phenytoin levels remained unchanged at PER doses of 2 mg/d and 4 mg/d (2.1 vs 2.0 mg/dL), I can rule out decreased PER albumin-binding due to phenytoin.1,15\n\nIt is possible that food aversion can be a complex interplay between PER and frontal lobe epilepsy, neurocircuitry changes due to partial frontal and temporal dissections, and pharmacogenomic differences in CYP3A4 and/or AMPA receptors. It can also be postulated that a 2-month delay in return to baseline appetite and eating habits after PER discontinuation could be due to its long half-life.\n\nConclusion\nThis patient experienced new-onset total food aversion 3 days after a PER dose increase to 6 mg/d. A temporal relationship was observed between dose-increase of PER and development of food aversion as well as between dose decrease and discontinuation of PER with return to normal appetite and eating habits. However, at this time, the exact mechanism(s) behind this is unknown.\n==== Refs\nReferences\n1 Eisai Inc FYCOMPA (perampanel) tablets, package insert [Internet] Bethesda (MD) National Library of Medicine (US) c2018 [updated 2017 Jul; cited 2018 Jun 14] Available from: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=71cf3309-e182-473c-8b0b-280cabd0e122&type=display \n2 Steinhoff BJ Introduction: Perampanel--new mode of action and new option for patients with epilepsy Epilepsia 2014 55 Suppl 1 1 2 DOI: 10.1111/epi.12495 PubMed PMID: 10.1111/epi.12495 24400689 PubMed PMID: 24400689 \n3 French JA Krauss GL Wechsler RT Wang X-F Diventura B Brandt C Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy: a randomized trial Neurology 2015 85 11 950 7 DOI: 10.1212/WNL.0000000000001930 PubMed PMID: 10.1212/WNL.0000000000001930 26296511 PubMed PMID: 26296511 26296511 \n4 French JA Krauss GL Biton V Squillacote D Yang H Laurenza A Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304 Neurology 2012 79 6 589 96 DOI: 10.1212/WNL.0b013e3182635735 PubMed PMID: 10.1212/WNL.0b013e3182635735 22843280 PubMed PMID: 22843280 22843280 \n5 French JA Krauss GL Steinhoff BJ Squillacote D Yang H Kumar D Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: results of randomized global phase III study 305 Epilepsia 2013 54 1 117 25 DOI: 10.1111/j.1528-1167.2012.03638.x PubMed PMID: 10.1111/j.1528-1167.2012.03638.x 22905857 PubMed PMID: 22905857 22905857 \n6 Krauss GL Serratosa JM Villanueva V Endziniene M Hong Z French J Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures Neurology 2012 78 18 1408 15 DOI: 10.1212/WNL.0b013e318254473a PubMed PMID: 10.1212/WNL.0b013e318254473a 22517103 PubMed PMID: 22517103 22517103 \n7 Krauss GL Perucca E Ben-Menachem E Kwan P Shih JJ Clément J-F Long-term safety of perampanel and seizure outcomes in refractory partial-onset seizures and secondarily generalized seizures: results from phase III extension study 307 Epilepsia 2014 55 7 1058 68 DOI: 10.1111/epi.12643 PubMed PMID: 10.1111/epi.12643 24867391 PubMed PMID: 24867391 24867391 \n8 Cheng MY Lim SN Wu T Perampanel as an adjunctive therapy in patients with frontal lobe epilepsy in Taiwan J Neurol Sci [Internet] 2017 381 Suppl 338 9 10.1016/j.jns.2017.08.961 \n9 Montouris G Yang H Williams B Zhou S Laurenza A Fain R Efficacy and safety of perampanel in patients with drug-resistant partial seizures after conversion from double-blind placebo to open-label perampanel Epilepsy Res 2015 114 131 40 DOI: 10.1016/j.eplepsyres.2015.04.011 PubMed PMID: 10.1016/j.eplepsyres.2015.04.011 26088896 PubMed PMID: 26088896 26088896 \n10 Youn SE Kim SH Ko A Lee SH Lee YM Kang H-C Adverse events during perampanel adjunctive therapy in intractable epilepsy J Clin Neurol 2018 14 3 296 DOI: 10.3988/jcn.2018.14.3.296 PubMed PMID: 29971974 PubMed Central PMCID: 10.3988/jcn.2018.14.3.296 29971974 PMC6031997 PubMed PMID: 29971974 PubMed Central PMCID: PMC6031997 29971974 \n11 Logue AW The psychology of eating and drinking. 4th ed New York and London Routledge; 2015 \n12 Bowen DJ Taste and food preference changes across the course of pregnancy Appetite 1992 19 3 233 42 10.1016/0195-6663(92)90164-2 1482161 \n13 Logue AW Conditioned food aversion learning in humans Ann N Y Acad Sci 1985 443 316 29 DOI: 10.1111/j.1749-6632.1985.tb27082.x PubMed PMID: 10.1111/j.1749-6632.1985.tb27082.x 3860075 PubMed PMID: 3860075 3860075 \n14 Brodie MJ Stephen LJ Prospective audit with adjunctive perampanel: preliminary observations in focal epilepsy Epilepsy Behav 2016 54 100 3 DOI: 10.1016/j.yebeh.2015.11.002 PubMed PMID: 10.1016/j.yebeh.2015.11.002 26700063 PubMed PMID: 26700063 26700063 \n15 Patsalos PN The clinical pharmacology profile of the new antiepileptic drug perampanel: a novel noncompetitive AMPA receptor antagonist Epilepsia 2015 56 1 12 27 DOI: 10.1111/epi.12865 PubMed PMID: 10.1111/epi.12865 25495693 PubMed PMID: 25495693 25495693 \n16 Padulo C Delli Pizzi S Bonanni L Edden RAE Ferretti A Marzoli D GABA levels in the ventromedial prefrontal cortex during the viewing of appetitive and disgusting food images Neuroscience 2016 333 114 22 DOI: 10.1016/j.neuroscience.2016.07.010 PubMed PMID: 27436536 PubMed Central PMCID: 10.1016/j.neuroscience.2016.07.010 27436536 PMC5523136 PubMed PMID: 27436536 PubMed Central PMCID: PMC5523136 27436536 \n17 Stamatakis AM Van Swieten M Basiri ML Blair GA Kantak P Stuber GD Lateral hypothalamic area glutamatergic neurons and their projections to the lateral habenula regulate feeding and reward J Neurosci 2016 36 2 302 11 DOI: 10.1523/JNEUROSCI.1202-15.2016 PubMed PMID: 26758824 PubMed Central PMCID: 10.1523/JNEUROSCI.1202-15.2016 26758824 PMC4710762 PubMed PMID: 26758824 PubMed Central PMCID: PMC4710762 26758824 \n18 Bromberg-Martin ES Matsumoto M Hikosaka O Dopamine in motivational control: rewarding, aversive, and alerting Neuron 2010 68 5 815 34 DOI: 10.1016/j.neuron.2010.11.022 PubMed PMID: 21144997 PubMed Central PMCID: 10.1016/j.neuron.2010.11.022 21144997 PMC3032992 PubMed PMID: 21144997 PubMed Central PMCID: PMC3032992 21144997 \n19 Yasoshima Y Morimoto T Yamamoto T Different disruptive effects on the acquisition and expression of conditioned taste aversion by blockades of amygdalar ionotropic and metabotropic glutamatergic receptor subtypes in rats Brain Res 2000 869 1-2 15 24 DOI: 10.1016/S0006-8993(00)02397-0 PubMed PMID: 10.1016/S0006-8993(00)02397-0 10865054 PubMed PMID: 10865054 10865054 \n20 Hettes SR Gonzaga WJ Heyming TW Nguyen JK Perez S Stanley BG Stimulation of lateral hypothalamic AMPA receptors may induce feeding in rats Brain Res 2010 1346 112 20 DOI: 10.1016/j.brainres.2010.05.008 PubMed PMID: 10.1016/j.brainres.2010.05.008 20580634 PubMed PMID: 20580634 20580634 \n21 Echo JA Lamonte N Christian G Znamensky V Ackerman TF Bodnar RJ Excitatory amino acid receptor subtype agonists induce feeding in the nucleus accumbens shell in rats: opioid antagonist actions and interactions with μ-opioid agonists Brain Res 2001 921 1-2 86 97 DOI: 10.1016/S0006-8993(01)03094-3 PubMed PMID: 10.1016/S0006-8993(01)03094-3 11720714 PubMed PMID: 11720714 11720714 \n22 Stratford TR Swanson CJ Kelley A Specific changes in food intake elicited by blockade or activation of glutamate receptors in the nucleus accumbens shell Behav Brain Res 1998 93 1-2 43 50 DOI: 10.1016/S0166-4328(97)00140-X PubMed PMID: 10.1016/S0166-4328(97)00140-X 9659985 PubMed PMID: 9659985 9659985 \n23 Chiang H-I Lim S-N Hsieh H-Y Cheng M-Y Chang C-W Johnny Tseng W-E Preliminary Asian experience of using perampanel in clinical practice Biomed J 2017 40 6 347 54 DOI: 10.1016/j.bj.2017.09.003 PubMed PMID: 29433838 PubMed Central PMCID: 10.1016/j.bj.2017.09.003 29433838 PMC6138609 PubMed PMID: 29433838 PubMed Central PMCID: PMC6138609 29433838 \n24 Gidal BE Ferry J Majid O Hussein Z Concentration-effect relationships with perampanel in patients with pharmacoresistant partial-onset seizures Epilepsia 2013 54 8 1490 7 DOI: 10.1111/epi.12240 PubMed PMID: 10.1111/epi.12240 23772853 PubMed PMID: 23772853 23772853 \n25 Majid O Laurenza A Ferry J Hussein Z Impact of perampanel on pharmacokinetics of concomitant antiepileptics in patients with partial-onset seizures: pooled analysis of clinical trials Br J Clin Pharmacol 2016 82 2 422 30 DOI: 10.1111/bcp.12951 PubMed PMID: 27038098 PubMed Central PMCID: 10.1111/bcp.12951 27038098 PMC4972158 PubMed PMID: 27038098 PubMed Central PMCID: PMC4972158 27038098\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2168-9709",
"issue": "9(2)",
"journal": "The mental health clinician",
"keywords": "AMPA receptor; CYP3A4; food aversion; frontal lobe epilepsy; medically refractory epilepsy; perampanel; phenytoin",
"medline_ta": "Ment Health Clin",
"mesh_terms": null,
"nlm_unique_id": "101728585",
"other_id": null,
"pages": "100-104",
"pmc": null,
"pmid": "30842918",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports",
"references": "10865054;11720714;1482161;20580634;21144997;22517103;22843280;22905857;23772853;24400689;24867391;25495693;26088896;26296511;26700063;26758824;27038098;27436536;29433838;29971974;3860075;9659985",
"title": "Perampanel-induced, new-onset food aversion in a 29-year-old female with medically refractory frontal lobe epilepsy.",
"title_normalized": "perampanel induced new onset food aversion in a 29 year old female with medically refractory frontal lobe epilepsy"
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"abstract": "Here we report a critically ill patient who was cured of SARS-CoV-2 infection in Changsha, China. A 66-year-old Chinese woman, with no significant past medical history, developed severe pneumonia-like symptoms and later diagnosed as severe COVID-19 pneumonia. Within 2 months of hospitalization, the patient deteriorated to ARDS including pulmonary edema and SIRS with septic shock. When treatment schemes such as antibiotics plus corticosteroids showed diminished therapeutic value, hUCMSC therapy was compassionately prescribed under the patient's consent of participation. After treatment, there was significant improvement in disease inflammation-related indicators such as IL-4, IL-6, and IL-10. Eventually, it confirmed the therapeutic value that hUCMSCs could dampen the cytokine storm in the critically ill COVID-19 patient and modulated the NK cells. In the continued hUCMSC treatment, gratifying results were achieved in the follow-up of the patient. The data we acquired anticipate a significant therapeutic value of MSC treatment in severe and critically ill patients with COVID-19, while further studies are needed.",
"affiliations": "Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China.;Department of Critical Care Medicine, First Hospital of Changsha, Changsha, China.;Department of Critical Care Medicine, First Hospital of Changsha, Changsha, China.;Department of Critical Care Medicine, First Hospital of Changsha, Changsha, China.;Department of Critical Care Medicine, First Hospital of Changsha, Changsha, China.;Department of Critical Care Medicine, First Hospital of Changsha, Changsha, China.;School of Basic Medical Sciences, Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha, China.;School of Basic Medical Sciences, Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha, China.;Department of Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China.;Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China.;Department of Critical Care Medicine, First Hospital of Changsha, Changsha, China.",
"authors": "Zhang|Quan|Q|;Huang|Kang|K|;Lv|Jianlei|J|;Fang|Xiang|X|;He|Jun|J|;Lv|Ailian|A|;Sun|Xuan|X|;Cheng|Lamei|L|;Zhong|Yanjun|Y|;Wu|Shangjie|S|;Dai|Yao|Y|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fmed.2021.691329",
"fulltext": "\n==== Front\nFront Med (Lausanne)\nFront Med (Lausanne)\nFront. Med.\nFrontiers in Medicine\n2296-858X\nFrontiers Media S.A.\n\n10.3389/fmed.2021.691329\nMedicine\nCase Report\nCase Report: Human Umbilical Cord Mesenchymal Stem Cells as a Therapeutic Intervention for a Critically Ill COVID-19 Patient\nZhang Quan 1†\n\nHuang Kang 2†\nLv Jianlei 2\nFang Xiang 2\nHe Jun 2\nLv Ailian 2\nSun Xuan 34\nCheng Lamei 34\n\nZhong Yanjun 5\n\nWu Shangjie 1*\n\nDai Yao 2*\n1Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China\n2Department of Critical Care Medicine, First Hospital of Changsha, Changsha, China\n3School of Basic Medical Sciences, Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha, China\n4National Engineering and Research Center of Human Stem Cells, Changsha, China\n5Department of Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China\nEdited by: Fabio Sallustio, University of Bari Aldo Moro, Italy\n\nReviewed by: Athina Samara, Karolinska Institutet (KI), Sweden; Selim Kuci, University Hospital Frankfurt, Germany\n\n*Correspondence: Yao Dai dy13574871178@sina.com\nShangjie Wu wushangjie@csu.edu.cn\nThis article was submitted to Gene and Cell Therapy, a section of the journal Frontiers in Medicine\n\n†These authors have contributed equally to this work and share first authorship\n\n08 7 2021\n2021\n08 7 2021\n8 69132906 4 2021\n31 5 2021\nCopyright © 2021 Zhang, Huang, Lv, Fang, He, Lv, Sun, Cheng, Zhong, Wu and Dai.\n2021\nZhang, Huang, Lv, Fang, He, Lv, Sun, Cheng, Zhong, Wu and Dai\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.\nHere we report a critically ill patient who was cured of SARS-CoV-2 infection in Changsha, China. A 66-year-old Chinese woman, with no significant past medical history, developed severe pneumonia-like symptoms and later diagnosed as severe COVID-19 pneumonia. Within 2 months of hospitalization, the patient deteriorated to ARDS including pulmonary edema and SIRS with septic shock. When treatment schemes such as antibiotics plus corticosteroids showed diminished therapeutic value, hUCMSC therapy was compassionately prescribed under the patient's consent of participation. After treatment, there was significant improvement in disease inflammation-related indicators such as IL-4, IL-6, and IL-10. Eventually, it confirmed the therapeutic value that hUCMSCs could dampen the cytokine storm in the critically ill COVID-19 patient and modulated the NK cells. In the continued hUCMSC treatment, gratifying results were achieved in the follow-up of the patient. The data we acquired anticipate a significant therapeutic value of MSC treatment in severe and critically ill patients with COVID-19, while further studies are needed.\n\nCOVID-19\nmesenchymal stem cells\ncritically ill\ntherapy\ncase report\n==== Body\nIntroduction\n\nAt the end of 2019, several cases of severe respiratory infections were identified in Wuhan, China, which were triggered by a novel virus that was later assigned the name SARS-CoV-2 or COVID-19. Individuals of all ages are vulnerable to COVID-19 infection; however, those aged over 60 and have preexisting medical conditions, such as cardiovascular disease, diabetes, or high blood pressure, are prone to become critically ill and exhibit higher risk of suffering from the condition. According to the Centers for Disease Control and Prevention, the symptoms of COVID-19, in some cases, include fever, cough, shortness of breath, fatigue, and sudden loss of sense of smell and taste, while corresponding typical characteristics are pneumonia that requires hospitalization and even death, in case of absence of timely intervention. Anti-inflammatory treatment has been proposed and implemented but challenged with the dilemma of balancing the risk of secondary infection.\n\nThis newly emerging virus infection pandemic may lead to multiple organ damage, and there is, so far, still lack of specific treatments or available drugs. It is especially suitable for stem cell therapy. Mesenchymal stem cells (MSCs) are multipotent stromal cells that are capable of inducing immunomodulation and regeneration, and have trilineage differentiation when stimulated in vitro (1). It is now understood that MSCs have wide-ranging physiological effects, in addition to their regenerative and immunoregulatory capacities (2), which also exhibit anti-inflammation activity (3). Furthermore, MSCs can release a variety of cytokines through paracrine function, or directly interact with immune cells, resulting in immune regulation and inflammation alleviation (4). Based on these prepositional studies, our center is currently working on another randomized and more sophisticated study to verify the therapeutic value of MSC treatment in severe and critically ill patients with COVID-19 pneumonia, with the expectation to promote its potential long-term efficacy and decrease its toxicity.\n\nIn consideration of the current dire situation, we would like to share our experience in critical care of an elderly patient who had no existing medical conditions and later transformed into critically ill COVID-19 case. This patient had developed multiple severe virus-induced syndrome and yet successfully recovered after continuous treatments of combined antibiotic therapy and an innovative human umbilical cord mesenchymal stem cell (hUCMSC) intervention. This case highlights our patient's clinical course, including relevant medical history, diagnostic work-up, medical management, and challenges in respiratory function and immunologic function supplement, as well as pulmonary fibrosis repairing.\n\nCase Description\n\nA 66-year-old Chinese woman without a smoking or drinking habit and significant past medical history presented to our institution on February 3, 2020. The chief complaints of this patient were dizziness and vomiting, with diarrhea of watery stool (five times per day) that developed after returning to Changsha from Wuhan 7 days before. On February 2, she visited a local hospital for medical diagnosis and received complete blood count (CBC) test, with a low white blood cell (WBC) count, and chest CT scan showed multiple lesions in the lung. The primary diagnosis was viral pneumonia. Further RT-PCR detection for COVID-19 pathogen was conducted, and the result proved to be positive. Then the patient was transferred to our Institute of Changsha Public Health Center. She had no cough or fever, and showed clear conscience at admission, with vitals: body temperature: 37.3°C, pulse: 72 beats/min, blood pressure: 108/66 mmHg, respiratory rate: 19 breaths/mine, and oxygen saturation: 98% on oxygen inhalation. The patient had thick breath sounds in bilateral lungs. Chest CT examination was performed to evaluate the abnormal breath sounds, which revealed bilateral pneumonia (Figure 1A).\n\nFigure 1 Chest CT of this patient. (A) Chest CT was obtained on February 6, 2020 (hospital day 3, illness day 5). Multiple patchy shadows, ground-glass opacity (GGO) under the pleura, streak-like density-increased shadows in the bilateral lungs were observed. (B) Chest CT was obtained on February 23, 2020 (day 21). The texture of the trachea and blood vessels in both lungs showed thickening. Both the GGO and patchy shadows increased, and the original was consolidated. (C) Chest CT was obtained on April 10, 2020 (day 68). The patchy lesions and consolidations in both lungs were absorbed, and the fiber shadows increased in size partially in the lower lung.\n\nDuring the first development phase ranging from hospital day 121 (illness days 3–23), the patient presented with dizziness, vomiting, and diarrhea, yet with a little cough and no fever. Our continuous bedside monitoring of her vital signs showed a temperature fluctuation between 37.4 and 38.2°C, except inflammation-induced fever-like symptoms in the initial 2 days (Supplementary Figure 1). Results of CBC test were consistent with those of the viral-infection ramification of high WBC count and low lymphocyte percentage. Chest CT scans from hospital day 20 showed a continuous lesion development in the bilateral lower lobe, with visible fibrosis and necrosis in the lung tissue (Figure 1B). According to the guideline for Diagnosis and Treatment of Pneumonitis with COVID-19 Infection published by the National Health Commission of China (Trial 4th Edition), the patient was treated with antiviral therapy of Arbidol, combined with moxifloxacin, methylprednisolone (40 mg QD), and immunoglobulin (10–20 g QD) from day 3 to 14 for anti-inflammation and reducing overimmunoreaction. A non-invasive mechanical ventilator was used to reduce hypoxia and prevent respiratory muscle fatigue of the patient with oxygen provided through a nasal cannula, after which, high-flow nasal cannula oxygen therapy (HFNC) was provided to her.\n\nOn day 22, the patient started to develop hyperthermia symptoms, with the highest body temperature at 38.4°C, indicating failure in antibiotic solution and aggravation of inflammation. In this case, the antibiotic was adjusted to piperacillin/tazobactam to tackle this situation, yet the fever continues. On day 25, meropenem, along with the convalescent plasma (CP) derived from recently recovered donors with neutralizing antibody, substituting previous antibiotics, was introduced to reduce the inflammatory symptoms that continuously occurred. However, the situation got worse, and we reevaluated the patient that she lived in a stage of inflammatory factor storm with high risk to develop into the critically ill type (e.g., multiple organ injury) that required close follow-up. There is an urgent need for safe and alternative therapeutic options to alleviate the storm. Considering the characteristics of hUCMSCs, we speculated that they might be homing to the injured tissues (especially to the lung) and elicit anti-inflammatory function. Thus, our group made a decision to take the hUCMSCs as a therapeutic intervention. The informed consent was obtained by the family member and patient to perform hUCMSC adoptive transfer therapy. The treatment scheme was then discussed, formulated, and approved by the ethics committee of our hospital, with consent forms signed by the family member prior to the treatment. The hUCMSCs were freely derived from the National Engineering Research Center of Human Stem Cells, Changsha, Hunan, China, and belonged to clinical-grade MSCs. The hUCMSCs were prepared on the same day and stored and transported at 4–8°C in strict accordance with standard operating procedures. The total number of infused cells was 1 × 106 cells per kilogram. The allogenic hUCMSCs were administrated intravenously two times (6.4 × 107 cells each time) in the patient on day 28 and 31, at a rate of about 40 drops/min for about 40–50 min. During the treatment, tigecycline, polymyxin B, and voriconazole were added once to resolve the bacterial infections. Following these treatments, the patient temperature stabilized. However, on the midnight of day 29, the patient began to breathe faster, which could not be alleviated by adjusting the ventilator's parameter. The blood oxygen saturation was continuously lower than 86%, and intratracheal intubation was urgently performed to decrease the respiratory distress. However, owing to the continuously deteriorated respiratory function, the patient was provided with the extracorporeal membrane oxygenation (ECMO) support and officially declared a critically ill case with severe pneumonia (mixed type), acute respiratory distress, sepsis, and multiorgan injury (kidney, respiratory system, and heart). Continuous renal replacement therapy (CRRT) was installed for the life support and daptomycin as the temporary critical antibiotic solution. Besides, the planned third infusion on day 34 was suspended owing to the presence of severe mixed coinfections.\n\nDuring the period from day 31 to 57, the patient was sedated most of the time, accompanied by successive administration of meropenem, or piperacillin/tazobactam, tigecycline, polymyxin B, voriconazole, daptomycin, or linezolid for the antibacteria therapy, as well as continuous thymalfasin and respiratory support. The veno-venous ECMO support was provided through day 30 to 36, but the patient failed to receive endotracheal extubation, and was forced to have a tracheotomy. CBC test showed fluctuated high WBC count, increased hypersensitive C-reactive protein (hCRP) and D-dimer, continuously low lymphocyte counts (Supplementary Table 1), suggesting continued existence of inflammation-inducing sources. Bedside chest X-ray revealed continuous development of ground-glass opacity (GGO) of the whole lung area. All these results indicated a possibly ineffective therapeutic outcome of combined antibiotics and antifungal therapy.\n\nOn day 58, physical reexamination of the patient showed weakness of breathing and muscles that led to the dependence on a ventilator. Moreover, she had always suffered from a low-to-moderate fever, and comparison of current CT scanning results with the previous showed partial absorption of bilateral patchy lesions in the lungs of the patient, yet accompanied by a great deal of GGO, non-homogeneous density, and air bronchus signs (Figure 1C). Considering the benefits of organ injury recovery caused by inflammatory responses, allogenic hUCMSCs were administrated intravenously for the second round three times (6.5 × 107 cells each time) on days 59, 63, and 66. After the second round of the hUCMSC injection, the patient stayed in the critical care unit (CCU) for continuous monitoring and attentive care for over 20 days. Most of the vital signs and clinical laboratory indexes recovered in the normal range, with certain recovery in the chest CT images as well (Figure 2). On day 87, the patient was transferred out of the CCU for further rehabilitation and finally discharged on hospital day 133. In the subsequent follow-up, the patient can complete proper body exercise, whose activity tolerance was much better than we predicted. For the rehabilitation of pulmonary fibrosis, a third round of hUCMSC administration has been applied on July 7,14, and 21, 2020 (6.5 × 107cells each time). Long-term follow-up is currently ongoing to monitor changes in the lung lesion of the patient (Supplementary Figure 2).\n\nFigure 2 Chest CT of this patient. (A) CT images on day 78 indicate that patchy shadows and GGO increased in the right lower lung lobe but decreased in the left upper lung. (B) CT images on day 129 indicate that patchy shadows, GGO, and consolidations were absorbed, and some air bronchogram signs and fiber strands were left. (C) CT images on day 150 by follow-up indicate that the fiber strands were reduced, and GGO decreased gradually.\n\nObserved and Measured Variables\n\nFrom admission to discharge, clinical symptoms, laboratory tests, and radiological evaluations were recorded and confirmed by a team of trained doctors, especially after receiving hUCMSC infusion. No infusion or allergic reactions, secondary infections, and treatment-related adverse events were found during the observation period. The only controversial hyperthermia and dyspnea occurred on day 29; however, they were not considered to be related to treatment with MSCs because this therapy was just based on the rapid deterioration of the patient's condition, which was characterized by hyperthermia and dyspnea prior to entering the trial. No obvious abnormality was found in the detected concentrations of aspartate aminotransferase, total bilirubin, and creatinine. Collectively, these findings indicated that the use of hUCMSCs was safe and well-tolerated by the patient.\n\nDiscussion and Conclusions\n\nIt is commonly known that COVID-19 patients, severe- and critically ill-type cases, in particular, are frequently accompanied by “cytokine storm.” It involves elevated levels of circulating cytokines and immune-cell hyperactivation that can, in turn, lead to lung tissue damage, repair imbalance, and respiratory failure. Cytokine storm is characterized by constitutional symptoms, systemic inflammation, and multiorgan dysfunction that may develop into multiorgan failure if inadequately treated. In our practice, what confuses us is why some COVID-19 patients progress seriously or even die, while some others only show slight clinical symptoms and recover rapidly. Traditional immunology viewpoints cannot well explain the broad spectrum of the disease, and Shi et al. suggested that the course of COVID-19 shall be divided into immune defense-based protective phase and inflammation-driven damaging phase (5). Studies concluded that the first approach in evaluating a patient with cytokine storm is to identify the underlying disorder based on the clinical characteristics and complete workup for laboratory assessment (6). From February 25 (day 22), our case had fever again with progressed dyspnea, accompanied by obvious increase in neutrophil counts, hCRP, ESR, and D-dimer along with chest imaging. Unexpectedly, the same situation happened again on March 25 (day 52). All these findings in our case also supported twice occurrence of cytokine storms. For the long term of disease procession, CP is suitable for early application, which, however, cannot completely reverse the storm and does not benefit critically ill patients with COVID-19 (7). After the second cytokine storm, we adjusted the treatment schedule by not infusing CP any more. With CP and MSC infusion treatment, the patient showed an improved symptom of dyspnea, but got myasthenia and subsequent infection that still required mechanical ventilation for treatment. In addition to descended oxygenation index to below 150, the patchy shadows and GGO increased in the right lower lung conversely. After the second round of MSC infusion, another chest CT in the patient showed that bilateral lesions were mostly absorbed. In terms of clinical symptoms, we observed that she no longer had fever, and showed improved muscle strength of limbs through daily activities, yet with restricted movement and no ability to stand alone. Besides, the patient successfully changed to HFNC and then to the nasal catheter only. The above may be attributed partially to MSCs' regulation of the pulmonary microenvironment (8), through restoring impaired alveolar fluid clearance and alveolar protein permeability (9).\n\nAssembling evidence indicates that SARS-CoV-2 spreads mainly through the respiratory tract, either in the form of droplets, breathing secretions, or direct contact. Furthermore, the abundant presence of the ACE2 receptor in lung alveolar epithelial cells promotes the binding of SARS-CoV-2 spike-S-glycoprotein, thus, accelerating viral infection. Critically ill COVID-19 patient data showed the increased levels, to name a few, of IL-2, IL-6, IL-7, IL-10, monocyte chemoattractant protein-1 (MCP-1), and TNF-α (10, 11). MSCs have specific properties to endow them attractive candidates for the therapeutic use of autoimmune inflammatory and tissue damage repairing or tissue homeostasis maintaining. It is well-founded that the primary mechanism by which MSCs exert its therapeutic effects is realized through the secretion of paracrine soluble factors known as secretomes and exosomes (12, 13). This may promote a direct interaction of MSCs with immune cells and perform immune response paracrine modulation by releasing cytokines such as IL-10, IL-1RA, TGF-β, indoleamine 2,3 dioxygenase (IDO), and nitric oxide production. These mechanisms further modulate the proliferation and activation of an anti-inflammatory phenotype of naive and effector T cells, natural killer (NK) cells, and mononuclear cells. Functional modulation of T cells involves inhibition of the Th17 response, induction of regulatory T cells (Treg cells), and shifting from a Th1 to a Th2 cell phenotype (14, 15). It has been documented that MSCs can secrete IL-6 and induce B lymphocytes to produce IgG in vitro (16). Additionally, MSCs can prevent neutrophils from apoptosis and degranulation in culture without inhibiting their phagocytic or chemotactic capabilities (17). Based on these knowledge and presumption, an analysis of multiplex cytokine using the patient's whole blood was performed when the patient received hUCMSCs infusion. According to the dynamic changes in IL levels of this patient during the hUCMSC treatment period (Figure 3), IL-6 and IL-10 showed a significant downward trend after infusion and recovered to a certain extent. Similarly, the same changes were observed in WBC, hCRP, and D-dimer as well. These results may indicate that hUCMSCs may reduce inflammation response, and promote the recovery of antiviral T cells and injured tissues when combined with other immunomodulators.\n\nFigure 3 The dynamic changes in the three interleukin levels of the patient during the human umbilical cord mesenchymal stem cell (hUCMSC) treatment period (BD™ Cytometric Bead Array Human Th1/Th2/Th17 Cytokine Kit). *The day of hUCMSC therapy.\n\nBased on their satisfactory immunomodulatory effect, MSCs have been studied as a promising candidate for treating some inflammatory and immunologic diseases, such as graft-versus-host disease (GvHD), inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), and ARDS (18–21). As has been clarified, MSCs control both innate and adaptive immune response behavior through release of trophic factors, which are mediated by cell-contact-dependent and -independent mechanisms through the direct cell–cell interaction (22). COVID-19 patients, severe cases in particular, present a consistent decrease in T cells, lower lymphocyte, and higher neutrophil counts in the peripheral blood (23). In comparison, MSCs may increase the generation of Treg cells. Previous validated works have demonstrated its role in inhibiting the proliferation, activation, and maturation of CD19+ B cells, CD4+ Th1 cells, CD8+ T cells, macrophages, monocytes, and neutrophils (19, 24). In the present case, we found that CD4+ T cells, CD8+ T cells, and NK cells all were significantly lower than normal range during a great time of hospitalization (Table 1). These immune cells all play an important role in the immune response of antivirus. It was observed that MSC infusion moderately increased the frequency and count of CD4+ T lymphocytes, suggesting that MSCs most likely affected the T cell subpopulation. In addition, there existed a temporary decline in the count of NK cells, accompanied by decreased counts of WBC and NK cells to a certain extent at different time points after MSC infusions (Supplementary Table 1). Generally speaking, the immunosuppressive effect of MSCs on NK cells is dominant, but substantial data suggests that MSCs can variably affect NK cells and can be affected in turn. The findings support that the controversy depends largely on the ratio of MSC:NK ratios used and sources from which the MSCs and NK cells are isolated (25). On the basis of their abnormal immunophenotype, NK cells have been shown to possess dual roles in the context of COVID-19: an early protective antiviral role and a deteriorative inflammation-promoting role induced by certain subsets (26). Main routes between MSCs and NK cells are considered to include (a) direct cell-to-cell contact, (b) via soluble mediators, and (c) indirectly through modulating the function of other regulatory immune cells like Treg cells (27). In accordance with the aforementioned interpretation, we deem that the improved therapeutic outcome in this patient after MSC infusions in multiple medical conditions can be explained primarily by the development of paracrine factors based on regulation of T lymphocytes, inflammatory mediators, and cytokines, eventually resulting in immunomodulation. The current knowledge herein suggests that MSCs can be regarded as one therapeutic choice possessing a great potential in the management of COVID-19 through targeting NK cells.\n\nTable 1 Results of T-lymphocyte cell subsets (BD Multitest™ six-color TBNK).\n\nItems\tNormal range (106/L)\tFeb 19\tFeb 27\tApr 1*\tApr 5*\tApr 8*\tApr 21\tJul 1\tJul 14*\tJul 21*\tAug 5\t\nCD3+\t1,185–1,901\t296\t501\t127\t201\t271\t358\t1,154\t1,291\t1,098\t1,174\t\nCD3+CD8+\t404–754\t76\t175\t77\t82\t119\t159\t574\t610\t485\t524\t\nCD3+CD4+\t361–937\t187\t325\t50\t117\t151\t203\t592\t644\t583\t609\t\nCD4/CD8\t1.4–2.0\t2.46\t1.86\t0.65\t1.43\t1.27\t1.27\t1.03\t1.06\t1.20\t1.16\t\nCD3–CD19+\t180–324\t39\t20\t39\t70\t85\t57\t46\t36\t47\t58\t\nCD3–CD56+\n(NK cell)\t175–567\t85\t158\t37\t34\t72\t–\t522\t552\t407\t529\t\n* The day of hUCMSC therapy.\n\nAs supported by the published meta-analysis, quite a number of severe and critically ill COVID-19 patients have received MSC treatment without serious adverse event evidence. The proposed therapy has suggested benefits in reducing mortality and improving pulmonary function in patients with ARDS, as well as in mitigating the physiologic and immunologic responses leading to ARDS (28). In addition, MSCs have powerful antifibrotic effects and may alleviate lung fibrosis. In our case report, according to the follow-up data of chest CT, our patient recovers obviously from pulmonary fibrosis after several times of hUCMSC treatments. Despite no clear evidence to reveal that treatment with stem cells can eradicate coronavirus, preliminary findings are encouraging at this stage, indicating that the patients who are critically ill will be more likely to survive from the infection under this therapy.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by the ethics committee of First hospital of Changsha. 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\nAll authors contributed to the study conception and design. KH, JH, and AL conceived the proposal for the therapy. KH, JL, XF, and YD organized the clinical study and interpreted the results. QZ and KH prepared the report manuscript. KH, JL, and XF contributed to the clinical observations, material preparation, and image collection. AL, KH, and YZ analyzed and interpreted the X-ray and CT images. XS and LC participated in stem cell production and testing. YD and SW reviewed the manuscript. All authors read and approved the final manuscript.\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\nThe authors thank the National Engineering Research Center of Human Stem Cell, Changsha, Hunan, China, which provides UC-MSCs for free. Thanks to all the medical staff who participated in the treatment of patients in the case.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2021.691329/full#supplementary-material\n\nClick here for additional data file.\n\nClick here for additional data file.\n\nClick here for additional data file.\n\nClick here for additional data file.\n\nFunding. This study was sponsored by the New Coronavirus Pneumonia Emergency Project of Changsha Science and Technology Bureau (kq2001007), and the study was also supported by the Special Emergency Project for COVID-19 from the Science and Technology Department of Hunan Province (2020SK3016), Emergency Project of Prevention and Control for COVID-19 of Central South University (160260005).\n==== Refs\nReferences\n\n1. Dominici M Le Blanc K Mueller I Slaper-Cortenbach I Marini F Krause D . Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. (2006) 8 :315–7. 10.1080/14653240600855905 16923606\n2. Levy O Kuai R Siren EMJ Bhere D Milton Y Nissar N . Shattering barriers toward clinically meaningful MSC therapies. Sci Adv. (2020) 6 :eaba6884. 10.1126/sciadv.aba6884 32832666\n3. Bernardo ME Fibbe WE . Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell. (2013) 13 :392–402. 10.1016/j.stem.2013.09.006 24094322\n4. Prockop DJ Oh JY . Mesenchymal stem/stromal cells (MSCs): role as guardians of inflammation. Mol Ther. (2012) 20 :14–20. 10.1038/mt.2011.211 22008910\n5. 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\n6. Fajgenbaum DC June CH . Cytokine storm. N Engl J Med. (2020) 383 :2255–73. 10.1056/NEJMra2026131 33264547\n7. Omrani AS Zaqout A Baiou A Daghfal J Elkum N Alattar RA . Convalescent plasma for the treatment of patients with severe coronavirus disease 2019: a preliminary report. J Med Virol. (2021) 93 :1678–86. 10.1002/jmv.26537 32965715\n8. Antunes MA Laffey JG Pelosi P Rocco PR . Mesenchymal stem cell trials for pulmonary diseases. J Cell Biochem. (2014) 115 :1023–32. 10.1002/jcb.24783 24515922\n9. Loy H Kuok DIT Hui KPY Choi MHL Yuen W Nicholls JM . Therapeutic implications of human umbilical cord mesenchymal stromal cells in attenuating influenza A(H5N1) virus-associated acute lung injury. J Infect Dis. (2019) 219 :186–96. 10.1093/infdis/jiy478 30085072\n10. Huang C Wang Y Li X Ren L Zhao J Hu Y . Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. (2020) 395 :497–506. 10.1016/S0140-6736(20)30183-5 31986264\n11. Liuzzo G Patrono C . COVID 19: in the eye of the cytokine storm. Eur Heart J. (2021) 42 :150–1. 10.1093/eurheartj/ehaa1005 33462598\n12. Lee JW Gupta N Serikov V Matthay MA . Potential application of mesenchymal stem cells in acute lung injury. Expert Opin Biol Ther. (2009) 9 :1259–70. 10.1517/14712590903213651 19691441\n13. Askenase PW . COVID-19 therapy with mesenchymal stromal cells (MSC) and convalescent plasma must consider exosome involvement: do the exosomes in convalescent plasma antagonize the weak immune antibodies? J Extracell Vesicles. (2020) 10 :e12004. 10.1002/jev2.12004 33304473\n14. Pittenger MF Discher DE Peault BM Phinney DG Hare JM Caplan AI . Mesenchymal stem cell perspective: cell biology to clinical progress. NPJ Regen Med. (2019) 4 :22. 10.1038/s41536-019-0083-6 31815001\n15. Chow L Johnson V Impastato R Coy J Strumpf A Dow S . Antibacterial activity of human mesenchymal stem cells mediated directly by constitutively secreted factors and indirectly by activation of innate immune effector cells. Stem Cells Transl Med. (2020) 9 :235–49. 10.1002/sctm.19-0092 31702119\n16. Rasmusson I Le Blanc K Sundberg B Ringden O . Mesenchymal stem cells stimulate antibody secretion in human B cells. Scand J Immunol. (2007) 65 :336–43. 10.1111/j.1365-3083.2007.01905.x 17386024\n17. Raffaghello L Bianchi G Bertolotto M Montecucco F Busca A Dallegri F . Human mesenchymal stem cells inhibit neutrophil apoptosis: a model for neutrophil preservation in the bone marrow niche. Stem Cells. (2008) 26 :151–62. 10.1634/stemcells.2007-0416 17932421\n18. Wilson JG Liu KD Zhuo H Caballero L McMillan M Fang X . Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Respir Med. (2015) 3 :24–32. 10.1016/S2213-2600(14)70291-7 25529339\n19. Gao L Zhang Y Hu B Liu J Kong P Lou S . Phase II multicenter, randomized, double-blind controlled study of efficacy and safety of umbilical cord-derived mesenchymal stromal cells in the prophylaxis of chronic graft-versus-host disease after HLA-haploidentical stem-cell transplantation. J Clin Oncol. (2016) 34 :2843–50. 10.1200/JCO.2015.65.3642 27400949\n20. Hosseini-Asl SK Mehrabani D Karimi-Busheri F . Therapeutic effect of mesenchymal stem cells in ulcerative colitis: a review on achievements and challenges. J Clin Med. (2020) 9 :3922. 10.3390/jcm9123922 33287220\n21. Wang D Li J Zhang Y Zhang M Chen J Li X . Umbilical cord mesenchymal stem cell transplantation in active and refractory systemic lupus erythematosus: a multicenter clinical study. Arthritis Res Ther. (2014) 16 :R79. 10.1186/ar4520x 24661633\n22. Corcione A Benvenuto F Ferretti E Giunti D Cappiello V Cazzanti F . Human mesenchymal stem cells modulate B-cell functions. Blood. (2006) 107 :367–72. 10.1182/blood-2005-07-2657 16141348\n23. Diao B Wang C Tan Y Chen X Liu Y Ning L . Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). Front Immunol. (2020) 11 :827. 10.3389/fimmu.2020.00827 32425950\n24. Leyendecker A Jr. Pinheiro CCG Amano MT Bueno DF . The use of human mesenchymal stem cells as therapeutic agents for the in vivo treatment of immune-related diseases: a systematic review. Front Immunol. (2018) 9 :2056. 10.3389/fimmu.2018.02056 30254638\n25. Thomas H Jager M Mauel K Brandau S Lask S Flohe SB . Interaction with mesenchymal stem cells provokes natural killer cells for enhanced IL-12/IL-18-induced interferon-gamma secretion. Mediators Inflamm. (2014) 2014 :143463. 10.1155/2014/143463 24876666\n26. Alrubayyi A . NK cells in COVID-19: protectors or opponents? Nat Rev Immunol. (2020) 20 :520. 10.1038/s41577-020-0408-0 32753763\n27. Moloudizargari M Govahi A Fallah M Rezvanfar MA Asghari MH Abdollahi M . The mechanisms of cellular crosstalk between mesenchymal stem cells and natural killer cells: therapeutic implications. J Cell Physiol. (2021) 236 :2413–29. 10.1002/jcp.30038 32892356\n28. Qu W Wang Z Hare JM Bu G Mallea JM Pascual JM . Cell-based therapy to reduce mortality from COVID-19: systematic review and meta-analysis of human studies on acute respiratory distress syndrome. Stem Cells Transl Med. (2020) 9 :1007–22. 10.1002/sctm.20-0146 32472653\n\n",
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"title": "Case Report: Human Umbilical Cord Mesenchymal Stem Cells as a Therapeutic Intervention for a Critically Ill COVID-19 Patient.",
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"abstract": "BACKGROUND\nKlebsiella pneumoniae is an important cause of nosocomial infections, but its role in severe acute pancreatitis (SAP) is not well defined. Few cases of K. pneumoniae associated SAP have been reported. Due to the emergence of extended-spectrum beta-lactamases (ESBLs) and carbapenemases, treatment of multidrug-resistant (MDR) K. pneumoniae presents a challenge. Tigecycline and colistin have gained recent attention for their broad-spectrum antimicrobial activity.\n\n\nMETHODS\nWe describe a case of SAP due to K. pneumoniae bearing K. pneumoniae carbapenemase (KPC) treated successfully with colistin plus tigecycline and offer a review of similar experiences published in the literature.\n\n\nRESULTS\nThe case reported herein required surgical drainage of multiple pancreatic abscesses and treatment with tigecycline and colistin. Our comparative analysis revealed a number of unique features associated with SAP due to K. pneumoniae: 1) underlying pancreatic injury, 2) multiple drug resistance determinants and virulence factors that complicate treatment, and 3) surgical debridement as a requirement for cure.\n\n\nCONCLUSIONS\nAs the prevalence of K. pneumoniae bearing KPC continues to increase in the healthcare setting, SAP caused by this MDR pathogen will become more common. Tigecycline plus colistin was a successful antibiotic regimen for the treatment of SAP due to K. pneumoniae bearing KPC.",
"affiliations": "1 Department of Medicine, University Hospitals Case Medical Center , Cleveland, Ohio.",
"authors": "Tugal|Derin|D|;Lynch|Melanie|M|;Hujer|Andrea M|AM|;Rudin|Susan|S|;Perez|Federico|F|;Bonomo|Robert A|RA|",
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"title": "Multi-drug-resistant Klebsiella pneumoniae pancreatitis: a new challenge in a serious surgical infection.",
"title_normalized": "multi drug resistant klebsiella pneumoniae pancreatitis a new challenge in a serious surgical infection"
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"abstract": "BACKGROUND\nChronic eosinophilic pneumonia (CEP) is rare and an idiopathic disorder. The disease has been associated with drugs, infection, or irradiation, and its relationship with asthma remains unclear.\nWe reported a case of a 49-year-old female patient after trastuzumab and radiation therapy for breast cancer. Two months after radiation treatment, the patient complained of productive cough, progressive breathlessness, occasional wheezing, and left pectoralgia.\nComputed tomography (CT) scan revealed infiltrates in lungs. Without evidence of infection, marked increased eosinophils in a transbronchial biopsy performed from the left upper lobe confirmed the diagnosis of CEP after trastuzumab and radiation therapy.\n\n\nMETHODS\nThe patient was started with oral prednisone at 0.5 mg/kg/day.\n\n\nRESULTS\nA CT scan of the chest obtained 2 weeks after steroid treatment showed diminishment of the lesions, and at the 6-month follow-up, the patient had no complaints of discomfort with no relapse of pulmonary lesions.\n\n\nCONCLUSIONS\nPhysicians should consider CEP as a diagnosis in patients who have had previous exposure to trastuzumab and radiation therapy, especially with a history of asthma. Timely diagnosis and treatment may benefit these patients.",
"affiliations": "Department of Internal Medicine.;Department of Respiratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.",
"authors": "Jin|Fan|F|;Wang|Shao-Ting|ST|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D005938:Glucocorticoids; D000068878:Trastuzumab; D011241:Prednisone",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30608451MD-D-18-0604010.1097/MD.0000000000014017140176700Research ArticleClinical Case ReportChronic eosinophilic pneumonia after trastuzumab and radiation therapy for breast cancer A case reportJin Fan MDaWang Shao-ting MDb∗NA. a Department of Internal Medicine,b Department of Respiratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.∗ Correspondence: Shao-ting Wang, Department of Respiratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing 100730, China (e-mail: bird0162@163.com).1 2019 04 1 2019 98 1 e1401726 8 2018 7 12 2018 13 12 2018 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0.Abstract\nRationale:\nChronic eosinophilic pneumonia (CEP) is rare and an idiopathic disorder. The disease has been associated with drugs, infection, or irradiation, and its relationship with asthma remains unclear.\n\nPatient concerns:\nWe reported a case of a 49-year-old female patient after trastuzumab and radiation therapy for breast cancer. Two months after radiation treatment, the patient complained of productive cough, progressive breathlessness, occasional wheezing, and left pectoralgia.\n\nDiagnoses:\nComputed tomography (CT) scan revealed infiltrates in lungs. Without evidence of infection, marked increased eosinophils in a transbronchial biopsy performed from the left upper lobe confirmed the diagnosis of CEP after trastuzumab and radiation therapy.\n\nInterventions:\nThe patient was started with oral prednisone at 0.5 mg/kg/day.\n\nOutcomes:\nA CT scan of the chest obtained 2 weeks after steroid treatment showed diminishment of the lesions, and at the 6-month follow-up, the patient had no complaints of discomfort with no relapse of pulmonary lesions.\n\nLessons:\nPhysicians should consider CEP as a diagnosis in patients who have had previous exposure to trastuzumab and radiation therapy, especially with a history of asthma. Timely diagnosis and treatment may benefit these patients.\n\nKeywords\nbreast cancerchronic eosinophilic pneumoniaradiation therapytrastuzumabOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nChronic eosinophilic pneumonia (CEP) is an idiopathic disorder characterized by an abnormal and marked accumulation of eosinophils in the interstitium and alveolar spaces of the lung.[1] CEP is a rare disorder, in registries of interstitial lung disease (ILD) in Europe, which accounts for up to 2.5% of cases of ILD.[2] Clinical manifestations are nonspecific with subacute to chronic respiratory symptoms. It is usually idiopathic, however, it has been associated with drugs or toxin, parasite or fungi, irradiation for cancer, and rheumatoid arthritis.[3–5] In this case, a female patient with a history of asthma and breast cancer developed CEP two months after she completed radiation and trastuzumab therapy.\n\n2 Case report\nA 49-year-old female with a medical history significant for left-sided breast cancer underwent lumpectomy in 2017, for which the pathology was ductal carcinoma, HER2 positive. Then, she was treated with trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks intravenously) and oral capecitabine (1000 mg/m2 twice a day on days 1–14 every 3 weeks) for 7 cycles from September 2017 to February 2018. During chemotherapy, a course of radiotherapy was performed, delivering 50 Gy in 25 fractions to left chest wall and supraclavicular fossa (2 Gy every fraction and 5 fractions per week) from November 17 to December 22, 2017. Two months after radiation treatment, the patient complained of productive cough and progressive breathlessness, occasional wheezing, and left pectoralgia. Her chest X-ray showed infiltrates in the left apical segment and was prescribed ipratropium inhalers and antibiotics. With no improvement in her symptoms, the computed tomography (CT) scan of the chest (Fig. 1A) revealed a left upper lobe consolidation. Half a month later, the range and density of the consolidation increased, and the left pleural effusion was newly seen (Fig. 1B).\n\nFigure 1 (A) CT showing a left upper lobe consolidation. (B) CT showing the consolidation increased and newly seen small-sized pleural effusion. (C) CT showing the consolidations diminished after steroid treatment for 2 weeks. (D) At 6-month follow-up, CT showing no relapse of pulmonary lesions.\n\nOn review of systems, the patient reported suffering from nocturnal sweats but no fevers, no change in appetite, and no weight loss. She had a full-time job as an office worker and denied any significant environmental exposure history. She is a never smoker with a 6-year past medical history of well-controlled asthma.\n\nLaboratory studies revealed 56% eosinophils (6.16 × 109/L) in peripheral blood, IgE 154.0 kU/L. Her blood biochemical profiles as well as serum immunoglobulins were all unremarkable. Infectious disease etiologies workup including serologies for aspergillus, filarial worms, lungworms, cysticercosis, and trichinella spiralis was negative. Stool examinations for ova and parasites were negative. Vasculitides and connective tissue diseases workup including antinuclear antibody, anti-double-stranded DNA, rheumatoid factor, and anti-neutrophil cytoplasmic antibody was negative. Bone marrow biopsy and FIP1L1-PDGFR alpha test excluded hematological diseases such as myeloproliferative neoplasms and hypereosinophilic syndrome. Pulmonary function tests revealed forced expiratory volume in the first second of 2.88 L (97.0% predicted), FEV1/FVC ratio of 73.73%, total lung capacity of 4.68 L (96.9% predicted), and diffusing capacity for carbon monoxide of 6.41 mmol/min/kPa (79.8% predicted). She underwent bronchoscopy, and bronchoalveolar lavage (BAL) fluid demonstrated eosinophil count of 85%. A transbronchial biopsy performed from the left upper lobe was suggestive of eosinophilic pneumonia with marked increased eosinophils without evidence of vasculitis, malignancy, or infection (Fig. 2). The diagnosis of chronic eosinophilic pneumonia (CEP) was made based on peripheral eosinophilia, pulmonary consolidation with pleural effusion, high percentage of BAL eosinophils, the finding of eosinophilic pneumonia on transbronchial biopsy, and the absence of other causes of eosinophilia. Our patient was given oral prednisone at 0.5 mg/kg/day and all antibiotics were discontinued. She had an excellent rapid clinical improvement. A CT scan of the chest (Fig. 1C) obtained 2 weeks after steroid treatment showed diminishment of the consolidations. Her prednisone was tapered slowly over 1 month and consequently stopped. At 6-month follow-up, the patient had no complaints of discomfort with no relapse of pulmonary lesions (Fig. 1D).\n\nFigure 2 Transbronchial biopsy showing eosinophilic infiltrates within lung parenchyma. No vasculitis or microorganisms were seen; H&E, ×200 magnification.\n\n3 Discussion\nThe pathophysiology of CEP remains incompletely delineated, though elevations of several cytokine, chemokine, and immunomodulatory products in studies of BAL fluid existed.[1,3] Women develop CEP about twice as often as men and a majority of patients are nonsmokers. A third to a half of affected patients have a history of asthma.[6] The diagnosis of CEP is typically based on the combination of clinical presentation, and typical symptoms include a productive cough, fever, breathlessness, weight loss, and night sweats, occurring over 2 months.[7] Chest imaging may show predominantly peripheral or pleural-based opacities. The BAL eosinophil count is always more than 25% in CEP.[6–8] CEP is usually a diagnosis of exclusion and the differential diagnosis includes acute eosinophilic pneumonia, allergic bronchopulmonary aspergillosis, infectious causes, eosinophilic granulomatosis with polyangiitis, or hypereosinophilic syndrome.[9] Lung biopsy is not necessary unless the BAL does not show eosinophilia, the chest imaging features are atypical, or the patient does not respond promptly to systemic glucocorticoid therapy. Response to steroids aids in confirming the diagnosis and is usually with dramatic improvement in symptoms within 24–48 h.[8]\n\nTherapy is indicated once the diagnosis of CEP has been made, as fewer than 10% of patients with CEP spontaneously recover. In addition, CEP occasionally leads to irreversible fibrosis, although death secondary to CEP is extremely unusual.[1,7] Initial therapy consists of oral prednisone at a dose of 0.5 mg/kg per day. We usually continue the initial dose for 2 weeks after the complete resolution of symptoms and abnormal plain chest radiographic (usually 4–6 weeks).[9] Symptomatic or radiographic recurrence is common (50–80% of cases) either after cessation of therapy, or less commonly, with tapering of the glucocorticoid dose. In managing a relapse, the prednisone dose can be restored to 0.5 mg/kg per day. Treatment usually lasts at least 3 months, usually 6–9 months. Occasionally, glucocorticoid therapy continues indefinitely.[9] Alternative therapies have been explored for patients with recurrent flares of CEP that are associated with radiographic opacities, including high-dose inhaled glucocorticoids and omalizumab (monoclonal antibody to IgE).[10,11] Inhaled glucocorticoids (1000–1500 μg per 24 h) have been reported to be effective in CEP. Inhaled glucocorticoids are not recommended as an initial or monotherapy, but may help in reducing the maintenance dose of oral glucocorticoid.[10]\n\nOur patient met the diagnosis of CEP, and the therapeutic effects of glucocorticoid have proved the diagnosis. After exclusion of other causes, the pneumonitis appeared to be the consequence of trastuzumab or radiotherapy. Radiation therapy has been associated with the development of eosinophilic pneumonia, especially in those who have underlying allergies such as asthma.[12,13] Cottin and Chaaban successively reported cases of patient with CEP in breast patients post-radiation therapy, and all patients rapidly improved with oral corticosteroids without sequelae.[13,14] In addition to radiotherapy, triggers, such as drugs, toxins, and environmental exposure, are usually needed.[13,15] No case of trastuzumab causing CEP has been reported, but there are reports of trastuzumab related to pulmonary interstitial disease in the NSABP B-31 and N9831 trials, which revealed that 9 patients in the trastuzumab group had interstitial pneumonitis.[16] Physicians should be aware of a causative association between trastuzumab and pulmonary toxicity, and consider CEP as a diagnosis in patients who have had previous exposure to trastuzumab and radiation therapy for breast cancer.\n\nAcknowledgments\nThe authors thank Dr Dachun Zhao of Department of Pathology, PUMCH for his valuable help and advice.\n\nAuthor contributions\nWriting – original draft: Fan Jin, Shaoting Wang.\n\nWriting – review & editing: Fan Jin, Shaoting Wang.\n\nAbbreviations: CEP = chronic eosinophilic pneumonia, CT = computed tomography.\n\nSTW and FJ designed the case report and both were major contributors in writing the manuscript.\n\nFunding: No funding was received.\n\nAvailability of data and materials: All data generated or analyzed during this study are included in this article.\n\nEthics approval and consent to participate: In accordance with the Declaration of Helsinki, informed consent was obtained from the patient.\n\nCompeting interests: The authors declare that they have no competing interests.\n==== Refs\nReferences\n[1] Allen JN Davis WB \nEosinophilic lung diseases . Am J Respir Crit Care Med \n1994 ;150 :1423–38 .7952571 \n[2] Thomeer MJ Costabe U Rizzato G \nComparison of registries of interstitial lung diseases in three European countries . Eur Respir J Suppl \n2001 ;32 :114s–8s .11816817 \n[3] Akuthota P Weller PF \nEosinophilic pneumonias . Clin Microbiol Rev \n2012 ;25 :649–60 .23034324 \n[4] Jaimes-Hernández J Mendoza-Fuentes A Meléndez-Mercado CI \nChronic eosinophilic pneumonia: autoimmune phenomenon or immunoallergic disease? Case report and literature review . Reumatol Clin \n2012 ;8 :145–8 .22196999 \n[5] Campos LE Pereira LF \nPulmonary eosinophilia . J Bras Pneumol \n2009 ;35 :561–73 .19618037 \n[6] Sveinsson OA Isaksson HJ Gudmundsson G \n[Chronic eosinophilic pneumonia in Iceland: clinical features, epidemiology and review] . Laeknabladid \n2007 ;93 :111–6 .17277407 \n[7] Jederlinic PJ Sicilian L Gaensler EA \nChronic eosinophilic pneumonia. A report of 19 cases and a review of the literature . Medicine (Baltimore) \n1988 ;67 :154–62 .3285120 \n[8] Järvenpää R Holli K Pitkänen M \nRadiological pulmonary findings after breast cancer irradiation: a prospective study . Acta Oncol \n2006 ;45 :16–22 .16464791 \n[9] Marchand E Reynaud-Gaubert M Lauque D \nIdiopathic chronic eosinophilic pneumonia. A clinical and follow-up study of 62 cases. The Groupe d’Etudes et de Recherche sur les Maladies “Orphelines” Pulmonaires (GERM“O”P) . Medicine (Baltimore) \n1998 ;77 :299–312 .9772920 \n[10] Minakuchi M Niimi A Matsumoto H \nChronic eosinophilic pneumonia: treatment with inhaled corticosteroids . Respiration \n2003 ;70 :362–6 .14512670 \n[11] Cazzola M Mura M Segreti A \nEosinophilic pneumonia in an asthmatic patient treated with omalizumab therapy: forme-fruste of Churg-Strauss syndrome? \nAllergy \n2009 ;64 :1389–90 .19392997 \n[12] Guerriero G Battista C Montesano M \nUnusual complication after radiotherapy for breast cancer bronchiolitis obliterans organizing pneumonia case report and review of the literature . Tumori \n2005 ;91 :421–3 .16459640 \n[13] Cottin V Frognier R Monnot H \nChronic eosinophilic pneumonia after radiation therapy for breast cancer . Eur Respir J \n2004 ;23 :9–13 .14738224 \n[14] Chaaban S Salloum V \nChronic eosinophilic pneumonia in a breast cancer patient post-radiation therapy: a case report . Respir Care \n2014 ;59 :e81–3 .24026185 \n[15] Cordier JF \nSchwarz MI King TE \nEosinophilic pneumonias. \nInterstitial Lung Disease. \n4th edn. Hamilton, Ontario, B.C. : Decker Inc ; 2003 \n657–700 .\n[16] Romond EH Perez EA Bryant J \nTrastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer . N Engl J Med \n2005 ;353 :1673–84 .16236738\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "98(1)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000284:Administration, Oral; D000074322:Antineoplastic Agents, Immunological; D001943:Breast Neoplasms; D002908:Chronic Disease; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D008875:Middle Aged; D011241:Prednisone; D011657:Pulmonary Eosinophilia; D011878:Radiotherapy; D014057:Tomography, X-Ray Computed; D000068878:Trastuzumab; D016896:Treatment Outcome",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e14017",
"pmc": null,
"pmid": "30608451",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17277407;24026185;3285120;9772920;23034324;14512670;11816817;19392997;16459640;7952571;19618037;16464791;22196999;16236738;14738224",
"title": "Chronic eosinophilic pneumonia after trastuzumab and radiation therapy for breast cancer: A case report.",
"title_normalized": "chronic eosinophilic pneumonia after trastuzumab and radiation therapy for breast cancer a case report"
} | [
{
"companynumb": "CN-MYLANLABS-2019M1012786",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": "3",
... |
{
"abstract": "Palliative sedation is increasingly being utilised when patients are close to death. Despite clear guidelines, its implementation is often problematic. In this clinical lesson we describe two patients in whom sedation did not go according to plan. The first case concerns a relative overdose of the medication which resulted in agitation, and the second case concerns the premature initiation of palliative sedation which caused the period of sedation to last too long. Suggestions are made to prevent these problems occurring.",
"affiliations": "Integraal Kankercentrum Nederland.;Integraal Kankercentrum Nederland.;Integraal Kankercentrum Nederland.;Integraal Kankercentrum Nederland.",
"authors": "Rolf|C A M|CAM|;Cost Budde|Paul|P|;van Heest|Florien|F|;Schuit|Karel|K|",
"chemical_list": "D006993:Hypnotics and Sedatives",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2162",
"issue": "162()",
"journal": "Nederlands tijdschrift voor geneeskunde",
"keywords": null,
"medline_ta": "Ned Tijdschr Geneeskd",
"mesh_terms": "D016292:Conscious Sedation; D006801:Humans; D006993:Hypnotics and Sedatives; D019300:Medical Errors; D010166:Palliative Care; D013727:Terminal Care",
"nlm_unique_id": "0400770",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30020568",
"pubdate": "2018-05-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "If problems arise during palliative sedation: considerations in sedation in the terminal phase.",
"title_normalized": "if problems arise during palliative sedation considerations in sedation in the terminal phase"
} | [
{
"companynumb": "NL-PURDUE-GBR-2019-0064208",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "MIDAZOLAM HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "Severe combined immunodeficiency (SCID) is a fatal childhood disease unless immune reconstitution is performed early in life, with either hematopoietic stem cell transplantation or gene therapy. One of its subtypes is caused by adenosine deaminase (ADA) enzyme deficiency, which leads to the accumulation of toxic metabolites that impair lymphocyte development and function. With the development of polyethylene glycol-conjugated adenosine deaminase (PEG-ADA) enzyme replacement therapy, many ADA-deficient children with SCID who could not receive a hematopoietic stem cell transplantation or gene therapy survived and had longer and healthier lives. We report a 24-year course of treatment in a patient who was diagnosed with ADA deficiency at 4 months of age. The patient was treated with PEG-ADA, which was the only therapy available for him. The patient's plasma ADA level was regularly monitored and the PEG-ADA dose adjusted accordingly. This treatment has resulted in near-normalization of lymphocyte counts, and his clinical course has been associated with only minor to moderate infections. Thus far, he has had no manifestations of autoimmune or lymphoproliferative disorders. This patient is among the longest to be maintained on PEG-ADA enzyme replacement therapy.",
"affiliations": "Allergy and Immunology Section, Louisiana State University Health Sciences Center, Shreveport, Louisiana; and.;Department of Biochemistry, Duke University Medical Center, Durham, North Carolina.;Allergy and Immunology Section, Louisiana State University Health Sciences Center, Shreveport, Louisiana; and sbahna@lsuhsc.edu.",
"authors": "Tartibi|Hana M|HM|;Hershfield|Michael S|MS|;Bahna|Sami L|SL|",
"chemical_list": "D000243:Adenosine Deaminase",
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2015-2169",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "137(1)",
"journal": "Pediatrics",
"keywords": null,
"medline_ta": "Pediatrics",
"mesh_terms": "D000243:Adenosine Deaminase; D000361:Agammaglobulinemia; D056947:Enzyme Replacement Therapy; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008297:Male; D016511:Severe Combined Immunodeficiency; D055815:Young Adult",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26684479",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A 24-Year Enzyme Replacement Therapy in an Adenosine-deaminase-Deficient Patient.",
"title_normalized": "a 24 year enzyme replacement therapy in an adenosine deaminase deficient patient"
} | [
{
"companynumb": "US-SIGMA-TAU US-2016STPI000254",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PEGADEMASE BOVINE"
},
"drugadditional":... |
{
"abstract": "BACKGROUND\nHip fractures due to falls cause significant morbidity and mortality among geriatric patients. A significant unmet need is an optimal pain management strategy. Consequently, patients are treated with standard analgesic care (SAC) regimens, which deliver high narcotic doses. However, narcotics are associated with delirium as well as gastrointestinal and respiratory failure risks. The purpose of this pilot study was to determine the safety and effectiveness of ultrasound-guided continuous compartmental fascia iliaca block (CFIB) in patients 60 years or older with hip fractures in comparison with SAC alone.\n\n\nMETHODS\nWe performed a retrospective study of 108 patients 60 years or older, with acute pain secondary to hip fracture (2012-2013). Patient variables were age, sex, comorbidities, and Injury Severity Score (ISS). Primary outcome was pain scores; secondary outcomes included hospital length of stay, discharge disposition, morbidity, and mortality. Statistical analysis was performed using (IBM SPSS version 22). For group comparison (SAC vs. SAC + CFIB) median test, repeated-measures analysis and Student's t test of transformed pain scores were used.\n\n\nRESULTS\nSixty-four patients received SAC only, and 44 patients received SAC + CFIB. Each CFIB placement was successful on first attempt without complications. Median time from emergency department arrival to block placement was 12.5 hours (interquartile range, 4-22 hours). Patients who received SAC + CFIB had significantly lower pain score ratings than patients treated with SAC alone. There were no differences in inpatient morbidity and mortality rates. Patients treated with SAC + CFIB were discharged home more often (p < 0.05).\n\n\nCONCLUSIONS\nUltrasound-guided CFIB is safe, practical, and readily integrated into the G-60 service for improved pain management of hip fractures. We are now conducting a prospective randomized control trial to confirm our observations.\n\n\nMETHODS\nTherapeutic study, level IV.",
"affiliations": "From the John C. Lincoln North Mountain Hospital (A.J.M., A.K.H., L.P., A.S., M.C., J.F.S., F.A.-O., J.K.D.); and Valley Surgical Clinics, LTD (O.F.O.), Phoenix, Arizona.",
"authors": "Mangram|Alicia J|AJ|;Oguntodu|Olakunle F|OF|;Hollingworth|Alexandra K|AK|;Prokuski|Laura|L|;Steinstra|Arleen|A|;Collins|Mary|M|;Sucher|Joseph F|JF|;Ali-Osman|Francis|F|;Dzandu|James K|JK|",
"chemical_list": "D000700:Analgesics",
"country": "United States",
"delete": false,
"doi": "10.1097/TA.0000000000000841",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2163-0755",
"issue": "79(6)",
"journal": "The journal of trauma and acute care surgery",
"keywords": null,
"medline_ta": "J Trauma Acute Care Surg",
"mesh_terms": "D000058:Accidental Falls; D000368:Aged; D000369:Aged, 80 and over; D000700:Analgesics; D005260:Female; D005267:Femoral Nerve; D006620:Hip Fractures; D006801:Humans; D015601:Injury Severity Score; D008297:Male; D009407:Nerve Block; D059408:Pain Management; D010147:Pain Measurement; D010865:Pilot Projects; D012042:Registries; D012189:Retrospective Studies; D018084:Ultrasonography, Interventional",
"nlm_unique_id": "101570622",
"other_id": null,
"pages": "1067-72; discussion 1072",
"pmc": null,
"pmid": "26680143",
"pubdate": "2015-12",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Geriatric trauma G-60 falls with hip fractures: A pilot study of acute pain management using femoral nerve fascia iliac blocks.",
"title_normalized": "geriatric trauma g 60 falls with hip fractures a pilot study of acute pain management using femoral nerve fascia iliac blocks"
} | [
{
"companynumb": "US-JNJFOC-20151221547",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRAMADOL"
},
"drugadditional": null,
"d... |
{
"abstract": "Hepatic cytochrome P450 enzyme induction is associated with certain antiepileptic drugs (AEDs) and may result in hypocalcaemia secondary to vitamin D deficiency. We report a case of a 44-year-old man with a history of epilepsy, who presented with breakthrough seizures after having previously been seizure-free for 11 years. Investigations revealed severe hypocalcaemia with a corrected calcium of 1.7 mmol/L. His phenytoin dose was increased, and he was started on calcium supplementation. He was discharged with a corrected calcium level of 2.05 mmol/L but was readmitted 1 week later with further seizures and a corrected calcium of 1.89 mmol/L. 25-hydroxyvitamin D was low. AED-induced hypocalcaemia was suspected, which had been made paradoxically worse by the increase in phenytoin dose. Alfacalcidol was prescribed and he was switched from phenytoin to levetiracetam with resolution of hypocalcaemia and no further seizures. The authors recommend screening for calcium and vitamin D deficiency in patients on enzyme-inducing AEDs.",
"affiliations": "Department of Medicine, Mater Dei Hospital, Msida, Malta.;Department of Diabetes and Endocrinology, Mater Dei Hospital, Msida, Malta.;Department of Diabetes and Endocrinology, Mater Dei Hospital, Msida, Malta mifsudsimon@hotmail.com.;Department of Diabetes and Endocrinology, Mater Dei Hospital, Msida, Malta.",
"authors": "Gauci|Zachary|Z|;Rizzo|Christopher|C|;Mifsud|Simon|S|;Cachia|Mario J|MJ|",
"chemical_list": "D000927:Anticonvulsants; D010672:Phenytoin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-232429",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(12)",
"journal": "BMJ case reports",
"keywords": "Calcium and bone; Neurology (drugs and medicines)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000927:Anticonvulsants; D003937:Diagnosis, Differential; D004827:Epilepsy; D006801:Humans; D006996:Hypocalcemia; D008297:Male; D008875:Middle Aged; D010672:Phenytoin; D012640:Seizures",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31811093",
"pubdate": "2019-12-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17201695;23738537;27843822;15084684;22928072;19730969;29597231;12011279;6726133;25810356;19693326;17634462;24063762",
"title": "Paradoxical deterioration in seizure control due to anticonvulsant-induced hypocalcaemia.",
"title_normalized": "paradoxical deterioration in seizure control due to anticonvulsant induced hypocalcaemia"
} | [
{
"companynumb": "MT-PFIZER INC-2019546990",
"fulfillexpeditecriteria": "1",
"occurcountry": "MT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PHENYTOIN"
},
"drugadditional": "1",
... |
{
"abstract": "The combination of lomustine and bevacizumab is a commonly used salvage treatment for recurrent glioblastoma (GBM). We investigated the toxicity and efficacy of lomustine plus bevacizumab (lom-bev) in a community-based patient cohort and made a comparison to another frequently used combination therapy consisting of irinotecan plus bevacizumab (iri-bev). Seventy patients with recurrent GBM were treated with lomustine 90 mg/m2 every 6 weeks and bevacizumab 10 mg/kg every 2 weeks. Toxicity was registered and compared to the toxicity observed in 219 recurrent GBM patients who had previously been treated with irinotecan 125 mg/m2 and bevacizumab 10 mg/kg every 2 weeks. The response rate was 37.1% for lom-bev and 30.1% for iri-bev. Median progression-free survival (PFS) was 23 weeks for lom-bev and 21 weeks for iri-bev (p = 0.9). Overall survival (OS) was 37 weeks for lom-bev and 32 weeks for iri-bev (p = 0.5). Lom-bev caused a significantly higher frequency of thrombocytopenia (11.4% grade 3-4) compared to iri-bev (3.5% grade 3-4). Iri-bev patients had more gastrointestinal toxicity with regard to nausea, vomiting, diarrhea, constipation and stomatitis. Within the limitations of the study lom-bev is a well-tolerated treatment for recurrent GBM, although hematological toxicity may be a dose limiting factor. No significant differences between lom-bev and iri-bev were observed with regard to PFS or OS. The differences in toxicity profiles between lom-bev and iri-bev could guide treatment decision in recurrent GBM therapy as efficacy is equal and no predictive factors for efficacy exist.",
"affiliations": "Department of Oncology, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark. jan.nyrop.jakobsen@regionh.dk.;Department of Oncology, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark.;Department of Radiation Biology, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark.;Department of Radiation Biology, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark.;Department of Radiation Biology, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark.;Department of Oncology, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark.;Department of Surgical Gastroenterology, Hvidovre Hospital, Kettegårds Alle 30, Hvidovre, Denmark.;Department of Oncology, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark.;Department of Radiation Biology, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark.",
"authors": "Jakobsen|J N|JN|;Urup|T|T|;Grunnet|K|K|;Toft|A|A|;Johansen|M D|MD|;Poulsen|S H|SH|;Christensen|I J|IJ|;Muhic|A|A|;Poulsen|H S|HS|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000068258:Bevacizumab; D000077146:Irinotecan; D008130:Lomustine",
"country": "United States",
"delete": false,
"doi": "10.1007/s11060-017-2736-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-594X",
"issue": "137(2)",
"journal": "Journal of neuro-oncology",
"keywords": "Bevacizumab; Chemotherapy; Glioblastoma; Irinotecan; Lonustine; Recurrent glioblastoma",
"medline_ta": "J Neurooncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D001932:Brain Neoplasms; D005260:Female; D005500:Follow-Up Studies; D005909:Glioblastoma; D006801:Humans; D000077146:Irinotecan; D008130:Lomustine; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D016879:Salvage Therapy; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8309335",
"other_id": null,
"pages": "439-446",
"pmc": null,
"pmid": "29330749",
"pubdate": "2018-04",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "19031176;15933418;27262894;2358840;20231676;24327581;19720927;25035291;26828563;21468776;29141164;21385110;26490307;22548369;15758009",
"title": "Toxicity and efficacy of lomustine and bevacizumab in recurrent glioblastoma patients.",
"title_normalized": "toxicity and efficacy of lomustine and bevacizumab in recurrent glioblastoma patients"
} | [
{
"companynumb": "DK-PFIZER INC-2018529641",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Large outbreaks of acute hepatitis E, caused by hepatitis E virus (HEV) genotypes 1 and 2, are known from developing countries with suboptimal sanitation infrastructure. An increasing incidence of HEV infections is being reported in industrialised countries, caused mainly by HEV genotypes 3 and 4, which are often found among pigs. Recent evidence suggests that in immunocompromised patients about 50% of the cases of acute hepatitis E evolve to chronic hepatitis with rapid progression to cirrhosis. Thus, HEV should be considered a cause of chronic hepatitis in immunocompromised patients, such as solid organ transplant recipients. Because an antibody response to HEV may be absent in these patients, an HEV RNA test should be carried out when serum liver tests are elevated over months. In small case series, ribavirin has been shown to represent a promising treatment option for chronic HEV infection. To increase the awareness for HEV infection in immunocompromised patients, a representative case report of an HEV-infected renal transplant recipient with chronic hepatitis E, successfully treated with ribavirin, is presented. Studies are required to determine the optimal duration of ribavirin therapy and to assess outcome for solid organ transplant recipients with chronic HEV infection.",
"affiliations": "Departments of Gastroenterology & Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.",
"authors": "de Niet|A|A|;Zaaijer|H L|HL|;ten Berge|I|I|;Weegink|C J|CJ|;Reesink|H W|HW|;Beuers|U|U|",
"chemical_list": "D012367:RNA, Viral; D012254:Ribavirin",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-2977",
"issue": "70(6)",
"journal": "The Netherlands journal of medicine",
"keywords": null,
"medline_ta": "Neth J Med",
"mesh_terms": "D000818:Animals; D016751:Hepatitis E; D016752:Hepatitis E virus; D006521:Hepatitis, Chronic; D006801:Humans; D016867:Immunocompromised Host; D012367:RNA, Viral; D012254:Ribavirin",
"nlm_unique_id": "0356133",
"other_id": null,
"pages": "261-6",
"pmc": null,
"pmid": "22859417",
"pubdate": "2012-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Chronic hepatitis E after solid organ transplantation.",
"title_normalized": "chronic hepatitis e after solid organ transplantation"
} | [
{
"companynumb": "NL-ACCORD-046196",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "1",
"dru... |
{
"abstract": "OBJECTIVE\nTo explore the safety and effectiveness of the individually determined application granulocyte-colony stimulating factor (G-CSF) after autologous peripheral blood stem cell transplantation (ASCT).\n\n\nMETHODS\nThe administration of G-CSF from day +5 (arm A) was compared in a randomised, controlled trial with delayed, individually determined administration (G-CSF started when WBC >or= 0.5 x 10(9)/L and ANC >or= 0.1 x 10(9)/L or at day +10; arm B), and with placebo (arm C).\n\n\nRESULTS\nOne hundred and six patients, median age 45 (range 21-64), all with malignant lymphoma treated with BEAM chemotherapy were analysed. A significant difference in the time to neutrophil engraftment and in the duration of neutropenia <0.5 x 10(9)/L and <1.0 x 10(9)/L was observed between the arms (P = 0.04-<0.0001) with a 1-d prolongation of the median durations in arm B in comparison with arm A but a 2-4-d prolongation in the placebo arm C in comparison with arm B. The median number and range of days to neutrophil engraftment >0.5 x 10(9)/L after graft re-infusion was 10 (9-14) in arm A; 11 (9-19) in arm B; and 14 (10-30) in arm C (P < 0.0001). Engraftment of platelets to >20 x 10(9)/L and >50 x 10(9)/L was significantly delayed in the arms using G-CSF in comparison with placebo (P = 0.04-0.002) without any increase in bleeding or in transfusion requirement. There was no difference in the incidence and duration of transplant-related complications and their treatment between the arms.\n\n\nCONCLUSIONS\nOur study has confirmed the safety of individually determined administration of G-CSF. The optimal timing of G-CSF application after ASCT in patients with good-quality grafts is shortly before expected spontaneous engraftment.",
"affiliations": "Department of Hemato-Oncology, University Hospital, Olomouc, Czech Republic. edgar.faber@fnol.cz",
"authors": "Faber|Edgar|E|;Pytlík|Robert|R|;Slabý|Jirí|J|;Zapletalová|Jana|J|;Kozák|Tomás|T|;Raida|Ludek|L|;Papajík|Tomás|T|;Zikesová|Eva|E|;Maresová|Ivana|I|;Hamouzová|Marie|M|;Indrák|Karel|K|;Trnený|Marek|M|",
"chemical_list": "D010919:Placebos; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D000069585:Filgrastim",
"country": "England",
"delete": false,
"doi": "10.1111/j.1600-0609.2006.00741.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "77(6)",
"journal": "European journal of haematology",
"keywords": null,
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000328:Adult; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D008223:Lymphoma; D008297:Male; D008875:Middle Aged; D009504:Neutrophils; D036102:Peripheral Blood Stem Cell Transplantation; D010919:Placebos; D011446:Prospective Studies; D011994:Recombinant Proteins; D013997:Time Factors; D014182:Transplantation, Autologous",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "493-500",
"pmc": null,
"pmid": "17042769",
"pubdate": "2006-12",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Individually determined dosing of filgrastim after autologous peripheral stem cell transplantation in patients with malignant lymphoma--results of a prospective multicentre controlled trial.",
"title_normalized": "individually determined dosing of filgrastim after autologous peripheral stem cell transplantation in patients with malignant lymphoma results of a prospective multicentre controlled trial"
} | [
{
"companynumb": "CZ-AMGEN-CZESP2020072728",
"fulfillexpeditecriteria": "2",
"occurcountry": "CZ",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MELPHALAN"
},
"drugadditional": null,
... |
{
"abstract": "A 33-year-old woman with history of HIV presented with 4 months of gradually progressing right hip pain and was found to have avascular necrosis (AVN) of both femoral heads. She had no other risk factors for AVN including sickle cell disease, systemic lupus erythematosus, prolonged steroid used or trauma. She initially failed conservative management and ultimately had bilateral hip core decompressions. After decompression therapy, the left femoral head collapsed and patient underwent a left total hip arthroplasty. Her postsurgical course was complicated by the left sciatic nerve neuropathy for which she is currently being managed with duloxetine. She has yet to follow-up with her orthopaedic surgeon for further evaluation.",
"affiliations": "Department of Internal Medicine, University of Florida Health, Jacksonville, Florida, USA.;Department of Internal Medicine, University of Florida Health, Jacksonville, Florida, USA.;Department of Internal Medicine, University of Florida Health, Jacksonville, Florida, USA.;Department of Internal Medicine, University of Florida Health, Jacksonville, Florida, USA.",
"authors": "Green|Kevin R|KR|;Hernandez-Jimenez|Jarelys M|JM|;Isache|Carmen Liliana|CL|;Jacob|Rafik|R|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-221678",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "Hiv / aids; musculoskeletal syndromes",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D018771:Arthralgia; D019644:Arthroplasty, Replacement, Hip; D005260:Female; D005271:Femur Head Necrosis; D015658:HIV Infections; D006621:Hip Joint; D006801:Humans; D011183:Postoperative Complications; D011859:Radiography; D012307:Risk Factors; D020426:Sciatic Neuropathy; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29880618",
"pubdate": "2018-06-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15507502;22820515;17625723;29619587;24098826;27047876;16863626",
"title": "Avascular necrosis: a growing concern for the HIV population.",
"title_normalized": "avascular necrosis a growing concern for the hiv population"
} | [
{
"companynumb": "US-CIPLA LTD.-2019US01330",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"drugadditional": "3",
... |
{
"abstract": "Primary adenosquamous carcinoma (ASC) of the liver is a rare subtype of cholangiocarcinoma that comprises both adenocarcinoma and squamous cell carcinoma components. We report a 48-year-old woman with advanced primary ASC and small cell carcinoma of the liver who had extrahepatic metastasis and received multiple chemotherapy regimens. After first presenting with upper abdominal pain, imaging revealed a 10.2 × 9.5 cm mass in the right lobe of the liver with lymph node and lung metastases. A liver tumor biopsy revealed adenocarcinoma and squamous cell carcinoma components, leading to a diagnosis of advanced primary ASC of the liver. The tumor shrank with gemcitabine/cisplatin therapy; however, neuron-specific enolase (NSE) and CYFRA levels were increased and the tumor grew. Next, hepatic arterial infusion chemotherapy using 5-fluorouracil and cisplatin decreased NSE and CYFRA levels and suppressed tumor growth. However, due to tumor growth, she died 14 months post-initial diagnosis. Post-autopsy pathology revealed a mixture of CD56- and synaptophysin-positive small cell carcinoma component in addition to ASC. We report a rare advanced primary ASC with small cell carcinoma of the liver diagnosed at autopsy.",
"affiliations": "Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan.;Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan.;Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan.;Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan.;Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan.;Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan.;Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan.;Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan.;Division of Diagnostic Pathology/Surgical Pathology, University of Fukui Hospital, Fukui, Japan.;Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan. nakamoto-med2@med.u-fukui.ac.jp.",
"authors": "Nosaka|Takuto|T|http://orcid.org/0000-0002-1929-7305;Ohtani|Masahiro|M|;Namikawa|Shouichi|S|;Takahashi|Kazuto|K|;Naito|Tatsushi|T|;Ofuji|Kazuya|K|;Matsuda|Hidetaka|H|;Hiramatsu|Katsushi|K|;Imamura|Yoshiaki|Y|;Nakamoto|Yasunari|Y|http://orcid.org/0000-0002-3160-3555",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-021-01474-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "14(5)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Chemotherapy; Primary adenosquamous carcinoma of the liver; Small cell carcinoma",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D001344:Autopsy; D001650:Bile Duct Neoplasms; D001653:Bile Ducts, Intrahepatic; D018196:Carcinoma, Adenosquamous; D018288:Carcinoma, Small Cell; D005260:Female; D006801:Humans; D008099:Liver; D008875:Middle Aged",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "1496-1502",
"pmc": null,
"pmid": "34216375",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "2411107",
"title": "Advanced primary adenosquamous carcinoma of the liver with a small cell carcinoma component: an autopsy case report.",
"title_normalized": "advanced primary adenosquamous carcinoma of the liver with a small cell carcinoma component an autopsy case report"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-319007",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GEMCITABINE"
},
"dru... |
{
"abstract": "BACKGROUND\nThe study was carried out in Riyadh City Hospital to determine the hospital prevalence of acute rheumatic fever (ARF), its characteristics and to determine the proportion of the ARF population that have recurrent attacks.\n\n\nMETHODS\nThe study was an analysis of 83 children with ARF, admitted to the Children's Hospital, Riyadh, over a 10-year period (1994-2003). The diagnosis of ARF was based on clinical features as defined in the modified Jones criteria with evidence of recent streptococcal infection. The diagnosis of recurrence of rheumatic fever in children with rheumatic heart disease was based on the presence of one major criterion apart from carditis or two minor criteria, in addition to evidence of preceding streptococcal infection.\n\n\nRESULTS\nThe mean age at presentation was 9 years. In 31 (37%) cases, arthritis was the only major Jones criterion. In 30 (36%) others, arthritis was associated with carditis and in 3 (4%), with chorea. Cardiac involvement was documented in 44 (53%) cases; it occurred alone in 5 (6%), with arthritis in 30 (36%), and with chorea in 9 (11%) others. Among the 44 with carditis, the pattern of cardiac involvement was valvular only (mild carditis) in 30 (68%), while it was severe in the remaining 14 (32%) cases who also had heart failure. The involvement of the mitral valve alone occurred in 26 (59%) cases in the form mitral regurgitation, while both aortic and mitral valve regurgitation were present in 11 (25%) cases, and aortic valve regurgitation alone in four (9%) others. Chorea was the only major criterion of ARF in 5 children (6%), while it occurred in association with other major criteria in 12 (15%) others. Nineteen (23%) children had recurrent attacks of ARF.\n\n\nCONCLUSIONS\nARF continues to occur in Saudi Arabia in the period (1994-2003), despite the progress made in the socio-economic development of the country, and this is often associated with severe cardiac involvement.",
"affiliations": "Al-Yamamah Hospital, P.O. Box 60989, Riyadh 11555, Saudi Arabia.",
"authors": "Qurashi|Mansour Al|MA|",
"chemical_list": null,
"country": "Saudi Arabia",
"delete": false,
"doi": "10.1016/j.jsha.2009.10.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1016-7315",
"issue": "21(4)",
"journal": "Journal of the Saudi Heart Association",
"keywords": "Children; Rheumatic fever; Saudi Arabia",
"medline_ta": "J Saudi Heart Assoc",
"mesh_terms": null,
"nlm_unique_id": "9887261",
"other_id": null,
"pages": "215-20",
"pmc": null,
"pmid": "23960577",
"pubdate": "2009-10",
"publication_types": "D016428:Journal Article",
"references": "12192255;15543494;16297251;2107309;11176244;18845020;1404745;14500407;17671252;8637788;17049647;8461241;10990177;16940843;17201202;9109143;10657336;19246689;14602504;12150180;15024446;15965814;11129913;18695275;18392063;8637787;9746998;23008668;16330700;9652675;11438128;8469638;12131934;19204317;8637785;12070681;7837966;17414410;12691285;9417157",
"title": "The pattern of acute rheumatic fever in children: Experience at the children's hospital, Riyadh, Saudi Arabia.",
"title_normalized": "the pattern of acute rheumatic fever in children experience at the children s hospital riyadh saudi arabia"
} | [
{
"companynumb": "SA-SUN PHARMACEUTICAL INDUSTRIES LTD-2015R1-101815",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": null,
"drugadditional": null,
"drugadministrationroute": "... |
{
"abstract": "Eosinophilic granulomatosis (EGPA), or Churg-Strauss syndrome, is a rare and necrotizing systemic vasculitis, which affects small-to-medium-sized vessels and often manifests with severe asthma and eosinophilia. We report a case of a 72 year-old male with a two-year lung-biopsy proven history of EGPA who presented with retiform purpura and patchy necrosis on his bilateral shins, which progressed to sharply demarcated, stellate ulcerations with surrounding erythema within two weeks. Laboratory work up revealed elevated anti-Cardiolipin IgM, rheumatoid factor, erythrocyte sedimentation rate, and C-reactive protein, although P-neutrophil cytoplasmic antibody (P-ANCA) and C-neutrophil cytoplasmic antibody (C-ANCA) were negative. Vascular studies revealed long anterior tibial and dorsalis pedis artery occlusion and severe small vessel disease in plantar digital arteries. Despite treatment with intravenous cyclophosphamide, pulse-dose methylprednisolone, and pentoxifylline, the patient experienced disease progression and limb threatening arterial thrombosis. This case highlights the importance of vascular and neuropathic sequelae that may result from untreated or undertreated EGPA in P-ANCA-negative patients without active pulmonary symptoms.",
"affiliations": "University of North Dakota, Fargo, ND, USA.;University of Colorado Hospital, Aurora, CO, USA.;University of Colorado Hospital, Aurora, CO, USA.;University of Colorado Hospital, Aurora, CO, USA.;University of Colorado Hospital, Aurora, CO, USA.",
"authors": "Braunberger|Taylor|T|;Mounessa|Jessica S|JS|;O'Leary|Ryan|R|;Carlson|Ekama|E|;Newman|Sabrina|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jccw.2017.03.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2213-5103",
"issue": "8(1-3)",
"journal": "The journal of the American College of Clinical Wound Specialists",
"keywords": "Churg-Strauss syndrome; Eosinophilic granulomatosis with polyangiitis; Gangrene; P-ANCA; Thrombosis",
"medline_ta": "J Am Coll Clin Wound Spec",
"mesh_terms": null,
"nlm_unique_id": "101620247",
"other_id": null,
"pages": "28-30",
"pmc": null,
"pmid": "30276121",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "24289197;22977665;21314005;25003763;19833618;17143092;2202307;27191665;25695917",
"title": "Limb-Threatening Arterial Thrombosis in a Patient with Eosinophilic Granulomatosis with Polyangiitis.",
"title_normalized": "limb threatening arterial thrombosis in a patient with eosinophilic granulomatosis with polyangiitis"
} | [
{
"companynumb": "US-VALIDUS PHARMACEUTICALS LLC-US-2017VAL001564",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadd... |
{
"abstract": "A 32-year-old man developed lumbar discitis and osteomyelitis after receiving a cell-based injection for the treatment of degenerative disc disease. Initial cultures were negative, but he continued to worsen, and a repeat set of cultures was taken. On day 10, Cutibacterium acnes was isolated. He was then successfully treated with 12 weeks of intravenous antibiotics.\n\n\n\nThere is minimal regulation on the preparation or administration of cell-based interventions. It is important to consider slow growing organisms such as C. acnes in patients presenting with spinal infection with insidious onset after these treatments.",
"affiliations": "1Department of Orthopaedic Surgery, Loma Linda University, Loma Linda, California.",
"authors": "Ramos|Omar|O|;Speirs|Joshua N|JN|;Danisa|Olumide|O|",
"chemical_list": "D000900:Anti-Bacterial Agents; D019690:Technetium Tc 99m Exametazime; D017576:Daptomycin",
"country": "United States",
"delete": false,
"doi": "10.2106/JBJS.CC.19.00636",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2160-3251",
"issue": "10(3)",
"journal": "JBJS case connector",
"keywords": null,
"medline_ta": "JBJS Case Connect",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D017576:Daptomycin; D015299:Discitis; D006801:Humans; D055959:Intervertebral Disc Degeneration; D007405:Intervertebral Disc Displacement; D008279:Magnetic Resonance Imaging; D008297:Male; D010019:Osteomyelitis; D011423:Propionibacteriaceae; D011877:Radionuclide Imaging; D033581:Stem Cell Transplantation; D019690:Technetium Tc 99m Exametazime; D014182:Transplantation, Autologous",
"nlm_unique_id": "101596828",
"other_id": null,
"pages": "e1900636",
"pmc": null,
"pmid": "32773702",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Lumbar Discitis and Osteomyelitis After a Spinal Stem Cell Injection?: A Case Report and Literature Review.",
"title_normalized": "lumbar discitis and osteomyelitis after a spinal stem cell injection a case report and literature review"
} | [
{
"companynumb": "US-009507513-2103USA008344",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DAPTOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe management of the Coronavirus disease 2019 (COVID-19) infected patients continues to be challenging. Critically ill COVID patients are at increased risk of serious thrombotic events and hence increased mortality. On the other side, COVID-19 patients are also showing major life-threatening bleeds, especially when systemic anticoagulation is used. Pro-coagulant propensity in critically ill COVID-19 patients have been published, but very few have described the incidence of major bleeding and its characteristics.\n\n\nMETHODS\nIn this study, we retrospectively observed the incidence of major bleed in 25 critically ill COVID-19 patients admitted to the Intensive Care Unit at the American University of Beirut Medical Center. Six cases were identified and described together with their outcome.\n\n\nRESULTS\nMajor bleeding occurred in six of the 25 studied patients. Four patients were on therapeutic anticoagulation at the onset of the bleed, two required embolization for bleeding control and one died from hemorrhagic shock. Half of the described cases had unusual sites of bleeding including gluteal and abdominal wall muscles.\n\n\nCONCLUSIONS\nA high rate of major bleeding was witnessed in our sample of critically ill patients with COVID-19 infection, with the majority being on therapeutic anticoagulation. This rate may be higher than previously reported, necessitating additional attention from the treating physician when considering empiric therapeutic anticoagulation. Moreover, the uncommon sites of bleeding shed the light on the need for additional studies in our population to identify the predisposing risk factors and mechanisms behind it.",
"affiliations": "Pulmonary and Critical Care Division, Department of Internal Medicine, American University of Beirut Medical Center, Riad El-Solh, P.O. Box 11-236, Beirut, 1107 2020, Lebanon.;Pulmonary and Critical Care Division, Department of Internal Medicine, American University of Beirut Medical Center, Riad El-Solh, P.O. Box 11-236, Beirut, 1107 2020, Lebanon.;Pulmonary and Critical Care Division, Department of Internal Medicine, American University of Beirut Medical Center, Riad El-Solh, P.O. Box 11-236, Beirut, 1107 2020, Lebanon.;Pulmonary and Critical Care Division, Department of Internal Medicine, American University of Beirut Medical Center, Riad El-Solh, P.O. Box 11-236, Beirut, 1107 2020, Lebanon. ah51@aub.edu.lb.",
"authors": "Koubaissi|Salwa A|SA|;Daou|Michella Abi Zeid|MAZ|;Mohamad|Rayan|R|;Husari|Ahmad|A|http://orcid.org/0000-0002-2317-1385",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11239-021-02461-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0929-5305",
"issue": null,
"journal": "Journal of thrombosis and thrombolysis",
"keywords": "Coronavirus; Critical illness; Hemorrhage; Heparin; Thromboembolism",
"medline_ta": "J Thromb Thrombolysis",
"mesh_terms": null,
"nlm_unique_id": "9502018",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34047936",
"pubdate": "2021-05-28",
"publication_types": "D016422:Letter",
"references": "32467443;32948243;23942857;32468143;32689588;32381264;32487122;15842354;32492712",
"title": "Increased incidence of massive hemorrhage at uncommon sites after initiation of systemic anticoagulation in critically ill patients with coronavirus disease 2019 (COVID-19) infection.",
"title_normalized": "increased incidence of massive hemorrhage at uncommon sites after initiation of systemic anticoagulation in critically ill patients with coronavirus disease 2019 covid 19 infection"
} | [
{
"companynumb": "LB-Fresenius Kabi-FK202202364",
"fulfillexpeditecriteria": "1",
"occurcountry": "LB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null... |
{
"abstract": "Previous studies of oral contraceptives and breast cancer indicate that recent use slightly increases risk, but most studies relied on self-reported use and did not examine contemporary oral contraceptive formulations. This nested case-control study was among female enrollees in a large U.S. integrated health care delivery system. Cases were 1,102 women ages 20 to 49 years diagnosed with invasive breast cancer from 1990 to 2009. Controls were randomly sampled from enrollment records (n = 21,952) and matched to cases on age, year, enrollment length, and medical chart availability. Detailed oral contraceptive use information was ascertained from electronic pharmacy records and analyzed using conditional logistic regression, ORs, and 95% confidence intervals (CI). Recent oral contraceptive use (within the prior year) was associated with an increased breast cancer risk (OR, 1.5; 95% CI, 1.3-1.9) relative to never or former OC use. The association was stronger for estrogen receptor-positive (ER(+); OR, 1.7; 95% CI, 1.3-2.1) than estrogen receptor-negative (ER(-)) disease (OR, 1.2, 95% CI, 0.8-1.8), although not statistically significantly different (P = 0.15). Recent use of oral contraceptives involving high-dose estrogen (OR, 2.7; 95% CI, 1.1-6.2), ethynodiol diacetate (OR, 2.6; 95% CI, 1.4-4.7), or triphasic dosing with an average of 0.75 mg of norethindrone (OR, 3.1; 95% CI, 1.9-5.1; Pheterogeneity compared with using other oral contraceptives = 0.004) was associated with particularly elevated risks, whereas other types, including low-dose estrogen oral contraceptives, were not (OR, 1.0; 95% CI, 0.6-1.7). Our results suggest that recent use of contemporary oral contraceptives is associated with an increased breast cancer risk, which may vary by formulation. If confirmed, consideration of the breast cancer risk associated with different oral contraceptive types could impact discussions weighing recognized health benefits and potential risks.",
"affiliations": "Group Health Research Institute, Group Health Cooperative, Seattle, Washington. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Epidemiology, University of Washington, Seattle, Washington. ebeaber@fhcrc.org.;Group Health Research Institute, Group Health Cooperative, Seattle, Washington. Department of Epidemiology, University of Washington, Seattle, Washington.;Department of Biostatistics, University of Washington, Seattle, Washington.;Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Epidemiology, University of Washington, Seattle, Washington.;Group Health Research Institute, Group Health Cooperative, Seattle, Washington. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Epidemiology, University of Washington, Seattle, Washington. Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington.;Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Epidemiology, University of Washington, Seattle, Washington.",
"authors": "Beaber|Elisabeth F|EF|;Buist|Diana S M|DS|;Barlow|William E|WE|;Malone|Kathleen E|KE|;Reed|Susan D|SD|;Li|Christopher I|CI|",
"chemical_list": "D003276:Contraceptives, Oral",
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"doi": "10.1158/0008-5472.CAN-13-3400",
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"issue": "74(15)",
"journal": "Cancer research",
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"medline_ta": "Cancer Res",
"mesh_terms": "D000328:Adult; D001943:Breast Neoplasms; D016022:Case-Control Studies; D003276:Contraceptives, Oral; D005260:Female; D006801:Humans; D008875:Middle Aged; D012307:Risk Factors; D014481:United States; D055815:Young Adult",
"nlm_unique_id": "2984705R",
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"references": "22067757;20802021;10024199;8133534;15697108;24988814;8237985;16427730;19074777;14670641;9822222;11261832;12215716;8899264;12087137;12556959;20647407;3698594;12749720;10752798;2019467;12433714;8656904;9494771;15073830;19336554;18342649;17657739;1983923;20068186;18657146",
"title": "Recent oral contraceptive use by formulation and breast cancer risk among women 20 to 49 years of age.",
"title_normalized": "recent oral contraceptive use by formulation and breast cancer risk among women 20 to 49 years of age"
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"abstract": "Aromatase inhibitors (AIs) are most commonly used for breast cancer patients with hormone receptor positive disease. Although the side effect profile of aromatase inhibitors is well known, including common side effects like arthralgia, bone pain, arthritis, hot flashes, and more serious problems like osteoporosis, we present a case of an uncommon side effect of these medications. We report the case of a postmenopausal woman on adjuvant hormonal therapy with anastrozole after completing definitive therapy for stage IIIB estrogen receptor-positive breast cancer, who was referred to hematology service for evaluation of persistent erythrocytosis. Primary and known secondary causes of polycythemia were ruled out. On further evaluation, we found that her erythrocytosis began after initiation of anastrozole and resolved after it was discontinued. We discuss the pathophysiology of aromatase inhibitor-induced erythrocytosis and reference of similar cases reported in the literature.",
"affiliations": "Division of Hematology and Oncology, Howard University Hospital, 2041 Georgia Avenue, NW, Washington, DC 20060, USA.;Division of Hematology and Oncology, Howard University Hospital, 2041 Georgia Avenue, NW, Washington, DC 20060, USA.;Division of Hematology and Oncology, Howard University Hospital, 2041 Georgia Avenue, NW, Washington, DC 20060, USA.;Division of Hematology and Oncology, Howard University Hospital, 2041 Georgia Avenue, NW, Washington, DC 20060, USA.",
"authors": "Yeruva|Sri Lakshmi Hyndavi|SL|;Nwabudike|Stanley Madu|SM|0000-0003-3075-7541;Ogbonna|Onyekachi Henry|OH|;Oneal|Patricia|P|",
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"doi": "10.1155/2015/784783",
"fulltext": "\n==== Front\nCase Rep HematolCase Rep HematolCRIHEMCase Reports in Hematology2090-65602090-6579Hindawi Publishing Corporation 10.1155/2015/784783Case ReportAromatase Inhibitor-Induced Erythrocytosis in a Patient Undergoing Hormonal Treatment for Breast Cancer Yeruva Sri Lakshmi Hyndavi http://orcid.org/0000-0003-3075-7541Nwabudike Stanley Madu \n*\nOgbonna Onyekachi Henry Oneal Patricia \n*\nDivision of Hematology and Oncology, Howard University Hospital, 2041 Georgia Avenue, NW, Washington, DC 20060, USA*Stanley Madu Nwabudike: stan.nwabudike@yahoo.com and *Patricia Oneal: poneal@howard.eduAcademic Editor: Eduardo Arellano-Rodrigo\n\n2015 2 6 2015 2015 78478320 4 2015 26 5 2015 Copyright © 2015 Sri Lakshmi Hyndavi Yeruva et al.2015This 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.Aromatase inhibitors (AIs) are most commonly used for breast cancer patients with hormone receptor positive disease. Although the side effect profile of aromatase inhibitors is well known, including common side effects like arthralgia, bone pain, arthritis, hot flashes, and more serious problems like osteoporosis, we present a case of an uncommon side effect of these medications. We report the case of a postmenopausal woman on adjuvant hormonal therapy with anastrozole after completing definitive therapy for stage IIIB estrogen receptor-positive breast cancer, who was referred to hematology service for evaluation of persistent erythrocytosis. Primary and known secondary causes of polycythemia were ruled out. On further evaluation, we found that her erythrocytosis began after initiation of anastrozole and resolved after it was discontinued. We discuss the pathophysiology of aromatase inhibitor-induced erythrocytosis and reference of similar cases reported in the literature.\n==== Body\n1. Introduction\nAn estimated 234,190 patients will be diagnosed with invasive breast cancer in 2015 and 40,730 patients will die from the disease this year, as per the American Cancer Society [1]. Of these patients, those that have estrogen receptor-positive tumors receive hormonal therapy designed to suppress the tumor by reducing estrogen levels. In postmenopausal women with estrogen receptor-positive breast cancer, the hormonal therapy of choice is an aromatase inhibitor whose mechanism of action ultimately causes a reduction in estrogen production. The most common side effects of aromatase inhibitors are related to their antiestrogen effect and are widely known. We, however, present a case of aromatase inhibitor-induced erythrocytosis, an uncommon side effect of aromatase inhibitor use.\n\n2. Case Report\nWe report a case of a 57-year-old woman who developed erythrocytosis while on anastrozole for estrogen receptor-positive breast cancer. Our patient has a history of hypertension and invasive poorly differentiated ductal carcinoma of the right breast, clinical stage T4N0M0 (IIIB), estrogen receptor-positive and progesterone receptor-positive, and human epidermal growth factor receptor-negative. Her breast cancer had been treated initially with neoadjuvant chemotherapy (Adriamycin and cyclophosphamide) followed by lumpectomy with positive margins and then subsequent bilateral simple mastectomy with reconstruction. She then completed adjuvant chemotherapy with paclitaxel and was started on hormonal therapy with anastrozole subsequently. On routine follow-up MRI scans, she was discovered to have breast implant rupture and was scheduled for implant replacement. However, on preoperative workup, she was found to have erythrocytosis and, thus, was referred to our hematology clinic in January 2015 for evaluation and management.\n\nAt the time of consultation, she reported feeling well except for intermittent headaches and difficulty sleeping. She denied neurologic, cardiovascular, and respiratory symptoms. She had no erythromelalgia or constitutional symptoms. She also had no evidence of bleeding diathesis or recent infections. She smoked crack cocaine about twice per week and also endorsed drinking about 3 to 12 ounces of beers daily. She had a 2-pack-year smoking history but quit 1 year prior to consultation. She endorsed using marijuana.\n\nHer medications included hydrochlorothiazide, lisinopril, and anastrozole. Physical examination was unremarkable. Particularly, she had no hepatosplenomegaly, hirsutism, or elevated blood pressure. Laboratory studies at this point revealed the persistence of erythrocytosis, with hemoglobin of 16.8 g/dL and hematocrit of 51.3%, white blood cell count of 5,500/mm3, and platelet count of 189,000/mm3. Complete metabolic panel was normal. Serum erythropoietin level was 3.4 (reference: 2.6–18.5). We requested additional work-up to exclude a myeloproliferative process: we obtained a JAK2 mutation analysis with reflex to exon 12 testing to rule out polycythemia vera. Fluorescent In Situ Hybridization (FISH) analysis of BCR-ABL translocation was ordered to rule out chronic myeloid leukemia. Both tests were negative, hence ruling out a myeloproliferative process.\n\nHaving ruled out myeloproliferative disorders, we decided to look for possible secondary causes of polycythemia and requested chest X-ray, pulmonary function tests, and echocardiography. These, also, were unremarkable. There was no suggestion of chronic lung disease or structural heart disease. On close review of her laboratory data and medication history, however, we noted that her polycythemia started in September 2014; around the same time, patient was started on anastrozole. Further laboratory investigation showed elevated serum total testosterone of 84 ng/dL (7–40 ng/dL), free testosterone of 2.4 (0–9.5 ng/mL), and DHEA sulfate of 253 μg/dL (29.4–220.5 μg/dL). With a possible diagnosis of secondary polycythemia due to medication, she was asked to discontinue anastrozole for one month.\n\nOn return to clinic for followup in February 2015, four weeks after anastrozole was discontinued, repeat hemoglobin and hematocrit were 13.8 g/dL and 40.6%, respectively, serum total testosterone was 50 ng/dL, free testosterone was 1.2 ng/dL, and DHEA sulfate was 170 μg/dL. Upon discussion with her oncologist, her hormonal therapy was switched to tamoxifen and her hemoglobin remained in normal range.\n\n3. Discussion\nAromatase inhibitors (AIs) are recommended for adjuvant hormonal therapy in postmenopausal women with hormone receptor-positive breast cancer. There are two types of aromatase inhibitors: nonsteroidal inhibitors such as anastrozole and letrozole and irreversible steroidal inhibitors such as exemestane. The most common side effects seen are related to deficiency of estrogen and include increased risk of bone loss and fractures, arthralgia and bone pain, hypercholesterolemia, vaginal dryness and atrophy, dyspareunia with decreased libido, hot flashes, night sweat, and heat intolerance [2]. These adverse effects mirror those seen in menopause and perimenopause due to estrogen deficiency. Other less common side effects include nausea, diarrhea, rash, hair thinning, headache, neurologic effects, and visual disturbance [2, 3].\n\nThough erythrocytosis is not a major side effect reported with aromatase inhibitor use, aromatase inhibitors prevent peripheral conversion of testosterone to estradiol (and androstenedione to estrone), leading to increased levels of testosterone, which would explain the erythrocytosis seen in our case. Androgens have been known to have a stimulatory role in red blood cell production, which is one of the reasons why men have a higher red cell count. This effect of androgens on erythrocytosis is also seen at higher altitudes as reported by Gonzales et al. [4, 5]. The complete mechanisms by which testosterone induces erythrocytosis are still largely unknown. Recent investigations have shown a direct relationship between testosterone and increased erythropoietin (EPO) levels. This increase in erythropoietin is thought to be one of the mechanisms of testosterone-induced erythrocytosis. In a study by Bachman et al., increased EPO was seen in the first 3 months of administration of testosterone [6]. Ip et al. demonstrated that higher trough serum levels of testosterone, rather than duration of treatment, were shown to be predictive for the development of polycythemia in hypogonadal men receiving testosterone replacement therapy [7]. This supports the theory of testosterone-induced erythrocytosis and, by extension, aromatase inhibitor-induced erythrocytosis.\n\nAnother proposed mechanism of testosterone-induced erythrocytosis is by the suppression of hepcidin levels [6, 8]. Hepcidin is a liver derived peptide, which is an important regulator of iron homeostasis. Low hepcidin is associated with increased iron absorption, increased systemic iron transport, and iron bioavailability for erythropoiesis [6, 8, 9]. Testosterone also upregulates the expression of genes involved in erythrocytosis such as GATA-1, FOG-1, and other GATA-dependent genes [6]. This could increase erythropoietin sensitivity and stimulate erythropoiesis. It is noteworthy that these studies about the hematologic effects of testosterone were in hypogonadal men receiving exogenous androgens.\n\nIn our case, we noted a significantly elevated serum total and free testosterone level in our postmenopausal patient with erythrocytosis, which was abnormal. Erythropoietin level, however, was normal. Regardless, we held her aromatase inhibitor for a month and noted a drastic decline in both her testosterone level and erythrocyte counts upon repeated testing. This shows the association between testosterone and erythrocytosis and reveals one of the pathophysiologic mechanisms behind aromatase inhibitor-induced erythrocytosis.\n\nOn review of the medical literature, to the best of our knowledge, only three cases of polycythemia following the administration of aromatase inhibitors have been reported. The first case was of two boys treated with letrozole for hypogonadism who subsequently developed erythrocytosis. [10]. The second case involved a 79-year-old lady with localized hormone positive breast cancer who was treated with exemestane and developed erythrocytosis. She had initially been treated with letrozole, but that was discontinued secondary to nausea according to the authors of that report. The patient had required phlebotomies while she was undergoing hematologic evaluation for erythrocytosis, prior to discontinuation of the aromatase inhibitor [11].\n\nAlthough aromatase inhibitors are used frequently in postmenopausal breast cancer patients, erythrocytosis seems to be an uncommon side effect as most of these patients have anemia either due to the cancer itself or due to treatment administered. Our patient was treated with anastrozole, a different aromatase inhibitor compared to what is described in earlier reported cases associated with increased erythrocyte counts. As noted in prior case reports, erythrocytosis has been noted in patients on both steroidal and nonsteroidal aromatase inhibitors and is, therefore, not peculiar to a particular class.\n\n4. Conclusion\nAs erythrocytosis in our patient resolved within one month after discontinuation of anastrozole without need for aggressive invasive intervention, we hypothesize that the mechanism of aromatase inhibitor-induced erythrocytosis involved a physiologic increase in testosterone as seen with exogenous testosterone administration [12]. Oncologists, therefore, need to be mindful of the possibility of erythrocytosis as a side effect of aromatase inhibitors and consider discontinuing the drug before subjecting patients to more invasive procedures like phlebotomies. Since not many patients on aromatase inhibitors develop erythrocytosis, determining which patients are susceptible to this effect is subject for further research.\n\nConflict of Interests\nThe authors state no conflict of interests and have received no payment in the preparation of this paper or in conducting the study.\n==== Refs\n1 American Cancer Society Cancer Facts & Figures 2015 2015 Atlanta, Ga, USA American Cancer Society \n2 Files J. A. Ko M. G. Pruthi S. Managing aromatase inhibitors in breast cancer survivors: not just for oncologists Mayo Clinic Proceedings 2010 85 6 560 566 10.4065/mcp.2010.0137 2-s2.0-77952910240 20511486 \n3 Nabholtz J.-M. A. Long-term safety of aromatase inhibitors in the treatment of breast cancer Therapeutics and Clinical Risk Management 2008 4 1 189 204 2-s2.0-41549083745 18728707 \n4 Gonzales G. F. Tapia V. Gasco M. Gonzales-Castaeda C. Aromatase activity after a short-course of letrozole administration in adult men at sea level and at high altitude (with or without excessive erythrocytosis) Hormone and Metabolic Research 2012 44 2 140 145 10.1055/s-0031-1301280 2-s2.0-84857052590 22274717 \n5 Gonzales G. F. Chaupis D. Higher androgen bioactivity is associated with excessive erythrocytosis and chronic mountain sickness in Andean Highlanders: a review Andrologia 2014 10.1111/and.12359 \n6 Bachman E. Travison T. G. Basaria S. Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point Journals of Gerontology, Series A, Biological Sciences and Medical Sciences 2014 69 6 725 735 10.1093/gerona/glt154 2-s2.0-84896285751 \n7 Ip F. F. di Pierro I. Brown R. Cunningham I. Handelsman D. J. Liu P. Y. Trough serum testosterone predicts the development of polycythemia in hypogonadal men treated for up to 21 years with subcutaneous testosterone pellets European Journal of Endocrinology 2010 162 2 385 390 10.1530/eje-09-0717 2-s2.0-75149116750 19903801 \n8 Bachman E. Feng R. Travison T. Testosterone suppresses hepcidin in men: a potential mechanism for testosterone-induced erythrocytosis Journal of Clinical Endocrinology and Metabolism 2010 95 10 4743 4747 10.1210/jc.2010-0864 2-s2.0-77957779215 20660052 \n9 Peyssonnaux C. Zinkernagel A. S. Schuepbach R. A. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs) Journal of Clinical Investigation 2007 117 7 1926 1932 10.1172/JCI31370 2-s2.0-34447120059 17557118 \n10 Diaz-Thomas A. D. T. Too much of a good thing: polycythemia and aromatase inhibitors AAP Capital Letters 2010 abstract P3-680 \n11 Iyengar A. Sheppard D. A case of erythrocytosis in a patient treated with an aromatase inhibitor for breast cancer Case Reports in Hematology 2013 2013 3 615189 10.1155/2013/615189 \n12 Rochira V. Zirilli L. Madeo B. Maffei L. Carani C. Testosterone action on erythropoiesis does not require its aromatization to estrogen: insights from the testosterone and estrogen treatment of two aromatase-deficient men Journal of Steroid Biochemistry and Molecular Biology 2009 113 3–5 189 194 10.1016/j.jsbmb.2008.12.007 2-s2.0-61349136872 19159688\n\n",
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"title": "Aromatase Inhibitor-Induced Erythrocytosis in a Patient Undergoing Hormonal Treatment for Breast Cancer.",
"title_normalized": "aromatase inhibitor induced erythrocytosis in a patient undergoing hormonal treatment for breast cancer"
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"abstract": "BACKGROUND\nA 2017 systematic review (SR) identified 59 studies examining gabapentinoid (pregabalin and gabapentin) misuse/abuse. Evidence of gabapentinoid misuse/abuse has since grown substantially.\n\n\nOBJECTIVE\nUpdate previous SR and describe new insights regarding gabapentinoid abuse.\n\n\nMETHODS\nA SR of PubMed was conducted to identify studies published from 7/29/2016-8/31/2020. Four searches were performed using the following terms: \"gabapentin [MeSH] OR pregabalin [MeSH] OR gabapentinoid\" AND one of the following substance misuse/abuse-related terms: \"substance-related disorders [MeSH]\", \"overdose\", \"abuse\", or \"misuse\". Clinicaltrials.gov and the Cochrane Library database were searched to identify ongoing studies or similar SRs. Reference lists of included studies were reviewed to identify additional literature. All studies with novel data related to pregabalin and/or gabapentin abuse, misuse, or overdose conducted during the study period were included. Articles not written in English, review articles, and animal studies were excluded.\n\n\nRESULTS\nFifty-five studies were included (29 [52.7%] from North America, 17 [30.9%] Europe, 6 [10.9%] Asia, and 3 [5.5%] Australia). Forty-six observational studies and 10 case reports/series were included (one manuscript included both). Twenty (36.4%) studied gabapentin only, 18 (32.7%) pregabalin only, and 17 (30.9%) both pregabalin/gabapentin. These studies corroborate findings from the previous SR that gabapentinoids are increasingly abused or misused to self-medicate, that gabapentinoids can produce desirable effects alone but are often used concomitantly with other drugs, and that opioid use disorder is the greatest risk factor for gabapentinoid abuse. While the original SR identified the largest studies having been published in Europe, this review identified several more generalisable US studies that have subsequently been conducted. The most concerning finding was increased evidence of associated patient harm, including increased hospital utilisation and opioid-related overdose mortality risk.\n\n\nCONCLUSIONS\nEvidence suggests that gabapentinoid misuse/abuse represents a growing trend that is causing significant patient harm. Prescribers should exercise appropriate caution with use in high-risk populations and monitor for signs of misuse or abuse.",
"affiliations": "College of Pharmacy, The University of Texas at Austin, 7703 Floyd Curl Dr., MC 6220, San Antonio, TX, 78229, USA. evoy@uthscsa.edu.;College of Pharmacy, The University of Texas at Austin, 7703 Floyd Curl Dr., MC 6220, San Antonio, TX, 78229, USA.;College of Pharmacy, The University of Texas at Austin, 7703 Floyd Curl Dr., MC 6220, San Antonio, TX, 78229, USA.;School of Pharmacy, Duquesne University, 600 Forbes Avenue, 418D Mellon Hall, Pittsburgh, PA, 15282, USA.;School of Pharmacy, Northeastern University, 140 The Fenway, Boston, MA, 02115, USA.;PharmToTable, LLC, PO Box 169, Bellbrook, OH, 45440, USA.",
"authors": "Evoy|Kirk E|KE|http://orcid.org/0000-0003-0913-7145;Sadrameli|Sarvnaz|S|;Contreras|Jillian|J|;Covvey|Jordan R|JR|;Peckham|Alyssa M|AM|;Morrison|Megan D|MD|",
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"title": "Abuse and Misuse of Pregabalin and Gabapentin: A Systematic Review Update.",
"title_normalized": "abuse and misuse of pregabalin and gabapentin a systematic review update"
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"affiliations": "Medizinische Poliklinik, University of Wuerzburg, Klinikstr. 6-8, 97070, Wuerzburg, Germany. p.reimer@medizin.uni-wuerzburg.de",
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"title": "Subcutaneous panniculitis-like T-cell lymphoma during pregnancy with successful autologous stem cell transplantation.",
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"abstract": "Hemophagocytic syndrome is a life-threatening disease characterized by the uncontrolled activation of macrophages, resulting in hemophagocytosis of blood cells in the bone marrow. A 20-year-old gravida at 23-week and 5-day gestation was admitted to hospital to evaluate fever up to 104°F of unknown origin, moderate cytopenia, and elevated levels of liver enzymes. Bone marrow biopsy confirmed hemophagocytic syndrome, and polymerase chain reaction came back positive for Mycobacterium tuberculosis. Supportive care and tuberculosis treatment resulted in clinical improvement. At 27 weeks and 5 days, premature rupture of the membranes occurred, and because of the high probability of reactivating the hemophagocytic syndrome, a cesarean section was performed at 29-week and 2-day gestation. Hemophagocytic syndrome is an uncommon disease which rarely appears during pregnancy. Early diagnosis and treatment can save both maternal and fetal lives.",
"affiliations": "Department of Obstetrics and Gynecology, Virgen de la Salud Hospital, Toledo, Spain.;Department of Internal Medicine, Fundación Alcorcón Universitary Hospital, Alcorcón, Madrid, Spain.;Department of Obstetrics and Gynecology, Virgen de la Salud Hospital, Toledo, Spain.;Department of Obstetrics and Gynecology, Virgen de la Salud Hospital, Toledo, Spain.;Department of Obstetrics and Gynecology, Virgen de la Salud Hospital, Toledo, Spain.;Department of Obstetrics and Gynecology, Virgen de la Salud Hospital, Toledo, Spain.",
"authors": "Fernández|Alexandra Arteaga|AA|;de Velasco Pérez|David Fernández|DF|;Fournier|M C Jiménez|MC|;Moreno Del Prado|J C|JC|;Torras|B Paraíso|BP|;Cañete Palomo|M L|ML|",
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"issue": "6(1)",
"journal": "International journal of mycobacteriology",
"keywords": null,
"medline_ta": "Int J Mycobacteriol",
"mesh_terms": "D002585:Cesarean Section; D005260:Female; D005334:Fever; D006801:Humans; D007231:Infant, Newborn; D007362:Intensive Care Units; D051359:Lymphohistiocytosis, Hemophagocytic; D009169:Mycobacterium tuberculosis; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D014376:Tuberculosis; D055815:Young Adult",
"nlm_unique_id": "101615660",
"other_id": null,
"pages": "108-110",
"pmc": null,
"pmid": "28317816",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Hemophagocytic syndrome secondary to tuberculosis at 24-week gestation.",
"title_normalized": "hemophagocytic syndrome secondary to tuberculosis at 24 week gestation"
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"abstract": "An 89-year-old woman with recurrent hormone receptor-positive and HER2-negative breast cancer was treated with fulvestrant-palbociclib combination therapy. However, 3 months after therapy initiation, she presented to our emergency room with dyspnea and fever and was admitted to our hospital because of respiratory failure. After radiological and microbiological evaluation, she was diagnosed with palbociclib-related pneumonitis. Accordingly, corticosteroids were administered, and the patient exhibited initial clinical and radiological improvement. However, pneumonitis recurred following corticosteroid tapering; her condition did not improve with high-dose intravenous corticosteroid administration, leading to death. Palbociclib- related pneumonitis is rare, but clinicians need to pay attention to this potentially lethal adverse event.",
"affiliations": "Dept. of Surgery, Tama-Hokubu Medical Center.",
"authors": "Okura|Fuminori|F|;Sato|Yuri|Y|;Murakami|Erika|E|;Komatsu|Haruka|H|;Yamamura|Yasuhiko|Y|;Ito|Yuji|Y|",
"chemical_list": "D010879:Piperazines; D011725:Pyridines; D004958:Estradiol; D018719:Receptor, ErbB-2; C500026:palbociclib",
"country": "Japan",
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"issue": "47(6)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
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"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D018572:Disease-Free Survival; D004958:Estradiol; D005260:Female; D006801:Humans; D017563:Lung Diseases, Interstitial; D009364:Neoplasm Recurrence, Local; D010879:Piperazines; D011725:Pyridines; D018719:Receptor, ErbB-2",
"nlm_unique_id": "7810034",
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"pages": "997-999",
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"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Interstitial Pneumonitis Induced by Palbociclib.",
"title_normalized": "a case of interstitial pneumonitis induced by palbociclib"
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"abstract": "BACKGROUND\nLactic acidosis (LA) can be categorized as type A, which occurs in the presence of tissue hypoxia, or type B, occurring in the absence of tissue hypoxia. Hematologic malignancies are an uncommon cause of type B LA.\n\n\nMETHODS\nA 63-year-old man, HIV-negative, with a history of diabetes mellitus, hypothyroidism, and non-alcoholic fatty liver disease (NAFLD), presented to the ED complaining of acute-on-chronic lumbar pain, and was found to have high serum anion gap (AG) LA. The rest of chemistry and infectious workup was within normal limits. Despite bicarbonate therapy and fluid resuscitation, the patient remained with persistent AG metabolic acidosis and increasing lactic acid up to 14.5 mmol/L. An abdominal computerized tomography (CT) revealed multiple bilateral enhancing lesions in the kidneys, as well as gastric wall thickening. Upper gastrointestinal endoscopy with biopsy showed a high-grade Burkitt's lymphoma. Further staging showed bone marrow involvement and extensive abdominal adenopathy. After two cycles of inpatient chemotherapy with dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab), the patient developed multifocal pneumonia complicated by respiratory failure. Following a prolonged ICU stay, after discussion with the family members, a decision of withdrawal of life-sustaining therapy was reached.\n\n\nCONCLUSIONS\nPersistent LA, without identifiable causes of tissue hypoxia, should prompt clinicians to suspect non-hypoxic etiologies, including occult high-grade malignancies. Hematological malignancies constitute an extremely rare cause of type-B LA, carrying a poor prognosis.",
"affiliations": "Department of Medicine, Nephrology Section, University of Miami Miller School of Medicine/Miami VAMC, and.;Department of Medicine, Nephrology Section, University of Miami Miller School of Medicine/Miami VAMC, and.;Department of Medicine, Nephrology Section, University of Miami Miller School of Medicine/Miami VAMC, and.;Department of Medicine, Nephrology Section, University of Miami Miller School of Medicine/Miami VAMC, and.;Department of Pathology and Laboratory Medicine, University of Miami, Jackson Memorial Hospital, Miami, FL, USA.;Department of Pathology and Laboratory Medicine, University of Miami, Jackson Memorial Hospital, Miami, FL, USA.;Department of Medicine, Nephrology Section, University of Miami Miller School of Medicine/Miami VAMC, and.",
"authors": "Salcedo Betancourt|Juan D|JD|;Garcia Valencia|Oscar A|OA|;Becerra-Gonzales|Victor G|VG|;Carias Martinez|Karla G|KG|;Chapman|Jennifer|J|;Yanchenko|Natalia|N|;Ladino|Marco A|MA|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.5414/CNCS110123",
"fulltext": "\n==== Front\nClin Nephrol Case Stud\nDustri\nClinical Nephrology. Case Studies\n2196-5293\nDustri-Verlag Dr. Karl Feistle\n\n10.5414/CNCS110123\nCase Report\nNephrology\nSevere type-B lactic acidosis in a patient with bilateral renal Burkitt’s lymphoma\nSalcedo Betancourt Juan D. 1\nGarcia Valencia Oscar A. 1\nBecerra-Gonzales Victor G. 1\nCarias Martinez Karla G. 1\nChapman Jennifer 2\nYanchenko Natalia 2\nLadino Marco A. 1\n1 Department of Medicine, Nephrology Section, University of Miami Miller School of Medicine/Miami VAMC, and\n2 Department of Pathology and Laboratory Medicine, University of Miami, Jackson Memorial Hospital, Miami, FL, USA\nCorrespondence to Juan D. Salcedo Betancourt, MD Department of Medicine, Nephrology Section, University of Miami Miller School of Medicine/Miami VAMC, 1611 NW 12th Ave, Miami, FL 33136, USA salcedo.juandavid@hotmail.com\n2021\n26 4 2021\n9 4953\n6 2 2020\n23 11 2020\n© Dustri-Verlag Dr. K. Feistle\n2021\nhttps://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nIntroduction: Lactic acidosis (LA) can be categorized as type A, which occurs in the presence of tissue hypoxia, or type B, occurring in the absence of tissue hypoxia. Hematologic malignancies are an uncommon cause of type B LA. Case presentation: A 63-year-old man, HIV-negative, with a history of diabetes mellitus, hypothyroidism, and non‐alcoholic fatty liver disease (NAFLD), presented to the ED complaining of acute-on-chronic lumbar pain, and was found to have high serum anion gap (AG) LA. The rest of chemistry and infectious workup was within normal limits. Despite bicarbonate therapy and fluid resuscitation, the patient remained with persistent AG metabolic acidosis and increasing lactic acid up to 14.5 mmol/L. An abdominal computerized tomography (CT) revealed multiple bilateral enhancing lesions in the kidneys, as well as gastric wall thickening. Upper gastrointestinal endoscopy with biopsy showed a high-grade Burkitt’s lymphoma. Further staging showed bone marrow involvement and extensive abdominal adenopathy. After two cycles of inpatient chemotherapy with dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab), the patient developed multifocal pneumonia complicated by respiratory failure. Following a prolonged ICU stay, after discussion with the family members, a decision of withdrawal of life-sustaining therapy was reached. Conclusion: Persistent LA, without identifiable causes of tissue hypoxia, should prompt clinicians to suspect non-hypoxic etiologies, including occult high-grade malignancies. Hematological malignancies constitute an extremely rare cause of type-B LA, carrying a poor prognosis.\n\nlactic acidosis\nBurkitt’s lymphoma\nnon-Hodgkin lymphoma\nkidney neoplasms\n==== Body\nIntroduction\n\nUnder anaerobic conditions, lactic acid is produced from pyruvate at the end of the glycolytic pathway. It is primarily produced from skeletal muscle (25%), skin (25%), brain (20%), erythrocytes (20%), and the intestine (10%), and is metabolized by the liver (60%) and the kidney (30%), where it is a substrate for gluconeogenesis [1, 2].\n\nBasal lactate production is ~ 0.8 mmol/kg/hour, with a normal serum lactate concentration of < 2 mmol/L [3, 4]. Intermediate lactic acidosis (LA) is defined as levels > 2 mmol/L, and severe LA (≥ 4 mmol/L) is associated with an increased mortality risk, independently of organ failure and shock [5]. LA usually occurs with an elevated serum anion gap above 12 mEq/L, due to secondary loss of bicarbonate from buffering [1].\n\nLA can occur from either increased production and/or decreased clearance, and can be categorized as either type A, which occurs in the presence of tissue hypoxia, or type B, occurring in the absence of tissue hypoxia. Type A LA is associated with conditions such as: systemic hypoperfusion (shock), local hypoperfusion (limb or mesenteric ischemia), severe hypoxemia, severe anemia, carbon monoxide poisoning, or increased glycolysis (seizures, exercise). On the other hand, type B LA occurs when increased glucose metabolism exceeds the oxidation capacity of the mitochondria, thereby increasing lactate production, and has been associated with conditions such as: underlying diseases (liver disease, human immunodeficiency virus, malignancies, thiamine deficiency, diabetic ketoacidosis, pheochromocytoma), medications/toxins (β2-agonists, toxic alcohols, metformin, salicylates, acetaminophen, cyanide, propofol), and inborn errors of metabolism (mitochondrial myopathies, pyruvate dehydrogenase deficiency, among others) [1, 2, 3]. Hematologic malignancies are an uncommon cause of type B LA, usually carrying a very poor prognosis [6]. We describe a case of persistent LA that led to a discovery of underlying Burkitt’s lymphoma.\n\nCase report\n\nA 63-year-old HIV-negative man, with a history of well controlled diabetes mellitus, hypothyroidism, and Non‐alcoholic fatty liver disease (NAFLD), presented to the ED complaining of acute-on-chronic lumbar pain. His home medications included insulin, atorvastatin, and levothyroxine. Upon arrival, patient was afebrile, with a blood pressure (BP) of 86/52 mmHg with orthostatic changes, rest of vital signs within normal limits. Patient was found somnolent, with tenderness on the left upper quadrant, without rebound. Rest of physical exam was within normal limits. Laboratory results showed a hemoglobin 9.4 g/dL (14 – 18 g/dL), leukocytes 17 × 103 leukocytes/µL (4 – 11 × 103/µL), serum bicarbonate 15 mmol/L (22 – 29 mmol/L), serum lactate 5.0 mmol/L (0.5 – 1.8 mmol/L) with anion gap (AG) LA of 28 (6 – 12), arterial blood gases pH 7.26 (7.38 – 7.44), paO2 83.4 mmHg (75 – 100 mmHg), paCO2 24.5 mmHg (38 – 42 mmHg), HCO3 10.8 mmol/L (23 – 26 mmol/L). Lactate dehydrogenase (LDH) was 1,041 U/L (80 – 225 U/L). The rest of chemistry and infectious workup was within normal limits. Of note, 2 months prior to presentation, patient was incidentally found to have a left perinephric hematoma after he had an abdominal computer tomography (CT) for NAFLD workup. Upon admission, a repeat abdominal CT scan showed interval increase of the perinephric hematoma as well as gastric wall thickening (Figure 1). Urology recommended no surgical intervention. He was resuscitated with isotonic intravenous fluids, and was admitted to the intensive care unit (ICU), where he continued supportive care. Two days after admission, despite bicarbonate therapy and fluid resuscitation with complete resolution of shock, the patient remained with persistent AG metabolic acidosis and increasing lactic acid up to 14.5 mmol/L. A subsequent abdominal magnetic resonance imaging (MRI) showed multiple rounded hypoenhancing lesions noted throughout the renal parenchyma bilaterally (Figure 2). A kidney biopsy was planned but aborted since the patient became acutely anemic (hemoglobin 5.6 g/dL) after an episode of melena. Upper gastrointestinal endoscopy with biopsy showed a high-grade Burkitt’s lymphoma (Figure 3). Further staging showed bone marrow involvement and extensive abdominal adenopathy. After two cycles of inpatient chemotherapy with dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab), the patient developed multifocal pneumonia complicated by respiratory failure. Following a prolonged ICU stay, after discussion with the family members, a decision of withdrawal of life-sustaining therapy was reached.\n\nDiscussion\n\nMalignancy-related LA is defined as a plasma level > 4 mmol/L in the setting of a tumor, even in the absence of overt acidemia [7]. LA has been associated with both solid (15%) and hematological malignancies (85%), of which non-Hodgkin’s lymphoma (NHL) accounts for 50% of cases [8, 9]. However, type B LA in the setting of NHL is an uncommon and devastating complication, carrying a very poor prognosis with a mortality rate of up to 92% [6, 9, 10].\n\nBurkitt’s lymphoma is an uncommon and highly aggressive B-cell lymphoma accounting for < 1% of adult NHL [11]. It most commonly affects the ileocecal area; however, it may also involve extra nodal sites (such as bone marrow, ovaries, kidneys, and breasts) [12]. Renal involvement is usually asymptomatic [13], and requires a high degree of suspicion to prevent early complications such as multisystem organ dysfunction [14]. Only a few cases of severe LA in patients with Burkitt’s lymphoma have been previously reported in the literature [6, 15, 16, 17, 18, 19, 20].\n\nIt is proposed that an acidic microenvironment is critical for tumor progression, since extracellular acidity induces genome instability, tumorigenesis, angiogenesis, and metastasis. Also, lactate and acidosis have shown to inhibit anti-tumor immune surveillance [21, 22]. Suggested mechanisms for malignancy-related LA include: the Warburg effect (increased glycolytic activity of malignant cells), tumor tissue hypoxia leading to anaerobic glycolysis, and decreased lactate clearance in the setting of liver metastases [1, 6, 23]. At the molecular level, it has been shown that c-MYC induces overexpression of glycolytic enzymes, glucose transporters, and lactate dehydrogenase [24]. In our case, it is also possible that the lymphomatous kidney infiltration may have contributed to decreased lactate renal clearance, as it has been previously described [11].\n\nConclusion\n\nLA is commonly used as a marker for tissue hypoxia in the critically ill patient (type A). However, it may also occur in the absence of tissue hypoxia (type B), when increased glucose metabolism exceed the oxidation capacity of the mitochondria, thereby increasing lactate production. Hematologic malignancies are an unusual etiology of type B LA, usually carrying a devastating prognosis. Persistent LA, without identifiable causes of tissue hypoxia, should prompt clinicians to suspect non-hypoxic etiologies, including occult high-grade malignancies. Treatment should focus on identifying and correcting the underlying etiology.\n\nFunding\n\nThe authors received no funding for this project.\n\nConflict of interest\n\nThe authors have no conflicts of interest to disclose.\n\nFigure 1 Abdominal CT scan with contrast. Findings of bilateral enhancing lesions in the kidneys. Multiple rounded hyperdense lesions throughout the renal parenchyma bilaterally, more pronounced in the left kidney. Left perinephric hematoma 8.8 × 5.2 cm. Axial view (left). Diffuse thickening of the stomach wall. No evidence of liver lesions. Axial view (right).\n\nFigure 2 Abdominal MRI. Multiple rounded hypo enhancing lesions noted throughout the renal parenchyma bilaterally. Axial view (left). Coronal view (right).\n\nFigure 3 Microscopic appearance of the high-grade Burkitt’s lymphoma. Stomach. Gastric mucosa with a dense lymphoid infiltrate in the lamina propria consisting of intermediate size monotonous lymphoma cells with round nuclei, fine chromatin, and multiple nucleoli. Mitoses are conspicuous. Multiple apoptotic bodies impart a starry sky pattern to the lesion (A, B: hematoxylin & eosin). Immunohistochemistry was positive for CD20, CD10, BCL6 (C), c-MYC (D), and MUM1, and are negative for CD5, BCL2, CD30, and terminal deoxynucleotidyl transferase (TdT). Fluorescence in situ hybridization (FISH) was 73% positive for MYC-IGH fusion and negative for IGH-BCL2 and BCL6 rearrangements.\n==== Refs\nReferences\n\n1 Seheult J Fitzpatrick G Boran G Lactic acidosis: an update. Clin Chem Lab Med. 2017; 55 : 322–333. 27522622\n2 Foucher CD Tubben RE “Lactic Acidosis” in StatPearls, StatPearls Publishing, 2019; https:// www.ncbi.nlm.nih.gov/books/NBK470202/.\n3 Reddy AJ Lam SW Bauer SR Guzman JA Lactic acidosis: Clinical implications and management strategies. Cleve Clin J Med. 2015; 82 : 615–624. 26366959\n4 Kruse O Grunnet N Barfod C Blood lactate as a predictor for in-hospital mortality in patients admitted acutely to hospital: a systematic review. Scand J Trauma Resusc Emerg Med. 2011; 19 : 74. 22202128\n5 Mikkelsen ME Miltiades AN Gaieski DF Goyal M Fuchs BD Shah CV Bellamy SL Christie JD Serum lactate is associated with mortality in severe sepsis independent of organ failure and shock. Crit Care Med. 2009; 37 : 1670–1677. 19325467\n6 Glasheen JJ Sorensen MD Burkitt’s lymphoma presenting with lactic acidosis and hypoglycemia – a case presentation. Leuk Lymphoma. 2005; 46 : 281–283. 15621814\n7 Devita VT Hellman S Rosenberg SA Cancer: Principles and practice of oncology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins Publishers; 2001; p. 2640-2642.\n8 Wahab A Kesari K J Smith S Liu Y Barta SK Type B lactic acidosis, an uncommon paraneoplastic syndrome. Cancer Biol Ther. 2018; 19 : 101–104. 29293400\n9 Friedenberg AS Brandoff DE Schiffman FJ Type B lactic acidosis as a severe metabolic complication in lymphoma and leukemia: a case series from a single institution and literature review. Medicine (Baltimore). 2007; 86 : 225–232. 17632264\n10 Claudino WM Dias A Tse W Sharma VR Type B lactic acidosis: a rare but life threatening hematologic emergency. A case illustration and brief review. Am J Blood Res. 2015; 5 : 25–29. 26171281\n11 Ferry JA Burkitt’s lymphoma: clinicopathologic features and differential diagnosis. Oncologist. 2006; 11 : 375–383. 16614233\n12 Dunleavy K Approach to the diagnosis and treatment of adult Burkitt’s Lymphoma. J Oncol Pract. 2018; 14 : 665–671. 30423267\n13 Aminde JA Adze NE Dedino GA Aminde LN Acute kidney injury as initial presentation of renal lymphoma: Diagnostic and therapeutic challenges in a resource-limited setting. SAGE Open Med Case Rep. 2019; 7 : 2050313X19845251.\n14 Gastwirt JP Roschewski M Management of adults with Burkitt lymphoma. Clin Adv Hematol Oncol. 2018; 16 : 812–822. 30843890\n15 Kulkarni K Kaur S Sibal A Jerath N Arya LS Severe lactic acidosis, hypertriglyceridemia, and extensive axial skeleton involvement in a case of disseminated Burkitt’s lymphoma. Int J Hematol. 2010; 91 : 546–548. 20213117\n16 Rastogi MV Desai N Quintos JB Non-islet-cell tumor hypoglycemia and lactic acidosis in a child with congenital HIV and Burkitt’s lymphoma. J Pediatr Endocrinol Metab. 2008; 21 : 805–810. 18825882\n17 López rodríguez M Vázquez muñoz E Gómez cerezo J Pagán muñoz B Ruiz bravo-burguillos E Barbado hernández FJ Lactic acidosis, severe hypoglycemia and hepatosplenomegaly Rev Clin Esp. 2007; 207 : 521–522. 17988600\n18 Révész T Obeid K Mpofu C Severe lactic acidosis and renal involvement in a patient with relapsed Burkitt’s lymphoma. Pediatr Hematol Oncol. 1995; 12 : 283–288. 7640182\n19 Block JB Bronson WR Bell WR Metabolic abnormalities of lactic acid in Burkitt-type lymphoma with malignant effusions. Ann Intern Med. 1966; 65 : 101–108. 5936657\n20 Sillos EM Shenep JL Burghen GA Pui CH Behm FG Sandlund JT Lactic acidosis: a metabolic complication of hematologic malignancies: case report and review of the literature. Cancer. 2001; 92 : 2237–2246. 11745277\n21 Ibrahim-Hashim A Estrella V Acidosis and cancer: from mechanism to neutralization. Cancer Metastasis Rev. 2019; 38 : 149–155. 30806853\n22 Kraut JA Madias NE Lactic acidosis. N Engl J Med. 2014; 371 : 2309–2319. 25494270\n23 Kirsch BJ Chang SJ Le A Non-Hodgkin lymphoma metabolism. Adv Exp Med Biol. 2018; 1063 : 95–106. 29946778\n24 Soleja M Mims M Rivero G Uncovering molecular abnormalities leading to the Warburg effect in primary refractory diffuse large B-cell lymphoma. Blood Cancer J. 2016; 6 : e502. 27911436\n\n",
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"issn_linking": "2196-5293",
"issue": "9()",
"journal": "Clinical nephrology. Case studies",
"keywords": "Burkitt’s lymphoma; kidney neoplasms; lactic acidosis; non-Hodgkin lymphoma",
"medline_ta": "Clin Nephrol Case Stud",
"mesh_terms": null,
"nlm_unique_id": "101638685",
"other_id": null,
"pages": "49-53",
"pmc": null,
"pmid": "33928009",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "16614233;30423267;5936657;27522622;25494270;20213117;22202128;26366959;18825882;29293400;19325467;17632264;31065357;11745277;30806853;17988600;27911436;29946778;7640182;15621814;30843890;26171281",
"title": "Severe type-B lactic acidosis in a patient with bilateral renal Burkitt's lymphoma.",
"title_normalized": "severe type b lactic acidosis in a patient with bilateral renal burkitt s lymphoma"
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"abstract": "Medulloblastomas may occur in a predisposition context, including familial adenomatosis polyposis. Medulloblastomas related to a germline pathogenic variant of adenomatous polyposis coli (APC) remain rare and poorly described. Their similarities with sporadic WNT medulloblastomas still require description.\n\n\n\nWe performed a multicentric retrospective review of 12 patients treated between 1988 and 2018 for medulloblastoma with an identified or highly suspected (personal or familial history) APC germline pathogenic variant. We report personal and familial history APC gene pathogenic variants whenever available: clinical and histologic characteristics of the medulloblastoma, treatments, and long-term outcome, including second tumor and late sequelae.\n\n\n\nMedulloblastomas associated with APC pathogenic variants are mainly classic (11/11 patients, 1 not available), nonmetastatic (10/12 patients) medulloblastomas, with nuclear immunoreactivity for ß-catenin (9/9 tested cases). Ten of 11 assessable patients are disease free with a median follow-up of 10.7 years (range, 1-28 y). Secondary tumors included desmoid tumors in 7 patients (9 tumors), 1 thyroid carcinoma, 2 pilomatricomas, 1 osteoma, 1 vertebral hemangioma, and 1 malignant triton in the radiation field, which caused the only cancer-related death in our series.\n\n\n\nMedulloblastomas associated with an APC pathogenic variant have an overall favorable outcome, even for metastatic tumors. Yet, long-term survival is clouded by second tumor occurrence; treatment may play some role in some of these second malignancies. Our findings raise the question of applying a de-escalation therapeutic protocol to treat patients with APC germline pathogenic variants given the excellent outcome, and reduced intensity of craniospinal irradiation may be further evaluated.",
"affiliations": "Curie Institute, SIREDO Cancer Center (Care, Innovation and Research in Pediatric, Adolescents, and Young Adults Oncology), Paris, France.;Paris Descartes University, Sorbonne Paris Cité, Paris, France.;Gustave Roussy Cancer Center, Department of Pediatric and Adolescent Oncology, Paris-Saclay University, Villejuif, France.;CRESS Equipe 7 UMRS 1153, INSERM, Paris Descartes University, Paris, and National Registry of Solid Tumors, Nancy University Hospital, Vandoeuvre-les-Nancy, France.;Centre Leon Berard, Pediatric Hemato-oncology Institute (IHOP), Lyon, France.;Centre Oscar Lambret, Pediatric Oncology Department, Lille, France.;Toulouse University Hospital, Pediatric Hemato-oncology Department, Toulouse, France.;Saint-Etienne University Hospital, Pediatric Hemato-oncology Department, Saint-Etienne, France.;Aix Marseille University, La Timone, Pediatric Hemato-oncology Department, AP-HM, Marseille, France.;Hôpital des Enfants, Unité Cancer, Bruxelles, Belgique.;Gustave Roussy Cancer Center, Department of Pediatric and Adolescent Oncology, Paris-Saclay University, Villejuif, France.;Saint-Etienne University Hospital, Genetic Department, Saint-Etienne, France.;Centre Leon Berard, Department of Medical Oncology, Lyon, France.;Marseille University, La Timone, Genetic Department, Marseille, France.;Centre Claudius Regaud, Oncogenetic Department, Toulouse, France.;University Hospital Lariboisière, Department of Pathology, Paris, France.;Toulouse University Hospital, Department of Pathology, Toulouse, France.;Hospices Civils de Lyon, Department of Pathology, Lyon, France.;Lille University Hospital, Department of Pathology, Lille, France.;Marseille University Hospital, Department of Pathology, Marseille, France.;Pitié Salpêtrière hospital, Genetic Department, Paris, France.;Gustave Roussy Cancer Center, Department of Pediatric and Adolescent Oncology, Paris-Saclay University, Villejuif, France.;Curie Institute, Department of Radiation Oncology, Paris, France.;Gustave Roussy Cancer Center, Department of Pediatric and Adolescent Oncology, Paris-Saclay University, Villejuif, France.;Curie Institute, Genetic Department, Paris, France.;Curie Institute, SIREDO Cancer Center (Care, Innovation and Research in Pediatric, Adolescents, and Young Adults Oncology), Paris, France.;Curie Institute, SIREDO Cancer Center (Care, Innovation and Research in Pediatric, Adolescents, and Young Adults Oncology), Paris, France.",
"authors": "Surun|Aurore|A|;Varlet|Pascale|P|;Brugières|Laurence|L|;Lacour|Brigitte|B|;Faure-Conter|Cécile|C|;Leblond|Pierre|P|;Bertozzi-Salomon|Anne-Isabelle|AI|;Berger|Claire|C|;André|Nicolas|N|;Sariban|Eric|E|;Raimbault|Sandra|S|;Prieur|Fabienne|F|;Desseigne|Françoise|F|;Zattara|Hélène|H|;Guimbaud|Rosine|R|;Polivka|Marc|M|;Delisle|Marie-Bernadette|MB|;Vasiljevic|Alexandre|A|;Maurage|Claude-Alain|CA|;Figarella-Branger|Dominique|D|;Coulet|Florence|F|;Guerrini-Rousseau|Léa|L|;Alapetite|Claire|C|;Dufour|Christelle|C|;Colas|Chrystelle|C|;Doz|François|F|;Bourdeaut|Franck|F|",
"chemical_list": "C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; C495270:CTNNB1 protein, human; D051176:beta Catenin",
"country": "England",
"delete": false,
"doi": "10.1093/neuonc/noz154",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1522-8517",
"issue": "22(1)",
"journal": "Neuro-oncology",
"keywords": "APC; Gardner syndrome; WNT; familial adenomatosis polyposis; medulloblastoma",
"medline_ta": "Neuro Oncol",
"mesh_terms": "D011125:Adenomatous Polyposis Coli; D025601:Adenomatous Polyposis Coli Protein; D000293:Adolescent; D000328:Adult; D002528:Cerebellar Neoplasms; D002648:Child; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008527:Medulloblastoma; D012189:Retrospective Studies; D051176:beta Catenin",
"nlm_unique_id": "100887420",
"other_id": null,
"pages": "128-138",
"pmc": null,
"pmid": "31504825",
"pubdate": "2020-01-11",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": "24651015;4983156;11241320;17172831;2846249;23325524;27157931;223949;18384785;17238184;26179480;29167993;9014661;14523376;3040919;22851561;20528895;19273707;27056662;19197950;28792655;25403219;28901970;16258095;8515724;7623725;22508808;29753700;7661930;24115570;10984057;16034048;24831600;18039127;7515658;16919771",
"title": "Medulloblastomas associated with an APC germline pathogenic variant share the good prognosis of CTNNB1-mutated medulloblastomas.",
"title_normalized": "medulloblastomas associated with an apc germline pathogenic variant share the good prognosis of ctnnb1 mutated medulloblastomas"
} | [
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"companynumb": "FR-MYLANLABS-2020M1045116",
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"abstract": "Previous reports have suggested a possible association between tumour necrosis factor alpha (TNF-α) inhibitors, used in the treatment of immune-mediated inflammatory diseases, and medication-related osteonecrosis of the jaw (MRONJ). However, a comprehensive assessment of the frequency and severity of MRONJ caused by these agents is lacking. The aim of this cohort study was to investigate the occurrence of MRONJ in a population of patients with inflammatory bowel disease (IBD) treated with TNF-α inhibitors at a tertiary care medical centre. A total of 2701 IBD patients under current or former treatment with TNF-α inhibitors were identified in an IBD registry covering the period 1994-2018. These patients were cross-matched with all patients diagnosed with MRONJ. This resulted in three patients with a definite diagnosis of MRONJ, without concomitant treatment with bisphosphonates. All three patients required surgical treatment with sequestrectomy. Mucosal healing occurred at 4-15 months and one patient developed recurrence. In conclusion, this study identified and described anti-TNF-α-related MRONJ occurring in a large cohort of IBD patients, and reported the severity and treatment strategies used.",
"affiliations": "OMFS IMPATH Research Group, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium; Oral and Maxillofacial Surgery, University Hospitals Leuven, Leuven, Belgium.;OMFS IMPATH Research Group, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium; Oral and Maxillofacial Surgery, University Hospitals Leuven, Leuven, Belgium.;Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium.;Oral and Maxillofacial Surgery, CHR-Namur, Namur, Belgium.;OMFS IMPATH Research Group, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium; Oral and Maxillofacial Surgery, University Hospitals Leuven, Leuven, Belgium. Electronic address: constantinus.politis@uzleuven.be.",
"authors": "Brijs|K|K|;Miclotte|I|I|;Vermeire|S|S|;Darche|V|V|;Politis|C|C|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D014409:Tumor Necrosis Factor-alpha",
"country": "Denmark",
"delete": false,
"doi": "10.1016/j.ijom.2019.08.007",
"fulltext": null,
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"issn_linking": "0901-5027",
"issue": "49(3)",
"journal": "International journal of oral and maxillofacial surgery",
"keywords": "MRONJ; TNF-α inhibitors; inflammatory bowel disease; osteonecrosis of the jaw",
"medline_ta": "Int J Oral Maxillofac Surg",
"mesh_terms": "D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D050071:Bone Density Conservation Agents; D015331:Cohort Studies; D004164:Diphosphonates; D006801:Humans; D015212:Inflammatory Bowel Diseases; D010020:Osteonecrosis; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "8605826",
"other_id": null,
"pages": "317-324",
"pmc": null,
"pmid": "31466830",
"pubdate": "2020-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Osteonecrosis of the jaw in patients with inflammatory bowel disease treated with tumour necrosis factor alpha inhibitors.",
"title_normalized": "osteonecrosis of the jaw in patients with inflammatory bowel disease treated with tumour necrosis factor alpha inhibitors"
} | [
{
"companynumb": "BE-CELLTRION INC.-2020BE020414",
"fulfillexpeditecriteria": "1",
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"activesubstance": {
"activesubstancename": "ADALIMUMAB"
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... |
{
"abstract": "Pembrolizumab is an immune checkpoint inhibitor with antitumor activity in other organ malignancies. We present this case -demonstrating multiple inflammatory adverse events associated with Pembrolizumab (in a single patient), in order to increase awareness and facilitate earlier identification of the wide-ranging cutaneous side effects associated with immunotherapy.",
"affiliations": "Monash Health Melbourne Victoria Australia.;Department of Dermatology Peter MacCallum Cancer Centre Melbourne Victoria Australia.;Department of Dermatology Peter MacCallum Cancer Centre Melbourne Victoria Australia.;Department of Pathology Peter MacCallum Cancer Centre Melbourne Victoria Australia.;Department of Dermatology Peter MacCallum Cancer Centre Melbourne Victoria Australia.;Department of Dermatology Peter MacCallum Cancer Centre Melbourne Victoria Australia.",
"authors": "Honigman|Anthony D|AD|https://orcid.org/0000-0002-4872-6340;Lai|Franics|F|;Elakis|Joshua|J|;Prall|Owen|O|;Goh|Michelle|M|;McCormack|Christopher|C|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.2090",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 3099708410.1002/ccr3.2090CCR32090Case ReportCase ReportsPembrolizumab‐induced sarcoid granulomatous panniculitis and bullous pemphigoid in a single patient HONIGMAN et al.Honigman Anthony D. https://orcid.org/0000-0002-4872-6340anthonyhonigman@gmail.com \n1\nLai Francis \n2\nElakis Joshua \n2\nPrall Owen \n3\nGoh Michelle \n2\nMcCormack Christopher \n2\n\n1 \nMonash Health\nMelbourne\nVictoria\nAustralia\n\n2 \nDepartment of Dermatology\nPeter MacCallum Cancer Centre\nMelbourne\nVictoria\nAustralia\n\n3 \nDepartment of Pathology\nPeter MacCallum Cancer Centre\nMelbourne\nVictoria\nAustralia\n* Correspondence\n\nAnthony D. Honigman, Monash Health, Melbourne, Vic., Australia.\n\nEmail: anthonyhonigman@gmail.com\n11 3 2019 4 2019 7 4 10.1002/ccr3.2019.7.issue-4773 775 04 1 2019 12 2 2019 © 2019 The Authors. Clinical Case Reports published by 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.Key Clinical Message\nPembrolizumab is an immune checkpoint inhibitor with antitumor activity in other organ malignancies. We present this case —demonstrating multiple inflammatory adverse events associated with Pembrolizumab (in a single patient), in order to increase awareness and facilitate earlier identification of the wide‐ranging cutaneous side effects associated with immunotherapy.\n\ngranulomatous panniculitisimmunotherapyPD‐1 inhibitorPembrolizumab source-schema-version-number2.0component-idccr32090cover-dateApril 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:01.05.2019\n\n\nHonigman \nAD \n, \nLai \nF \n, \nElakis \nJ \n, \nPrall \nO \n, \nGoh \nM \n, \nMcCormack \nC \n. Pembrolizumab‐induced sarcoid granulomatous panniculitis and bullous pemphigoid in a single patient . Clin Case Rep . 2019 ;7 :773 –775 . 10.1002/ccr3.2090 \n30997084\n==== Body\nPembrolizumab is a humanized monoclonal antibody IgG4 programmed cell death‐1 (PD‐1) antagonist, immune checkpoint inhibitor approved for treatment of metastatic melanoma, with antitumor activity in other solid organ malignancies.1 We report a case of sarcoidal granulomatous panniculitis and bullous pemphigoid associated with Pembrolizumab in a single patient.\n\nA 56‐year‐old woman was treated with Pembrolizumab in mismatch repair‐deficient (absent PMS2) metastatic endometrial adenocarcinoma. Four months into treatment she presented with red‐brown fixed, indurated, and tender papules and plaques on the lower legs (Figure 1), the largest plaque measuring 2 cm. Histopathology from both lower legs showed multiple small well‐formed, non‐necrotizing sarcoidal granulomata in the dermis and subcutis (Figure 2) with no foreign material or vasculitis. Periodic acid‐Schiff, Ziehl‐Neelson, Wade‐Fite, and Gram stains were negative for organisms, and Mycobacterium tuberculosis PCR was negative. Serum interferon‐gamma release assay for Mycobacterium tuberculosis (QuantiFERON‐TB Gold®) was indeterminate. Connective tissue disease screen was unremarkable. Angiotensin‐converting enzyme was elevated at 83 (12‐40 U/L) and chest computed tomography showed bilateral small subpleural pulmonary nodules and mediastinal and hilar lymphadenopathy, presenting two months after starting Pembrolizumab, stabilizing from four months. Absence of progression on serial chest imaging in correlation with granulomata of the skin, pulmonary nodules, and lymphadenopathy were thought consistent with a granulomatous process rather than metastatic disease. Skin lesions improved with topical Betamethasone dipropionate 0.05% ointment. Fourteen months into Pembrolizumab treatment, a second skin eruption with widespread pruritus and excoriated papules on limbs and torso (Figure 3) presented and biopsy confirmed bullous pemphigoid with subepidermal vesicles and eosinophils. Immunofluorescence demonstrated IgG and C3c at the dermo‐epidermal junction. Oral prednisolone induced remission, enabling continuation of Pembrolizumab.\n\nFigure 1 Red/brown fixed, indurated, and tender papules and plaques\n\nFigure 2 H&E stain at magnification of punch biopsy showing well‐formed, non‐necrotizing granulomas and histiocytes\n\nFigure 3 Excoriated papules on torso\n\nPD‐1 inhibitors are a mainstay of metastatic melanoma treatment due to its efficacy,1 yet are implicated in multi‐system autoimmune inflammatory adverse events. They cause a release from normal immune inhibition, analogous to “releasing the brake” on immune tolerance.2 Adverse dermatological events such as lichen planus, lichenoid drug eruptions, dermatitis, bullous pemphigoid, acute localized exanthematous pustulosis, and Stevens‐Johnson syndrome/ Toxic epidermal necrolysis have been reported.1, 3 Some events have even been suggested as positive prognostic factors, with improvements in melanoma patient survival with Pembrolizumab.1\n\n\nGranulomatous reactions in the form of extensive panniculitis and granulomatous inflammation reactivation affecting the lungs in metastatic melanoma patients undergoing Pembrolizumab therapy have been described.4, 5 Cases of bullous pemphigoid associated with Pembrolizumab have also been reported, many with prior treatment with Ipilimumab.5 In our case, we describe an individual presenting with granulomatous panniculitis as well as bullous pemphigoid associated with pembrolizumab therapy. Our report appears to be the only recorded case showing multiple cutaneous immune‐related adverse events in the same patient, expanding the clinical spectrum of cutaneous manifestations of Pembrolizumab therapy to include possibility of granulomatous panniculitis and polymorphic cutaneous autoimmune conditions in a single patient. As the use of PD‐1 inhibitors grows, clinicians must be cognizant of potential for associated immune‐mediated cutaneous adverse effects. Here we aim to increase awareness of atypical presentations of Pembrolizumab therapy to facilitate earlier identification of the wide‐ranging cutaneous side effects associated with immunotherapy.\n\nCONFLICT OF INTEREST\nNo author has any conflicts of interest or relevant financial activities to disclose.\n\nAUTHOR CONTRIBUTION\nAH: first author and is a corresponding author. FL: involved in clinical care of patient and assisted in drafting the manuscript. JE: assisted in drafting the manuscript. OP: consultant pathologist involved in clinical care of patient and assisted in drafting the manuscript. MG and CM: consultants involved in clinical care of patient and assisted in drafting the manuscript.\n==== Refs\nREFERENCES\n1 \n\nSanlorenzo \nM \n, \nVujic \nI \n, \nDaud \nA \n, et al. Pembrolizumab cutaneous adverse events and their association with disease progression . JAMA Dermatology . 2015 ;151 (11 ):1206 ‐1212 .26222619 \n2 \n\nOkazaki \nT \n, \nWang \nJ \n. PD‐1/PD‐L pathway and autoimmunity . Autoimmunity . 2005 ;38 (5 ):353 ‐357 .16227150 \n3 \n\nSibaud \nV \n. Dermatologic reactions to immune checkpoint inhibitors: skin toxicities and immunotherapy . Am J Clin Dermatol . 2018 ;19 :345 ‐361 .29256113 \n4 \n\nBurillo‐Martinez \nS \n, \nMorales‐Raya \nC \n, \nPrieto‐Barrios \nM \n, \nRodriguez‐Peralto \nJ‐L \n, \nOrtiz‐Romero \nP‐L \n. Pembrolizumab‐induced extensive panniculitis and nevus regression: Two novel cutaneous manifestations of the post‐immunotherapy granulomatous reactions spectrum . JAMA Dermatology . 2017 ;153 (7 ):721 ‐722 .28467548 \n5 \n\nLopez \nAT \n, \nKhana \nT \n, \nAntonov \nN \n, \nAudrey‐Bayan \nC \n, \nGeskin \nL \n. A review of bullous pemphigoid associated with PD‐1 and PD‐L1 inhibitors . Int J Dermatol . 2018 ;57 :664 ‐669 .29630716\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "7(4)",
"journal": "Clinical case reports",
"keywords": "PD‐1 inhibitor; Pembrolizumab; granulomatous panniculitis; immunotherapy",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "773-775",
"pmc": null,
"pmid": "30997084",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports",
"references": "30997084;28467548;29630716;26222619;29256113;16227150",
"title": "Pembrolizumab-induced sarcoid granulomatous panniculitis and bullous pemphigoid in a single patient.",
"title_normalized": "pembrolizumab induced sarcoid granulomatous panniculitis and bullous pemphigoid in a single patient"
} | [
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"companynumb": "AU-009507513-1904AUS008468",
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"occurcountry": "AU",
"patient": {
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"activesubstancename": "PEMBROLIZUMAB"
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... |
{
"abstract": "Postpartum hemorrhage (PPH) contributes to 25% of maternal deaths worldwide. Abnormal placentation is a well-known culprit of PPH. Although controversial, iliac artery balloon occlusion has been used in patients to decrease bleeding. The use of antifibrinolytic agents, such as tranexamic acid (TXA), have gained popularity in the management of PPH. We present a 35-year-old parturient with placenta percreta that was managed with internal iliac artery balloon occlusion with concomitant use of TXA during urgent cesarean hysterectomy with subsequent aortoiliac thrombosis formation. The role of both TXA and arterial balloons in PPH, along with their respective limitations, are discussed.",
"affiliations": "From the Department of Anesthesiology, Division of Obstetric Anesthesia, Miller School of Medicine, University of Miami, Jackson Memorial Hospital, Miami, Florida.",
"authors": "Hajmurad|Omar S|OS|;Choxi|Ankeet A|AA|;Zahid|Zahira|Z|;Dudaryk|Roman|R|",
"chemical_list": "D000933:Antifibrinolytic Agents; D014148:Tranexamic Acid",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000535",
"fulltext": null,
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"issn_linking": "2325-7237",
"issue": "9(3)",
"journal": "A & A case reports",
"keywords": null,
"medline_ta": "A A Case Rep",
"mesh_terms": "D000328:Adult; D000933:Antifibrinolytic Agents; D001012:Aorta, Abdominal; D021721:Balloon Occlusion; D002585:Cesarean Section; D005260:Female; D006801:Humans; D007044:Hysterectomy; D007083:Iliac Artery; D010923:Placenta Previa; D011247:Pregnancy; D013927:Thrombosis; D014148:Tranexamic Acid",
"nlm_unique_id": "101637720",
"other_id": null,
"pages": "90-93",
"pmc": null,
"pmid": "28459723",
"pubdate": "2017-08-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Aortoiliac Thrombosis Following Tranexamic Acid Administration During Urgent Cesarean Hysterectomy: A Case Report.",
"title_normalized": "aortoiliac thrombosis following tranexamic acid administration during urgent cesarean hysterectomy a case report"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201708143",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TRANEXAMIC ACID"
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"drugadditional": nul... |
{
"abstract": "Inadvertent intra-arterial drug injection occurs rarely, but it can cause very serious clinical complications, and thus, awareness of inadvertent intra-arterial drug injection is needed. The complications mainly result from iatrogenic reasons and can occur because of vascular variations in the arteries, under circumstances where normal intravenous injection is difficult, or in drug abusers who perform self-injection. The adverse effect associated with intra-arterial drug injection is serious and may lead to necrosis, requiring amputation of the affected extremity, infection, pseudoaneurysm, rhabdomyolysis, compartment syndrome, and permanent disability. However, the etiology of such adverse effects has not been clearly identified and treatment methods have not yet been established. We encountered a patient who developed necrosis of the thumb after an inadvertent injection of diclofenac sodium in the radial artery due to variations in the forearm arteries. Here, we report the prevention and treatment of, and precautions against, the dangers of intra-arterial drug injection.",
"affiliations": "Department of Orthopaedic Surgery, College of Medicine, Chungbuk National University, Cheongju, Korea.;Department of Orthopaedic Surgery, College of Medicine, Chungbuk National University, Cheongju, Korea.;Department of Orthopaedic Surgery, College of Medicine, Chungbuk National University, Cheongju, Korea.;Department of Orthopaedic Surgery, College of Medicine, Chungbuk National University, Cheongju, Korea.",
"authors": "Shon|Hyun-Chul|HC|;Park|Ji-Kang|JK|;Kang|Sang-Woo|SW|;Yang|Jae-Young|JY|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/JPR.S150306",
"fulltext": "\n==== Front\nJ Pain ResJ Pain ResJournal of Pain ResearchJournal of Pain Research1178-7090Dove Medical Press 10.2147/JPR.S150306jpr-10-2803Case ReportNecrosis of the thumb after inadvertent injection of diclofenac in the radial artery: a case report Shon Hyun-Chul Park Ji-Kang Kang Sang-Woo Yang Jae-Young Department of Orthopaedic Surgery, College of Medicine, Chungbuk National University, Cheongju, KoreaCorrespondence: Ji-Kang Park, Department of Orthopaedic Surgery, 776 1 Sunhawn-ro, Heungdeok-gu, Cheongju 28644, Korea, Tel +82 43 269 6077, Fax +82 43 274 8719, Email carm0916@hanmail.net2017 13 12 2017 10 2803 2806 © 2017 Shon et al. This work is published and licensed by Dove Medical Press Limited2017The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Inadvertent intra-arterial drug injection occurs rarely, but it can cause very serious clinical complications, and thus, awareness of inadvertent intra-arterial drug injection is needed. The complications mainly result from iatrogenic reasons and can occur because of vascular variations in the arteries, under circumstances where normal intravenous injection is difficult, or in drug abusers who perform self-injection. The adverse effect associated with intra-arterial drug injection is serious and may lead to necrosis, requiring amputation of the affected extremity, infection, pseudoaneurysm, rhabdomyolysis, compartment syndrome, and permanent disability. However, the etiology of such adverse effects has not been clearly identified and treatment methods have not yet been established. We encountered a patient who developed necrosis of the thumb after an inadvertent injection of diclofenac sodium in the radial artery due to variations in the forearm arteries. Here, we report the prevention and treatment of, and precautions against, the dangers of intra-arterial drug injection.\n\nKeywords\nintra-arterial drug injectiondiclofenac sodiumthumb necrosis\n==== Body\nIntroduction\nSince the report by Macintosh in 1943 about the complications arising from an inadvertent intra-arterial injection of thiopental, the dangers of intra-arterial drug injection have been reported in various papers.1 Intra-arterial drug injections mostly occur accidentally, mainly as iatrogenic complications during anesthesia procedures.2 The adverse effects, which were reported to occur in up to 29% of patients, are serious, including necrosis, leading to amputation of the affected extremity, infection, pseudoaneurysm, rhabdomyolysis, and compartment syndrome.2 However, the etiology of such adverse effects has not been clearly identified and treatment methods have not been established yet. Therefore, prevention of inadvertent intra-arterial drug injection is the most important solution to this problem. Persons who belong to the high-risk group for inadvertent intra-arterial drug injection include obese individuals whose veins are difficult to find, drug abusers who perform self-injection without any anatomical knowledge, and those with vascular variations in the forearms.3 We had encountered a case of necrosis of the thumb after an intra-arterial injection of diclofenac sodium in an artery that was mistaken for a vein in a patient with arterial variation in the forearm. In this study, we report the dangers of intra-arterial drug injection, and the prevention and treatment of its associated effects, along with a literature review.\n\nCase\nA 63-year-old male patient (180 cm, 75 kg, retired office worker, Korean) was admitted with the chief complaint of necrosis of the left thumb. He was healthy and a non-smoker with no underlying disease, including vascular disease, diabetes, or hypertension and family history. One week before admission, he visited a private clinic because of a cold, and received an injection of diclofenac sodium (OS-beta, Unimed®) 90 mg in the left wrist. He developed numbness and severe pain in the distal part of the wrist immediately upon receiving the injection, as well as hypesthesia in the thumb and index finger after several hours. On the following day, he developed swelling and cyanosis of the thumb and index finger. Necrosis of the distal end of the thumb started developing from the third day after the injection. Subsequent ultrasonography at another hospital indicated reduced blood flow to all fingers of the left hand and no measurable blood flow in the left thumb. Consequently, the patient was prescribed beraprost 40 mg twice a day. Even though he was taking the medication, his symptoms and necrosis worsened, and he visited our hospital after becoming aware of the possibility of needing an amputation. At the time of admission to our hospital, necrosis from the interphalangeal joint to the distal end on the left thumb was observed and an injection mark was visible in the proximal portion of the radial styloid process (Figure 1). But there was no abnormality in the patient’s laboratory data. Strong pulse was palpable in the proximal portion of the radial styloid process of both wrists, but not where the radial artery is generally located. Variation in the superficial dorsal antebrachial artery was identified on angiographic CT (Figure 2). After confirming the boundary of the necrotic area, the proximal phalanx was amputated. Thumb reconstruction was not performed because the patient chose not to undergo the procedure.\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nDiscussion\nSince the introduction of thiopental in 1943, other reported drugs for intra-arterial injection have included psychotropic drugs or anesthetics such as promethazine, propofol, diazepam, methohexital, depomedrol, and benzodiazepine.1 Intra-arterial drug injections mostly occur because of iatrogenic complications during anesthesia procedures, as well as in drug abusers who perform self-injection without any anatomical knowledge.2 However, normal arterial drug injection is used for the treatment of femoral artery pseudoaneurysm, chemotherapy for some tumors and monitoring catheter during anesthesia or in the intensive care unit. Diclofenac sodium, which was injected in the patient in this case, is a nonsteroidal anti-inflammatory drug commonly used in clinical settings, and usually administered through intramuscular or intravenous injection. The known adverse effects of intramuscular injection of diclofenac include rhabdomyolysis and myopathy.4 Samanta and Samanta5 and Kumar et al6 reported cases of amputation due to necrosis of the finger after an intra-arterial injection of diclofenac in a radial artery mistaken for a vein. The rate of amputation of an extremity due to the adverse effects of intra-arterial drug injection is 29%. Among such cases, the rate of amputation resulting from intra-arterial benzodiazepine injection is high (up to 50%).2\n\nThe risk factors of inadvertent intra-arterial drug injection include obesity, which makes the veins difficult to find; self-injection by drug abusers with no anatomical knowledge; and vascular variations in the forearm. Juric et al7 introduced the subcutaneous vein detection solution using near-infrared spectroscopy. This is the most recent technology to become available that can be used as a guidance tool to facilitate vein identification. It is especially beneficial for high-risk populations. Among the high-risk populations, variations in the forearm radial artery are the most common cause of inadvertent intra-arterial injection. The most common variation in the forearm radial artery is a high-rising radial artery that forms superficial branches, terminates in the thenar region or binds with the ulnar artery to form a palmar arch that eventually forms superficial palmar branches.7 Another variation of the radial artery involves the superficial dorsal antebrachial artery that forms an incomplete palmar arch between the thumb and index finger.8 This crosses the cephalic vein on the superficial portion of the radial styloid process, causing it to be mistaken for an intravenous injection site. Among radial artery variations, superficial dorsal antebrachial artery variation has been reported to have a prevalence of ~1%. As it shows no specific symptoms, it may not be detected unless angiography is performed. Brown et al9 performed angiography in patients with superficial dorsal antebrachial artery variation and reported that ~13% of the patients had an incomplete form of such variation, in which the superficial palmar arch that supplies blood to the thumb does not anastomose with the ulnar artery. In such cases, when drug is injected in the radial artery or vascular damage occurs, necrosis of the thumb may occur because of the absence of blood supply to the ulnar artery. In our case, we believe that as the superficial dorsal antebrachial artery, which branches in the forearm, passed above the radial styloid process, it was mistaken for the cephalic vein, which is commonly used for intravenous injections.\n\nSymptoms that appear after intra-arterial drug injection include acute pain, numbness, and burning sensation in the peripheral and distal areas from the injection site, as well as neurosensory symptoms such as an abnormal sensation. Pseudoaneurysm, rhabdomyolysis, and compartment syndrome and tissue necrosis may occur within a few days and cause permanent functional damage.3 Of the total patients, 78% had severe pain, 37% had neurological symptoms, and 17% had terminal necrosis.2 Although the exact mechanism of such tissue damage has not been identified, vasoconstriction, thrombus formation, crystallization, endothelial inflammatory response, cytotoxicity response, and hyperosmolarity have been reported as possible causes.3 Therefore, the treatment decision should be based on the mechanism, including the use of an arterial vasodilator, anticoagulant therapy, selective use of thrombolytic agent, use of inflammatory antagonist, and steroid therapy, whereas prophylactic antibiotics should be used to prevent infection.2,3 Devulapalli et al2 reported an amputation rate of 4% within 14 h of intra-arterial drug injection and an amputation rate of 46% after 14 h.\n\nInadvertent intra-arterial drug injection can cause serious adverse effects such as necrosis and amputation of the ends of the extremities, regardless of the drug; however, the etiology of such adverse effects has not been identified and treatment methods have not been established yet. Therefore, the best option would be to identify the associated risk factors and symptoms, along with the prevention of inadvertent intra-arterial drug injection and treatment of its adverse effects upon early detection. In the present case, severe pain and numbness were identified immediately after the injection. Had these signs been used to suspect intra-arterial drug injection and appropriate treatment administered early, the possibility of amputation could have been reduced.\n\nConclusion\nClinically, it is not easy to prevent inadvertent intra-arterial drug injection. Therefore, early detection of an event and initiation of treatment is a way to reduce the amputation rate of distal extremities. Although the subsequent treatments such as pain control, anticoagulation, rehabilitation, and specific therapy are relatively standardized methods, the correlation with pathophysiology remains unclear.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 At the time of admission, necrosis of the left distal thumb phalanx was observed and an injection mark (black circle) was visible in the proximal portion of the radial styloid process.\n\nFigure 2 (A) The radial artery normally passes through the entire radial bone (arrow). (B) and (C) In the present patient, angiographic computed tomography revealed a variation of the radial artery where it was coursing above the styloid process as a superficial dorsal antebrachial artery (arrows).\n==== Refs\nReferences\n1 Keene JR Buckley KM Small S Geldzahler G Accidental intra-arterial injection: a case report, new treatment modalities, and a review of the literature J Oral Maxillofac Surg 2006 64 6 965 968 16713815 \n2 Devulapalli C Han KD Bello RJ LaPorte DM Hepper CT Katz RD Inadvertent intra-arterial drug injections in the upper extremity: systematic review J Hand Surg Am 2015 40 11 2262 2268.e5 26409581 \n3 Sen S Chini EN Brown MJ Complications after unintentional intra-arterial injection of drugs: risks, outcomes, and management strategies Mayo Clin Proc 2005 80 6 783 795 15945530 \n4 Selimoglu O Basaran M Ugurlucan M Ogus TN Rhabdomyolysis following accidental intra-arterial injection of local anesthetic Angiology 2009 60 1 120 121 18388104 \n5 Sukhen Samanta Sujay Samanta Accidental intra arterial injection of diclofenac sodium and their consequences: report of two cases Anaesth Pain Intensive Care 2013 17 1 101 102 \n6 Kumar M Singh J Sharma P Khera A Singh P Accidental intra-arterial injection of diclofenac -case report J Clin Diagn Res 2015 9 1 PD16 PD17 25738031 \n7 Juric S Flis V Debevc M Holzinger A Zalik B Towards a low-cost mobile subcutaneous vein detection solution using near-infrared spectroscopy Sci World J 2014 2014 365902 \n8 Gonzalez-Compta X Origin of the radial artery from the axillary artery and associated hand vascular anomalies J Hand Surg Am 1991 16 2 293 296 2022840 \n9 Brown MJ Edstrom LE Zienowicz RJ A symptomatic radial artery anomaly and its surgical treatment J Hand Surg Am 1999 24 1 178 181 10048534\n\n",
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"title": "Necrosis of the thumb after inadvertent injection of diclofenac in the radial artery: a case report.",
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"abstract": "Breast cancer is the most common tumor in women and the first cause of death for malignancy in the female. Bile ducts are not among the common sites of metastasis from breast cancer. Few cases of obstructive jaundice due to metastatic breast cancer have been described in the literature and they mostly resulted from widespread liver metastases that eventually involved the bile ducts. We report an exceptional case of ampullary metastasis in the absence of liver metastases. Sporadic reports have been published about the involvement of the ampulla by breast cancer metastasis. This case emphasizes the need to consider this diagnosis in women presenting with obstructive jaundice, especially when there is a clinical possibility of breast cancer.",
"affiliations": "Gastroenterology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.;Gastroenterology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.;Gastroenterology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.;Gastroenterology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.;Gastroenterology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.;Pathology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.;Gastroenterology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.",
"authors": "Giestas|Sílvia|S|;Lopes|Sandra|S|;Souto|Paulo|P|;Agostinho|Cláudia|C|;Camacho|Ernestina|E|;Cipriano|Maria|M|;Sofia|Carlos|C|",
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"fulltext": "\n==== Front\nGE Port J GastroenterolGE Port J GastroenterolGE Portuguese Journal of Gastroenterology2341-45452387-1954Karger Publishers S2341-4545(16)30015-110.1016/j.jpge.2016.03.001Clinical CaseAmpullary Metastasis From Breast Cancer: A Rare Cause of Obstructive Jaundice Metástase Ampular de Neoplasia da Mama: Uma Causa Rara de Icterícia Obstrutiva Giestas Sílvia silviagiestas@gmail.coma⁎Lopes Sandra aSouto Paulo aAgostinho Cláudia aCamacho Ernestina aCipriano Maria bSofia Carlos aa Gastroenterology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugalb Pathology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal⁎ Corresponding author. silviagiestas@gmail.com21 6 2016 Nov-Dec 2016 21 6 2016 23 6 300 303 13 11 2015 8 3 2016 © 2016 Sociedade Portuguesa de Gastrenterologia. Published by Elsevier Espa˜na, S.L.U.2016Sociedade Portuguesa de GastrenterologiaThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Breast cancer is the most common tumor in women and the first cause of death for malignancy in the female. Bile ducts are not among the common sites of metastasis from breast cancer. Few cases of obstructive jaundice due to metastatic breast cancer have been described in the literature and they mostly resulted from widespread liver metastases that eventually involved the bile ducts. We report an exceptional case of ampullary metastasis in the absence of liver metastases.\n\nSporadic reports have been published about the involvement of the ampulla by breast cancer metastasis. This case emphasizes the need to consider this diagnosis in women presenting with obstructive jaundice, especially when there is a clinical possibility of breast cancer.\n\nResumen\nO cancro da mama é o tumor mais comum em mulheres e a principal causa de morte por neoplasia nesta população. A via biliar não é um local comum de metastização desta neoplasia. Poucos casos de icterícia obstrutiva devido a metástases mamárias têm sido descritos na literatura e ocorrem principalmente devido a metástases hepáticas que comprimem a via biliar. Relatamos um caso excepcional de metástase ampular na ausência de metástases hepáticas.\n\nExistem apenas relatos esporádicos do envolvimento da ampola por metástase mamárias. Este caso enfatiza a necessidade de considerar este diagnóstico perante um quadro de icterícia obstrutiva, especialmente em doentes com possível neoplasia mamária.\n\nKeywords\nBreast NeoplasmsAmpulla of VaterJaundice, Obstructive/etiologyNeoplasm MetastasisPalavras-chave\nNeoplasias da MamaAmpola HepatopancreáticaIcterícia Obstrutiva/etiologiaMetástase Neoplásica\n==== Body\n1 Introduction\nBreast cancer is the most common malignancy in women, with over a million newly diagnosed cases each year and being one of the leading causes of cancer death among them.1, 2, 3\n\nIn 10% of the cases distant metastases are already present at the time of the diagnosis.4, 5, 6 Breast cancer metastases occur through contiguous, lymphatic and hematogenous spread. Common sites of metastasis include bone, lung, lymph nodes, liver and brain. Virtually every site of the human body can be targeted by hematogenous spread of breast cancer. However, metastases to the digestive tract, the kidneys and retroperitoneal organs have only been occasionally reported.4, 5, 6 Gastrointestinal tract involvement is detected in only 10% of all the cases.4, 5, 6 Widespread liver metastases that compress or infiltrate the bile ducts can sometimes cause obstructive jaundice, whilst a direct metastatic involvement of the extrahepatic bile ducts in absence of hepatic lesions is exceptional.4, 5, 6\n\nWe report a singular case of obstructive jaundice due to a metastatic breast cancer to the ampulla of Vater. To the best of our knowledge and review of the literature there have been only few similar reports.7, 8, 9, 10\n\nThis case emphasize that diagnosis can be difficult and controversial when metastasis from breast cancer occurs at uncommon sites, but quick and accurate diagnosis is needed for an adequate treatment choice.\n\n2 Case presentation\nA 59-year-old female was admitted to the emergency department with mucocutaneous jaundice associated with pruritus. No dark urine, acholic stools, abdominal pain, fever, anorexia or weight loss were present. Personal history included systemic lupus erythematosus (treated with hydroxychloroquine sulfate and mycophenolate mofetil), type 2 diabetes mellitus non-insulin treated and a breast lump (detected about a month ago in breast cancer screening mammography) under investigation (histology ongoing). The laboratory tests showed an obstructive pattern with total bilirubin 9 mg/dL, direct bilirubin 6.4 mg/dL, aspartate aminotransferase 126 IU/L, alanine aminotransferase 208 IU/L, gamma glutamyl transpeptidase 796 IU/L, alkaline phosphatase 726 IU/L and negative inflammatory parameters. Blood tumor markers (cancer antigen 19.9 and carcinoembryonic antigen) were within normal ranges. The abdominal ultrasound study was limited by bowel gas interposition but allowed view marked dilatation of intrahepatic bile ducts and common bile duct 14 mm and could not define the cause of obstruction. Abdominal tomography confirmed dilatation of hepatic bile ducts (common bile duct with 15 mm without evidence of choledocholitiasis) and showed an ampullary mass with 13 mm of diameter suggestive of ampullary adenoma without suspicious abdominal lymph nodes (Fig. 1). Endoscopic retrograde cholangiopancreatography (ERCP) showed papilla of Vater with moderately increased volume and irregular mucosal suggestive of congestive ampullary adenoma. Biopsies were performed and two plastic biliary stents were placed. Histology showed infiltration by invasive ductal carcinoma of the breast (Fig. 2). During hospitalization the histology of the breast nodule revealed an invasive breast carcinoma and the patient initiated chemotherapy (including transtuzumab). Further evaluation with chest tomography and radionuclide bone scanning revealed the presence of bone metastases. For better palliation, three months after the plastic stent implantation, patient underwent repeat ERCP with the placement of a metal stent due to its better efficiency. At discharge and several weeks later the repeated laboratory tests revealed regression of cholestasis. The patient succumbed to metastatic disease 1 year later of the diagnostic without jaundice or abnormal liver function tests.Figure 1 Computed tomography showed an ampullary mass with 13 mm suggestive of ampullary adenoma.\n\nFigure 2 Histology of the ampulla of Vater: papilla showed infiltration by invasive ductal carcinoma of the breast.\n\n\n\n3 Discussion\nBreast cancer is the most commonly diagnosed cancer worldwide, with more than 1,384,000 cases detected each year. It is the main cause of death from cancer in females and the second in the general population, after lung cancer.1, 2, 3\n\nDistant metastases of breast carcinoma are present in about 10% of patients at the time of diagnosis, while 30% of patients will develop metastatic disease following surgery and/or chemotherapy, radiotherapy or endocrine therapy.3\n\nThe most common sites of breast cancer metastases are the bone, lung, liver and brain, while the involvement of gastrointestinal tract is rare and can pose a diagnostic challenge.4, 5, 6 Metastatic breast cancer can cause obstructive jaundice when multiple liver lesions are present, the bile duct is compressed by enlarged lymph nodes or, more rarely, when the head of the pancreas is involved.4, 5, 6 The biliary tract is very rarely affected by metastases in general, and in these cases, colorectal cancer is the most frequent malignancy involved. Other reported primary tumors causing metastatic biliary obstruction include malignant melanoma, lymphoma, gallbladder, stomach, esophagus, liver, ovary, cervix, uterus, muscle, kidney, prostate, bone and brain. Isolated breast cancer metastasis to the biliary tract, gallbladder and Vater ampulla are exceptional.4, 5, 6 It is important to recognize this group of patients because in patients with normal liver function, relief of biliary obstruction using surgical bypass or biliary stenting extends their survival to over 1 year, in comparison to those with liver metastases, whose mean survival is only about 1 month.11, 12, 13\n\nBy reviewing the literature there were only a few cases of extrahepatic biliary tract metastasis from breast cancer involving the periampullary area.7, 8, 9, 10 A permanent feature of all the reports available in the literature is that the diagnosis was not achieved nor suspected before endoscopy biopsy and/or surgery. Similarly, in the majority of the cases there was a long interval between the diagnosis of the primary tumor and the development of metastases affecting the biliary tract. This timing can make it hard to suspect a relationship between the breast cancer and the biliary disease.7, 8, 9, 10 In our case this was the first evidence of metastatic breast cancer. Patients with a history of malignancy found to have obstructive jaundice from an ampullary mass should undergo further investigation to determine primary biliary cancer versus metastatic disease in order to provide appropriate surgical and medical management. Nowadays, numerous modalities such as extracorporeal ultrasonography (US), esophagogastroduodenoscopy, biopsy, computed tomography (TC), magnetic resonance (MRI), endoscopic ultrasonography (EUS), ERCP, intraductal US and angiography are available for diagnosing ampullary neoplasms. Appropriate and efficient selection of such modalities is necessary for lessening procedure-related complications as well as the burden on the patients.14 It is not always possible to distinguish adenoma from carcinoma or metastatic involvement of the ampulla with duodenoscopy only, and histological evaluation by forceps biopsy is mandatory for establishment of a definitive diagnosis. The diagnostic accuracy of forceps biopsy in ampullary neoplasms reportedly ranges from 47 to 95%.14 Immunohistochemistry plays a key role for indicating the histological type of the tumor, since the metastases of breast carcinoma to the gastrointestinal tract have an endoscopic, radiological and histological aspect similar to the adenocarcinoma poorly differentiated with signet ring cells.10 Tumor stating with EUS and/or intraductal US can provide useful information for making therapeutic decisions, especially in the selection of patients for endoscopic papillectomy.14 CT/MRI is recommended for the detection of distant metastases. EUS can be performed in a single session with ERCP, biopsy and biliary stent placement (if indicated).14\n\nPatients with metastatic breast cancer in the biliary tract need a long-term palliative treatment strategy. The use of novel chemotherapy, hormonal therapy and irradiation in conjunction with biliary decompression or surgical intervention may lead to even more prolonged survival and improve quality of life.15, 16 A variety of chemotherapy strategies are available for metastatic breast cancer and should be tailored for each patient along with endocrine therapy in tumors positive for estrogen and progesterone receptors.16, 17, 18 HER2 receptor-positive metastatic disease should be treated with trastuzumab in addition to chemotherapy.19\n\nBiliary stenting is a commonly used procedure in treating patients with pancreaticobiliary malignancies, metastatic disease and external biliary compression by lymph nodes. It is used both as a bridge to surgery in patients with resectable disease and for palliation in those with biliary obstruction caused by inoperable disease.20, 21 For palliation endoscopic biliary drainage is effective in more than 80% of cases.21, 22, 23, 24, 25 Multiple trials have demonstrated that placement of self-expanding metallic stents in patients with malignant obstruction of the common bile duct offers higher technical and clinical success rates as well as lower complication rates and a superior cumulative stent patency when compared with plastic stent placement.21, 22, 23, 24, 25 Initial insertion of a plastic stent is most cost-effective if patient life expectancy is shorter than 4 months, if it is longer than 4 months then initial insertion of a self-expanding metallic stents is more cost-effective.21, 22, 23, 24, 25 In our case, we first placed a plastic stent to gain symptomatic relief, but after knowing the result of histology, we replaced it with a metal one 3 months after the first intervention.\n\nThe present report provides evidence that metastases from breast cancer can target the extrahepatic bile ducts in the absence of liver involvement, and the invasion of the bile duct wall can also be the first sign of advanced disease, thus making the diagnosis particularly difficult. Although gastrointestinal involvement in breast cancer is rare, in patients with a history of a breast lump, the possibility of biliary localization of metastatic disease should be always considered in the differential diagnosis of obstructive jaundice whose origin is unclear, especially because this condition is amenable to palliation and improve survival rate.\n\nEthical disclosures\nProtection of human and animal subjects\nThe authors declare that the procedures followed were in accordance with the regulations of the relevant clinical research ethics committee and with those of the Code of Ethics of the World Medical Association (Declaration of Helsinki).\n\nConfidentiality of data\nThe authors declare that no patient data appear in this article.\n\nRight to privacy and informed consent\nThe authors declare that no patient data appear in this article.\n\nConflicts of interest\nThe authors have no conflicts of interest to declare.\n==== Refs\nReferences\n1 Ferlay J. Shin H.R. Bray F. Forman D. Mathers C. Parkin D.M. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008 Int J Cancer 127 2010 2893 2917 21351269 \n2 Jemal A. Bray F. Center M.M. Ferlay J. Ward E. Forman D. Global cancer statistics CA Cancer J Clin 61 2011 69 90 21296855 \n3 Petracci E. Decarli A. Schairer C. Pfeiffer R.M. Pee D. Masala G. Risk factor modification and projections of absolute breast cancer risk J Natl Cancer Inst 103 2011 1037 1048 21705679 \n4 Stellato T.A. Zollinger R.M. Shuck J.M. Metastatic malignant biliary obstruction Am Surg 53 1987 385 388 3605855 \n5 Franco D. Martin B. Smadja C. Szekely A.M. Rougier P. Biliary metastases of breast carcinoma. The case for resection Cancer 60 1987 96 99 2438031 \n6 Taal B.G. den Hartog Jager F.C. Steinmetz R. Peterse H. The spectrum of gastrointestinal metastases of breast carcinoma Gastrointest Endosc 38 1992 136 141 1568609 \n7 Titus A.S. Baron A.S. Todd H. Solitary breast metastasis to the ampulla and distal common Am Surg 63 1977 512 515 \n8 Rego R.F. Atiq M. Velchala N. Nevin D. McElreath D.P. McKnight W.D. Ampullary metastasis from breast cancer: an unusual finding Endoscopy 41 2009 E278 E279 19866428 \n9 Ferrari A.B. Pulcini G. Gheza F. Vinco A. Manenti S. Cervi E. Duodenal metastasis from male breast cancer: a case report and review of the literature J Med Case Rep 3 2009 8331 19830225 \n10 Bastos T. Souza T.F. Otoch J.P. Grecco E. Ávila F. Artifon E.L.A. Metastasis of breast cancer to major duodenal papilla Rev Gastroenterol Peru 34 2014 149 150 25028907 \n11 Ellis M. Levey J. Endoscopic biliary drainage for breast carcinoma metastatic to the duodenum Am J Gastroenterol 98 2003 S167 \n12 Budimir I. Pusic M.S. Nikolic M. Dorosulic Z. Ljubicic N. Stajduhar E. Obstructive jaundice as an uncommon manifestation of metastatic breast cancer World J Oncol 6 2015 297 300 \n13 Pappo I. Feigin E. Uziely B. Amir G. Biliary and pancreatic metastases of breast carcinoma: is surgical palliation indicated J Surg Oncol 46 1991 211 214 1707119 \n14 Ito K. Fujita N. Noda Y. Kobayashi G. Horaguchi J. Diagnosis of ampullary cancer Dig Surg 27 2010 115 118 20551654 \n15 Kesson E.M. Allardice G.M. George W.D. Burns H.J. Morrison D.S. Effects of multidisciplinary team working on breast cancer survival: retrospective, comparative, interventional cohort study of 13 722 women BMJ 344 2012 e2718 22539013 \n16 Cardoso F. Costa A. Norton L. Senkus E. Aapro M. André F. ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2) Ann Oncol 25 2014 1871 1888 25234545 \n17 Carrick S. Parker S. Thornton C.E. Ghersi D. Simes J. Wilcken N. Single agent versus combination chemotherapy for metastatic breast cancer Cochrane Database Syst Rev 2 2009 CD003372 \n18 Smith I.E. Dowsett M. Aromatase inhibitors in breast cancer N Engl J Med 348 2003 2431 2442 12802030 \n19 Moja L. Tagliabue L. Balduzzi S. Parmelli E. Pistotti V. Guarneri V. Trastuzumab containing regimens for early breast cancer Cochrane Database Syst Rev 4 2012 CD006243 \n20 Chun H.J. Kim E.S. Hyun J.J. Kwon Y.D. Keum B. Kim C.D. Gastrointestinal and biliary stents J Gastroenterol Hepatol 25 2010 234 243 20136988 \n21 Perdue D.G. Freeman M.L. DiSario J.A. Nelson D.B. Fennerty M.B. Lee J.G. Plastic versus self-expanding metallic stents for malignant hilar biliary obstruction: a prospective multicenter observational cohort study J Clin Gastroenterol 42 2008 1040 1046 18719507 \n22 Moss A.C. Morris E. Leyden J. MacMathuna P. Malignant distal biliary obstruction: a systematic review and meta-analysis of endoscopic and surgical bypass results Cancer Treat Rev 33 2007 213 221 17157990 \n23 Larghi A. Tringali A. Lecca P.G. Giordano M. Costamagna G. Management of hilar biliary strictures Am J Gastroenterol 103 2008 458 473 18028506 \n24 Cochrane J. Schlepp G. Metastatic breast cancer to the common bile duct presenting as obstructive jaundice Case Rep Gastroenterol 9 2015 278 284 26351417 \n25 Liberato M.J. Canena J.M. Endoscopic stenting for hilar cholangiocarcinoma: efficacy of unilateral and bilateral placement of plastic and metal stents in a retrospective review of 480 patients BMC Gastroenterol 12 2012 103 22873816\n\n",
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"keywords": "Ampulla of Vater; Breast Neoplasms; Jaundice, Obstructive/etiology; Neoplasm Metastasis",
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"title": "Ampullary Metastasis From Breast Cancer: A Rare Cause of Obstructive Jaundice.",
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"abstract": "OBJECTIVE\nBoth cisplatin and epirubicin have been shown to enhance the antitumor activity of paclitaxel in vitro. Weekly administration could result in a substantial improvement in the therapeutic index of cisplatin and paclitaxel. This study was aimed at determining the MTDs of epirubicin and paclitaxel given weekly with a fixed dose of cisplatin.\n\n\nMETHODS\nSixty-three breast cancer patients with advanced disease (24 locally advanced and 39 metastatic), who had not received prior chemotherapy (except adjuvant), received weekly cisplatin (CDDP) doses of 30 mg/m2 together with escalating doses of paclitaxel (PTX) and epirubicin (EPI) for a minimum of six cycles. The dose escalation was stopped if DLT occurred during the first six treatment cycles in > 33% of patients of a given cohort.\n\n\nRESULTS\nNine different dose levels were tested, for a total of 506 weekly cycles delivered. G-CSF support on days 3-5 of each week was also given in the last four cohorts (24 patients). An overall 11 patients showed DLT in the first six cycles. EPI and PTX doses up to 40 and 85 mg/m2/week, respectively, were safely delivered without G-CSF support. However, the actually delivered mean dose intensity was only 64% in this cohort. Therefore, the dose escalation continued with the addition of filgrastim from day 3 to day 5 each week. Doses of EPI and PTX up to 50 and 120 mg/m2/week were administered without observing DLT in the first six cycles in more than one third of the patients enrolled. No toxic deaths were observed. Only two patients had to be hospitalized because of sepsis. Grade 3-4 neutropenia, thrombocytopenia, and anemia occurred in 25, 9, and 16 patients, respectively. Alopecia was almost universal. Other nonhematologic toxicities were generally mild, being of grade 3-4 in only eight patients (fatigue and loss of appetite in two cases, diarrhoea in four cases, peripheral neuropathy and mucositis in one case). Fifteen complete and 37 partial responses have been registered for an 82% (95% CI = 71-91) overall clinical response rate (ORR). Eight complete and 14 partial responses occurred in the 24 patients with locally advanced disease, for a 92% (95% CI = 73-99) ORR, as compared to seven complete and 23 partial responses in the 39 women with metastatic disease, 77% (95% CI = 61-89). A clear dose-response relationship was not observed, since an overall response rate of at least 70% was achieved at all dose levels. However, the ORR increased to 92% in the last four cohorts which included patients who received higher doses of EPI and PTX with G-CSF support. All of the 24 patients with locally advanced disease underwent modified radical mastectomy with axillary dissection. Three of them showed no invasive cancer on pathologic examination, and in another five patients a tumor smaller than 1 cm was found in the surgical specimen of the breast. At a nine-month median follow-up (range 2-14), 11 patients have progressed and three have died. Twenty-three out of 24 patients who underwent surgery are still free from progression. The one-year projected progression-free survival is 77% for the whole population.\n\n\nCONCLUSIONS\nThe CDDP/EPI/PTX weekly administration is a well tolerated and very effective approach in advanced breast cancer patients. Full doses of all the three drugs can be delivered even in absence of G-CSF support. A very impressive increment of the dose-intensity can be obtained, however, by adding filgrastim. A phase II study is under way to better define the therapeutic efficacy of this regimen in patients with advanced breast cancer.",
"affiliations": "Division of Medical Oncology A, National Tumor Institute, Naples, Italy. gifrasei@sirio-oncology.it",
"authors": "Frasci|G|G|;D'Aiuto|G|G|;Comella|P|P|;Apicella|A|A|;Thomas|R|R|;Capasso|I|I|;Di Bonito|M|M|;Cartenì|G|G|;Biglietto|M|M|;De Lucia|L|L|;Maiorino|L|L|;Piccolo|S|S|;Bianchi|U|U|;D'Aniello|R|R|;Lapenta|L|L|;Comella|G|G|",
"chemical_list": "D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D015251:Epirubicin; D017239:Paclitaxel; D002945:Cisplatin",
"country": "Netherlands",
"delete": false,
"doi": "10.1023/a:1006263226099",
"fulltext": null,
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"issn_linking": "0167-6806",
"issue": "56(3)",
"journal": "Breast cancer research and treatment",
"keywords": null,
"medline_ta": "Breast Cancer Res Treat",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D002945:Cisplatin; D004334:Drug Administration Schedule; D004357:Drug Synergism; D015251:Epirubicin; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D017239:Paclitaxel; D011994:Recombinant Proteins",
"nlm_unique_id": "8111104",
"other_id": null,
"pages": "239-52",
"pmc": null,
"pmid": "10573115",
"pubdate": "1999-08",
"publication_types": "D016430:Clinical Trial; D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Cisplatin-epirubicin-paclitaxel weekly administration in advanced breast cancer: a phase I study of the Southern Italy Cooperative Oncology Group.",
"title_normalized": "cisplatin epirubicin paclitaxel weekly administration in advanced breast cancer a phase i study of the southern italy cooperative oncology group"
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"companynumb": "IT-PFIZER INC-2020449201",
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"abstract": "More than half of infants with new-onset epilepsy have electroencephalographic and clinical features that do not conform to known electroclinical syndromes (ie, nonsyndromic epilepsy). Levetiracetam and phenobarbital are the most commonly prescribed medications for epilepsy in infants, but their comparative effectiveness is unknown.\n\n\n\nTo compare the effectiveness of levetiracetam vs phenobarbital for nonsyndromic infantile epilepsy.\n\n\n\nThe Early Life Epilepsy Study-a prospective, multicenter, observational cohort study conducted from March 1, 2012, to April 30, 2015, in 17 US medical centers-enrolled infants with nonsyndromic epilepsy and a first afebrile seizure between 1 month and 1 year of age.\n\n\n\nUse of levetiracetam or phenobarbital as initial monotherapy within 1 year of the first seizure.\n\n\n\nThe binary outcome was freedom from monotherapy failure at 6 months, defined as no second prescribed antiepileptic medication and freedom from seizures beginning within 3 months of initiation of treatment. Outcomes were adjusted for demographics, epilepsy characteristics, and neurologic history, as well as for observable selection bias using propensity score weighting and for within-center correlation using generalized estimating equations.\n\n\n\nOf the 155 infants in the study (81 girls and 74 boys; median age, 4.7 months [interquartile range, 3.0-7.1 months]), those treated with levetiracetam (n = 117) were older at the time of the first seizure than those treated with phenobarbital (n = 38) (median age, 5.2 months [interquartile range, 3.5-8.2 months] vs 3.0 months [interquartile range, 2.0-4.4 months]; P < .001). There were no other significant bivariate differences. Infants treated with levetiracetam were free from monotherapy failure more often than those treated with phenobarbital (47 [40.2%] vs 6 [15.8%]; P = .01). The superiority of levetiracetam over phenobarbital persisted after adjusting for covariates, observable selection bias, and within-center correlation (odds ratio, 4.2; 95% CI, 1.1-16; number needed to treat, 3.5 [95% CI, 1.7-60]).\n\n\n\nLevetiracetam may have superior effectiveness compared with phenobarbital for initial monotherapy of nonsyndromic epilepsy in infants. If 100 infants who received phenobarbital were instead treated with levetiracetam, 44 would be free from monotherapy failure instead of 16 by the estimates in this study. Randomized clinical trials are necessary to confirm these findings.",
"affiliations": "Department of Healthcare Policy & Research, Weill Cornell Medicine, New York, New York.;Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor.;Department of Pediatrics, Oregon Health & Sciences University, Portland.;Department of Neurology, University of California, San Francisco.;Department of Neurology, Mayo Clinic, Rochester, Minnesota.;Department of Pediatrics, Nationwide Children's Hospital, The Ohio State University, Columbus.;Department of Neurology, Children's National Health System, George Washington University School of Medicine, Washington, DC.;Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland.;Section of Neurology, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, Pennsylvania.;Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora.;Division of Child Neurology, Stanford University, Palo Alto, California.;Comprehensive Epilepsy Program, Jane and John Justin Neuroscience Center, Cook Children's Medical Center, Fort Worth, Texas.;Division of Neurology, The Children's Hospital of Philadelphia, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia.;Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.;Department of Neurology, Massachusetts General Hospital, Boston.;Division of Pediatric Neurology, Seattle Children's Hospital, Seattle, Washington.;Epilepsy Center, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.;Epilepsy Center, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.",
"authors": "Grinspan|Zachary M|ZM|;Shellhaas|Renée A|RA|;Coryell|Jason|J|;Sullivan|Joseph E|JE|;Wirrell|Elaine C|EC|;Mytinger|John R|JR|;Gaillard|William D|WD|;Kossoff|Eric H|EH|;Valencia|Ignacio|I|;Knupp|Kelly G|KG|;Wusthoff|Courtney|C|;Keator|Cynthia|C|;Ryan|Nicole|N|;Loddenkemper|Tobias|T|;Chu|Catherine J|CJ|;Novotny|Edward J|EJ|;Millichap|John|J|;Berg|Anne T|AT|",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D010634:Phenobarbital",
"country": "United States",
"delete": false,
"doi": "10.1001/jamapediatrics.2017.5211",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2168-6203",
"issue": "172(4)",
"journal": "JAMA pediatrics",
"keywords": null,
"medline_ta": "JAMA Pediatr",
"mesh_terms": "D000927:Anticonvulsants; D015331:Cohort Studies; D011307:Drug Prescriptions; D004827:Epilepsy; D005260:Female; D006801:Humans; D007223:Infant; D000077287:Levetiracetam; D008297:Male; D010634:Phenobarbital; D014481:United States",
"nlm_unique_id": "101589544",
"other_id": null,
"pages": "352-360",
"pmc": null,
"pmid": "29435578",
"pubdate": "2018-04-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": "23937191;23266150;24526342;22689735;26122601;24730690;17544607;15342834;28284397;9489721;26876768;18830435;17368928;22581672;23205961;25963534;27106855;19243423;21818162;19757444;2242106;28807611;12853301;21483818;24051577;18448575;28759667;24021692;23458993",
"title": "Comparative Effectiveness of Levetiracetam vs Phenobarbital for Infantile Epilepsy.",
"title_normalized": "comparative effectiveness of levetiracetam vs phenobarbital for infantile epilepsy"
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"abstract": "Renal artery stenosis is a notorious cause of secondary hypertension which classically presents as chronic refractory hypertension, recurrent flash pulmonary edema or renal insufficiency after initiation of an angiotensin converting enzyme inhibitor. Rarely, there have been reported cases of pregnant patients presenting with new onset or superimposed preeclampsia secondary to renovascular hypertension. In this subset of patients, renovascular hypertension carries significantly higher risks including obstetric, fetal and medical emergencies and death. Prompt treatment is required. However, the teratogenic risks of radiological investigations and antihypertensive medications limit diagnostic and management options thus posing quite a dilemma.\nA 38-year-old female, at 33 weeks of gestation, was hospitalized for preeclampsia with severe features. A viable neonate had been expeditiously delivered yet the patient's post-partum blood pressures remained severely elevated despite multi-class anti-hypertensive therapy. Renal artery dopplers revealed greater than 60% stenosis of the proximal left renal artery and at least 60% stenosis of the right renal artery. Renal angiography showed 50% stenosis of the left proximal renal artery for which balloon angioplasty and stenting was performed. The right renal artery demonstrated less than 50% stenosis with an insignificant hemodynamic gradient, thus was not stented. Following revascularization, the patient's blood pressure improved within 48 h, on dual oral antihypertensive therapy.\nPreeclampsia that is refractory to multi-drug antihypertensive therapy should raise suspicion for renal artery stenosis. Suspected patients can be screened safely with Doppler ultrasonography which can be then followed by angiography. Even if renal artery stenosis does not seem severe, early renal revascularization may be considered in patients with severe preeclampsia who do not respond to antihypertensive management.",
"affiliations": "1Department of Medicine, University of Florida College of Medicine-Jacksonville, Jacksonville, USA.;1Department of Medicine, University of Florida College of Medicine-Jacksonville, Jacksonville, USA.;2Division of Medical Oncology and Hematology, University of Louisville, Louisville, USA.;1Department of Medicine, University of Florida College of Medicine-Jacksonville, Jacksonville, USA.",
"authors": "Omar|Michael Brandon|MB|;Kogler|William|W|;Maharaj|Satish|S|;Aung|Win|W|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s40885-020-00140-4",
"fulltext": "\n==== Front\nClin Hypertens\nClin Hypertens\nClinical Hypertension\n2056-5909 BioMed Central London \n\n140\n10.1186/s40885-020-00140-4\nCase Report\nRenal artery stenosis presenting as preeclampsia\nOmar Michael Brandon michael.omar@jax.ufl.edu 1 Kogler William 1 Maharaj Satish 2 Aung Win 1 1 grid.413116.00000 0004 0625 1409Department of Medicine, University of Florida College of Medicine-Jacksonville, Jacksonville, USA \n2 grid.266623.50000 0001 2113 1622Division of Medical Oncology and Hematology, University of Louisville, Louisville, USA \n1 4 2020 \n1 4 2020 \n2020 \n26 613 9 2019 3 3 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nRenal artery stenosis is a notorious cause of secondary hypertension which classically presents as chronic refractory hypertension, recurrent flash pulmonary edema or renal insufficiency after initiation of an angiotensin converting enzyme inhibitor. Rarely, there have been reported cases of pregnant patients presenting with new onset or superimposed preeclampsia secondary to renovascular hypertension. In this subset of patients, renovascular hypertension carries significantly higher risks including obstetric, fetal and medical emergencies and death. Prompt treatment is required. However, the teratogenic risks of radiological investigations and antihypertensive medications limit diagnostic and management options thus posing quite a dilemma.\n\nCase presentation\nA 38-year-old female, at 33 weeks of gestation, was hospitalized for preeclampsia with severe features. A viable neonate had been expeditiously delivered yet the patient’s post-partum blood pressures remained severely elevated despite multi-class anti-hypertensive therapy. Renal artery dopplers revealed greater than 60% stenosis of the proximal left renal artery and at least 60% stenosis of the right renal artery. Renal angiography showed 50% stenosis of the left proximal renal artery for which balloon angioplasty and stenting was performed. The right renal artery demonstrated less than 50% stenosis with an insignificant hemodynamic gradient, thus was not stented. Following revascularization, the patient’s blood pressure improved within 48 h, on dual oral antihypertensive therapy.\n\nConclusions\nPreeclampsia that is refractory to multi-drug antihypertensive therapy should raise suspicion for renal artery stenosis. Suspected patients can be screened safely with Doppler ultrasonography which can be then followed by angiography. Even if renal artery stenosis does not seem severe, early renal revascularization may be considered in patients with severe preeclampsia who do not respond to antihypertensive management.\n\nKeywords\nPreeclampsiaRenal artery stenosisRenovascular hypertensionSecondary hypertensionissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nRenal artery stenosis is a notorious cause of secondary hypertension resulting from the activation of the renin-angiotensin system in response to reduced renal blood flow. Classic presentations include chronic refractory hypertension, recurrent flash pulmonary edema and renal insufficiency after initiation of an angiotensin converting enzyme inhibitor. Although rare, there have also been reported cases of pregnant patients presenting with new onset or superimposed preeclampsia secondary to renovascular hypertension [1, 2]. In this subset of patients, renovascuar hypertension carries significantly higher risks including obstetric, fetal and medical emergencies and death. Prompt treatment is required. However, the teratogenic risks of radiological investigations and antihypertensive medications such as angiotensin converting enzyme inhibitors or aldosterone antagonists limit management options and poses quite the dilemma. When possible, expedited delivery is beneficial; notwithstanding the fact that there has been success with interventional treatment prior to successful delivery. Furthermore, even after delivery, the mortality risk of pre-eclampsia continues into the post-partum period thus urgent and aggressive treatment strategies should continue to be pursued for these patients including consideration of early revascularization.\n\nCase presentation\nA 38-year-old female, gravida 3 para 2 at 33 weeks of gestation, was hospitalized for preeclampsia with severe features. A viable neonate had been expeditiously delivered yet the patient’s post-partum blood pressures remained severely elevated ranging from 230/130 mmHg to 280/170 mmHg. She had no antenatal care but reported a history of uncomplicated hypertension during her prior pregnancies and tobacco abuse which was stopped 8 months prior. At the bedside, she complained of mild headaches but denied visual disturbances or upper abdominal pain. She was alert and well oriented with a pulse of 80 bpm. There was no hyperreflexia, clonus, papilledema, peripheral edema or signs of pulmonary edema. Her examination was otherwise unremarkable including the absence of renal bruits. Apart from an elevated random urine protein to creatinine ratio of 0.7, the laboratory investigations were within normal limits including serum creatinine, electrolytes, platelet count, liver function and coagulation studies. There were no laboratory features of hemolysis. She was treated with multiple anti-hypertensives over the next 72 h including oral nifedipine, labetalol and clonidine as well as intravenous infusions of labetalol, nicardipine, hydralazine. Magnesium was used for eclampsia prophylaxis. Of note, a single dose of intravenous enalapril was given with a subsequent 60% increase in serum creatinine that returned to baseline within 24 h of discontinuation. Renal artery dopplers (Fig. 1) were performed which revealed greater than 60% stenosis of the proximal left renal artery and at least 60% stenosis of the distal right renal artery. Computerized tomography angiography showed approximately 50% stenosis of the proximal left renal artery without stenosis of the right renal artery (Fig. 2). At this juncture, in the setting of recalcitrant severe preeclampsia and the mortality risk of impending eclampsia, an invasive strategy for better evaluation and possible intervention was deemed net beneficial. Renal angiography showed 50% stenosis of the left proximal renal artery for which balloon angioplasty and stenting was performed (Fig. 3). The right renal artery demonstrated less than 50% stenosis with an insignificant hemodynamic gradient, thus was not stented. Following revascularization, the patient’s blood pressure improved, ranging from 180/100 mmHg to 160/90 mmHg within 48 h, on dual oral antihypertensive therapy. She was ultimately discharged to titrate further anti-hypertensive therapy as an outpatient.\nFig. 1 Doppler ultrasonography with peak systolic velocities (PSV) of the right proximal (a), left proximal (b), right distal (c) and left distal (d) renal arteries [Normal PSV < 180 cm/s]\n\nFig. 2 Computerized tomography of the right (a) and left (b) proximal renal arteries (arrows). Approximately 50% stenosis of the left renal artery is noted\n\nFig. 3 Percutaneous renal angiography showing the proximal left renal artery (arrows) with 50% stenosis prior to stent placement (a) and improved flow post stent placement (b)\n\n\n\nDiscussion\nRenal artery stenosis is a well-established cause of secondary hypertension resulting from the activation of the renin-angiotensin system in response to reduced renal blood flow. Atherosclerosis is the most common etiology and is usually suspected in patients over the age of 45, dyslipidemic patients, or smokers. However, other etiologies such as fibromuscular dysplasia in younger patients or Takayasu’s arteritis should be considered. Atherosclerotic stenosis typically affects the proximal main renal artery near the ostium compared to fibromuscular dysplasia which typically affects the distal segments.\n\nClassic presentations include chronic refractory hypertension, recurrent flash pulmonary edema and renal insufficiency- notably after initiating an angiotensin converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB). Although rare, there have also been reported cases of pregnant patients presenting with new onset or superimposed preeclampsia secondary to renovascular hypertension [1, 2].\n\nOf the different modalities used to investigate renal artery stenosis, doppler ultrasonography is the safest and has a sensitivity of at least 85%, though it frequently overestimates stenoses as in our case [3, 4]. Magnetic resonance or computerized tomography angiography have superior diagnostic accuracy with a sensitivity of 94% but the gold standard remains conventional catheter based angiography [5]. Supplemental studies such as direct renal vein renin, captopril renography or plasma renin activity to aldosterone ratios may be helpful in diagnostic dilemmas, though not currently routinely recommended [6].\n\nTreatment may involve aggressive medical therapy with statins, antiplatelets and antihypertensives and/or renal artery revascularization. Historically, ACE-I or ARB therapy has been cautioned especially in bilateral renal artery stenosis because of the possibility of reduced post-stenotic renal perfusion pressures and subsequent ischemic nephropathy and renal failure. However, there have been observational studies suggesting a mortality benefit to closely monitored ACE-I or ARB treatment [7].\n\nIn terms of invasive treatment, percutaneous transluminal renal angioplasty with or without stenting has become the standard versus surgical revascularization. Although a recent systematic review showed only marginal benefit to this approach compared to medical therapy alone, there is evidence that select patient do have significant benefits in blood pressure control [2, 8, 9]. Furthermore, studies have shown that usually at least 80% stenosis is required to produce any significant hemodynamic stimulus to the renin-angiotensin system and thus may be a threshold for invasive treatment [10, 11]. However, as in our case, few patients have been shown to benefit from revascularization at stenoses of as low as 50% [8, 11]. Additionally, these hemodynamic studies were performed in non-pregnant patients. Thus, whilst these data are important to avoid unnecessary procedures, clinical acumen remains necessary for select cases where revascularization of seemingly insignificant stenoses may yet produce a clinical response.\n\nIn women with preeclampsia due to renovascular hypertension, there is significant risk for obstetric and medical complications including death especially with severe preeclampsia (blood pressures more than or equal to 160/90 mmHg even without signs of end organ dysfunction or hemolysis). Prompt treatment is required. Yet, the teratogenic risks of radiological investigations and antihypertensive medications such as ACE-I/ARB’s limit diagnostic and management options and pose quite a dilemma. When possible, expedited delivery is beneficial. However, there has been some success with interventional treatment prior to delivery [2]. The high mortality risk of eclampsia continues into the the post-partum period and it is uncertain when blood pressures can be expected to normalize in preeclampsia even in the absence of renovascular hypertension [12]. Therefore, an urgent and aggressive management strategy should be pursued for these patients with consideration for early revascularization if a rapid clinical response is not seen with medical management.\n\nConclusions\nPreeclampsia that is refractory to multi-drug antihypertensive therapy should raise suspicion for renal artery stenosis. Suspected patients can be screened safely with Doppler ultrasonography which can be then followed by angiography. Even if renal artery stenosis does not seem severe, early renal revascularization may be considered in patients with severe preeclampsia who do not respond to antihypertensive management.\n\nAbbreviations\nACE-IAngiotensin converting enzyme inhibitor\n\nARBAngiotensin receptor blocker\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNone.\n\nAuthors’ contributions\nMO was responsible for initial case writing and discussion. WK was responsible for image collection and preparation. SM was responsible for manuscript preparation/formatting and proof reading. WA was responsible for proof reading, corrections, case formatting and journal selection. The authors read and approved the final manuscript.\n\nFunding\nNone.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of their individual details and accompanying images in this manuscript. The consent form is held by the authors and is available for review by the Editor-in-Chief.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Heyborne KD Schultz MF Goodlin RC Durham JD Renal artery stenosis during pregnancy: a review Obstet Gynecol Surv 1991 46 8 509 514 10.1097/00006254-199108000-00002 1832213 \n2. Margueritte F Velasco S Pourrat O Pierre F Successful angioplasty during pregnancy for renal artery stenosis J Obstet Gynaecol Res 2016 42 341 345 10.1111/jog.12886 26818942 \n3. Williams GJ Macaskill P Chan SF Karplus TE Yung W Hodson EM Craig JC Comparative accuracy of renal duplex sonographic parameters in the diagnosis of renal artery stenosis: paired and unpaired analysis AJR Am J Roentgenol 2007 188 798 811 10.2214/AJR.06.0355 17312071 \n4. Drieghe B Madaric J Sarno G Manoharan G Bartunek J Heyndrickx GR De Bruyne B Assessment of renal artery stenosis: side-byside comparison of angiography and duplex ultrasound with pressure gradient measurements Eur Heart J 2008 29 517 524 10.1093/eurheartj/ehm631 18276621 \n5. Vasbinder GB Nelemans PJ Kessels AG Kroon AA Maki JH Leiner T Beek FJ Korst MB Flobbe K de Haan MW van Zwam WH Postma CT Hunink MG de Leeuw PW van Engelshoven JM Renal Artery Diagnostic Imaging Study in Hypertension (RADISH) Study Group Accuracy of computed tomographic angiography and magnetic resonance angiography for diagnosing renal artery stenosis Ann Intern Med 2004 141 674 682 10.7326/0003-4819-141-9-200411020-00007 15520423 \n6. Kotiliar C Inserra F Forcada P Are plasma renin activity and aldosterone levels useful as a screening test to differentiate between unilateral and bilateral renal artery stenosis in hypertensive patients? J Hypertens 2010 28 594 601 10.1097/HJH.0b013e32833487d4 20104188 \n7. Chrysochou C Foley RN Young JF Khavandi K Cheung CM Kalra PA Dispelling the myth: the use of renin-angiotensin blockade in atheromatous renovascular disease Nephrol Dial Transplant 2012 27 1403 1409 10.1093/ndt/gfr496 21993376 \n8. Raman G Adam GP Halladay CW Langberg VN Azodo IA Balk EM Comparative effectiveness of management strategies for renal artery stenosis: an updated systematic review Ann Intern Med 2016 165 635 649 10.7326/M16-1053 27536808 \n9. Ziakka S Ursu M Poulikakos D Papadopoulos C Karakasis F Kaperonis N Papagalanis N Predictive factors and therapeutic approach of Renovascular disease: four years’ follow-up Ren Fail 2008 30 965 970 10.1080/08860220802389334 19016147 \n10. De Bruyne B Manoharan G Pijls NHJ Verhamme K Madaric J Bartunek J Vanderheyden M Heyndrickx GR Assessment of renal artery stenosis severity by pressure gradient measurements J Am Coll Cardiol 2006 48 1851 1855 10.1016/j.jacc.2006.05.074 17084261 \n11. Simon G What is critical renal artery stenosis? Implications for treatment Am J Hypertens 2000 13 1189 1193 10.1016/S0895-7061(00)01179-1 11078179 \n12. Podymow T August P Postpartum course of gestational hypertension and preeclampsia Hypertens Pregnancy 2010 29 294 300 10.3109/10641950902777747 20670153\n\n",
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"journal": "Clinical hypertension",
"keywords": "Preeclampsia; Renal artery stenosis; Renovascular hypertension; Secondary hypertension",
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"title": "Renal artery stenosis presenting as preeclampsia.",
"title_normalized": "renal artery stenosis presenting as preeclampsia"
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{
"abstract": "Pancreas transplantation (PT) is a relatively uncommon therapy for non-uremic type 1 diabetes, as the severity of diabetes must warrant the risk of immunosuppression. In pediatric diabetic patients, who are less likely to display uremia because of the duration of diabetes, there is very little experience with pancreas transplantation alone (PTA). This report describes a 13-yr-old male PTA recipient. This patient was initially diagnosed with type 1 diabetes mellitus at the age of four yr. Following a multidisciplinary evaluation, PTA was found to be indicated based on a history of severe labile diabetes and hypoglycemic unawareness resulting in frequent episodes of hypoglycemia and hospital admissions. Because of the failure of medical management of the patient's diabetes, a whole organ bladder and systemic drained PTA was performed. Immunosuppression included thymoglobulin, tacrolimus, mycophenolate mofetil, and steroids. Early outcome was uneventful and patient was discharged 12 d after surgery normoglycemic and insulin-free. An episode of acute rejection (Maryland grade II) 20-d post-transplant was successfully treated with corticosteroids. A second and more severe episode of rejection (Maryland grade IV) occurred 13 months post-transplant, requiring treatment with thymoglobulin and conversion from steroid to sirolimus. On tacrolimus, sirolimus, and mycophenolic acid, he remains euglycemic and insulin-free 38 months after PTA. His quality-of-life is judged to be superior to his insulin dependent state prior to transplantation. According to the medical literature, this is the youngest patient ever to undergo PTA.",
"affiliations": "Pancreas Transplant Service, Albert Einstein Hospital, São Paulo, Brazil.",
"authors": "Perosa|Marcelo|M|;Crescentini|Fabio|F|;Antunes|Irina|I|;Rangel|Erika B|EB|;Rangel|Erika|E|;Guimaro|Melissa|M|;de Sá|João Roberto|JR|;Carneiro|Arie|A|;Yonezawa|Eva|E|;Genzini|Tercio|T|",
"chemical_list": "D001786:Blood Glucose; D007166:Immunosuppressive Agents; D007328:Insulin; D000681:Amylases",
"country": "Denmark",
"delete": false,
"doi": "10.1111/j.1399-0012.2009.01058.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-0063",
"issue": "23(6)",
"journal": "Clinical transplantation",
"keywords": null,
"medline_ta": "Clin Transplant",
"mesh_terms": "D000293:Adolescent; D000681:Amylases; D001786:Blood Glucose; D003922:Diabetes Mellitus, Type 1; D005500:Follow-Up Studies; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D007328:Insulin; D008297:Male; D010179:Pancreas; D016035:Pancreas Transplantation",
"nlm_unique_id": "8710240",
"other_id": null,
"pages": "964-7",
"pmc": null,
"pmid": "19719729",
"pubdate": "2009",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pancreas transplantation alone in children: a case report.",
"title_normalized": "pancreas transplantation alone in children a case report"
} | [
{
"companynumb": "GXKR2009BR12401",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Primary Sjogren's syndrome (pSS) can have a myriad of presentations, ranging from mild xerostomia to more diffuse systemic involvement. It is well established that pSS is associated with a variety of pulmonary pathologies, and it is also known that pSS patients are at higher risk for lymphoma development. Here, we present an unusual case of a woman with primary Sjogren's syndrome who had both diffuse cystic lung disease as well as extranodal MALT lymphoma, successfully treated for both conditions with the CD-20 monoclonal antibody rituximab.",
"affiliations": "Division of Rheumatology, University of Southern California, Los Angeles, CA, USA. Leanna.wise@med.usc.edu.;Division of Rheumatology, University of Southern California, Los Angeles, CA, USA.",
"authors": "Wise|Leanna M|LM|http://orcid.org/0000-0002-6172-9474;Arkfeld|Daniel G|DG|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000069283:Rituximab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10067-019-04886-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0770-3198",
"issue": "39(4)",
"journal": "Clinical rheumatology",
"keywords": "Cystic lung disease; Lymphoma; Rituximab; Sjogren’s syndrome",
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D000074322:Antineoplastic Agents, Immunological; D005260:Female; D006801:Humans; D008171:Lung Diseases; D018442:Lymphoma, B-Cell, Marginal Zone; D008875:Middle Aged; D000069283:Rituximab; D012859:Sjogren's Syndrome; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "8211469",
"other_id": null,
"pages": "1357-1362",
"pmc": null,
"pmid": "31863212",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "16039337;25222653;24938285;17099028;27682894;15579729;22658853;27231156;27514593;27231867;25808075;11920410;29452667;16477017;24097066;23857130;28522454;19192049;21383240;17393395;10587360;12525388;10320647;10782819;19038581;15489070;20008923;14711775;9275871;27659405;20546191;19390161;19935226;27246587;25316606;16287762;26606524;23276851;17243572",
"title": "A patient with primary Sjogren's syndrome, cystic lung disease, and MALT lymphoma treated successfully with rituximab: a case-based review.",
"title_normalized": "a patient with primary sjogren s syndrome cystic lung disease and malt lymphoma treated successfully with rituximab a case based review"
} | [
{
"companynumb": "US-ROCHE-2506333",
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"patient": {
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{
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"activesubstance": {
"activesubstancename": "RITUXIMAB"
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"drugadditional": null,
"druga... |
{
"abstract": "Adverse drug reaction is defined as any harmful, unintended, and undesired effect of a drug that occurs at doses used for treatment, prevention, or diagnoses. Most of these reactions are classified as type A reactions, which by definition are predictable, common, dose-dependent, and caused by known pharmacological actions of the drug, drug toxicity, and side effects. Allergic reactions are qualified as type B reactions independent of dose, affecting a small population, suggesting that individual patient host factors are important. In pediatric population, β-lactam antibiotics are the most common reason for adverse drug reactions, followed by nonsteroidal anti-inflammatory drugs. In this article, we report the case of a child with several anaphylactic reactions to several drugs, including cefuroxime, amoxicillin/clavulanate, clarithromycin, ibuprofen, and budesonide, in a context of suspected Helicobacter pylori infection.",
"affiliations": "N. Copernicus Memorial Hospital, Lodz, Poland, Medical University of Lodz, Poland.;N. Copernicus Memorial Hospital, Lodz, Poland, Medical University of Lodz, Poland.;N. Copernicus Memorial Hospital, Lodz, Poland, Medical University of Lodz, Poland.;N. Copernicus Memorial Hospital, Lodz, Poland, Medical University of Lodz, Poland.",
"authors": "Podlecka|Daniela|D|;Jerzynska|Joanna|J|;Malewska-Kaczmarek|Kamila|K|;Stelmach|Iwona|I|https://orcid.org/0000-0002-1475-8221",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/2333794X19855287",
"fulltext": "\n==== Front\nGlob Pediatr HealthGlob Pediatr HealthGPHspgphGlobal Pediatric Health2333-794XSAGE Publications Sage CA: Los Angeles, CA 10.1177/2333794X1985528710.1177_2333794X19855287Case Report and Literature ReviewA Case of a Child With Several Anaphylactic Reactions to Drugs Podlecka Daniela MD, PhD1Jerzynska Joanna MD, PhD1Malewska-Kaczmarek Kamila MD1https://orcid.org/0000-0002-1475-8221Stelmach Iwona MD, PhD11 N. Copernicus Memorial Hospital, Lodz, Poland, Medical University of Lodz, PolandIwona Stelmach, Pilsudskiego 71 Street, Łodz 90-328, Poland. Email: alergol@kopernik.lodz.pl19 6 2019 2019 6 2333794X1985528716 8 2018 30 4 2019 10 5 2019 © The Author(s) 20192019SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Adverse drug reaction is defined as any harmful, unintended, and undesired effect of a drug that occurs at doses used for treatment, prevention, or diagnoses. Most of these reactions are classified as type A reactions, which by definition are predictable, common, dose-dependent, and caused by known pharmacological actions of the drug, drug toxicity, and side effects. Allergic reactions are qualified as type B reactions independent of dose, affecting a small population, suggesting that individual patient host factors are important. In pediatric population, β-lactam antibiotics are the most common reason for adverse drug reactions, followed by nonsteroidal anti-inflammatory drugs. In this article, we report the case of a child with several anaphylactic reactions to several drugs, including cefuroxime, amoxicillin/clavulanate, clarithromycin, ibuprofen, and budesonide, in a context of suspected Helicobacter pylori infection.\n\nAnaphylactic shockb-lactam antibioticsallergychildrencover-dateJanuary-December 2019\n==== Body\nIntroduction\nAccording to the statement of the World Health Organization, an adverse drug reaction (ADR) is defined as any harmful, unintended, and undesired effect of a drug that occurs at doses used for treatment, prevention, or diagnoses.1 Most of these reaction are classified as type A reactions, which by definition are predictable, common, dose-dependent, and caused by known pharmacological actions of the drug, drug toxicity, and side effects.1 Allergic reactions are qualified as type B reactions independent of dose, affecting a small population, suggesting that individual patient host factors are mportant.1 In the pediatric population, β-lactam (BL) antibiotics are the most common reason for ADRs, followed by nonsteroidal anti-inflammatory drugs (NSAIDs).1 As viral infections are very common in children, it is considered that these infections may also act like cofactors in susceptible individuals, resulting in skin rashes occurring during BL treatment.1\n\nBeta-lactams are the most common prescribed antibiotics and are responsible for the majority of hypersensitivity reactions to drugs.1,2 Cross-reactivity is important in hypersensitivity to BL because these drugs have a similar structure and side chains.3 Acute reactions are a consequence of previous exposure to penicillin, resulting in release of histamine and other mediators from mast cells. The signs and symptoms are typical for anaphylactic reaction.\n\nEthical Approval and Informed Consent\nWritten consent on the case report was obtained from the parents (institutional review board: RNN/147/18/KE; dated May 15, 2018).\n\nCase Report and Hospital Course\nWe present a case of a 7.5-year-old boy admitted to our Pediatric and Allergology Clinic due to allergy to BL antibiotics for full diagnostics. The patient was born G1P1 with a birth weight of 3450 g and Apgar score of 9/10 points. His neonatal period was uncomplicated. The patient had a history of frequent respiratory tract infections (average once a month) since the beginning of preschool, usually requiring antibiotics. He was vaccinated according to the schedule. A family history of atopic diseases was negative. The boy was diagnosed with asthma and allergic rhinitis due to house dust allergy, and since 2016, he went under subcutaneous immunotherapy. Previously, he had been hospitalized several times due to pneumonia and asthma exacerbation (at the age of 5 and 6 years) and one time for orchitis (at the age of 2 years). According to the interview collected from his mother, due to infection in May 2017, the child had been given oral cefuroxime. About 15 minutes after the first dose of this antibiotic, a disseminated urticaria appeared, followed by edema of the face tissues. He was seen by a medical doctor and had been given intramuscular corticosteroids and antihistamines, achieving improvement of symptoms; the antibiotic had been changed to clarithromycin. After a course of 5 days of treatment, a similar situation developed—disseminated urticaria and difficulties in breathing. The boy had been hospitalized, and he had been treated with intravenous corticosteroids and antihistamines. Up to the date of first hospitalization for anaphylaxis, the patient had been treated with different BL antibiotics without any adverse reactions. The child was referred to our Allergic Department for drug allergy diagnostics. We performed this diagnostic in 3 months after the adverse event, according to the European Academy of Allergology and Clinical Immunology (EAACI) guidelines.1 Medical examination and laboratory findings confirmed no current infection. Skin prick tests were performed with amoxicillin, amoxicillin/clavulanate, and cefuroxime in concentrations as recommended in previous studies4-6; skin prick test was strongly positive only for cefuroxime (wheal 6 mm + pseudopodium). Because of the boy’s medical history of severe anaphylactic reaction and a positive skin prick test for cefuroxime, we decided to abandon the oral drug provocation test (DPT) with cefuroxime, defining it as a culprit drug. We performed a provocation test with the alternative BL drug—amoxicillin. According to the EAACI guidelines,1,2 it was a 2-day blinded provocation test (placebo and the drug given in titrated doses up to the dispensable dose) performed under the control of spirometry parameters and vital signs (heart rate, respiratory rate). During the whole provocation test with amoxicillin, we did not notice any adverse reaction; thus, the parents were informed that oral amoxicillin may be used safely in case of infections needing therapy with antibiotics.\n\nThe parents were advised to come back to our department in 2 months for another diagnosis of clarithromycin sensitivity. In October 2017 (2 months after the first provocation), skin prick test performed with clarithromycin was negative. Intradermal test was not performed, because it is painful, time consuming, and its role has been widely debated in children.7 DPT with clarithromycin was performed as described previously (blinded and placebo-controlled oral provocation with titrated doses up to the dispensable dose) without any adverse events. The patient was discharged and referred to the Allergy Outpatient Clinic for further observation and immunotherapy continuation.\n\nBetween October 2017 and April 2018, the boy had been treated twice with amoxicillin and azithromycin (for pharyngitis and pneumonia); no adverse events were noticed. At the end of April 2018, the child was admitted to our department because of asthma exacerbation due to pneumonia. Treatment with amoxicillin/clavulanic acid was administered. Fifteen minutes after the first intravenous dose, the boy declared feet itching, followed by disseminated urticaria, face edema, bronchospasm, and drop in blood pressure. An immediate treatment with epinephrine, antihistamines, β2 agonists, and oxygen were given with rapid improvement in the boy’s general condition. The treatment was continued with intravenous aminoglycoside (biodacine) administered in a slow drip infusion for 5 more days. During the hospitalization, the boy developed a rota viral infection manifested by diarrhea, fever, vomiting, and general malaise. Because of the fever, our patient was treated with paracetamol followed by ibuprofen. About 5 minutes after an oral dose of ibuprofen, the patient developed an anaphylaxis; 2 doses of epinephrine were needed to achieve stabilization of vital signs. The patient was given drip infusions, dexamethasone, and inhaled budesonide. After 2 days, the patient presented disseminated urticaria and bronchoconstriction during the inhalation with budesonide. Several measurements of tryptase level were normal. A positive test for stool antigen Helicobacter pylori was found.\n\nFinal Diagnosis\nThe patient was diagnosed as allergic to BL antibiotics.\n\nDiscussion\nBeta-lactams are the most frequent cause of antibiotic hypersensitivity in children, more specifically amoxicillin alone or with clavulanic acid. According to EAACI guidelines for drug allergy diagnosis, only the oral DPT is a gold standard for identification of the culprit drug in patients with drug hypersensitivity reactions.1,2,8 In the presented patient, with immediate reaction after cefuroxime in the past and positive skin prick test with this drug, we performed the prick test and the DPT with amoxicillin, both of which were negative. We did not perform intradermal test with amoxicillin, since the patient was treated with this drug several times, with no adverse reactions. The anaphylaxis appeared after an intravenous dose of amoxicillin/clavulanate. In some reports, clavulanic acid has been associated with very few allergic reactions, suggesting a low allergenic potential.3,9,10 Others state that selective reactions to clavulanate account for around 30% of allergic reactions to the combination amoxicillin/clavulanate.11 However, our patient was not suspected for hypersensitivity to clavulanic acid because he was treated with amoxicillin/clavulanate several times in the past without adverse reactions and had negative skin prick test with amoxicillin/clavulanate.\n\nThe second anaphylaxis appeared after administering an oral ibuprofen. The questions to be addressed is whether this was an immunoglobulin E-mediated allergy or other mechanism are involved. In the future, diagnosis of hypersensitivity to ibuprofen or alternate NSAIDs as well as with cephalosporins of first, second, and third generations should be performed. However, our patient had several severe reactions and DPT should be done with caution. Until full diagnostics are performed, the patient was recommended to use antihistamine drugs and lower the high temperature naturally during infection. In the case of infections requiring the treatment with antibiotics, the hospitalization was recommended.\n\nAccording to the National Institute of Allergy and Infectious Diseases (NIAID) and the Food Allergy and Anaphylaxis Network (FAAN), anaphylaxis is a serious reaction that has a rapid onset and may cause death.12,13 It is a systemic immunoglobulin E-mediated reaction resulting from the sudden release of multiple mediators from mast cells and basophils. If the NIAID/FAAN criteria are met and anaphylaxis is diagnosed, epinephrine administration is mandatory. All patients with anaphylaxis, regardless the age, require immediate treatment. The administration of epinephrine at a dose of 0.01 mg/kg (1:1000) is the first-line treatment for anaphylaxis. There are no absolute contraindications to this treatment.12-14 Second-line interventions include removal of the trigger, proper posture to diminish the respiratory distress, oxygen supply, fluid support, inhaled short-acting β2-agonists and H1 and H2 antihistamines, and glucocorticosteroids.12-14\n\nConclusion\nIn conclusion, in our patient, we cannot rule out the hypersensitivity to clavulanate or presence of nonspecific factors, for example, Helicobacter pylori, as the direct cause of immediate allergic reaction to amoxicillin treatment.\n\nClavulanic acid is inherently unstable in solution, requiring the use of excipients; therefore, hypersensitivity diagnostics is very difficult. We should also be aware that many factors, for example, infections, other diseases, or genetic factors, may affect the development of ADRs. Some of these factors are patient-related, drug-related, or socially related factors. Age, for instance, has a very critical impact on the occurrence of ADRs; very young patients are more vulnerable to these reactions than other age groups. Other factors are gender, race, kidney problems, liver function, drug dose, and frequency.15\n\nFurther studies and in vitro tests of subject groups of children suspected for drug hypersensitivity are needed to provide important knowledge to this critical process. Pharmacogenomics is a very recent science, which emphasizes the genetic predisposition of ADRs.\n\nAs the administration of epinephrine is first-line treatment for anaphylaxis, parents and patients should be educated on how to recognize the symptoms of anaphylaxis and on how to use adrenaline auto-injectors. An individualized emergency action plan should be developed for each patient at risk for anaphylaxis.12-14\n\nAccording to the guidelines of the EAACI, the absolute indications for adrenaline auto-injector are previous anaphylaxis with food, latex, animal allergens or unavoidable triggers, previous exercise-induced anaphylaxis or idiopathic anaphylaxis, coexistent moderate to severe unstable asthma with food allergy, untreated venom allergy, and mast cell disorder.13\n\nAuthor Contributions: DP: Contributed to conception and design.\n\nJJ: Contributed to acquisition; agrees to be accountable for all aspects of work ensuring integrity and accuracy.\n\nKMK: Drafted manuscript.\n\nIS: Critically revised manuscript; gave final approval.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nInformed Consent: We obtained written permission from the parents for the publication of this case history.\n\nORCID iD: Iwona Stelmach \nhttps://orcid.org/0000-0002-1475-8221\n==== Refs\nReferences\n1 \nGomes ER Brockow K Kuyucu S et al ; ENDA/EAACI Drug Allergy Interest Group . Drug hypersensitivity in children: report from the pediatric task force of the EAACI Drug Allergy Interest Group . Allergy . 2016 ;71 :149 -161 .26416157 \n2 \nDemoly P Adkinson NF Brockow K et al \nInternational consensus on drug allergy . Allergy . 2014 ;69 :420 -437 .24697291 \n3 \nPonvert C Perrin Y Bados-Albiero A et al \nAllergy to betalactam antibiotics in children: results of a 20-year study based on clinical history, skin and challenge tests . Pediatr Allergy Immunol . 2011 ;22 :411 -418 .21535179 \n4 \nCo Minh HB Bousquet PJ Fontaine C Kvedariene V Demoly P. \nSystemic reactions during skin tests with beta-lactams: a risk factor analysis . J Allergy Clin Immunol . 2006 ;117 :466 -468 .16461151 \n5 \nBousquet PJ Pipet A Bousquet-Rouanet L Demoly P. \nOral challenges are needed in the diagnosis of beta-lactam hypersensitivity . Clin Exp Allergy . 2008 ;38 :185 -190 .17976216 \n6 \nManuyakorn W Singvijarn P Benjaponpitak S et al \nSkin testing with β-lactam antibiotics for diagnosis of β-lactam hypersensitivity in children . Asian Pac J Allergy Immunol . 2016 ;34 :242 -247 .27543729 \n7 \nMoral L Caubet JC. \nOral challenge without skin tests in children with non-severe beta-lactam hypersensitivity: time to change the paradigm? \nPediatr Allergy Immunol . 2017 ;28 :724 -727 .28892222 \n8 \nTorres MJ Romano A Celik G et al \nApproach to the diagnosis of drug hypersensitivity reactions: similarities and differences between Europe and North America . Clin Transl Allergy . 2017 ;7 :7 .28293415 \n9 \nZambonino MA Corzo JL Muñoz C et al \nDiagnostic evaluation of hyper-sensitivity reactions to beta-lactam antibiotics in a large population of children . Pediatr Allergy Immunol . 2014 ;25 :80 -87 .24329898 \n10 \nSánchez-Morillas L Pérez-Ezquerra PR Reaño-Martos M Laguna-Martínez JJ Sanz ML Martinez LM. \nSelective allergic reactions to clavulanic acid: a report of 9 cases . J Allergy Clin Immunol . 2010 ;126 :177 -179 .20434202 \n11 \nTorres MJ Montañez MI Ariza A et al \nThe role of IgE recognition in allergic reactions to amoxicillin and clavulanic acid . Clin Exp Allergy . 2016 ;46 :264 -274 .26662186 \n12 \nAnagnostou K. \nAnaphylaxis in children: epidemiology, risk factors and management . Curr Pediatr Rev . 2018 ;14 :180 -186 .29732976 \n13 \nMuraro A Roberts G Worm M et al ; EAACI Food Allergy and Anaphylaxis Guidelines Group . Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology . Allergy . 2014 ;69 :1026 -1045 .24909803 \n14 \nAzevedo J Gaspar  Mota I et al \nAnaphylaxis to beta-lactam antibiotics at pediatric age: six-year survey . Allergol Immunopathol (Madr) . 2019 ;47 :128 -132 .30249451 \n15 \nAlomar MJ. \nFactors affecting the development of adverse drug reactions (Review article) . Saudi Pharm J . 2014 ;22 :83 -94 .24648818\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2333-794X",
"issue": "6()",
"journal": "Global pediatric health",
"keywords": "Anaphylactic shock; allergy; b-lactam antibiotics; children",
"medline_ta": "Glob Pediatr Health",
"mesh_terms": null,
"nlm_unique_id": "101670224",
"other_id": null,
"pages": "2333794X19855287",
"pmc": null,
"pmid": "31259207",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "16461151;17976216;20434202;21535179;24329898;24648818;24697291;24909803;26416157;26662186;27543729;28293415;28892222;29732976;30249451",
"title": "A Case of a Child With Several Anaphylactic Reactions to Drugs.",
"title_normalized": "a case of a child with several anaphylactic reactions to drugs"
} | [
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"companynumb": "PL-JNJFOC-20190730105",
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"activesubstancename": "AMOXICILLIN"
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{
"abstract": "Barth syndrome (BTHS) is an X-linked disease characterized by defective remodeling of phospholipid side chains in mitochondrial membranes. Major features include neutropenia, dilated cardiomyopathy, motor delay and proximal myopathy, feeding problems, and constitutional growth delay. We conducted this review of neutropenia in BTHS to aid in the diagnosis of this disease, and to improve understanding of both the consequences of neutropenia and the benefits of treatment with granulocyte colony-stimulating factor (G-CSF).\n\n\n\nIn 88 patients with BTHS, neutropenia, that is, at least one count below 1.5 × 10/l, was detected in 74 (84%) and 44% had severe chronic neutropenia, with multiple counts below 0.5 × 10/l. The pattern of neutropenia varied between intermittent and unpredictable, chronic and severe, or cyclical with mathematically regular oscillations. Monocytosis, that is, monocytes more than 1.0 × 10/l, was observed at least once in 64 of 85 (75%) patients. G-CSF was administered to 39 of 88 patients (44%). Weekly average G-CSF doses ranged from 0.12 to 10.92 μg/kg/day (mean 1.16 μg/kg/day, median 1.16 μg/kg/day). Antibiotic prophylaxis was additionally employed in 21 of 26 neutropenic patients. Pretreatment bone marrow evaluations predominantly showed reduced myeloid maturation which normalized on G-CSF therapy in seven of 13 examined. Consistent clinical improvement, with reduced signs and symptoms of infections, was observed in response to prophylactic G-CSF ± prophylactic antibiotics. However, despite G-CSF and antibiotics, one adult patient died with multiple infections related to indwelling medical devices and gastrostomy site infection after 15.5 years on G-CSF and a pediatric patient required gastrostomy removal for recurrent abdominal wall cellulitis.\n\n\n\nBTHS should be considered in any men with neutropenia accompanied by any of the characteristic features of this syndrome. Prophylaxis with G-CSF ± antibiotics prevents serious bacterial infections in the more severe neutropenic patients although infections remain a threat even in patients who are very compliant with therapy, especially in those with indwelling devices.",
"affiliations": "NHS Specialised Services Barth Syndrome Service, Royal Hospital for Children.;School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.;Department of Pediatrics, Division of Cardiology, Children's Hospital, Medical University of South Carolina, Charleston, South Carolina.;Natera, San Carlos, California, USA.;Department of Immunology/Hematology and BMT, University Medical Center Utrecht, Utrecht, The Netherlands.;Department of Clinical Genetics, St Michael's Hospital, Bristol, UK.;Former: University Children's Hospital, Geneva.;Barth Syndrome Trust, Romsey, UK.;Barth Syndrome Foundation, Inc., Larchmont, New York, USA.;Barth Syndrome Foundation, Inc., Larchmont, New York, USA.;Departments of Physiology, Physics, and Mathematics, Centre for Applied Mathematics in Bioscience and Medicine, McGill University, Montreal, Québec, Canada.;Severe Chronic Neutropenia International Registry.;Department of Medicine, University of Washington, Seattle, Washington, USA.",
"authors": "Steward|Colin G|CG|;Groves|Sarah J|SJ|;Taylor|Carolyn T|CT|;Maisenbacher|Melissa K|MK|;Versluys|Birgitta|B|;Newbury-Ecob|Ruth A|RA|;Ozsahin|Hulya|H|;Damin|Michaela K|MK|;Bowen|Valerie M|VM|;McCurdy|Katherine R|KR|;Mackey|Michael C|MC|;Bolyard|Audrey A|AA|;Dale|David C|DC|",
"chemical_list": "D000900:Anti-Bacterial Agents; D016179:Granulocyte Colony-Stimulating Factor",
"country": "United States",
"delete": false,
"doi": "10.1097/MOH.0000000000000472",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1065-6251",
"issue": "26(1)",
"journal": "Current opinion in hematology",
"keywords": null,
"medline_ta": "Curr Opin Hematol",
"mesh_terms": "D000900:Anti-Bacterial Agents; D056889:Barth Syndrome; D001853:Bone Marrow; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D012307:Risk Factors",
"nlm_unique_id": "9430802",
"other_id": null,
"pages": "6-15",
"pmc": null,
"pmid": "30451719",
"pubdate": "2019-01",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "24751896;23398819;22023389;24887148;11430723;28108107;10484787;26724946;23656970;10089901;8630491;7616547;28183324;14764526;17394203;25112388;19057200;6142097;9332651;16548007;15098233;26845103;23109063;18070816;15124852;18781126;21932011;19118303",
"title": "Neutropenia in Barth syndrome: characteristics, risks, and management.",
"title_normalized": "neutropenia in barth syndrome characteristics risks and management"
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"companynumb": "GB-PFIZER INC-2019013514",
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"abstract": "Dapsone (4,4'- diaminodiphenylsulfone) is the parent compound of the sulfones, and it has potent antiparasitic, anti-inflammatory, and immunomodulatory effects. It is used in the treatment of leprosy, dermatitis herpetiformis, and prophylactically to prevent Pneumocystis pneumonia and toxoplasmosis in patients unable to tolerate trimethoprim with sulfamethoxazole. We hereby report a case of dapsone toxicity who developed pure red cell aplasia and cholestatic jaundice in a suspected case of dermatitis herpetiformis. Patient had an excellent response to corticosteroids after withdrawal of dapsone.",
"affiliations": "Department of Medicine, King George Medical University, Lucknow, Uttar Pradesh, India.;Department of Medicine, King George Medical University, Lucknow, Uttar Pradesh, India.;Department of Medicine, King George Medical University, Lucknow, Uttar Pradesh, India.;Department of Medicine, King George Medical University, Lucknow, Uttar Pradesh, India.;Department of Clinical Hematology and Oncology, King George Medical University, Lucknow, Uttar Pradesh, India.;Department of Pathology, King George Medical University, Lucknow, Uttar Pradesh, India.",
"authors": "Sawlani|Kamal Kumar|KK|;Chaudhary|Shyam Chand|SC|;Singh|Jitendra|J|;Raja|Deep Chandh|DC|;Mishra|Sanjay|S|;Goel|Madhu Mati|MM|",
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"doi": "10.4103/2279-042X.185743",
"fulltext": "\n==== Front\nJ Res Pharm PractJ Res Pharm PractJRPPJournal of Research in Pharmacy Practice2319-96442279-042XMedknow Publications & Media Pvt Ltd India JRPP-5-21510.4103/2279-042X.185743Case ReportDapsone-induced pure red cell aplasia and cholestatic jaundice: A new experience for diagnosis and management Sawlani Kamal Kumar 1Chaudhary Shyam Chand 1Singh Jitendra 1Raja Deep Chandh 1Mishra Sanjay 2Goel Madhu Mati 31 Department of Medicine, King George Medical University, Lucknow, Uttar Pradesh, India2 Department of Clinical Hematology and Oncology, King George Medical University, Lucknow, Uttar Pradesh, India3 Department of Pathology, King George Medical University, Lucknow, Uttar Pradesh, IndiaCorresponding author: Dr. Jitendra Singh, E-mail: drjitengsvm@gmail.comJul-Sep 2016 5 3 215 218 1 2016 3 2016 Copyright: © 2016 Journal of Research in Pharmacy Practice2016This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Dapsone (4,4’- diaminodiphenylsulfone) is the parent compound of the sulfones, and it has potent antiparasitic, anti-inflammatory, and immunomodulatory effects. It is used in the treatment of leprosy, dermatitis herpetiformis, and prophylactically to prevent Pneumocystis pneumonia and toxoplasmosis in patients unable to tolerate trimethoprim with sulfamethoxazole. We hereby report a case of dapsone toxicity who developed pure red cell aplasia and cholestatic jaundice in a suspected case of dermatitis herpetiformis. Patient had an excellent response to corticosteroids after withdrawal of dapsone.\n\nCholestatic jaundiceDapsonedermatitis herpetiformispure red cell aplasia\n==== Body\nINTRODUCTION\nDapsone is generally well tolerated. The common side effects of dapsone include hemolysis, methemoglobinemia, hypersensitivity syndrome, and toxic hepatitis. Dapsone-induced cholestatic jaundice and pure red cell aplasia are rare entities but have been reported separately.[12] To the best of our knowledge, it is the first case of dapsone therapy who developed these two dangerous adverse effects in the same case.\n\nCASE REPORT\nA 30-year-old female presented with generalized weakness, fever, jaundice, and pruritus all over the body for 7 days. On examination, she was febrile (temperature, 102°F), blood pressure was 110/70 mm Hg, and pulse rate was 112/min. She had icterus and pallor. Pruritic papulovesicular rashes and urticarial plaques were present all over the body with predominantly involvement of lower extremities without mucosal involvement. On systemic examination, hepatomegaly was present. Patient had a history of on and off pruritic skin lesions for the last 2 years. A general practitioner diagnosed her as a case of suspected dermatitis herpetiformis, and dapsone therapy was started. She was taking tablet dapsone 100 mg/day for the last 3 months. On inquiry, we found a normal report of complete blood count prior dapsone therapy.\n\nOn the day of admission, her hemoglobin was 2.6 g/dl, total leukocyte count 12,480/mm3, platelet count 310,000 cells/mm3, and reticulocyte count was 0.08%. Peripheral smear showed normocytic normochromic anemia. Liver function tests revealed bilirubin (total), 24.3 mg/dl (direct bilirubin - 17.7), aspartate aminotransferase - 365 U/L, alanine aminotransferase - 345 U/L, alkaline phosphatase - 2840 U/L, serum protein - 7.7 g/dl (serum albumin - 3.4 g/dl), and prothrombin time 13.0 s (INR 1.0). Her blood urea, creatinine, random blood sugar, uric acid, electrolytes, urine analysis, and stool examination were within normal limits. Significant complete blood counts and liver function tests are summarized in Table 1.\n\nTable 1 Significant laboratory parameters of patient\n\nSerologic tests for hepatitis A, B, C, E viruses and HIV screening were negative. Coombs test and polymerase chain reaction for parvo B19 virus were negative. Autoimmune hepatitis was ruled out by the absence of antinuclear (ANA), anti-mitochondrial (AMA), and anti-lysosomal kidney mitochondrial antibodies (anti-LKM. Serum assays for C3, C4, haptoglobin, and glucose 6-phosphatase dehydrogenase were within normal limits. Urinary porphobilinogen excretion test was negative. Rapid malarial test was negative. X-ray chest was normal.\n\nRepeated ultrasonography of abdomen showed hepatomegaly with normal echotexture without any evidence of extrahepatic biliary obstruction. Bone marrow aspiration showed cellular fragments with preponderance of myeloid cells with normal morphology and maturation [Figure 1]. Liver biopsy revealed ballooning of hepatocytes and canalicular cholestasis without any obvious inflammation suggestive of drug-induced cholestasis [Figure 2].\n\nFigure 1 Bone marrow aspirate showing mainly myeloid precursors with very few erythroid precursors suggestive of pure red cell aplasia\n\nFigure 2 Liver parenchyma with ballooning of hepatocytes and canalicular cholestasis. No obvious inflammation. Findings suggestive of drug-induced cholestasis\n\nOn the basis of clinical and laboratory findings, she was diagnosed as a case of dapsone-induced pure red cell aplasia and cholestatic jaundice. We stopped dapsone immediately and prednisolone 40 mg/day was started. Four units of packed red blood cells were transfused. She was also given antipyretics and oral antihistamines. Patient had fever and mild elevated leukocytes count which might be due to secondary infection, so broad spectrum antibiotics were given. Patient improved day by day and her laboratory parameters returned to normal after 3 weeks. During her 2-years follow-up, she was doing well.\n\nDISCUSSION\nDapsone (4,4’-diaminodiphenylsulfone) has been in clinical use for almost 50 years. Dapsone is used in dermatology for its anti-inflammatory properties, particularly in sterile (noninfectious) pustular diseases of the skin. Dapsone is approved for the use in dermatitis herpetiformis and leprosy. It is particularly useful in the treatment of linear immunoglobulin A (IgA) dermatosis, bullous systemic lupus erythematosus, erythema elevatum diutinum, and subcorneal pustular dermatosis.\n\nPotential side effects of dapsone are included in Table 2.[34] Other adverse reactions of dapsone include dramatic generalized hypersensitivity syndrome termed as “dapsone syndrome.” This syndrome has a frequency of 0.2–0.5% in patients on dapsone therapy. The constellation of features included in this syndrome is fever, exfoliative dermatitis, lymphadenopathy, lymphocytosis, methemoglobinemia, hemolytic anemia, and hepatotoxicity. Hyperbilirubinemia present in dapsone syndrome may partly be due to hemolysis in addition to hepatotoxicity. Both hepatocellular and cholestatic injury have been described. Cholestatic pattern may have less severe course and is characterized by high alkaline phosphatase level and modest increase of transaminases level. Rarely, dapsone can cause cholangitic liver injury.[1] The mechanism of injury, including hepatotoxicity in dapsone syndrome, seems to be hypersensitivity reaction.[5]\n\nTable 2 Potential adverse effects of dapsone\n\nPure red cell aplasia is the term now widely applied to isolated anemia secondary to failure of erythropoiesis. The cardinal findings are a low hemoglobin level, reticulocytopenia, and absent or extremely infrequent erythroid precursor cells in the marrow. Like other marrow failure syndromes, pure red cell aplasia can be inherited or acquired, and its pathophysiology is heterogeneous. Idiosyncratic drug reactions account for a far smaller proportion of red cell aplasia than for agranulocytosis.[6] The acquired form of pure red cell aplasia presents either as an acute self-limiting disease, predominantly seen in children or as a chronic illness that is more frequently seen in adults. It may present as a primary hematologic disorder in the absence of any other disease, or secondary to parvovirus infection, collagen vascular disease, leukemia, lymphoma, solid tumors, and treatment with recombinant human erythropoietin or other drugs.[7] Case reports have implicated various agents such as diphenylhydantoin, sulfa and sulfonamide drugs, azathioprine, allopurinol, isoniazid, procainamide, ticlopidine, ribavirin, and D-penicillamine.[6]\n\nPure red cell aplasia and cholestatic liver injury associated with dapsone therapy are life-threatening adverse reactions. Therefore, it is necessary for clinicians to confirm the diagnosis by histopathologic tests including skin biopsy before starting therapy. Furthermore, early diagnosis and aggressive management are necessary for a good outcome.\n\nThis case highlights an unusual and potentially fatal toxicity of dapsone therapy. Hence, treating physicians should have clear justification for diagnosis and use of dapsone therapy. Patient must also be counseled for any adverse reaction before starting dapsone therapy and should be advised to visit a respective doctor immediately.\n\nAUTHORS’ CONTRIBUTION\nThis manuscript is designed, studied, prepared and reviewed by all contributors. Beside this, Dr. Sanjay Mishra examined the bone Marrow and histopathological study was done by Dr. Madhu Mati Goel.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Itha S Kumar A Dhingra S Choudhuri G Dapsone induced cholangitis as a part of dapsone syndrome: A case report BMC Gastroenterol 2003 3 21 12911838 \n2 Borrás-Blasco J Conesa-García V Navarro-Ruiz A Devesa P Matarredona J Marín-Jiménez F Pure red cell aplasia associated with dapsone therapy Ann Pharmacother 2005 39 1137 8 15870135 \n3 Fox LP Merk HF Bickers DR Brunton LL Lazo JS Parker KL Dermatological pharmacology. Goodman & Gilman's The Pharmacological Basis of Therapeutics 2006 11th ed New York McGraw-Hill 1679 706 \n4 Zhu YI Stiller MJ Dapsone and sulfones in dermatology: Overview and update J Am Acad Dermatol 2001 45 420 34 11511841 \n5 Johnson DA Cattau EL Jr Kuritsky JN Zimmerman HJ Liver involvement in the sulfone syndrome Arch Intern Med 1986 146 875 7 3963977 \n6 Young NS Lichtman MA Beutler E Kipps TJ Seligsohn U Kaushansky K Prchal JT Pure red cell aplasia. Williams Hematology 2010 8th ed New York McGraw-Hill 485 95 \n7 Sawada K Fujishima N Hirokawa M Acquired pure red cell aplasia: Updated review of treatment Br J Haematol 2008 142 505 14 18510682\n\n",
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"issue": "5(3)",
"journal": "Journal of research in pharmacy practice",
"keywords": "Cholestatic jaundice; Dapsone; dermatitis herpetiformis; pure red cell aplasia",
"medline_ta": "J Res Pharm Pract",
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"nlm_unique_id": "101614023",
"other_id": null,
"pages": "215-8",
"pmc": null,
"pmid": "27512715",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "3963977;11511841;12911838;15870135;18510682",
"title": "Dapsone-induced pure red cell aplasia and cholestatic jaundice: A new experience for diagnosis and management.",
"title_normalized": "dapsone induced pure red cell aplasia and cholestatic jaundice a new experience for diagnosis and management"
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"companynumb": "IN-NORTH CREEK PHARMACEUTICALS LLC-2016VTS00066",
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"abstract": "OBJECTIVE\nTo observe the clinical efficacy of noninvasive ventilation (NIV) on the treatment of acute respiratory distress syndrome (ARDS) caused by severe pneumonia after kidney transplantation.\n\n\nMETHODS\nThe clinical data of 17 patients who were diagnosed as ARDS caused by severe pneumonia after kidney transplantation and treated with NIV in Sichuan Provincial People's Hospital from January 1st, 2014 to June 1st, 2016 were collected and retrospectively analyzed. According to the result of NIV treatment, the patients were divided into NIV success group (n = 9) and NIV failure group (n = 8). The differences in gender, age, underlying diseases, acute physiology and chronic health evaluation II (APACHE II) score, laboratory parameters on the day when ARDS was diagnosed, daily immunosuppressive dosage, NIV support condition and duration, arterial blood gas analysis and adverse reactions between the two groups were compared. Receiver operating characteristic curve (ROC) was plotted, and the predictive value of each parameters for NIV results was evaluated.\n\n\nRESULTS\nThe two groups were similar in gender, age, and underlying diseases. The APACHE II score, serum levels of procalcitonin (PCT) and brain natriuretic peptide (BNP), serum creatinine (SCr), daily tacrolimus dose, and NIV support condition in NIV failure group were significantly higher than those in NIV success group [APACHE II score: 16.7±5.7 vs. 10.3±2.1, PCT (μg/L): 32.8 (1.2, 187.7) vs. 0.3 (0.1, 2.9), BNP (ng/L): 832.4 (263.7, 1 180.2) vs. 157.0 (33.9, 218.5), SCr (μmol/L): 284.8 (90.5, 474.2) vs. 186.6 (76.7, 206.3), daily tacrolimus dose (mg): 3.6 (3.1, 4.0) vs. 2.6 (2.0, 3.5), inspiratory positive airway pressure (IPAP, cmH2O, 1 cmH2O = 0.098 kPa): 14.8±4.1 vs. 9.0±1.1, expiratory positive airway pressure (EPAP, cmH2O): 7.6±1.8 vs. 4.7±0.8, fraction of inspired oxygen (FiO2): 0.75±0.25 vs. 0.43±0.06, all P < 0.05], and the oxygenation index (PaO2/FiO2) after treatment was significantly lower than that of NIV success group [mmHg (1 mmHg = 0.133 kPa): 107.4±65.2 vs. 268.7±98.8, P < 0.05]. There was no significant difference in albumin (Alb), white blood cell count (WBC), daily mycophenolate mofetil dose, use of glucocorticold, NIV duration, pH value, arterial partial pressure of carbon dioxide (PaCO2), or the incidence of sputum drainage disorder or pneumothorax between the two groups. ROC curve analysis showed that the predictive value of APACHEII score, serum PCT and BNP levels, tacrolimus daily dosage and PaO2/FiO2 changes after NIV treatment for the efficacy of NIV was high, the area under the ROC curve (AUC) was 0.813, 0.778, 0.903, 0.778, 0.764, respectively; when the cut-off value of APACHE II score was 16.0, PCT was 4.1 μg/L, BNP was 180.5 ng/L, tacrolimus daily dosage was 2.5 mg, PaO2/FiO2 increased 49.5 mmHg, the sensitivity was 87.5%, 75.2%, 87.5%, 87.5% and 75.0%, respectively, and the specificity was 77.8%, 66.7%, 88.9%, 74.4%, 88.9%, respectively. However, SCr was not sensitive to the NIV effect prediction.\n\n\nCONCLUSIONS\nNIV in the treatment of ARDS caused by severe pneumonia after kidney transplantation has a certain value. The fewer tacrolimus daily dosage, the lower APACHE II score and levels of PCT and BNP, the more effective promotion of PaO2/FiO2 after NIV treatment, and the better curative effect is suggested.",
"affiliations": "Department of Respiratory and Critical Care Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu 610072, Sichuan, China. Corresponding author: Liu Xiaoshu, Email: 17708130302@163.com.",
"authors": "Liu|Xiaoshu|X|;Xie|Zhengliang|Z|;Teng|Hong|H|;Chen|Lijuan|L|;Zhang|Jing|J|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.3760/cma.j.issn.2095-4352.2017.11.007",
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"issue": "29(11)",
"journal": "Zhonghua wei zhong bing ji jiu yi xue",
"keywords": null,
"medline_ta": "Zhonghua Wei Zhong Bing Ji Jiu Yi Xue",
"mesh_terms": "D006801:Humans; D016030:Kidney Transplantation; D063087:Noninvasive Ventilation; D011014:Pneumonia; D012128:Respiratory Distress Syndrome; D012189:Retrospective Studies",
"nlm_unique_id": "101604552",
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"pages": "994-998",
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"pubdate": "2017-11",
"publication_types": "D016428:Journal Article",
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"title": "Efficacy of noninvasive ventilation on treatment of ARDS caused by severe pneumonia after kidney transplantation.",
"title_normalized": "efficacy of noninvasive ventilation on treatment of ards caused by severe pneumonia after kidney transplantation"
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"companynumb": "CN-ASTELLAS-2017US050862",
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"abstract": "First-line chemotherapy for advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastro-oesophageal junction adenocarcinoma has a median overall survival (OS) of less than 1 year. We aimed to evaluate first-line programmed cell death (PD)-1 inhibitor-based therapies in gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma. We report the first results for nivolumab plus chemotherapy versus chemotherapy alone.\n\n\n\nIn this multicentre, randomised, open-label, phase 3 trial (CheckMate 649), we enrolled adults (≥18 years) with previously untreated, unresectable, non-HER2-positive gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma, regardless of PD-ligand 1 (PD-L1) expression from 175 hospitals and cancer centres in 29 countries. Patients were randomly assigned (1:1:1 while all three groups were open) via interactive web response technology (block sizes of six) to nivolumab (360 mg every 3 weeks or 240 mg every 2 weeks) plus chemotherapy (capecitabine and oxaliplatin every 3 weeks or leucovorin, fluorouracil, and oxaliplatin every 2 weeks), nivolumab plus ipilimumab, or chemotherapy alone. Primary endpoints for nivolumab plus chemotherapy versus chemotherapy alone were OS or progression-free survival (PFS) by blinded independent central review, in patients whose tumours had a PD-L1 combined positive score (CPS) of five or more. Safety was assessed in all patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT02872116.\n\n\n\nFrom March 27, 2017, to April 24, 2019, of 2687 patients assessed for eligibility, we concurrently randomly assigned 1581 patients to treatment (nivolumab plus chemotherapy [n=789, 50%] or chemotherapy alone [n=792, 50%]). The median follow-up for OS was 13·1 months (IQR 6·7-19·1) for nivolumab plus chemotherapy and 11·1 months (5·8-16·1) for chemotherapy alone. Nivolumab plus chemotherapy resulted in significant improvements in OS (hazard ratio [HR] 0·71 [98·4% CI 0·59-0·86]; p<0·0001) and PFS (HR 0·68 [98 % CI 0·56-0·81]; p<0·0001) versus chemotherapy alone in patients with a PD-L1 CPS of five or more (minimum follow-up 12·1 months). Additional results showed significant improvement in OS, along with PFS benefit, in patients with a PD-L1 CPS of one or more and all randomly assigned patients. Among all treated patients, 462 (59%) of 782 patients in the nivolumab plus chemotherapy group and 341 (44%) of 767 patients in the chemotherapy alone group had grade 3-4 treatment-related adverse events. The most common any-grade treatment-related adverse events (≥25%) were nausea, diarrhoea, and peripheral neuropathy across both groups. 16 (2%) deaths in the nivolumab plus chemotherapy group and four (1%) deaths in the chemotherapy alone group were considered to be treatment-related. No new safety signals were identified.\n\n\n\nNivolumab is the first PD-1 inhibitor to show superior OS, along with PFS benefit and an acceptable safety profile, in combination with chemotherapy versus chemotherapy alone in previously untreated patients with advanced gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma. Nivolumab plus chemotherapy represents a new standard first-line treatment for these patients.\n\n\n\nBristol Myers Squibb, in collaboration with Ono Pharmaceutical.",
"affiliations": "Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA.;Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan. Electronic address: kshitara@east.ncc.go.jp.;Department of Medicine, Johannes-Gutenberg University Clinic, Mainz, Germany.;Department of Hemato-Oncology, Clinica San Carlos de Apoquindo, Pontificia Universidad Católica, Santiago, Chile.;Department of Medical Oncology, Oncovida Cancer Center, Fundación Arturo López Pérez, Providencia, Chile.;Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing, Peking University Cancer Hospital and Institute, Beijing, China.;Klinika Onkologii i Radioterapii, Narodowy Instytut Onkologii, Warsaw, Poland.;Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.;II Klinika Chirurgii Ogólnej, Gastroenterologicznej i Nowotworów Układu Pokarmowego, Medical University of Lublin, Lublin, Poland.;Department of Medical Oncology, Fundacao Pio Xii Hosp Cancer De Barretos, Barretos, Brazil.;Department of Medical Oncology, Zhongshan Hospital Fudan University, Shanghai, China.;Department of Medical Oncology, Sfantul Nectarie Oncology Center, Dolj, Romania.;Department of Internal Medicine, Oncology Unit, Universidad de La Frontera, Temuco, Chile.;Hematology-Oncology, Oncology Center-Centre Hospitalier de l'Universite de Montreal, Montreal, QC, Canada.;Instituto Multidisciplinario de Oncologia, Clinica Viedma SA, Viedma, Argentina.;Department of Biological Chemistry and Laiko General Hospital Medical School, National and Kapodistrian University of Athens, Athens, Greece.;Internal Medicine, Clinical Oncology, Instituto Nacional de Cancerología Empresa Social del Estado, Bogotá, Colombia.;Department of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düesseldorf, University Hospital of Cologne, Cologne, Germany.;Department of Medical Oncology, Hospital Universitario Miguel Servet, Zaragoza, Spain.;Department of Chemotherapy, National Institute of Oncology, Budapest, Hungary.;Department of Oncology, Haematology and Palliative Care, St John of God Murdoch Hospital, Murdoch, WA, Australia.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.;Bristol Myers Squibb, Princeton, NJ, USA.;Bristol Myers Squibb, Princeton, NJ, USA.;Bristol Myers Squibb, Princeton, NJ, USA.;Bristol Myers Squibb, Princeton, NJ, USA.;Bristol Myers Squibb, Princeton, NJ, USA.;Bristol Myers Squibb, Princeton, NJ, USA.;Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.",
"authors": "Janjigian|Yelena Y|YY|;Shitara|Kohei|K|;Moehler|Markus|M|;Garrido|Marcelo|M|;Salman|Pamela|P|;Shen|Lin|L|;Wyrwicz|Lucjan|L|;Yamaguchi|Kensei|K|;Skoczylas|Tomasz|T|;Campos Bragagnoli|Arinilda|A|;Liu|Tianshu|T|;Schenker|Michael|M|;Yanez|Patricio|P|;Tehfe|Mustapha|M|;Kowalyszyn|Ruben|R|;Karamouzis|Michalis V|MV|;Bruges|Ricardo|R|;Zander|Thomas|T|;Pazo-Cid|Roberto|R|;Hitre|Erika|E|;Feeney|Kynan|K|;Cleary|James M|JM|;Poulart|Valerie|V|;Cullen|Dana|D|;Lei|Ming|M|;Xiao|Hong|H|;Kondo|Kaoru|K|;Li|Mingshun|M|;Ajani|Jaffer A|JA|",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors; D000077594:Nivolumab",
"country": "England",
"delete": false,
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"issue": "398(10294)",
"journal": "Lancet (London, England)",
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"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D004359:Drug Therapy, Combination; D004938:Esophageal Neoplasms; D004943:Esophagogastric Junction; D005260:Female; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D008297:Male; D008875:Middle Aged; D000077594:Nivolumab; D000077982:Progression-Free Survival; D013274:Stomach Neoplasms",
"nlm_unique_id": "2985213R",
"other_id": null,
"pages": "27-40",
"pmc": null,
"pmid": "34102137",
"pubdate": "2021-07-03",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "22143936;21780108;22689179;28052061;19164454;32489322;32616848;27918764;31724072;18349393;28042031;31345380;29880231;28993052;32880601;27664260;30718072;29866946;32642082;23788757;28958504;24872026;18172173;25038874;32606208;23594786;28569272;30885279",
"title": "First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial.",
"title_normalized": "first line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric gastro oesophageal junction and oesophageal adenocarcinoma checkmate 649 a randomised open label phase 3 trial"
} | [
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"companynumb": "US-PFIZER INC-2021795418",
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"activesubstancename": "OXALIPLATIN"
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{
"abstract": "In the midst of the COVID-19 pandemic, we herein report the case of an elderly female with multiple comorbidities coming with typical symptoms of the viral infection in addition to the unusual presentation of bradycardia due to complete heart block requiring pacemaker placement. This may be a rare complication of the disease but one has to keep a high index of suspicion since this virus has an ability to affect multiple organ systems with many ways yet to be uncovered. <Learning objective: 1. COVID-19 might affect the conduction system of the heart as part of its disease process. 2. Future studies are needed to address the mechanism of which COVID-19 affects the conduction system to improve the recognition of this phenomenon. 3. It is pertinent to recognize any metabolic and pharmacological risk factors related to conduction block in patients with COVID-19, and to provide close monitoring to high-risk patients in order to recognize this rare complication and treat it early on.>.",
"affiliations": "Department of Medicine at Mount Sinai St Luke's and West, New York, NY, USA.;Department of Medicine at Saint Elizabeth's Medical Center, Brighton, MA, USA.;Department of Medicine at Saint Elizabeth's Medical Center, Brighton, MA, USA.;Department of Medicine at Mount Sinai St Luke's and West, New York, NY, USA.;Faculty of Medicine, University of Jordan, Amman, Jordan.;The New England Cardiac Arrhythmia Center, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA.",
"authors": "Haddadin|Faris I|FI|;Mahdawi|Tala Eneizat|TE|;Hattar|Laith|L|;Beydoun|Hassan|H|;Fram|Farah|F|;Homoud|Munther|M|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1016/j.jccase.2020.08.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-5409",
"issue": "23(1)",
"journal": "Journal of cardiology cases",
"keywords": "Bradycardia; COVID-19; Complete heart block",
"medline_ta": "J Cardiol Cases",
"mesh_terms": null,
"nlm_unique_id": "101549579",
"other_id": null,
"pages": "27-30",
"pmc": null,
"pmid": "32904735",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports",
"references": "32494896;32085846;32031570;32535142;32285920;32360126;27493633",
"title": "A case of complete heart block in a COVID-19 infected patient.",
"title_normalized": "a case of complete heart block in a covid 19 infected patient"
} | [
{
"companynumb": "US-NEUROCRINE BIOSCIENCES INC.-2021NBI00559",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ILOPERIDONE"
},
"drugaddit... |
{
"abstract": "A drug interaction leading to greater exposure to tacrolimus.\n\n\n\nTacrolimus and Beni-Madonna (a new cultivar citrus categorized as 'Tangor').\n\n\n\nA 9-month-old girl with biliary atresia (body weight, 7.5 kg) taking tacrolimus after liver transplantation.\n\n\n\nThe time course was consistent with the appearance of the interaction, which was confirmed by an increase in the blood concentration of tacrolimus. Dihydroxybergamottin was detected in peel of Beni-Madonna and in peel and fruit pulp of grapefruit.\n\n\n\nAvoiding Beni-Madonna intake.\n\n\n\nInhibition of activity of CYP3A4, P-glycoprotein, or both, by Beni-Madonna.\n\n\n\nClinicians should be aware of this potential interaction, and patients taking drugs such as tacrolimus (the kinetics of which are affected by grapefruit juice) should avoid Beni-Madonna intake.\n\n\n\nFurther study is required to determine if other Citrus species categorized as Tangor contain furanocoumarins.",
"affiliations": "Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke, Japan.;Division of Transplant Surgery, Department of Surgery, Jichi Medical University, Shimotsuke, Japan.;Department of Pharmacy, Jichi Medical University Hospital, Shimotsuke, Japan.;Department of Pharmacy, Jichi Medical University Hospital, Shimotsuke, Japan.;Division of Transplant Surgery, Department of Surgery, Jichi Medical University, Shimotsuke, Japan.;Division of Transplant Surgery, Department of Surgery, Jichi Medical University, Shimotsuke, Japan.;Division of Transplant Surgery, Department of Surgery, Jichi Medical University, Shimotsuke, Japan.;Division of Transplant Surgery, Department of Surgery, Jichi Medical University, Shimotsuke, Japan.;Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke, Japan.;Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke, Japan.",
"authors": "Ushijima|Kentaro|K|0000-0003-2637-3916;Mizuta|Koichi|K|;Otomo|Shinya|S|;Ogaki|Keiko|K|;Sanada|Yukihiro|Y|;Hirata|Yuta|Y|;Ihara|Yoshiyuki|Y|;Urahashi|Taizen|T|;Imai|Yasushi|Y|;Fujimura|Akio|A|0000-0002-5160-5777",
"chemical_list": "D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065692:Cytochrome P-450 CYP3A Inhibitors; D011564:Furocoumarins; D007166:Immunosuppressive Agents; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus",
"country": "England",
"delete": false,
"doi": "10.1111/bcp.13743",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0306-5251",
"issue": "84(12)",
"journal": "British journal of clinical pharmacology",
"keywords": "drug interaction; liver transplantation; tacrolimus",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002957:Citrus; D032083:Citrus paradisi; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D005260:Female; D018565:Food-Drug Interactions; D011564:Furocoumarins; D006801:Humans; D007166:Immunosuppressive Agents; D007223:Infant; D016031:Liver Transplantation; D016559:Tacrolimus",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "2933-2935",
"pmc": null,
"pmid": "30218442",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports",
"references": "15258108;21254874;29149325;12698101;10903978;29055034;30218442;29055035",
"title": "Increased tacrolimus blood concentration by Beni-Madonna - a new hybrid citrus cultivar categorized as 'Tangor', in a liver transplant patient: likely furanocoumarin-mediated inhibition of CYP3A4 or P-glycoprotein.",
"title_normalized": "increased tacrolimus blood concentration by beni madonna a new hybrid citrus cultivar categorized as tangor in a liver transplant patient likely furanocoumarin mediated inhibition of cyp3a4 or p glycoprotein"
} | [
{
"companynumb": "JP-ACCORD-072745",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"drug... |
{
"abstract": "OBJECTIVE\nA hyperintense appearance of the dentate nucleus on T1-weighted MR images has been related to various clinical conditions, but the etiology remains indeterminate. We aimed to investigate the possible associations between a hyperintense appearance of the dentate nucleus on T1-weighted MR images in patients exposed to radiation and factors including, but not limited to, the cumulative number of contrast-enhanced MR images, amount of gadolinium administration, dosage of ionizing radiation, and patient demographics.\n\n\nMETHODS\nThe medical records of 706 consecutive patients who were treated with brain irradiation at The Johns Hopkins Medical Institutions between 1995 and 2010 were blindly reviewed by 2 readers.\n\n\nRESULTS\nOne hundred eighty-four subjects were included for dentate nuclei analysis. Among the 184 subjects who cumulatively underwent 2677 MR imaging studies following intravenous gadolinium administration, 103 patients had hyperintense dentate nuclei on precontrast T1-weighted MR images. The average number of gadolinium-enhanced MR imaging studies performed in the group with normal dentate nuclei was significantly lower than that of the group with hyperintense dentate nuclei. The average follow-up time was 62.5 months. No significant difference was observed between hyperintense and normal dentate nuclei groups in terms of exposed radiation dose, serum creatinine and calcium/phosphate levels, patient demographics, history of chemotherapy, and strength of the scanner. No dentate nuclei abnormalities were found on the corresponding CT scans of patients with hyperintense dentate nuclei (n = 44). No dentate nuclei abnormalities were found in 53 healthy volunteers.\n\n\nCONCLUSIONS\nRepeat performance of gadolinium-enhanced studies likely contributes to a long-standing hyperintense appearance of dentate nuclei on precontrast T1-weighted-MR images.",
"affiliations": "From the Division of Neuroradiology (M.E.A., E.Z., S.M., D.M.Y.), The Russell H. Morgan Department of Radiology and Radiological Science emin.adin@gmail.com.;Department of Radiation Oncology and Radiation Molecular Sciences (L.K.).;Johns Hopkins Bloomberg School of Public Health (D.V.), The Johns Hopkins Medical Institutions, Baltimore, Maryland.;From the Division of Neuroradiology (M.E.A., E.Z., S.M., D.M.Y.), The Russell H. Morgan Department of Radiology and Radiological Science.;From the Division of Neuroradiology (M.E.A., E.Z., S.M., D.M.Y.), The Russell H. Morgan Department of Radiology and Radiological Science.;From the Division of Neuroradiology (M.E.A., E.Z., S.M., D.M.Y.), The Russell H. Morgan Department of Radiology and Radiological Science.",
"authors": "Adin|M E|ME|;Kleinberg|L|L|;Vaidya|D|D|;Zan|E|E|;Mirbagheri|S|S|http://orcid.org/0000-0002-3689-7273;Yousem|D M|DM|http://orcid.org/0000-0002-1222-6643",
"chemical_list": "D003287:Contrast Media; D005682:Gadolinium",
"country": "United States",
"delete": false,
"doi": "10.3174/ajnr.A4378",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0195-6108",
"issue": "36(10)",
"journal": "AJNR. American journal of neuroradiology",
"keywords": null,
"medline_ta": "AJNR Am J Neuroradiol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D002529:Cerebellar Nuclei; D002648:Child; D002675:Child, Preschool; D003287:Contrast Media; D016371:Cranial Irradiation; D005260:Female; D005682:Gadolinium; D006801:Humans; D007089:Image Enhancement; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D011829:Radiation Dosage; D055815:Young Adult",
"nlm_unique_id": "8003708",
"other_id": null,
"pages": "1859-65",
"pmc": null,
"pmid": "26294649",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article",
"references": "10955675;24872007;612395;2105032;2014310;1414839;7502957;8938312;10228533;15891176;17712863;17619195;18374532;18545998;19401576;19744599;21045180;24321333;24475844;24052507;12812932",
"title": "Hyperintense Dentate Nuclei on T1-Weighted MRI: Relation to Repeat Gadolinium Administration.",
"title_normalized": "hyperintense dentate nuclei on t1 weighted mri relation to repeat gadolinium administration"
} | [
{
"companynumb": "US-GE HEALTHCARE MEDICAL DIAGNOSTICS-OSCN-PR-1508L-0172",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GADOLINIUM"
},
... |
{
"abstract": "Pediatric anaplastic large-cell lymphoma (ALCL), which is characterized by strong expression of CD30, is usually responsive to multidrug chemotherapy. Brentuximab vedotin (BV) which is an anti-CD30 antibody-drug conjugate is a promising drug with effects on relapsing or refractory ALCL. However, its effects may not be sufficient for the central nervous system disease. The authors herein reported an 11-year-old boy with ALCL that progressed as central nervous system disease receiving intensive induction chemotherapy has achieved and maintained remission by BV and high-dose methotrexate administrated alternately. Alternate therapy with high-dose methotrexate may complement these shortcomings of BV to provide safe treatment without worsening adverse events.",
"affiliations": "Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.",
"authors": "Mitsunobu|Takuro|T|;Nishikawa|Takuro|T|;Kusuda|Masaki|M|;Nakagawa|Shunsuke|S|;Kodama|Yuichi|Y|;Okamoto|Yasuhiro|Y|;Kawano|Yoshifumi|Y|",
"chemical_list": "D000079963:Brentuximab Vedotin; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000001550",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "42(6)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000079963:Brentuximab Vedotin; D002493:Central Nervous System Diseases; D002648:Child; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic; D008297:Male; D008727:Methotrexate; D009364:Neoplasm Recurrence, Local; D011379:Prognosis",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e456-e458",
"pmc": null,
"pmid": "31274669",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Brentuximab Vedotin and High-dose Methotrexate Administrated Alternately for Refractory Anaplastic Large-cell Lymphoma With Central Nervous System Disease.",
"title_normalized": "brentuximab vedotin and high dose methotrexate administrated alternately for refractory anaplastic large cell lymphoma with central nervous system disease"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-274931",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINBLASTINE"
},
"dru... |
{
"abstract": "BACKGROUND\nDysregulation of complement activation is the most common cause of the atypical haemolytic uraemic syndrome (aHUS). Many patients with aHUS develop end-stage renal disease and consider kidney transplantation. However, the recurrence rate after transplantation ranges from 45-90% in patients with known abnormalities in circulating complement proteins. It was recently proposed that patients with aHUS should be treated prophylactically with plasma exchange or eculizumab to prevent recurrence after transplantation.\n\n\nMETHODS\nA case series describing the successful outcome of kidney transplantation without prophylactic therapy in four adult patients with aHUS and a high risk of disease recurrence. Patients received a living donor kidney and immunosuppression consisting of basiliximab induction, low-dose tacrolimus, prednisone and mycophenolate mofetil. Patients received a statin, and were targeted to a low blood pressure preferably using blockers of the renin-angiotensin system.\n\n\nRESULTS\nAfter a follow-up of 16-21 months, none of the patients developed recurrent aHUS. Also, no rejection was observed.\n\n\nCONCLUSIONS\nKidney transplantation in adult patients with aHUS can be successful without prophylactic eculizumab, using a protocol that minimises cold ischaemia time, reduces the risk of rejection and provides endothelial protection. Our data suggest that in patients with aHUS, controlled trials are needed to demonstrate the optimal strategy.",
"affiliations": "Department of Nephrology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.",
"authors": "Verhave|J C|JC|;Westra|D|D|;van Hamersvelt|H W|HW|;van Helden|M|M|;van de Kar|N C A J|NC|;Wetzels|J F M|JF|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D011993:Recombinant Fusion Proteins; D000077552:Basiliximab; C481642:eculizumab; D009173:Mycophenolic Acid; D011241:Prednisone; D016559:Tacrolimus",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-2977",
"issue": "71(7)",
"journal": "The Netherlands journal of medicine",
"keywords": null,
"medline_ta": "Neth J Med",
"mesh_terms": "D000328:Adult; D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D065766:Atypical Hemolytic Uremic Syndrome; D000077552:Basiliximab; D050377:Cold Ischemia; D004359:Drug Therapy, Combination; D005260:Female; D006463:Hemolytic-Uremic Syndrome; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D011241:Prednisone; D011993:Recombinant Fusion Proteins; D055502:Secondary Prevention; D016559:Tacrolimus; D055815:Young Adult",
"nlm_unique_id": "0356133",
"other_id": null,
"pages": "342-7",
"pmc": null,
"pmid": "24038559",
"pubdate": "2013-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Living kidney transplantation in adult patients with atypical haemolytic uraemic syndrome.",
"title_normalized": "living kidney transplantation in adult patients with atypical haemolytic uraemic syndrome"
} | [
{
"companynumb": "PHHY2013NL176296",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
"druga... |
{
"abstract": "OBJECTIVE\nAdult sarcomas of the head and neck region (HNSs) are considered a rare clinicopathological entity. They account for only 2-15% of all adult sarcomas and for less than 1% of all head and neck malignancies. The preferred initial treatment option is wide surgical excision. Whenever surgery is considered infeasible, a frontline combined-modality approach including radiotherapy and chemotherapy might be proposed. We here report on a case of localized sarcoma of the maxillary sinus treated with induction chemotherapy and subsequent intensity-modulated radiation therapy (IMRT), achieving a persistent complete remission status.\n\n\nMETHODS\nA 66-year-old man was referred to our institution hospital for left-sided facial pain with swollen left cheek and ipsilateral facial palsy. Magnetic resonance imaging showed a mass within the left maxillary sinus extending to the orbital floor and adjacent alveolar bones. Histological examination of the biopsy specimen demonstrated a myxofibrosarcoma. The patient underwent induction chemotherapy with gemcitabine 900 mg/m2 (days 1-8) and taxotere 80 mg/m2 every 3 weeks for 3 cycles and sequential simultaneous integrated boost (SIB) IMRT up to a total dose of 70 Gy/35 fractions to the macroscopic disease with 59.5 Gy/35 fractions to the level IB-II lymph nodes in the left neck.\n\n\nRESULTS\nTreatment was well tolerated with mild acute toxicity. Complete remission was achieved at restaging MRI 6 months after the end of the combined modality approach. The patient remains in complete, unmaintained clinical and instrumental complete remission 18 months after treatment, with no late side effects.\n\n\nCONCLUSIONS\nCombination therapy with induction chemotherapy and sequential SIB-IMRT could therefore be a promising modality for head and neck sarcomas, allowing for simultaneous tumor control and normal tissue sparing.",
"affiliations": "Department of Radiation Oncology, ASL TO4, Ospedale Civile di Ivrea, Ivrea, Italy. domecante@yahoo.it",
"authors": "Cante|Domenico|D|;Franco|Pierfrancesco|P|;Sciacero|Piera|P|;Girelli|Giuseppe Franco|GF|;Casanova Borca|Valeria|V|;Pasquino|Massimo|M|;Tofani|Santi|S|;Bombaci|Sebastiano|S|;Migliaccio|Fernanda|F|;Marra|Annamaria|A|;Numico|Gianmauro|G|;La Porta|Maria Rosa|MR|;Ricardi|Umberto|U|",
"chemical_list": "D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; C056507:gemcitabine",
"country": "United States",
"delete": false,
"doi": "10.1700/1283.14214",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8916",
"issue": "99(2)",
"journal": "Tumori",
"keywords": null,
"medline_ta": "Tumori",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D003841:Deoxycytidine; D000077143:Docetaxel; D019583:Dose Fractionation, Radiation; D006258:Head and Neck Neoplasms; D051677:Histiocytoma, Malignant Fibrous; D006801:Humans; D060828:Induction Chemotherapy; D008279:Magnetic Resonance Imaging; D008297:Male; D008444:Maxillary Sinus Neoplasms; D009367:Neoplasm Staging; D018714:Radiotherapy, Adjuvant; D050397:Radiotherapy, Intensity-Modulated; D043823:Taxoids; D016896:Treatment Outcome",
"nlm_unique_id": "0111356",
"other_id": null,
"pages": "e80-3",
"pmc": null,
"pmid": "23748836",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Combined chemoradiation for head and neck region myxofibrosarcoma of the maxillary sinus.",
"title_normalized": "combined chemoradiation for head and neck region myxofibrosarcoma of the maxillary sinus"
} | [
{
"companynumb": "IT-PFIZER INC-2017498195",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "GEMCITABINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "We present a case of callosal disconnection syndrome as a rare manifestation of acute disseminated encephalomyelitis (ADEM). A dextral 48-year-old Japanese woman received trivalent inactivated influenza vaccine in mid-November 2011. Twenty days later, she was found to be in a daze. Subsequently, she developed abnormal behavior and gait disturbance, and she was disoriented regarding time and place. Nystagmus and abnormal ocular movements were absent. Upper limb power was normal, whereas her lower limbs were mildly weak. Tendon reflexes were normally evoked without pathological reflexes. There was no sensory impairment. Serum CRP levels were slightly elevated; other routine laboratory tests, thyroid functions, and vitamin B1 levels were within the normal range. Cerebrospinal fluid examination revealed that it was acellular with a protein level of 54 mg/dl and high myelin basic protein level. Fluid-attenuated inversion recovery MR images revealed a large hyperintense lesion in the corpus callosum, but the lower part of the splenium was spared. Flow voids were observed in the pericallosal arteries. She was diagnosed with post-vaccination ADEM and vigorously treated with an intravenous infusion of methylprednisolone (1 g/day for 6 days) and immunoglobulin (1.2 g/kg). Gait disturbance and disorientation rapidly improved; however, tactile anomia, ideomotor apraxia, ideational apraxia, and agraphia of the left hand were present one month after onset. She had no aphasia or alexia.Interestingly, the patient's left unilateral agraphia was more prominent in kana than kanji (an article in Japanese text) for polysyllabic words, whereas she could write kana characters to dictation. Changes in the sequential order of kana characters within a word were observed. These findings were similar to those observed in pure agraphia associated with lesions in the posterior part of the left middle frontal gyrus. Thus, an interhemispheric mechanism is probably involved in the selection and arrangement of kana characters to form words.",
"affiliations": "Department of Neurology, Seirei Mikatahara General Hospital.",
"authors": "Arai|Motomi|M|;Takagi|Daisuke|D|;Nagao|Ryosuke|R|",
"chemical_list": "D007252:Influenza Vaccines",
"country": "Japan",
"delete": false,
"doi": "10.5692/clinicalneurol.54.135",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-918X",
"issue": "54(2)",
"journal": "Rinsho shinkeigaku = Clinical neurology",
"keywords": null,
"medline_ta": "Rinsho Shinkeigaku",
"mesh_terms": "D000381:Agraphia; D001072:Apraxias; D004673:Encephalomyelitis, Acute Disseminated; D005260:Female; D006801:Humans; D007252:Influenza Vaccines; D008875:Middle Aged; D013577:Syndrome",
"nlm_unique_id": "0417466",
"other_id": null,
"pages": "135-9",
"pmc": null,
"pmid": "24583588",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Acute disseminated encephalomyelitis following influenza vaccination: report of a case with callosal disconnection syndrome.",
"title_normalized": "acute disseminated encephalomyelitis following influenza vaccination report of a case with callosal disconnection syndrome"
} | [
{
"companynumb": "JP-BAXTER-2014BAX059548",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
"drugadditional": nu... |
{
"abstract": "Olanzapine, a 2(nd) generation antipsychotic, is in use in the clinical practice for nearly a decade and a half now. It is classified as a category C drug with very few reports of its toxic effects on the fetus. In general, the risk benefit analysis warrants its use in pregnancy. We report a case of microcephaly and anopthalmos associated with the use of olanzapine in pregnancy. Although a causal role cannot be unequivocally proven, it calls for larger studies to explore this issue.",
"affiliations": "Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India.;Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India.",
"authors": "Prakash|Sathya|S|;Chadda|Rakesh Kumar|RK|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4103/0253-7176.127266",
"fulltext": "\n==== Front\nIndian J Psychol MedIndian J Psychol MedIJPsyMIndian Journal of Psychological Medicine0253-71760975-1564Medknow Publications & Media Pvt Ltd India IJPsyM-36-9110.4103/0253-7176.127266Case ReportTeratogenicity with Olanzapine Prakash Sathya Chadda Rakesh Kumar Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, IndiaAddress for correspondence: Dr. Sathya Prakash Department of Psychiatry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029, India. E-mail: dr.sathyaprakashtbts@gmail.comJan-Mar 2014 36 1 91 93 Copyright: © Indian Journal of Psychological Medicine2014This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Olanzapine, a 2nd generation antipsychotic, is in use in the clinical practice for nearly a decade and a half now. It is classified as a category C drug with very few reports of its toxic effects on the fetus. In general, the risk benefit analysis warrants its use in pregnancy. We report a case of microcephaly and anopthalmos associated with the use of olanzapine in pregnancy. Although a causal role cannot be unequivocally proven, it calls for larger studies to explore this issue.\n\nOlanzapinepregnancyteratogenicity\n==== Body\nINTRODUCTION\nPrescribing psychotropic medication in pregnancy is a complex issue involving assessment of the risk of leaving an untreated psychiatric illness with its attendant complications versus the risk of adverse effects on the fetus. Most of the 2nd generation antipsychotics have been in use since the 1990s. Olanzapine, one of the 2nd generation antipsychotics, is a category C drug and there is no unequivocal evidence of harm to the fetus. Here, we report a case of microcephaly with anopthalmos in a patient who was treated with olanzapine for unspecified non-organic psychosis. To the best of our knowledge, such a complication has not been reported earlier.\n\nCASE REPORT\nMs. A, a 25-year-old married lady presented in the hospital's Walk-in clinic with the symptoms of suspiciousness and hearing voices. The symptoms had been present for about 5 years. She was very irritable and was unable to sleep. She also suffered few episodes suggestive of dissociative spells in which she would call herself “Goddess Kali.” There was also occasional history of disinhibition in the form of taking of her clothes in front of her family members.\n\nDetailed evaluation revealed delusions of persecution and second person auditory hallucination. There were no features suggestive of a mood disturbance or organicity. She was diagnosed as having unspecified non-organic psychosis on International Classification of Diseases, tenth edition.[1] Olanzapine was started and gradually increased to 15 mg/day. The psychotic symptoms were controlled over a period of 2 months with olanzapine. After 1 month of treatment with olanzapine, the patient became pregnant (this was her first pregnancy) and sought consultation for safety of medications during the 2nd month of gestation. Considering the severity of the symptoms in the past and duration of illness, on mutual discussions, it was decided to continue olanzapine. She was referred to the obstetrics service of the hospital to keep a close watch for any untoward event. She followed-up there regularly as advised by the obstetrician. A discussion with the consulting obstetrician and review of records revealed no major untoward event during pregnancy. Careful history revealed absence of fever, rashes or other skin lesions. Antibody titers for herpes simplex, varicella, cytomegalovirus, toxoplasma and rubella were conducted and found to be normal. Fasting and postprandial blood glucose levels performed at the time of first consultation and repeated in the 2nd and 3rd trimesters were found to be in the normal range. On follow-up, the fetus was detected to have microcephaly on ultrasonography. No other major anomalies were detectable.\n\nMs. A delivered a female baby weighing 3.4 kg with microcephaly and congenital anopthalmos (bilateral) at full term. The head circumference was 30.5 cm at birth, which falls below the third percentile.[2] The baby was seen at department of pediatrics, genetics and ophthalmology. B scan ultrasound revealed absence of ocular tissue. No additional causative factors could be elicited despite the above mentioned specialist referrals. However, detailed imaging and genetic investigations could not be done due to cost limitations. She was not on any other medication known to cause teratogenicity during the period. There was no history of any substance use or family history of congenital anomalies. Patient had adequate nutrition and rest during her pregnancy. There was no history of trauma or exposure to radiation either. The history was corroborated by the patient's mother as well as husband Although this adverse event scored only three on the the Naranjo et al. adverse drug reaction probability scale,[3] the lower scores were due to non-applicability of some questions to this situation. For instance, the issue of improvement on discontinuation of drug or administration of antagonist obviously does not apply to this case. Similarly, re-administration and replication of the adverse effect also cannot be done in this case for ethical reasons.\n\nDISCUSSION\nOlanzapine is considered pregnancy category C drug. One study involving pregnancy outcomes in 151 patients on different atypical antipsychotics (60 were on olanzapine) did not find any statistically significant differences in various pregnancy outcomes between the exposed and comparison groups, except the rate of low birth weight, which was 5 times higher in the exposed babies and a higher rate of therapeutic abortions. One case of encephalocoele with cleft lip and aqueductal stenosis was reported in a patient on olanzapine.[4] Arora and Praharaj[5] reported a case of meningocoele and ankyloblepharon in the child of a patient on olanzapine. Reis and Källén[6] reported craniosynostosis and ureteral reflux in one, an upper limb reduction defect in a second and a ventricular septal defect and upper gastrointestinal tract malformation in the third infant whose mothers were exposed to olanzapine during pregnancy. Our patient, however, had a normal birth weight. Another study[7] on 37 prospective and 11 retrospective pregnancies with exposure to olanzapine did not find any increase in the rate of spontaneous abortion and malformation compared with the general population. Of the prospective pregnancies, 84% had normal delivery and postnatal course. The remaining 16% suffered problems such as prematurity, postmaturity and low or high birth weight. At least two of the mothers were noted to have gestational diabetes. Newport et al.[8] measured placental passage of medication from mother to fetus by measuring levels in umbilical cord serum and documented neonatal outcomes in 54 women followed through pregnancy. They concluded that olanzapine has the highest rate of placental passage, compared with haloperidol, risperidone and quetiapine. Neonates exposed to olanzapine showed trends toward lower birth weights and more neonatal intensive care unit admissions than neonates exposed to other antipsychotic medication. Some authors have reported varying results among pregnant women treated with olanzapine[9] while others have not reported any harm to either mother or fetus.[10] To the best of our knowledge, this is the first report of microcephaly along with anopthalmos following intranatal exposure to olanzapine. We made attempts to rule out alternative causes and several of the causes that are responsible for baseline rates of congenital anomalies were ruled out. Our patient was continuously exposed to olanzapine even before conception until birth of the infant. Authors[5] have earlier hypothesized that this may increase the risk as the early developmental period is crucial for organogenesis. They also highlighted that many negative studies had olanzapine exposure after the 8th week of pregnancy. Thus, we hypothesize that early and sustained exposure to olanzapine may impair embryonic development in ways that may not occur with shorter or later periods of exposure. Calmodulin antagonism during early development has been proposed as a possible mechanism for antipsychotics in general; although, its specificity to olanzapine is unclear.[11] However, our report by virtue of being a case report has its obvious limitations of not being able to conclusively prove a causal link. Furthermore, for reasons mentioned earlier, some of the investigations could not be performed. The largest of the studies in pregnant women so far had only 60 patients on olanzapine. Whether these studies had sufficient power to detect risk of congenital anomalies is debatable. Careful studies are therefore needed to clarify the situation. The purpose of this case report is more to stimulate further research in this direction.\n\nSource of Support: Nil\n\nConflict of Interest: None.\n==== Refs\nREFERENCES\n1 World Health Organisation. The International Statistical Classification of Diseases and Related Health Problems 1992 1 10th ed Geneva World Health Organization \n2 World Health Organization. WHO Child Growth Standards: Growth Velocity Based on Weight, Height and Head Circumference 2009 Geneva World Health Organization \n3 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 45 7249508 \n4 McKenna K Koren G Tetelbaum M Wilton L Shakir S Diav-Citrin O Pregnancy outcome of women using atypical antipsychotic drugs: A prospective comparative study J Clin Psychiatry 2005 66 444 9 15816786 \n5 Arora M Praharaj SK Meningocele and ankyloblepharon following in utero exposure to olanzapine Eur Psychiatry 2006 21 345 6 16545547 \n6 Reis M Källén B Maternal use of antipsychotics in early pregnancy and delivery outcome J Clin Psychopharmacol 2008 28 279 88 18480684 \n7 Goldstein DJ Corbin LA Fung MC Olanzapine-exposed pregnancies and lactation: Early experience J Clin Psychopharmacol 2000 20 399 403 10917399 \n8 Newport DJ Calamaras MR DeVane CL Donovan J Beach AJ Winn S Atypical antipsychotic administration during late pregnancy: Placental passage and obstetrical outcomes Am J Psychiatry 2007 164 1214 20 17671284 \n9 Ramkisson R Campbell M Agius M The clinical dilemma - Prescribing in pregnancy Psychiatr Danub 2008 20 88 90 18376337 \n10 Kirchheiner J Berghöfer A Bolk-Weischedel D Healthy outcome under olanzapine treatment in a pregnant woman Pharmacopsychiatry 2000 33 78 80 10761825 \n11 Donohoe DR Aamodt EJ Osborn E Dwyer DS Antipsychotic drugs disrupt normal development in Caenorhabditis elegans via additional mechanisms besides dopamine and serotonin receptors Pharmacol Res 2006 54 361 72 16962336\n\n",
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"journal": "Indian journal of psychological medicine",
"keywords": "Olanzapine; pregnancy; teratogenicity",
"medline_ta": "Indian J Psychol Med",
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"title": "Teratogenicity with olanzapine.",
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"abstract": "OBJECTIVE\nEosinophilia is rare in severe sepsis in temperate areas. We present a case of suspected severe sepsis with eosinophilia that proved fatal and was subsequently diagnosed as drug rash with eosinophilia and systemic symptoms. We aim to determine how common eosinophilia in severe sepsis is in the tropics, where there is a higher background rate of eosinophilia due to parasitic infection.\n\n\nMETHODS\nRetrospective analysis of prospective cohort study.\n\n\nMETHODS\nTertiary hospital in tropical northern Australia.\n\n\nMETHODS\nProspectively recruited cohort including all patients at least 15 years old admitted to a 350-bed teaching hospital in northern Australia between May 6, 2007, and May 5, 2008, with community-onset severe sepsis.\n\n\nMETHODS\nNone.\n\n\nRESULTS\nPeripheral eosinophil counts on days 1 and 3 of admission and at the time of discharge were recorded for each patient. Eosinopenia was defined as less than 0.1×10 9/L and eosinophilia as greater than 0.6×10 9/L. The median eosinophil count on day 1 was 0.0 (interquartile range, 0.0-0.1; range, 0.0-0.7×10 9/L). Out of 245 patients, 243 patients (99.1%) had a normal or low eosinophil count at admission. Lower counts correlated with higher Acute Physiology and Chronic Health Evaluation II score and 28-day mortality (p=0.02 for both correlations). The median count rose during the course of admission to 0.2 (interquartile range, 0.1-0.4) at the time of discharge (p<0.001 compared with day 1 count). Patients with eosinophilia at discharge were more likely to be Indigneous or remote-dwelling than those without eosinophilia, suggesting an unmasking of preexisting eosinophilia as sepsis resolves.\n\n\nCONCLUSIONS\nEosinophilia is rare in severe sepsis, even in the tropics. Patients with suspected severe sepsis and eosinophilia should have diagnoses other than sepsis excluded. One such diagnosis is drug rash with eosinophilia and systemic symptoms.",
"affiliations": "1Department of Infectious Diseases, Royal Darwin Hospital, Tiwi, Northern Territory, Australia. 2Global and Tropical Health Division, Menzies School of Health Research, Casuarina, Northern Territory, Australia.",
"authors": "Pitman|Matthew C|MC|;Anstey|Nicholas M|NM|;Davis|Joshua S|JS|",
"chemical_list": "D000900:Anti-Bacterial Agents",
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"doi": "10.1097/CCM.0b013e3182923755",
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"issue": "41(10)",
"journal": "Critical care medicine",
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"medline_ta": "Crit Care Med",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D015897:Comorbidity; D057210:Delayed Diagnosis; D003937:Diagnosis, Differential; D003875:Drug Eruptions; D004802:Eosinophilia; D004804:Eosinophils; D005076:Exanthema; D017809:Fatal Outcome; D005260:Female; D006784:Hospitals, Teaching; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D044468:Native Hawaiian or Other Pacific Islander; D015876:Northern Territory; D011446:Prospective Studies; D012189:Retrospective Studies; D018805:Sepsis; D014329:Tropical Climate",
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"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Eosinophils in severe sepsis in northern australia: do the usual rules apply in the tropics?",
"title_normalized": "eosinophils in severe sepsis in northern australia do the usual rules apply in the tropics"
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"abstract": "BACKGROUND\nPatients with common variable immunodeficiency (CVID) have an increased risk of developing lymphoproliferative diseases, including non-Hodgkins lymphoma (Blood 116:1228-1234, 2010; Blood 119:1650-7, 2012). The incidence and prognosis of Hodgkin lymphoma in this population is not clear, with only a few case reports in the literature. Conventional cytotoxic chemotherapy, although highly efficacious in treating Hodgkin lymphoma in immune competent patients, is problematic in patients with CVID due to the increased risk of infectious complications (Ther Umsch 69:687-91, 2012; Pediatr Hematol Oncol 24:337-42, 2012). Rituximab and brentuximab vedotin are both targeted agents used to treat lymphomas that express CD20 and CD30, respectively. Compared to cytotoxic chemotherapy typically used in Hodgkin lymphoma, these agents are better tolerated with minimal side effects. This makes them an attractive option for treating lymphoma in patients who have significant co-morbidities, including those with immune deficiencies. Additionally, rituximab has been used safely to treat autoimmune cytopenias in patients with CVID5. However, the role of these targeted therapies in CVID-associated Hodgkin lymphoma has not been reported.\n\n\nMETHODS\nHere we report the case of a 25 year old female diagnosed with CVID-associated classic Hodgkin lymphoma, who achieved a complete remission following treatment with rituximab followed by brentuximab vedotin.\n\n\nCONCLUSIONS\nWe demonstrate that rituximab and brentuximab are likely safe and effective in CVID-associated Hodgkin lymphoma, providing a feasible and potentially optimal treatment option for this patient population.",
"affiliations": "Department of Allergy and Immunology, Stanford University, School of Medicine, Stanford, CA 94305 USA.;Penn State Hershey Cancer Institute, Penn State University College of Medicine, 500 University Drive, P.O. Box 850, Hershey, PA 17033 USA.;Penn State Hershey Cancer Institute, Penn State University College of Medicine, 500 University Drive, P.O. Box 850, Hershey, PA 17033 USA.;Department of Pathology, Penn State Hershey Medical Center, Penn State University College of Medicine, Hershey, PA 17033 USA.;Department of Allergy and Immunology, Stanford University, School of Medicine, Stanford, CA 94305 USA.;Penn State Hershey Cancer Institute, Penn State University College of Medicine, 500 University Drive, P.O. Box 850, Hershey, PA 17033 USA.",
"authors": "Rael|Efren|E|;Rakszawski|Kevin|K|;Koller|Kristian|K|;Bayerl|Michael|M|;Butte|Manish|M|;Zheng|Hong|H|",
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"country": "England",
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"doi": "10.1186/s40364-016-0061-8",
"fulltext": "\n==== Front\nBiomark ResBiomark ResBiomarker Research2050-7771BioMed Central London 6110.1186/s40364-016-0061-8Case ReportTreatment with rituximab and brentuximab vedotin in a patient of common variable immune deficiency-associated classic Hodgkin lymphoma Rael Efren erael@stanford.edu Rakszawski Kevin krakszawski@hmc.psu.edu Koller Kristian kkoller@hmc.psu.edu Bayerl Michael mbayerl@hmc.psu.edu Butte Manish mjbutte@stanford.edu Zheng Hong 717-531-7309hzheng@hmc.psu.edu Department of Allergy and Immunology, Stanford University, School of Medicine, Stanford, CA 94305 USA Penn State Hershey Cancer Institute, Penn State University College of Medicine, 500 University Drive, P.O. Box 850, Hershey, PA 17033 USA Department of Pathology, Penn State Hershey Medical Center, Penn State University College of Medicine, Hershey, PA 17033 USA 9 3 2016 9 3 2016 2016 4 714 12 2015 1 3 2016 © Rael et al. 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nPatients with common variable immunodeficiency (CVID) have an increased risk of developing lymphoproliferative diseases, including non-Hodgkins lymphoma (Blood 116:1228–1234, 2010; Blood 119:1650–7, 2012). The incidence and prognosis of Hodgkin lymphoma in this population is not clear, with only a few case reports in the literature. Conventional cytotoxic chemotherapy, although highly efficacious in treating Hodgkin lymphoma in immune competent patients, is problematic in patients with CVID due to the increased risk of infectious complications (Ther Umsch 69:687–91, 2012; Pediatr Hematol Oncol 24:337–42, 2012). Rituximab and brentuximab vedotin are both targeted agents used to treat lymphomas that express CD20 and CD30, respectively. Compared to cytotoxic chemotherapy typically used in Hodgkin lymphoma, these agents are better tolerated with minimal side effects. This makes them an attractive option for treating lymphoma in patients who have significant co-morbidities, including those with immune deficiencies. Additionally, rituximab has been used safely to treat autoimmune cytopenias in patients with CVID5. However, the role of these targeted therapies in CVID-associated Hodgkin lymphoma has not been reported.\n\nCase Presentation\nHere we report the case of a 25 year old female diagnosed with CVID-associated classic Hodgkin lymphoma, who achieved a complete remission following treatment with rituximab followed by brentuximab vedotin.\n\nConclusions\nWe demonstrate that rituximab and brentuximab are likely safe and effective in CVID-associated Hodgkin lymphoma, providing a feasible and potentially optimal treatment option for this patient population.\n\nKeywords\nBrentuximabRituximabCVIDHodgkin lymphomaissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nCommon variable immunodeficiency (CVID) is a rare immune disorder characterized by decreased immunoglobulin production resulting from a variety of gene defects. Clinically, patients with CVID have a diverse phenotype, but can commonly present with recurrent infections, autoimmune disorders, and lymphoproliferative disorders including malignancies [1]. Treatment of CVID consists of lifelong immunoglobulin replacement [2].\n\nThe overall incidence of malignant disease appears to be increased in CVID, with a nearly 5-fold increase compared to the general population. In a long-term study of 416 patients with CVID, 38 patients were found to have malignancies, with non-Hodgkin lymphoma (NHL) representing 29 % of the total [3]. Other studies have also shown that NHL is the most frequent CVID-associated malignancy, with estimates ranging from 3 to 8 % [1, 3, 4]. However, there are far fewer reports of Hodgkin lymphoma in CVID compared to that of NHL. In one cohort of 473 patients with CVID, 32 patients (6.7 %) developed non-Hodgkin lymphoma, while there were only 4 cases (0.8 %) of Hodgkin lymphoma [5]. Data concerning the prognosis of CVID-related Hodgkin lymphoma are scarce. Among the four patients mentioned in the prior study, three developed a B-cell lymphoma years after their initial treatment, two of whom died of their lymphomas. An additional report demonstrated a poor clinical outcome in two siblings with CVID-associated Hodgkin lymphoma. Both patients died of severe sepsis 6–12 months post chemotherapy with MOPP/ABVD [6].\n\nRituximab, a monoclonal antibody to CD20, has been widely used in B cell NHL. Blockade of CD20 leads to impaired plasma cell differentiation. The rituximab therapy is associated with re-distribution of B cell populations to predominantly naïve cells (IgD+ CD27−) with proportional reductions in switched memory B cells (IgD− CD27+). Transitional B cells (CD38++ IgM++) can be elevated or normal post rituximab [7]. IgG levels typically remain low 9 months after rituximab completion with impaired carbohydrate pneumococcal vaccine responses [7]. Rituximab has also been applied in the treatment for lymphocyte-predominant Hodgkin lymphoma, which are usually CD20+ [8]. The role of rituximab in classic Hodgkin lymphoma is less well established. Twenty to thirty percent of classic Hodgkin lymphoma expresses CD20 [9, 10]. It is speculated that rituximab would be effective in treating CD20+ classic Hodgkin lymphoma for a variety of reasons including the elimination of CD20-positive reactive B cells supporting Hodgkin and Reed Sternberg (HRS) cells, as well as elimination of presumptive CD20-positive HRS stem cells [11, 12]. However, clinical data are extremely limited. Brentuximab vedotin is an immunotoxin targeting CD30-expressing cells, including those in Hodgkin lymphoma [13]. It is approved for treatment of relapse/refractory Hodgkin lymphoma [14]. Ongoing clinical studies are testing its efficacy as first line treatment of Hodgkin lymphoma. Compared to conventional chemotherapy, both rituximab and brentuximab vedotin are better tolerated with less toxicity. Additionally, rituximab has been successfully used in a population of CVID patients to treat immune cytopenias [15]. Therefore these targeted agents represent attractive options for patients with CVID-associated Hodgkin lymphoma. To date, clinical data of the role of rituximab and/or brentuximab vedotin in CVID- associated Hodgkin lymphoma have not been available.\n\nHere we report a case of a 25 year old female with CVID-associated classic Hodgkin lymphoma, who achieved complete remission with treatment of rituximab and brentuximab vedotin.\n\nCase presentation\nA 25 year old female was diagnosed of CVID in 2006 (at age of 18) with initial presentation of recurrent episodes of bacterial sinusitis and outbreaks of genital herpes. Laboratory work revealed hypogammaglobulinemia with poor antibody responses to both polysaccharide and protein antigens. She was found to have IL-2-Inducible T-cell kinase (ITK) mutation, which is potentially involved in the pathogenesis of her CVID. She was started on IVIG and has been receiving it every month.\n\nThe patient has additional history of type 1 diabetes diagnosed at 18 months of age, for which she has been depending on insulin, as well as immune thrombocytopenia purpura (ITP) diagnosed at age of 11. She had multiple episodes of recurrent thrombocytopenia managed with IVIG and corticosteroids. In 2002, at the age of 14, she was hospitalized with a presentation of fever and pain, and found to have lymphadenopathy, lymphopenia, neutropenia, and thrombocytopenia. An extensive infectious workup was negative. She had bone marrow biopsy, which was unremarkable with the exception of findings consistent with cytopenias. She ultimately underwent a splenectomy and lymph node resection in 2002. Lymph node and spleen pathology revealed noncaseating granuloma. After the splenectomy, her fevers and pain resolved. Her blood counts have remained relatively normal since splenectomy.\n\nIn June 2013 when she was 25 year old, she presented with left flank pain and fever. A CT scan showed diffuse lymphadenopathy in chest, abdomen, and pelvis with the largest node measuring 4.7 × 2.9 cm in the mid abdomen. A biopsy of left peri-aortic lymph node showed non-necrotizing granulomatous inflammation. Extensive infectious disease and rheumatology workup were all negative. She was started with prednisone 60 mg daily for 7 days before being tapered down, with clinical improvement. In September 2013, she was hospitalized again with abdominal pain and fever. A PET scan was done and showed extensive hypermetabolic lymphadenopathy involving the supraclavicular, bilateral axillary, right internal mammary, mediastinal, retroperitoneal, mesenteric, and pelvic lymph node chains. In addition, there were hypermetabolic sclerotic lesions within the bone marrow of L3 and the left iliac bone (Fig. 2a). She underwent left iliac bone marrow biopsy which revealed a diagnosis of EBV-positive immunodeficiency (CVID)-associated lymphoproliferative disorder, classical Hodgkin’s lymphoma morphology and immunophenotype. The abnormal cells were large cells positive for CD30, CD15, CD20 (weak to moderate), and PAX-5 (weak), EBER positive (Fig. 1). She had no other constitutional symptoms. Laboratory work demonstrated normal CBC. LDH was mildly elevated at 853 unit/L (normal range 313–618 unit/L).Fig. 1 Histology of the bone marrow biopsy at the diagnosis CVID-associated classic Hodgkin lymphoma. a Photomicrograph of the infiltrate in the marrow comprising very large Hodgkin and Reed-Sternberg (HRS) cells in a fibroinflammatory background (Hematoxylin and eosin stain, 1000X). b & c CD30 and CD20 immunohistochemistry is positive in HRS cells respectively (3′,3′-diaminobenzidine chromogen with hematoxylin counterstain, 1000X). d In situ hybridization for Epstein-Barr-virus-encoded RNA 1 (EBER 1) is positive in HRS cells (INFORM EBER probe and iVIEWTMblue detection, Ventana Medical Systems, Inc., Tuscon, AZ. 1000X)\n\n\n\nGiven her history of CVID, with the immunophenotype of her lymphoma, the decision was made to start therapy with rituximab monotherapy. The patient completed four weekly doses of rituximab dosed at 375 mg/m2. She had significant clinical improvement with resolution of fever and abdominal pain. LDH decreased to normal range as well. Follow-up PET/CT in January 2014 showed near-complete metabolic response in the hilar, mediastinal, axillary, retroperitoneal, mesenteric, iliac, and inguinal lymph nodes. However, there was only a partial metabolic response of the lesions in the left iliac bone, vertebral bodies T9 and L3 (Fig. 2b). Subsequently, an L3 vertebral body biopsy was pursued, with pathology consistent with the previous diagnosis of classic Hodgkin lymphoma, although with an immunophenotype that was now CD20-negative. She was referred to Radiation Oncology and received a course of 4000 cGy to the spine. She then received four additional weekly treatments of rituximab. Repeat PET/CT in June 2014 showed resolution of the L3 lesion, but revealed new sites of osseous disease in the right humerus, left posterior 5th rib, left 10th spinous process, mid sacrum, right iliac wing, and left femoral head (Fig. 2c). Brentuximab vedotin 1.8 mg/kg every 3 weeks was initiated in July 2014. The patient completed ten doses of brentuximab vedotin before discontinuing due to moderate neuropathy. She also received maintenance rituximab every 2 months. A follow-up PET/CT in December 2014 showed a complete metabolic response (Fig. 2d). Rituximab bimonthly has been maintained with good tolerance. She is doing well with no evidence of disease recurrence to date.Fig. 2 PET scan prior to and post treatment. a PET scan on initial diagnosis of CVID-associated classic Hodgkin lymphoma. b Post 4 weekly doses of rituximab. c Prior to brentuximab vidotin. d Post brentuximab\n\n\n\nDiscussion\nThe risk of lymphoma among patients with CVID is clearly higher than that of general population. In a combined Danish and Swedish study of 176 patients with CVID, the incidence of non-Hodgkin lymphoma was 12.1-fold higher, and the incidence of Hodgkin lymphoma was 16.7-fold higher compared to that of regular population [16]. CVID-associated lymphomas are typically extra-nodal, B-cell derived and EBV negative [17]. The diagnosis of lymphoma in patients with CVID can be challenging as localized or systemic granulomatous disease and lymphoid hyperplasia are also frequently observed in this patient population [18]. As occurred in this case, initial lymph node biopsy when lymphadenopathy is discovered on body imaging is often nonspecific and nonmalignant. Repeat tissue sampling, given the chronicity of CVID, is essential to provide a timely diagnosis of malignancy in these patients.\n\nThe pathogenesis of lymphomas among patients with CVID is not well understood, but likely attributes to genetic disorder, immune dysregulation, and chronic infections. It has been postulated that the underlying immune deficient status increases the susceptibility to virus infection and the development of viral-related lymphoma (e.g. EBV associated lymphoma). In contrast to this hypothesis, most CVID-associated lymphoma is EBV negative [17]. Our patient does have EBV positive CVID-associated lymphoma. Whether the EBV status contributes to the pathogenesis of her lymphoma or it is just co-incident remains unknown. Genetic disorders in patient with CVID are heterogeneous. Our patient does have a mutation of ITK, which belongs to the Tec family of non-receptor tyrosine kinases. There are five members in Tec family: ITK, RLK (Resting lymphocyte kinase), BTK (Bruton’s tyrosine kinase), TEC (Tyrosine kinase expressed in hepatocellular carcinoma), and BMX (Bone marrow tyrosine kinase gene on chromosome X). ITK deficiency is a T-cell immunodeficiency that has been implicated in the development of EBV-positive lymphoproliferative disorders, including Hodgkins and Hodgkins-like lymphoma [19]. Our case provides the first clinic association between ITK mutation and CVID. Whether ITK plays a role in the pathogenesis of CVID-associated Hodgkin lymphoma and thus a potential target for the therapeutics of this disease is worth further studying.\n\nGranulomatous disease is a common manifestation of CVID, occurring in 8–22 % patients [20–22]. As in our case, it is frequently noted even before the diagnosis of CVID. It has been observed that granulomatosis in CVID is associated with poor prognosis and there is no standard treatment. Most physicians choose to observation or a course of steroid if symptomatic. Long term steroid is challenging given multiple side effects including high risk of infections. Our patient did have non-caseating granulomas proved by multiple lymph node biopsies. Interestingly after initial treatment of rituximab, in addition to improvement of the metabolic active bone lesions, there was near-completed response in the extensive lymphadenopathy. Some of the lymph nodes were biopsy proven non-caseating granulomas. Therefore rituximab is potentially a promising therapeutic CVID related granulomatosis. Further study is warrantied to determine the efficacy and long term survival.\n\nThe prognosis for patients with CVID-associated Hodgkin lymphomas is unfortunately not well defined, likely due to the rareness of this disease. Our extensive literature search only located a case report in which two siblings found to have CVID-associated Hodgkin lymphoma at age of 11 and 15 respectively. However both died of severe infection 6–12 months post intensive chemotherapy [6]. One challenge is that the standard chemotherapy (e.g. ABVD) that are applied to patients with Hodgkin lymphoma who are immune competent, may not be tolerated by CVID patients because of the high risk and severity of infections resulting from immune deficiency. In our case, we chose rituximab and brentuximab instead of conventional chemotherapy as the first line treatment. The majority of classic Hodgkin lymphoma express CD30. In addition, 20 to 30 % of them express CD20 [9, 10]. Our patient did have expression of both CD20 and CD30 in her classic Hodgkin lymphoma, making a strong rationale for the treatment with rituximab and brentuximab, agents targeting CD20 and CD30 respectively. In fact, we were able to achieve complete response without major complications.\n\nConclusion\nIn summary, we report a case of a 25 year old female diagnosed with CVID-associated classic Hodgkin lymphoma, who achieved a complete remission following treatment with rituximab followed by brentuximab vedotin. To our knowledge, our case is the first to demonstrate that rituximab and brentuximab are likely safe and effective in CVID-associated Hodgkin lymphoma, providing a feasible and potentially optimal treatment option for this patient population.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests\n\nAuthors’ contributions\n\nER participated in the design and coordination of the study, as well as manuscript preparation. KR, KK and MB participated in patient management, data acquisition, analyses, and manuscript draft. HZ participated in patient management, conceived the study, and prepared the manuscript. All authors read and approved the final manuscript.\n==== Refs\nReferences\n1. Chapel H Lucas M Lee M Common variable immunodeficiency disorders: division into distinct clinical phenotypes Blood 2008 112 277 286 10.1182/blood-2007-11-124545 18319398 \n2. Cunningham-Rundles C How I, treat common variable immune deficiency Blood 2010 116 7 15 10.1182/blood-2010-01-254417 20332369 \n3. Vajdic CM Mao L van Leeuwen MT Kirkpatrick P Grulich AE Riminton S Are antibody deficiency disorders associated with a narrower range of cancers than other forms of immunodeficiency? Blood 2010 116 1228 1234 10.1182/blood-2010-03-272351 20466855 \n4. Cunningham-Rundles C Bodian C Common variable immunodeficiency: clinical and immunological features of 248 patients Clin Immunol 1999 92 34 48 10.1006/clim.1999.4725 10413651 \n5. Resnick ES Moshier EL Godbold JH Cunningham-Rundles C Morbidity and mortality in common variable immune deficiency over 4 decades Blood 2012 119 1650 1657 10.1182/blood-2011-09-377945 22180439 \n6. Aghamohammadi A Rezaei N Gharagozlou M Hodgkin lymphoma in two siblings with common variable immunodeficiency Pediatr Hematol Oncol 2007 24 337 342 10.1080/08880010701369982 17613878 \n7. 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 In Pract. 2014 2 594 600 10.1016/j.jaip.2014.06.003 25213054 \n8. Saini KS Azim HA Jr Cocorocchio E Rituximab in Hodgkin lymphoma: is the target always a hit? Cancer Treat Rev 2011 37 385 390 10.1016/j.ctrv.2010.11.005 21183282 \n9. Anagnostopoulos I Hansmann ML Franssila K European Task Force on Lymphoma project on lymphocyte predominance Hodgkin disease: histologic and immunohistologic analysis of submitted cases reveals 2 types of Hodgkin disease with a nodular growth pattern and abundant lymphocytes Blood 2000 96 1889 1899 10961891 \n10. Rassidakis GZ Medeiros LJ Viviani S CD20 expression in Hodgkin and Reed-Sternberg cells of classical Hodgkin’s disease: associations with presenting features and clinical outcome J. Clin. Oncol. 2002 20 1278 1287 10.1200/JCO.20.5.1278 11870170 \n11. Oki Y Younes A Does rituximab have a place in treating classic hodgkin lymphoma? Curr Hematol Malig Rep 2010 5 135 139 10.1007/s11899-010-0052-z 20490723 \n12. Jones RJ Gocke CD Kasamon YL Circulating clonotypic B cells in classic Hodgkin lymphoma Blood 2009 113 5920 5926 10.1182/blood-2008-11-189688 19188663 \n13. Bartlett NL Chen R Fanale MA Retreatment with brentuximab vedotin in patients with CD30-positive hematologic malignancies J. Hematol. Oncol. 2014 7 24 10.1186/1756-8722-7-24 24642247 \n14. Younes A Gopal AK Smith SE Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma J. Clin. Oncol. 2012 30 2183 2189 10.1200/JCO.2011.38.0410 22454421 \n15. Gobert D Bussel JB Cunningham-Rundles C Efficacy and safety of rituximab in common variable immunodeficiency-associated immune cytopenias: a retrospective multicentre study on 33 patients Br J Haematol 2011 155 498 508 10.1111/j.1365-2141.2011.08880.x 21981575 \n16. Mellemkjaer L Hammarstrom L Andersen V Cancer risk among patients with IgA deficiency or common variable immunodeficiency and their relatives: a combined Danish and Swedish study Clin Exp Immunol 2002 130 495 500 10.1046/j.1365-2249.2002.02004.x 12452841 \n17. Cunningham-Rundles C Hematologic complications of primary immune deficiencies Blood Rev 2002 16 61 64 10.1054/blre.2001.0185 11913998 \n18. Gangemi S Allegra A Musolino C Lymphoproliferative disease and cancer among patients with common variable immunodeficiency Leuk Res 2015 39 389 396 10.1016/j.leukres.2015.02.002 25711943 \n19. Bienemann K Borkhardt A Klapper W Oschlies I High incidence of Epstein-Barr virus (EBV)-positive Hodgkin lymphoma and Hodgkin lymphoma-like B-cell lymphoproliferations with EBV latency profile 2 in children with interleukin-2-inducible T-cell kinase deficiency Histopathology 2015 67 607 616 10.1111/his.12677 25728094 \n20. Ardeniz O Cunningham-Rundles C Granulomatous disease in common variable immunodeficiency Clin. Immunol. 2009 133 198 207 10.1016/j.clim.2009.05.001 19716342 \n21. Cunningham-Rundles C Common variable immunodeficiency Curr. Allergy Asthma Rep. 2001 1 421 429 10.1007/s11882-001-0027-1 11892068 \n22. Morimoto Y Routes JM Granulomatous disease in common variable immunodeficiency Curr. Allergy Asthma Rep. 2005 5 370 375 10.1007/s11882-005-0008-x 16091208\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-7771",
"issue": "4()",
"journal": "Biomarker research",
"keywords": "Brentuximab; CVID; Hodgkin lymphoma; Rituximab",
"medline_ta": "Biomark Res",
"mesh_terms": null,
"nlm_unique_id": "101607860",
"other_id": null,
"pages": "7",
"pmc": null,
"pmid": "26966541",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "24642247;11892068;25728094;17613878;21183282;10413651;20332369;22454421;11913998;25711943;16091208;12452841;20466855;19716342;11870170;19188663;25213054;21981575;22180439;20490723;18319398;10961891",
"title": "Treatment with rituximab and brentuximab vedotin in a patient of common variable immune deficiency-associated classic Hodgkin lymphoma.",
"title_normalized": "treatment with rituximab and brentuximab vedotin in a patient of common variable immune deficiency associated classic hodgkin lymphoma"
} | [
{
"companynumb": "US-MYLANLABS-2017M1012276",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo report two cases of spontaneous Retisert implant dissociation with dislocation of the medication reservoir into the anterior chamber.\n\n\nMETHODS\nCase reports.\n\n\nRESULTS\nTwo patients with chronic, noninfectious uveitis following Retisert implantation between 6 and 7 years prior presented with a complaint of a \"white spot\" in their right eyes. Both patients had previous pars plana vitrectomies. Anterior segment examination revealed a dislocated medication reservoir of the Retisert implant in the inferior portion of anterior chamber with associated reservoir-corneal endothelial touch and stromal edema. The reservoirs were subsequently retrieved via a pars plana approach and removed from the anterior chamber through a corneal incision.\n\n\nCONCLUSIONS\nSpontaneous dissociation of the Retisert implant with dislocation of the medication reservoir into the anterior chamber can be a late complication of Retisert implantation. Eye care professionals and patients should be aware of this complication, particularly with long-term intraocular retention of this device.",
"affiliations": "a Department of Ophthalmology , The New York Eye & Ear Infirmary of Mt. Sinai , New York , USA .;a Department of Ophthalmology , The New York Eye & Ear Infirmary of Mt. Sinai , New York , USA .;a Department of Ophthalmology , The New York Eye & Ear Infirmary of Mt. Sinai , New York , USA .;a Department of Ophthalmology , The New York Eye & Ear Infirmary of Mt. Sinai , New York , USA .",
"authors": "Chang|Peter Y|PY|;Kresch|Zvi|Z|;Samson|C Michael|CM|;Gentile|Ronald C|RC|",
"chemical_list": "D003692:Delayed-Action Preparations; D004343:Drug Implants; D005938:Glucocorticoids; D005446:Fluocinolone Acetonide",
"country": "England",
"delete": false,
"doi": "10.3109/09273948.2014.902074",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0927-3948",
"issue": "23(6)",
"journal": "Ocular immunology and inflammation",
"keywords": "Anterior chamber; Retisert; dislocation; dissociation; fluocinolone acetonide; implant; separation; spontaneous; uveitis",
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": "D000328:Adult; D000867:Anterior Chamber; D003692:Delayed-Action Preparations; D004343:Drug Implants; D005260:Female; D005446:Fluocinolone Acetonide; D005548:Foreign-Body Migration; D005938:Glucocorticoids; D006801:Humans; D008875:Middle Aged; D015866:Uveitis, Posterior; D014821:Vitrectomy; D014822:Vitreous Body",
"nlm_unique_id": "9312169",
"other_id": null,
"pages": "454-7",
"pmc": null,
"pmid": "24724735",
"pubdate": "2015",
"publication_types": "D016422:Letter; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Spontaneous Dissociation of Fluocinolone Acetonide Sustained Release Implant (Retisert) with Dislocation into the Anterior Chamber.",
"title_normalized": "spontaneous dissociation of fluocinolone acetonide sustained release implant retisert with dislocation into the anterior chamber"
} | [
{
"companynumb": "US-BAUSCH-BL-2016-009964",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUOCINOLONE ACETONIDE"
},
"drugadditional": n... |
{
"abstract": "Elbasvir/grazoprevir with or without ribavirin has excellent efficacy and safety for the treatment of hepatitis C virus (HCV) genotype 1 and 4 patients. The real-world experience has been reported but the detailed analysis of liver and renal adverse effects is lacking. This study evaluated the real-world experience relating to the effectiveness and liver/renal safety of elbasvir/grazoprevir in HCV genotype 1 patients with compensated liver disease. In the four medical centres of Chang Gung Medical System, 350 HCV genotype 1 patients with compensated liver disease who were treated with elbasvir/grazoprevir were enrolled. Clinical characteristics and laboratory data were collected. The effectiveness (sustained virologic response 12 weeks after end of treatment, SVR12) and safety were assessed. A consecutive series of 350 patients with a mean age of 68.8 ± 10.0 years old were enrolled. The majority were treatment-naïve (72.3%), genotype 1b (97.7%) and advanced fibrosis/cirrhosis (94.3%). Seventy-nine (22.6%) had hepatocellular carcinoma and 23 (6.6%) had coinfection with hepatitis B. The effectiveness of SVR12 was 94.6% (95% CI: 92.2%-97.0%) in the full analysis set and 99.1% (95% CI: 98.1%-100.1%) in the per-protocol set. There were two relapses and one nonresponder. Seven (2.0%) patients had adverse events resulting in premature discontinuation of treatment. Five of them were considered drug-related. One was due to autoimmune hepatitis. Contrary to previous reports, around 49% of ALT elevation was observed after 8 weeks, and in two patients was due to hepatitis B flares. As to the renal function during the course of therapy, a minor deterioration of eGFR was observed in patients with baseline eGFR ≥60 mL/min/1.73 m2 , but not in those with baseline eGFR <60, <60-30 or <30 mL/min/1.73 m2 . In this real-world data, elbasvir/grazoprevir was effective with few liver/renal adverse effects. One patient developed autoimmune hepatitis.",
"affiliations": "Division of Hepatogastroenterology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.;Division of Hepatogastroenterology, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan.;Division of Hepatogastroenterology, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan.;College of Medicine, Chang Gung University, Taoyuan, Taiwan.;Division of Hepatogastroenterology, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan.;Division of Hepatogastroenterology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.;College of Medicine, Chang Gung University, Taoyuan, Taiwan.;Division of Hepatogastroenterology, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan.;Division of Hepatogastroenterology, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan.;Division of Hepatogastroenterology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.",
"authors": "Hsieh|Yi-Chung|YC|0000-0002-1191-4399;Lin|Chih-Lang|CL|;Hung|Chao-Hung|CH|;Chen|Chien-Hung|CH|;Tung|Shui-Yi|SY|;Lin|Chun-Yen|CY|0000-0003-3007-3190;Hu|Tsung-Hui|TH|;Lu|Sheng-Nan|SN|;Chien|Rong-Nan|RN|;Sheen|I-Shyan|IS|",
"chemical_list": "C000589335:2-(pyrrolidin-2-yl)-5-(2-(4-(5-(pyrrolidin-2-yl)-1H-imidazol-2-yl)phenyl)benzofuran-5-yl)-1H-imidazole; D000577:Amides; D000998:Antiviral Agents; D001572:Benzofurans; D002219:Carbamates; D003521:Cyclopropanes; D004338:Drug Combinations; D007093:Imidazoles; D011810:Quinoxalines; D013449:Sulfonamides; C578009:grazoprevir",
"country": "England",
"delete": false,
"doi": "10.1111/jvh.13262",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1352-0504",
"issue": "27(5)",
"journal": "Journal of viral hepatitis",
"keywords": "adverse effect; elbasvir/grazoprevir; hepatitis C; real-world experience",
"medline_ta": "J Viral Hepat",
"mesh_terms": "D000368:Aged; D000577:Amides; D000998:Antiviral Agents; D001572:Benzofurans; D002219:Carbamates; D003521:Cyclopropanes; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005838:Genotype; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D007093:Imidazoles; D007668:Kidney; D008099:Liver; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011810:Quinoxalines; D013449:Sulfonamides; D013624:Taiwan",
"nlm_unique_id": "9435672",
"other_id": null,
"pages": "505-513",
"pmc": null,
"pmid": "32039536",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Real-world experience of elbasvir/grazoprevir in Taiwan: This study was focused on liver and renal adverse effects.",
"title_normalized": "real world experience of elbasvir grazoprevir in taiwan this study was focused on liver and renal adverse effects"
} | [
{
"companynumb": "TW-ROCHE-2588884",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "BACKGROUND\nBrain malformations represent a major cause of refractory seizures. Standardized protocols to treat status epilepticus of newborn are not available in the literature.\n\n\nMETHODS\nWe present a case report of use of ketamine administered to a late preterm with Pierre Robin sequence, lissencephaly, polymicrogyria, and severe epilepsy.\n\n\nRESULTS\nThe infusion of ketamine permitted resolution of status epilepticus, cardiorespiratory stabilization, and improved parental care for 15 days. No significant side effects were noted.\n\n\nCONCLUSIONS\nIn the literature there are few studies regarding the use of ketamine for refractory status epilepticus, and only in nine of these described the use of, ketamine in children (2 months-18 years). This is the first report to document the effective use of ketamine in the newborn with status epilepticus.",
"affiliations": "Department of Medical Sciences, Pediatric Section, S. Anna University Hospital, Ferrara, Italy.;Department of Medical Sciences, Neonatology and NICU, S. Anna University Hospital, Ferrara, Italy. Electronic address: elisa.ballardini@unife.it.;Department of Medical Sciences, Neonatology and NICU, S. Anna University Hospital, Ferrara, Italy.",
"authors": "Tarocco|Anna|A|;Ballardini|Elisa|E|;Garani|Giampaolo|G|",
"chemical_list": "D000927:Anticonvulsants; D007649:Ketamine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-8994",
"issue": "51(1)",
"journal": "Pediatric neurology",
"keywords": "cortical malformations; ketamine; newborn; refractory status epilepticus",
"medline_ta": "Pediatr Neurol",
"mesh_terms": "D000927:Anticonvulsants; D005260:Female; D006801:Humans; D007223:Infant; D007649:Ketamine; D013226:Status Epilepticus",
"nlm_unique_id": "8508183",
"other_id": null,
"pages": "154-6",
"pmc": null,
"pmid": "24938144",
"pubdate": "2014-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Use of ketamine in a newborn with refractory status epilepticus: a case report.",
"title_normalized": "use of ketamine in a newborn with refractory status epilepticus a case report"
} | [
{
"companynumb": "IT-MYLANLABS-2020M1004852",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "KETAMINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nRisk prediction in paracetamol (acetaminophen, or APAP) poisoning treated with acetylcysteine helps guide initial patient management and disposition. The paracetamol-aminotransferase multiplication product may be a useful and less time-sensitive risk predictor.\n\n\nOBJECTIVE\nThe aim of this study was to validate this multiplication product in an independent cohort of patients with paracetamol overdose.\n\n\nMETHODS\nUsing an existing toxicology dataset of poisoned patients from two large inner-city United Kingdom teaching hospitals, we retrospectively identified by electronic search all paracetamol overdoses from February 2005 to March 2013. We assessed the diagnostic accuracy of the multiplication product (serum APAP concentration × alanine transaminase [ALT] activity), especially at the pre-specified cut-off points of 1 500 mg/L × IU/L (10 000 micromol/L × IU/L) and 10 000 mg/L × IU/L (66 000 micromol/L × IU/L). The primary outcome was hepatotoxicity defined by a peak ALT > 1000 IU/L.\n\n\nRESULTS\nOf 3823 total paracetamol overdose presentations, there were 2743 acute single, 452 delayed single (> 24 h post overdose), 426 staggered (ingestion over > 1 h), and 202 supratherapeutic ingestions. Altogether, 34 patients developed hepatotoxicity. Among the acute single-ingestion patients, a multiplication product > 10 000 mg/L × IU/L had a sensitivity of 80% (95% confidence interval [CI]: 44%, 96%) and specificity of 99.6% [99.3%, 99.8%], while a product > 1 500 mg/L × IU/L had a sensitivity of 100% [66%, 100%] and specificity of 92% [91%, 93%]. Overall, 16 patients with a multiplication product > 10 000 mg/L × IU/L developed hepatotoxicity (likelihood ratio: 250, 95% CI: 130, 480), and 4 patients with a multiplication product between 1 500 and 10 000 (likelihood ratio: 2.5, 95% CI: 1.0, 6.0). No patient with a product < 1 500 mg/L × IU/L who received acetylcysteine developed hepatotoxicity.\n\n\nCONCLUSIONS\nRegardless of ingestion type, a product > 10 000 mg/L × IU/L was associated with a very high likelihood, and < 1 500 mg/L × IU/L with a very low likelihood, of developing hepatotoxicity in patients treated with acetylcysteine.",
"affiliations": "Emergency Physician and Clinical Toxicologist, Victorian Poisons Information Centre and Austin Toxicology Service, Austin Hospital , Victoria , Australia.",
"authors": "Wong|Anselm|A|;Sivilotti|Marco L A|ML|;Dargan|Paul I|PI|;Wood|David M|DM|;Greene|Shaun L|SL|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000931:Antidotes; D015415:Biomarkers; D000082:Acetaminophen; D000410:Alanine Transaminase; D000111:Acetylcysteine",
"country": "England",
"delete": false,
"doi": "10.3109/15563650.2015.1066507",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "53(8)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "Acetaminophen; Liver; Poisoning; Risk; Score",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000082:Acetaminophen; D000111:Acetylcysteine; D000328:Adult; D000410:Alanine Transaminase; D018712:Analgesics, Non-Narcotic; D000931:Antidotes; D015415:Biomarkers; D056486:Chemical and Drug Induced Liver Injury; D004796:Clinical Enzyme Tests; D016208:Databases, Factual; D003661:Decision Support Techniques; D062787:Drug Overdose; D005260:Female; D006784:Hospitals, Teaching; D006801:Humans; D016013:Likelihood Functions; D008297:Male; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D006113:United Kingdom",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "807-14",
"pmc": null,
"pmid": "26175095",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D023361:Validation Study",
"references": null,
"title": "External validation of the paracetamol-aminotransferase multiplication product to predict hepatotoxicity from paracetamol overdose.",
"title_normalized": "external validation of the paracetamol aminotransferase multiplication product to predict hepatotoxicity from paracetamol overdose"
} | [
{
"companynumb": "AU-JNJFOC-20150607908",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "We report a 55 year old woman with post-ET PV for 12 years, who experienced resolution of severe constitutional symptoms within 3 days, a marked reduction in splenomegaly and a rapid decline in the JAK2V617F allele burden during combination therapy with interferon-alpha2a and ruxolitinib. Within 4 weeks the patient achieved complete hematological remission with normalization of peripheral blood counts and within 10 months the JAK2V617F-allele burden was reduced from 90% to 28%. Such a rapid decline in the JAK2V617F allele burden is highly unusual in PV-patients during low-dose IFN-alpha2 monotherapy and this finding warrants a prospective study with combination therapy.",
"affiliations": "Department of Hematology, Roskilde University Hospital, Køgevej 7-13, 4000 Roskilde, Denmark.;Department of Pathology, Odense University Hospital, Sdr. Boulevard 29, 5000 Odense, Denmark.;Department of Hematology, Roskilde University Hospital, Køgevej 7-13, 4000 Roskilde, Denmark.;Department of Neurology, Roskilde University Hospital, Køgevej 7-13, 4000 Roskilde, Denmark.;Department of Hematology, Roskilde University Hospital, Køgevej 7-13, 4000 Roskilde, Denmark.",
"authors": "Bjørn|M E|ME|;de Stricker|K|K|;Kjær|L|L|;Ellemann|K|K|;Hasselbalch|H C|HC|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.lrr.2014.05.003",
"fulltext": "\n==== Front\nLeuk Res RepLeuk Res RepLeukemia Research Reports2213-0489Elsevier S2213-0489(14)00010-710.1016/j.lrr.2014.05.003Case ReportCombination therapy with interferon and JAK1-2 inhibitor is feasible: Proof of concept with rapid reduction in JAK2V617F-allele burden in polycythemia vera Bjørn M.E. meb@c.dka⁎de Stricker K. bKjær L. aEllemann K. cHasselbalch H.C. aa Department of Hematology, Roskilde University Hospital, Køgevej 7-13, 4000 Roskilde, Denmarkb Department of Pathology, Odense University Hospital, Sdr. Boulevard 29, 5000 Odense, Denmarkc Department of Neurology, Roskilde University Hospital, Køgevej 7-13, 4000 Roskilde, Denmark⁎ Correspondence to: Department of Hematology, Roskilde University Hospital, University of Copenhagen, Denmark. meb@c.dk1 8 2014 1 8 2014 2014 3 2 73 75 13 3 2014 13 5 2014 19 5 2014 © 2014 The Authors2014This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).We report a 55 year old woman with post-ET PV for 12 years, who experienced resolution of severe constitutional symptoms within 3 days, a marked reduction in splenomegaly and a rapid decline in the JAK2V617F allele burden during combination therapy with interferon-alpha2a and ruxolitinib. Within 4 weeks the patient achieved complete hematological remission with normalization of peripheral blood counts and within 10 months the JAK2V617F-allele burden was reduced from 90% to 28%. Such a rapid decline in the JAK2V617F allele burden is highly unusual in PV-patients during low-dose IFN-alpha2 monotherapy and this finding warrants a prospective study with combination therapy.\n\nHighlights\n• Combination therapy with low-dose Interferon (IFN) and ruxolitinib (rux) is feasible.\n\n• IFN and rux promptly alleviates symptoms and rapidly induces complete hematological remission.\n\n• IFN and rux reduces allelic burden more effectively than seen in conventional IFN or rux regimens.\n\n• The combinatorial approach was successful in a patient with prior side-effects to IFN.\n\n\n\nKeywords\nPolycythemia veraJAK2V617F-allele burdenCombination therapyInterferonRuxolitinib\n==== Body\n1 Case report\nA 55-year old woman with PV diagnosed in the precursor stage of ET 12 years ago was referred due to intolerance to hydroxyurea (HU) (fever and exanthema) and pegylated interferon-alpha2b (PEG-Intron) (exanthema). Since 2009 the patient had suffered two episodes of transitory cerebral ischemia (TCI). Accordingly, permanent treatment with clopidogrel had been instituted. Several CT-scans were normal. At the time of referral, the patient received treatment with anagrelide and clopidogrel. On admission, the patient׳s hemoglobin concentration was 11.9 g/dL, the leukocyte count was 21.9×109/L and the platelet count was elevated at 526×109/L. CRP and plasma lactate dehydrogenase (LDH) levels were normal. A bone marrow biopsy was compatible with a diagnosis of PV with grade 1 reticulin fibrosis. A peripheral blood-smear showed no leucoerythroblastosis. The patient still needed phlebotomies to keep the hematocrit below 0.42, a total of four being performed within the last six months prior to referral. An abdominal ultrasound revealed a spleen length of 20 cm giving rise to intermittent spleen pain and abdominal discomfort. Because of hypermetabolic symptoms, pronounced abdominal discomfort, and intolerance of PEG-Intron and HU, treatment with Rux was initiated at a dose of 20 mg twice daily and anagrelide was discontinued. Within the first 3 days of Rux therapy, the patient experienced remarkable clinical improvement with resolution of severe fatigue, night sweats, abdominal pain and pruritus, which had negatively influenced the patient׳s quality of life during the past 2–3 years. Four days after starting Rux, the patient acutely experienced TCI-like symptoms with transient decrease of strength in the left arm and abnormal sensations in the left half of the tongue and neck. The symptoms were very similar to those which the patient had experienced during previous attacks of TCIs. The blood values disclosed a slight decrease in the leukocyte count (17.6×109/L) but an increase in the platelet count (573×109/L). A CT-scan was normal. Because the platelets were elevated, Rux therapy was combined with PEG-IFN-alpha2a (Pegasys) at a low dose of 45 µg every second week. After 1 month a complete hematologic remission (CHR) was achieved (Fig. 1) and after 2.5 months an abdominal ultrasound revealed a reduction in spleen length from 20 cm to 13.8 cm. After 6 months the spleen was no longer palpable.\n\nThe combination therapy was exceedingly well tolerated without any side effects to either drug. Remarkably, despite an advanced PV-stage the JAK2V617F allele burden was rapidly lowered from 90% mutated alleles at referral to 59% at 6 months, 28% at 10 months and 12% at 16 months of therapy (Fig. 2).\n\nFurthermore, the patient had both her carotid arteries scanned by ultrasound because of the TCI-symptoms, and the physician (not knowing that the patient had started therapy) described an improvement of the blood-flow (initially turbulent flow, but approximately one year later the flow was more laminar).\n\n2 Discussion\nThis case report – being the first on combination therapy with IFN and a JAK1-2 inhibitor – has convincingly shown that this combinatorial approach is highly efficacious in a PV-patient with advanced disease and a large tumor burden, as evidenced by pronounced splenomegaly and a high JAK2V617F-allele burden. Most importantly, the treatment was associated with a rapid decline in the JAK2V617F-allele burden within a few months, which has been argued not to be possible due to inhibition of IFN-signaling during JAK-inhibitor treatment. Of note, serial ultrasound examinations of the carotid arteries showed an improvement of the blood-flow. Whether this improvement was attributed to normalization of the hematocrit, leukocyte and platelet-counts or might be due to the anti-inflammatory potential of Rux within the carotid artery wall diminishing inflammation (atherosclerosis being a chronic inflammatory disease) is elusive but certainly warrants further investigation.\n\nThe potent efficacy of this combination therapy in our patient may be explained by several mechanisms [1]. Firstly, using Rux with a half-life of approximately 3 h may leave a time-window of a several hours daily in which efficient IFN-signaling is possible. Also the possibility exists that – at a certain level of JAK-inhibition by Rux – the IFN-signaling is merely modulated rather than totally abolished. Secondly, the potent anti-inflammatory effect of JAK1-2 inhibition may have reduced or eliminated the (transient) systemic inflammation response, mediated by the release of inflammatory cytokines in the context of the IFN- mediated tumor killing. Thirdly, by reducing the release of TNF-alpha – a cytokine, which has been shown to facilitate clonal evolution – concomitant JAK1-2 inhibition with Rux might have improved the tumor-reducing effect of IFN. Fourthly, the possibility exists that IFN might actually have augmented the effects of JAK1-2 inhibition, as IFN blocks the intramedullary release of cytokines from bone marrow stroma. These cytokines have been shown to protect JAK2V617F-positive tumor cells from the JAK1-2 inhibitor-induced tumor killing [2]. Fifthly, most recently, chronic inflammation with oxidative stress and generation of reactive oxygen species (ROS) has been argued to be of major importance for clonal evolution and disease progression in MPNs [1–3]. Indeed, MPNs have been shown most recently to be associated with pronounced oxidative stress and ROS accumulation and most lately the JAK2V617F mutation per se has been demonstrated to generate ROS [4]. Since IFN-signaling is impaired by oxidative stress it is most intriguing to consider, if a combinatorial approach with a JAK1-2 inhibitor indeed might improve IFN-signaling – otherwise potentially impaired by oxidative stress mediated by the MPN-clone itself [2,4].\n\nAccordingly, considering all the above anti-inflammatory actions, a combinatorial approach with IFN and a JAK1-2 inhibitor may prove to be more efficacious than single-agent therapy [5]. Furthermore, IFN-a2 also activates dormant stem cells [6] and mobilizes them to be targets for potent JAK1-2 inhibition. Thus, by concurrently depleting dormant JAK2V617F MPN propagating stem cells with IFN-alpha [7] and targeting the proliferating downstream progeny with JAK1-2 inhibitors [6,8], a combination of IFN and a JAK1-2 inhibitor may be a highly efficacious treatment modality in MPNs with superior tumor control and less IFN side-effects [1,2].\n\nOur patient tolerated the combination therapy exceedingly well without side effects or myelosuppression, which otherwise might be a concern, taking into consideration that both JAK inhibition and IFN may be associated with myelosuppression. However, in the context of treating MPN patients with elevated cell counts (the pancytopenic myelofibrosis patient with severe myelofibrosis is not a candidate for IFN and accordingly neither for combination therapy) myelosuppression is not likely to occur provided that low-dose IFN (e.g., Pegasys 45 µg subcutaneously once weekly) and low-dose Rux (e.g., ruxolitinib 10 mg twice daily) are being used. Otherwise, combination therapy with IFN+Rux is not expected to be associated with any particular risk or side effects. In fact, the flue-like symptoms during the initial phase of IFN treatment, being likely associated with “a systemic inflammation response”, may actually vanish, when IFN-a2 is combined with a potent anti-inflammatory agent such as Rux.\n\nIn conclusion, describing a single case observation of a PV-patient we have for the first time delivered the “proof of concept” that combination therapy with Rux and “low-dose” IFN is safe, tolerable and highly efficacious in PV, as evidenced by a rapid reduction in the JAK2V617F-allele burden in concert with normalization of blood counts and resolution of pronounced splenomegaly and constitutional symptoms. This observation warrants prospective trials of this combinatorial approach in patients with PV and hyperproliferative MF to assess, if combination therapy induces a more rapid decline in the JAK2V617F-allele burden compared to monotherapy with either drug. In addition, studies are urgently needed to elucidate, if combination therapy – by alleviating potential side effects of IFN, which otherwise might disqualify for further IFN- treatment, might actually rescue IFN-intolerant or IFN-non-responsive patients, thereby improving their quality of life and likely maintaining the goal of achieving major molecular remission and hopefully “minimal residual disease” as well [1,2,9,10].\n\nAcknowledgments\nAll authors contributed to the writing and editing of the article. Hans Hasselbalch has received a research Grant from Novartis. Novartis had no knowledge regarding this case report and consequently had no influence on the manuscript.\n\nFig. 1 Hemoglobin, leukocyte and platelet levels during combination therapy with Ruxolitinib and Peg-IFN-alpha2a.\n\nFig. 2 JAK2 V617F allele burden over time.\n==== Refs\nReferences\n1 Hasselbalch H.C. Perspectives on the impact of JAK-inhibitor therapy upon inflammation-mediated comorbidities in myelofibrosis and related neoplasms Expert Rev Hematol 7 2014 203 216 24524202 \n2 Hasselbalch H.C. The role of cytokines in the initiation and progression of myelofibrosis Cytokine Growth Factor Rev 24 2013 133 145 23415024 \n3 Hasselbalch H.C. Chronic inflammation as a promotor of mutagenesis in essential thrombocythemia, polycythemia vera and myelofibrosis A human inflammation model for cancer development? 37 2013 214 220 Leuk Res 37 2013 214 220 \n4 Marty C. Lacout C. Droin N. Le Couédic J.-P. Ribrag V. Solary E. A role for reactive oxygen species in JAK2 V617F myeloproliferative neoplasm progression Leukemia 27 2013 2187 2195 23558526 \n5 Verstovsek S. Mesa R.A. Gotlib J. Levy R.S. Gupta V. DiPersio J.F. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis N Engl J Med 366 2012 799 807 22375971 \n6 Essers M.A.G. Offner S. Blanco-Bose W.E. Waibler Z. Kalinke U. Duchosal M.A. IFNalpha activates dormant haematopoietic stem cells in vivo Nature 458 2009 904 908 19212321 \n7 Kiladjian J.-J. Cassinat B. Chevret S. Turlure P. Cambier N. Roussel M. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera Blood 112 2008 3065 3072 18650451 \n8 Hasan S. Lacout C. Marty C. Cuingnet M. Solary E. Vainchenker W. JAK2V617F expression in mice amplifies early hematopoietic cells and gives them a competitive advantage that is hampered by IFNα Blood 122 2013 1464 1477 23863895 \n9 Silver R.T. Kiladjian J.-J. Hasselbalch H.C. Interferon and the treatment of polycythemia vera, essential thrombocythemia and myelofibrosis Expert Rev Hematol 6 2013 49 58 23373780 \n10 Larsen T.S. Moller M.B. de S.K. Norgaard P. Samuelsson J. Marcher C. Minimal residual disease and normalization of the bone marrow after long-term treatment with alpha-interferon2b in polycythemia vera. A report on molecular response patterns in seven patients in sustained complete hematological remission Hematology 14 2009 331 334 19941739\n\n",
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"keywords": "Combination therapy; Interferon; JAK2V617F-allele burden; Polycythemia vera; Ruxolitinib",
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"title": "Combination therapy with interferon and JAK1-2 inhibitor is feasible: Proof of concept with rapid reduction in JAK2V617F-allele burden in polycythemia vera.",
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"abstract": "A 76-year-old male presented with a recurrent depressive episode, an unsteady gait and cognitive impairment. Extensive blood tests, including hemogram, biochemical tests, folic acid, vitamin B12, and thyroid hormone, showed normal results. With the exception of the unsteady gait, neurological examination was negative. Brian magnetic resonance imaging (MRI) showed the typical feature of central pontine myelinolysis (CPM); however, there was no history of alcoholism, liver transplantation, malnutrition or rapid correction of hyponatremia. The patient had taken venlafaxine to treat major depressive disorder for more than 20 years. After discontinuation of venlafaxine, the unsteady gait gradually resolved, and subsequent MRI revealed reduction of the lesions over 6 months. We discuss herein the possible correlation between chronic use of venlafaxine and CPM.",
"affiliations": "Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.;Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.;Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.;Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.",
"authors": "Liu|Yu Chia|YC|https://orcid.org/0000-0002-0079-4715;Yang|Yen Kuang|YK|https://orcid.org/0000-0001-9355-9636;Chen|Po See|PS|https://orcid.org/0000-0003-4963-578X;Chang|Wei Hung|WH|https://orcid.org/0000-0002-5964-106X",
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"doi": "10.9758/cpn.2021.19.3.564",
"fulltext": "\n==== Front\nClin Psychopharmacol Neurosci\nClin Psychopharmacol Neurosci\nClinical Psychopharmacology and Neuroscience\n1738-1088\n2093-4327\nKorean College of Neuropsychopharmacology\n\n34294627\n10.9758/cpn.2021.19.3.564\ncpn-19-3-564\nCase Report\nCentral Pontine Myelinolysis in a Normonatremic Patient with Depression\nhttps://orcid.org/0000-0002-0079-4715\nLiu Yu Chia 12\nhttps://orcid.org/0000-0001-9355-9636\nYang Yen Kuang 134\nhttps://orcid.org/0000-0003-4963-578X\nChen Po See 135\nhttps://orcid.org/0000-0002-5964-106X\nChang Wei Hung 15\n1 Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan\n2 Department of Psychiatry, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan, Taiwan\n3 Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan\n4 Department of Psychiatry, Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan\n5 Department of Psychiatry, National Cheng Kung University Hospital, Dou-Liou Branch, Yunlin, Taiwan\nAddress for correspondence: Wei Hung Chang Department of Psychiatry, National Cheng Kung University Hospital, 138 Sheng Li Road, North Dist., Tainan 70403, Taiwan, E-mail: weihung2364009@gmail.com, ORCID: https://orcid.org/0000-0002-5964-106X\n31 8 2021\n31 8 2021\n31 8 2021\n19 3 564567\n25 10 2020\n7 12 2020\n15 12 2020\nCopyright© 2021, Korean College of Neuropsychopharmacology\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nA 76-year-old male presented with a recurrent depressive episode, an unsteady gait and cognitive impairment. Extensive blood tests, including hemogram, biochemical tests, folic acid, vitamin B12, and thyroid hormone, showed normal results. With the exception of the unsteady gait, neurological examination was negative. Brian magnetic resonance imaging (MRI) showed the typical feature of central pontine myelinolysis (CPM); however, there was no history of alcoholism, liver transplantation, malnutrition or rapid correction of hyponatremia. The patient had taken venlafaxine to treat major depressive disorder for more than 20 years. After discontinuation of venlafaxine, the unsteady gait gradually resolved, and subsequent MRI revealed reduction of the lesions over 6 months. We discuss herein the possible correlation between chronic use of venlafaxine and CPM.\n\nMyelinolysis, central pontine\nNormonatremia\nVenlafaxine hydrochloride\n==== Body\nINTRODUCTION\n\nCentral pontine myelinolysis (CPM) is a neurologic disorder characterized by symmetrical and non-inflammatory demyelination within the central basis pons. According to the study by Lampl and Yazdi [1], chronic alcoholism is the most common underlying disease correlated with CPM, the second and third most common being rapid correction of hyponatremia and liver trans-plantation. In addition, although relatively less common, CPM may occur in patients with burns, malnutrition, diabetes mellitus, brain tumor/cerebral edema, leukemia, chemotherapy, acquired immune deficiency syndrome, Wernicke’s encephalopathy, Wilson’s disease, adrenal insufficiency, renal disease, sepsis, sickle cell disease, and hyperemesis gravidarum [1,2]. The clinical manifestations of CPM include dysphagia, dysarthria, quadriparesis, movement disorders, seizures, lethargy, confusion, and coma [3]. However, few reports have described neuropsychiatric symptoms in CPM. In a review by Lampl and Yazdi [1], neuropsychiatric manifestations of CPM were reported to include cognitive dysfunction (deficits in attention, concentration, short-term memory, visual motor and fine motor speeds and learning ability), a pseudobulbar state with pathological laughing and crying, and even catatonia. The etiology and pathogenesis of CPM is still obscure. Herein, we describe a case of CPM without typical risk factors and symptoms.\n\nCASE\n\nThis study was approved by the ethics committee of National Cheng Kung University Hospital (No. A-EC-109- 019). A written informed consent was obtained from the patient for the publication of this case report. A 76-year- old male was evaluated in the geriatric ward due to syncope and depression with suicidal ideation. He had received a diagnosis of major depressive disorder from a psychiatrist when he divorced at 26 years of age, after which he suffered depressive episodes related to psychosocial stressors. Trials of fluoxetine, sertraline, mirtazapine, and trazodone were ineffective, but the patient’s depression diminished with the use of venlafaxine 150 mg, and he continued to use venlafaxine to control his depression for more than 20 years. Other notable medical history included hypertension, hyperlipidemia, coronary artery disease, and benign prostate hyperplasia. The patient took bisoprolol 5 mg, atorvastatin 20 mg, clopidogrel 75 mg, and silodosin 4 mg per day. His clinical history and laboratory findings excluded alcohol abuse, malnutrition, and electrolyte imbalance. The patient had three master’s degrees and had worked as a scientific editor for more than 10 years.\n\nSix months ago, the patient complained of frequent dizziness with near-syncope. Holter monitoring for 24 hours was performed to assess control of heart rate, and showed an average heart rate of 73 beats per minute (bpm), a maximum heart rate of 118 bpm, and a minimal heart rate of 50 bpm; no episodes of arrhythmia were detected. The tilt table test showed negative findings. At the same time, the patient reported recurrent depression, with depressed mood, loss of interest, fatigue, poor appetite, insomnia, poor attention, feeling of helplessness, and suicidal ideation after he deleted an important document on his computer. In addition, he misplaced his belongings frequently, and had difficulty in using the internet and smart phones prior to this depressive episode. He also complained of short-term memory impairment.\n\nDuring hospitalization, extensive blood tests were carried out, and the results were all within normal limits, including hemogram, renal function, liver function, electrolytes (sodium, potassium, calcium, magnesium), folic acid, vitamin B12, and thyroid hormone measurements. The cranial nerve and upper and lower limb function were normal on neurological examination, with the exception of the unsteady gait. Cranial magnetic resonance imaging (MRI) showed (i) nodules with hyperintensity on T2 fluid-attenuated inversion recovery and hypointensity on diffusion-weighted images in the bilateral basal ganglia, left thalamus, bilateral cerebellum, periventricular and subcortical white matter, which were suspected to be related to an old infarction; (ii) symmetric hyperintensity on T2 imaging in the pons, which is typical of CPM (Fig. 1A); and (iii) generalized cerebral atrophy. Carotid artery sonography revealed moderate to severe carotid atherosclerosis of the right internal carotid artery with significant hemodynamic change. Thus, stent placement and angioplasty were performed.\n\nAfter discharge, there was no obvious near-syncope episode, but the patient still had an unsteady gait, depressive symptoms, and poor cognitive function. Thus, psychological assessment was arranged for cognitive evaluation. The Wechsler adult intelligence scale (third edition) revealed the following: full-scale intelligence quotient (IQ): 127; verbal IQ: 139 (Verbal Comprehension Index: 148, Working Memory Index: 115), performance IQ: 107 (Perceptual Organization Index: 118, Processing Speed Index: 79). These results indicated that the patient’s processing speed was below average as compared with the other cognitive domains. The Wisconsin Card-Sorting Test showed that the patient’s ability to utilize environmental feedback to shift cognitive sets was below average (perseveration errors: 35, percentile score: 19 and number of categories completed: 1, percentile score: > 16). Because venlafaxine was ineffective for depression at this time, various other medications, including aripiprazole (5 mg per day for 2 weeks), mirtazapine (15 mg per day for 3 weeks), lithium (300 mg per day for 8 weeks), and lurasidone (40 mg per day for 8 weeks), were administered, but failed to have an effect. The patient subsequently began treatment with agomelatine and quetiapine, and partial improvement of depressive symptoms was noted. Six months later, the patient was able to walk slowly without assistance. Subsequent brain imaging and cognitive evaluation were performed six months later, and the second cranial MRI showed a reduction in the area of hyperintensity on T2 imaging in the pons (Fig. 1B). A cognitive abilities screening instrument revealed definite neurocognitive deficit (total score: 83, cut-off point: 87), especially in orientation and animal-name fluency. \n\nDISCUSSION\n\nIn our patient, a neurological symptom of CPM may have been an unsteady gait, as when the unsteady gait improved, a simultaneous reduction in the area of hyperintensity on T2 imaging in the pons was noted. Initial cognitive testing showed deficits in processing speed and executive function, but the tests were performed during a depressive episode, and so the results may have been influenced by depression [4]. Although signs of cognitive dysfunction were present prior to depression, there was no definite evidence to indicate that the cognitive dysfunction was associated with CPM.\n\nThe pathogenesis of CPM is not completely under-stood. Although CPM is usually associated with rapid correction of hyponatremia, it has also occurred in normonatremic [5,6] and even hypernatremic patients [7]. Thus, a rapid increase in sodium concentration is not likely to be the only cause of CPM. Shah et al. [8] suggested that CPM may develop in susceptible patients with hypertonic stress, which may result from the correction or development of an electrolyte imbalance or disturbance in tonicity. Susceptible patients are those who have alcoholism, liver disease/orthotopic liver transplantation, malnutrition, malignancy, pregnancy/postpartum state, severe illness/sepsis, adrenal insufficiency, and metabolic derangements (hypo-glycemia, hypokalemia, hypophosphatemia). In our patient, there were none of the potential risk factors mentioned above. In addition, after venlafaxine was discontinued, we prescribed various medications for different weeks, including aripiprazole, mirtazapine, lithium, and lurasidone, but there was no obvious effect. Finally, agomelatine and quetiapine were administered and the depressive symptoms were improved. About six months later, the patient’s gait became steady, and the area of hyperintensity on T2 imaging in the pons decreased. Thus, pharmacological factors should be considered as a possible etiology of CPM in our case and venlafaxine is the most likely factor according to the sequence of medi-cation. Most antidepressants have been noted to be associated with hyponatremia, especially selective serotonin reuptake inhibitors and venlafaxine, and the most likely mechanism of this adverse effect is the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) [9]. This means that antidepressants may change tonicity by regulating antidiuretic hormones. We searched published articles that reported antidepressant-related CPM without other risk factors, and found only two related reports. Twardowschy et al. [10] described a 53-year-old female with fluoxetine-induced hyponatremia after fluoxetine had been administered for 9 days. After hyponatremia correction, the patient exhibited cognitive deficits in language, memory, and psychomotor retardation. Finally, pontine and extrapontine osmotic myelinolysis were diag-nosed. In the report of Lupato et al. [11], a 69-year-old male was diagnosed with asymptomatic CPM, the possible etiology of which was chronic use of clomipramine (for about 10 years) and exposure to glue and chemical agents. The latter patient was relatively more similar to our case than the former, because we did not find any episode of hyponatremia or other known risk factors. Lupato et al. [11] also assumed that the pathogenesis of CPM could be a direct myelion-toxic mechanism or osmotic damage secondary to antidepressant-induced asymptomatic SIADH. Thus, we speculated that a similar osmotic injury that causes the myelinolytic process is associated with chronic use of specific antidepressants.\n\nIn conclusion, we described a case of CPM in which no hyponatremia was present. We hypothesized that patients who use antidepressants may be susceptible to disturbance in tonicity. This case also implied that when patients using antidepressants have new onset of neurological and psychiatric symptoms, we should consider the possibility of CPM, even if the sodium level is normal.\n\nFig. 1 Axial T2 fluid-attenuated inversion recovery image on magnetic resonance imaging scan. (A) Image showing a symmetrical area of hyperintensity in the basis points (arrow indicates site of lesion). (B) Image obtained 6 months later showing the decreased signal intensity of the lesion within the pons (arrowhead indicates site of lesion).\n\nConflicts of Interest\n\nNo potential conflict of interest relevant to this article was reported.\n\nAuthor Contributions\n\nConceptualization: Wei Hung Chang. Data acquisition: Yu Chia Liu. Formal analysis: Yu Chia Liu. Supervision: Po See Chen. Writing−original draft: Yu Chia Liu. Writing−review & editing: Yen Kuang Yang, Po See Chen, Wei Hung Chang.\n==== Refs\nReferences\n\n1 Lampl C Yazdi K 2002 Central pontine myelinolysis Eur Neurol 47 3 10 10.1159/000175124 11803185\n2 Ashrafian H Davey P 2001 A review of the causes of central pontine myelinosis: yet another apoptotic illness? Eur J Neurol 8 103 109 10.1046/j.1468-1331.2001.00176.x 11430268\n3 Martin RJ 2004 Central pontine and extrapontine myelinolysis: the osmotic demyelination syndromes J Neurol Neurosurg Psychiatry 75 Suppl 3 Suppl 3 iii22 iii28 10.1136/jnnp.2004.045906 15316041\n4 Liu J Dong Q Lu X Sun J Zhang L Wang M 2019 Exploration of major cognitive deficits in medication-free patients with major depressive disorder Front Psychiatry 10 836 10.3389/fpsyt.2019.00836 31798480\n5 Bose P Kunnacherry A Maliakal P 2011 Central pontine myelinolysis without hyponatraemia J R Coll Physicians Edinb 41 211 214 10.4997/JRCPE.2011.305 21949915\n6 Kilinç M Benli US Can U 2002 Osmotic myelinolysis in a normonatremic patient Acta Neurol Belg 102 87 89 12161906\n7 Han MJ Kim DH Kim YH Yang IM Park JH Hong MK 2015 A case of osmotic demyelination presenting with severe hyper-natremia Electrolyte Blood Press 13 30 36 10.5049/EBP.2015.13.1.30 26240598\n8 Shah MK Mandayam S Adrogué HJ 2018 Osmotic demyelination unrelated to hyponatremia Am J Kidney Dis 71 436 440 10.1053/j.ajkd.2017.10.010 29277507\n9 De Picker L Van Den Eede F Dumont G Moorkens G Sabbe BG 2014 Antidepressants and the risk of hyponatremia: a class-by- class review of literature Psychosomatics 55 536 547 10.1016/j.psym.2014.01.010 25262043\n10 Twardowschy CA Bertolucci CB Gracia Cde M 2007 Pontine and extrapontine osmotic myelinolysis after the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with fluoxetine: case report Arq Neuropsiquiatr 65 858 864 10.1590/s0004-282x2007000500027 17952298\n11 Lupato A Fazio P Fainardi E Cesnik E Casetta I Granieri E 2010 A case of asymptomatic pontine myelinolysis Neurol Sci 31 361 364 10.1007/s10072-009-0215-7 20148277\n\n",
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"pubdate": "2021-08-31",
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"abstract": "The management of cancer pain still poses a major challenge for clinicians. Tramadol is a centrally acting synthetic opioid analgesic. Its well-known side effects include nausea, vomiting, and dizziness; seizures are a rare side effect. Some reports have found that tramadol triggers seizure activity at high doses, whereas a few preclinical studies have found that this seizure activity is not dose-related. We herein present a case involving a patient with laryngeal cancer who developed seizures while on low-dose oral tramadol.",
"affiliations": "Department of Anesthesiology and Pain Medicine, Faculty of Medicine, Sakarya University, Sakarya, Turkey.;Department of Anesthesiology, Sakarya University Training and Research Hospital, Sakarya, Turkey.;Department of Anesthesiology, Sakarya University Training and Research Hospital, Sakarya, Turkey.;Department of Anesthesiology and Pain Medicine, Faculty of Medicine, Sakarya University, Sakarya, Turkey.",
"authors": "Beyaz|Serbülent Gökhan|SG|;Sonbahar|Tuğba|T|;Bayar|Fikret|F|;Erdem|Ali Fuat|AF|",
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"doi": "10.4103/0259-1162.177181",
"fulltext": "\n==== Front\nAnesth Essays ResAnesth Essays ResAERAnesthesia, Essays and Researches0259-11622229-7685Medknow Publications & Media Pvt Ltd India AER-10-37610.4103/0259-1162.177181Case ReportSeizures associated with low-dose tramadol for chronic pain treatment Beyaz Serbülent Gökhan Sonbahar Tuğba 1Bayar Fikret 1Erdem Ali Fuat Department of Anesthesiology and Pain Medicine, Faculty of Medicine, Sakarya University, Sakarya, Turkey1 Department of Anesthesiology, Sakarya University Training and Research Hospital, Sakarya, TurkeyCorresponding author: Dr. Serbülent Gökhan Beyaz, Department of Anesthesiology and Pain Medicine, Faculty of Medicine, Sakarya University, 54290 Adapazar, Sakarya, Turkey. E-mail: sgbeyaz@gmail.comMay-Aug 2016 10 2 376 378 Copyright: © Anesthesia: Essays and Researches2016This is an open access article distributed under the terms of the Creative Commons Attribution NonCommercial ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non commercially, as long as the author is credited and the new creations are licensed under the identical terms.The management of cancer pain still poses a major challenge for clinicians. Tramadol is a centrally acting synthetic opioid analgesic. Its well-known side effects include nausea, vomiting, and dizziness; seizures are a rare side effect. Some reports have found that tramadol triggers seizure activity at high doses, whereas a few preclinical studies have found that this seizure activity is not dose-related. We herein present a case involving a patient with laryngeal cancer who developed seizures while on low-dose oral tramadol.\n\nCancerlow dosepainseizurestramadol\n==== Body\nINTRODUCTION\nManagement of cancer pain is very important considering the rapidly increasing number of patients with cancer. The revised recommendations regarding analgesic treatment published by the World Health Organization must be followed to achieve successful pain management.\n\nTramadol hydrochloride is a synthetic, centrally acting, opiate-like analgesic that is used to treat acute and chronic pain. Tramadol and its active metabolite O-desmethyltramadol bind the µ-receptors of opioids, thus inhibiting gamma-amino butyric acid. Tramadol inhibits the re-uptake of monoamines such as noradrenaline and serotonin via two mechanisms.[1] However, its opioid component causes side effects including vomiting, nausea, constipation, and somnolence, whereas its monoaminergic effects include dizziness, sweating, and xerostomia.[2] Selective cyclooxygenase-2 inhibitors decrease the side effects of opioid analgesics, such as tramadol and transdermal fentanyl patches, which can be used to reduce pain for up to 72 h.[3]\n\nSeizures are a rare side effect of tramadol. Tramadol-related seizures are short, tonic-clonic seizures that, like other drug-related seizures, are self-limiting. This epileptogenic effect of tramadol occurs at both low and high doses.[4] We herein report the development of seizures after the use of low-dose tramadol in a patient with laryngeal cancer. We also present a short review of the relevant literature.\n\nCASE REPORT\nA 51-year-old man had been diagnosed with laryngeal cancer 1.5 years prior to presentation. He had undergone total laryngectomy and tracheostomy followed by 2 months of postoperative radiotherapy and chemotherapy. He presented to our pain clinic with severe head, neck, and shoulder pain that was unilateral, throbbing, cutting, and did not change with movement or rest.\n\nUsing a visual analog scale, the severity of his pain was assessed as 6/10. The patient regularly used paracetamol (Parol 500 mg tablet, Atabey Pharma, Turkey) at 2 g/day, piroxicam (Felden Flush 20 mg tablet, Cardinal Health, UK) at 20 mg/day, and ondansetron (Zofer 4 mg tablet, Adeka Pharma, Turkey) at 4 mg/day. He consumed a liquid diet. His Eastern Cooperative Oncology Group performance scale score was 3 (reduced ability to care for himself and bedridden >50% of the time). This disrupted the patient's sleep habits and affected his daily life.\n\nThe patient was treated with oral tramadol drops in divided doses equal to 75 mg per day. Two days later, he returned to the clinic. His wife reported that 10 min after taking the drug, he began shaking, lost consciousness for approximately 1 min, and was diaphoretic. The patient was hospitalized and monitored. Although the oral tramadol was stopped, he had two short generalized tonic-clonic seizures while hospitalized that day. Cranial computed tomography and electroencephalography findings were normal and neurological metastasis findings were not determined. No seizures occurred during his follow-up.\n\nDISCUSSION\nTramadol is a synthetic opioid consisting of (+) and (−) enantiomers that contribute to the analgesic activity via different mechanisms. The (+) enantiomer of tramadol is an opioid µ-receptor agonist that also stimulates serotonin release and inhibits its re-uptake, whereas the (−) enantiomer inhibits norepinephrine re-uptake.[5] After a single oral dose, tramadol is rapidly and almost completely absorbed, but its bioavailability is only 68% because of first-pass elimination in the liver. The bioavailability of tramadol reaches 90–100% after multiple oral doses after saturation of the first-pass effect of the liver.\n\nA preclinical study of rats found that tramadol is both a pro-convulsant and anti-convulsant.[6] Tramadol has anti-convulsant effects at normal analgesic doses, but when increased to medium–high doses, myoclonic activity and generalized convulsions occur due to the interaction of the two tramadol enantiomers.[6] Nevertheless, our patient had seizures while treated with the normal therapeutic dose (75 mg/day). The pro-convulsant effects of low-dose opioids are reportedly associated with opioid receptor affinity or variation in cerebral and intrinsic activity.[3578]\n\nThere are many reports of seizures following tramadol overdoses,[9] including seizures associated with intravenous tramadol as a premedication,[10] seizures in drug abusers, and seizures in association with tramadol intoxication.[11] In all of these cases, high blood tramadol concentrations likely induced the seizure activity. However, the relationship between the tramadol dose and seizure activity is controversial. One study reported that high doses of tramadol triggered the seizure activity, suggesting that seizure activity is dependent on the dose.[12] However, other studies reported that the seizure activity was not associated with the dose of tramadol.[47] We believe that tramadol can induce seizures at low doses, as in our case. We found no reports of seizure activity with low-dose oral tramadol used in the treatment of chronic pain in cancer therapy. However, we did find a report of a 5-month-old patient with a teratoma who developed a seizure when using patient-controlled analgesia with intravenous tramadol.[13]\n\nTramadol oral drops, capsules, and intravenous forms are frequently used to treat both cancer and noncancer pain. We believe that it is important to monitor them for seizure activity and other side effects of prolonged tramadol use, especially in the treatment of cancer pain.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest\n==== Refs\nREFERENCES\n1 Rehni AK Singh I Kumar M Tramadol-induced seizurogenic effect: A possible role of opioid-dependent γ-aminobutyric acid inhibitory pathway Basic Clin Pharmacol Toxicol 2008 103 262 6 18684224 \n2 Fujimoto Y Funao T Suehiro K Takahashi R Mori T Nishikawa K Brain serotonin content regulates the manifestation of tramadol-induced seizures in rats: Disparity between tramadol-induced seizure and serotonin syndrome Anesthesiology 2015 122 178 89 25208083 \n3 Ripamonti CI Santini D Maranzano E Berti M Roila F ESMO Guidelines Working Group. Management of cancer pain: ESMO Clinical Practice Guidelines Ann Oncol 2012 23 Suppl 7:vii 139 54 \n4 Talaie H Panahandeh R Fayaznouri M Asadi Z Abdollahi M Dose-independent occurrence of seizure with tramadol J Med Toxicol 2009 5 63 7 19415589 \n5 Barry JD Wills BK Neurotoxic emergencies Neurol Clin 2011 29 539 63 21803209 \n6 Potschka H Friderichs E Löscher W Anticonvulsant and proconvulsant effects of tramadol, its enantiomers and its M1 metabolite in the rat kindling model of epilepsy Br J Pharmacol 2000 131 203 12 10991912 \n7 Raffa RB Stone DJ Jr Unexceptional seizure potential of tramadol or its enantiomers or metabolites in mice J Pharmacol Exp Ther 2008 325 500 6 18292293 \n8 Gholami M Saboory E Roshan-Milani S Proconvulsant effects of tramadol and morphine on pentylenetetrazole-induced seizures in adult rats using different routes of administration Epilepsy Behav 2014 36 90 6 24892755 \n9 Reichert C Reichert P Monnet-Tschudi F Kupferschmidt H Ceschi A Rauber-Lüthy C Seizures after single-agent overdose with pharmaceutical drugs: Analysis of cases reported to a poison center Clin Toxicol (Phila) 2014 52 629 34 24844578 \n10 Raiger LK Naithani U Bhatia S Chauhan SS Seizures after intravenous tramadol given as premedication Indian J Anaesth 2012 56 55 7 22529421 \n11 Shadnia S Soltaninejad K Heydari K Sasanian G Abdollahi M Tramadol intoxication: A review of 114 cases Hum Exp Toxicol 2008 27 201 5 18650251 \n12 Taghaddosinejad F Mehrpour O Afshari R Seghatoleslami A Abdollahi M Dart RC Factors related to seizure in tramadol poisoning and its blood concentration J Med Toxicol 2011 7 183 8 21735309 \n13 Li X Zuo Y Dai Y Children's seizures caused by continuous intravenous infusion of tramadol analgesia: Two rare case reports Paediatr Anaesth 2012 22 308 9 22272680\n\n",
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"issue": "10(2)",
"journal": "Anesthesia, essays and researches",
"keywords": "Cancer; low dose; pain; seizures; tramadol",
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"title": "Seizures associated with low-dose tramadol for chronic pain treatment.",
"title_normalized": "seizures associated with low dose tramadol for chronic pain treatment"
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"abstract": "BACKGROUND\nRomosozumab is a bone-forming antibody that increases bone formation and decreases bone resorption. We conducted a double-blinded, randomized, phase-2, dose-finding trial to evaluate the effect of romosozumab on the clinical outcomes of open reduction and internal fixation of intertrochanteric or femoral neck hip fractures.\n\n\nMETHODS\nPatients (55 to 94 years old) were randomized 2:3:3:3 to receive 3 subcutaneous injections of romosozumab (70, 140, or 210 mg) or a placebo postoperatively on day 1 and weeks 2, 6, and 12. The primary end point was the difference in the mean timed \"Up & Go\" (TUG) score over weeks 6 to 20 for romosozumab versus placebo. Additional end points included the time to radiographic evidence of healing and the score on the Radiographic Union Scale for Hip (RUSH).\n\n\nRESULTS\nA total of 332 patients were randomized: 243 to receive romosozumab (70 mg, n = 60; 140 mg, n = 93; and 210 mg, n = 90) and 89 to receive a placebo. Although TUG scores improved during the study, they did not differ significantly between the romosozumab and placebo groups over weeks 6 to 20 (p = 0.198). The median time to radiographic evidence of healing was 16.4 to 16.9 weeks across treatment groups. The RUSH scores improved over time across treatment groups but did not differ significantly between the romosozumab and placebo groups. The overall safety and tolerability profile of romosozumab was comparable with that of the placebo.\n\n\nCONCLUSIONS\nRomosozumab did not improve the fracture-healing-related clinical and radiographic outcomes in the study population.\n\n\nMETHODS\nTherapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.",
"affiliations": "Department of Surgery, University of Western Ontario, London, Ontario, Canada.;Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, California.;Orthopaedic Department UGHL, School of Health Sciences, University of Thessalia, Larissa, Greece.;Department of Surgery, University of Western Ontario, London, Ontario, Canada.;Sancheti Institute of Orthopaedics and Rehabilitation, Pune, India.;Joint Research, OLVG, Amsterdam, the Netherlands.;Sanofi Genzyme, Bridgewater, New Jersey.;Amgen, Inc., Thousand Oaks, California.;Amgen, Inc., Thousand Oaks, California.;Amgen, Inc., Thousand Oaks, California.;Amgen, Inc., Thousand Oaks, California.;Amgen, Inc., Thousand Oaks, California.;Amgen, Inc., Thousand Oaks, California.;McMaster University, Hamilton, Ontario, Canada.",
"authors": "Schemitsch|Emil H|EH|0000-0002-6435-9069;Miclau|Theodore|T|0000-0003-1975-2061;Karachalios|Theofilos|T|0000-0002-9043-0535;Nowak|Lauren L|LL|0000-0002-4388-3128;Sancheti|Parag|P|0000-0002-8903-1430;Poolman|Rudolf W|RW|0000-0003-3178-2247;Caminis|John|J|0000-0002-8734-7327;Daizadeh|Nadia|N|0000-0002-4136-4068;Dent-Acosta|Ricardo E|RE|0000-0003-3436-0031;Egbuna|Ogo|O|0000-0003-0548-3809;Chines|Arkadi|A|0000-0003-3682-6798;Maddox|Judy|J|0000-0001-7214-0545;Grauer|Andreas|A|0000-0001-5098-8262;Bhandari|Mohit|M|0000-0003-3556-9179",
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"fulltext": "\n==== Front\nJ Bone Joint Surg Am\nJ Bone Joint Surg Am\njbjsam\nThe Journal of Bone and Joint Surgery. American Volume\n0021-9355 1535-1386 Journal of Bone and Joint Surgery, Inc. \n\n31977817\nJBJS-D-19-00790\n10.2106/JBJS.19.00790\n00009\n0170\nScientific Articles\nA Randomized, Placebo-Controlled Study of Romosozumab for the Treatment of Hip Fractures\nSchemitsch Emil H. MD, FRCS(C)1a Miclau Theodore MD23 Karachalios Theofilos MD4 Nowak Lauren L. MSc1 Sancheti Parag FRCS(Ed), MS(Orth), DNB(Orth), MCh(UK), PhD5 Poolman Rudolf W. MD, PhD6 Caminis John MD7 Daizadeh Nadia PhD8 Dent-Acosta Ricardo E. MD8 Egbuna Ogo MD, MSc8 Chines Arkadi MD8 Maddox Judy DO8 Grauer Andreas MD8 Bhandari Mohit MD, PhD9 1 Department of Surgery, University of Western Ontario, London, Ontario, Canada\n2 Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, California\n3 Orthopaedic Trauma Institute, Zuckerberg San Francisco General Hospital, San Francisco, California\n4 Orthopaedic Department UGHL, School of Health Sciences, University of Thessalia, Larissa, Greece\n5 Sancheti Institute of Orthopaedics and Rehabilitation, Pune, India\n6 Joint Research, OLVG, Amsterdam, the Netherlands\n7 Sanofi Genzyme, Bridgewater, New Jersey\n8 Amgen, Inc., Thousand Oaks, California\n9 McMaster University, Hamilton, Ontario, Canada\na Email address for E.H. Schemitsch: emil.schemitsch@lhsc.on.ca\n15 4 2020 \n22 1 2020 \n22 1 2020 \n102 8 693 702\nCopyright © 2020 The Authors. Published by The Journal of Bone and Joint Surgery, Incorporated. All rights reserved.2020This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.Background:\nRomosozumab is a bone-forming antibody that increases bone formation and decreases bone resorption. We conducted a double-blinded, randomized, phase-2, dose-finding trial to evaluate the effect of romosozumab on the clinical outcomes of open reduction and internal fixation of intertrochanteric or femoral neck hip fractures.\n\nMethods:\nPatients (55 to 94 years old) were randomized 2:3:3:3 to receive 3 subcutaneous injections of romosozumab (70, 140, or 210 mg) or a placebo postoperatively on day 1 and weeks 2, 6, and 12. The primary end point was the difference in the mean timed “Up & Go” (TUG) score over weeks 6 to 20 for romosozumab versus placebo. Additional end points included the time to radiographic evidence of healing and the score on the Radiographic Union Scale for Hip (RUSH).\n\nResults:\nA total of 332 patients were randomized: 243 to receive romosozumab (70 mg, n = 60; 140 mg, n = 93; and 210 mg, n = 90) and 89 to receive a placebo. Although TUG scores improved during the study, they did not differ significantly between the romosozumab and placebo groups over weeks 6 to 20 (p = 0.198). The median time to radiographic evidence of healing was 16.4 to 16.9 weeks across treatment groups. The RUSH scores improved over time across treatment groups but did not differ significantly between the romosozumab and placebo groups. The overall safety and tolerability profile of romosozumab was comparable with that of the placebo.\n\nConclusions:\nRomosozumab did not improve the fracture-healing-related clinical and radiographic outcomes in the study population.\n\nLevel of Evidence:\nTherapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.\n\nOPEN-ACCESSTRUE\n==== Body\nHip fractures are a devastating clinical manifestation of osteoporosis. The almost 2 million hip fractures that occur each year in people older than 50 years are associated with substantial morbidity, excess mortality, and high health-care costs1-4. Almost all hip fractures are treated surgically. In the elderly, compromised mechanical and biological capacity, comorbidities, and possible complications make the management of hip fractures challenging, and the acceleration of fracture-healing is the desirable therapeutic outcome5. The systemic bone-forming agent teriparatide was investigated to assess its ability to accelerate fracture-healing, and while the results of a retrospective analysis were promising6, randomized controlled studies yielded inconclusive results7-9.\n\nRomosozumab is a bone-forming antibody that increases bone formation and decreases bone resorption and is indicated to treat osteoporosis in postmenopausal women at high risk for fracture10. Romosozumab increased bone mineral density (BMD)11; reduced the prevalence of vertebral and clinical (a composite of nonvertebral and symptomatic vertebral) fractures (compared with a placebo)12; and, when followed by alendronate, reduced the risk of vertebral, nonvertebral, and hip fractures (compared with alendronate alone)13.\n\nPreclinical studies showed that romosozumab enhances fracture-healing. Romosozumab significantly increased bone mass and strength at the fracture site in a closed femoral fracture model in rats by week 7 and in a fibular osteotomy model in cynomolgus monkeys by week 1014, promoted fracture-healing and increased bone strength in a mouse femoral osteotomy model by week 615, and increased the area of newly formed bone in a rat femoral osteotomy model by week 616.\n\nOn the basis of these preclinical data, we hypothesized that romosozumab would accelerate healing of hip fractures and improve physical functioning of human subjects. We conducted a phase-2, dose-finding trial to evaluate the effect of romosozumab administered over 12 weeks on the clinical outcomes of open reduction and internal fixation of intertrochanteric or femoral neck hip fractures.\n\nMaterials and Methods\nStudy Design\nThis phase-2, multicenter, international, randomized, double-blinded, placebo-controlled study enrolled patients with an acute, unilateral, low-energy hip fracture (sustained from a standing height or less) and treated with open reduction and internal fixation. The study was registered in ClinicalTrials.gov (NCT01081678). Dosing regimens were based on phase-1 single and multiple-dose studies that demonstrated a pharmacologic effect of romosozumab on bone formation markers17,18. An interactive voice response system was used to randomize patients 2:3:3:3 to receive 70, 140, or 210 mg of romosozumab or a placebo (Fig. 1); randomization was stratified into 7 strata by the type of fracture and fixation device and age. All participants and study personnel were blinded to the type of treatment.\n\nFig. 1 Study schema. Randomization was stratified into 7 strata: (1) intertrochanteric fracture, sliding hip screw, 55 to 75 years old; (2) intertrochanteric fracture, sliding hip screw, ≥76 years old; (3) intertrochanteric fracture, intramedullary nail, 55 to 75 years old; (4) intertrochanteric fracture, intramedullary nail, ≥76 years old; (5) displaced femoral neck fracture, sliding hip screw; (6) displaced femoral neck fracture, cancellous screws; and (7) undisplaced femoral neck fracture. Within each stratum, patients were randomized using an allocation ratio of 2:3:3:3 to receive subcutaneous injections of romosozumab (70, 140, or 210 mg) or a placebo. The placebo group received 3 vials of placebo solution; the 70-mg group, 1 vial containing 70 mg of romosozumab and 2 vials of matched placebo solution; the 140-mg group, 2 vials each containing 70 mg of romosozumab and 1 vial of matched placebo solution; and the 210-group, 3 vials each containing 70 mg of romosozumab. Black arrows indicate study visits with administration of the investigational product, gray arrows indicate study visits without administration of the investigational product, and brown arrows indicate telephone visits. D = day, SC = subcutaneous, W = week.\n\nPatients received 3 subcutaneous injections of romosozumab or a placebo postoperatively on day 1 and at weeks 2, 6, and 12. All patients took 50,000 IU of vitamin D once postoperatively and ≥1,000 mg of calcium and ≥800 IU of vitamin D daily from the time of screening to week 36. The timing of study visits is shown in Figure 1.\n\nThe primary end point was the timed “Up & Go” (TUG) score over weeks 6 to 20. Additional end points included the time to radiographic evidence of healing (defined as effacement of the fracture lines by newly formed bone along the cortices and within the trabecular bone on anteroposterior and lateral [or oblique] radiographs), the Radiographic Union Scale for Hip (RUSH) score, the Harris hip score (HHS), and hip pain on a visual analog scale (VAS).\n\nThe study was performed in accordance with the World Medical Association Declaration of Helsinki. The protocol was approved by the independent ethics committee or institutional review board at each site. All participants provided written informed consent.\n\nParticipants\nEligible patients were 55 to 95 years old and had a radiographically confirmed primary, acute, unilateral, low-energy intertrochanteric or femoral neck fracture amenable to repair by internal fixation. Exclusion criteria included severe lower-extremity osteoarthritis, a preinjury inability to rise independently from an armchair or walk 200 m, use of bone grafts or substitutes at the time of fracture fixation, major polytrauma or substantial axial trauma, and a pathological fracture or history of metabolic or bone disease (except osteoporosis). All eligibility criteria are listed in the Appendix.\n\nStudy Procedures\nAnteroposterior and lateral (or oblique) radiographs of the proximal part of the femur were obtained at every clinic visit starting from week 2. The quality of surgical fixation and radiographic evidence of fracture-healing were determined by independent reviewers (orthopaedic/trauma surgeons and radiologists), blinded to treatment. Radiographic evaluation ended once healing was confirmed, except for mandatory radiographs at weeks 52 (end of study) and 104 (long-term follow-up).\n\nThe TUG test is a validated and reliable tool used to assess functional mobility of persons with impaired mobility19-22. Since TUG correlates well with activities of daily living, it was used to assess functional recovery in our study. Clinicians timed the patient while they stood up from a seated position in a chair, walked 3 m, turned around, walked back to the chair, and returned to the seated position. Study staff were trained on how to administer the TUG test via a training video.\n\nThe RUSH score is a validated and reliable tool developed to objectively assess hip (femoral neck) fracture-healing after surgical repair23-26. RUSH quantifies 10 measures of fracture-healing: cortical bridging and disappearance of the cortical fracture line in the anterior, posterior, medial, and lateral femoral neck regions and trabecular consolidation and disappearance of the trabecular fracture line (trabecular healing is indicated by consolidation of the matrix and disappearance of the fracture line). Each of the 10 healing measures are scored as 1, 2, or 3; a minimum total score of 10 indicates no healing, and a maximum total score of 30 indicates complete healing.\n\nAdverse events were recorded at each study visit and coded using MedDRA (Medical Dictionary for Regulatory Activities), version 15.1. To determine the immunogenicity of romosozumab and its relationship to safety, blood samples taken on day 1 and weeks 6, 12, 20, 24, 36, and 52 were assessed for the presence of anti-romosozumab binding and neutralizing antibodies.\n\nStatistical Analyses\nThe sample size calculation assumed that romosozumab would reduce the mean TUG scores over weeks 6 to 20 by 25% compared with the score associated with a placebo, which was approximately 36 seconds according to Ingemarsson et al.27. Allowing for a 20% withdrawal rate by week 24 and a type-I error of 5%, the calculation showed that approximately 90 patients per group (and 60 for the 70-mg group) would provide ≥80% power to detect differences between romosozumab and placebo with the use of a 2-sided t test.\n\nA linear mixed-effects model was fit with log-transformed TUG scores as the dependent variable and treatment group, sex, prefracture community dwelling status, prefracture use of a walking aid, geographic region, quality of surgical fixation, visit week, and visit-by-treatment interaction as independent variables, stratified by the randomization strata.\n\nThe difference in the least-squares-mean (LSM) TUG scores over weeks 6 to 20 between the romosozumab and placebo groups was determined. Measurements obtained after unplanned revision surgery (indicative of poor healing) were assigned the visit-dependent worst value, which was imputed if a patient could not perform or complete the TUG test. Results based on log-transformed data were back-transformed to seconds.\n\nFor time to radiographic evidence of healing, a proportional-hazards model was fitted, adjusted for sex, prefracture community dwelling status, prefracture use of a walking aid, and quality of surgical fixation as independent covariates, stratified by the randomization strata. Patients were censored for unplanned revision surgery before radiographic evidence of healing. The estimate of the treatment effect was the hazard ratio (with 95% confidence interval [CI]) of romosozumab versus placebo with respect to time to revision-surgery-free healing28,29. The cumulative incidence function was determined for each treatment group.\n\nTreatment differences in the total RUSH score were assessed using the van Elteren stratified rank test (adjusting for randomization strata) at each time point30. Missing scores were imputed using the last-observation-carried-forward approach.\n\nThe final analysis was conducted after completion of the week-52 assessments. Analyses of efficacy and safety were performed after unblinding and included all randomized patients who had received ≥1 dose of the investigational product.\n\nResults\nPatient Disposition and Baseline Characteristics\nA total of 332 patients were randomized at 63 sites in 22 countries (see Appendix Table) between June 2010 and January 2013: 243 were randomized to receive romosozumab (70 mg, n = 60; 140 mg, n = 93; 210 mg, n = 90) and 89, to receive a placebo. Overall, 325 patients received ≥1 dose of the investigational product, and 263 (79.2%) and 229 (69.0%) completed 24 and 52 weeks of the study, respectively. Discontinuation rates and reasons for discontinuation were comparable among the treatment groups (Fig. 2).\n\nFig. 2 Flow of patients through the study. SC = subcutaneous.\n\nBaseline demographics and disease characteristics were generally balanced across the treatment groups; however, there was a higher percentage of women in the placebo group (75.3%) than in the total romosozumab group (66.3%) and a higher percentage of Asian patients in the 210-mg romosozumab group (21.1%) than in the other groups (11.7% to 13.5%) (Table I). Across the treatment groups, approximately 80% of the patients were classified as either healthy or having mild, systematic disease according to the American Society of Anesthesiologists (ASA) classification; 61.8% to 72.0% of the patients had an intertrochanteric hip fracture, 16.1% to 23.6% had an intertrochanteric hip fracture with extension into the subtrochanteric region, and 10.0% to 14.6% had a femoral neck fracture. Most patients were injured falling from a standing height or less. Most internal fixation implants were intramedullary nails (range across groups, 54.4% to 55.9%).\n\nTABLE I Baseline Demographics and Disease Characteristics\n\n\tPlacebo (N = 89)\tSubcutaneous Romosozumab\t\n70 mg (N = 60)\t140 mg (N = 93)\t210 mg (N = 90)\tTotal Romosozumab Group (N = 243)\t\nSex (no. [%])\t\t\t\t\t\t\n Female\t67 (75.3)\t42 (70.0)\t64 (68.8)\t55 (61.1)\t161 (66.3)\t\n Male\t22 (24.7)\t18 (30.0)\t29 (31.2)\t35 (38.9)\t82 (33.7)\t\nMedian age (range) (yr)\t78 (55-91)\t78.5 (55-94)\t79 (55-94)\t79 (55-93)\t79 (55-94)\t\nGeriatric age group (no. [%])\t\t\t\t\t\t\n ≥65 yr\t79 (88.8)\t52 (86.7)\t76 (81.7)\t79 (87.8)\t207 (85.2)\t\n ≥75 yr\t54 (60.7)\t37 (61.7)\t56 (60.2)\t56 (62.2)\t149 (61.3)\t\nRace (no. [%])\t\t\t\t\t\t\n White\t77 (86.5)\t52 (86.7)\t81 (87.1)\t70 (77.8)\t203 (83.5)\t\n Asian\t12 (13.5)\t7 (11.7)\t11 (11.8)\t19 (21.1)\t37 (15.2)\t\n Black\t0 (0.0)\t0 (0.0)\t0 (0.0)\t1 (1.1)\t1 (0.4)\t\n Hispanic\t0 (0.0)\t1 (1.7)\t1 (1.1)\t0 (0.0)\t2 (0.8)\t\nGeographic region (no. [%])\t\t\t\t\t\t\n Eastern Europe\t27 (30.3)\t22 (36.7)\t41 (44.1)\t25 (27.8)\t88 (36.2)\t\n Western Europe\t30 (33.7)\t15 (25.0)\t29 (31.2)\t27 (30.0)\t71 (29.2)\t\n India\t10 (11.2)\t7 (11.7)\t10 (10.8)\t18 (20.0)\t35 (14.4)\t\n North America\t14 (15.7)\t11 (18.3)\t4 (4.3)\t8 (8.9)\t23 (9.5)\t\n Latin America\t5 (5.6)\t4 (6.7)\t6 (6.5)\t9 (10.0)\t19 (7.8)\t\n Australia and New Zealand\t1 (1.1)\t1 (1.7)\t2 (2.2)\t2 (2.2)\t5 (2.1)\t\n Other\t2 (2.2)\t0 (0.0)\t1 (1.1)\t1 (1.1)\t2 (0.8)\t\nASA classification*\n(no. [%])\t\t\t\t\t\t\n Class I\t24 (27.0)\t19 (31.7)\t32 (34.4)\t32 (35.6)\t83 (34.2)\t\n Class II\t49 (55.1)\t30 (50.0)\t43 (46.2)\t43 (47.8)\t116 (47.7)\t\n Class III\t16 (18.0)\t9 (15.0)\t17 (18.3)\t14 (15.6)\t40 (16.5)\t\n Class IV\t0 (0.0)\t2 (3.3)\t1 (1.1)\t1 (1.1)\t4 (1.6)\t\nMean body mass index (SD)†\n(kg/m2)\t\t\t\t\t\t\n Women\t25.0 (4.5)\t24.4 (3.5)\t23.6 (4.0)\t23.7 (3.4)\t23.9 (3.6)\t\n Men\t24.7 (4.7)\t24.4 (2.9)\t25.2 (4.6)\t24.1 (4.2)\t24.5 (4.1)\t\nLocation of hip fracture (no. [%])\t\t\t\t\t\t\n Intertrochanteric\t55 (61.8)\t41 (68.3)\t67 (72.0)\t62 (68.9)\t170 (70.0)\t\n Intertrochanteric extending into subtrochanteric region\t21 (23.6)\t11 (18.3)\t15 (16.1)\t19 (21.1)\t45 (18.5)\t\n Femoral neck\t13 (14.6)\t8 (13.3)\t11 (11.8)\t9 (10.0)\t28 (11.5)\t\nMechanism of injury (no. [%])\t\t\t\t\t\t\n Fall from standing height or less\t76 (85.4)\t54 (90.0)\t82 (88.2)\t79 (87.8)\t215 (88.5)\t\n Fall on stairs, steps, or curb\t8 (9.0)\t2 (3.3)\t9 (9.7)\t3 (3.3)\t14 (5.8)\t\n Fall from ∼20 in (51 cm)\t3 (3.4)\t2 (3.3)\t2 (2.2)\t2 (2.2)\t6 (2.5)\t\n Fall from higher than ∼20 in (51 cm)\t2 (2.2)\t2 (3.3)\t0 (0.0)\t4 (4.4)\t6 (2.5)\t\n Spontaneous (stress) fracture\t0 (0.0)\t0 (0.0)\t0 (0.0)\t2 (2.2)\t2 (0.8)\t\nMethod of internal fixation (no. [%])\t\t\t\t\t\t\n Intramedullary nail\t49 (55.1)\t33 (55.0)\t52 (55.9)\t49 (54.4)\t134 (55.1)\t\n Sliding hip screw\t31 (34.8)\t22 (36.7)\t32 (34.4)\t35 (38.9)\t89 (36.6)\t\n Cancellous screws\t9 (10.1)\t5 (8.3)\t9 (9.7)\t6 (6.7)\t20 (8.2)\t\n* Class I = healthy patient with no medical problems, Class II = mild systemic disease, Class III = severe systemic disease but not incapacitating, and Class IV = severe systemic disease that is a constant threat to life.\n\n† SD = standard deviation.\n\nEfficacy\nTUG Scores by Visit\nThe LSM TUG scores improved from weeks 2 to 52 for each treatment group (Fig. 3). From weeks 2 to 20, the LSM TUG scores for the placebo and 70-mg, 140-mg, and 210-mg romosozumab groups improved from 82 to 24, 71 to 22, 77 to 23, and 86 to 29 seconds, respectively; the scores leveled off after week 20. There were no significant differences in the LSM TUG scores over weeks 6 to 20 between the romosozumab and placebo groups (primary end point, p = 0.198). At week 52, the LSM (and 95% CI) TUG score ratios (romosozumab:placebo) were 0.9 (0.7 to 1.2), 1.0 (0.8 to 1.3), and 1.3 (1.0 to 1.6) for the 70, 140, and 210-mg groups, respectively.\n\nFig. 3 TUG scores by visit. Estimates are based on a linear mixed-effects model for repeated measures, adjusting for treatment, sex, prefracture community-dwelling status, prefracture walking aid use, geographic region (group 1: Greece, India, Italy, and Lithuania; group 2: Switzerland, Denmark, Estonia, Finland, Latvia, the Netherlands, Hungary, and New Zealand; group 3: Argentina, Australia, Belgium, Bulgaria, Canada, Germany, U.K., Hong Kong, Poland, and U.S.), quality of surgical fixation, visit, treatment-by-visit interaction, and randomization strata. Log-transformed scores were back-transformed to seconds using the exponential transformation. The results are presented as LSMs with 95% CIs. The p value is based on an F test of multilinear contrasts at weeks 6 to 20.\n\nTime to Radiographic Evidence of Healing\nThe cumulative incidence function estimate of patients who had radiographic evidence of healing at weeks 24 and 52 was similar across treatment groups (range, 66.2% to 78.6% at week 24 and 89.1% to 93.2% at week 52; Table II). There were no apparent dose or treatment-group-related trends in the median time to radiographic evidence of healing (range, 16.4 to 16.9 weeks across groups) and no significant differences between the romosozumab and placebo groups (Table II). Nonunion was reported in 2 patients in the placebo group at week 52.\n\nTABLE II Radiographic Evidence of Healing*\n\n\tPlacebo (N = 87)\tSubcutaneous Romosozumab\t\n70 mg (N = 60)\t140 mg (N = 89)\t210 mg (N = 89)\t\nPatients with radiographic healing at wk 24\t\t\t\t\t\n CIF estimate (95% CI) (%)\t73.2 (62.6-82.8)\t78.6 (66.7-88.5)\t72.8 (62.3-82.3)\t66.2 (55.1-77.1)\t\nPatients with radiographic healing at wk 52\t\t\t\t\t\n CIF estimate (95% CI) (%)\t93.2 (85.1-97.8)\t90.1 (79.5-96.6)\t93.1 (85.6-97.4)\t89.1 (79.9-95.3)\t\nMedian time to radiographic evidence of healing†\t\t\t\t\t\n CIF estimate (95% CI) (wk)\t16.4 (15.3-20.1)\t16.9 (12.9-20.3)\t16.6 (13.3-17.1)\t16.9 (13.3-20.9)\t\n HR‡ (95% CI), p value\t\t1.1 (0.7-1.6), p = 0.79\t1.1 (0.8-1.6), p = 0.62\t1.1 (0.7-1.6), p = 0.76\t\n* N = number of randomized patients who received ≥1 dose of investigational product. Data are presented as point estimates. CIF = cumulative incidence function, CI = confidence interval, and HR = hazard ratio.\n\n† From fracture fixation date.\n\n‡ HR is based on a Cox proportional-hazards model with treatment groups as the independent variable, stratified by randomization strata, and adjusted for sex, prefracture community dwelling status, use of prefracture walking aid, and quality of surgical fixation. An HR of >1 favors romosozumab.\n\nWhen evaluated by subgroup (age, sex, fracture type, and fixation type), the results were consistent with the overall study population (data not shown).\n\nRUSH Scores by Visit\nThe RUSH scores improved over time across all treatment groups, plateauing between weeks 36 and 52 (Fig. 4). There were no significant differences in the RUSH scores between the romosozumab and placebo groups at any time. The mean total RUSH scores across treatment groups ranged from 28.2 to 29.1 at week 36 and from 28.5 to 29.6 at week 52.\n\nFig. 4 RUSH scores by visit. N = number of randomized patients who received ≥1 dose of investigational product. The results are presented as the mean and standard deviation (SD). The dashed line represents the maximum total RUSH score (30 points).\n\nHHS\nThe HHS improved over time for all of the romosozumab groups and the placebo group. The values were similar between the placebo group and all of the romosuzumab groups up to week 24. For weeks 36 and 52, the repeated-measures model indicated a significant difference for the 140-mg romosozumab group, favoring romosozumab compared with placebo. At week 36, the LSM (and 95% CI) was 86.8 (83.5 to 90.2) in the 140-mg romosozomab group and 80.3 (77.0 to 83.6) in the placebo group (p = 0.0062). At week 52, the LSM (and 95% CI) was 89.0 (85.9 to 92.1) in the 140-mg romosozomab group and 84.3 (81.3 to 87.4) in the placebo group (p = 0.0365). However, this was likely a chance finding, as the p values were not corrected for multiplicity and the 210-mg group did not show a significant difference.\n\nVAS Hip Pain\nThe difference in the LSM VAS hip pain between the placebo group and individual romosozumab groups was not significant at any time point.\n\nSafety\nA total of 325 patients (87 in the placebo group and 238 in the total romosozumab group) received ≥1 dose of the investigational product over the 12-week dosing period and were included in the 52-week safety analysis. Sixty-nine patients (79.3%) in the placebo group and 157 (66.0%) in the total romosozumab group reported ≥1 adverse event that emerged during treatment (Table III). No trends were apparent in the pattern or types of adverse events across treatment groups; however, a higher percentage of patients in the romosozumab group than in the placebo group reported back pain (6.7% versus 0%) and arthralgia (5.9% versus 2.3%), and a lower percentage reported constipation (8.8% versus 12.6%), diarrhea (3.8% versus 9.2%), and pain in an extremity (0.8% versus 5.7%).\n\nTABLE III Adverse Events*\n\n\tPlacebo (N = 87)\tSubcutaneous Romosozumab\t\n70 mg (N = 60)\t140 mg (N = 89)\t210 mg (N = 89)\tTotal Romosozumab Group (N = 238)\t\nAdverse events during treatment (no. [%])\t69 (79.3)\t39 (65.0)\t54 (60.7)\t64 (71.9)\t157 (66.0)\t\nSerious adverse events†\n(no. [%])\t25 (28.7)\t9 (15.0)\t15 (16.9)\t26 (29.2)\t50 (21.0)\t\n Acute myocardial infarction\t1 (1.1)\t0 (0.0)\t1 (1.1)\t2 (2.2)\t3 (1.3)\t\n Pneumonia\t1 (1.1)\t0 (0.0)\t1 (1.1)\t2 (2.2)\t3 (1.3)\t\n Cardiac arrest\t0 (0.0)\t1 (1.7)\t1 (1.1)\t1 (1.1)\t3 (1.3)\t\n Hip fracture\t0 (0.0)\t0 (0.0)\t1 (1.1)\t2 (2.2)\t3 (1.3)\t\n Postoperative wound infection\t0 (0.0)\t0 (0.0)\t0 (0.0)\t3 (3.4)\t3 (1.3)\t\n Cellulitis\t3 (3.4)\t0 (0.0)\t1 (1.1)\t1 (1.1)\t2 (0.8)\t\n Acute pulmonary edema\t1 (1.1)\t0 (0.0)\t0 (0.0)\t2 (2.2)\t2 (0.8)\t\n Cardiac failure\t0 (0.0)\t0 (0.0)\t1 (1.1)\t1 (1.1)\t2 (0.8)\t\n Cerebrovascular accident\t0 (0.0)\t1 (1.7)\t0 (0.0)\t1 (1.1)\t2 (0.8)\t\n Diverticulitis\t0 (0.0)\t0 (0.0)\t1 (1.1)\t1 (1.1)\t2 (0.8)\t\n Lower respiratory tract infection\t0 (0.0)\t0 (0.0)\t1 (1.1)\t1 (1.1)\t2 (0.8)\t\n Medical device complication\t0 (0.0)\t1 (1.7)\t0 (0.0)\t1 (1.1)\t2 (0.8)\t\n Bacterial pneumonia\t0 (0.0)\t1 (1.7)\t0 (0.0)\t1 (1.1)\t2 (0.8)\t\n Osteoarthritis\t2 (2.3)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t\nFatal adverse events‡\n(no. [%])\t2 (2.3)\t2 (3.3)\t2 (2.2)\t6 (6.7)\t10 (4.2)\t\nAdverse events leading to discontinuation of investigational product (no. [%])\t4 (4.6)\t2 (3.3)\t5 (5.6)\t3 (3.4)\t10 (4.2)\t\nAdverse events leading to study discontinuation (no. [%])\t2 (2.3)\t1 (1.7)\t2 (2.2)\t2 (2.2)\t5 (2.1)\t\nAdverse events of interest§\n(no. [%])\t\t\t\t\t\t\n Hypersensitivity\t2 (2.3)\t1 (1.7)\t0 (0.0)\t2 (2.2)\t3 (1.3)\t\n Hypocalcemia\t0 (0.0)\t0 (0.0)\t1 (1.1)\t0 (0.0)\t1 (0.4)\t\n Injection-site reactions\t1 (1.1)\t1 (1.7)\t0 (0.0)\t1 (1.1)\t2 (0.8)\t\n Hyperostosis#\t1 (1.1)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t\n Malignancy\t1 (1.1)\t0 (0.0)\t1 (1.1)\t2 (2.2)\t3 (1.3)\t\n Osteoarthritis\t3 (3.4)\t4 (6.7)\t5 (5.6)\t2 (2.2)\t11 (4.6)\t\n* N = number of patients randomized who received ≥1 dose of investigational product.\n\n† Includes those that occurred in at least 2 patients in the total romosozumab or placebo group.\n\n‡ Fatal events were reported as death (day 273) and coronary artery hemorrhage (day 3) in the placebo group; respiratory failure (day 3) and cardiac arrest (day 72) in the 70-mg romosozumab group; cardiac arrest (day 14) and cardiac failure (day 187) in the 140-mg romosozumab group; and cardiac arrest (day 2), cardiorespiratory arrest (day 75), cerebrovascular accident (day 258), bacterial pneumonia (day 3), cardiac disorder (day 119), and acute respiratory failure (day 12) in the 210-mg romosozumab group.\n\n§ Adverse events of interest at the time of this study were prospectively defined.\n\n# Reported as extraskeletal ossification.\n\nSerious adverse events were reported for 25 (28.7%) of the patients in the placebo group and 50 (21.0%) in the total romosozumab group; no serious adverse event was reported for >3 patients in any group. Serious adverse events in the system order class of cardiac, vascular, and nervous system disorders were generally comparable between groups, except for cardiac disorders (placebo, 3.4%; total romosozumab group, 5%), most of which occurred during the follow-up period. Adverse events leading to discontinuation of use of the investigational product or participation in the study were comparable between treatment groups (Table III).\n\nAdverse events of interest included hypersensitivity, hypocalcemia, injection-site reactions, hyperostosis, malignancy, and osteoarthritis; all were comparable among treatment groups (Table III). Of note, 1 patient (in the 210-mg romosozumab group) had a serious hypersensitivity adverse event of acute generalized exanthematous pustulosis on study day 2 that resolved with topical steroid treatment; 1 (140-mg group) had a non-serious adverse event of hypocalcemia (day 10) in the setting of congestive heart failure; 1 (210-mg group) had a serious adverse event of acute myeloid leukemia after the last injection; and 2 (placebo group) had serious adverse events of radiographically evident worsening of preexisting osteoarthritis, with 1 of them also having worsening of symptoms of preexisting osteoarthritis.\n\nNone of the patients who received romosozumab stopped using it because of injection-site reactions, and none of the adverse events were suggestive of osteonecrosis of the jaw or atypical femoral fracture. Ten (4.2%) of the patients in the total romosozumab group and 2 (2.3%) in the placebo group had fatal adverse events; none were considered related to the investigational product (Table III).\n\nAnti-romosozumab binding antibodies were detected in 20 (9.4%) of 213 patients treated with romosozumab and were transient in 8 of them. The transient neutralizing antibodies to romosozumab were detected in 5 patients (2.3%) and did not appear to affect the safety profile of romosozumab.\n\nDiscussion\nAlthough romosozumab was shown to increase bone formation, reduce bone resorption, improve BMD, and decrease fracture rates in postmenopausal women11,13, stimulation of bone formation associated with short-term romosozumab treatment did not significantly accelerate fracture-healing following hip fracture fixation in our study population. The TUG scores and median time to radiographic healing were similar across treatment groups and were within the range observed in other hip-fracture-fixation studies of patients with comparable demographics31-35. The RUSH scores at the end of the study period indicated that almost all fractures were sufficiently healed.\n\nThe prevalence of adverse events was comparable among the treatment groups and consistent with the type of events that would be expected in this population of mostly elderly patients. A slightly higher prevalence of cardiac serious adverse events was reported in the romosozumab groups, and while some were recorded during the active treatment phase, most occurred during the follow-up period. The heterogeneous nature of the reported events, their low number, and a 3:1 randomization may limit definitive interpretation. Two much larger pivotal fracture trials of women with postmenopausal osteoporosis showed discordant results with regard to the number of positively adjudicated cardiovascular serious adverse events12,13. While a higher number was observed in the romosozumab group in the trial comparing romosozumab with alendronate13, no difference was observed in the larger, 7,000-patient placebo-controlled trial12.\n\nSimilar to the current study, a pair of trials comparing teriparatide with a placebo showed no acceleration of hip fracture-healing in the teriparatide group8. In a study comparing the effects of teriparatide and risedronate on recovery after hip fractures7,9, patients in the teriparatide group completed the TUG test in a shorter time, but there was no significant difference in the time to radiographic evidence of healing; the authors noted that the TUG test was a secondary end point, and the results should be interpreted with caution7. The time to radiographic evidence of healing in the teriparatide versus risedronate study was approximately 12 weeks in both arms compared with 16 weeks in our study, probably because of differences in the study populations—the teriparatide study enrolled patients with low-trauma pertrochanteric hip fractures. The reason for the absence of accelerated healing, despite stimulation of bone formation, is unclear. In our study, patients were treated at sites carefully selected for high surgical standards of care, and they had an overall rapid improvement in their functional scores and radiographic signs of healing regardless of treatment group. The near-perfect RUSH scores at week 36 suggest that complete fracture-healing had occurred in most patients by that time.\n\nOur study had several methodological strengths, including stratified randomization to reduce possible bias as well as the use of outcome measures proven to be valid and achievable in elderly populations and patients with hip fracture20,23,26. The study population, however, may not have been at sufficient risk for delayed healing to demonstrate benefit from an intervention for acceleration of fracture-healing.\n\nOur study has some limitations. The TUG tests were performed locally and not recorded with videography; therefore, no central adjudication of the results was possible. Intertrochanteric fractures, the most common type of fracture in our study, are usually not complicated by issues with fracture union, and it is plausible that the lack of treatment effect in our study was due to the inclusion of these fracture types. In addition, we were unable to fully assess prefracture morbidity, but since this was a randomized study, outcomes were unlikely to have been confounded by presurgery imbalances. Finally, differences among the sites regarding patient instruction and encouragement for the TUG test, which is considered challenging in this patient population, are possible and may have skewed some of the results; a patient-reported outcome measure reflecting improvement in quality of life might have been a more appropriate end point.\n\nThis phase-2 dose-finding study did not identify a difference with respect to its primary end point and adds to published evidence7-9 failing to show acceleration of fracture-healing with the use of bone-forming agents at the doses and schedules tested in the respective study populations. The quality of the surgical devices and methods used at the academic centers in our study likely outweighed any effect of romosozumab on fracture-healing. Future studies should focus on augmentation of fracture repair when fracture-healing is at risk or potentially delayed or compromised.\n\nAppendix\nSupporting material provided by the authors is posted with the online version of this article as a data supplement at jbjs.org (http://links.lww.com/JBJS/F703).\n\nNote: The authors thank Cassandra Milmont for statistical input. Medical writing support for this paper was funded by Amgen, Inc. and provided by Kathryn Boorer, PhD, of KB Scientific Communications, LLC.\n\nDisclosure: This study was funded by Amgen, Inc. and UCB Pharma. On the Disclosure of Potential Conflicts of Interest forms, which are provided with the online version of the article, one, or more of the authors checked “yes” to indicate that the author had a relevant financial relationship in the biomedical arena outside the submitted work (including employment with Amgen Inc., the sponsor of the study) (http://links.lww.com/JBJS/F702).\n\nData Sharing\nA data-sharing statement is provided with the online version of the article (http://links.lww.com/JBJS/F704).\n==== Refs\nReferences\n1 Odén A McCloskey EV Johansson H Kanis JA \nAssessing the impact of osteoporosis on the burden of hip fractures\n. Calcif Tissue Int. \n2013 \n1 ;92 (1 ):42 -9\n. Epub 2012 Nov 8 .23135744 \n2 Johnell O Kanis JA \nAn estimate of the worldwide prevalence, mortality and disability associated with hip fracture\n. Osteoporos Int. \n2004 \n11 ;15 (11 ):897 -902\n. 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Medicine (Baltimore). \n2016 \n5 ;95 (19 ):e3626 .27175673 \n7 Aspenberg P Malouf J Tarantino U García-Hernández PA Corradini C Overgaard S Stepan JJ Borris L Lespessailles E Frihagen F Papavasiliou K Petto H Caeiro JR Marin F \nEffects of teriparatide compared with risedronate on recovery after pertrochanteric hip fracture: results of a randomized, active-controlled, double-blind clinical trial at 26 weeks\n. J Bone Joint Surg Am. \n2016 \n11 \n16 ;98 (22 ):1868 -78\n.27852903 \n8 Bhandari M Jin L See K Burge R Gilchrist N Witvrouw R Krohn KD Warner MR Ahmad QI Mitlak B \nDoes teriparatide improve femoral neck fracture healing: results from a randomized placebo-controlled trial\n. Clin Orthop Relat Res. \n2016 \n5 ;474 (5 ):1234 -44\n. Epub 2016 Mar 1 .26932738 \n9 Malouf-Sierra J Tarantino U García-Hernández PA Corradini C Overgaard S Stepan JJ Borris L Lespessailles E Frihagen F Papavasiliou K Petto H Aspenberg P Caeiro JR Marin F \nEffect of teriparatide or risedronate in elderly patients with a recent pertrochanteric hip fracture: final results of a 78-week randomized clinical trial\n. J Bone Miner Res. \n2017 \n5 ;32 (5 ):1040 -51\n. Epub 2017 Jan 26 .28019683 \n10 Amgen Inc. EVENITY™ (romosozumab-aqqg) injection, for subcutaneous use. \n2019 \n4 Accessed 2019 Sep 4. https://www.pi.amgen.com/∼/media/amgen/repositorysites/pi-amgen-com/evenity/evenity_pi_hcp_english.ashx\n11 McClung MR Grauer A Boonen S Bolognese MA Brown JP Diez-Perez A Langdahl BL Reginster JY Zanchetta JR Wasserman SM Katz L Maddox J Yang YC Libanati C Bone HG \nRomosozumab in postmenopausal women with low bone mineral density\n. N Engl J Med. \n2014 \n1 \n30 ;370 (5 ):412 -20\n. Epub 2014 Jan 1 .24382002 \n12 Cosman F Crittenden DB Adachi JD Binkley N Czerwinski E Ferrari S Hofbauer LC Lau E Lewiecki EM Miyauchi A Zerbini CA Milmont CE Chen L Maddox J Meisner PD Libanati C Grauer A \nRomosozumab treatment in postmenopausal women with osteoporosis\n. N Engl J Med. \n2016 \n10 \n20 ;375 (16 ):1532 -43\n. Epub 2016 Sep 18 .27641143 \n13 Saag KG Petersen J Brandi ML Karaplis AC Lorentzon M Thomas T Maddox J Fan M Meisner PD Grauer A \nRomosozumab or alendronate for fracture prevention in women with osteoporosis\n. N Engl J Med. \n2017 \n10 \n12 ;377 (15 ):1417 -27\n. Epub 2017 Sep 11 .28892457 \n14 Ominsky MS Li C Li X Tan HL Lee E Barrero M Asuncion FJ Dwyer D Han CY Vlasseros F Samadfam R Jolette J Smith SY Stolina M Lacey DL Simonet WS Paszty C Li G Ke HZ \nInhibition of sclerostin by monoclonal antibody enhances bone healing and improves bone density and strength of nonfractured bones\n. J Bone Miner Res. \n2011 \n5 ;26 (5 ):1012 -21\n.21542004 \n15 Cui L Cheng H Song C Li C Simonet WS Ke HZ Li G \nTime-dependent effects of sclerostin antibody on a mouse fracture healing model\n. J Musculoskelet Neuronal Interact. \n2013 \n6 ;13 (2 ):178 -84\n.23728104 \n16 Suen PK He YX Chow DH Huang L Li C Ke HZ Ominsky MS Qin L \nSclerostin monoclonal antibody enhanced bone fracture healing in an open osteotomy model in rats\n. J Orthop Res. \n2014 \n8 ;32 (8 ):997 -1005\n. Epub 2014 Apr 30 .24782158 \n17 Padhi D Allison M Kivitz AJ Gutierrez MJ Stouch B Wang C Jang G \nMultiple doses of sclerostin antibody romosozumab in healthy men and postmenopausal women with low bone mass: a randomized, double-blind, placebo-controlled study\n. J Clin Pharmacol. \n2014 \n2 ;54 (2 ):168 -78\n. Epub 2013 Dec 11 .24272917 \n18 Padhi D Jang G Stouch B Fang L Posvar E \nSingle-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody\n. J Bone Miner Res. \n2011 \n1 ;26 (1 ):19 -26\n.20593411 \n19 Kristensen MT Foss NB Kehlet H \nTimed “Up & Go” test as a predictor of falls within 6 months after hip fracture surgery\n. Phys Ther. \n2007 \n1 ;87 (1 ):24 -30\n. Epub 2006 Dec 1 .17142643 \n20 Podsiadlo D Richardson S \nThe timed “Up & Go”: a test of basic functional mobility for frail elderly persons\n. J Am Geriatr Soc. \n1991 \n2 ;39 (2 ):142 -8\n.1991946 \n21 Lin MR Hwang HF Hu MH Wu HD Wang YW Huang FC \nPsychometric comparisons of the Timed Up and Go, one-leg stand, functional reach, and Tinetti balance measures in community-dwelling older people\n. J Am Geriatr Soc. \n2004 \n8 ;52 (8 ):1343 -8\n.15271124 \n22 Steffen TM Hacker TA Mollinger L \nAge- and gender-related test performance in community-dwelling elderly people: Six-Minute Walk Test, Berg Balance Scale, Timed Up & Go Test, and gait speeds\n. Phys Ther. \n2002 \n2 ;82 (2 ):128 -37\n.11856064 \n23 Chiavaras MM Bains S Choudur H Parasu N Jacobson J Ayeni O Petrisor B Chakravertty R Sprague S Bhandari M \nThe Radiographic Union Score for Hip (RUSH): the use of a checklist to evaluate hip fracture healing improves agreement between radiologists and orthopedic surgeons\n. Skeletal Radiol. \n2013 \n8 ;42 (8 ):1079 -88\n. Epub 2013 Apr 7 .23564001 \n24 Bhandari M Chiavaras M Ayeni O Chakraverrty R Parasu N Choudur H Bains S Sprague S Petrisor B ; Assessment Group for Radiographic Evaluation and Evidence (AGREE) Study Group (AGREE Investigators Writing Committee). Assessment of radiographic fracture healing in patients with operatively treated femoral neck fractures\n. J Orthop Trauma. \n2013 \n9 ;27 (9 ):e213 -9\n.23287749 \n25 Bhandari M Chiavaras MM Parasu N Choudur H Ayeni O Chakravertty R Bains S Hak A Sprague S Petrisor B \nRadiographic Union Score for Hip substantially improves agreement between surgeons and radiologists\n. BMC Musculoskelet Disord. \n2013 \n2 \n25 ;14 :70 .23442540 \n26 Frank T Osterhoff G Sprague S Garibaldi A Bhandari M Slobogean GP ; FAITH Investigators \nThe Radiographic Union Score for Hip (RUSH) identifies radiographic nonunion of femoral neck fractures\n. Clin Orthop Relat Res. \n2016 Jun ;474 (6 ):1396 -404\n.26728521 \n27 Ingemarsson AH Frändin K Mellström D Möller M \nWalking ability and activity level after hip fracture in the elderly—a follow-up\n. J Rehabil Med. \n2003 \n3 ;35 (2 ):76 -83\n.12691337 \n28 Fine JP Gray RJ \nA proportional hazards model for the subdistribution of a competing risk\n. J Am Stat Assoc. \n1999 ;94 (446 ):496 -509\n.\n29 Prentice RL Kalbfleisch JD Peterson AV JrFlournoy N Farewell VT Breslow NE \nThe analysis of failure times in the presence of competing risks\n. Biometrics. \n1978 \n12 ;34 (4 ):541 -54\n.373811 \n30 van Elteren PH \nOn the combination of independent two-sample test of Wilcoxon\n. Bull Int Stat Inst. \n1960 ;37 :351 -61\n.\n31 Reindl R Harvey EJ Berry GK Rahme E ; Canadian Orthopaedic Trauma Society (COTS). \nIntramedullary versus extramedullary fixation for unstable intertrochanteric fractures: a prospective randomized controlled trial\n. J Bone Joint Surg Am. \n2015 \n12 \n2 ;97 (23 ):1905 -12\n.26631990 \n32 Matre K Vinje T Havelin LI Gjertsen JE Furnes O Espehaug B Kjellevold SH Fevang JM \nTRIGEN INTERTAN intramedullary nail versus sliding hip screw: a prospective, randomized multicenter study on pain, function, and complications in 684 patients with an intertrochanteric or subtrochanteric fracture and one year of follow-up\n. J Bone Joint Surg Am. \n2013 \n2 \n6 ;95 (3 ):200 -8\n.23389782 \n33 Boese CK Buecking B Schwarting T Debus F Ruchholtz S Bliemel C Frink M Lechler P \nThe influence of pre-existing radiographic osteoarthritis on functional outcome after trochanteric fracture\n. Int Orthop. \n2015 \n7 ;39 (7 ):1405 -10\n. Epub 2015 Jan 21 .25876225 \n34 Herrera A Domingo LJ Calvo A Martínez A Cuenca J \nA comparative study of trochanteric fractures treated with the Gamma nail or the proximal femoral nail\n. Int Orthop. \n2002 ;26 (6 ):365 -9\n. Epub 2002 Jul 31 .12466870 \n35 Zhu F Liu G Shao HG Wang YJ Li RQ Yang HL Geng DC Xu YZ \nTreatment of femoral neck fracture with percutaneous compression plate: preliminary results in 74 patients\n. Orthop Surg. \n2015 \n5 ;7 (2 ):132 -7\n.26033994\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0021-9355",
"issue": "102(8)",
"journal": "The Journal of bone and joint surgery. American volume",
"keywords": null,
"medline_ta": "J Bone Joint Surg Am",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D050071:Bone Density Conservation Agents; D004311:Double-Blind Method; D005260:Female; D006620:Hip Fractures; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "0014030",
"other_id": null,
"pages": "693-702",
"pmc": null,
"pmid": "31977817",
"pubdate": "2020-04-15",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "A Randomized, Placebo-Controlled Study of Romosozumab for the Treatment of Hip Fractures.",
"title_normalized": "a randomized placebo controlled study of romosozumab for the treatment of hip fractures"
} | [
{
"companynumb": "CA-AMGEN-CANNI2021129614",
"fulfillexpeditecriteria": "2",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VITAMIN D NOS"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThere is limited information regarding the outcome of patients treated for leukemia during pregnancy. This study was performed on all cases of leukemia during pregnancy identified in our institution leukemia database.\n\n\nMETHODS\nIt is a retrospective study from our existing database. Thirty two cases were identified among the cohort of patients treated for acute and chronic leukemia between January 1991 and July 2003.\n\n\nRESULTS\nAmong the acute leukemia patients (n=21), 10 patients (47.6%) received chemotherapy during pregnancy, seven had live birth and three had spontaneous abortion. No teratogenicity or congenital malformations or postnatal complication were reported. The remaining 11 (52.4%) were not given chemotherapy while pregnant; three patients presented after 34 weeks of gestation ending in normal live births and then received chemotherapy and eight patients had abortion before starting chemotherapy. Among the chronic myeloid leukemia (CML) patients (n=11), nine patients received hydroxyurea, one patient received alfa-interferon and one patient was treated with leukapheresis. Eight patients had normal live births and three patients had abortion. Out of the 32 patients, 18 patients (56.2%) subsequently underwent HLA matched sibling allogeneic stem cell transplantation, seven for acute myeloid leukemia (AML), two for acute lymphocytic leukemia (ALL) and nine for CML. After a median follow up of 16 years, five patients (15.6%) are alive in remission (one from chemotherapy group and four from SCT group).\n\n\nCONCLUSIONS\nOur report lends credence to the safety and feasibility of administering anti-leukemic therapy in acute and chronic leukemias during pregnancy although acute leukemia patients had possibly a poor long term outcome compared to non-pregnant patients.",
"affiliations": "King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.;King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.;King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.;King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.;King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.;King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.;King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.;King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.;King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.;King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.;King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.;King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.;King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.;King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.;King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia. Electronic address: chaudhri@kfshrc.edu.sa.;King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.",
"authors": "Saleh|A J M|AJ|;Alhejazi|Ayman|A|;Ahmed|Syed Osman|SO|;Al Mohareb|Fahad|F|;AlSharif|Fahad|F|;AlZahrani|Hazza|H|;Mohamed|Said Yousuf|SY|;Rasheed|Walid|W|;AlDawsari|Ghuzayel|G|;Ibrahim|Khalid|K|;Ahmed|Shad|S|;Chebbo|Wahiba|W|;ElGohary|Ghada|G|;Almahayni|Muhamad|M|;Chaudhri|Naeem|N|;Aljurf|Mahmoud|M|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "7(2)",
"journal": "Hematology/oncology and stem cell therapy",
"keywords": "Acute leukemia; Chemotherapy; Chronic leukemia; Pregnancy",
"medline_ta": "Hematol Oncol Stem Cell Ther",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007938:Leukemia; D011247:Pregnancy; D011248:Pregnancy Complications; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "101468532",
"other_id": null,
"pages": "63-8",
"pmc": null,
"pmid": "24816335",
"pubdate": "2014-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Leukemia during pregnancy: long term follow up of 32 cases from a single institution.",
"title_normalized": "leukemia during pregnancy long term follow up of 32 cases from a single institution"
} | [
{
"companynumb": "SA-JNJFOC-20140617579",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": ... |
{
"abstract": "Malakoplakia is a rare, granulomatous disorder that is typically triggered by infections in immunocompromised patients. Although it most commonly affects the urinary tract, cases may occasionally occur in the gastrointestinal tract. There are case reports of malakoplakia of the pancreas with associated pathologic description, but none with detailed imaging and endoscopic findings. In addition, description of magnetic resonance imaging characteristics of mass-forming malakoplakia in the literature is sparse. We present a case of pancreaticoduodenal malakoplakia in an immunocompromised patient, including detailed description of magnetic resonance imaging, computed tomography, and endoscopic findings with radiology-pathology correlation. Classic pathologic features of malakoplakia (eg, hypercellularity, inflammation, and mineralization of Michaelis-Gutmann bodies) lead to specific features on imaging, such as marked diffusion restriction, heterogeneous enhancement, calcification, and increased attenuation on nonenhanced computed tomography. These features may help differentiate malakoplakia from other more common lesions that occur in this location, especially if present in an immunocompromised patient.",
"affiliations": "From the University of Utah School of Medicine.;Divisions of Gastroenterology.;Infectious Disease.;Infectious Disease.;Divisions of Gastroenterology.;Department of Radiology and Imaging Sciences, University of Utah Medical Center, Salt Lake City, UT.",
"authors": "Hubbard|Lauren|L|;Iriana|Sentia|S|;Carey|Adrienne|A|;Odrobina|Robert|R|;Sossenheimer|Michael|M|;Rogers|Douglas|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MPA.0000000000001497",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0885-3177",
"issue": "49(3)",
"journal": "Pancreas",
"keywords": null,
"medline_ta": "Pancreas",
"mesh_terms": "D000368:Aged; D001706:Biopsy; D002760:Cholangiopancreatography, Endoscopic Retrograde; D003937:Diagnosis, Differential; D004378:Duodenal Diseases; D019160:Endosonography; D006801:Humans; D016867:Immunocompromised Host; D008279:Magnetic Resonance Imaging; D008287:Malacoplakia; D008297:Male; D064847:Multimodal Imaging; D010182:Pancreatic Diseases; D011237:Predictive Value of Tests; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8608542",
"other_id": null,
"pages": "455-460",
"pmc": null,
"pmid": "32168251",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Radiographic and Endoscopic Features of Pancreaticoduodenal Malakoplakia.",
"title_normalized": "radiographic and endoscopic features of pancreaticoduodenal malakoplakia"
} | [
{
"companynumb": "US-TEVA-2020-US-1851273",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "Empiric antibiotic usage is very common in clinical practice and Trimethoprim-Sulfamethoxazole (TMP-SMX) is one such antibiotic used extensively in primary care practice. Some patients experience serious adverse effects to the antibiotics that markedly increase the morbidity and the cost of medical care. We describe one such patient, a previously healthy 40-year-old Hispanic female who developed myositis and rhabdomyolysis secondary to TMP-SMX. To the best of our knowledge, this is the first report of TMP-SMX-induced rhabdomyolysis in an immunocompetent host.",
"affiliations": "Department of Clinical Medicine, University of Arizona College of Medicine, Tucson, AZ.",
"authors": "Ainapurapu|Bujji|B|;Kanakadandi|Uday B|UB|",
"chemical_list": "D000890:Anti-Infective Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0b013e31824567fe",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-2765",
"issue": "21(3)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000328:Adult; D000890:Anti-Infective Agents; D005260:Female; D006801:Humans; D009220:Myositis; D012206:Rhabdomyolysis; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e78-9",
"pmc": null,
"pmid": "23689093",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Trimethoprim-sulfamethoxazole induced rhabdomyolysis.",
"title_normalized": "trimethoprim sulfamethoxazole induced rhabdomyolysis"
} | [
{
"companynumb": "NL-PFIZER INC-2013208278",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"drugadditional": null,
... |
{
"abstract": "In 2017, Massachusetts General Hospital implemented the Severe Immunotherapy Complications (SIC) Service, a multidisciplinary care team for patients hospitalized with immune-related adverse events (irAEs), a unique spectrum of toxicities associated with immune checkpoint inhibitors (ICIs). This study's objectives were to evaluate the intervention's (1) effect on patient outcomes and healthcare utilization, and (2) ability to collect biological samples via a central infrastructure, in order to study the mechanisms responsible for irAEs.\n\n\n\nA hospital database was used to identify patients who received ICIs for a malignancy and were hospitalized with severe irAEs, before (April 2, 2016-October 3, 2017) and after (October 3, 2017-October 24, 2018) SIC Service initiation. The primary outcome was readmission rate after index hospitalization. Secondary outcomes included length of stay (LOS) for admissions, corticosteroid and non-steroidal second-line immunosuppression use, ICI discontinuation, and inpatient mortality.\n\n\n\nIn the pre-SIC period, 127 of 1169 patients treated with ICIs were hospitalized for irAEs; in the post-SIC period, 122 of 1159. After SIC service initiation, reductions were observed in irAE readmission rate (14.8% post-SIC vs 25.9% pre-SIC; OR 0.46; 95% CI 0.22 to 0.95; p=0.036) and readmission LOS (median 6 days post-SIC vs 7 days pre-SIC; 95% CI -16.03 to -0.14; p=0.046). No significant pre-initiation and post-initiation differences were detected in corticosteroid use, second-line immunosuppression, ICI discontinuation, or inpatient mortality rates. The SIC Service collected 789 blood and tissue samples from 234 patients with suspected irAEs.\n\n\n\nThis is the first study to report that establishing a highly subspecialized care team focused on irAEs is associated with improved patient outcomes and reduced healthcare utilization. Furthermore, the SIC Service successfully integrated blood and tissue collection safety into routine care.",
"affiliations": "Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Oncology, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.;Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Palliative Care, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Gastroenterology, Department of Medicine, Mass General Center for Cancer Research, Division of Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Neuroendocrine Unit, Division of Endocrinology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Endocrinology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Neuromuscular Disorders, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Rheumatology, Allergy, Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Rheumatology, Allergy, Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Rheumatology, Allergy, Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Cardio-Oncology Program, Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Cardio-Oncology Program, Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Allergy and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Massachusetts General Hospital Center for Immunology and Inflammatory Diseases, Mass General Center for Cancer Research, Division of Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA kreynolds7@partners.org.",
"authors": "Zubiri|Leyre|L|0000-0003-4226-7443;Molina|Gabriel E|GE|;Mooradian|Meghan J|MJ|0000-0002-8289-8015;Cohen|Justine|J|;Durbin|Sienna M|SM|;Petrillo|Laura|L|;Boland|Genevieve M|GM|;Juric|Dejan|D|;Dougan|Michael|M|0000-0001-9266-2009;Thomas|Molly F|MF|;Faje|Alex T|AT|;Rengarajan|Michelle|M|;Guidon|Amanda C|AC|0000-0003-0843-2935;Chen|Steven T|ST|;Okin|Daniel|D|;Medoff|Benjamin D|BD|;Nasrallah|Mazen|M|;Kohler|Minna J|MJ|;Schoenfeld|Sara R|SR|;Karp-Leaf|Rebecca S|RS|;Sise|Meghan E|ME|;Neilan|Tomas G|TG|;Zlotoff|Daniel A|DA|;Farmer|Jocelyn R|JR|;Bardia|Aditya|A|;Sullivan|Ryan J|RJ|0000-0001-5344-6645;Blum|Steven M|SM|0000-0001-6030-7192;Semenov|Yevgeniy R|YR|;Villani|Alexandra-Chloé|AC|;Reynolds|Kerry L|KL|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/jitc-2021-002886",
"fulltext": "\n==== Front\nJ Immunother Cancer\nJ Immunother Cancer\njitc\njitc\nJournal for Immunotherapy of Cancer\n2051-1426\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\n34544895\njitc-2021-002886\n10.1136/jitc-2021-002886\nClinical/Translational Cancer Immunotherapy\n1506\n2435\nOriginal researchEffect of a multidisciplinary Severe Immunotherapy Complications Service on outcomes for patients receiving immune checkpoint inhibitor therapy for cancer\nhttp://orcid.org/0000-0003-4226-7443\nZubiri Leyre 1\nMolina Gabriel E 1\nhttp://orcid.org/0000-0002-8289-8015\nMooradian Meghan J 1\nCohen Justine 2\nDurbin Sienna M 1\nPetrillo Laura 3\nBoland Genevieve M 4\nJuric Dejan 1\nhttp://orcid.org/0000-0001-9266-2009\nDougan Michael 5\nThomas Molly F 6\nFaje Alex T 7\nRengarajan Michelle 8\nhttp://orcid.org/0000-0003-0843-2935\nGuidon Amanda C 9\nChen Steven T 10\nOkin Daniel 11\nMedoff Benjamin D 11\nNasrallah Mazen 12\nKohler Minna J 12\nSchoenfeld Sara R 12\nLeaf Rebecca K 1\nSise Meghan E 13\nNeilan Tomas G 14\nZlotoff Daniel A 14\nFarmer Jocelyn R 15\nBardia Aditya 1\nhttp://orcid.org/0000-0001-5344-6645\nSullivan Ryan J 1\nhttp://orcid.org/0000-0001-6030-7192\nBlum Steven M 1\nSemenov Yevgeniy R 10\nVillani Alexandra-Chloé 16\nReynolds Kerry L 1\n1 Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA\n2 Division of Oncology, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA\n3 Division of Palliative Care, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA\n4 Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA\n5 Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA\n6 Division of Gastroenterology, Department of Medicine, Mass General Center for Cancer Research, Division of Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA\n7 Neuroendocrine Unit, Division of Endocrinology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA\n8 Division of Endocrinology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA\n9 Division of Neuromuscular Disorders, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA\n10 Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA\n11 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA\n12 Division of Rheumatology, Allergy, Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA\n13 Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA\n14 Cardio-Oncology Program, Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA\n15 Division of Allergy and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA\n16 Massachusetts General Hospital Center for Immunology and Inflammatory Diseases, Mass General Center for Cancer Research, Division of Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA\nCorrespondence to Dr Kerry L Reynolds; kreynolds7@partners.org\n2021\n20 9 2021\n9 9 e00288613 7 2021\n© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.\n\nBackground\n\nIn 2017, Massachusetts General Hospital implemented the Severe Immunotherapy Complications (SIC) Service, a multidisciplinary care team for patients hospitalized with immune-related adverse events (irAEs), a unique spectrum of toxicities associated with immune checkpoint inhibitors (ICIs). This study’s objectives were to evaluate the intervention’s (1) effect on patient outcomes and healthcare utilization, and (2) ability to collect biological samples via a central infrastructure, in order to study the mechanisms responsible for irAEs.\n\nMethods\n\nA hospital database was used to identify patients who received ICIs for a malignancy and were hospitalized with severe irAEs, before (April 2, 2016–October 3, 2017) and after (October 3, 2017–October 24, 2018) SIC Service initiation. The primary outcome was readmission rate after index hospitalization. Secondary outcomes included length of stay (LOS) for admissions, corticosteroid and non-steroidal second-line immunosuppression use, ICI discontinuation, and inpatient mortality.\n\nResults\n\nIn the pre-SIC period, 127 of 1169 patients treated with ICIs were hospitalized for irAEs; in the post-SIC period, 122 of 1159. After SIC service initiation, reductions were observed in irAE readmission rate (14.8% post-SIC vs 25.9% pre-SIC; OR 0.46; 95% CI 0.22 to 0.95; p=0.036) and readmission LOS (median 6 days post-SIC vs 7 days pre-SIC; 95% CI −16.03 to –0.14; p=0.046). No significant pre-initiation and post-initiation differences were detected in corticosteroid use, second-line immunosuppression, ICI discontinuation, or inpatient mortality rates. The SIC Service collected 789 blood and tissue samples from 234 patients with suspected irAEs.\n\nConclusions\n\nThis is the first study to report that establishing a highly subspecialized care team focused on irAEs is associated with improved patient outcomes and reduced healthcare utilization. Furthermore, the SIC Service successfully integrated blood and tissue collection safety into routine care.\n\nimmunotherapy\nbiomarkers\ntumor\ncytotoxicity\nimmunologic\ndrug therapy\ncombination\ninflammation\nSpanish Society of Medical Oncology SEOM (Sociedad Española de Oncología Médica) Grant for a 2-year translational project at MGH special-featureunlocked\n==== Body\npmcBackground\n\nAs of November 2020, there are 55 Food and Drug Administration-approved indications for immune checkpoint inhibitors (ICIs) in the treatment of cancer.1 Concordant with the increase in approvals, the number of patients eligible for ICI therapy has exponentially grown; whereas only 1.5% of patients with cancer were eligible for ICI therapy in 2011, by 2019 the percentage had risen to 36% or 233,790 patients annually.2 The actual number of patients treated with ICIs may be underestimated as a result of new approved indications and enrollment in clinical trials, and this number will continue to increase as new ICIs and combination immune and non-immune treatment regimens are developed.3 4 Despite these successes, ICI therapy may be associated with the development of treatment-related toxicities—called immune-related adverse events (irAEs)—which are thought to reflect autoinflammatory sequelae of immune activation and downstream effects that occur with ICI administration.5 6 In clinical trials, approximately 60%–85% of participants receiving single-agent ICI therapy develop irAEs (of any grade), with even higher numbers for those administered combination therapy.7–14 Approximately 10%–30% of participants develop grade ≥3 irAEs,7 with a recent meta-analysis reporting 14% with programmed death-1 (PD-1) single agent, 34% with cytotoxic T-lymphocyte antigen-4 (CTLA-4) monotherapy and as high as 55% with combination ICI therapy.8 These serious toxicities may require hospitalization and high-dose immunosuppression. To date, the molecular mechanisms responsible for irAE development remain poorly understood, and we currently lack predictive markers to identify individuals at risk of developing these toxicities, which are fatal in 0.4%–1.2% of patients.15 As ICI therapy becomes a core pillar of cancer care, the incidence of irAEs will significantly increase alongside ICI use. Therefore, it is essential that the healthcare community is aware of and educated on the identification and management of irAEs.\n\nManaging irAEs represents a major clinical challenge in oncologic care, even in large academic centers.16 17 Although the dermatological, gastrointestinal (GI), endocrine, and hepatic systems are most commonly involved, any organ system can be affected,9 and different subspecialist consultations may be required for each specific organ toxicity.10 The National Comprehensive Cancer Network (NCCN) currently recommends subspecialty consultation for (1) grade ≥2 colitis, hepatitis, or pancreatitis; (2) grade ≥2 pneumonitis; (3) grade ≥2 renal failure; (4) moderate myositis; (5) myasthenia gravis; (6) hyperglycemia >200, primary adrenal insufficiency, or hypophysitis, (7) mild eye changes; (8) grade 3 or 4 rash; and (9) for any potential cardiac toxicity. Moreover, it is critical that irAEs be detected early18 through proper assessment and diagnostic testing, and that specialist care be coordinated rapidly to prevent irAEs from progressing to more severe grade ≥3 events. In recent years, several institutions have described the multidisciplinary team approaches they have developed for responding to irAEs.19–21 However, the effect of such approaches on healthcare utilization and patient outcomes has not yet been reported.\n\nIn addition, the molecular mechanisms driving treatment-induced toxicity are poorly understood, in part because it has been challenging to study irAEs using mouse models.22 23 An improved understanding of the mechanisms underlying irAEs development and the identification of predictive biomarkers may allow for improved management protocols and even preventive strategies for these toxicities.5 24 25 Our lack of mechanistic understanding of irAEs has led experts in the field to call for international registries and translational efforts to collect real-world data on irAEs.5\n\nIn October 2017, the Massachusetts General Hospital (MGH) altered the inpatient oncology clinical practice model to implement the Severe Immunotherapy Complications (SIC) Service—a service dedicated to caring for patients with suspected serious irAEs. This multidisciplinary effort was launched by medical oncologists who partnered with dedicated subspecialty expert consultants from 11 subspecialties to refine the clinical identification and management of irAEs. In addition to providing clinical care, the SIC Service also supports a clinical–translational research effort to study these novel toxicities. To achieve the translational goals, a standardized infrastructure was implemented that enrolls patients with suspected irAEs into studies focused on the collection of relevant clinical data and paired blood and tissue specimens.\n\nHere, we present data on the SIC Service’s multidisciplinary clinical and translational research effort with the goals of (1) evaluating this intervention’s effect on healthcare utilization and outcomes for patients experiencing irAEs; and (2) determining the feasibility of using a central infrastructure to collect blood and tissue samples to study the mechanisms responsible for irAEs across toxicity types.\n\nMethods\n\nStudy population\n\nUsing pharmacy and hospital admission databases, a list of patients was identified who received ICI (ipilimumab, pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, or any ICI combination) for a malignancy and were hospitalized at MGH between April 2, 2016 and October 24, 2018. The start date, April 2, 2016, was selected to maintain consistency of data storage as that was the implementation date of the new EPIC electronic medical record at MGH. The SIC Service was established on October 3, 2017 and patients whose admission and discharge dates spanned this date were excluded from analysis. To ensure at least a 1-year follow-up, October 24, 2018 was chosen as the end date. The ‘pre-SIC period’ was therefore defined as an admission between April 2, 2016 through October 3, 2017 (before SIC Service implementation), and the ‘post-SIC period’ was defined as an admission from October 3, 2017 through October 24, 2018 (after SIC service implementation).\n\nData collection\n\nAdmissions underwent a two-stage review process where each hospitalization was first screened for the presence of a potential irAE based on documentation in the electronic health record. Subsequently, specialists (allergy: JRF; cardiology: TGN, DZ; dermatology: STC; endocrinology: ATF, MR; gastroenterology/hepatology: MD, MFT; hematology: RSKL; nephrology: MES; neurology: ACG; pulmonology: DO, BDM; rheumatology: MN, MK, SS) followed published organ-specific diagnostic criteria to identify cases of suspected or confirmed irAEs admitted to the hospital.26 In patients with multiple confirmed toxicities, the primary irAE was defined as that which prompted hospitalization and/or determined treatment.\n\nSIC Service intervention\n\nOn October 3, 2017, the SIC Service was established to care for patients hospitalized with severe irAEs. All patients who present to MGH with suspected irAEs are evaluated by 1 of 12 SIC Service oncologists with expertise in irAEs. SIC oncologists coordinate patient care with ward services and expert subspecialists that belong to the broader SIC Service care team and represent providers in allergy/immunology, cardiology, dermatology, endocrinology, gastroenterology, hematology, nephrology, neurology, ophthalmology, pulmonology, and rheumatology. Since the time the SIC Service began, efforts have been made to inform all emergency department providers, hospitalists, trainees, internal medicinephysicians, and MGH Cancer Center providers of this team of subspecialists with irAE expertise so that patients with suspected toxicity can be referred accordingly. All admitted patients are then captured by an electronic report generated every morning that identifies all patients treated with ICIs admitted to any floor of the hospital. Every morning, these patients’ charts are reviewed for suspected toxicity by a nurse practitioner or an oncologist and added to the SIC Service list if there is clinical suspicion of toxicity (figure 1). On discharge, patients are scheduled for outpatient follow-up with the disease-specific subspecialist, when appropriate, as well as the oncologist. Finally, referrals to outpatient subspecialty clinics are streamlined to permit urgent evaluation with irAEs experts in order to avoid hospitalization when possible.\n\nFigure 1 Patient identification for Severe Immunotherapy Complications (SIC) Service. ICI, immune checkpoint inhibitor; irAE, immune-related adverse event; MD, Doctor of Medicine; MGH, Massachusetts General Hospital.\n\nTranslational research program\n\nUnder the SIC Service’s translational research infrastructure, patients with suspected irAEs are identified, communicated to research staff, and consented for blood and tissue collection to occur alongside preplanned diagnostic or therapeutic procedures (figure 2). For a subset of patients, sequential specimens are collected at various points during their toxicity course including at the time of presentation before initiation of immunosuppressive therapy, diagnosis, after immunosuppression initiation and/or escalation, and at time of irAE resolution or recurrence. In specific cases of irAE, the SIC Service partners with the MGH Rapid Autopsy program (principal investigator: DJ) to collect blood as well as tissue specimens immediately after death from tumor and all involved irAE sites. All specimens are immediately couriered to the laboratory for processing and storage on the day of collection.\n\nFigure 2 Standard operation procedure for sample collection and processing. CTLA-4, cytotoxic T-lymphocyte antigen-4; PBMCs, peripheral blood mononuclear cells; PD-1, programmed death-1; PD-L1, programmed death-ligand 1.\n\nPrimary and secondary outcomes\n\nThe primary outcome in the study was the rate of hospital readmissions for irAEs in the pre-SIC and post-SIC periods. Secondary outcomes included length of stay (LOS) for both initial irAE admissions and readmissions, use of corticosteroids and non-steroidal second-line immunosuppression, ICI discontinuation, and inpatient mortality in the pre-SIC and post-SIC periods.\n\nStatistical analysis\n\nStatistical analyses were performed using Stata, V.15.0 (StataCorp). Descriptive statistics with unpaired t-test for continuous data and Pearson χ2 test for categorical data were used for comparison of baseline characteristics. Multivariable linear and logistic regressions were used to analyze primary and secondary outcomes. Modeling covariates included age, sex, irAE confirmation status, malignancy, ICI class, primary toxicity type, and presence of multiple toxicities. P<0.05 was considered statistically significant.\n\nResults\n\nFrom April 2, 2016 through October 3, 2017 (18-month ‘pre-SIC’ study period), 1169 patients were treated with ICIs at our institution and 127 patients were hospitalized for irAEs. From October 3, 2017 through October 24, 2018 (12-month ‘post-SIC’ study period), our institution treated 1159 patients with ICIs and 122 patients were hospitalized for irAEs. There were no statistically significant differences in baseline characteristics of patients admitted for irAEs before and after SIC Service implementation (table 1).\n\nTable 1 Characteristics of patients admitted for irAE before and after SIC Service implementation\n\nCharacteristic\tPre-SIC*\tPost-SIC†\tP value‡\t\n(n=127 patients)\t(n=122 patients)\t\nAge, mean (SD), years\t62.6 (13.9)\t64.6 (11.1)\t0.216\t\nFemale sex\t44 (34.7%)\t55 (45.1%)\t0.093\t\nCancer type\t\t\t\t\n Melanoma\t48 (37.8%)\t31 (25.4%)\t0.156\t\n Thoracic\t35 (27.6%)\t38 (31.2%)\t\n Gastrointestinal\t14 (11.0%)\t26. (21.3%)\t\n Genitourinary\t8 (6.3%)\t9 (7.4%)\t\n Hematologic\t3 (2.4%)\t7 (5.7%)\t\n Gynecologic\t5 (3.9%)\t3 (2.5%)\t\n Head and neck\t5 (3.9%)\t2 (1.6%)\t\n Neurologic\t3 (2.4%)\t4 (3.3%)\t\n Breast\t5 (3.9%)\t2 (1.6%)\t\n Sarcoma\t1 (0.8%)\t0\t\nICI type\t\t\t\t\n CTLA-4\t9 (7.1%)\t3 (2.5%)\t0.147\t\n PD-1\t84 (66.1%)\t92 (75.4%)\t\n PD-L1\t8 (6.3%)\t10 (8.2%)\t\n CTLA-4+PD-1\t26 (20.5%)\t17 (13.9%)\t\nirAE type\t\t\t\t\n Allergy\t3 (2.4%)\t1 (0.8%)\t0.311\t\n Cardiac\t9 (7.1%)\t11 (9.0%)\t\n Dermatologic\t9 (7.1%)\t3 (2.5%)\t\n Endocrine\t15 (11.8%)\t13 (10.7%)\t\n Gastrointestinal\t28 (22.1%)\t20 (16.4%)\t\n Hepatic\t20 (15.8%)\t23 (18.9%)\t\n Hematologic\t4 (3.2%)\t2 (1.6%)\t\n Neurologic\t10 (7.9%)\t14 (11.5%)\t\n Pulmonary\t26 (20.5%)\t26 (21.3%)\t\n Renal\t1 (0.8%)\t7 (5.7%)\t\n Rheumatologic\t2 (1.6%)\t2 (1.6%)\t\n*Data are presented as number (percentage) of patients, unless otherwise indicated; pre-SIC date range is April 2, 2016–October 2, 2017.\n\n†Data are presented as number (percentage) of patients, unless otherwise indicated; post-SIC date range is October 3, 2017–October 24, 2018.\n\n‡Unpaired t-test for continuous data; Pearson χ2 test for categorical data.\n\nCTLA-4, cytotoxic T-lymphocyte antigen-4; ICI, immune checkpoint inhibitor; irAE, immune-related adverse event; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; SIC, Severe Immunotherapy Complications.\n\nThe majority of admitted patients both pre-SIC and post-SIC had melanoma, a thoracic malignancy, or a GI malignancy and were treated with either anti-PD-1 monotherapy or combination anti-CTLA-4 and anti-PD-1 therapy. There was a diverse mix of primary toxicity types leading to admission before and after SIC service initiation, with pulmonary, GI, and hepatic irAEs representing the most common toxicities (table 1).\n\nImpact of SIC Service on the primary and secondary outcomes\n\nCritical outcomes data after SIC Service implementation are shown in table 2.\n\nIn multivariable modeling, SIC Service implementation was associated with a significant reduction in irAE readmission rates (post-SIC 14.8% vs pre-SIC 25.9%; OR 0.46; 95% CI 0.22 to 0.95; p=0.036) and shorter LOS than pre-SIC readmissions (post-SIC median 6 days vs pre-SIC median 7 days; 95% CI −16.03 to –0.14; p=0.046). We observed a trend toward lower LOS (post-SIC 5 days vs pre-SIC 5.5 days (p=0.078)) but this was not statistically significant.\n\nOverall rates of corticosteroid use, second-line immunosuppression, and ICI discontinuation for irAE, as well as inpatient mortality rates, were not significantly different before and after SIC Service implementation (table 2). A second analysis analyzing the data by first admission only also revealed no significant difference before and after SIC Service implementation in LOS (p=0.758), discharged on steroids (p=0.141), use of non-steroidal immunosuppression (p=0.878), ICI discontinuation for irAE (p=0.526), or inpatient mortality (p=0.361) indicating first admission acuity was similar among the two groups (online supplemental table 1).\n\n10.1136/jitc-2021-002886.supp1 Supplementary data\n\nTable 2 Impact of SIC Service implementation on key outcomes—logistic regressions\n\nOutcome\tPre-SIC*\tPost-SIC†\tCoefficient/OR (95% CI)‡\tP value\t\n(n=166 admits)\t(n=149 admits)\t\nLength of stay, median (IQR), days\t5.5 (3–11)\t5 (3–9)\t−1.7 (−3.56 to 0.19)§\t0.078\t\nDischarged on corticosteroids¶\t121 (75.6%)\t96 (69.1%)\t0.60 (0.33 to 1.10)**\t0.101\t\nUse of non-steroidal immunosuppression\t24 (14.5%)\t18 (12.1%)\t0.87 (0.43 to 1.77)**\t0.702\t\nICI discontinuation for irAE††\t74 (66.1%)\t61 (67.0%)\t1.04 (0.55 to 1.98)**\t0.897\t\nDied during irAE admission\t11 (6.6%)\t13 (8.7%)\t1.46 (0.60 to 3.55)**\t0.398\t\nIrAE readmission\t43 (25.9)\t22 (14.8)\t0.46 (0.22 to 0.95)‡‡\t0.036\t\n Length of stay of irAE readmission, median (IQR), days\t7 (3–16)\t6 (3–10)\t−8.08 (−16.03 to 0.14)§\t0.046\t\nBold values are statistically significant,\n\n*Data are presented as number (percentage) of admissions, unless otherwise indicated; pre-SIC date range is April 2, 2016–October 2, 2017.\n\n†Data are presented as number (percentage) of admissions, unless otherwise indicated; post-SIC date range is October 3, 2017–October 24, 2018.\n\n‡Data are presented as coefficient (95% CI) for linear regressions (continuous variables) and OR (95% CI) for logistic regressions (categorical variables).\n\n§Multivariable linear regression with covariates: age, sex, irAE confirmation status, malignancy, ICI class and primary toxicity type.\n\n¶Excludes patients with thyroid toxicities or diabetes mellitus (given steroids are not indicated) as the irAE. Pre-SIC n=160; post-SIC n=139.\n\n**Multivariable logistic regression with covariates: age, sex, irAE confirmation status, malignancy, ICI class, primary toxicity type and presence of multiple toxicities.\n\n††Excludes patients with endocrine toxicities (given ICI discontinuation is not indicated) as well as patients who previously discontinued ICI prior to admission or discontinued ICI for any non-irAE reason (disease progression). Pre-SIC n=112; post-SIC n=91.\n\n‡‡Multivariable logistic regression with covariates: age, sex, irAE confirmation status, malignancy, ICI class, primary toxicity type, presence of multiple toxicities and ICI discontinuation for toxicity.\n\nICI, immune checkpoint inhibitor; irAE, immune-related adverse event; SIC, Severe Immunotherapy Complications.\n\nSpecimen collection\n\nThe sample collection effort began on January 1, 2018. All samples were collected after informed consent from each participant and only when performing clinically indicated diagnostic procedures or at the time of autopsy. The first sample was collected on January 12, 2018. From that date until December 28, 2019, a total of 789 samples were collected from 234 patients with suspected irAEs post-SIC. These samples include 496 blood specimens, 71 bodily fluids (bronchoalveolar lavage n=8, cerebrospinal fluid n=9, synovial fluid n=28, urine n=26) and 222 tissue samples collected during routine care (myocardial, liver, muscle, kidney and GI biopsies, as well as brain, lung and endocrine organ samples from autopsy) (figure 3). Specimens were either processed immediately on arrival to the lab (analysis ongoing), or frozen for future processing and analysis. An illustrative case example is a 53-year-old man with renal cell carcinoma treated with ipilimumab/nivolumab for two cycles who developed presumed ICI-related hepatitis requiring high-dose steroids. The hepatitis resolved and he was re-challenged with nivolumab for eight doses with a course complicated by hypothyroidism, myocarditis with congestive heart failure, and acute kidney injury with significant proteinuria. Nine blood, two urine, and two tissue samples (myocardium, muscle) were collected over the course of his illness (figure 4).\n\nFigure 3 Number of patient samples (blood, bodily fluids, tissues) collected. *Other=one case of hematological toxicity and one case of pancreatitis. BAL, bronchoalveolar lavage; CSF, cerebrospinal fluid.\n\nFigure 4 Serial blood and tissue samples in an irAE patient with multiple toxicities. irAE, immune-related adverse event.\n\nDiscussion\n\nIn this study, we evaluate the impact of altering a clinical practice model to care for patients with irAEs and creating a clinical–translational research model to study these events. Other services with multidisciplinary toxicity teams include Johns Hopkins University School of Medicine where an electronic referral system for immune-related toxicities was shown to be feasible and helpful to identify patterns of irAEs requiring subspecialist care.19 Dana-Farber Cancer Institute/Brigham Women’s Hospital has initiated a service through which they admitted 194 irAE patients in the first year and found the most common reasons for admission were colitis, hepatitis, and pneumonitis.27 To date, feasibility of these toxicity services has been demonstrated but evidence about the impact pre/post-implementation has not been reported.\n\nOf note, our irAE admission rate of 10%–11% pre/post-SIC intervention is lower than the 41% reported for suspected irAEs and 23% rate for confirmed irAEs in another recent study, conducted at a major academic medical center over a much shorter 7-month period.28 This suggests that although a percentage of irAEs hospitalizations can be avoided, around 10% of patients receiving ICIs develop irAEs that inevitably end in hospitalization.\n\nImportantly, the 6-month irAE readmission rate at our hospital decreased from 25.9% of patients to 14.8% after controlling for age, sex, irAE confirmation status, type of cancer, type of ICI regimen used, and primary toxicity type. Readmissions reduction is critically important as it is an opportunity to improve patient care and satisfaction, improve quality, and decrease healthcare costs. One potential explanation for the decrease in readmissions may have been the comprehensive inpatient care by SIC experts and consultants, the streamlined transition on discharge to outpatient care, and the network of outpatient subspecialists who provide significant continuity.\n\nIn addition, the post-SIC Service LOS for irAE readmissions also decreased from 7 to 6 days in comparison with the pre-SIC study period, a key finding which has implications for patients and healthcare systems. These findings are particularly important as readmission rates are commonly used measures for quality of care; it is estimated that Medicare spends $17 billion a year on avoidable readmissions, and in recent years, the US Hospital Readmissions Reduction Program has begun penalizing hospitals with high 30-day readmission rates.29 Thus, if a dedicated SIC Service can significantly improve these quality of care measures, it could result in meaningful gains for both patients and hospitals.\n\nAfter instituting the SIC Service, the mortality rate for patients hospitalized for irAEs did not significantly change. Our pre-SIC mortality rate of 6.6% (over 12 months) and post-SIC mortality rate of 8.7% (over 18 months) are similar to the 7.3% mortality rate reported in a 7-month irAE study conducted by another major academic medical center where clinical outcomes on patients hospitalized for irAEs were also analyzed.28 Further steps to decrease inpatient mortality relating to irAEs likely await new developments in the treatment for toxicity.\n\nImportantly, the data presented indicate SIC Service implementation was not associated with any negative outcomes despite integrating research blood and tissue collection into routine care. There were numerous samples collected but no sign of detrimental impact on clinical care—no difference in LOS, inpatient mortality, or readmission rate. Therefore, this study demonstrates safety and feasibility of collecting a wide range of biological samples from patients with irAE on an inpatient service. These specimens are being used for an ongoing effort to investigate predictive blood biomarkers for irAEs and identify mechanisms of irAE development. In this study, 789 blood and tissue samples were collected from 234 patients who developed irAEs in the first 2 years of the service. We found that the effort required to obtain timely patient consent for study participation and to collect the samples prior to steroids was considerable. Staff had to overcome a number of challenges including (1) seriously ill patients spread over 15 different floors of the hospital with staff often unfamiliar with the protocol; (2) patients who were often absent from their rooms to undergo imaging studies or procedures; (3) language barriers; (4) difficulty in obtaining blood; (5) delays and frequent rescheduling of inpatient procedures; (6) insufficient tissue quantity of specimen remaining for research after the necessary clinical samples were obtained; and (7) access to rapid and adequate processing in a timely fashion. Thus, if the oncology research community is to respond to the call for biomarker-based studies of irAE mechanisms and identification of potential biomarkers to detect patients at high risk of irAE, funding along with dedicated and coordinated services, or a central infrastructure, will likely be needed in order to scale efforts sufficiently.5 30 In order to propel this type of translational discovery, it will take a multi-institutional effort to pool samples in order to (1) uncover set of predictive factors for irAEs; (2) understand early mechanisms driving irAEs; (3) identify novel drug targets; and (4) develop better therapeutic strategies. This study is the first to report this type of effort is feasible and safe, and can be embedded in clinical care.\n\nThis study has several important limitations. First, it describes observations at a single institution and therefore results may not be representative of other institutions. Second, because our institution is an academic medical center housed within a general hospital, we were able to recruit numerous subspecialists focused on autoimmunity with an interest in irAEs across the spectrum; this may limit the study’s generalizability. Third, to ensure accuracy, in this study we only included data from patients who received both ICI therapy and irAE care at our institution; thus, our results do not reflect the experience of patients transferred to our hospital for irAE care, who tend to be in more critical condition, or patients who were treated with ICIs at our institution but hospitalized for irAEs elsewhere. Finally, a general improvement in knowledge and experience over time in managing irAEs may have led to the observed differences in the pre-SIC and post-SIC groups. During the time period of this study, new sets of guidelines from the American Society of Clinical Oncology and NCCN emerged. Therefore, we cannot exclude that increased irAE awareness and management skills among care providers, independent of the SIC service, affected the readmission rate and LOS.\n\nIn conclusion, this study is, to the best of our knowledge, the first to report that establishing a highly subspecialized care team focused on irAEs can be associated with improved clinical outcomes for patients receiving ICI therapy, while also building the infrastructure needed to drive future clinical research on ICI toxicities. Such care teams are likely to serve as a model and may play an essential role in improving irAE care: defining phenotypes, identifying diagnostics for early detection, developing biomarkers to assess irAE severity, and generating preliminary data to guide next-generation clinical trials for the treatment of irAEs. In addition, maintaining a central registry of patients, fostering a collegial group dynamic, having regular meetings, and a focus on collaboration across subspecialties and oncology have the potential to foster that future discovery. These teams will also play a key role in bringing these advances back to the bedside to benefit patients.\n\nLZ would like to acknowledge the Spanish Society of Medical Oncology (SEOM; Sociedad Española de Oncología Médica), her grant for a 2-year translational project at the Massachusetts General Hospital (MGH) Cancer Center.\n\nData availability statement\n\nData are available upon reasonable request.\n\nEthics statements\n\nPatient consent for publication\n\nNot required.\n\nEthics approval\n\nThis cohort study conducted at MGH was approved by the Massachusetts General Brigham Institutional Review Board (#2017P000501).\n\nLZ and GEM contributed equally.\n\nA-CV and KLR contributed equally.\n\nCorrection notice: This article has been corrected since it was first published. Author name has been corrected to '\n\nRebecca K Leaf'.\n\nContributors: LZ and GEM devised the project idea, acquired and analyzed data, performed statistical analysis, and wrote the manuscript. MJM, JC, SD, LP, GMB, DJ, MD, MFT, ATF, MR, ACG, STC, DO, BDM, MN, MK, SS, RKL, MES, TGN, DZ, JRF, AB, RS, SB, YRS and A-CV provided critical intellectual input to study design and analysis and edited the manuscript. KLR created the registry of immunotherapy toxicity cases and samples, devised the project idea, designed the study, and supervised the statistical analysis and manuscript development.\n\nFunding: This work was supported by the Spanish Society of Medical Oncology (SEOM; grant for a 2-year translational project at the MGH Cancer Center to LZ).\n\nCompeting interests: LZ—Merck consultant. JC—consultant for BMS and Sanofi-Genzyme. DJ—scientific advisory board fee from Eisai, EMD Serono, Genentech, Ipsen, Novartis, Guardant, Petra Pharma, Mapkure, Vibliome Therapeutics, and Relay Therapeutics; institutional research funds from Novartis, Genentech, EMD Serono, Eisai, Takeda, Placon Therapeutics, Syros, Ribon Therapeutics, Infinity Pharmaceuticals, InventisBio and Amgen. GMB—sponsored research agreements with Palleon Therapeutics and Olink Proteomics; scientific advisory board for Novartis and Nektar Therapeutics; consulting for Merck. MD—consultant for Moderna, Tillotts Pharma, ORIC Pharmaceuticals, and Partner Therapeutics; research funding from Novartis and Eli Lilly; scientific advisory board for Neoleukin Therapeutics. ACG—consultant for Momenta, Alexion, UCB/Ra pharma; royalties from Oakstone Publishing; research funding from Myasthenia Gravis Foundation of America, MGNET and Project Datasphere. BDM—consultant for Sanofi, AbbVie, and Celestial Pharmaceuticals. He has also received sponsored research agreements from Boehringer-Ingelheim, Bayer, and Bristol-Myers Squib. MK—consultant for Novartis and Mymee; speaker fees for Lilly. TGN—advisory fees from Parexel, BMS, H3 Biomedicine, AbbVie, and Intrinsic Imaging; grant support from AstraZeneca. JRF—research grants from Bristol Myers Squibb and X4 Pharmaceuticals. MJM—received honarium/acted as a consultant for AstraZeneca, Nektar Therapeutics, Catalyst Pharmaceuticals, Immunai Aditya Bardia; consulting or advisory role for bioTheranostics, Genentech, Genentech/Roche (Inst), Immunomedics, Immunomedics (Inst), Innocrin Pharma (Inst), Merck, Merck (Inst), Novartis, Novartis (Inst), Pfizer, Pfizer (Inst), Radius Health (Inst), Radius Pharma, Sanofi, Spectrum Pharmaceuticals; research funding from bioTheranostics. RS—consultant/scientific advisory board member for AstraZeneca, Bristol-Myers Squibb, Eisai, Iovance, Merck, Novartis, OncoSec, Pfizer, Replimune; research funding from Merck and Amgen. SB—consultant for Third Rock Consulting and Two River Consulting; equity holdings in Kronos Bio and Allogene Therapeutics. YRS—consultant for Castle Biosciences.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nSupplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.\n==== Refs\nReferences\n\n1 VaddepallyRK, KharelP, PandeyR, et al . Review of indications of FDA-approved immune checkpoint inhibitors per NCCN guidelines with the level of evidence. Cancers 2020;12 :738. 10.3390/cancers12030738\n2 HaslamA, GillJ, PrasadV. Estimation of the percentage of US patients with cancer who are eligible for immune checkpoint inhibitor drugs. JAMA Netw Open 2020;3 :e200423. 10.1001/jamanetworkopen.2020.0423 32150268\n3 QinS, XuL, YiM, et al . Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4. Mol Cancer 2019;18 :155. 10.1186/s12943-019-1091-2 31690319\n4 Xin YuJ, HodgeJP, OlivaC, et al . Trends in clinical development for PD-1/PD-L1 inhibitors. Nat Rev Drug Discov 2020;19 :163–4. 10.1038/d41573-019-00182-w 32127660\n5 PostowMA, SidlowR, HellmannMD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 2018;378 :158–68. 10.1056/NEJMra1703481 29320654\n6 Ramos-CasalsM, BrahmerJR, CallahanMK, et al . Immune-related adverse events of checkpoint inhibitors. Nat Rev Dis Primers 2020;6 :38. 10.1038/s41572-020-0160-6 32382051\n7 HaanenJBAG, CarbonnelF, RobertC, et al . Corrections to “Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann of Oncology 2018;29 :iv264–6. 10.1093/annonc/mdy162\n8 Arnaud-CoffinP, MailletD, GanHK, et al . A systematic review of adverse events in randomized trials assessing immune checkpoint inhibitors. Int J Cancer 2019;145 :639–48. 10.1002/ijc.32132 30653255\n9 BrahmerJR, LacchettiC, SchneiderBJ, et al . Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of clinical oncology clinical practice guideline. J Clin Oncol 2018;36 :1714–68. 10.1200/JCO.2017.77.6385 29442540\n10 National Comprehensive Cancer Network. Management of Immunotherapy-Related toxicities (version 2.2021). Available: https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf\n11 PuzanovI, DiabA, AbdallahK, et al . Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for immunotherapy of cancer (SITC) toxicity management Working group. J Immunother Cancer 2017;5 :95. 10.1186/s40425-017-0300-z 29162153\n12 AntoniaSJ, López-MartinJA, BendellJ, et al . Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol 2016;17 :883–95. 10.1016/S1470-2045(16)30098-5 27269741\n13 PostowMA, ChesneyJ, PavlickAC, et al . Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015;372 :2006–17. 10.1056/NEJMoa1414428 25891304\n14 LarkinJ, Chiarion-SileniV, GonzalezR, et al . Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med Overseas Ed 2019;381 :1535–46. 10.1056/NEJMoa1910836\n15 WangDY, SalemJ-E, CohenJV, et al . Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol 2018;4 :1721–8. 10.1001/jamaoncol.2018.3923 30242316\n16 JohnsonDB, ReynoldsKL, SullivanRJ, et al . Immune checkpoint inhibitor toxicities: systems-based approaches to improve patient care and research. Lancet Oncol 2020;21 :e398–404. 10.1016/S1470-2045(20)30107-8 32758477\n17 ColeS, ZibelmanM, BertinoE, et al . Managing immuno-oncology toxicity: top 10 innovative institutional solutions. Am Soc Clin Oncol Educ Book 2019;39 :96–104. 10.1200/EDBK_100018 31099682\n18 ZhangL, ZlotoffDA, AwadallaM, et al . Major adverse cardiovascular events and the timing and dose of corticosteroids in immune checkpoint inhibitor-associated myocarditis. Circulation 2020;141 :2031–4. 10.1161/CIRCULATIONAHA.119.044703 32539614\n19 NaidooJ, ZhangJ, LipsonEJ, et al . A multidisciplinary toxicity team for cancer Immunotherapy–Related adverse events. J Natl Compr Canc Netw 2019;17 :712–20. 10.6004/jnccn.2018.7268 31200355\n20 LäubliH, DirnhoferS, ZippeliusA. Immune tumor board: integral part in the multidisciplinary management of cancer patients treated with cancer immunotherapy. Virchows Archiv 2019;474 :485–95. 10.1007/s00428-018-2435-9 30143868\n21 MichotJ-M, LapparaA, Le PavecJ, et al . The 2016–2019 ImmunoTOX assessment board report of collaborative management of immune-related adverse events, an observational clinical study. Eur J Cancer 2020;130 :39–50. 10.1016/j.ejca.2020.02.010 32172197\n22 LiuJ, BlakeSJ, SmythMJ, et al . Improved mouse models to assess tumour immunity and irAEs after combination cancer immunotherapies. Clin Trans Immunol 2014;3 :e22. 10.1038/cti.2014.18\n23 OlsonB, LiY, LinY, et al . Mouse models for cancer immunotherapy research. Cancer Discov 2018;8 :1358–65. 10.1158/2159-8290.CD-18-0044 30309862\n24 EsfahaniK, ElkriefA, CalabreseC, et al . Moving towards personalized treatments of immune-related adverse events. Nat Rev Clin Oncol 2020;17 :504–15. 10.1038/s41571-020-0352-8 32246128\n25 WeinmannSC, PisetskyDS. Mechanisms of immune-related adverse events during the treatment of cancer with immune checkpoint inhibitors. Rheumatology 2019;58 :vii59–67. 10.1093/rheumatology/kez308 31816080\n26 MolinaGE, ZubiriL, CohenJV, et al . Temporal trends and outcomes among patients admitted for immune-related adverse events: a single-center retrospective cohort study from 2011 to 2018. Oncologist 2021;26 :514–22. 10.1002/onco.13740 33655682\n27 Abu-ShawerO, SinghP, YenulevichE, et al . Novel platform Leveraging electronic medical record (EMR) to triage patients admitted with high-grade immune-related adverse events (irAEs) to the immune-toxicity (ITOX) service. J Immunother Cancer 2020;8 :e000992. 10.1136/jitc-2020-000992 32817360\n28 BalajiA, ZhangJ, WillsB, et al . Immune-related adverse events requiring hospitalization: spectrum of toxicity, treatment, and outcomes. J Oncol Pract 2019;15 :e825–34. 10.1200/JOP.18.00703 31386608\n29 BoozaryAS, ManchinJ, WickerRF. The Medicare Hospital readmissions reduction program: time for reform. JAMA 2015;314 :347–8. 10.1001/jama.2015.6507 26219049\n30 ZubiriL, AllenIM, TaylorMS, et al . Immune-Related adverse events in the setting of PD-1/L1 inhibitor combination therapy. Oncologist 2020;25 :e398–404. 10.1634/theoncologist.2018-0883 32162817\n\n",
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"journal": "Journal for immunotherapy of cancer",
"keywords": "biomarkers; combination; cytotoxicity; drug therapy; immunologic; immunotherapy; inflammation; tumor",
"medline_ta": "J Immunother Cancer",
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"pmid": "34544895",
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"title": "Effect of a multidisciplinary Severe Immunotherapy Complications Service on outcomes for patients receiving immune checkpoint inhibitor therapy for cancer.",
"title_normalized": "effect of a multidisciplinary severe immunotherapy complications service on outcomes for patients receiving immune checkpoint inhibitor therapy for cancer"
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"abstract": "OBJECTIVE\nNeuroinflammation contributes to motor neuron degeneration in ALS. Thalidomide (THL) shows potent anti-inflammatory properties and increased the lifespan in ALS transgenic mice. Thalidomide was therefore suggested as atherapeutic intervention for the treatment of ALS.We conducted a pilot, randomized clinical trial of THL in patients with ALS to assess safety, feasibility, and preliminary estimates of treatment efficacy.\n\n\nMETHODS\nPatients were randomized to THL in combination with riluzole (n = 18) or riluzole alone (n = 19). THL was initiated at 100 mg per day for 6 weeks. Thereafter, the dose was increased every week by 50 mg until reaching the dose of 400 mg per day and planned to continue for another 12 weeks.\n\n\nRESULTS\nWithin 12 weeks of THL treatment, nine THL patients (50%) developed bradycardia defined as a heart rate below 60 beats per minute (bpm) and ranged from 46 to 59 bpm. Mean heart rate dropped by 17 bpm with THL treatment. Severe symptomatic bradycardia of 30 bpm occurred in one patient. A further patient died from sudden unexpected death. The study was terminated prematurely for safety concerns. The secondary outcome variables showed similar results for both groups.\n\n\nCONCLUSIONS\nBradycardia was the most common adverse event of THL treatment in ALS. THL-related bradycardia does not appear to be ALS-specific. It is conceivable, however, that the unexpected frequency and severity of THL-induced bradycardia may be related to subclinical involvement of the autonomic nervous system in ALS. The cardiac toxicity discourages further clinical trials and compassionate use of THL in ALS. ClinicalTrials.gov Identifier: NCT00231140.",
"affiliations": "Dept. of Neurology, Charité University Hospital, Campus Virchow-Klinikum, Ambulanz für ALS und andere Motoneuronenerkrankungen, Augustenburger Platz 1, 13353 Berlin, Germany. thomas.meyer@charite.de",
"authors": "Meyer|Thomas|T|;Maier|André|A|;Borisow|Nadja|N|;Dullinger|Jörn S|JS|;Splettstösser|Gerald|G|;Ohlraun|Stephanie|S|;Münch|Christoph|C|;Linke|Peter|P|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D018691:Excitatory Amino Acid Antagonists; D007166:Immunosuppressive Agents; D013792:Thalidomide; D019782:Riluzole",
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"issue": "255(4)",
"journal": "Journal of neurology",
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"medline_ta": "J Neurol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis; D000893:Anti-Inflammatory Agents; D001146:Arrhythmia, Sinus; D001919:Bradycardia; D003645:Death, Sudden; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004562:Electrocardiography; D018691:Excitatory Amino Acid Antagonists; D006801:Humans; D007166:Immunosuppressive Agents; D007249:Inflammation; D008875:Middle Aged; D017574:Parasystole; D010865:Pilot Projects; D019782:Riluzole; D013792:Thalidomide; D016896:Treatment Outcome",
"nlm_unique_id": "0423161",
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"pmid": "18425621",
"pubdate": "2008-04",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
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"title": "Thalidomide causes sinus bradycardia in ALS.",
"title_normalized": "thalidomide causes sinus bradycardia in als"
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"abstract": "Sarcoidosis is a multisystem granulomatous disorder. Neurological manifestations as a presenting symptom are relatively rare. A 26-year-old male presented with a five-week history of headache suggestive of raised intracranial pressure. He subsequently developed transient episodes of mild right-sided hemiparesis and numbness. Magnetic resonance imaging (MRI) of brain revealed widespread inflammatory white matter lesions, an ischaemic focus in the left corona radiata, and widespread microhaemorrhages consistent with a more diffuse vasculopathy. Serum angiotensin-converting enzyme (ACE) level was normal. Lumbar puncture revealed an elevated opening pressure (36 cmH2O) and inflammatory cerebrospinal fluid (CSF). Computerised tomography (CT) of chest, abdomen, and pelvis revealed widespread lymphadenopathy and biopsy of axillary lymph nodes revealed the presence of noncaseating granulomata in keeping with systemic sarcoidosis. The patient responded well to corticosteroids. This case highlights the importance of considering sarcoidosis to be a rare but potentially treatable cause of stroke in younger patients.",
"affiliations": "Department of Neurology, Royal Victoria Hospital, Belfast BT12 6BA, UK.;Department of Neurology, Royal Victoria Hospital, Belfast BT12 6BA, UK.;Department of Neuroradiology, Royal Victoria Hospital, Belfast BT12 6BA, UK.;Department of Neuroradiology, Royal Victoria Hospital, Belfast BT12 6BA, UK.;Neurology Centre, Altnagelvin Area Hospital, Londonderry BT47 6SB, UK.;Department of Neurology, Royal Victoria Hospital, Belfast BT12 6BA, UK.",
"authors": "Campbell|J|J|;Kee|R|R|;Bhattacharya|D|D|;Flynn|P|P|;McCarron|M|M|;Fulton|A|A|",
"chemical_list": null,
"country": "Egypt",
"delete": false,
"doi": "10.1155/2015/619867",
"fulltext": "\n==== Front\nCase Reports ImmunolCase Reports ImmunolCRIICase Reports in Immunology2090-66092090-6617Hindawi Publishing Corporation 10.1155/2015/619867Case ReportSystemic Sarcoidosis Presenting with Headache and Stroke-Like Episodes Campbell J. \n1\n\n*\nKee R. \n1\nBhattacharya D. \n2\nFlynn P. \n2\nMcCarron M. \n3\nFulton A. \n1\n1Department of Neurology, Royal Victoria Hospital, Belfast BT12 6BA, UK2Department of Neuroradiology, Royal Victoria Hospital, Belfast BT12 6BA, UK3Neurology Centre, Altnagelvin Area Hospital, Londonderry BT47 6SB, UK*J. Campbell: jcampbell@talk21.comAcademic Editor: Takahisa Gono\n\n2015 29 9 2015 2015 61986710 6 2015 13 9 2015 Copyright © 2015 J. Campbell et al.2015This 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.Sarcoidosis is a multisystem granulomatous disorder. Neurological manifestations as a presenting symptom are relatively rare. A 26-year-old male presented with a five-week history of headache suggestive of raised intracranial pressure. He subsequently developed transient episodes of mild right-sided hemiparesis and numbness. Magnetic resonance imaging (MRI) of brain revealed widespread inflammatory white matter lesions, an ischaemic focus in the left corona radiata, and widespread microhaemorrhages consistent with a more diffuse vasculopathy. Serum angiotensin-converting enzyme (ACE) level was normal. Lumbar puncture revealed an elevated opening pressure (36 cmH2O) and inflammatory cerebrospinal fluid (CSF). Computerised tomography (CT) of chest, abdomen, and pelvis revealed widespread lymphadenopathy and biopsy of axillary lymph nodes revealed the presence of noncaseating granulomata in keeping with systemic sarcoidosis. The patient responded well to corticosteroids. This case highlights the importance of considering sarcoidosis to be a rare but potentially treatable cause of stroke in younger patients.\n==== Body\n1. Introduction\nSarcoidosis is a multisystem granulomatous disorder characterised by noncaseating granulomata. The respiratory system is one of the most commonly involved sites and patients may present with cough and dyspnoea [1].\n\nThe nervous system is affected in approximately 5% of patients with sarcoidosis [2]. The neurological manifestations can be diverse but most commonly include cranial neuropathies (particularly involving the facial or optic nerves) [2, 3]. Other less frequent presentations include meningoencephalitis, hydrocephalus, intracranial mass lesions, psychiatric symptoms, spinal cord disease, peripheral nerve involvement, or even myopathy [4–7].\n\nDespite pathological evidence of granulomatous involvement of cerebral blood vessels in neurosarcoidosis [8], stroke or transient ischaemic episodes are reported only very rarely. We report a case of an unusual presentation of systemic sarcoidosis with headache and stroke-like symptoms.\n\n2. Case Report\nA 26-year-old right-handed male was admitted to a district general hospital with a five-week history of gradual onset, dull, and global headache that was worse when supine and exacerbated by valsalva manoeuvres. There was associated nausea and frequent early morning vomiting. He also complained of prominent lethargy and approximately 5 kg of weight loss in the preceding four months.\n\nHe denied visual disturbance or other focal neurological symptoms at presentation. There was no history of febrile illness or recent travel. Soon after admission he experienced several transient episodes of sudden onset right upper limb weakness and numbness lasting up to 15 minutes without impairment of consciousness.\n\nHis past medical history was notable for an episode of right-sided uveitis six years prior to this presentation. He also had a history of well-controlled childhood epilepsy.\n\nApproximately eighteen months prior to his current admission he was discovered to have renal impairment (urea 14.8 mmol/L and creatinine 226 umol/L) after a routine check-up revealed hypertension. He underwent renal biopsy that was consistent with interstitial nephritis and which was attributed to sodium valproate that he had been taking for treatment of epilepsy. The sodium valproate was switched to levetiracetam and he was started on prednisolone and lisinopril. Renal function subsequently stabilised, blood pressure normalised, and the prednisolone was gradually weaned over the following 18 months and had been stopped several weeks prior to this admission.\n\nMedications on this admission were levetiracetam 2500 mg daily, omeprazole 20 mg daily, and lisinopril 2.5 mg daily.\n\n3. Examination\nOn examination chest was clear on auscultation. There was no hepatosplenomegaly. On neurological examination tone, power, and coordination were normal. Reflexes were symmetrically brisk; however both plantar responses were flexor. Visual acuity was 6/6 in both eyes. On fundoscopy there was blurring of the optic disc margins bilaterally as well as absent spontaneous venous pulsations in both eyes. Blood pressure was 150/107. Systemic examination revealed the presence of diffuse, nontender cervical and axillary lymphadenopathy. There were no visible skin lesions. The remainder of the examination was normal.\n\nInitial investigations included a mild normocytic anaemia (Hb 11.6 g/dL). Serum white cell count, erythrocyte sedimentation rate, C-reactive protein, liver function tests, and serum electrolytes (including calcium) were normal. Blood urea was 7.1 mmol/L; creatinine was 282 umol/L.\n\nOther laboratory tests including tests for human immunodeficiency virus, VDRL, double stranded DNA, anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies, serum angiotensin-converting enzyme, antibodies to extractable nuclear antigens, anti-Ro, anti-La, anti-Sm, anti-RNP, anti-Scl, and anti-Jo1 as well as tuberculosis quantiferon and mantoux testing were normal or negative. Serology for herpes simplex virus, cytomegalovirus, Epstein-Barr virus, and varicella virus was negative. Chest radiograph was normal on admission.\n\nCT brain on admission was normal. Cerebrospinal fluid analysis revealed an opening pressure of 36 cmH2O. CSF protein was 0.74 g/L and glucose was 2.9 mmol/L (no paired serum was sent for analysis). There were 9 lymphocytes/μL and 72 erythrocytes/μL. CSF was sterile. Oligoclonal bands were not detected.\n\nMRI brain showed multiple small T2-weighted hyperintense lesions predominantly within the subcortical white matter throughout both cerebral hemispheres and also within the right pons. Microhaemorrhages were also observed on susceptibility weighted imaging (SWI) and an area of restricted diffusion was observed in the left centrum semiovale on diffusion weighted MRI consistent with a small acute infarct (Figure 1).\n\nRepeat MRI imaging upon transfer to a tertiary neurology unit revealed further linear areas of T2 hyperintensity with postcontrast T1 enhancement extending from the periventricular regions into the centrum semiovale bilaterally.\n\nA differential diagnosis of cerebral vasculitis, a neoplastic process, or granulomatous disease was considered. CT of chest, abdomen, and pelvis revealed multiple lymph nodes in both axillae measuring up to 14 mm, as well as mediastinal and left para-aortic lymphadenopathy (Figure 2).\n\nThe patient underwent excision of one of the axillary lymph nodes, which revealed the presence of noncaseating granulomata in keeping with sarcoidosis (Figure 3). The original kidney biopsy was subsequently reviewed but did not contain evidence of granulomata.\n\n4. Treatment and Outcome\nThe patient was treated with one gram of intravenous methylprednisolone for three days followed by 60 mg daily of oral prednisolone with rapid clinical improvement. Renal function improved to baseline following commencement of steroids. Repeat lumbar puncture one month following introduction of steroids revealed opening pressure of 19 cmH2O, protein 0.29 g/L, glucose 4.6 mmol, 2 lymphocytes/μL, and 72 erythrocytes/μL. Oligoclonal bands remained negative. At 12-month follow-up, the patient was well with no relapse of symptoms. He was maintained on 5 mg of prednisolone daily.\n\n5. Discussion\nSarcoidosis is a systemic granulomatous disorder most commonly presenting between the ages of 20 and 40 years and is particularly prevalent among African Americans and Northern Europeans [9, 10]. The diagnosis of sarcoidosis most often relies on identifying systemic manifestations of the condition and obtaining histological demonstration of noncaseating granulomata on biopsy of affected tissue. Histologically, a central collection of macrophages is seen to exist with an oligoclonal T-cell population situated peripherally [11].\n\nAbout 30–60% of patients with sarcoidosis develop granulomatous uveitis at some point in the course of the disease [12] but this can precede the systemic manifestations by up to eleven years [13]. Renal involvement may appear as interstitial nephritis and long-term treatment is often required to prevent progression to end stage renal failure [14].\n\nNeurosarcoidosis is known to affect a minority of patients with sarcoidosis. The neurological features of sarcoidosis can be diverse and where neurological symptoms are the sole manifestation of the condition it can be particularly challenging to make a definitive diagnosis [15]. To further the investigation of suspected neurosarcoidosis, investigation with CSF analysis and measurement of CSF ACE levels are often undertaken. Both have limited sensitivity and specificity in the diagnosis of neurosarcoidosis [16]. Although tissue diagnosis remains the gold standard, it is invasive and not always feasible. MRI therefore remains an important investigation. The most common MRI findings in neurosarcoidosis include cranial nerve involvement, enhancing and nonenhancing parenchymal lesions, dural thickening, and leptomeningeal enhancement. Occasionally intracranial mass lesions are seen [17].\n\nOur case is of interest for several reasons. The interval between the initial manifestations of sarcoidosis (presumed to be anterior uveitis) and subsequent symptoms was significant (over six years). The episode of acute onset right-sided weakness was shown to be related to an area of diffusion restriction on MRI. Focal ischaemic change in conjunction with MRI evidence of more diffuse microhaemorrhages was felt consistent with a vasculopathy. The neurovascular complications of neurosarcoidosis are extremely rare.\n\nAlthough granulomatous involvement of cerebral blood vessels is described in neurosarcoidosis [8], stroke or transient ischaemic episodes are only rarely reported and such case reports largely precede the routine use of MRI [18–20]. Only isolated case reports exist of ischaemic stroke in the context of neurosarcoidosis confirmed on diffusion weighted MRI [21, 22]. Haemorrhagic manifestations of neurosarcoidosis are also reported but are a rare presentation [23–26]. Vascular complications of this nature are felt to result from a small-vessel vasculopathy, usually due to the destruction of elastic lumen by inflammatory cells and subsequent luminal occlusion. Acute necrotizing vasculopathy has also been observed [27].\n\nThe optimum treatment of neurosarcoidosis is unclear. Corticosteroids are generally considered the first-line treatment; however high doses may be required and relapse can occur during drug taper [28]. A number of agents including methotrexate, chloroquine, azathioprine, mycophenolate mofetil, cyclophosphamide, and infliximab can be used as second-line or steroid sparing agents [29–32]. Due to the rarity of neurosarcoidosis, large scale randomized controlled trial evidence is lacking.\n\n6. Conclusion\nWe report a case of biopsy proven systemic sarcoidosis presenting with neurological features of raised intracranial pressure and transient neurological deficits, which were felt to be of vascular origin. Serial MRI over a short period showed significant change both revealing an area of restriction diffusion indicative of ischaemia and showing evidence of cerebral microhaemorrhages on susceptibility weighted imaging sequences as a result of small-vessel granulomatous vasculopathy.\n\nIn retrospect, the past medical history of anterior uveitis and interstitial nephritis is felt to be in keeping with systemic sarcoidosis and serves to highlight the considerable variation that can be seen in the natural history of this condition.\n\nThis case highlights that neurosarcoidosis should be considered a potentially treatable cause of otherwise unexplained vasculopathy or stroke, particularly in the context of other atypical neurological features or salient past medical history.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 MRI scan of brain. MRI of brain. Axial T2-weighted image showing T2 hyperintense lesion within the right pons (arrow) (a). Axial DWI (B1000) demonstrates restricted diffusion within the left centrum semiovale (arrow) (b). Gradient recalled ECHO T2 susceptibility weighted imaging showing diffuse hypointense lesions suggestive of microhaemorrhages (arrow) (c).\n\nFigure 2 CT scan of thorax. CT of chest showing enlarged axillary nodes (arrow).\n\nFigure 3 Axillary lymph node biopsy showing noncaseating granulomata (arrow) at ×50 magnification (a) and noncaseating granulomata (arrow) at ×200 magnification (b).\n==== Refs\n1 Baughman R. P. Lower E. E. du Bois R. M. Sarcoidosis The Lancet 2003 361 9363 1111 1118 10.1016/s0140-6736(03)12888-7 2-s2.0-0037471855 \n2 Burns T. M. Neurosarcoidosis Archives of Neurology 2003 60 8 1166 1168 10.1001/archneur.60.8.1166 2-s2.0-0041522700 12925378 \n3 Zajicek J. P. Scolding N. J. Foster O. Central nervous system sarcoidosis—diagnosis and management QJM: Monthly Journal of the Association of Physicians 1999 92 2 103 117 10.1093/qjmed/92.2.103 2-s2.0-0032982056 10209662 \n4 Stern B. J. Krumholz A. Johns C. Scott P. Nissim J. Sarcoidosis and its neurological manifestations Archives of Neurology 1985 42 9 909 917 10.1001/archneur.1985.04060080095022 2-s2.0-0021889161 3896208 \n5 Sponsler J. L. Werz M. A. Maciunas R. Cohen M. Neurosarcoidosis presenting with simple partial seizures and solitary enhancing mass: case reports and review of the literature Epilepsy and Behavior 2005 6 4 623 630 10.1016/j.yebeh.2005.02.016 2-s2.0-18744411568 15907759 \n6 Fayad F. Lioté F. Berenbaum F. Orcel P. Bardin T. Muscle involvement in sarcoidosis: a retrospective and followup studies Journal of Rheumatology 2006 33 1 98 103 2-s2.0-30144435039 16395757 \n7 Wang L. Li Y. Longitudinal ultra-extensive transverse myelitis as a manifestation of neurosarcoidosis Journal of the Neurological Sciences 2015 355 1-2 64 67 10.1016/j.jns.2015.05.017 26027786 \n8 Herring A. B. Urich H. Sarcoidosis of the central nervous system Journal of the Neurological Sciences 1969 9 3 405 422 10.1016/0022-510x(69)90086-0 2-s2.0-0014605391 5367038 \n9 Rybicki B. A. Major M. Popovich J. Jr. Maliarik M. J. Iannuzzi M. C. Racial differences in sarcoidosis incidence: a 5-year study in a health maintenance organization American Journal of Epidemiology 1997 145 3 234 241 10.1093/oxfordjournals.aje.a009096 2-s2.0-0030609489 9012596 \n10 Reich J. M. A critical analysis of sarcoidosis incidence assessment Multidisciplinary Respiratory Medicine 2013 8 1, article 57 10.1186/2049-6958-8-57 \n11 Moller D. R. Cells and cytokines involved in the pathogenesis of sarcoidosis Sarcoidosis Vasculitis and Diffuse Lung Disease 1999 16 1 24 31 2-s2.0-0032939961 \n12 Takase H. Shimizu K. Yamada Y. Hanada A. Takahashi H. Mochizuki M. Validation of international criteria for the diagnosis of ocular sarcoidosis proposed by the first international workshop on ocular sarcoidosis Japanese Journal of Ophthalmology 2010 54 6 529 536 10.1007/s10384-010-0873-2 2-s2.0-78751613563 21191712 \n13 Rizzato G. Angi M. Fraioli P. Montemurro L. Pilotto E. Tommasini A. Uveitis as a presenting feature of chronic sarcoidosis European Respiratory Journal 1996 9 6 1201 1205 10.1183/09031936.96.09061201 2-s2.0-0030016232 8804938 \n14 Rajakariar R. Sharples E. J. Raftery M. J. Sheaff M. Yaqoob M. M. Sarcoid tubulo-interstitial nephritis: long-term outcome and response to corticosteroid therapy Kidney International 2006 70 1 165 169 10.1038/sj.ki.5001512 2-s2.0-33745697870 16688117 \n15 Oksanen V. Neurosarcoidosis: clinical presentations and course in 50 patients Acta Neurologica Scandinavica 1986 73 3 283 290 2-s2.0-0022628083 3716768 \n16 Borucki S. J. Nguyen B. V. Ladoulis Ch. T. McKendall R. R. Cerbrospinal fluid immunoglobulin abnormalities in neurosarcoidosis Archives of Neurology 1989 46 3 270 273 10.1001/archneur.1989.00520390036012 2-s2.0-0024476950 2919980 \n17 Miller D. H. Kendall B. E. Barter S. Magnetic resonance imaging in central nervous system sarcoidosis Neurology 1988 38 3 378 383 10.1212/wnl.38.3.378 2-s2.0-0023864671 3347340 \n18 Brown M. M. Thompson A. J. Wedzicha J. A. Swash M. Sarcoidosis presenting with stroke Stroke 1989 20 3 400 405 10.1161/01.str.20.3.400 2-s2.0-0024539237 2922780 \n19 Corse A. M. Stern B. J. Neurosarcoidosis and stroke Stroke 1990 21 1 152 153 2-s2.0-0025190794 2300985 \n20 Michotte A. Dequenne P. Jacobovitz D. Hildebrand J. Focal neurological deficit with sudden onset as the first manifestation of sarcoidosis: a case report with MRI follow-up European Neurology 1991 31 6 376 379 10.1159/000116697 2-s2.0-0025938707 1756760 \n21 Hodge M. H. Williams R. L. Fukui M. B. Neurosarcoidosis presenting as acute infarction on diffusion-weighted MR imaging: summary of radiologic findings American Journal of Neuroradiology 2007 28 1 84 86 2-s2.0-33846422396 17213430 \n22 González-Aramburu I. Ruiz-Pérez E. Gómez-Román J. Quirce R. Larrosa D. Pascual J. Sarcoidosis presenting as transient ischemic attack status Journal of Stroke and Cerebrovascular Diseases 2012 21 6 515 517 10.1016/j.jstrokecerebrovasdis.2010.12.003 2-s2.0-84864139020 21295493 \n23 Ferroir J.-P. Khalil A. Gounant V. Milleron B. Brain and medullar neurosarcoidosis, complicated by stroke with local vasculitis Revue Neurologique 2009 165 6-7 596 600 10.1016/j.neurol.2008.08.010 2-s2.0-68149150727 18947844 \n24 O'Dwyer J. P. Al-Moyeed B. A. Farrell M. A. Neurosarcoidosis-related intracranial haemorrhage: three new cases and a systematic review of the literature European Journal of Neurology 2013 20 1 71 78 10.1111/j.1468-1331.2012.03783.x 2-s2.0-84871645515 22681045 \n25 Dakdouki G. K. Kanafani Z. A. Ishak G. Hourani M. Kanj S. S. Intracerebral bleeding in a patient with neurosarcoidosis while on corticosteroid therapy Southern Medical Journal 2005 98 4 492 494 10.1097/01.SMJ.0000146621.42198.31 2-s2.0-17244372855 15898534 \n26 Berek K. Kiechl S. Willeit J. Birbamer G. Vogl G. Schmutzhard E. Subarachnoid hemorrhage as presenting feature of isolated neurosarcoidosis The Clinical Investigator 1993 71 1 54 56 10.1007/bf00210965 2-s2.0-0027446538 8453261 \n27 Reske-Nielsen E. Harmsen A. Periangiitis and panangiitis as a manifestation of sarcoidosis of the brain: report of a case The Journal of Nervous and Mental Disease 1962 135 399 412 10.1097/00005053-196211000-00003 2-s2.0-10544235608 13981735 \n28 Dumas J.-L. Valeyre D. Chapelon-Abric C. Central nervous system sarcoidosis: follow-up at MR imaging during steroid therapy Radiology 2000 214 2 411 420 10.1148/radiology.214.2.r00fe05411 2-s2.0-0033957994 10671588 \n29 Sharma O. P. Effectiveness of chloroquine and hydroxychloroquine in treating selected patients with sarcoidosis with neurological involvement Archives of Neurology 1998 55 9 1248 1254 10.1001/archneur.55.9.1248 2-s2.0-0031721906 9740120 \n30 Stern B. J. Schonfeld S. A. Sewell C. Krumholz A. Scott P. Belendiuk G. The treatment of neurosarcoidosis with cyclosporine Archives of Neurology 1992 49 10 1065 1072 10.1001/archneur.1992.00530340089023 2-s2.0-0026644087 1329698 \n31 Kouba D. J. Mimouni D. Rencic A. Nousari H. C. Mycophenolate mofetil may serve as a steroid-sparing agent for sarcoidosis British Journal of Dermatology 2003 148 1 147 148 10.1046/j.1365-2133.2003.05042.x 2-s2.0-0037244356 12534610 \n32 Sollberger M. Fluri F. Baumann T. Successful treatment of steroid-refractory neurosarcoidosis with infliximab Journal of Neurology 2004 251 6 760 761 2-s2.0-3042621451 15311358\n\n",
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"journal": "Case reports in immunology",
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"medline_ta": "Case Reports Immunol",
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"nlm_unique_id": "101622188",
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"pages": "619867",
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"pmid": "26491579",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
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"title": "Systemic Sarcoidosis Presenting with Headache and Stroke-Like Episodes.",
"title_normalized": "systemic sarcoidosis presenting with headache and stroke like episodes"
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"abstract": "BACKGROUND\nHydrothorax is an uncommon but well-recognized complication of peritoneal dialysis. It is a potentially serious condition that frequently requires cessation of peritoneal dialysis and permanent transition to hemodialysis. Hydrothorax is produced by movement of peritoneal dialysate through pleuroperitoneal fistulas. Pleural fluid analysis typically detects a high glucose concentration, and contrast imaging reveals tracer uptake transgressing the diaphragm. Experience with the treatment of hydrothorax related to peritoneal dialysis is limited.\n\n\nMETHODS\nWe describe the case of a 54-year-old female on peritoneal dialysis for end-stage renal failure who developed a hydrothorax soon after beginning treatment.\n\n\nCONCLUSIONS\nThis case describes a classical presentation of hydrothorax in the context of peritoneal dialysis. Treatment is frequently unsuccessful. All clinicians prescribing peritoneal dialysis should be aware of this complication.",
"affiliations": "Department of Internal Medicine, Redcliffe Hospital, Redcliffe, Queensland, Australia.;Department of Surgery, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia.",
"authors": "Yaxley|Julian|J|;Twomey|Kevin|K|",
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"country": "United States",
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"issn_linking": "1524-5012",
"issue": "17(1)",
"journal": "The Ochsner journal",
"keywords": "Ascitic fluid; hernias–diaphragmatic–congenital; hydrothorax; peritoneal dialysis",
"medline_ta": "Ochsner J",
"mesh_terms": null,
"nlm_unique_id": "101125795",
"other_id": null,
"pages": "124-127",
"pmc": null,
"pmid": "28331461",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "26054713;21751113;2679094;21480997;12969393;9527025;21059200;22111056;12322829;10383035;20056973;8445842;15220759;10836975;12118762;1912026",
"title": "Peritoneal Dialysis Complicated by Pleuroperitoneal Communication and Hydrothorax.",
"title_normalized": "peritoneal dialysis complicated by pleuroperitoneal communication and hydrothorax"
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"companynumb": "AU-BAXTER-2017BAX015458",
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"abstract": "The GEMINI trials established the efficacy of vedolizumab in moderate-to-severe inflammatory bowel disease (IBD) and demonstrated a favorable safety profile, suggesting it may be advantageous in older patients at greater risk of treatment-related complications. However, there is a paucity of data exploring the outcomes of vedolizumab in this group. Our objective was to determine the clinical effectiveness and safety of vedolizumab in older IBD patients within a real-world multicenter UK cohort.\nA retrospective review of electronic records across 6 UK hospitals was undertaken to evaluate the clinical effectiveness and safety outcomes of vedolizumab in IBD patients aged ≥60 at start of therapy. Rates of clinical response, remission and corticosteroid-free remission were assessed at weeks 14 and 52, using validated clinical indices, and were compared to historical controls from real-world vedolizumab-treated cohorts unstratified by age.\nOf 74 patients aged 60 years or above (median 66 years), 48 were included in our effectiveness analysis (29 ulcerative colitis, 19 Crohn's disease). Rates of clinical response, remission and corticosteroid-free remission at week 14 were 64%, 48% and 30%, respectively. By week 52, the rates of clinical response, remission, and corticosteroid-free remission were 52%, 38%, and 32%, respectively. Six (8%) patients experienced adverse effects. Effectiveness and safety outcomes were comparable to those of age-unstratified vedolizumab-treated cohorts.\nOur 1-year outcome data suggests that vedolizumab is safe and effective in older IBD patients and broadly comparable to cohorts unselected by age.",
"affiliations": "IBD Centre, Guy's and St. Thomas' NHS Foundation Trust, London (Hajir Ibraheim, Mark A. Samaan, Jonathan Digby-Bell, Peter M. Irving, Irena Norman, Nick Powell).;IBD Centre, Guy's and St. Thomas' NHS Foundation Trust, London (Hajir Ibraheim, Mark A. Samaan, Jonathan Digby-Bell, Peter M. Irving, Irena Norman, Nick Powell).;Translational Gastroenterology Unit, Oxford University Hospitals Trust, Oxford (Ashish Srinivasan, Oliver Brain).;Translational Gastroenterology Unit, Oxford University Hospitals Trust, Oxford (Ashish Srinivasan, Oliver Brain).;IBD Centre, Guy's and St. Thomas' NHS Foundation Trust, London (Hajir Ibraheim, Mark A. Samaan, Jonathan Digby-Bell, Peter M. Irving, Irena Norman, Nick Powell).;IBD Centre, Guy's and St. Thomas' NHS Foundation Trust, London (Hajir Ibraheim, Mark A. Samaan, Jonathan Digby-Bell, Peter M. Irving, Irena Norman, Nick Powell).;IBD Centre, Guy's and St. Thomas' NHS Foundation Trust, London (Hajir Ibraheim, Mark A. Samaan, Jonathan Digby-Bell, Peter M. Irving, Irena Norman, Nick Powell).;Department of Gastroenterology, University College London Hospital, London (Issrah Jawad).;Department of Gastroenterology, King's College Hospital, Denmark Hill, London (Julia Biedermann, Bu'Hussain Hayee).;Department of Gastroenterology, Barts Health NHS Trust, London (Ana Ibarra, Klaartje Bel Kok, Gareth Parkes).;Department of Gastroenterology, Barts Health NHS Trust, London (Ana Ibarra, Klaartje Bel Kok, Gareth Parkes).;Department of Gastroenterology, Barts Health NHS Trust, London (Ana Ibarra, Klaartje Bel Kok, Gareth Parkes).;Department of Gastroenterology, Addenbrooke's Hospital, Cambridge (Joanna Rimmer, Elisabeta Compot, Miles Parkes).;Department of Gastroenterology, Addenbrooke's Hospital, Cambridge (Joanna Rimmer, Elisabeta Compot, Miles Parkes).;Department of Gastroenterology, Addenbrooke's Hospital, Cambridge (Joanna Rimmer, Elisabeta Compot, Miles Parkes).;St. Mark's Hospital, IBD Unit, Harrow, London (Jonathan Segal, Philip Oppong, Ailsa Hart).;St. Mark's Hospital, IBD Unit, Harrow, London (Jonathan Segal, Philip Oppong, Ailsa Hart).;St. Mark's Hospital, IBD Unit, Harrow, London (Jonathan Segal, Philip Oppong, Ailsa Hart).;Department of Gastroenterology, King's College Hospital, Denmark Hill, London (Julia Biedermann, Bu'Hussain Hayee).;IBD Centre, Guy's and St. Thomas' NHS Foundation Trust, London (Hajir Ibraheim, Mark A. Samaan, Jonathan Digby-Bell, Peter M. Irving, Irena Norman, Nick Powell).",
"authors": "Ibraheim|Hajir|H|;Samaan|Mark A|MA|;Srinivasan|Ashish|A|;Brain|Oliver|O|;Digby-Bell|Jonathan|J|;Irving|Peter M|PM|;Norman|Irena|I|;Jawad|Issrah|I|;Biedermann|Julia|J|;Ibarra|Ana|A|;Kok|Klaartje Bel|KB|;Parkes|Gareth|G|;Rimmer|Joanna|J|;Compot|Elisabeta|E|;Parkes|Miles|M|;Segal|Jonathan|J|;Oppong|Philip|P|;Hart|Ailsa|A|;Hayee|Bu'Hussain|B|;Powell|Nick|N|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.20524/aog.2020.0447",
"fulltext": "\n==== Front\nAnn Gastroenterol\nAnn Gastroenterol\nAnnals of Gastroenterology\n1108-7471 1792-7463 Hellenic Society of Gastroenterology Greece \n\nAnnGastroenterol-33-170\n10.20524/aog.2020.0447\nOriginal Article\nEffectiveness and safety of vedolizumab in inflammatory bowel disease patients aged 60 and over: an observational multicenter UK experience\nIbraheim Hajir ab* Samaan Mark A. a* Srinivasan Ashish c Brain Oliver c Digby-Bell Jonathan a Irving Peter M. a Norman Irena a Jawad Issrah d Biedermann Julia e Ibarra Ana f Kok Klaartje Bel f Parkes Gareth f Rimmer Joanna g Compot Elisabeta g Parkes Miles g Segal Jonathan hi Oppong Philip h Hart Ailsa hi Hayee Bu’Hussain e** Powell Nick ab** a IBD Centre, Guy’s and St. Thomas’ NHS Foundation Trust, London (Hajir Ibraheim, Mark A. Samaan, Jonathan Digby-Bell, Peter M. Irving, Irena Norman, Nick Powell)\nb Centre for Inflammation Biology and Cancer Immunology (CIBCI), King’s College London (Hajir Ibraheim, Nick Powell)\nc Translational Gastroenterology Unit, Oxford University Hospitals Trust, Oxford (Ashish Srinivasan, Oliver Brain)\nd Department of Gastroenterology, University College London Hospital, London (Issrah Jawad)\ne Department of Gastroenterology, King’s College Hospital, Denmark Hill, London (Julia Biedermann, Bu’Hussain Hayee)\nf Department of Gastroenterology, Barts Health NHS Trust, London (Ana Ibarra, Klaartje Bel Kok, Gareth Parkes)\ng Department of Gastroenterology, Addenbrooke’s Hospital, Cambridge (Joanna Rimmer, Elisabeta Compot, Miles Parkes)\nh St. Mark’s Hospital, IBD Unit, Harrow, London (Jonathan Segal, Philip Oppong, Ailsa Hart)\ni Division of Integrative Systems Medicine and Digestive disease, Department of Surgery and Cancer, Faculty of medicine, Imperial College London, London (Jonathan Segal, Ailsa Hart), UK\n\nCorrespondence to: Dr Nick Powell, Centre for Inflammation Biology and Cancer Immunology (CIBCI), New Hunts House, Guy’s Campus, King’s College London, SE1 1UL, UK, e-mail: nick.powell@kcl.ac.uk* Should be considered joint first authors\n\n** Should be considered joint last authors\n\n\nMar-Apr 2020 \n07 1 2020 \n33 2 170 177\n18 9 2019 04 11 2019 Copyright: © Hellenic Society of Gastroenterology2020This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nThe GEMINI trials established the efficacy of vedolizumab in moderate-to-severe inflammatory bowel disease (IBD) and demonstrated a favorable safety profile, suggesting it may be advantageous in older patients at greater risk of treatment-related complications. However, there is a paucity of data exploring the outcomes of vedolizumab in this group. Our objective was to determine the clinical effectiveness and safety of vedolizumab in older IBD patients within a real-world multicenter UK cohort.\n\nMethods\nA retrospective review of electronic records across 6 UK hospitals was undertaken to evaluate the clinical effectiveness and safety outcomes of vedolizumab in IBD patients aged ≥60 at start of therapy. Rates of clinical response, remission and corticosteroid-free remission were assessed at weeks 14 and 52, using validated clinical indices, and were compared to historical controls from real-world vedolizumab-treated cohorts unstratified by age.\n\nResults\nOf 74 patients aged 60 years or above (median 66 years), 48 were included in our effectiveness analysis (29 ulcerative colitis, 19 Crohn’s disease). Rates of clinical response, remission and corticosteroid-free remission at week 14 were 64%, 48% and 30%, respectively. By week 52, the rates of clinical response, remission, and corticosteroid-free remission were 52%, 38%, and 32%, respectively. Six (8%) patients experienced adverse effects. Effectiveness and safety outcomes were comparable to those of age-unstratified vedolizumab-treated cohorts.\n\nConclusion\nOur 1-year outcome data suggests that vedolizumab is safe and effective in older IBD patients and broadly comparable to cohorts unselected by age.\n\nInflammatory bowel diseaseulcerative colitisCrohn’s diseasevedolizumabolder onset IBD\n==== Body\nIntroduction\nThe incidence of older onset inflammatory bowel disease (IBD), typically defined as onset >60 years of age, is 10-15% [1] and rising, with one Dutch population-based study reporting a 2-fold increase in incidence between 1991 and 2011 [2]. The majority of cases are diagnosed between 60-70 years, 25% between 70-80 years, and 10% over 80 years [3,4]. Several studies have highlighted differences in the disease trajectory of these patients compared with the younger population [5,6], with a suggestion that the natural history is less aggressive [6-9]. For example perianal and fistulizing disease occur less frequently in older onset IBD patients with Crohn’s disease (CD) [7]. Up to 30% of IBD patients are over 60 years old [8], and given the aging population and the small impact of IBD on mortality, the prevalence of IBD among the elderly is expected to increase.\n\nTherapeutic options are theoretically the same in older and younger patients, but there are gaps in our understanding of the specific needs of the older group. Older patients are either excluded from or under-represented in clinical trials, hampering insights into the safety and efficacy of therapy as a function of age. Additional considerations that influence the optimal management strategy in this group include polypharmacy, multiple comorbidities, functional status and, crucially, adverse effects of therapy secondary to infection and malignancy. Safety data have consistently shown that advanced age is an independent risk factor for serious adverse events and death in patients treated with anti-tumor necrosis factor (TNF) medications [9,10], rendering older patients more likely to discontinue therapy [9,11]. In a Belgian retrospective study with 743 anti-TNF-treated patients, older age at first infusion was the only predictor of death (P<0.01) [12]. Older age is also an independent risk factor for lymphoproliferative disorders in thiopurine-treated patients; their incidence increases to more than 5-fold in the 50-65 age group, and even more in the >65 group [13].\n\nIn terms of efficacy of biologic agents, older patients have lower rates of short-term clinical response to anti-TNF therapy compared to younger patients, even after adjustment for confounding factors, although once an initial response is achieved they have a comparable long-term clinical response [9]. A similar pattern is observed from the rheumatology experience, which is based on larger patient numbers and longer follow-up data [14].\n\nThe advent of vedolizumab, a gut-selective humanised monoclonal antibody targeting the a4b7 integrin expressed by gut-homing lymphocytes, represents an important advance in IBD therapy. The GEMINI trials demonstrated the clinical efficacy of vedolizumab for induction and maintenance of remission in moderate-to-severe active ulcerative colitis (UC) and CD, with a safety profile comparable to that of placebo [15,16]. Integrated safety data, from 2830 patients followed over 5 years, confirmed that vedolizumab was not associated with an increased risk of infection or malignancy. Moreover, infusion-related reactions, enteric infections and autoimmune events occurred infrequently [17]. Similarly, in a 4-year post-marketing safety analysis based on 208,050 patient years of vedolizumab exposure, the rates of gastrointestinal and infection-related adverse events were comparable between patients aged ≥70 years and those <70 years [18].\n\nClinical and safety outcomes have been corroborated in observational studies of “real-world” practice [4,17,19-25]. The gut-selective mechanism of action of vedolizumab is an especially attractive property in high-risk groups such as those with advanced age, or a history of malignancy or immunosuppression. However, there is a relative paucity of data in these groups. Yajnik et al conducted a post hoc analysis of the efficacy and safety of vedolizumab in GEMINI trial patients stratified by age, of whom 230 (130 UC, 90 CD) were in the >55 years group and 56 patients were aged >65 years. Efficacy (induction and maintenance) and safety profiles between vedolizumab and placebo were similar in all age groups, with no age-related differences in the incidence of malignancy or death [26]. Whilst these outcomes are promising, there are challenges in extrapolating data from clinical trials, given that they are highly selective and often exclude patients with significant comorbidities prevalent in the older population. We therefore aimed to determine the clinical effectiveness and safety of vedolizumab in older IBD patients in a multicenter UK cohort.\n\nPatients and methods\nThis study included patients from 6 UK hospitals: Guy’s and St. Thomas’, King’s College, St. Mark’s, The Royal London, Addenbrooke’s, and The John Radcliffe. Older age was defined as ≥60 years. A retrospective review of electronic records was performed to identify patients who started vedolizumab between January 2015 and 2018. Inclusion criteria were age ≥60 and the availability of at least 12 months of follow-up data (irrespectively of whether vedolizumab was continued). Exclusion criteria for the clinical effectiveness analysis included clinically inactive disease at baseline, as defined using validated clinical indices—Harvey Bradshaw Index (HBI) for CD (HBI<5) or the Simple Clinical Colitis Activity Index (SCCAI) for UC (SCCAI<3)—missing baseline activity score data, and the presence of a stoma.\n\nData collection was performed using a standardized form. Extracted data included demographics, baseline disease characteristics (subtype, disease duration, phenotype according to the Montreal classification for CD, history of surgery), baseline disease activity, history of malignancy, prior anti-TNF exposure, and concomitant immunomodulation. Patients with unclassified IBD were included in the UC group for analysis.\n\nEffectiveness and safety data were extracted at week 14 and week 52. Effectiveness measures were clinical response (reduction in HBI or SCCAI scores by ≥3 points), clinical remission (HBI<5 or SCCAI<3) and corticosteroid-free remission (HBI<5 or SCCAI<3 without concomitant steroids) [27,28]. An intention-to-treat strategy was used. Safety data included any adverse events. Where relevant, time to discontinuation of therapy was also collated alongside reasons for discontinuation.\n\nStatistical analysis\nDescriptive statistics were used to summarize differences in demographic and baseline characteristics among study groups. Continuous variables are presented as median and categorical variables are expressed as proportions. Data are presented to the nearest significant figure. The comparator groups were patients from previously published studies describing real-world, observational experience of vedolizumab unstratified by age, identified via a structured PubMed and Embase search.\n\nResults\nPatient characteristics\nDuring the study period, 74 patients aged ≥60 years received at least 1 dose of vedolizumab and had follow-up data for at least 1 year. Forty-eight patients were included in the clinical effectiveness analysis (Table 1). The other 26 were excluded for the following reasons: 3 had a stoma, 13 had missing clinical data for week 14 and week 52, 9 had inactive baseline clinical activity scores, and 1 had surgery very shortly after the first infusion. Of the 48 patients included, the median age on starting vedolizumab was 66 (range 60-85) years; 17 patients were in the ≥70 age group. Of these, 10 (21%) were between 70-79 years and 7 (15%) were aged ≥80. Seventeen patients (35%) had older-onset IBD. Analysis of adverse events was performed for all 74 patients who received at least 1 dose of vedolizumab (Table 2).\n\nTable 1 Baseline characteristics of patients included in clinical effectiveness analysis (n=48)\n\nTable 2 Baseline characteristics of patients included in safety analysis (n=74)\n\nClinical effectiveness\nIn patients ≥60 years, 28 (64%) had a clinical response at week 14. Of these, 21 (48%) were in clinical remission (Table 3), a higher rate than those reported in the majority of observational studies from age-unstratified populations [19-21,23,24,29,30] (Fig. 1A,B). Thirty percent achieved corticosteroid-free remission (Fig. 1C). At week 52, 21 (81%) had a clinical response (Fig. 2A), 16 (62%) had clinical remission (Fig. 2B) and 13 (52%) had corticosteroid-free remission (Fig. 2C). These rates were relatively lower than those reported in the age-unstratified populations.\n\nTable 3 Clinical effectiveness of vedolizumab in patients aged ≥60 years (n=48)\n\nFigure 1 Week 14 clinical response (A), clinical remission (B) and corticosteroid-free remission rates (C) in patients with inflammatory bowel disease, comparing those aged ≥60 in our UK multicenter cohort with a non-age-stratified real-world series. The pooled data bar only represents studies from the age-unstratified real-world studies. Error bars represent ± 1 standard deviation. The age is represented on the X-axis as a median or mean. In some studies, the median or mean age was calculated for each subgroup (Crohn’s disease vs. ulcerative colitis) and not a group as a whole: in these cases both numbers are depicted\n\nFigure 2 Week 52 clinical response (A), clinical remission (B) and corticosteroid-free remission rates (C) in patients with inflammatory bowel disease, comparing those aged ≥60 in our UK multicenter cohort with a non-age-stratified real-world series. The pooled data bar only represents studies from the age-unstratified real-world studies. Error bars represent ± 1 standard deviation. The age is represented on the X-axis as a median or mean. In some studies, the median or mean age was calculated for each subgroup (Crohn’s disease vs. ulcerative colitis) and not a group as a whole: in these cases both numbers are depicted\n\nWhen taking into account disease type (UC vs. CD), the mean SCCAI scores in UC patients at baseline, week 14 and week 52 were 8 with a standard deviation (SD) of 3, 2 (SD 2) and 2 (SD 2), respectively. In CD patients, the mean HBI scores at baseline, week 14 and week 52 were 8 (SD 3), 5 (SD 3), and 4 (SD 3), respectively.\n\nUC patients were numerically more likely than CD patients to experience clinical response or remission at week 14 (76% vs. 47% and 60% vs. 32% respectively). Findings in the UC group were generally more favorable than most of the age-unstratified comparator studies where rates of clinical response and remission ranged between 43%-57% (UC), whilst findings in the CD group were more comparable (22-42%) (Supplementary Fig. 1). At week 52, rates of clinical response, clinical remission and steroid-free remission were comparable between UC and CD patients (52% vs. 53%, 40% vs. 35%, 33% vs. 29%, respectively (Supplementary Fig. 2).\n\nSafety\nAdverse events were reported in 6/74 (8%) patients, leading to permanent discontinuation in 4/6 (Table 4). Three of these 6 patients were on concomitant immunosuppressive treatment: 1 with relapsed chronic myelomonocytic leukemia (CMML) on mycophenolate mofetil and prednisolone, 1 with pneumonia requiring intensive care support on azathioprine, and 1 with Escherichia coli O157 on azathioprine. Of the 3/6 patients on vedolizumab monotherapy, 2 experienced arthralgia necessitating permanent discontinuation of therapy after 1 and 5 months, and 1 patient-developed deranged liver function tests, which resolved on cessation of treatment. According to age, 4/6 were in the 60-69 group and 2 were aged ≥70 years. There were no reported infusion reactions. One death occurred during the study period: a patient with relapsed CMML who had 8 months of vedolizumab therapy prior to the diagnosis.\n\nTable 4 Safety of vedolizumab in patients ≥60 years (n=74)\n\nDiscussion\nOur study represents the largest cohort of older vedolizumab-treated patients reported to date and represents a real-world context for its use. Although randomized controlled trials represent the gold standard for establishing efficacy, patients are highly selected and not entirely representative of those encountered in clinical practice. Notably, 44% of our patients would have been excluded from the GEMINI studies because of concomitant medications, extensive CD surgery, and older age. Whilst the GEMINI trials included older patients, those over 80 were excluded. Our study included 7 patients over 80 years, 2 of whom were on concomitant thiopurine therapy while 3 had a past history of malignancy.\n\nWe report outcomes largely comparable to the majority of the age-unstratified observational studies, although interestingly we found more favorable week-14 outcomes. This may be attributed to a cohort that included a higher proportion of anti-TNF-naïve patients (73% compared to fewer than 25% in comparator studies), given how closely our findings resemble those from the European study in anti-TNF-naïve patients [25]. Additionally, over a third of our study group had older-onset IBD, ostensibly associated with a less aggressive disease course [5]. These merit further investigation, but to date, Navaneethan et al are the only group to report real-world clinical outcomes of vedolizumab-treated older patients (>60 years old) [31]. In their single-center study, which included 29 IBD patients, clinical response and remission rates were lower than in our group (Fig. 1,2). Corticosteroid-free remission was only reported for week 14, but was similar to our data. Although caution should be exercised when interpreting studies with small patient numbers, an important difference again relates to the lower proportion of anti-TNF-experienced patients included in our study (27% vs. 68.9%).\n\nYajnik et al performed a post hoc subgroup analysis of data from GEMINI 1 and 2, which analyzed moderately to severely active UC or CD, respectively, stratified into age groups: <35, 35 to <55, and ≥55 years. Two hundred and twenty patients (130 UC, 90 CD) were in the older group, and apart from having a longer duration of disease, and the CD patients having lower clinical activity scores at baseline, other baseline features were consistent amongst the groups. Similar percentages of vedolizumab-treated patients from each age group achieved a durable clinical response, durable clinical remission, mucosal healing, and corticosteroid-free remission at week 52, with no age-related trends [26].\n\nDespite 42% of our patients being on an immunomodulator (compared to a range of 14-80.4% in the non-age-stratified real world studies), we, like others [21], did not observe a larger clinical benefit compared with vedolizumab monotherapy. Although our sample size may be too small to detect a difference, this finding was also apparent from a post hoc analysis of the pivotal trials, where the use of concomitant immunomodulators was 18.9% in GEMINI 1 and 16.1% in GEMINI 2 [15,16].\n\nConsistent with the post hoc and post-marketing analyses, we found that the safety profile of vedolizumab in older patients was favorable [17,18]. The adverse event rate of 8% is comparable to other real-world series, where rates of 8.2% [19], 10.7% [21], and 14.2% [23] were reported. The 3 patients who developed either a serious infection or recurrence of malignancy were also on concomitant immunomodulators, which have a well-documented association with these outcomes. Two patients discontinued therapy secondary to arthralgia.\n\nLimitations of our study include a lack of endoscopic data and a limited cohort size (particularly the CD group), which made subgroup analyses challenging. The majority of patients were on corticosteroids at baseline, thus introducing a confounding variable that may have influenced the perceived effectiveness of vedolizumab in the short term. Additionally, the risk of infective events associated with corticosteroids is well documented. The retrospective nature of the data may also have resulted in an underestimation of the number of adverse events. However, such biases are inevitable features of real-world studies and are therefore not dissimilar to other published real-world series.\n\nIn conclusion, our multicenter experience of vedolizumab in IBD patients aged 60 or older demonstrated that treatment was effective and well-tolerated at 1 year, and likely to be broadly comparable to cohorts unselected by age. Given the absence of prospective controlled studies of vedolizumab in elderly patients, our study provides reassuring insights into the potential benefit of vedolizumab as an effective and safe therapeutic option in this patient group.\n\nSummary Box\nWhat is already known:\n\n\nThe prevalence of inflammatory bowel disease in the older population is rising, with up to 30% being over 60 years of age\n\nAdvanced age is an independent risk factor for serious adverse events and death in anti-tumor necrosis factor-treated patients\n\nPost hoc analysis of GEMINI trial data suggests efficacy and safety profiles between vedolizumab and placebo are similar in all age groups\n\n\n\n\nWhat the new findings are:\n\n\nAdvanced age was not a barrier to the efficacy and safety of vedolizumab\n\nVedolizumab and concomitant immunomodulation did not incur a clinical benefit over vedolizumab monotherapy\n\n\n\n\nSupplementary Figure 1 Supplementary Figure 1 Week 14 clinical response, clinical remission and corticosteroid-free remission rates in patients with ulcerative colitis (A) and Crohn’s disease (B), comparing those aged ≥60 in our UK multicenter cohort with a non-age-stratified real-world series\n\nClick here for additional data file.\n\n Supplementary Figure 2 Supplementary Figure 2 Week 52 clinical response, clinical remission and corticosteroid-free remission rates in patients with ulcerative colitis (A) and Crohn’s disease (B), comparing those aged ≥60 in our UK multicenter cohort with a non-age-stratified real-world series\n\nClick here for additional data file.\n\n Conflict of Interest: Mark A. Samaan: Served as a speaker, a consultant and/or an advisory board member for Janssen, Takeda, MSD, Falk. Oliver Brain: Served as a speaker for Bristol-Myers Squibb and Janssen. Jonathan Digby-Bell: Served as a speaker for AbbVie and Takeda. Peter M. Irving: Served as a speaker, a consultant and/or an advisory board member for Janssen, AbbVie, Warner Chilcott, Ferring, Falk Pharma, Takeda, MSD, Johnson and Johnson, Shire, Vifor Pharma, Pharmacosmos, Topivert, Genentech, Hospira, Samsung Bioepis, and has received research funding from MSD, Takeda. Ana Ibarra: Served as a speaker for Janssen. Klaartje Bel Kok: Served as a speaker for Janssen. Gareth Parkes: Served as a speaker for Takeda, AbbVie and Janssen. Miles Parkes: Served as a speaker for Takeda. Jonathan Segal: Served as a consultant for Takeda. Ailsa Hart: Served as a consultant, advisory board member or speaker for AbbVie, Atlantic, Bristol-Myers Squibb, Celltrion, Falk, Ferring, Janssen, MSD, Napp Pharmaceuticals, Pfizer, Pharmacosmos, Shire and Takeda. ALH also serves on the Global Steering Committee for Genentech. Bu’Hussain Hayee: Served as a speaker and consultant for Takeda. Nick Powell: Served as a speaker for Allergan, Falk, Janssen, Tillotts and Takeda a consultant and/or an advisory board member for AbbVie, Allergan, Debiopharm International, Ferring and Vifor Pharma\n\nGuy’s and St. Thomas’ NHS Foundation Trust, London; King’s College, London; Oxford University Hospitals Trust; University College London Hospital; King’s College Hospital, Denmark Hill, London; Barts Health NHS Trust, London; Addenbrooke’s Hospital, Cambridge; St. Mark’s Hospital, London; Imperial College London, UK\n==== Refs\n1 Piront P Louis E Latour P Plomteux O Belaiche J Epidemiology of inflammatory bowel diseases in the elderly in the province of Liège Gastroenterol Clin Biol 2002 26 157 161 11938067 \n2 Jeuring SF van Heuvel Zeegers MP Epidemiology and long-term outcome of inflammatory bowel disease diagnosed at elderly age-an increasing distinct entity? Inflamm Bowel Dis 2016 22 1425 1434 26933752 \n3 Loftus CG Loftus J EV Harmsen SW Update on the incidence and prevalence of Crohn's disease and ulcerative colitis in Olmsted County, Minnesota 1940-2000 Inflamm Bowel Dis 2007 13 254 261 17206702 \n4 Loftus EV Jr Silverstein MD Sandborn WJ Tremaine WJ Harmsen WS Zinsmeister AR Ulcerative colitis in Olmsted County, Minnesota 1940-1993: incidence, prevalence, and survival Gut 2000 46 336 343 10673294 \n5 Charpentier C Salleron J Savoye G Natural history of elderly-onset inflammatory bowel disease:a population-based cohort study Gut 2014 63 423 432 23408350 \n6 Lakatos PL David G Pandur T IBD in the elderly population:results from a population-based study in Western Hungary 1977-2008 J Crohns Colitis 2011 5 5 13 21272797 \n7 Viola A Monterubbianesi R Scalisi G Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) Late-onset Crohn's disease:a comparison of disease behaviour and therapy with younger adult patients:the Italian Group for the Study of Inflammatory Bowel Disease 'AGED'study Eur J Gastroenterol Hepatol 2019 31 1361 1369 31567640 \n8 Katz S Pardi DS Inflammatory bowel disease of the elderly:frequently asked questions (FAQs) Am J Gastroenterol 2011 106 1889 1897 21862997 \n9 Lobatón T Ferrante M Rutgeerts P Ballet V Van Assche G Vermeire S Efficacy and safety of anti-TNF therapy in elderly patients with inflammatory bowel disease Aliment Pharmacol Ther 2015 42 441 451 26104047 \n10 Cottone M Kohn A Daperno M Advanced age is an independent risk factor for severe infections and mortality in patients given anti-tumor necrosis factor therapy for inflammatory bowel disease Clin Gastroenterol Hepatol 2011 9 30 35 20951835 \n11 Desai A Zator ZA de Silva P Older age is associated with higher rate of discontinuation of anti-TNF therapy in patients with inflammatory bowel disease Inflamm Bowel Dis 2013 19 309 315 22605668 \n12 Fidder HH Schnitzler F Ferrante M Long-term safety of infliximab for the treatment of inflammatory bowel disease:a single center cohort study Gut 2008 58 501 508 18832524 \n13 Beaugerie L Brousse N Bouvier AM CESAME Study Group Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease:a prospective observational cohort study Lancet 2009 374 1617 1625 19837455 \n14 Filippini M Bazzani C Favalli EG Efficacy and safety of anti-tumour necrosis factor in elderly patients with rheumatoid arthritis:an observational study Clin Rev Allergy Immunol 2010 38 90 96 19548124 \n15 Feagan BG Rutgeerts P Sands BE Vedolizumab as induction and maintenance therapy for ulcerative colitis N Engl J Med 2013 369 699 710 23964932 \n16 Sandborn WJ Feagan BG Rutgeerts P Vedolizumab as induction and maintenance therapy for Crohn's disease N Engl J Med 2013 369 711 721 23964933 \n17 Colombel JF Sands BE Rutgeerts P The safety of vedolizumab for ulcerative colitis and Crohn's disease Gut 2017 66 839 851 26893500 \n18 Cohen RD Bhayat F Blake A Travis S The safety profile of vedolizumab in ulcerative colitis and Crohn's disease:4 years of global post-marketing data J Crohns Colitis 2020 14 192 204 31504340 \n19 Amiot A Grimaud JC Peyrin-Biroulet L Groupe d'Etude Therapeutique des Affections Inflammatoires du tube Digestif Effectiveness and safety of vedolizumab induction therapy for patients with inflammatory bowel disease Clin Gastroenterol Hepatol 2016 14 1593 1601 26917043 \n20 Eriksson C Marsal J Bergemalm D SWIBREG Vedolizumab Study Group Long-term effectiveness of vedolizumab in inflammatory bowel disease:a national study based on the Swedish National Quality Registry for Inflammatory Bowel Disease (SWIBREG) Scand J Gastroenterol 2017 52 722 729 28362144 \n21 Shelton E Allegretti JR Stevens B Efficacy of vedolizumab as induction therapy in refractory IBD patients:a multicenter cohort Inflamm Bowel Dis 2015 21 2879 2885 26288002 \n22 Ananthakrishnan AN McGinley EL Binion DG Inflammatory bowel disease in the elderly is associated with worse outcomes:a national study of hospitalizations Inflamm Bowel Dis 2009 15 182 189 18668678 \n23 Kopylov U Ron Y Avni-Biron I Efficacy and safety of vedolizumab for induction of remission in inflammatory bowel disease—the Israeli real-world experience Inflamm Bowel Dis 2017 23 404 408 28178003 \n24 Samaan MA Pavlidis P Johnston E Vedolizumab:early experience and medium-term outcomes from two UK tertiary IBD centres Frontline Gastroenterol 2017 8 196 202 28839909 \n25 Kopylov U Verstockt B Biedermann L Effectiveness and safety of vedolizumab in anti-TNF-naïve patients with inflammatory bowel disease—a multicenter retrospective European Study Inflamm Bowel Dis 2018 24 2442 2451 29788318 \n26 Yajnik V Khan N Dubinsky M Efficacy and safety of vedolizumab in ulcerative colitis and Crohn's disease patients stratified by age Adv Ther 2017 3 4 542 559 \n27 Higgins P Schwartz M Mapili J Krokos I Leung J Zimmermann EM Patient defined dichotomous end points for remission and clinical improvement in ulcerative colitis Gut 2005 54 782 788 15888785 \n28 Vermeire S Schreiber S Sandborn WJ Dubois C Rutgeerts P Correlation between the Crohn's disease activity and Harvey–Bradshaw indices in assessing Crohn's disease severity Clin Gastroenterol Hepatol 2010 8 357 363 20096379 \n29 Stallmach A Langbein C Atreya R Vedolizumab provides clinical benefit over 1 year in patients with active inflammatory bowel disease - a prospective multicenter observational study Aliment Pharmacol Ther 2016 44 1199 1212 27714831 \n30 Baumgart DC Bokemeyer B Drabik A Stallmach A Schreiber S Vedolizumab Germany Consortium Vedolizumab induction therapy for inflammatory bowel disease in clinical practice—a nationwide consecutive German cohort study Aliment Pharmacol Ther 2016 43 1090 1102 27038247 \n31 Navaneethan U Edminister T Zhu X Kommaraju K Glover S Vedolizumab is safe and effective in elderly patients with inflammatory bowel disease Inflamm Bowel Dis 2017 23 E17 28296827\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1108-7471",
"issue": "33(2)",
"journal": "Annals of gastroenterology",
"keywords": "Crohn’s disease; Inflammatory bowel disease; older onset IBD; ulcerative colitis; vedolizumab",
"medline_ta": "Ann Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101121847",
"other_id": null,
"pages": "170-177",
"pmc": null,
"pmid": "32127738",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "19837455;21862997;20096379;17206702;26288002;21272797;20951835;26104047;10673294;26893500;28296827;18668678;23964932;26917043;28178003;23964933;15888785;27038247;19548124;29788318;27714831;28070861;31567640;23408350;28362144;31504340;28839909;11938067;26933752;22605668;18832524",
"title": "Effectiveness and safety of vedolizumab in inflammatory bowel disease patients aged 60 and over: an observational multicenter UK experience.",
"title_normalized": "effectiveness and safety of vedolizumab in inflammatory bowel disease patients aged 60 and over an observational multicenter uk experience"
} | [
{
"companynumb": "GB-TAKEDA-2020TJP007445AA",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": ... |
{
"abstract": "Purpose: Ras/MEK/ERK pathway activation is common in oral cavity squamous cell carcinoma (OCSCC). We performed a neoadjuvant (preoperative) trial to determine the biomarker and tumor response of OCSCC to MEK inhibition with trametinib.Experimental Design: Patients with stage II-IV OCSCC received trametinib (2 mg/day, minimum 7 days) prior to surgery. Primary tumor specimens were obtained before and after trametinib to evaluate immunohistochemical staining for p-ERK1/2 and CD44, the primary endpoint. Secondary endpoints included changes in clinical tumor measurements and metabolic activity [maximum standardized uptake values (SUVmax) by F-18 fluorodeoxyglucose positron emission tomography/CT), and in tumor downstaging. Drug-related adverse events (AE) and surgical/wound complications were evaluated.Results: Of 20 enrolled patients, 17 (85%) completed the study. Three patients withdrew because of either trametinib-related (n = 2: nausea, duodenal perforation) or unrelated (n = 1: constipation) AEs. The most common AE was rash (9/20 patients, 45%). Seventeen patients underwent surgery. No unexpected surgical/wound complications occurred. Evaluable matched pre- and posttrametinib specimens were available in 15 (88%) of these patients. Reduction in p-ERK1/2 and CD44 expression occurred in 5 (33%) and 2 (13%) patients, respectively. Clinical tumor response by modified World Health Organization criteria was observed in 11 of 17 (65%) evaluable patients (median 46% decrease, range 14%-74%). Partial metabolic response (≥25% reduction in SUVmax) was observed in 6 of 13 (46%) evaluable patients (median 25% decrease, range 6%-52%). Clinical-to-pathologic tumor downstaging occurred in 9 of 17 (53%) evaluable patients.Conclusions: Trametinib resulted in significant reduction in Ras/MEK/ERK pathway activation and in clinical and metabolic tumor responses in patients with OCSCC. Clin Cancer Res; 23(9); 2186-94. ©2016 AACR.",
"affiliations": "Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri. Ravindra_Uppaluri@DFCI.Harvard.edu.;Department of Otolaryngology, Washington University in St. Louis, St. Louis, Missouri.;Department of Otolaryngology, Washington University in St. Louis, St. Louis, Missouri.;Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.;Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.;Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.;Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.;Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.;Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.;Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.;Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.;Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.;Department of Otolaryngology, Washington University in St. Louis, St. Louis, Missouri.;Department of Otolaryngology, Washington University in St. Louis, St. Louis, Missouri.;Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.;Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.;Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.;Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.;Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.;Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.",
"authors": "Uppaluri|Ravindra|R|;Winkler|Ashley E|AE|;Lin|Tianxiang|T|;Law|Jonathan H|JH|;Haughey|Bruce H|BH|;Nussenbaum|Brian|B|;Paniello|Randal C|RC|;Rich|Jason T|JT|;Diaz|Jason A|JA|;Michel|Loren P|LP|;Wildes|Tanya|T|;Dunn|Gavin P|GP|;Zolkind|Paul|P|;Kallogjeri|Dorina|D|;Piccirillo|Jay F|JF|;Dehdashti|Farrokh|F|;Siegel|Barry A|BA|;Chernock|Rebecca D|RD|;Lewis|James S|JS|;Adkins|Douglas R|DR|",
"chemical_list": "D014408:Biomarkers, Tumor; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib",
"country": "United States",
"delete": false,
"doi": "10.1158/1078-0432.CCR-16-1469",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-0432",
"issue": "23(9)",
"journal": "Clinical cancer research : an official journal of the American Association for Cancer Research",
"keywords": null,
"medline_ta": "Clin Cancer Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D002294:Carcinoma, Squamous Cell; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D009055:Mouth; D009062:Mouth Neoplasms; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones",
"nlm_unique_id": "9502500",
"other_id": null,
"pages": "2186-2194",
"pmc": null,
"pmid": "28151720",
"pubdate": "2017-05-01",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": "18349857;26351343;10655437;22663011;10673991;17496923;16702406;25643909;18485877;21523318;19734941;23663449;11234901;20149254;25081631;24727329;18805044;11522647;25631445;22086849;7459811;12511867;21245089;20385094;21626606;23020132;26351335",
"title": "Biomarker and Tumor Responses of Oral Cavity Squamous Cell Carcinoma to Trametinib: A Phase II Neoadjuvant Window-of-Opportunity Clinical Trial.",
"title_normalized": "biomarker and tumor responses of oral cavity squamous cell carcinoma to trametinib a phase ii neoadjuvant window of opportunity clinical trial"
} | [
{
"companynumb": "PHHY2017US076481",
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"occurcountry": "US",
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"actiondrug": "1",
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"activesubstancename": "TRAMETINIB DIMETHYL SULFOXIDE"
},
"drugadditional": nu... |
{
"abstract": "Treatment options for radioiodine resistant metastatic thyroid cancer patients are limited, and chemotherapy is considered an outdated therapeutic method for differentiated thyroid carcinoma. In this study, we evaluated the activity and safety of gemcitabine and oxaliplatin combination which is considered an out of label therapeutic method in patients with differentiated metastatic thyroid cancer refractory to 131-I treatment. Fourteen refractory patients (8 papillary, 6 follicular), six men/eight women with median age of 63 years and performance status (0-3) were included. Patients received gemcitabine (1,000 mg/m(2)) plus oxaliplatin (100 mg/m(2)) every 2 weeks until 12-cycles and each cycle correspond to 2 weeks treatment. This protocol was approved by the local Institutional Review Boards. Response rate was assessed every four cycles. Progression-free and overall survivals were calculated. Median treatment was 9.5 cycles (range 2-17) with 22 weeks duration. Overall response rate was 57%, with 7% achieving a complete response (1/14), 50% a partial response (7/14), and 28% with a stable disease. All patients with follicular subtype showed objective responses. Eleven patients progressed at a median time of 10.1 months; 10 of 14 patients still alive and the median survival was not reached (median follow-up of 19.8 months). The combination was generally well tolerated. No deaths occurred due to therapy and no grade IV toxicity was recorded. The most common treatment-related adverse events grade 1/3 includes asthenia, peripheral neuropathy, diarrhea, anemia, thrombocytopenia, and neutropenia. In conclusion, the GEMOX regimen is well tolerated and effective in advanced differentiated thyroid cancer. However, this retrospective data on a small sample size are considered preliminary and needs to be evaluated prospectively in a higher number of patients in a clinical trial.",
"affiliations": "Medical Oncology Department, GH Pitié-Salpêtrière, Université Paris 6, Paris, France. jean-philippe.spano@psl.aphp.fr",
"authors": "Spano|Jean-Philippe|JP|;Vano|Y|Y|;Vignot|S|S|;De La Motte Rouge|T|T|;Hassani|L|L|;Mouawad|R|R|;Menegaux|F|F|;Khayat|D|D|;Leenhardt|L|L|",
"chemical_list": "D009944:Organoplatinum Compounds; D003841:Deoxycytidine",
"country": "United States",
"delete": false,
"doi": "10.1007/s12032-011-0070-2",
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"issn_linking": "1357-0560",
"issue": "29(3)",
"journal": "Medical oncology (Northwood, London, England)",
"keywords": null,
"medline_ta": "Med Oncol",
"mesh_terms": "D018263:Adenocarcinoma, Follicular; D000231:Adenocarcinoma, Papillary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D056687:Off-Label Use; D009944:Organoplatinum Compounds; D016879:Salvage Therapy; D013964:Thyroid Neoplasms",
"nlm_unique_id": "9435512",
"other_id": null,
"pages": "1421-8",
"pmc": null,
"pmid": "21947747",
"pubdate": "2012-09",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "19016336;10807064;12196375;18348081;10412945;22898678;3902203;16684830;9609103;12583960;20851682;18541894;12213865;17330837;19773371;19097774;4808917;20142332;17267329;19435690;15319238;3624802;16979888;18541897;20392874;19255327;15650358;15908661;11114643;18596272",
"title": "GEMOX regimen in the treatment of metastatic differentiated refractory thyroid carcinoma.",
"title_normalized": "gemox regimen in the treatment of metastatic differentiated refractory thyroid carcinoma"
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"abstract": "Traditional hepatitis C virus treatment was limited by low cure rates, side effects, and stringent monitoring requirements. Sofosbuvir, a direct-acting antiviral agent with a cure rate of 96%, was introduced in 2013. However, trials frequently excluded patients with advanced liver disease and prior treatment experience. This study aims to elucidate the real-world cure rates and sofosbuvir safety profile.\n\n\n\nA retrospective cohort study was conducted at Kaiser Permanente Southern California involving patients with hepatitis C virus who received sofosbuvir treatment. Patients age 18 years and older were included, and pregnant patients were excluded. The primary end point was sustained virologic response at 12 weeks posttreatment. Secondary end points were safety and medication adherence. Multiple logistic regression analysis was used to compare patients with genotypes 1 and 2 infections.\n\n\n\nOf the 213 study patients, 42.3% had cirrhosis, and 38% were treatment-experienced. Most patients (69.5%) received dual therapy (sofosbuvir + ribavirin), whereas the remainder (30.5%) received triple therapy (sofosbuvir + ribavirin + interferon). The overall rate of sustained virologic response at 12 weeks posttreatment rate was 72.9% for genotype 1 infection, 64.7% in the treatment-experienced subgroup, and 66.7% in the cirrhosis subgroup. Rates of sustained virologic response at 12 weeks posttreatment for genotypes 2 and 3 were 90.8% and 55%, respectively. Most patients experienced anemia and fatigue. Women and patients with a lower baseline viral load were statistically more likely to be cured.\n\n\n\nReal-world cure rates were similar to rates seen in clinical trials for genotype 2 infection and lower for genotype 1 infection. Patients with genotype 1 and 3 infection did better with triple therapy compared with dual therapy. Patients tolerated therapy well with side effects, serious adverse events, and discontinuation rates similar to clinical trials. Women and patients with lower baseline hepatitis C viral load were more likely to achieve sustained virological response at 12 weeks posttreatment.",
"affiliations": "Ambulatory Care Pharmacist at the Los Angeles Medical Center in CA. vincent.x.louie@kp.org.;Gastroenterology Fellow at the Los Angeles Medical Center in CA. latt.nyan@mayo.edu.;Clinical Operations Manager for Pharmacy Operations at the Los Angeles Medical Center in CA. derenik.x.gharibian@kp.org.;Hepatologist at the Los Angeles Medical Center in CA. amandeep.sahota@kp.org.;Gastroenterology Fellow at the Los Angeles Medical Center in CA. beshoy.t.yanny@kp.org.;Gastroenterology Fellow at the Los Angeles Medical Center in CA. drrasham@gmail.com.;Biostatistician in the Department of Research and Evaluation of Kaiser Permanente Southern California in Pasadena. zoe.bider@kp.org.;Researcher in the Department of Research and Evaluation for Kaiser Permanente Southern California in Pasadena.",
"authors": "Louie|Vincent|V|;Latt|Nyan L|NL|;Gharibian|Derenik|D|;Sahota|Amandeep|A|;Yanny|Beshoy T|BT|;Mittal|Rasham|R|;Bider-Canfield|Zoe|Z|;Cheetham|T Craig|TC|",
"chemical_list": "D000998:Antiviral Agents; D012254:Ribavirin; D007372:Interferons; D000069474:Sofosbuvir",
"country": "United States",
"delete": false,
"doi": "10.7812/TPP/16-096",
"fulltext": null,
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"issn_linking": "1552-5767",
"issue": "21()",
"journal": "The Permanente journal",
"keywords": null,
"medline_ta": "Perm J",
"mesh_terms": "D000368:Aged; D000740:Anemia; D000998:Antiviral Agents; D002140:California; D004359:Drug Therapy, Combination; D005221:Fatigue; D005260:Female; D005838:Genotype; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D007372:Interferons; D008099:Liver; D008103:Liver Cirrhosis; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D012189:Retrospective Studies; D012254:Ribavirin; D012737:Sex Factors; D000069474:Sofosbuvir; D019562:Viral Load",
"nlm_unique_id": "9800474",
"other_id": null,
"pages": "16-096",
"pmc": null,
"pmid": "28368787",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "23607594;26743093;21720406;23607593;24361415;22293432;25322962;25034873;24795201;23580788;14678345",
"title": "Real-World Experiences With a Direct-Acting Antiviral Agent for Patients With Hepatitis C Virus Infection.",
"title_normalized": "real world experiences with a direct acting antiviral agent for patients with hepatitis c virus infection"
} | [
{
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"abstract": "BACKGROUND\nThe treatment of metastatic melanoma has been revolutionized in the past decade because of the development of immunotherapies and targeted therapies. Despite these developments, there is still an unmet clinical need for more advanced combination therapies for the subset of patients who remain resistant to immunotherapy or targeted therapy alone. To our knowledge, no reports have been published on combinations of PD-1 blockades and c-KIT inhibitors in melanoma patients. Furthermore, data are limited regarding the safety and efficacy of this combination in patients harboring KIT mutations.\nWe report a case of an 82-year-old female with metastatic melanoma who was found to have double KIT mutations at V559 and N822I.\n\n\nMETHODS\nShe was treated with a combination of c-KIT inhibitor and PD-1 blockade after being resistant to anti-PD-1 monotherapy.\n\n\nRESULTS\nPatient developed two episodes of grade 2 liver toxicity requiring treatment breaks followed by a dose reduction. Her transaminitis eventually resolved and patient remained on combination treatment for almost two years with good control of her disease prior to progression.\n\n\nCONCLUSIONS\nTreatment options for patients who progress after PD-1 inhibitors are very limited; therefore, there is a high unmet clinical need for this patient population. Combining Imatinib with checkpoint inhibitors may be efficacious in patients with metastatic melanoma and KIT mutations. This novel combination can cause additional toxicities which seem to be overall manageable.",
"affiliations": "Roswell Park Comprehensive Cancer Center, Buffalo.;Rochester General Hospital, Rochester, NY.;Roswell Park Comprehensive Cancer Center, Buffalo.;Roswell Park Comprehensive Cancer Center, Buffalo.",
"authors": "Abdou|Yara|Y|;Kapoor|Ankita|A|;Hamad|Lamya|L|;Ernstoff|Marc S|MS|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000068877:Imatinib Mesylate; C582435:pembrolizumab; C000628936:KIT protein, human; D019009:Proto-Oncogene Proteins c-kit",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000017769",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31689840MD-D-19-0451610.1097/MD.0000000000017769177695700Research ArticleClinical Case ReportCombination of pembrolizumab and imatinib in a patient with double KIT mutant melanoma A case reportAbdou Yara MDa∗Kapoor Ankita MBBSbHamad Lamya RPh, MPHaErnstoff Marc S. MDaNA. a Roswell Park Comprehensive Cancer Center, Buffalob Rochester General Hospital, Rochester, NY.∗ Correspondence: Yara Abdou, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA (e-mail: Yara.Abdou@RoswellPark.org).11 2019 01 11 2019 98 44 e1776907 6 2019 12 9 2019 03 10 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nThe treatment of metastatic melanoma has been revolutionized in the past decade because of the development of immunotherapies and targeted therapies. Despite these developments, there is still an unmet clinical need for more advanced combination therapies for the subset of patients who remain resistant to immunotherapy or targeted therapy alone. To our knowledge, no reports have been published on combinations of PD-1 blockades and c-KIT inhibitors in melanoma patients. Furthermore, data are limited regarding the safety and efficacy of this combination in patients harboring KIT mutations.\n\nPatient concerns and diagnosis:\nWe report a case of an 82-year-old female with metastatic melanoma who was found to have double KIT mutations at V559 and N822I.\n\nInterventions:\nShe was treated with a combination of c-KIT inhibitor and PD-1 blockade after being resistant to anti-PD-1 monotherapy.\n\nOutcomes:\nPatient developed two episodes of grade 2 liver toxicity requiring treatment breaks followed by a dose reduction. Her transaminitis eventually resolved and patient remained on combination treatment for almost two years with good control of her disease prior to progression.\n\nLessons:\nTreatment options for patients who progress after PD-1 inhibitors are very limited; therefore, there is a high unmet clinical need for this patient population. Combining Imatinib with checkpoint inhibitors may be efficacious in patients with metastatic melanoma and KIT mutations. This novel combination can cause additional toxicities which seem to be overall manageable.\n\nKeywords\nimatinibimmunotherapyKIT mutationliver toxicitymelanomaPD1-inhibitionpembrolizumabOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nMelanoma accounts for only about 1% of all skin cancers, yet it is responsible for a large majority of skin cancer deaths because of its aggressive nature. The treatment of metastatic melanoma has been revolutionized in the past decade because of the development of agents that target elements in the immune system including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein-1 (PD-1) and programmed cell death protein ligand 1 (PD-L1).[1] Checkpoint inhibitors (CPI) have played a fundamental role in melanoma treatment; however, many patients remain refractory. On the other hand, identification of targetable mutations in the mitogen-activated protein kinases (MAPK) pathway have also led to new therapies in melanoma. The most frequently activating mutation is in the BRAF kinase representing about 35% to 40% of melanomas.[2] The receptor tyrosine kinase c-Kit is less frequently mutated and seen mostly in mucosal and acral melanomas, and less often in melanomas with chronic sun-damaged skin.[3] The activating mutations can be blocked effectively with targeted therapies such as Imatinib.[4]\n\nDespite these developments, there is still an unmet clinical need for more advanced combination therapies for the subset of patients who remain resistant to check point inhibitors or targeted therapy alone. Therefore, it is essential to determine ways of combining these therapies and exploring potential toxicities that may arise. The ultimate goal is to discover potential novel combinations with a tolerable safety profile and enhanced efficacy.\n\nHere, we report a case of an 82-year-old woman with metastatic cutaneous melanoma, harboring double KIT mutations, that was treated with Imatinib and anti-PD-1 therapy after being resistant to anti-PD-1 monotherapy. This is the first time to our knowledge that this novel combination has been reported in metastatic melanoma.\n\n2 Case report\nAn 82-year-old woman with past medical history of hypertension and hyperlipidemia, presented with a right cheek nodule in December 2015. Biopsy result was consistent with ulcerated malignant melanoma, nodular type, Breslow depth of at least 2.7 mm. The nodule was locally resected, pathology results were consistent with extensive residual malignant melanoma, Breslow depth of 6.05 mm with multiple microsatellite metastases present, angiolymphatic invasion was identified and one sentinel lymph node was negative for melanoma (0/1). Melanoma in situ extended to the superior margin and medial and lateral specimen tips, therefore procedure was followed with Mohs surgery which showed no residual disease. Six months later, patient presented with two new nodules on her right cheek below the area of her prior excision. At that time, she was also noted to have right submandibular lymphadenopathy. Excisional biopsy of the nodule and FNA of submandibular lymph node showed recurrent malignant melanoma. Staging CT chest/abdomen/pelvis and brain MRI showed no evidence of distant metastatic disease. Multidisciplinary teams agreed on deferring surgery and proceeding with systemic therapy. Patient was subsequently started on anti-PD-1 therapy with Pembrolizumab at a fixed dose of 200 mg every 3 weeks. Patient continued to show a positive response until fourteen months of therapy when restaging CT scans demonstrated a left upper lobe nodule concerning for metastatic disease. PET scan demonstrated a high SUV uptake of 15, also consistent with metastatic disease. A left lung needle biopsy was subsequently completed which was consistent with metastatic malignant melanoma. Mutational analysis revealed double KIT mutations at V559 and N822I, therefore, Imatinib; a tyrosine kinase inhibitor known as Gleevec, was started at a dose of 400 mg daily. This was given in combination with Pembrolizumab at 200 mg every three weeks. Shortly after, patient developed a pruritic rash on her back and shoulders in addition to Grade 2 transaminitis. Imatinib was held for approximately 3 weeks until her symptoms and transaminitis resolved. No further intervention was needed. She then restarted Imatinib at half dose of 200 mg daily. One month later, patient developed another episode of grade 2 transaminitis. Imatinib was held for approximately three weeks and once her LFTs normalized, Imatinib was restarted at 400 mg 3 times a week (Monday/Wednesday/Friday). Restaging scans completed after 3 months of combination therapy showed significant decrease in size of lung nodule. In 6 months, restaging scans showed complete remission with no radiographical evidence of metastatic disease. Patient continued on combination therapy of Pembrolizumab and Imatinib, with no evidence of disease for almost 12 months. However, she ultimately developed recurrent disease with brain metastases after a total of 2 years on combination therapy. She was eventually transitioned to hospice care. Patient's health care proxy has provided informed consent for publication of the case\n\n3 Discussion\nImmunotherapy, particularly blockade of the inhibitory receptor, PD-1 or the ligand; PD-L1, has shown effectiveness in a variety of cancers, but in many patients this effect remains of transient importance due to development of resistance.\n\nEmerging data has shown that the tumor microenvironment is important for the effectiveness of immunotherapy.[5] Different approaches to modulate the tumor microenvironment have been pursued, including oncolytic modified herpes simplex virus, which has also been approved for the treatment of melanoma.[6] The ultimate goal is to create an immunogenic environment by increasing tumor-infiltrating lymphocytes and tumor antigen recognition.\n\nIn our case, we report the first use of combination c-KIT inhibitor and PD-1 blockade in an attempt to overcome anti-PD1 resistance.\n\nc-KIT is a type III receptor tyrosine kinase (RTK), which is involved in intracellular signaling and plays a significant role in cancer occurrence.[7] Previous studies have shown that point mutations in c-KIT result in constitutive activation of the c-KIT protein in melanoma cells, and this lead to activation of downstream proliferative and prosurvival signaling pathways. In vitro studies also showed that treatment with Imatinib, a tyrosine kinase inhibitor, led to apoptosis of melanoma cells.[8,9]\n\nIn experiments conducted in mouse models by Seifert et al, it has been shown that there is increased proliferation of intratumoral CD8+ T cells while inducing apoptosis of regulatory T cells, when a combination therapy of Imatinib and PD-1/PD-L1 blockade was used.[10] This in vivo model suggests that the combination therapy could have a role in altering the tumor microenvironment by changing the tumor from cold to hot, and ultimately making it more responsive to immunotherapy.\n\nCombinations of targeted therapy and immunotherapy have been safely reported with dual MAPK inhibitors and anti-PD1, however increased liver toxicities were seen when MAPK inhibitors were given with anti-CTLA4 agents.[11] To our knowledge, no reports have been published on combination of c-KIT inhibitor and PD-1 blockade.\n\nPrevious clinical trials with Imatinib have established that Imatinib is a relatively safe drug with fewer side effects profile.[12] Side effects are generally mild to moderate; the most common being: fluid retention, diarrhea, nausea, fatigue, rash, and muscle cramps, which can be managed effectively by either dose modifications or supportive care medicines. There is also the risk of more severe symptoms, though not common, such as liver toxicity, hemorrhage, and upper respiratory tract infections.[13] The patient described in our case study experienced grade 2 liver toxicity. For elevations of transaminases >5 IULN, Imatinib should be held until resolution to <2.5 IULN and restarted at a lower dose. The recommended dose reduction is 25% or 300 mg[14]; however, this patient was dose reduced by 50% mainly due to being on combination therapy with anti-PD1 which is also known to cause autoimmune hepatitis. It is difficult to determine which agent is the immediate cause of this patient's liver injury. However, it is reasonable to assume that the combination of both agents has made this event more likely.\n\nThere are no current guidelines for dealing with Imatinib side effects while on combination therapy with checkpoint inhibitors. To date, approximately 10 registered clinical trials have explored the safety and efficacy of Imatinib alone or with other agents in metastatic melanoma, however majority of the studies were not successfully completed.[13] One of which was an early phase trial of Pembrolizumab and Imatinib in patients with c-Kit mutations. The trial was withdrawn due to low accrual.\n\nWe report the first patient treated with combination Imatinib and pembrolizumab demonstrating that Imatinib toxicity may be increased but with close monitoring and dose modification can be managed successfully.\n\n4 Conclusion\nTreatment options for patients who progress after PD-1 inhibitors are very limited; therefore, there is a high unmet clinical need for this patient population. The addition of Imatinib to anti-PD1 therapy may create a favorable tumor microenvironment which enhances antitumor activity and subsequently improving efficacy of checkpoint inhibitors. This novel combination may cause additional toxicities that are overall manageable. Further information is needed on how to deal with serious side effects while on combination therapy.\n\nAuthor contributions\nResources: Yara Abdou.\n\nSupervision: Yara Abdou, Marc S. Ernstoff.\n\nWriting – original draft: Yara Abdou, Ankita Kapoor.\n\nWriting – review & editing: Yara Abdou, Ankita Kapoor, Lamya Hamad, Marc S. Ernstoff.\n\nYara Abdou orcid: 0000-0002-4827-8613.\n\nAbbreviations: CPI = checkpoint inhibitors, CTLA-4 = cytotoxic T-lymphocyte-associated protein 4, IULN = institutional upper limit of normal, MAPK = mitogen-activated protein kinases, PD-1 = programmed cell death protein-1, PD-L1 = programmed cell death protein ligand 1, RTK = receptor tyrosine kinase.\n\nHow to cite this article: Abdou Y, Kapoor A, Hamad L, Ernstoff MS. Combination of Pembrolizumab and Imatinib in a patient with double KIT mutant melanoma. Medicine. 2019;98:44(e17769).\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Carreau NA Pavlick AC \nNivolumab and ipilimumab: immunotherapy for treatment of malignant melanoma . Future Oncol \n2019 ;15 :349 –58 .30334646 \n[2] Mackiewicz J Mackiewicz A \nBRAF and MEK inhibitors in the era of immunotherapy in melanoma patients . Contemp Oncol (Pozn) \n2018 ;22 (1A) :68 –72 .29628797 \n[3] Curtin JA Busam K Pinkel D \nSomatic activation of KIT in distinct subtypes of melanoma . J Clin Oncol \n2006 ;24 :4340 –6 .16908931 \n[4] Hodi FS Corless CL Giobbie-Hurder A \nImatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin . J Clin Oncol \n2013 ;31 :3182 –90 .23775962 \n[5] Kitano S \nDevelopment of immune checkpoint inhibitors . Rinsho Ketsueki \n2017 ;58 :966 –76 .28883282 \n[6] Chesney J Imbert-Fernandez Y Telang S \nPotential clinical and immunotherapeutic utility of talimogene laherparepvec for patients with melanoma after disease progression on immune checkpoint inhibitors and BRAF inhibitors . Melanoma Res \n2018 ;28 :250 –5 .29561296 \n[7] Abbaspour Babaei M Kamalidehghan B Saleem M \nReceptor tyrosine kinase (c-Kit) inhibitors: a potential therapeutic target in cancer cells . Drug Des Devel Ther \n2016 ;10 :2443 –59 .\n[8] Jiang X Zhou J Yuen NK \nImatinib targeting of KIT-mutant oncoprotein in melanoma . Clin Cancer Res \n2008 ;14 :7726 –32 .19047099 \n[9] McDonnell K Betz B Fullen D \nV559A and N822I double KIT mutant melanoma with predictable response to imatinib? \nPigment Cell Melanoma Res \n2011 ;24 :390 –2 .21159146 \n[10] Seifert AM Zeng S Zhang JQ \nPD-1/PD-L1 Blockade Enhances T-cell activity and antitumor efficacy of imatinib in gastrointestinal stromal tumors . Clin Cancer Res \n2017 ;23 :454 –65 .27470968 \n[11] Hassel JC Lee SB Meiss F \nVemurafenib and ipilimumab: a promising combination? Results of a case series . Oncoimmunology \n2016 ;5 :e1101207 .27141385 \n[12] Yilmaz M Jabbour E \nTyrosine kinase inhibitors early in the disease course: lessons from chronic myelogenous leukemia . Semin Oncol \n2015 ;42 :876 –86 .26615132 \n[13] Wei X Mao L Chi Z \nEfficacy evaluation of imatinib for the treatment of melanoma: evidence from a retrospective study . Oncol Res \n2019 ;27 :495 –501 .30075827 \n[14] GLEEVEC (imatinib mesylate) tablets Label-FDA https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021588s024lbl.pdf \n(access date April 15, 2019)\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "98(44)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008545:Melanoma; D009154:Mutation; D009362:Neoplasm Metastasis; D019009:Proto-Oncogene Proteins c-kit; D012878:Skin Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e17769",
"pmc": null,
"pmid": "31689840",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Combination of pembrolizumab and imatinib in a patient with double KIT mutant melanoma: A case report.",
"title_normalized": "combination of pembrolizumab and imatinib in a patient with double kit mutant melanoma a case report"
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"abstract": "The prevalence, clinical significance, and spectrum of many HPV genotypes are currently largely untapped. We report a case of anal condyloma associated with a rare HPV genotype in a 11-year-old kidney transplant recipient. Eleven months post-graft, rectal bleeding revealed a 5-cm-large anal condyloma for which immuno-histopathology revealed typical papillomatosis. HPV genotyping performed on anal biopsy identified a HPV type 7, for which a single sequence was found in the GenBank sequence database. HPV7 is classically found in hand cutaneous warts, but HPV7-associated condyloma was only described in two patients. Total resection of the anal lesion was performed by electrocoagulation with no recurrence after 6 years. Post-transplant immunosuppression may promote anal condyloma with uncommon HPV types. HPV genotyping in such lesions is useful to get a better understanding of the epidemiology and clinical significance of such unusual HPV types as HPV7.",
"affiliations": "Pédiatrie Multidisciplinaire Timone AP-HM CHU Timone-Enfants, Marseille, France.;Chirurgie Viscérale Pédiatrique AP-HM CHU Timone-Enfants, Marseille, France.;Pédiatrie Multidisciplinaire Timone AP-HM CHU Timone-Enfants, Marseille, France.;IHU Méditerranée Infection, Marseille, France.;IHU Méditerranée Infection, Marseille, France.",
"authors": "Garaix|Florentine|F|;Hery|Geraldine|G|;Tsimaratos|Michel|M|;Colson|Philippe|P|0000-0001-6285-0308;Tamalet|Catherine|C|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13470",
"fulltext": null,
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"issn_linking": "1397-3142",
"issue": "23(5)",
"journal": "Pediatric transplantation",
"keywords": "HPV7; condyloma; genotyping; papillomavirus; pediatrics; renal transplantation",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D001004:Anus Diseases; D002648:Child; D003218:Condylomata Acuminata; D006801:Humans; D007165:Immunosuppression Therapy; D016030:Kidney Transplantation; D008297:Male; D030361:Papillomavirus Infections",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e13470",
"pmc": null,
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"publication_types": "D002363:Case Reports",
"references": null,
"title": "Human papillomavirus type 7-associated anal condyloma after renal transplantation in a child.",
"title_normalized": "human papillomavirus type 7 associated anal condyloma after renal transplantation in a child"
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"abstract": "Opportunistic invasive fungal infections (IFIs) comprise a heterogeneous spectrum of pathogens, whose early diagnosis remains challenging. Candida spp. and Aspergillus spp, the most frequent pathogens in immunocompromised patients, frequently affect lungs, liver, bone and skin.\nTo evaluate the impact of 18F-FDG PET/CT in the management of immunocompromised patients with IFI.\nA single-center retrospective study included 51 immunocompromised patients with IFI diagnosis undergoing 83 18F-FDG PET/CTs.\nTwenty-nine 18F-FDG PET/CTs were performed for primary work-up in 29 treatment-naïve patients. Fifty-four PET/CTs were performed during follow-up to confirm IFI suspicion in 22 patients who had anti-fungal drug therapy before PET/CT. When available, histological and/or microbiological criteria were used to assess IFI diagnosis.\nAspergillus spp. and Candida spp. were the most frequent microorganisms responsible for IFI in our population. 18F-FDG PET/CT sensitivity, specificity, positive and negative predictive values, and global accuracy were 93%, 81%, 95%, 72% and 90%, respectively. 18F-FDG PET/CT influenced the diagnostic work-up at primary staging in 16/29 patients (55%) by assessing the extent of infection and targeting the diagnostic procedure. 18F-FDG PET/CT results during treatment induced anti-fungal drugs dosage increase and/or new drugs addition in 8/54 cases (15%) and contributed to the reduction of anti-fungal drugs dosage or treatment withdraws in 17 cases (31%).\nWe recommend the utilization of 18F-FDG PET/CT to improve the primary staging work-up of immunocompromised patients with IFI and to assess treatment effectiveness or disease relapse. Both 18F-FDG PET/CT and conventional imaging should be integrated into a well-defined imaging diagnostic algorithm considering the clinical context and both strengths and limitations of each diagnostic modality.",
"affiliations": "From the Biophysics and Nuclear Medicine, Strasbourg University Hospitals, Strasbourg, France.;Nuclear Medicine and PET/CT Centre, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.;Federation of Translational Medicine of Strasbourg (FMTS), Faculty of Medicine, Strasbourg University, Strasbourg, France.;From the Biophysics and Nuclear Medicine, Strasbourg University Hospitals, Strasbourg, France.;Pneumology, Strasbourg University Hospitals, Strasbourg, France.;Oncology and Hematology, Strasbourg University Hospitals, Strasbourg, France.;From the Biophysics and Nuclear Medicine, Strasbourg University Hospitals, Strasbourg, France.",
"authors": "Leroy-Freschini|B|B|;Treglia|G|G|;Argemi|X|X|;Bund|C|C|;Kessler|R|R|;Herbrecht|R|R|;Imperiale|A|A|",
"chemical_list": "D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18",
"country": "England",
"delete": false,
"doi": "10.1093/qjmed/hcy128",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1460-2393",
"issue": "111(9)",
"journal": "QJM : monthly journal of the Association of Physicians",
"keywords": null,
"medline_ta": "QJM",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D016867:Immunocompromised Host; D000072742:Invasive Fungal Infections; D008297:Male; D008875:Middle Aged; D000072078:Positron Emission Tomography Computed Tomography; D019275:Radiopharmaceuticals; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D055815:Young Adult",
"nlm_unique_id": "9438285",
"other_id": null,
"pages": "613-622",
"pmc": null,
"pmid": "29917146",
"pubdate": "2018-09-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "18F-FDG PET/CT for invasive fungal infection in immunocompromised patients.",
"title_normalized": "18f fdg pet ct for invasive fungal infection in immunocompromised patients"
} | [
{
"companynumb": "FR-ACCORD-121883",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Clozapine-induced neutropenia occurs in 3-5% of individuals treated with clozapine. Current US guidelines require interruption of clozapine when the absolute neutrophil count (ANC) drops below 1000 cells/mm3. There is minimal available guidance for what dosing schedule to use when restarting clozapine after an episode of neutropenia. Here, we present a case of a 50-year-old Caucasian female with a history of schizoaffective disorder who was successfully rechallenged on clozapine one month after developing clozapine-induced neutropenia (ANC 600 cells/mm3). To understand published re-titration rates of clozapine after neutropenia, we conducted a literature review using a using the PubMed database and found only seven case reports that unambiguously reported a clozapine dosing schedule during re-challenge. All were successful except one, a case of clozapine rechallenge after agranulocytosis. Including this case presentation, six out of eight cases restarted clozapine more cautiously than recommended by the US guidelines for a new clozapine initiation. We cannot comment what role a slower or more rapid titration plays in a successful rechallenge after neutropenia with the available evidence. We encourage researchers to publish their dosing schedule in detail after an episode of neutropenia or agranulocytosis.",
"affiliations": "Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine.;Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine.;Department of Psychiatry & Behavioral Sciences, University of Miami Leonard Miller School of Medicine.;Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine.;Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine.;Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine.",
"authors": "Boazak|Mina|M|;Kahn|Benjamin|B|;Cox|Lindsay|L|;Ragazino|James|J|;Goldsmith|David R|DR|;Cotes|Robert O|RO|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.3371/CSRP.BOKA.061518",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1232",
"issue": null,
"journal": "Clinical schizophrenia & related psychoses",
"keywords": "agranulocytosis; clozapine; neutropenia; re-titration rate; rechallenge; schizophrenia",
"medline_ta": "Clin Schizophr Relat Psychoses",
"mesh_terms": null,
"nlm_unique_id": "101312513",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29944418",
"pubdate": "2018-06-26",
"publication_types": "D016428:Journal Article",
"references": "21969051;24039428;28817489;25716496;12506270;19188296;24167679;9366002;23557674;27049594;23345473;24167701;8515788;25214394;8938913;27232877;18480098;16841625;22244024;22113154;9541331;1349691;11094146;16585434;7884027;27109327;26267420;28922288;23372249;24004162;12404322;17893412;20587767;10789357;15738861;15738753;20439404;26646037;28984748;19567774;23525060;16507968;8071281;8894200;23395419;18593787;28882687;28097743;9534838;8925346;26266027;18407390;22831769;17190527;10890315;3046553;26522679;27168101",
"title": "Re-titration rates after clozapine-induced neutropenia or agranulocytosis: A case report and literature review.",
"title_normalized": "re titration rates after clozapine induced neutropenia or agranulocytosis a case report and literature review"
} | [
{
"companynumb": "US-JAZZ-2019-US-006277",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CLOZAPINE"
},
"drugadditional": null,
... |
{
"abstract": "Pericatheter bleeding (PB) following tunneled hemodialysis catheter (THC) placement is a common phenomenon. In addition to complicating securement of the THC, the PB may loosen the adhesive catheter dressing and delay wound healing. The primary aim of this study was to determine whether epinephrine-containing local anesthetics rather than plain ones reduce superficial PB after THC placement.\n\n\n\nThe study was based on the retrospective analysis of the prospectively gathered data. Forty-six patients receiving local analgesia during THC placement were randomly assigned in a double-blind manner to two groups according to local anesthetic mixtures used (n =22 to prilocaine group [group 1]; n =24 to epinephrine-containing lidocaine group [group 2]). Presence or absence of PB after the THC placement was evaluated. Differences between groups with and without controlling other variables were statistically analyzed.\n\n\n\nEpinephrine-containing lidocaine (group 2) significantly reduced PB in comparison with prilocaine, P = 0.003. Use of epinephrine-containing lidocaine (group 2) was associated with a reduction in the likelihood of PB (Odds ratio = 0.017). Meanwhile, use of prilocaine (group 1) had 59.7 times higher odds in the likelihood of PB after THC placement. Lower rate of systolic blood pressure (SBP) in group 2 patients after 5 minutes of injections was also noted, P = 0.008. Epinephrine-containing lidocaine was well tolerated and caused no significant cardiovascular disturbance.\n\n\n\nLocal infiltration of epinephrine-containing lidocaine instead of plain local anesthetics during THC insertion may reduce superficial PB and improve patient comfort.",
"affiliations": "Department of Diagnostic and Interventional Radiology, Istanbul Training and Research Hospital, Istanbul, Turkey.;Department of Diagnostic and Interventional Radiology, Istanbul Training and Research Hospital, Istanbul, Turkey.;Department of Diagnostic and Interventional Radiology, Istanbul Training and Research Hospital, Istanbul, Turkey.;Department of Diagnostic and Interventional Radiology, Istanbul Training and Research Hospital, Istanbul, Turkey.;Department of Diagnostic and Interventional Radiology, Istanbul Training and Research Hospital, Istanbul, Turkey.;Department of Diagnostic and Interventional Radiology, Istanbul Training and Research Hospital, Istanbul, Turkey.",
"authors": "Mutlu|Ilhan Nahit|IN|0000-0002-9326-5432;Kocak|Burak|B|;Baykara Ulusan|Melis|M|;Ulusan|Kivilcim|K|;Cakir|Mehmet Semih|MS|;Kilickesmez|Ozgur|O|",
"chemical_list": "D000779:Anesthetics, Local; D014662:Vasoconstrictor Agents; D008012:Lidocaine; D004837:Epinephrine",
"country": "Canada",
"delete": false,
"doi": "10.1111/hdi.12686",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1492-7535",
"issue": "23(1)",
"journal": "Hemodialysis international. International Symposium on Home Hemodialysis",
"keywords": "Anesthetics; bleeding; catheter; epinephrine; hemodialysis; lidocaine",
"medline_ta": "Hemodial Int",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000779:Anesthetics, Local; D002404:Catheterization; D004311:Double-Blind Method; D004837:Epinephrine; D005260:Female; D006470:Hemorrhage; D006801:Humans; D008012:Lidocaine; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D006435:Renal Dialysis; D012189:Retrospective Studies; D014662:Vasoconstrictor Agents",
"nlm_unique_id": "101093910",
"other_id": null,
"pages": "26-32",
"pmc": null,
"pmid": "30239113",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Regional anesthesia with epinephrine-containing lidocaine reduces pericatheter bleeding after tunneled hemodialysis catheter placement.",
"title_normalized": "regional anesthesia with epinephrine containing lidocaine reduces pericatheter bleeding after tunneled hemodialysis catheter placement"
} | [
{
"companynumb": "TR-DENTSPLY-2019SCDP000334",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PRILOCAINE"
},
"drugadditional": null,
... |
{
"abstract": "Onset during old age has been reported in upto 10% of total cases of inflammatory bowel disease (IBD).\n\n\n\nTo evaluate phenotypic characteristics and the use of therapeutic resources in patients with elderly onset IBD.\n\n\n\nCase-control study including all those patients diagnosed with IBD over the age of 60 years since 2000 who were followed-up for >12 months, identified from the IBD databases. Elderly onset cases were compared with IBD patients aged 18 to 40 years at diagnosis, matched by year of diagnosis, gender and type of IBD (adult-onset).\n\n\n\nOne thousand three hundred and seventy-four elderly onset and 1374 adult-onset cases were included (62% ulcerative colitis (UC), 38% Crohn's disease (CD)). Among UC patients, elderly onset cases had a lower proportion of extensive disease (33% vs 39%; P < 0.0001). In CD, elderly onset cases showed an increased rate of stenosing pattern (24% vs 13%; P < 0.0001) and exclusive colonic location (28% vs 16%; P < 0.0001), whereas penetrating pattern (12% vs 19%; P < 0.0001) was significantly less frequent. Regarding the use of therapeutic resources, there was a significantly lower use of corticosteroids (P < 0.0001), immunosuppressants (P < 0.0001) and anti-TNFs agents (P < 0.0001) in elderly onset cases. Regarding surgery, we found a significantly higher surgery rate among elderly onset UC cases (8.3% vs 5.1%; P < 0.009). Finally, elderly onset cases were characterised by a higher rate of hospitalisations (66% vs 49%; P < 0.0001) and neoplasms (14% vs 0.5%; P < 0.0001).\n\n\n\nElderly onset IBD shows specific characteristics and they are managed differently, with a lower use of immunosuppressants and a higher rate of surgery in UC.",
"affiliations": "Badalona, Spain.;Badalona, Spain.;Oviedo, Spain.;Córdoba, Spain.;Madrid, Spain.;Barcelona, Spain.;Madrid, Spain.;Valencia, Spain.;Valladolid, Spain.;L'Hospitalet, Spain.;Terrassa, Spain.;Valencia, Spain.;Manises, Spain.;Barcelona, Spain.;Santiago de Compostela, Spain.;Sabadell, Spain.;Terrassa, Spain.;Granada, Spain.;Santa Cruz de Tenerife, Spain.;Valencia, Spain.;Sevilla, Spain.;Ciudad Real, Spain.;Valladolid, Spain.;Girona, Spain.;Mendaro, Spain.;Cáceres, Spain.;Zaragoza, Spain.;Reus, Spain.;Madrid, Spain.;Huelva, Spain.;Madrid, Spain.;Badalona, Spain.;Badalona, Spain.;Badalona, Spain.",
"authors": "Mañosa|M|M|0000-0002-9051-2581;Calafat|M|M|;de Francisco|R|R|;García|C|C|;Casanova|M J|MJ|;Huelín|P|P|;Calvo|M|M|;Tosca|J|J|0000-0003-1258-9513;Fernández-Salazar|L|L|;Arajol|C|C|;Zabana|Y|Y|;Bastida|G|G|;Hinojosa|J|J|;Márquez|L|L|;Barreiro-de-Acosta|M|M|;Calvet|X|X|0000-0002-6278-9663;Monfort|D|D|;Gómez-Garcia|M R|MR|;Rodríguez|E|E|;Huguet|J M|JM|;Rojas-Feria|M|M|;Hervias|D|D|;Atienza|R|R|;Busquets|D|D|;Zapata|E|E|;Dueñas|C|C|;Charro|M|M|;Martínez-Cerezo|F J|FJ|;Plaza|R|R|;Vázquez|J M|JM|;Gisbert|J P|JP|0000-0003-2090-3445;Cañete|F|F|;Cabré|E|E|;Domènech|E|E|0000-0002-2315-7196;|||",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "England",
"delete": false,
"doi": "10.1111/apt.14494",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-2813",
"issue": "47(5)",
"journal": "Alimentary pharmacology & therapeutics",
"keywords": null,
"medline_ta": "Aliment Pharmacol Ther",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D015212:Inflammatory Bowel Diseases; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012189:Retrospective Studies; D013030:Spain; D055815:Young Adult",
"nlm_unique_id": "8707234",
"other_id": null,
"pages": "605-614",
"pmc": null,
"pmid": "29369387",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Phenotype and natural history of elderly onset inflammatory bowel disease: a multicentre, case-control study.",
"title_normalized": "phenotype and natural history of elderly onset inflammatory bowel disease a multicentre case control study"
} | [
{
"companynumb": "ES-JNJFOC-20180317958",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
"... |
{
"abstract": "A 57-year-old woman with severe bronchiectasis frequently received antibiotics, including penicillin, for acute exacerbations due to Pasteurella multocida. Although the bacteria showed a decrease in antibiotic susceptibility, her symptoms and X-ray findings became stable, and severe exacerbations were not observed for the last few years after a low-dose erythromycin treatment was started. The development of a respiratory infection with Pasteurella multocida is relatively uncommon, but it can be controlled by immunomodulation which is associated with long-term macrolide therapy.",
"affiliations": "Division of Infection Control and Prevention, Osaka University Hospital, Japan.",
"authors": "Seki|Masafumi|M|;Sakata|Tomomi|T|;Toyokawa|Masahiro|M|;Nishi|Isao|I|;Tomono|Kazunori|K|",
"chemical_list": "D000900:Anti-Bacterial Agents; D018942:Macrolides; D004917:Erythromycin",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.55.4929",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "55(3)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000900:Anti-Bacterial Agents; D001987:Bronchiectasis; D002908:Chronic Disease; D003371:Cough; D004334:Drug Administration Schedule; D004917:Erythromycin; D005260:Female; D006801:Humans; D018942:Macrolides; D008875:Middle Aged; D010326:Pasteurella Infections; D016979:Pasteurella multocida; D012141:Respiratory Tract Infections; D016896:Treatment Outcome",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "307-10",
"pmc": null,
"pmid": "26831030",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Chronic Respiratory Pasteurella multocida Infection Is Well-Controlled by Long-Term Macrolide Therapy.",
"title_normalized": "a chronic respiratory pasteurella multocida infection is well controlled by long term macrolide therapy"
} | [
{
"companynumb": "JP-BAUSCH-BL-2016-004301",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMOXICILLIN\\CLAVULANIC ACID"
},
"drugaddition... |
{
"abstract": "BACKGROUND\nIxabepilone is a member of the epothilone class of antineoplastic agents with activity against taxane-resistant tumors, and low susceptibility to common mechanisms of tumor resistance. This study evaluated ixabepilone in lieu of a taxane in combination with carboplatin and trastuzumab as neoadjuvant treatment for operable HER2-positive breast cancer.\n\n\nMETHODS\nPatients ≥ 18 years of age with histologically-confirmed HER2-positive adenocarcinoma of the breast (clinical T1-T3, N0-N2, M0), normal left ventricular ejection fraction, and adequate organ function received trastuzumab 6 mg/kg intravenous (I.V.) (with 8 mg/kg loading dose cycle 1), ixabepilone 40 mg/m(2) I.V., and carboplatin area under the curve = 6.0 I.V. on day 1 of each 21-day cycle. Prophylactic growth factor support was permitted. After completing 6 cycles, patients underwent definitive surgery. After surgery, patients continued trastuzumab every 3 weeks for a total of 1 year. Locoregional radiation therapy and endocrine therapy was administered per institutional guidelines. The primary end point was the rate of pCR.\n\n\nRESULTS\nFifty-eight eligible women (median tumor size, 3.0 cm; clinical axillary lymph node involvement, 67%) initiated treatment between April 2009 and February 2010. Fifty-two patients (90%) underwent surgery, and pCR was observed in 27 patients (52%). Grade 3/4 neutropenia was the most common toxicity, occurring in 69% of patients and complicated by fever in 4 patients.\n\n\nCONCLUSIONS\nThe combination of ixabepilone, carboplatin, and trastuzumab was feasible and active as a neoadjuvant regimen. Although the pCR rate of 52% falls within the range reported with other taxane/trastuzumab-based regimens, the greater incidence of severe neutropenia is a disadvantage for this regimen.",
"affiliations": "Sarah Cannon Research Institute, Nashville, TN; Tennessee Oncology, PLLC, Nashville, TN. Electronic address: dyardley@tnonc.com.;Sarah Cannon Research Institute, Nashville, TN; Tennessee Oncology, PLLC, Nashville, TN.;Florida Cancer Specialists, Fort Myers, FL.;Oncology Hematology Care, Cincinnati, OH.;Sarah Cannon Research Institute, Nashville, TN.;Sarah Cannon Research Institute, Nashville, TN; Tennessee Oncology, PLLC, Chattanooga, TN.;Sarah Cannon Research Institute, Nashville, TN; Tennessee Oncology, PLLC, Chattanooga, TN.;Sarah Cannon Research Institute, Nashville, TN; Tennessee Oncology, PLLC, Nashville, TN.",
"authors": "Yardley|Denise A|DA|;Zubkus|John D|JD|;Eakle|Janice F|JF|;Bechhold|Rebecca G|RG|;Finney|Lindsey|L|;Daniel|Davey|D|;Daniel|Brooke|B|;Hainsworth|John D|JD|",
"chemical_list": "D034261:Epothilones; D016190:Carboplatin; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; C430592:ixabepilone; D000068878:Trastuzumab",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1526-8209",
"issue": "15(4)",
"journal": "Clinical breast cancer",
"keywords": "Biologic; Chemotherapy; Monoclonal antibody",
"medline_ta": "Clin Breast Cancer",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D016190:Carboplatin; D017024:Chemotherapy, Adjuvant; D034261:Epothilones; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D018719:Receptor, ErbB-2; D000068878:Trastuzumab",
"nlm_unique_id": "100898731",
"other_id": null,
"pages": "251-8",
"pmc": null,
"pmid": "25640059",
"pubdate": "2015-08",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Neoadjuvant Ixabepilone/Carboplatin/Trastuzumab in HER2-Positive Operable Breast Cancer: A Phase II Trial of the Sarah Cannon Research Institute.",
"title_normalized": "neoadjuvant ixabepilone carboplatin trastuzumab in her2 positive operable breast cancer a phase ii trial of the sarah cannon research institute"
} | [
{
"companynumb": "US-CIPLA LTD.-2016US00035",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Late-onset noninfectious pulmonary complication after allogenic hematopoietic stem cell transplantation is an important contributing factor associated with high rate morbidity and mortality. We report a case with pleuroparenchymal fibroelastosis (PPFE) occurred after allogenic bone marrow transplantation. The onset was infiltrative shadows in upper lobes, and the haziness spread gradually throughout the lungs with recurrent episodes of pneumothorax in both lungs. Progressive respiratory failure in course of adrenocortical steroid administration eventually caused death. Histological examination in general autopsy showed patchy subpleural fibrosis predominantly distributed in the upper lobes with substantial density rise of elastic fibers in the subpleural area, consistent with the diagnosis of PPFE. PPFE after allogenic transplantation has been seldom reported to date, but it is one of the most important histological components of late-onset noninfectious pulmonary complication after allogenic transplantation characterized by recurrent pneumothorax. Retrospective analysis in our case indicates early diagnosis may be possible by histological evaluation of elastic fibers in lung specimen when pneumothorax is treated surgically. This case suspects that it is important for hematologist and pathologist to aware this progressive disease along with information of histological characteristics, therefore, leading to the establishment of therapeutic strategies and the improvement of poor prognosis.",
"affiliations": "Department of Hematology and Oncology, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan.;Department of Hematology and Oncology, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan. mtetsuo@bldon.med.osaka-u.ac.jp.;Department of Hematology and Oncology, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan.;Department of Hematology and Oncology, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan.;Department of Pathology, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan.;Department of Pathology, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan.;Department of Hematology and Oncology, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan.",
"authors": "Matsui|Takahiro|T|;Maeda|Tetsuo|T|;Kida|Toru|T|;Fujita|Jiro|J|;Tsuji|Hiromi|H|;Morii|Eiichi|E|;Kanakura|Yuzuru|Y|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-016-2038-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "104(4)",
"journal": "International journal of hematology",
"keywords": "Allogenic hematopoietic stem cell transplantation; Pleuroparenchymal fibroelastosis; Pneumothorax",
"medline_ta": "Int J Hematol",
"mesh_terms": "D064591:Allografts; D004547:Elastic Tissue; D017809:Fatal Outcome; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008171:Lung Diseases; D000072356:Parenchymal Tissue; D010994:Pleura; D011030:Pneumothorax; D012008:Recurrence",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "525-30",
"pmc": null,
"pmid": "27312041",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12907447;17321983;25367470;14755316;20577219;25454481;25234860;21822205;24390527;15596706",
"title": "Pleuroparenchymal fibroelastosis after allogenic hematopoietic stem cell transplantation: important histological component of late-onset noninfectious pulmonary complication accompanied with recurrent pneumothorax.",
"title_normalized": "pleuroparenchymal fibroelastosis after allogenic hematopoietic stem cell transplantation important histological component of late onset noninfectious pulmonary complication accompanied with recurrent pneumothorax"
} | [
{
"companynumb": "JP-APOPHARMA USA, INC.-2016AP014323",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugaddi... |
{
"abstract": "Pracinostat, a potent oral pan-histone deacetylase inhibitor with modest single-agent activity in acute myeloid leukemia (AML), has shown synergistic antitumor activity when combined with azacitidine. This single-group, multicenter phase 2 study assessed the safety and efficacy of pracinostat combined with azacitidine in patients who were at least 65 years old with newly diagnosed AML and who were ineligible for standard induction chemotherapy. Patients received pracinostat 60 mg/d, 3 d/wk, for 3 consecutive weeks, plus azacitidine 75 mg/m2 daily for 7 days in a 28-day cycle. Primary endpoints were complete remission (CR), CR with incomplete count recovery (CRi), and morphologic leukemia-free state (MLFS) rates of the combination. Secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS) of the regimen. Fifty patients (33 de novo, 12 secondary, and 5 therapy-related AML) were enrolled. Twenty-six patients (52%) achieved the primary endpoint of CR (42%), CRi (4%), and MLFS (6%). Median OS and PFS were 19.1 months (95% confidence interval [CI], 10-26.5 months) and 12.6 months (95% CI, 10-17.7 months), respectively, with a 1-year OS rate of 62%. Forty-three patients (86%) experienced at least 1 grade 3 or worse treatment-emergent adverse event with the combination, with infections (52%), thrombocytopenia (46%), and febrile neutropenia (44%) reported as the most common toxicities. The 30- and 60-day all-cause mortality rates were 2% and 10%, respectively. DNA sequencing revealed somatic mutations at baseline, and clearance rates correlated with response to treatment. Pracinostat plus azacitidine is a well-tolerated and active regimen in the frontline treatment of older patients with AML unfit for intensive therapy. A larger controlled trial is ongoing. This trial was registered at www.clinicaltrials.gov as #NCT01912274.",
"affiliations": "Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Hematology, Stanford University, Stanford, CA.;Department of Hematology, Emory University School of Medicine, Atlanta, GA.;Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA.;Department of Hematology, Mayo Clinic, Rochester, MN.;Division of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL.;Department of Hematology and Oncology, Indiana University, Indianapolis, IN.;Mercy Hospital, Springfield, MO.;Department of Hematology, University of Texas Southwestern Medical Center, Dallas, TX.;Department of Hematology and Oncology, University of Nebraska Medical Center, Omaha, NE.;Section of Hematological Malignancies and Blood/Marrow Transplantation, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC.;Department of Hematologic Malignancies, Oregon Health and Science University, Portland, OR.;Arizona Oncology, Tempe, AZ.;Department of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Cancer Center, Westwood, KS.;MEI Pharma, Inc., San Diego, CA.;Helsinn Healthcare, SA, Lugano, Switzerland; and.;Department of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI.",
"authors": "Garcia-Manero|Guillermo|G|;Abaza|Yasmin|Y|;Takahashi|Koichi|K|0000-0002-8027-9659;Medeiros|Bruno C|BC|;Arellano|Martha|M|;Khaled|Samer K|SK|;Patnaik|Mrinal|M|;Odenike|Olatoyosi|O|;Sayar|Hamid|H|;Tummala|Mohan|M|;Patel|Prapti|P|;Maness-Harris|Lori|L|;Stuart|Robert|R|;Traer|Elie|E|;Karamlou|Kasra|K|;Yacoub|Abdulraheem|A|;Ghalie|Richard|R|;Giorgino|Ruben|R|;Atallah|Ehab|E|",
"chemical_list": "D000970:Antineoplastic Agents; D001562:Benzimidazoles; C557525:SB939 compound; D001374:Azacitidine",
"country": "United States",
"delete": false,
"doi": "10.1182/bloodadvances.2018027409",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2473-9529",
"issue": "3(4)",
"journal": "Blood advances",
"keywords": null,
"medline_ta": "Blood Adv",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001374:Azacitidine; D001562:Benzimidazoles; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D016019:Survival Analysis; D016896:Treatment Outcome",
"nlm_unique_id": "101698425",
"other_id": null,
"pages": "508-518",
"pmc": null,
"pmid": "30760466",
"pubdate": "2019-02-26",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "29601269;25040094;18692693;21586629;24663049;26376137;28687581;22689805;12393614;15927669;29702001;25426838;20197387;24951123;12429021;16357841;24550281;20026804;16921040;9916800;25953722;21767242;22773600;17341661;26304885;25987659;20668231;16778214;16435386;14673054;28094841;28841236;28486043;12120280;27923552;16882711;17665331;25426837;11110676;21634430;22237025",
"title": "Pracinostat plus azacitidine in older patients with newly diagnosed acute myeloid leukemia: results of a phase 2 study.",
"title_normalized": "pracinostat plus azacitidine in older patients with newly diagnosed acute myeloid leukemia results of a phase 2 study"
} | [
{
"companynumb": "US-CELGENEUS-USA-2014114148",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AZACITIDINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nMacrophage activating factor (MAF)-based immunotherapy has a wide application for use in treating many diseases via macrophage activation. Sonodynamic therapy (SDT) using low-intensity ultrasound and tumor treating field (TTF) therapy are novel therapeutic modalities. SDT is usually combined with ozone therapy to improve local hypoxia within the tumor environment.\n\n\nMETHODS\nWe treated a 77-year-old male diagnosed with non-small cell lung cancer ((NSCLC) stage 3B) using second-generation serum GcMAF and oral colostrum MAF-based immunotherapy combined with SDT, TTF and ozone therapies.\n\n\nRESULTS\nThis case report demonstrates that GcMAF, oral colostrum MAF, SDT, TTF and ozone therapy can be used for NSCLC without adverse effects.\n\n\nCONCLUSIONS\nThis case report suggests a new concept of cancer treatment using local destruction of cancer tissue, in this case conducted with SDT and TTF therapy, to be used in combination with serum GcMAF and colostrum MAF immunotherapy as a systemic treatment.",
"affiliations": "Department of Life System, Institute of Technology and Science, Graduate School, Tokushima University, Tokushima, Japan Saisei Mirai Cell Processing Center, Osaka, Japan Kobe Saisei Mirai Clinic, Kobe, Japan Inui Immunotherapy Clinic, Osaka, Japan Tokyo Saisei Mirai Clinic, Tokyo, Japan contact@saisei-mirai.or.jp.;Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.;Saisei Mirai Cell Processing Center, Osaka, Japan.;Department of Life System, Institute of Technology and Science, Graduate School, Tokushima University, Tokushima, Japan Saisei Mirai Cell Processing Center, Osaka, Japan.;Department of Life System, Institute of Technology and Science, Graduate School, Tokushima University, Tokushima, Japan.;Frontiers of Innovative Research in Science and Technology (FIRST), Konan University, Kobe, Japan.;Inui Immunotherapy Clinic, Osaka, Japan contact@saisei-mirai.or.jp.",
"authors": "Inui|Toshio|T|;Amitani|Haruka|H|;Kubo|Kentaro|K|;Kuchiike|Daisuke|D|;Uto|Yoshihiro|Y|;Nishikata|Takahito|T|;Mette|Martin|M|",
"chemical_list": "D016215:Macrophage-Activating Factors; D014809:Vitamin D-Binding Protein; C101908:vitamin D-binding protein-macrophage activating factor; D000068437:Pemetrexed; D003841:Deoxycytidine; C056507:gemcitabine; D016190:Carboplatin",
"country": "Greece",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "36(7)",
"journal": "Anticancer research",
"keywords": "GcMAF; Immunotherapy; colostrum MAF; macrophage activating factor (MAF); non-small cell lung cancer; ozone therapy; sonodynamic therapy (SDT); tumor treating field (TTF) therapy",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002289:Carcinoma, Non-Small-Cell Lung; D003131:Combined Modality Therapy; D003841:Deoxycytidine; D006801:Humans; D008175:Lung Neoplasms; D016215:Macrophage-Activating Factors; D008297:Male; D000068437:Pemetrexed; D016896:Treatment Outcome; D014464:Ultrasonic Therapy; D014809:Vitamin D-Binding Protein",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "3767-70",
"pmc": null,
"pmid": "27354652",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case Report: A Non-small Cell Lung Cancer Patient Treated with GcMAF, Sonodynamic Therapy and Tumor Treating Fields.",
"title_normalized": "case report a non small cell lung cancer patient treated with gcmaf sonodynamic therapy and tumor treating fields"
} | [
{
"companynumb": "JP-PFIZER INC-2016545989",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEMETREXED"
},
"drugadditional": null,
... |
{
"abstract": "Cardiopulmonary bypass in cardiac surgery produces systemic inflammatory response and catabolic state. Severe stress frequently causes abnormalities in thyroid hormones in the absence of primary thyroid disease, defined as sick euthyroid syndrome (SES).\n\n\n\nSupplementation therapy with thyroid and anabolic hormones in combination with an adequate nutritional support has been used to improve outcome in critically ill patient after cardiac surgery.\n\n\n\nAdministration of thyroid and anabolic hormones significantly improved patient’s condition.\n\n\n\nSupplementation therapy with thyroid and anabolic hormones in combination with an adequate nutritional support could be used to improve hemodynamics, achieve transition to anabolic metabolism and enhance recovery, which could eventually help for a reduction in post-operative morbidity and mortality.",
"affiliations": "St Anna University Hospital, Sofia, Bulgaria.;Medical University - Sofia, Sofia, Bulgaria.;St Anna University Hospital, Sofia, Bulgaria.;St Anna University Hospital, Sofia, Bulgaria.;St Anna University Hospital, Sofia, Bulgaria.;Medical University - Pleven, Pleven, Bulgaria.;St Anna University Hospital, Sofia, Bulgaria.",
"authors": "Stoitsev|Georgi J|GJ|;Gavrilov|Veselin|V|;Manchev|Georgi|G|;Markov|Boyan|B|;Goranovska|Valya|V|;Tsankov|Boris|B|;Gegouskov|Vassil|V|",
"chemical_list": "D013739:Testosterone; D013974:Thyroxine",
"country": "Bulgaria",
"delete": false,
"doi": "10.3897/folmed.61.e47962",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0204-8043",
"issue": "61(4)",
"journal": "Folia medica",
"keywords": "L-thyroxine; anabolic metabolism; cardiac surgery; nutrition; testosterone",
"medline_ta": "Folia Med (Plovdiv)",
"mesh_terms": "D000368:Aged; D001011:Aorta; D001014:Aortic Aneurysm; D006348:Cardiac Surgical Procedures; D005067:Euthyroid Sick Syndromes; D005260:Female; D020249:Hormone Replacement Therapy; D006801:Humans; D013739:Testosterone; D013974:Thyroxine",
"nlm_unique_id": "2984761R",
"other_id": null,
"pages": "650-654",
"pmc": null,
"pmid": "32337877",
"pubdate": "2019-12-31",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Therapy with L-thyroxine and Omnadren after Cardiac Surgery. A Case Report.",
"title_normalized": "therapy with l thyroxine and omnadren after cardiac surgery a case report"
} | [
{
"companynumb": "NVSC2020BG091350",
"fulfillexpeditecriteria": "1",
"occurcountry": "BG",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VALSARTAN"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "METHODS\nMale, 81 FINAL DIAGNOSIS: Prostate cancer Symptoms: Anorexia • dark urine • joundice • letargy\n\n\nMETHODS\nCasodex Clinical Procedure: - Specialty: Oncology.\n\n\nOBJECTIVE\nAdverse events of drug therapy.\n\n\nBACKGROUND\nBicalutamide is a nonsteroidal anti-androgen used extensively during the initiation of androgen deprivation therapy with a luteinizing hormone-releasing hormone (LHRH) agonist to reduce the symptoms of tumor flare in patients with metastatic prostate neoplasm. It can cause gynecomastia, hot flashes, fatigue, and decreased libido through competitive androgen receptor blockade. Although not as common, acute drug-induced liver injury is also possible with bicalutamide therapy. Typically, this results in transient derangement of liver function and patients remain asymptomatic. We share our experience with a case of symptomatic acute hepatotoxicity secondary to the use of bicalutamide and use this opportunity to present a brief review of existing literature.\n\n\nMETHODS\nAn 81-year-old African American male with metastatic prostate neoplasm presented with nonspecific symptoms along with jaundice of 1-day duration. He was started on a trial of bicalutamide 3 weeks prior to presentation. On physical examination, scleral icterus was noted. Workup revealed acutely elevated liver transaminases (>5 times the upper limit of normal), alkaline phosphatase, conjugated hyperbilirubinemia, and coagulopathy. Other etiologies, including viruses, common toxins, drugs, autoimmune, and copper-induced hepatitis, were considered. Bicalutamide was discontinued and the patient was managed with supportive care. He showed improvement of clinical and laboratory abnormalities within days.\n\n\nCONCLUSIONS\nWhile rare, clinically significant and potentially life-threatening liver injury can result from use of bicalutamide. Prompt recognition and discontinuation of bicalutamide is necessary to avoid serious complications from this adverse reaction.",
"affiliations": "Department of Internal Medicine, Providence Hospital and Medical Centers, Southfield, MI, U.S.A.;Department of Internal Medicine, Providence Hospital and Medical Centers, Southfield, MI, U.S.A.;Department of Internal Medicine, Providence Hospital and Medical Centers, Southfield, MI, U.S.A.;Department of Internal Medicine, Division of Gastroenterology, Providence Hospital and Medical Centers, Southfield, MI, U.S.A.;Department of Internal Medicine, Division of Gastroenterology, Providence Hospital and Medical Centers, Southfield, MI, U.S.A.;Department of Internal Medicine, Division of Gastroenterology, Henry Ford Health System, Detroit, MI, U.S.A.",
"authors": "Hussain|Salwa|S|;Haidar|Abdallah|A|;Bloom|Robert E|RE|;Zayouna|Nafea|N|;Piper|Michael H|MH|;Jafri|Syed-Mohammed R|SM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.890679",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-5923",
"issue": "15()",
"journal": "The American journal of case reports",
"keywords": "Drug-Induced Liver Injury; Nonsteroidal Anti-Androgens; Prostatic Neoplasms",
"medline_ta": "Am J Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "266-70",
"pmc": null,
"pmid": "24967002",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": "16430622;18657023;14748655;8560681;9074908;17138490;10388026;18796378;26357608;9037299;16294367",
"title": "Bicalutamide-induced hepatotoxicity: A rare adverse effect.",
"title_normalized": "bicalutamide induced hepatotoxicity a rare adverse effect"
} | [
{
"companynumb": "PHHY2012US104989",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FOLIC ACID"
},
"drugadditional": null,
"dru... |
{
"abstract": "With advances in drug treatment of breast cancer, the number of patients experiencing cardiac toxicity or carcinomatous pericarditis is expected to increase. These conditions can cause cardiac tamponade, which is a potentially fatal condition requiring prompt diagnosis and treatment. We experienced 3 breast cancer patients with cardiac tamponade due to carcinomatous pericarditis who survived for prolonged periods after treatment with pericardiocentesis and intrapericardial instillation. The 3 women were 68, 46 and 46 years old, respectively, and receiving treatment for recurrent breast cancer after surgery. They developed dyspnea and cough and were diagnosed with cardiac tamponade by echocardiography. Pericardiocentesis was performed, and cytology of the effusion confirmed the diagnosis of carcinomatous pericarditis. Intrapericardial instillation of cisplatin reduced the cardiac effusion, ameliorating symptoms. The patients died 13, 31 and 14 months later, respectively. In our clinical review of 13 other cases of cardiac tamponade due to breast cancer, 85% achieved local control after the aforementioned local treatments, which were considered to be effective. Although the overall prognosis was poor with a median survival time of only 4 months, some patients were able to survive more than 1 year after local treatment with subsequent systemic therapy.",
"affiliations": "Division of Breast Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.",
"authors": "Konishi|Takanori|T|;Nakamura|Rikiya|R|;Yamamoto|Naohito|N|;Onai|Yasuhide|Y|;Okada|Toshi|T|;Itami|Makiko|M|;Miyazaki|Masaru|M|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000338615",
"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 10.1159/000338615cro-0005-0195Published online: April, 2012Carcinomatous Pericarditis in 3 Breast Cancer Patients with Long-Term Survival Konishi Takanori aNakamura Rikiya a*Yamamoto Naohito aOnai Yasuhide aOkada Toshi aItami Makiko bMiyazaki Masaru caDivision of Breast Surgery, Chiba University Graduate School of Medicine, Chiba, JapanbDivision of Diagnostic Pathology, Chiba Cancer Center Hospital, Chiba University Graduate School of Medicine, Chiba, JapancDepartment of General Surgery, Chiba University Graduate School of Medicine, Chiba, Japan*Rikiya Nakamura, Division of Breast Surgery, Chiba Cancer Center Hospital, 666-2 Nitona, Chuo-ku, Chiba 260-8717 (Japan), Tel. +81 43 262 8680, E-Mail rikiya@crux.ocn.ne.jpJan-Apr 2012 25 4 2012 25 4 2012 5 1 195 201 Copyright © 2012 by S. Karger AG, Basel2012This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial-No-Derivative-Works License (http://creativecommons.org/licenses/by-nc-nd/3.0/). Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.With advances in drug treatment of breast cancer, the number of patients experiencing cardiac toxicity or carcinomatous pericarditis is expected to increase. These conditions can cause cardiac tamponade, which is a potentially fatal condition requiring prompt diagnosis and treatment. We experienced 3 breast cancer patients with cardiac tamponade due to carcinomatous pericarditis who survived for prolonged periods after treatment with pericardiocentesis and intrapericardial instillation. The 3 women were 68, 46 and 46 years old, respectively, and receiving treatment for recurrent breast cancer after surgery. They developed dyspnea and cough and were diagnosed with cardiac tamponade by echocardiography. Pericardiocentesis was performed, and cytology of the effusion confirmed the diagnosis of carcinomatous pericarditis. Intrapericardial instillation of cisplatin reduced the cardiac effusion, ameliorating symptoms. The patients died 13, 31 and 14 months later, respectively. In our clinical review of 13 other cases of cardiac tamponade due to breast cancer, 85% achieved local control after the aforementioned local treatments, which were considered to be effective. Although the overall prognosis was poor with a median survival time of only 4 months, some patients were able to survive more than 1 year after local treatment with subsequent systemic therapy.\n\nKey Words\nBreast cancerCarcinomatous pericarditisCardiac tamponadePericardiocentesis\n==== Body\nIntroduction\nRecent developments in molecular targeting agents and new anticancer drugs have contributed to dramatic improvements in the life expectancy of patients with recurrent breast cancer [1, 2]. With the prolongation of survival, long-term treatment for recurrent cancer has become more frequent and the importance of systemic management has increasingly been recognized. It is particularly expected that the occurrence of cardiac tamponade due to cardiac toxicity associated with the use of molecular targeting agents or carcinomatous pericarditis will increase. Therefore, it is important to assure early diagnosis and appropriate treatment of heart failure in these patients [3]. We experienced 3 breast cancer patients with cardiac tamponade due to carcinomatous pericarditis who survived for a prolonged period after treatment with pericardiocentesis and intrapericardial instillation of cisplatin (CDDP). We retrospectively reviewed therapeutic outcomes of our patients, including 13 additional patients, who developed cardiac tamponade, to determine the usefulness of pericardiocentesis for carcinomatous pericarditis.\n\nCase Reports\nCase 1\nA 60-year-old woman underwent breast-conserving surgery and sentinel lymph node biopsy for left breast cancer. Histological examination showed a scirrhous carcinoma 1.6 cm in diameter (n0, ER positive, PgR positive and HER2 negative). Postoperative radiotherapy and tamoxifen were administered as adjuvant therapy. Four years and 8 months after surgery, she developed carcinomatous pleurisy, for which anastrozole treatment was started. After that, she had hepatic metastasis and peritoneal dissemination, for which capecitabine, paclitaxel and irinotecan were administered. Seven years and 9 months after surgery, when she was 68 years old, the patient developed dyspnea, and the presence of pericardial effusion was confirmed by echocardiography. Diuretics were administered but the symptoms worsened, and the patient was admitted to the hospital.\n\nAt the time of admission, her blood pressure was 107/70 mm Hg, pulse rate 84/min and SpO2 97% (room air). Chest X-ray showed an enlarged heart shadow (fig. 1a) and chest CT showed pericardial effusion (1.6 cm) and right pleural effusion (fig. 1b). Echocardiography revealed pericardial effusion and collapse of the right heart (fig. 1c), so cardiac tamponade was diagnosed. Pericardiocentesis was performed and a drainage tube was placed. Bloody pericardial fluid was drained, and the cytology was interpreted as class V. CDDP 10 mg was administered into the pericardial cavity on the 3rd hospital day, and the drainage tube was removed on the 4th hospital day. After discharge, the patient showed improvements in her activities of daily living (ADL) and restarted irinotecan. She then developed carcinomatous peritonitis, for which CDDP was administered into the abdominal cavity. Eight years and 10 months after surgery, the patient died (1 year and 1 month after the onset of cardiac tamponade).\n\nCase 2\nA 33-year-old woman underwent mastectomy of the right breast and axillary lymph node dissection for right breast cancer. Then, she underwent mastectomy of the left breast and axillary lymph node dissection for left breast cancer at age 38 years. Histological examination showed a solid-tubular carcinoma 4.0 cm in diameter (n1, ER negative, PgR positive and HER2 negative). Postoperative adjuvant treatment with tamoxifen and doxifluridine was administered. Lung metastasis was found 5 years and 5 months after surgery, for which CMF (cyclophosphamide + methotrexate + fluorouracil) and anastrozole were administered. Seven years and 5 months after surgery, when she was 46 years old, she developed cough and dyspnea. Chest CT showed pericardial effusion (2 cm) and multiple lung metastases. The patient was diagnosed with cardiac tamponade by echocardiography and admitted to the hospital.\n\nPericardiocentesis was performed and a drainage tube was placed. Bloody pericardial fluid was drained, and the cytology was interpreted as class V. CDDP 10 mg was administered into the pericardial cavity on the 2nd hospital day, and the drainage tube was removed on the 4th hospital day. After discharge, the patient showed improvements in her ADL and started exemestane. She then developed lung metastases, for which capecitabine was administered. She also developed brain metastasis, for which tumorectomy and whole-brain radiation were performed. Ten years after surgery for left breast cancer, the patient died (2 years and 7 months after the onset of cardiac tamponade).\n\nCase 3\nA 39-year-old woman underwent mastectomy and axillary lymph node dissection for left breast cancer. Histological examination showed a scirrhous carcinoma 2.5 cm in diameter (n1, ER positive, PgR positive and HER2 negative). Postoperative adjuvant treatment with tamoxifen and an LH-RH agonist was administered. Six years and 6 months after surgery, she developed a cervical lymph node recurrence, for which an LH-RH agonist and docetaxel were administered. Nine years and 7 months after surgery, when she was 46 years old, she developed dyspnea, and pericardial effusion (1.1 cm) and right pleural effusion were confirmed by echocardiography. The patient was admitted to the hospital with a diagnosis of cardiac tamponade.\n\nPericardiocentesis was performed and a drainage tube was placed. The cytology was interpreted as class IIIb. Carcinomatous pericarditis was strongly suspected from the clinical course. CDDP 10 mg was administered into the pericardial cavity on the 5th hospital day, and the drainage tube was removed on the 7th hospital day. After discharge, the patient showed improvements in her ADL and started EC (epirubicin + cyclophosphamide). She had an exacerbation of the cervical lymph node metastasis, for which capecitabine was administered. She also developed brain metastasis, for which whole-brain radiation therapy was performed. Ten years and 9 months after surgery, the patient died (1 year and 2 months after the onset of cardiac tamponade).\n\nDiscussion\nCarcinomatous pericarditis is observed in 10–20% of patients with malignancies, and the common cancers are lung cancer, breast cancer, leukemia and malignant lymphoma. Carcinomatous pericarditis is detected at autopsy in 10–20% of breast cancer patients, although the prevalence of this condition during the clinical course is relatively low at 6.1% [4, 5]. Cardiac tamponade is a life-threatening condition requiring prompt diagnosis and treatment.\n\nSubjective symptoms characterized by dyspnea and cough are useful for making an early diagnosis of cardiac tamponade. In addition, the characteristic physical findings include paradoxical pulse, carotid distention, edema and decreased heart sounds. Heart enlargement and pleural effusion are seen on chest X-ray and decreased voltage and tachycardia on electrocardiography. In particular, echocardiography is a simple and useful diagnostic tool that allows a definitive diagnosis of pericardial effusion, right heart collapse and decreased wall motion. Pericardial effusion is caused by a variety of conditions including carcinomatous pericarditis, drug therapy with molecular targeting agents or anticancer drugs, radiation therapy, inflammation and so on. Although cardiac dysfunction caused by molecular targeting agents is usually reversible and often resolves after cessation of administration [6], carcinomatous pericarditis requires aggressive treatment. Pericardial fluid cytology is useful in the differential diagnosis of carcinomatous pericarditis with a reported sensitivity of 90% [7]. In addition, coexisting carcinomatous pleurisy or lung metastasis is observed in 63–100% of patients, so physicians should be alert to the possible presence of such conditions [8].\n\nTreatments of cardiac tamponade include ‘pericardiocentesis and intrapericardial instillation’ and ‘pericardial window’, and no difference in recurrence rates between the two methods has been reported [9]. Pericardiocentesis and intrapericardial instillation is the first choice because of safety and wide availability. Pericardial window should be considered when the condition is intractable. According to Arao et al. [10], indications for this treatment are heart failure symptoms such as severe orthopnea and dyspnea (NYHA class III or IV) and echo-free space of at least 1 cm observed during the diastolic phase, which ensures the safety of the centesis procedure. Intrapericardial instillation is regarded as an important part of the treatment because the recurrence rate of pericardial effusion approached 70% when only pericardiocentesis and drainage were performed [11]. The complications of intrapericardial instillation include chest pain, pyrexia, inflammation and constrictive pericarditis. Bleomycin, mitomycin C, CDDP and epirubicin are reportedly effective treatments. The European Society of Cardiology guidelines has recommended the use of thiotepa for the treatment of carcinomatous pericarditis in breast cancer patients [12]. Bischiniotis et al. [13] recommended the use of CDDP for the following: (1) no cardiac toxicity; (2) no pain or hematological toxicity, owing to lower absorption from the pericardium, and (3) no occurrence of constrictive pericarditis. Thus, we chose CDDP in the present 3 patients.\n\nTable 1 shows 13 additional cases of cardiac tamponade encountered in our hospital. All 13 patients had recurrent carcinomas. HER2 overexpression was observed in 1 of 10 (10%) patients. Trastuzumab was not used in any of these patients, and none of the patients presented with congestive heart failure symptoms associated with the use of molecular targeting agents. The average time period between the first recurrence and the diagnosis of pericardial effusion was 34.7 months (range 3–90). Many patients had been treated with anticancer drugs for a prolonged period, so differential diagnosis from drug-induced heart failure was required. Pericardial fluid cytology was performed in 12 patients, and 10 patients were diagnosed with carcinomatous pericarditis. The remaining patients were also strongly suspected of having carcinomatous pericarditis based on their clinical courses and the presence of bloody pericardial fluid.\n\nThe procedure of pericardiocentesis and intrapericardial instillation employed in our hospital is shown in fig. 2. We perform pericardiocentesis under ultrasonic guidance using a subxiphoid approach or an intercostal approach. The complications of pericardiocentesis include ventricular perforation, ventricular arrhythmia and pneumothorax. Thus, this procedure must be performed by a sufficiently trained doctor. Intrapericardial instillation should be administered after the pericardial effusion has been drained in patients with carcinomatous pericarditis confirmed by cytology. CDDP was used for 11 of the reviewed patients, and CDDP + OK-432 for the other 2 patients. In most of these cases, pericardial effusion was markedly reduced after drug administration and the drainage tubes were subsequently removed. When the pericardial effusion was not reduced by treatment, drug administration was repeated. No recurrence of pericardial effusion was observed in 11 patients (85%) after the initial local treatment. In the remaining 2 patients who showed recurrence of pericardial effusion, repeat treatment with the same drug was effective. Therefore, pericardiocentesis and intrapericardial instillation of CDDP were considered to be effective for local control.\n\nCardiac tamponade as the initial manifestation of recurrence of breast cancer is rare [8]. This condition is occasionally observed in patients with aggravation of recurrent breast cancer. For the 13 patients reviewed herein, the median survival time after the onset of cardiac tamponade was only 4 months (fig. 3). Eight patients (62%) died within 6 months, and 6 of the 8 patients showed no improvements in ADL after local control. These 6 patients were considered to be in the end stage of breast cancer at the time they developed carcinomatous pericarditis. On the other hand, there are a few case reports of long-term survival after local treatment [14]. All 3 patients in the present study survived more than 1 year after the onset of cardiac tamponade and also showed improvements in ADL after receiving local treatment. They were able to receive systemic drug treatment: irinotecan in case 1, exemestane and capecitabine in case 2, and capecitabine in case 3. It is difficult to predict outcomes at the time of cardiac tamponade onset because general conditions are poor due to acute heart failure symptoms. However, for the cases whose distant metastases are controlled by drug treatment, local treatment not only leads to the relief of symptoms but also makes it possible to conduct subsequent systemic therapy and prolong survival time.\n\nConclusion\nPericardiocentesis and intrapericardial instillation of CDDP are considered to be effective local treatments for cardiac tamponade due to carcinomatous pericarditis. We have described 3 breast cancer patients with cardiac tamponade who showed improvements in ADL after local treatment and achieved long-term survival with subsequent systemic treatment.\n\nFig. 1 a Chest X-ray showing enlarged cardiac silhouette. b CT scan showing pericardial effusion and pleural effusion. c Echocardiogram showing pericardial effusion and right ventricular collapse.\n\nFig. 2 Method of treatment for malignant pericardial effusion.\n\nFig. 3 Overall survival rate of malignant pericardial effusion in breast cancer.\n\nTable 1 Cases of malignant effusion in breast cancer\n\nCase\tAge\tER\tPgR\tHER2\tPericardial effusion\tIntrapericardial sclerosis\tImprovement of ADL\tRecurrence of pericardial effusion\tSystemic therapy after tamponade\tSurvival time after tamponade months\t\n\t\t\t\t\tcharacteristic cytology\t\t\t\t\t\t\n1\t68\t+\t+\t–\tbloody\tclass V\tCDDP 10 mg\t+\t–\t+\t13\t\n2\t46\t+\t+\t–\tbloody\tclass V\tCDDP 10 mg\t+\t–\t+\t31\t\n3\t46\t+\t+\t–\t–\tclass IIIb\tCDDP 10 mg\t+\t–\t+\t14\t\n4\t33\t–\t+\tunknown\tbloody\tclass V\tCDDP 10 mg\t–\t+\t–\t3\t\n5\t61\t+\t+\tunknown\tbloody\tclass V\tCDDP 10 mg +\t–\t–\t–\t1\t\n\t\t\t\t\t\t\tOK-432 5KE\t\t\t\t\t\n6\t54\t–\t–\t+\tbloody\tclass V\tCDDP 10 mg +\t–\t–\t–\t1\t\n\t\t\t\t\t\t\tOK-432 5KE\t\t\t\t\t\n7\t54\t+\t+\tunknown\tbloody\tunknown\tCDDP 10 mg\t+\t–\t+\t4\t\n8\t51\t–\t–\t–\tbloody\tclass V\tCDDP 10 mg\t–\t–\t–\t1\t\n9\t46\t+\t+\t–\tbloody\tclass V\tCDDP 20 mg\t+\t+\t+\t8\t\n10\t51\t–\t–\t–\tserous\tclass IIa\tCDDP 20 mg\t–\t–\t–\t5\t\n11\t56\t+\t+\t–\tbloody\tclass V\tCDDP 10 mg\t–\t–\t–\t7\t\n12\t60\t+\t+\t–\tbloody\tclass V\tCDDP 10 mg\t+\t–\t–\t4\t\n13\t74\t+\t–\t–\tbloody\tclass V\tCDDP 10 mg\t–\t–\t–\t1\n==== Refs\nReferences\n1 Marty M Cognetti F Maraninchi D Snyder R Mauriac L Tubiana-Hulin M Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: The M77001 Study Group J Clin Oncol 2005 23 4265 4274 15911866 \n2 Twelves C Cortes J Vahdat LT Wanders J Akerele C Kaufman PA Phase III trials of eribulin mesylate (E7389) in extensively pretreated patients with locally recurrent or metastatic breast cancer Clin Breast Cancer 2010 10 160 163 20299316 \n3 Slamon DJ Leyland-Jones B Shak S Fuchs H Paton V Bajamonde A Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2 N Engl J Med 2001 344 783 792 11248153 \n4 Buck M Ingle JN Giuliani ER Gordon JR Therneau TM Pericardial effusion in women with breast cancer Cancer 1987 60 263 269 3594362 \n5 Kimijima I Abe R The palliative therapy for breast cancer patients –the characteristics of lung pleural and pericardial metastasis and their management Jpn J Breast Cancer 1997 12 440 447 \n6 Guarneri V Lenihan DJ Valero V Durand JB Broglio K Hess KR Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: The M.D. Anderson Cancer Center Experience J Clin Oncol 2006 24 4107 4115 16908934 \n7 Wilkes JD Fidias P Vaickus L Perez RP Malignancy-related pericardial effusion. 127 cases from Roswell Park Cancer Institute Cancer 1995 76 1377 1387 8620412 \n8 Swanepoel E Apffelstaedt JP Malignant pericardial effusion in breast cancer: terminal event or treatable complication? J Surg Oncol 1997 64 308 311 9142188 \n9 Girardi LN Ginsberg RJ Burt ME Pericardiocentesis and intrapericardial sclerosis: effective therapy for malignant pericardial effusions Ann Thorac Surg 1997 64 1422 1427 9386714 \n10 Arao M Kitahara Y Setsuta K The study of survival time after pericardiocentesis for the patients with carcinomatous pericarditis – the suggestion of a safer method of pericardiocentesis Heart 2008 40 691 697 \n11 Hosomi Y Ookuma Y Shibuya M Treatment of malignant pericardial effusion (in Japanese) Jpn J Cancer Chemother 2008 35 906 909 \n12 Maisch B Seferovic PM Ristic AD Erbel R Rienmüller R Adler Y Guidelines on the diagnosis and management of pericardial diseases executive summary Eur Heart J 2004 25 587 610 15120056 \n13 Bischiniotis TS Lafaras CT Platogiannis DN Moldovan L Barbetakis NG Katseas GP Intrapericardial cisplatin administration after pericardiocentesis in patients with lung adenocarcinoma and malignant cardiac tamponade Hellenic J Cardiol 2005 46 324 329 16295940 \n14 Ue N Kawabata H Ueno T Hirata M Tanaka K Cardiac tamponade due to malignant pericardial effusion in 3 patients with breast cancer J Jpn Surg Assoc 2002 63 1658 1661\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1662-6575",
"issue": "5(1)",
"journal": "Case reports in oncology",
"keywords": "Breast cancer; Carcinomatous pericarditis; Cardiac tamponade; Pericardiocentesis",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "195-201",
"pmc": null,
"pmid": "22649339",
"pubdate": "2012-01",
"publication_types": "D002363:Case Reports",
"references": "20299316;16295940;15120056;18633218;15911866;9142188;8620412;3594362;11248153;16908934;9386714",
"title": "Carcinomatous pericarditis in 3 breast cancer patients with long-term survival.",
"title_normalized": "carcinomatous pericarditis in 3 breast cancer patients with long term survival"
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"abstract": "OBJECTIVE\nTo report a case of second-degree atrioventricular block associated with concomitant use of aprepitant and amlodipine.\n\n\nMETHODS\nA 73-year-old man with lung cancer was treated with aprepitant for prophylactic use for the prevention of nausea and vomiting, concomitantly with cisplatin, gemcitabine, and an investigational drug (anti-epidermal growth factor receptor monoclonal antibody). He was diagnosed with first-degree atrioventricular block and was taking amlodipine for hypertension. During the first cycle of chemotherapy, 5 days after the start of aprepitant, he experienced Wenckebach second-degree atrioventricular block (Mobitz type I), and amlodipine was discontinued. After day 6, the atrioventricular block was not shown. According to the Naranjo adverse drug reaction scale, a score of 7 was obtained (causality: probable). In addition, using the Drug Interaction Probability Scale, a score of 6 was obtained (causality: probable).\n\n\nCONCLUSIONS\nThe drug-drug interaction between aprepitant and amlodipine was considered to have deteriorated his atrioventricular block, conceivably due to the inhibition of cytochrome P450 (CYP) 3A-mediated metabolism of amlodipine by aprepitant.",
"affiliations": null,
"authors": "Hibino|Hideyuki|H|;Makino|Yoshinori|Y|;Sakiyama|Naomi|N|;Makihara-Ando|Reiko|R|;Hashimoto|Hironobu|H|;Akiyoshi|Takeshi|T|;Imaoka|Ayuko|A|;Fujiwara|Yutaka|Y|;Ohe|Yuichiro|Y|;Yamaguchi|Masakazu|M|;Ohtani|Hisakazu|H|",
"chemical_list": "D000932:Antiemetics; D009025:Morpholines; D017311:Amlodipine; D000077608:Aprepitant",
"country": "Germany",
"delete": false,
"doi": "10.5414/CP203758",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0946-1965",
"issue": "59(4)",
"journal": "International journal of clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Int J Clin Pharmacol Ther",
"mesh_terms": "D000368:Aged; D017311:Amlodipine; D000932:Antiemetics; D000077608:Aprepitant; D054537:Atrioventricular Block; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D009025:Morpholines; D014839:Vomiting",
"nlm_unique_id": "9423309",
"other_id": null,
"pages": "328-332",
"pmc": null,
"pmid": "33355084",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Exacerbation of atrioventricular block associated with concomitant use of amlodipine and aprepitant in a lung cancer patient: A case report.",
"title_normalized": "exacerbation of atrioventricular block associated with concomitant use of amlodipine and aprepitant in a lung cancer patient a case report"
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"companynumb": "JP-TEVA-2021-JP-1877073",
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"activesubstancename": "APREPITANT"
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"abstract": "A 64-year-old man with acute myeloid leukemia underwent umbilical cord blood transplantation (UCBT). After 11 months of complete remission (CR) following UCBT, the bone marrow showed 7.5% myeloblasts. CR was obtained after a single course of azacitidine monotherapy, but the myeloblasts gradually increased in the blood. We made a diagnosis of acute megakaryoblastic leukemia derived from donor cell with a fluorescence in situ hybridization (FISH) analysis of the sex chromosomes and an immunophenotypic analysis. Azacitidine was administered again and produced a therapeutic effect of stable disease. This case suggests that azacitidine may be a useful therapy for patients with acute megakaryoblastic leukemia in situations in which intensive chemotherapy and transplantation are not indicated.",
"affiliations": "Department of Hematology and Oncology, Konan Kosei Hospital, Japan.;Department of Hematology and Oncology, Japanese Red Cross Nagoya Daini Hospital, Japan.;Department of Hematology and Oncology, Konan Kosei Hospital, Japan.;Department of Hematology and Oncology, Konan Kosei Hospital, Japan.;Department of Hematology and Oncology, Konan Kosei Hospital, Japan.;Department of Hematology and Oncology, Konan Kosei Hospital, Japan.;Department of Hematology and Oncology, Konan Kosei Hospital, Japan.",
"authors": "Adachi|Yoshitaka|Y|;Yamaguchi|Yohei|Y|;Sagou|Ken|K|;Yamaga|Yusuke|Y|;Fukushima|Nobuaki|N|;Ozeki|Kazutaka|K|;Kohno|Akio|A|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.9005-17",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2915150310.2169/internalmedicine.9005-17Case ReportAcute Megakaryoblastic Leukemia Developing as Donor Cell Leukemia after Umbilical Cord Blood Transplantation Adachi Yoshitaka 1Yamaguchi Yohei 2Sagou Ken 1Yamaga Yusuke 1Fukushima Nobuaki 1Ozeki Kazutaka 1Kohno Akio 1\n1 Department of Hematology and Oncology, Konan Kosei Hospital, Japan\n2 Department of Hematology and Oncology, Japanese Red Cross Nagoya Daini Hospital, JapanCorrespondence to Dr. Yoshitaka Adachi, adachi_y0216@yahoo.co.jp\n\n20 11 2017 15 2 2018 57 4 569 574 9 2 2017 14 7 2017 Copyright © 2018 by The Japanese Society of Internal Medicine2018The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 64-year-old man with acute myeloid leukemia underwent umbilical cord blood transplantation (UCBT). After 11 months of complete remission (CR) following UCBT, the bone marrow showed 7.5% myeloblasts. CR was obtained after a single course of azacitidine monotherapy, but the myeloblasts gradually increased in the blood. We made a diagnosis of acute megakaryoblastic leukemia derived from donor cell with a fluorescence in situ hybridization (FISH) analysis of the sex chromosomes and an immunophenotypic analysis. Azacitidine was administered again and produced a therapeutic effect of stable disease. This case suggests that azacitidine may be a useful therapy for patients with acute megakaryoblastic leukemia in situations in which intensive chemotherapy and transplantation are not indicated. \n\nacute megakaryoblastic leukemiaumbilical cord blood transplantationdonor cell leukemiaazacitidine\n==== Body\nIntroduction\nAcute megakaryoblastic leukemia has been described as a subtype of acute myelogenous leukemia (AML) (1) and was incorporated into the French-American-British (FAB) classification of AML as M7 (2). The associated bone marrow characteristics include the proliferation of abnormal megakaryoblasts identified by the presence of platelet-specific surface glycoprotein and frequently extensive myelofibrosis. Histopathologic evidence of M7 AML itself is an independent poor prognostic factor for the overall survival (3).\n\nAzacitidine, a demethylation agent, has demonstrated a significant survival benefit in patients with high-risk myelodysplastic syndrome (MDS) relative to conventional care and has also been proved effective in older patients with newly diagnosed AML with >30% blasts (4,5). However, whether or not azacitidine is effective for acute megakaryoblastic leukemia is unclear, as it is rare in adults.\n\nNo reports are available on acute megakaryoblastic leukemia developing as donor cell leukemia (DCL) after allogeneic hematopoietic stem cell transplantation (HSCT) and treatment with hypomethylating agents (azacitidine or decitabine). We herein report a case of acute megakaryoblastic leukemia developing as DCL after umbilical cord blood transplantation (UCBT) that was treated with azacitidine.\n\nCase Report\nA 64-year-old man had pancytopenia and was referred to our hospital (Table 1). An analysis of bone marrow aspirate revealed that myeloblasts comprised 49.5% of nucleated cells with multilineage dysplasia, so we made a diagnosis of AML with myelodysplasia-related changes. He achieved hematological complete remission (CR) after induction chemotherapy consisting of idarubicin and cytarabine and underwent UCBT with a reduced-intensity conditioning regimen from an unrelated female donor in first CR 8 months after the initial diagnosis.\n\nTable 1. The Laboratory Data at the Onset of Original Leukemia.\n\nBlood biochemistry\t\t\tFe\t201\tμg/dL\t\nTotal protein\t7.2\tg/dL\tUIBC\t184\tμg/dL\t\nAlbumin\t4.4\tg/dL\tFerritin\t144\tng/mL\t\nBUN\t12.8\tmg/dL\tIgG\t1,197\tmg/dL\t\nCreatinine\t0.94\tmg/dL\tIgA\t400\tmg/dL\t\nAST\t20\tIU/L\tIgM\t54\tmg/dL\t\nALT\t28\tIU/L\tTSH\t0.63\tμIU/mL\t\nLDH\t175\tIU/L\tFree-T3\t2.63\tpg/mL\t\nALP\t210\tIU/L\tFree-T4\t1.22\tng/dL\t\nUA\t5.3\tmg/dL\tWT-1 mRNA\t9.3×103\tcopies/μgRNA\t\nCPK\t65\tIU/L\t\t\t\t\nNa\t142\tmEq/L\tHematology\t\t\t\nK\t3.9\tmEq/L\tWBC\t1,100\t/μL\t\nCl\t108\tmEq/L\tNeutrophil\t12\t%\t\nCa\t9.6\tmg/dL\tLymphocyte\t86\t%\t\nP\t2.6\tmg/dL\tMonocyte\t2\t%\t\nGlucose\t129\tmg/dL\tMyeloblast\t0\t%\t\nCRP\t0.09\tmg/dL\tRBC\t275×104\t/μL\t\nPT-INR\t0.97\t\tHemoglobin\t9.6\tg/dL\t\nAPTT\t27.4\tsec\tMCV\t102.9\tfL\t\nFibrinogen\t300\tmg/dL\tPlatelet\t5.3×104\t/μL\t\nFDP\t<5.0\tμg/mL\tReticulocyte\t11\t‰\t\nD-dimer\t0.9\tμg/mL\t\t\t\t\nCRP: C-reactive protein, UIBC: unsaturated iron-binging capacity, TSH: thyroid stimulating hormone, WT-1: Wilm’s tumor 1, WBC: white blood cell, RBC: red blood cell, MCV: mean corpuscular volume\n\nOn day 28 of UCBT, a fluorescence in situ hybridization (FISH) analysis of the sex chromosomes and a chimerism evaluation by a short tandem repeat (STR) analysis revealed the complete donor type of the bone marrow cells and the peripheral blood cells. On day 56 of UCBT, however, a FISH analysis of the sex chromosomes revealed that 2% of all nucleated cells (ANC) in the bone marrow presented with XY signals, and a STR analysis revealed that the donor chimerism of T cells in the peripheral blood had decreased to 83.5%. We made a diagnosis of molecular relapse of the original disease and reduced the dose of the immunosuppressive agent.\n\nThereafter, complete donor chimerism was achieved, and hematological remission was sustained for 11 months. Progressive thrombocytopenia appeared, and the amount of Wilm’s tumor 1 (WT-1) mRNA in the peripheral blood was 2.0×104 copies/μgRNA as determined by a kit using quantitative reverse transcription-polymerase chain reaction (RT-PCR) (Otsuka Pharmaceutical Company, Tokyo, Japan; normally <50 copies/μgRNA) 11 months after UCBT (Table 2). A bone marrow examination showed normocellular marrow with 7.5% abnormal blasts, suggesting a relapse of the original disease. However, an immunophenotypic analysis by flow cytometry (FCM) was unable to differentiate the leukemic blasts in the bone marrow sample.\n\nTable 2. The Laboratory Data at the Onset of Donor Cell Leukemia.\n\nBlood biochemistry\t\t\tFe\t140\tμg/dL\t\nTotal protein\t7.0\tg/dL\tUIBC\t111\tμg/dL\t\nAlbumin\t4.3\tg/dL\tFerritin\t417\tng/mL\t\nBUN\t21.4\tmg/dL\tIgG\t1,359\tmg/dL\t\nCreatinine\t1.47\tmg/dL\tIgA\t249\tmg/dL\t\nAST\t20\tIU/L\tIgM\t41\tmg/dL\t\nALT\t14\tIU/L\t\t\t\t\nLDH\t233\tIU/L\tHematology\t\t\t\nALP\t266\tIU/L\tWBC\t6,100\t/μL\t\nUA\t6.8\tmg/dL\tNeutrophil\t49\t%\t\nCPK\t54\tIU/L\tLymphocyte\t39\t%\t\nNa\t145\tmEq/L\tMonocyte\t9\t%\t\nK\t3.9\tmEq/L\tEosinophil\t3\t%\t\nCl\t110\tmEq/L\tRBC\t331×104\t/μL\t\nCa\t9.2\tmg/dL\tHemoglobin\t10.8\tg/dL\t\nP\t3.6\tmg/dL\tMCV\t96.7\tfL\t\nGlucose\t115\tmg/dL\tPlatelet\t6.9×104\t/μL\t\nCRP\t0.09\tmg/dL\tReticulocyte\t14\t‰\t\nWT-1 mRNA\t2.0×104\tcopies/μgRNA\t\t\t\t\nCRP: C-reactive protein, WT-1: Wilm's tumor, UIBC: unsaturated iron-binging capacity, WBC: white blood cell, RBC: red blood cell, MCV: mean corpuscular volume\n\nThe subsequent clinical course is shown in Fig. 1. The patient was treated with azacitidine at a dose of 75 mg/m2 on 7 consecutive days because we initially assumed a relapse of the original disease. However, a FISH analysis before azacitidine monotherapy showed that 100% of the bone marrow cells had XX signals; therefore, we considered this to be a case of donor-derived hematologic malignancy. On day 27 of azacitidine monotherapy, a bone marrow examination revealed hematological CR. He was followed up as an outpatient without additional treatment; however, the blasts eventually reappeared and gradually increased in the peripheral blood with the elevation of lactate dehydrogenase (LDH) levels. On day 97 of azacitidine therapy, we conducted a bone marrow biopsy because of a dry tap in the bone marrow aspirate and found that myeloperoxidase-negative blasts had invaded the bone marrow (Fig. 2). An immunophenotypic analysis by FCM showed the expression of CD7, CD21, CD33, CD34, CD38, CD56 and human leukocyte antigen (HLA)-DR on the leukemic blasts. The blasts showed a normal female karyotype in a G-banding chromosomal examination. Another FISH analysis showed that 100% of the bone marrow cells had XX signals again. We therefore made a diagnosis of myeloid/natural killer cell precursor acute leukemia (M/NKPAL) derived from donor cells. Whole-body computed tomography (CT) revealed no extramedullary lesions.\n\nFigure 1. The clinical course of the present patient. AZA: azacitidine, BM: bone marrow, CA: cytarabine, IDR: idarubicin, L-ASP: L-asparaginase, LDH: lactate dehydrogenase, PB: peripheral blood, WT-1: Wilm’s tumor 1\n\nFigure 2. May-Grünwald-Giemsa-stained (Wright-Giemsa-stained) bone marrow cells (A) and peripheral blood cells (B) at the first relapse of DCL. The bone marrow was filled with myeloperoxidase-negative blast cells and a few blast cells were found in the peripheral blood. (×1,000, Wright-Giemsa staining). DCL: donor cell leukemia\n\nBecause it was not clear whether allogeneic HSCT could significantly improve the outcome of patients with DCL and because the patient refused to undergo any transplantation, we did not plan to give him a second HSCT.\n\nHe underwent chemotherapy consisting of idarubicin (10 mg/m2 on days 1-3) and cytarabine (100 mg/m2 on days 1-7). He demonstrated prolonged neutropenia, which caused a severe infection and acute kidney injury. After a single course of intensive chemotherapy, a bone marrow examination revealed CR, and the amount of WT-1 mRNA in the peripheral blood dropped below 50 copies/μgRNA.\n\nThe patient experienced a second relapse of DCL with WT-1 mRNA 8.1×104 copies/μgRNA and the appearance of blasts in the peripheral blood 2 months after achieving CR. He underwent L-asparaginase (L-ASP) monotherapy (6,000 IU/m2 on days 1-7), which caused febrile neutropenia and severe liver damage. After L-ASP monotherapy, we re-examined the surface markers of the leukemic cells by FCM, which showed positivity for CD41, as well as CD7, CD21, CD33, CD34, CD38, CD56 and HLA-DR (Fig. 3). This result led us to diagnose his DCL as acute megakaryoblastic leukemia rather than M/NKPAL.\n\nFigure 3. A flow cytometric analysis of DCL at the diagnosis of acute megakaryocytic leukemia. Blast cells were positive for CD7, CD21, CD33, CD34, CD38, CD41, CD56 and HLA-DR. DCL: donor cell leukemia\n\nThe L-ASP monotherapy was unfortunately ineffective; therefore, we started azacitidine monotherapy (75 mg/m2 on days 1-5, 8, 9) again. Following a single course of azacitidine, the number of abnormal blasts and amount of WT-1 mRNA in the peripheral blood were almost unchanged, but the patient's overall condition improved with a mild decrease in LDH levels; he continued to receive treatment with azacitidine alone as an outpatient. He underwent red blood cell transfusions regularly, but no severe adverse events such as febrile neutropenia were observed during azacitidine monotherapy. He demonstrated disease progression four months after azacitidine monotherapy. He underwent low-dose combination chemotherapy and gemtuzumab ozogamicin monotherapy, but they were ineffective and caused severe myelosuppression and sepsis. He ultimately died of brain hemorrhaging 28 months after UCBT.\n\nDiscussion\nAcute megakaryoblastic leukemia can develop as DCL after allogeneic HSCT. Table 3 shows the main characteristics of the original leukemia and donor cell leukemia in our report. HSCT is an effective treatment for many hematologic malignancies, but disease relapse remains a major cause of post-transplant mortality (6). DCL is de novo leukemia developing in donor-derived hematopoietic precursor cells and is a rare but severe complication after allogeneic HSCT. The incidence of DCL may have been underestimated because clinicians do not perform thorough examinations to distinguish between recipient-derived cells and donor-derived cells in cases of leukemia developing after HSCT. DCL has become well known, and a number of reports of DCL have been published in recent years (7-9). It is important to distinguish DCL from relapse of original diseases when patients develop leukemia mimicking the original diseases after allogeneic HSCT, especially in cases where a decision regarding treatment for the leukemia must be made.\n\nTable 3. Main Characteristics of the Original Leukemia and Donor Cell Leukemia.\n\n\tOriginal leukemia\tDonor cell leukemia\t\nMyeloperoxidase stain\tPositive\tNegative\t\nCell surface markers\tPositive: CD13, CD34, HLA-DR Negative: CD7, CD33, CD41, CD56\tPositive: CD7, CD13, CD21, CD34, CD33, CD38, CD41, CD56, HLA-DR\t\nG-banding stain\t47,XY,+1,der(1;7)(q10;p10),+8[13]/46,XY[7]\t46,XX[20]\t\nWHO classification\tAML with myelodysplasia-related changes\tAcute megakaryoblastic leukemia\t\nWHO: World Health Organization, AML: acute myelogenous leukemia\n\nIn the present report, we diagnosed DCL through a FISH analysis of the sex chromosomes, although we initially suspected relapse of the original disease. Compared to relapsed disease, which almost always occurs within 2 years post-transplant, DCL is commonly diagnosed later, with a median time to DCL of 31 months (range: 2-312 months) (10). Shiozaki et al. reported that the characteristics of DCL occurring after UCBT were different from those occurring after bone marrow transplantation (BMT), including the duration of time between transplantation and the occurrence of DCL, and the types of abnormal karyotypes (11). DCL occurred within a significantly shorter period after UCBT than after BMT, with a median duration of 14.5 months for UCBT and 36 months for BMT. The frequency of monosomy 7 observed in DCL after UCBT was significantly higher than that in DCL after BMT. Greaves reported that up to 5% of CB samples might harbor potentially pre-leukemic clones, raising the possibility that DCL might be disproportionately common after UCBT (12). It has been reported that risk factors for DCL include the use of cells obtained from elderly donors and cells obtained from cord blood (13). In our case, the use of cord blood for the cell source was a risk factor for developing DCL as well as for the early occurrence of DCL.\n\nAzacitidine may be effective for treating acute megakaryoblastic leukemia. Acute megakaryoblastic leukemia is a rare form of adult AML, occurring in about 1% of all AML cases (14). Because of its low incidence, clinical data on acute megakaryoblastic leukemia are limited.\n\nWe treated the present patient with anthracycline-based chemotherapy, which led to CR. However, such an intensive chemotherapy regimen caused severe complications, including prolonged neutropenia, severe infection, acute kidney injury and severe liver damage. We next treated the patient with L-ASP alone because of our initial diagnosis of M/NKPAL, with reference to the reports of two pediatric cases of M/NKPAL successfully treated with L-ASP-based therapy (15,16). However, we reached a correct diagnosis of acute megakaryoblastic leukemia by re-assessing surface markers of his DCL including CD41, after unsuccessful treatment with L-ASP. M/NKPAL is negative for the cytochemical myeloperoxidase (MPO) reaction, suggesting that this leukemia is incorporated into the FAB classification of AML as M0. It has been shown that some cases of CD7+ CD56+ AML with MPO-negative were categorized as M7 because of CD41 positivity and infrequently showed extramedullary involvement (17). We need to discriminate between these types of leukemia by examining surface markers, including CD41, when a patient is diagnosed with CD7+ CD56+ AML. We subsequently treated the patients with azacitidine, which is effective in patients with high-risk MDS or AML who are unfit for intensive chemotherapy (4,15,18). Azacitidine actually showed some degree of efficacy in our patient.\n\nIn conclusion, DCL should be considered in all cases of acute leukemia developing after allogeneic HSCT and should be differentiated from relapse of the original disease by a thorough examination with a chimerism analysis using molecular or cytogenetic technique in cases with leukemia mimicking the original disease. Azacitidine monotherapy may be an effective alternative therapy for patients with DCL of myeloid lineage who are unsuited for intensive chemotherapy because of various complications or organ damage after HSCT. Further reports should be accumulated to determine whether or not azacitidine is as effective against de novo acute megakaryoblastic leukemia as it is for the treatment of other types of AML.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nVon Boros J , Korenyi A \nUber einen fall von akuter megakaryocyblasten-leukamie, zugleich einige bemerkungen zum Problem der akuten leukemie . Z Klin Med \n118 : 679 -718 , 1931 .\n2. \nBennett JM , Catovsky D , Daniel MT , et al \nCriteria for the diagnosis of acute leukemia of megakaryocyte lineage (M7). A report of the French-American-British Cooperative Group . Ann Intern Med \n103 : 460 -462 , 1985 .2411180 \n3. \nOki Y , Kantarjian HM , Zhou X , et al \nAdult acute megakaryocytic leukemia: an analysis of 37 patients treated at M.D. Anderson Cancer Center . Blood \n107 : 880 -884 , 2006 .16123215 \n4. \nFenaux P , Mufti GJ , Hellstrom-Lindberg E , et al \nEfficacy of azacitidine compared with that of conventional care regimens in higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study . Lancet Oncology \n10 : 223 -232 , 2009 .19230772 \n5. \nDombret H , Seymour JF , Butrym A , et al \nInternational phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts . Blood \n126 : 291 -299 , 2015 .25987659 \n6. \nKumar L \nLeukemia: management of relapse after allogeneic bone marrow transplantation . J Clin Oncol \n12 : 1710 -1717 , 1994 .8040682 \n7. \nHertenstein B , Hambach L , Bacigalupo A , et al \nDevelopment of leukemia in donor cells after allogeneic stem cell transplantation-a survey of the European Group for Blood and Marrow Transplantation (EBMT) . Haematologica \n90 : 969 -975 , 2005 .15996934 \n8. \nSala-Torra O , Hanna C , Loken MR , et al \nEvidence of donor-derived hematologic malignancies after hematopoietic stem cell transplantation . Biol Blood Marrow Transplant \n12 : 511 -517 , 2006 .16635786 \n9. \nRuiz-Argüelles GJ , Ruiz-Delgado GJ , Garces-Eisele J , Ruiz-Arguelles A , Perez-Romano B , Reyes-Nuñez V \nDonor cell leukemia after non-myeloablative allogeneic stem cell transplantation: a single institution experience . Leuk Lymphoma \n47 : 1952 -1955 , 2006 .17065011 \n10. \nWiseman DH \nDonor cell leukemia: a review . Biol Blood Marrow Transplant \n17 : 771 -789 , 2011 .20951819 \n11. \nShiozaki H , Yoshinaga K , Kondo T , et al \nDonor cell-derived leukemia after cord blood transplantation and a review of the literature: differences between cord blood and BM as the transplant source . Bone Marrow Transplant \n49 : 102 -109 , 2014 .24013690 \n12. \nGreaves MF \nCord blood donor cell leukemia in recipients . Leukemia \n20 : 1633 -1634 , 2006 .16791267 \n13. \nKato M , Yamashita T , Suzuki R , et al \nDonor cell-derived hematological malignancy: a survey by the Japan Society for Hematopoietic Cell Transplantation . Leukemia \n30 : 1742 -1745 , 2016 .26867671 \n14. \nPagano L , Pulsoni A , Vignetti M , et al \nAcute megakaryoblastic leukemia: experience of GIMEMA trials . Leukemia \n16 : 1622 -1626 , 2002 .12200673 \n15. \nNagata T , Higashigawa M , Nagai M , et al \nA child case of CD34+, CD33-, HLA-DR-, CD7+, CD56+ stem cell leukemia with thymic involvement . Leuk Res \n20 : 983 -985 , 1996 .9009257 \n16. \nTezuka K , Nakayama H , Honda K , et al \nTreatment of a child with myeloid/NK cell precursor acute leukemia with L-asparaginase and unrelated cord blood transplantation . Int J Hematol \n75 : 201 -206 , 2002 .11939270 \n17. \nSuzuki R , Ohtake S , Takeuchi J , et al \nThe clinical characteristics of CD7+ CD56+ acute myeloid leukemias other than M0 . Int J Hematol \n91 : 303 -309 , 2010 .20111912 \n18. \nThépot S , Itzykson R , Seegers V , et al \nAzacitidine in untreated acute myeloid leukemia: a report on 149 patients . Am J Hematol \n89 : 410 -416 , 2014 .24375487\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "57(4)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "acute megakaryoblastic leukemia; azacitidine; donor cell leukemia; umbilical cord blood transplantation",
"medline_ta": "Intern Med",
"mesh_terms": "D036101:Cord Blood Stem Cell Transplantation; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "569-574",
"pmc": null,
"pmid": "29151503",
"pubdate": "2018-02-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "2411180;11939270;9009257;19230772;16635786;8040682;20111912;12200673;25987659;15996934;24375487;24013690;26867671;17065011;20951819;16123215;16791267",
"title": "Acute Megakaryoblastic Leukemia Developing as Donor Cell Leukemia after Umbilical Cord Blood Transplantation.",
"title_normalized": "acute megakaryoblastic leukemia developing as donor cell leukemia after umbilical cord blood transplantation"
} | [
{
"companynumb": "JP-JAZZ-2018-JP-004125",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ASPARAGINASE ERWINIA CHRYSANTHEMI"
},
"drugaddit... |
{
"abstract": "Optimal treatment options remain unknown for infective endocarditis (IE) caused by penicillin-resistant (PEN-R) viridans group streptococcal (VGS) strains. The aims of this study were to report two cases of highly PEN-R VGS IE, perform a literature review, and evaluate various antibiotic combinations in vitro and in vivo The following combinations were tested by time-kill studies and in the rabbit experimental endocarditis (EE) model: PEN-gentamicin, ceftriaxone-gentamicin, vancomycin-gentamicin, daptomycin-gentamicin, and daptomycin-ampicillin. Case 1 was caused by Streptococcus parasanguinis (PEN MIC, 4 μg/ml) and was treated with vancomycin plus cardiac surgery. Case 2 was caused by Streptococcus mitis (PEN MIC, 8 μg/ml) and was treated with 4 weeks of vancomycin plus gentamicin, followed by 2 weeks of vancomycin alone. Both patients were alive and relapse-free after ≥6 months follow-up. For the in vitro studies, except for daptomycin-ampicillin, all combinations demonstrated both synergy and bactericidal activity against the S. parasanguinis isolate. Only PEN-gentamicin, daptomycin-gentamicin, and daptomycin-ampicillin demonstrated both synergy and bactericidal activity against the S. mitis strain. Both strains developed high-level daptomycin resistance (HLDR) during daptomycin in vitro passage. In the EE studies, PEN alone failed to clear S. mitis from vegetations, while ceftriaxone and vancomycin were significantly more effective (P < 0.001). The combination of gentamicin with PEN or vancomycin increased bacterial eradication compared to that with the respective monotherapies. In summary, two patients with highly PEN-R VGS IE were cured using vancomycin-based therapy. In vivo, regimens of gentamicin plus either β-lactams or vancomycin were more active than their respective monotherapies. Further clinical studies are needed to confirm the role of vancomycin-based regimens for highly PEN-R VGS IE. The emergence of HLDR among these strains warrants caution in the use of daptomycin therapy for VGS IE.",
"affiliations": "Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.;Division of Infectious Diseases, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.;Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.;Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.;Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.;Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.;Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.;Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.;Hospital Clinic of Barcelona, ISGlobal, University of Barcelona, Barcelona, Spain.;Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.;LA Biomedical Research Institute, Torrance, California, USA.;Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain jmmiro@ub.edu.;Division of Infectious Diseases, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.",
"authors": "Pericàs|Juan M|JM|;Nathavitharana|Ruvandhi|R|0000-0002-3544-5021;Garcia-de-la-Mària|Cristina|C|;Falces|Carles|C|;Ambrosioni|Juan|J|;Almela|Manel|M|;García-González|Javier|J|;Quintana|Eduard|E|;Marco|Francesc|F|;Moreno|Asunción|A|;Bayer|Arnold S|AS|;Miró|José M|JM|;Karchmer|Adolf W|AW|;|||",
"chemical_list": "D010406:Penicillins; D014640:Vancomycin",
"country": "United States",
"delete": false,
"doi": "10.1128/AAC.00516-19",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0066-4804",
"issue": "63(8)",
"journal": "Antimicrobial agents and chemotherapy",
"keywords": "animal models; combination therapy; high-level penicillin resistance; in vitro; infective endocarditis; viridans group streptococci",
"medline_ta": "Antimicrob Agents Chemother",
"mesh_terms": "D000328:Adult; D024881:Drug Resistance, Bacterial; D004697:Endocarditis, Bacterial; D006801:Humans; D008297:Male; D008875:Middle Aged; D010406:Penicillins; D014640:Vancomycin; D034363:Viridans Streptococci",
"nlm_unique_id": "0315061",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31182540",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "20185277;18804349;5431862;13897087;22123698;10770721;24315788;23335735;252640;22508304;27211209;6607030;19273776;28475731;16938436;3644854;11462199;28401448;12594643;5182432;11952717;11325318;7588902;26373316;21460309;3846608;8849246;26320109;17516402;28204495;26658313;22985884;23478959;10366329;18444825;22964255;9736584;23357293",
"title": "Endocarditis Caused by Highly Penicillin-Resistant Viridans Group Streptococci: Still Room for Vancomycin-Based Regimens.",
"title_normalized": "endocarditis caused by highly penicillin resistant viridans group streptococci still room for vancomycin based regimens"
} | [
{
"companynumb": "ES-FRESENIUS KABI-FK201909852",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GENTAMICIN"
},
"drugadditional": "1",
... |
{
"abstract": "Clinical practice guidelines recommend protamine sulfate for reversal of enoxaparin associated bleeds dependent on the time from last administration and dose of enoxaparin. We present a case of a hemodynamically unstable patient with an enoxaparin induced abdominal wall hematoma/hemorrhage and the previous enoxaparin administration 21.5 h prior to presentation with a therapeutic anti-Xa assay (0.8 IU/mL) upon assessment in the emergency department. Along with resuscitative efforts, an interdisciplinary team collaborated to administer protamine sulfate 50 mg intravenous once (0.5 mg per 1 mg of enoxaparin) to reverse the therapeutic anticoagulation. Our case demonstrates the importance of monitoring renal function and the potential for accumulation of enoxaparin in patients with renal dysfunction leading to prolonged therapeutic anti-Xa assays. With the availability of anti-Xa assays, future reversal recommendations of enoxaparin associated bleeds using protamine sulfate should include the initial anti-Xa assay as a guide for the dosing regimen.",
"affiliations": "Department of Pharmacy, University Hospitals Cleveland Medical Center, Cleveland, OH, USA. Electronic address: Brian.lauer2@uhhospitals.org.;Department of Emergency Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.;Department of Surgery - Trauma Surgery, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.;Department of Medicine - Hematology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.;Department of Surgery - Vascular, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.;Department of Medicine - Hematology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.;Department of Pharmacy, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.",
"authors": "Lauer|Brian R|BR|;Nelson|Richard A|RA|;Adamski|John H|JH|;Gibbons|Joseph|J|;Janko|Matthew R|MR|;Ravi|Gayathri|G|;Barcelona|Robert A|RA|",
"chemical_list": "D000925:Anticoagulants; D017984:Enoxaparin; D006494:Heparin Antagonists; D011479:Protamines",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2018.09.043",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "37(1)",
"journal": "The American journal of emergency medicine",
"keywords": "Enoxaparin; Pharmacology; Protamine sulfate; Resuscitation; Toxicology",
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D034861:Abdominal Wall; D000368:Aged; D000925:Anticoagulants; D004334:Drug Administration Schedule; D004636:Emergency Service, Hospital; D017984:Enoxaparin; D005260:Female; D006406:Hematoma; D006494:Heparin Antagonists; D006801:Humans; D011479:Protamines; D051436:Renal Insufficiency, Chronic; D013997:Time Factors; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "174.e5-174.e6",
"pmc": null,
"pmid": "30274763",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Protamine sulfate for the reversal of enoxaparin associated hemorrhage beyond 12 h.",
"title_normalized": "protamine sulfate for the reversal of enoxaparin associated hemorrhage beyond 12 h"
} | [
{
"companynumb": "US-SAKK-2018SA278452AA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ENOXAPARIN SODIUM"
},
"drugadditional": "3",
... |
{
"abstract": "Coronavirus disease (COVID-19) has a wide spectrum of clinical manifestations. In this case report, we describe our first case of COVID-19 pneumonia that was complicated by cerebral venous thrombosis and bleeding in a patient with polycythemia vera. Madam A, a 72-year-old lady with polycythemia vera, ischemic stroke, hemorrhoids, diabetes mellitus, hypertension, and dyslipidemia was admitted to the hospital for COVID-19 pneumonia. She was treated with hydroxychloroquine and lopinavir/ritonavir as per hospital protocol. She continued taking hydroxyurea and aspirin for her treatment of polycythemia vera. Subsequently, she developed rectal bleeding when her platelet count was 1247 × 103/μl, even though she was not on an anticoagulant. Her aspirin was withheld. One week later, she was readmitted to the hospital for cerebral venous thrombosis and her D-dimer was 2.02 μg/ml. She was commenced on a therapeutic dose of low molecular weight heparin. Following that, her D-dimer level showed a decreasing trend and normalized upon her discharge. Patients with polycythemia vera are prone to develop thrombotic and bleeding complications. Management of this group of patients has become more complex with COVID-19 infection. It is crucial for us to decide when to start an anticoagulant especially when there is a history of recent bleeding. We need to balance the risks of further bleeding versus potentially fatal thrombotic events. Studies have shown that D-dimer can be used as a clinical marker to predict thrombotic events in COVID-19 infection. Patients with COVID-19 infection and polycythemia vera will benefit from both pharmacological thromboprophylaxis and close monitoring for bleeding.",
"affiliations": "Hematology Unit, Department of Medicine, Sarawak General Hospital, Ministry of Health Malaysia, Jalan Hospital, 93586 Kuching, Sarawak Malaysia.;Hematology Unit, Department of Medicine, Sarawak General Hospital, Ministry of Health Malaysia, Jalan Hospital, 93586 Kuching, Sarawak Malaysia.;Hematology Unit, Department of Medicine, Sarawak General Hospital, Ministry of Health Malaysia, Jalan Hospital, 93586 Kuching, Sarawak Malaysia.;Radiology Department, Sarawak General Hospital, Ministry of Health Malaysia, Jalan Hospital, 93586 Kuching, Sarawak Malaysia.;Infectious Disease Unit, Department of Medicine, Sarawak General Hospital, Ministry of Health Malaysia, Jalan Hospital, 93586 Kuching, Sarawak Malaysia.",
"authors": "Chow|Lai Chee|LC|0000-0002-8031-969X;Chew|Lee Ping|LP|;Leong|Tze Shin|TS|;Mohamad Tazuddin|Estrellita Elena|EE|;Chua|Hock Hin|HH|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1007/s42399-020-00537-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2523-8973",
"issue": null,
"journal": "SN comprehensive clinical medicine",
"keywords": "COVID-19; Case report; Cerebral venous thrombosis; D-dimer; Polycythemia vera",
"medline_ta": "SN Compr Clin Med",
"mesh_terms": null,
"nlm_unique_id": "101740833",
"other_id": null,
"pages": "1-5",
"pmc": null,
"pmid": "33043250",
"pubdate": "2020-10-04",
"publication_types": "D016428:Journal Article",
"references": "32405101;32838177;32838135;32421381;32291094;30478826;32415314;32091533;30848334;32838153;23899057;22611155;32492712",
"title": "Thrombosis and Bleeding as Presentation of COVID-19 Infection with Polycythemia Vera. A Case Report.",
"title_normalized": "thrombosis and bleeding as presentation of covid 19 infection with polycythemia vera a case report"
} | [
{
"companynumb": "MY-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-264938",
"fulfillexpeditecriteria": "1",
"occurcountry": "MY",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE SULFATE"
},... |
{
"abstract": "Accumulating evidence indicates that there is an increased risk of cardiovascular disease among patients with psoriatic disease. Although an emerging concern that the risk of atrial fibrillation (AF) may also be higher in this patient population adds to the growing support of initiating early interventions to control systemic inflammation, evidence on the comparative cardiovascular safety of current biologic treatments remains limited.\n\n\n\nTo evaluate the risk of AF and major adverse cardiovascular events (MACE) associated with use of ustekinumab vs tumor necrosis factor inhibitors (TNFi) in patients with psoriasis or psoriatic arthritis.\n\n\n\nThis cohort study included data from a nationwide sample of 78 162 commercially insured patients in 2 US commercial insurance databases (Optum and MarketScan) from September 25, 2009, through September 30, 2015. Patients were included if they were 18 years or older, had psoriasis or psoriatic arthritis, and initiated ustekinumab or a TNFi therapy. Exclusion criteria included history of AF or receipt of antiarrhythmic or anticoagulant therapy during the baseline period.\n\n\n\nInitiation of ustekinumab vs TNFi therapy.\n\n\n\nIncident AF and MACE, including myocardial infarction, stroke, or coronary revascularization.\n\n\n\nA total of 60 028 patients with psoriasis or psoriatic arthritis (9071 ustekinumab initiators and 50 957 TNFi initiators) were included in the analyses. The mean (SD) age was 46 (13) years in Optum and 47 (13) in MarketScan, and 29 495 (49.1%) were male. Overall crude incidence rates (reported per 1000 person-years) for AF were 5.0 (95% CI, 3.8-6.5) for ustekinumab initiators and 4.7 (95% CI, 4.2-5.2) for TNFi initiators, and for MACE were 6.2 (95% CI, 4.9-7.8) for ustekinumab initiators and 6.1 (95% CI, 5.5-6.7) for TNFi initiators. The combined adjusted hazard ratio for incident AF among ustekinumab initiators was 1.08 (95% CI, 0.76-1.54) and for MACE among ustekinumab initiators was 1.10 (95% CI, 0.80-1.52) compared with TNFi initiators.\n\n\n\nNo substantially different risk of incident AF or MACE after initiation of ustekinumab vs TNFi was observed in this study. This information may be helpful when weighing the risks and benefits of various systemic treatment strategies for psoriatic disease.",
"affiliations": "Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.;Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.;Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.;Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.;Center for Clinical Epidemiology and Biostatistics, Department of Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia.;Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.",
"authors": "Lee|Moa P|MP|;Desai|Rishi J|RJ|;Jin|Yinzhu|Y|;Brill|Gregory|G|;Ogdie|Alexis|A|;Kim|Seoyoung C|SC|",
"chemical_list": "D003879:Dermatologic Agents; D000079424:Tumor Necrosis Factor Inhibitors; D000069549:Ustekinumab",
"country": "United States",
"delete": false,
"doi": "10.1001/jamadermatol.2019.0001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2168-6068",
"issue": "155(6)",
"journal": "JAMA dermatology",
"keywords": null,
"medline_ta": "JAMA Dermatol",
"mesh_terms": "D000328:Adult; D015535:Arthritis, Psoriatic; D001281:Atrial Fibrillation; D002318:Cardiovascular Diseases; D015331:Cohort Studies; D003879:Dermatologic Agents; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D011565:Psoriasis; D012306:Risk; D000079424:Tumor Necrosis Factor Inhibitors; D000069549:Ustekinumab",
"nlm_unique_id": "101589530",
"other_id": null,
"pages": "700-707",
"pmc": null,
"pmid": "30916734",
"pubdate": "2019-06-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "22532629;22395580;23708166;25351522;21840930;24037646;20362755;27922533;24379001;27794626;29573294;28658137;26433318;22262598;26644232;20038753;27518205;15215798;21862748;29559399;22911151;24184141;21208778;22897416;28245350;22011907;19458634;25053228",
"title": "Association of Ustekinumab vs TNF Inhibitor Therapy With Risk of Atrial Fibrillation and Cardiovascular Events in Patients With Psoriasis or Psoriatic Arthritis.",
"title_normalized": "association of ustekinumab vs tnf inhibitor therapy with risk of atrial fibrillation and cardiovascular events in patients with psoriasis or psoriatic arthritis"
} | [
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"companynumb": "US-JNJFOC-20190307291",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"drug": [
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"actiondrug": "5",
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"activesubstancename": "INFLIXIMAB"
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{
"abstract": "Tapentadol is a centrally acting analgesic that has been available for the management of acute and chronic pain in routine clinical practice since 2009.\n\n\n\nThis is the first integrated descriptive analysis of post-marketing safety data following the use of tapentadol in a broad range of pain conditions relating to the topics overall safety, dose administration above approved dosages, administration during pregnancy, serotonin syndrome, respiratory depression, and convulsion. The data analyzed pertain to spontaneous reports from healthcare and non-healthcare professionals and were put in the context of safety information known from interventional and non-interventional trials.\n\n\n\nThe first years of routine clinical practice experience with tapentadol have confirmed the tolerability profile that emerged from the clinical trials. Moreover, the reporting of expected side effects such as respiratory depression and convulsion was low and no major risks were identified. The evaluation of available post-marketing data did not confirm the theoretical risk of serotonin syndrome nor did it reveal unexpected side effects with administration of higher than recommended doses.\n\n\n\nMore than 8 years after its first introduction, the favorable overall safety profile of tapentadol in the treatment of various pain conditions is maintained in the general population.\n\n\n\nGrünenthal GmbH.",
"affiliations": "Grünenthal GmbH, Aachen, Germany. ariane.stollenwerk@grunenthal.com.;Grünenthal GmbH, Aachen, Germany.;Grünenthal GmbH, Aachen, Germany.;Grünenthal GmbH, Aachen, Germany.;Grünenthal GmbH, Aachen, Germany.",
"authors": "Stollenwerk|Ariane|A|;Sohns|Melanie|M|;Heisig|Fabian|F|;Elling|Christian|C|;von Zabern|Detlef|D|",
"chemical_list": "D000701:Analgesics, Opioid; D000077432:Tapentadol",
"country": "United States",
"delete": false,
"doi": "10.1007/s12325-017-0654-0",
"fulltext": "\n==== Front\nAdv Ther\nAdv Ther\nAdvances in Therapy\n0741-238X\n1865-8652\nSpringer Healthcare Cheshire\n\n29270779\n654\n10.1007/s12325-017-0654-0\nReview\nReview of Post-Marketing Safety Data on Tapentadol, a Centrally Acting Analgesic\nStollenwerk Ariane ariane.stollenwerk@grunenthal.com\n\nSohns Melanie\nHeisig Fabian\nElling Christian\nvon Zabern Detlef\ngrid.428898.7 Grünenthal GmbH, Aachen, Germany\n21 12 2017\n21 12 2017\n2018\n35 1 1230\n13 10 2017\n© The Author(s) 2017\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.\nIntroduction\n\nTapentadol is a centrally acting analgesic that has been available for the management of acute and chronic pain in routine clinical practice since 2009.\n\nMethods\n\nThis is the first integrated descriptive analysis of post-marketing safety data following the use of tapentadol in a broad range of pain conditions relating to the topics overall safety, dose administration above approved dosages, administration during pregnancy, serotonin syndrome, respiratory depression, and convulsion. The data analyzed pertain to spontaneous reports from healthcare and non-healthcare professionals and were put in the context of safety information known from interventional and non-interventional trials.\n\nResults\n\nThe first years of routine clinical practice experience with tapentadol have confirmed the tolerability profile that emerged from the clinical trials. Moreover, the reporting of expected side effects such as respiratory depression and convulsion was low and no major risks were identified. The evaluation of available post-marketing data did not confirm the theoretical risk of serotonin syndrome nor did it reveal unexpected side effects with administration of higher than recommended doses.\n\nConclusion\n\nMore than 8 years after its first introduction, the favorable overall safety profile of tapentadol in the treatment of various pain conditions is maintained in the general population.\n\nFunding\n\nGrünenthal GmbH.\n\nElectronic supplementary material\n\nThe online version of this article (10.1007/s12325-017-0654-0) contains supplementary material, which is available to authorized users.\n\nKeywords\n\nAcute pain\nAnalgesia\nChronic pain\nPain\nRoutine clinical practice\nSafety profile\nTapentadol\nTolerability\nGrunenthalissue-copyright-statement© Springer Healthcare Ltd., part of Springer Nature 2018\n==== Body\nIntroduction\n\nTapentadol, a centrally acting analgesic, has been proposed as the first agent in a new class of drugs (MOR-NRI [1]) combining the two mechanisms of action µ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI) in one molecule [2]. MOR activation in tapentadol is considerably lower compared to classical opioids; however, the synergistic interaction of the two mechanisms allows for a strong analgesic effect and likely results in fewer opioid-typical side effects [2, 3]. Tapentadol can be considered a “clean” molecule, exerting its analgesic effects directly and having no active metabolites [4]; the main metabolic pathway is glucuronidation [5]. The potential for pharmacokinetic drug–drug interaction is low; clinically relevant interactions are unlikely to occur [6, 7].\n\nTapentadol is available as immediate release (IR) film-coated tablets (dose strengths 25, 50, 75, 100 mg), oral solution (4 and 20 mg/ml), and as prolonged release (PR) film-coated tablets (dose strengths 25, 50, 100, 150, 200, 250 mg). It is indicated in Europe “for the relief of moderate to severe acute pain in adults, which can be adequately managed only with opioid analgesics” (IR formulation/oral solution) and “for the management of severe chronic pain in adults, which can be adequately managed only with opioid analgesics” (PR formulation). In the USA, tapentadol is approved “for the relief of moderate to severe acute pain in patients 18 years of age or older” (IR formulation/oral solution) and “for the management of moderate to severe chronic pain in adults when a continuous, around-the-clock opioid analgesic is needed for an extended period of time” (PR formulation). In addition, the PR formulation is indicated in the USA for the management of painful diabetic peripheral neuropathy. A pediatric development program is currently ongoing both in Europe and the USA.\n\nBoth the IR and PR formulations demonstrated efficacy and tolerability in a broad range of pain conditions [8, 9]. Phase 2 and 3 clinical trials showed effective analgesia of tapentadol IR in moderate to severe acute postoperative pain [10–12] and osteoarthritis or low back pain [13, 14]. Tapentadol PR was proven effective in randomized clinical trials for the management of moderate to severe chronic pain conditions such as osteoarthritis pain [15, 16], low back pain [16–19], painful diabetic peripheral neuropathy [20, 21], and cancer pain [22, 23]. Long-term pain relief under tapentadol PR (for up to 2 years) could be safely maintained in the treatment of chronic osteoarthritis or low back pain without any signs of tolerance development [24].\n\nTapentadol has been available for the management of chronic pain in routine clinical practice in the USA since 2009 and in Germany as the first European country since October 2010; approval in Europe was prolonged with unlimited validity based on the available comprehensive body of evidence in 2015. Tapentadol is also currently approved in Latin America, Asia, Australia, Israel, Japan, and North America, in total in 56 countries worldwide. Recently, a panel of pain specialists reviewed the clinical trial program and discussed the role of tapentadol PR in routine clinical practice management of chronic pain [9]. Apart from effective pain relief and improvements of functionality, health status, and quality of life of the patients, they stated a good safety profile for tapentadol PR, in particular, a favorable gastrointestinal tolerability profile.\n\nThe present article provides a comprehensive review of substance-specific safety data collected in the Grünenthal global safety database relating to the topics overall safety, dose administration above approved dosages, administration during pregnancy, serotonin syndrome, respiratory depression, and convulsion. The topics were selected on the basis of their relevance for both patients and prescribers.\n\nMethods\n\nDatabases\n\nThe Grünenthal global safety database until May 20, 2016 contained 10,758 cases concerning tapentadol. Out of these, all 8199 spontaneous reports from healthcare and non-healthcare professionals and all 105 spontaneous reports obtained from the literature were included in this review (the remaining 2454 cases originated from solicited data sources such as clinical trials). The objective was to review all spontaneous reports related to overall safety, dose administration above approved dosages, administration during pregnancy, serotonin syndrome, respiratory depression, and convulsions, and to compare these data to relevant clinical trial data if feasible. Clinical trial data were obtained from the Grünenthal interventional and non-interventional trial databases. The interventional clinical trial (ICT) database included 49 prospective phase 2, 3, and 4 trials investigating tapentadol IR or PR; phase 1 (healthy volunteers) and pediatric trials were excluded. The database contained 12,506 adult subjects. The non-interventional trial (NIT) database included the first four observational trials assessing tapentadol PR in routine clinical practice in Germany and contained data of 10,689 adult patients. All cases of adverse drug reactions (ADRs) to tapentadol were retrieved from both the ICT and NIT database.\n\nSearch Strategies\n\nAdverse events in all three databases had been encoded with the Medical Dictionary for Regulatory Activities (MedDRA) versions 15.0 and later. All spontaneous report data and clinical trial data were searched using either standardized MedDRA queries (SMQs) or customized MedDRA queries (CMQs).\n\nDose Administration Above Approved Dosages\n\nDatabases were searched using the CMQ “overdose” (included MedDRA preferred term codes are listed in the online supplementary material).\n\nPregnancy\n\nDatabases were searched using the CMQ “pregnancy and lactation” consisting of the SMQs “fetal disorders”, “normal pregnancy conditions and outcomes”, “lactation-related topics” (including neonatal exposure through breast milk), “pregnancy, labor, and delivery complications and risk factors” (excluding abortions and stillbirth), “neonatal disorders”, and “termination of pregnancy and risk of abortion”. The ICT database was also checked for positive pregnancy tests.\n\nSerotonin Syndrome\n\nDatabases were searched using the MedDRA preferred term “serotonin syndrome”.\n\nRespiratory Depression\n\nDatabases were searched using the SMQ “acute central respiratory depression” (included MedDRA preferred term codes are listed in the online supplementary material).\n\nConvulsion\n\nDatabases were searched using the SMQ “convulsion” (included MedDRA preferred term codes are listed in the online supplementary material).\n\nCompliance with Ethics Guidelines\n\nThis article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.\n\nResults\n\nOverall Safety\n\nTable 1 shows the demographic data for all spontaneous report cases and all clinical trial cases documenting ADRs. A total of 7185 subjects (57.5% of the 12,506 subjects included in the ICT database) and 777 patients (7.3% of the 10,689 patients included in the NIT database) experienced ADRs.Table 1 Demographic profile of all included cases\n\n\tSpontaneous reports (n = 8304)\tInterventional clinical trial data (n = 7185)\tNon-interventional trial data (n = 777)\t\nGender\t\n Female\t4340 (52.3%)\t4731 (65.8%)\t529 (68.1%)\t\n Male\t2562 (30.9%)\t2454 (34.2%)\t247 (31.8%)\t\n No information available\t1402 (16.9%)\t0\t1 (0.1%)\t\nAge (years)\t\n 0–9\t1 (< 0.1%)\t0\tN/A\t\n 10–19\t31 (0.4%)\t64 (0.9%)\t0\t\n 20–29\t184 (2.2%)\t685 (9.5%)\t8 (1%)\t\n 30–39\t414 (5.0%)\t558 (7.8%)\t29 (3.7%)\t\n 40–49\t709 (8.5%)\t1299 (18.1%)\t81 (10.4%)\t\n 50–59\t853 (10.3%)\t1947 (27.1%)\t150 (19.3%)\t\n 60–69\t719 (8.7%)\t1606 (22.4%)\t143 (18.4%)\t\n 70–79\t537 (6.5%)\t867 (12.1%)\t239 (30.8%)\t\n 80–89\t333 (4.0%)\t155 (2.2%)\t114 (14.7%)\t\n 90–99\t48 (0.6%)\t4 (< 0.1%)\t10 (1.3%)\t\n 100–109\t1 (< 0.1%)\t0\t0\t\n No information available\t4474 (53.9%)\t0\t3 (0.4%)\t\nData are number of patients (%)\n\nN/A not applicable\n\nThe most frequent ADRs reported spontaneously and in clinical trials are listed in Table 2. A total of 18,028 ADRs were documented in the 8304 spontaneous reports, 21,312 ADRs were reported for 7185 subjects in ICTs, and 1659 ADRs for 777 patients in NITs. In all databases, gastrointestinal and CNS-related drug reactions were most common; in addition, 6.9% of the spontaneously reported cases cited “drug ineffective” as an ADR. In clinical trials, however, drug ineffectiveness is already included in efficacy analyses and not collected as ADR; “drug ineffective” is therefore not part of the ADR analysis from clinical trials provided here.Table 2 Most frequently reported adverse drug reactions (MedDRA preferred terms)\n\n\tAll patients\tElderly patients (≥ 65 years)\tPatients < 65 years\t\nSpontaneous reports (global database)\t\n All adverse drug reactions\t18,028 (100%)\t3569 (100%)\t8130 (100%)\t\n Drug ineffective\t1237 (6.9%)\t181 (5.1%)\t492 (6.1%)\t\n Nausea\t888 (4.9%)\t198 (5.6%)\t346 (4.3%)\t\n Dizziness\t644 (3.6%)\t177 (5.6%)\t245 (3%)\t\n Headache\t472 (2.6%)\t55 (1.5%)\t222 (2.7%)\t\n Hallucination\t336 (1.9%)\t64 (1.8%)\t122 (1.5%)\t\n Vomiting\t335 (1.9%)\t81 (2.3%)\t148 (1.8%)\t\n Somnolence\t321 (1.8%)\t76 (2.1%)\t148 (1.8%)\t\n Feeling abnormal\t297 (1.7%)\t33 (0.9%)\t140 (1.7%)\t\n Hyperhidrosis\t248 (1.4%)\t46 (1.3%)\t108 (1.3%)\t\n Fatigue\t245 (1.4%)\t53 (1.5%)\t114 (1.4%)\t\n Confusional state\t244 (1.4%)\t110 (3.1%)\t81 (1%)\t\n Constipation\t228 (1.3%)\t81 (2.3%)\t83 (1%)\t\n Dyspnea\t218 (1.2%)\t47 (1.3%)\t114 (1.4%)\t\n Pain\t245 (1.4%)\t44 (1.2%)\t127 (1.6%)\t\n\tAll subjects\tElderly subjects (≥ 65 years)\tSubjects < 65 years\t\nInterventional clinical trial database\t\n All adverse drug reactions\t21,312 (100%)\t5214 (100%)\t16,098 (100%)\t\n Nausea\t3429 (16.1%)\t640 (12.3%)\t2789 (17.3%)\t\n Dizziness\t2338 (11%)\t542 (10.4%)\t1796 (11.2%)\t\n Vomiting\t1689 (7.9%)\t316 (6.1%)\t1373 (8.5%)\t\n Somnolence\t1567 (7.4%)\t343 (6.6%)\t1224 (7.6%)\t\n Constipation\t1512 (7.1%)\t560 (10.7%)\t952 (5.9%)\t\n Headache\t1096 (5.1%)\t169 (3.2%)\t927 (5.8%)\t\n Fatigue\t706 (3.3%)\t191 (3.7%)\t515 (3.2%)\t\n Dry mouth\t602 (2.8%)\t183 (3.5%)\t419 (2.6%)\t\n Pruritus\t549 (2.6%)\t109 (2.1%)\t440 (2.7%)\t\n Hyperhidrosis\t432 (2%)\t110 (2.1%)\t322 (2%)\t\n Decreased appetite\t300 (1.4%)\t116 (2.2%)\t184 (1.1%)\t\n\tAll patients\tElderly patients (≥ 65 years)\tPatients < 65 years\t\nNon-interventional trial database\t\n All adverse drug reactions\t1659 (100%)\t886 (100%)\t773 (100%)\t\n Nausea\t268 (16.2%)\t152 (17.2%)\t116 (15%)\t\n Dizziness\t143 (8.6%)\t77 (8.7%)\t66 (8.5%)\t\n Fatigue\t78 (4.7%)\t39 (4.4%)\t39 (5.1%)\t\n Vomiting\t67 (4%)\t33 (3.7%)\t34 (4.4%)\t\n Constipation\t51 (3.1%)\t34 (3.8%)\t17 (2.2%)\t\n Hyperhidrosis\t50 (3%)\t23 (2.6%)\t27 (3.5%)\t\n Somnolence\t49 (3%)\t28 (3.2%)\t21 (2.7%)\t\n Headache\t45 (2.7%)\t11 (1.2%)\t34 (4.4%)\t\n Diarrhea\t40 (2.4%)\t20 (2.3%)\t20 (2.6%)\t\n Restlessness\t40 (2.4%)\t23 (2.6%)\t17 (2.2%)\t\n Abdominal pain upper\t28 (1.7%)\t18 (2%)\t10 (1.3%)\t\nData are number of adverse drug reactions (%). Information about age was not available for all reports\n\nStratification by age (≥ 65 and < 65 years) is shown in Table 2. Nausea and dizziness were most frequently documented for both age groups. Occurrences of nausea were higher in the elderly according to post-marketing data [spontaneous reports (5.6% vs. 4.3%) and NIT database (17.2% vs. 15%)] but lower than for subjects < 65 years in the ICT database (12.3% vs. 17.3% of all ADRs in this age group). Dizziness was more often reported in the elderly in spontaneous reports (5.6% vs. 3%), occurred more often in younger subjects in the ICT dataset (11.2% vs. 10.4%), and in similar proportions in both groups in the NIT trials (8.7% vs. 8.5%). Vomiting was experienced more frequently in the younger age group in the ICT database (8.5% vs. 6.1%). In all three databases, constipation was more prominent in the elderly (2.3% vs. 1% for spontaneous reports, 3.8% vs. 2.2% in the NIT database, and 10.7% vs. 5.9% in the ICT database), whereas headache was more often reported in the younger age group (2.7% vs. 1.5% for spontaneous reports, 4.4% vs. 2.7% in the NIT database, and 5.8% vs. 3.2% in the ICT database). Confusional state occurred more frequently in the elderly in spontaneous reports (3.1% vs. 1%).\n\nIn summary, the most common side effects of tapentadol were typical side effects under opioid treatment such as nausea; noradrenergic side effects did not seem to be prominent. No new major risks were identified after the product launch; the overall safety profile remains unchanged. Overall, tapentadol was well tolerated by adult patients including the elderly.\n\nDose Administration Above Approved Dosages\n\nRecommendations for upper dosage limits of the two oral tapentadol formulations are based on the dose range studied during clinical development, i.e., on a lack of study data for higher dosages and not on evidence for a risk associated with higher dosages. Daily doses greater than 700 mg on the first day of treatment and daily maintenance doses greater than 600 mg for tapentadol IR and greater than 500 mg for tapentadol PR have not been studied and are therefore not recommended [25, 26]. Unlike with tapentadol, maximum recommended dosages are often not included in the summary of product characteristics of classical opioids. Initial and maintenance doses of opioids depend on the patient’s pain severity and previous analgesic treatment. Higher than recommended tapentadol dosages have been administered both in the therapeutic setting and in abuse situations which is to be expected for a medication with MOR activity.\n\nPreclinical Data\n\nAdministration of high doses of tapentadol resulted in dose-dependent, predominantly CNS-related, reversible clinical signs such as fearfulness, sedation or excited behavior, recumbency and hunched posture, impaired respiratory function, convulsions (rarely), and, in dogs in particular, salivation, vomiting, and retching. These exaggerated pharmacodynamic effects limited the exposure margins of tapentadol in healthy animals. The LD50 ranged from approx. 350 mg/kg in mice to greater than 1000 mg/kg in rats after p.o. administration and was approx. 45 mg/kg in both species after i.v. administration [27].\n\nSearch Results\n\nClinical Trial Data\n\nThe ICT database contained three cases of tapentadol doses above the recommended daily intake leading to adverse events (Table 3).Table 3 Adverse events following tapentadol doses above the recommended daily intake (ICT database)\n\n\tCase 1\tCase 2\tCase 3\t\nGender\tFemale\tMale\tFemale\t\nTreatment indication\tChronic low back pain\tOsteoarthritis knee pain\tAcute pain\t\nTapentadol dosage\t14,250 mg tapentadol PR over 10 days\t1650 mg tapentadol IR over 13 days\t8475 mg tapentadol IR over 11 days\t\nConcomitant medication\tNo\tNo but drug screen was positive for methadone, benzodiazepines, opiates, and tricyclic antidepressants\tYes\t\nAdverse event\tSevere visual disturbance and euphoria (serious adverse event)\tSevere inadvertent multi-drug overdose with moderate somnolence and dysarthria\tNoa\t\nRelationship to tapentadol\tProbably/likely\tProbably/likely\tNot related\t\naSubject experienced moderate atrial flutter 9 days later which was possibly related; dose at onset was 1800 mg\n\nIn routine clinical practice, 48 patients (0.45% of all patients in the NIT database) received a daily dose of tapentadol PR greater than 500 mg at least once during treatment. A daily dose of greater than 750 mg was reported four times; the highest dosage was 875 mg tapentadol PR/day. Ten patients (20.8%) reported 19 ADRs, six of them severe. Three ADRs were listed as prescribed overdose, the others were restless legs syndrome, initial insomnia, insomnia, memory impairment, diarrhea, hyperhidrosis, withdrawal syndrome (two cases), disturbance in attention, dizziness, nausea, depression suicidal, abdominal distension, abdominal discomfort, head discomfort, and flushing. Recovery was documented for 52.6% and outcome was not known for the remainder.\n\nSpontaneous Reports in Safety Database\n\nA total of 208 cases were retrieved from the global database. In 17 cases, toxicity was reported for dosages within the recommended range; in five of these cases, the event was attributed to other medications. Figure 1 shows the dosage range for the other 191 cases. The highest documented daily tapentadol doses were 2050 mg/day (outcome: recovering from hallucinations, no other events reported) and 5000 mg for a single intake (outcome: recovered). In 47.5% of the 208 cases ADRs were reported (no ADRs in 37.5% and unknown in 14.9% of the cases). Table 4 lists the most frequently reported ADRs.Fig. 1 Dose administration above the recommended dosage (either the total daily dose or a single administered dose; n = 191; spontaneous reports)\n\nTable 4 Most common adverse drug reactions (MedDRA system organ class and preferred term) with tapentadol intake exceeding the recommended dosage (spontaneous reports)\n\nAll adverse drug reactions\t458 (100%)\t\nGeneral disorders and administration site conditions\t\n Drug ineffective\t35 (7.6%)\t\nPsychiatric disorders\t\n Withdrawal syndrome\t12 (2.6%)\t\n Hallucination\t11 (2.4%)\t\n Suicide attempt\t10 (2.2%)\t\n Drug abuse\t9 (2.0%)\t\nNervous system disorders\t\n Unresponsive to stimuli\t10 (2.2%)\t\n Somnolence\t9 (2.0%)\t\nInjury, poisoning, and procedural complications\t\n Toxicity to various agents\t15 (3.3%)\t\nRespiratory, thoracic, and mediastinal disorders\t\n Respiratory depression\t9 (2.0%)\t\nData are number of adverse drug reactions (%)\n\nSixteen fatalities were reported under tapentadol, two of those with a dosage in the recommended range. In 10 of these cases, the provided information indicates that the patient administered tapentadol together with other drugs or illicit substances; this precludes a clear assessment of the contribution of each substance to the fatal course. Of the remaining six cases, three were cancer patients who likely died from their underlying disease, two cases did not provide any information regarding the circumstances or cause of death, and one case reported on a patient who apparently died from septic shock. Overall, there is not one spontaneously reported case where a fatal outcome could be clearly attributed to a tapentadol intake exceeding the recommended dosage.\n\nA manual case review showed that ADR incidences differed according to dosage intake (Table 5; this information is not captured in the structured fields of our database). Fifty-one cases with unknown dosage and 17 cases with reported dosage in the recommended range were not included in this analysis. Of the 140 included cases 97 reported a dosage of less than 1000 mg and 43 a dosage of at least 1000 mg tapentadol. The 97 cases included 18 (18.6%) single intakes and 6 (6.2%) abuse/misuse cases; tapentadol was administered as pain medication in 51 cases (52.6%). A multiple drug overdose was reported in 8 cases (8.2%). ADRs occurred in 46 cases (47.4%). The 43 cases included 12 (27.9%) single intakes and 3 (7%) abuse/misuse cases; tapentadol was administered as pain medication in 16 cases (37.2%). A multiple drug overdose was reported in 2 cases (4.7%). ADRs occurred in 20 cases (46.5%).Table 5 Most common adverse drug reactions (MedDRA preferred term) according to tapentadol dosage (spontaneous reports)\n\n\t500–< 1000 mg (n = 97)\t≥ 1000 mg (n = 43)\t\nDrug ineffective\t22 (22.7%)\t6 (14%)\t\nHallucination\t7 (7.2%)\t1 (2.3%)\t\nSuicide attempt\t7 (7.2%)\t2 (4.7%)\t\nConstipation\t6 (6.2%)\t0\t\nWithdrawal syndrome\t6 (6.2%)\t3 (7%)\t\nConfusional state\t5 (5.2%)\t1 (2.3%)\t\nDizziness\t5 (5.2%)\t2 (4.7%)\t\nDrug abuse\t5 (5.2%)\t3 (7%)\t\nSomnolence\t5 (5.2%)\t1 (2.3%)\t\nDyspnea\t0\t2 (4.7%)\t\nHypersomnia\t0\t2 (4.7%)\t\nRespiratory depression\t2 (4.7%)\t2 (4.7%)\t\nUnresponsive to stimuli\t1 (2.3%)\t2 (4.7%)\t\nVomiting\t4 (9.3%)\t2 (4.7%)\t\nData are number of cases\n\nIn summary, administration of higher than recommended tapentadol doses was not associated with side effects in a third of the cases; furthermore, some of the side effects reported are also expected for therapeutic dosages. Many of the reported cases occurred during pain treatment in order to achieve stronger analgesia; in some cases, abuse and suicide attempts were the reason for a higher tapentadol intake, mostly in combination with other medications. The reporting rate of fatalities with tapentadol alone was low; these fatalities were mostly associated with the underlying disease and not with the use of tapentadol.\n\nPregnancy\n\nExposure to opioids in utero can lead to neonatal opioid withdrawal symptoms [neonatal abstinence syndrome (NAS)]. The absolute risk following prenatal exposure to prescription opioids was low in the absence of additional risk factors; long-term use and use in late pregnancy increased the risk independent of additional risk factors [28]. Opioids in early pregnancy may also be associated with birth defects such as congenital heart defects, neural tube defects, and clubfoot [29]. Owing to the MOR activity of tapentadol, the risk of respiratory depression for neonates also needs to be considered.\n\nFirst trimester pregnancy exposure to serotonin–noradrenaline reuptake inhibitors (SNRIs) such as venlafaxine and duloxetine which—like tapentadol—include the NRI mechanism of action have been reviewed for major congenital malformations [30]; there was no increased risk with venlafaxine treatment and no clinically important risk with duloxetine. Venlafaxine was also judged as relatively safe during pregnancy (relating to major malformations) but the authors could not draw a definite conclusion regarding breastfeeding [31].\n\nPreclinical Data\n\nTapentadol was not genotoxic in bacteria in the Ames test. Equivocal findings were observed in an in vitro chromosomal aberration test, but when the test was repeated the results were clearly negative. Tapentadol was not genotoxic in vivo, using the two endpoints of chromosomal aberration and unscheduled DNA synthesis, when tested up to the maximum tolerated dose. Long-term animal studies did not identify a potential carcinogenic risk relevant to humans [26]. Fertility was not influenced in male and female rats but there was reduced in utero survival at high doses [26]. Tapentadol showed no teratogenic effects in rats and rabbits following both intravenous and subcutaneous administration. However, delayed development and embryotoxicity were observed for doses resulting in exaggerated pharmacology (µ-opioid-related CNS effects linked to dosing above the therapeutic range). After intravenous dosing in rats, reduced in utero survival was seen [26].\n\nTapentadol is excreted in milk; rat pups suckled by dams administered tapentadol were exposed dose-dependently to tapentadol and tapentadol O-glucuronide [26]. Twice daily tapentadol doses which did not provoke maternal toxicity already caused increased mortality of first birth generation (F1) rat pups that were exposed via milk between days 1 and 4 postpartum. There were no effects on neurobehavioral parameters of the F1 generation [26].\n\nSearch Results\n\nClinical Trial Data\n\nThis analysis also included clinical data from phase 1 trials in healthy volunteers who received tapentadol. Overall, 14 pregnancies were reported (Table 6); 10 patients were exposed to tapentadol short-term (1–12 days) and four long-term (104–367 days). Outcome was unknown in three cases, one subject had a false positive pregnancy test, and two patients elected to terminate the pregnancy (documentation did not specify the reason but reported no anomaly). Fetal demise in utero approx. 6 weeks after a positive pregnancy test on day 183 of long-term tapentadol PR treatment (last dose 400 mg/day) was documented for one subject.Table 6 Outcome of pregnancy in patients exposed to tapentadol\n\n\tSpontaneous reports (global database)\tInterventional clinical trial database\t\nPregnancies reported\t39\t14\t\nOutcome unknown\t25\t3\t\nFalse positive pregnancy test\t0\t1\t\nOutcome pending\t5\t0\t\nElective termination\t1\t2\t\nFetal demise in utero\t0\t1\t\nLife birth\t8\t7\t\nNormal term delivery\t6\t5\t\nPremature birth\t1\t2\t\nBirth defects\t0\t0\t\nNeonates experiencing withdrawal syndrome\t2\t0\t\nExposure via breast milk\t4\t0\t\nAdverse reactions following breastfeeding\t0\t0\t\n\nSeven life births were documented: five term babies (no birth defects or neonatal problems) and two premature births (no anomaly reported). One subject was exposed to tapentadol PR for 367 days (most recent dose 500 mg/day) and delivered a healthy term baby approx. 36 weeks following study completion.\n\nThe NIT database did not contain any pregnancy cases.\n\nSpontaneous Reports in Safety Database\n\nIn total, 39 pregnancies were reported (Table 6). Outcome was unknown in 25 cases (64.1%), pending in 5 cases (12.8%); 8 life births (20.5%) and one termination were reported. The life birth cases included four term babies (no birth defects or neonatal problems), two term babies with neonates experiencing withdrawal syndrome (mothers had received other opioids concomitantly with tapentadol), one premature birth (no anomaly reported), and one unknown outcome. The termination was elective; documentation did not specify the reason but reported no anomaly.\n\nExposure to tapentadol via breast milk (i.e., administration to the breastfeeding mother) was reported in four cases (dosage known in one case: 100 mg tapentadol PR b.i.d.), all without adverse drug reactions.\n\nAccording to the summary of product characteristics [26], tapentadol should be used in pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. The medication should not be used during breastfeeding. Although our analysis of the clinical and safety databases showed no birth defects following exposure to tapentadol and mostly healthy, normal term babies, no reliable conclusions can be drawn because of the low number of cases.\n\nSerotonin Syndrome\n\nSerotonin syndrome is a spectrum of serotonergic adverse reactions resulting from overactivation of both central and peripheral serotonin receptors due to increased serotonin levels [32, 33]. The syndrome is characterized by a triad of neuro-excitatory features: neuromuscular hyperactivity, autonomic hyperactivity, and altered mental status [32, 33]. The most accepted diagnostic criteria are the Hunter serotonin toxicity criteria which are based on the following seven clinical features: clonus, agitation, diaphoresis, tremor, hyperreflexia, hypertonia, and temperature greater than 38 °C [34]. Serotonin symptoms can result from initiation of monotherapy with a serotonergic substance, dose increases or overdosing with a serotonergic medication, or through interactions of two serotonergic medications acting by different mechanisms [32, 33]. Mechanisms associated with the syndrome are inhibition of serotonin uptake, decreased serotonin metabolism, increased serotonin synthesis, increased serotonin release, activation of serotonergic receptors, and inhibition of certain cytochrome P450 enzymes.\n\nPreclinical Data\n\nThe pharmacological activity of tapentadol results from the synergistic interaction of the two mechanisms MOR agonism and NRI [2]. The inhibitory activity at the noradrenaline reuptake transporter (Ki value 0.48 µM) is approx. five times weaker than the binding affinity for the rat MOR (Ki value 0.096 µM) [35] and considerably weaker than a classical potent NRI agent such as desipramine (Ki value 0.001 µM) [27]. Tapentadol is also only a very weak inhibitor of the 5-HT reuptake transporter in rat brain synaptosomes (Ki value 2.37 µM) compared to the selective serotonin reuptake inhibitor (SSRI) fluoxetine and the SNRIs venlafaxine and duloxetine with Ki values of 0.026, 0.062, and 0.005 µM, respectively [35]. Furthermore, binding affinity to the human 5-HT reuptake transporter is low (Ki value 5.28 µM) compared to fluoxetine, venlafaxine, and duloxetine (0.002, 0.035, and 0.00035 µM, respectively [35]). Rat intracerebral microdialysis studies showed a large dose-dependent increase in extracellular hippocampal noradrenaline concentrations (approx. 450% above baseline at 10 mg/kg) and a much smaller increase in extracellular 5-HT concentrations (approx. 130% above baseline at 10 mg/kg) under tapentadol [35]; the reference compounds venlafaxine and duloxetine produced up to sixfold concentration increases for both substances [36].\n\nUsing the low-intensity tail flick rat model, the pharmacological activity of tapentadol was compared to the SSRI citalopram and the SNRI reboxetine [37]. The effects of citalopram were inhibited by the serotonin receptor antagonist ritanserin and the effects of reboxetine by the noradrenergic receptor antagonist yohimbine. Tapentadol effects were antagonized by yohimbine but not by ritanserin. This suggests that serotonergic activity is not contributing to the pharmacological activity of tapentadol in this animal model.\n\nSince tapentadol inhibits the 5-HT reuptake transporter only weakly, a clinically relevant influence on 5-HT leading to the development of serotonin syndrome is assessed as to be unlikely.\n\nSearch Results\n\nClinical Trial Data\n\nThere were no reports of serotonin syndrome in the ICT database of phase 2, 3, and 4 prospective trials and only one case in the NIT database which is described below.\n\nAn adult female participant in one of the NIT trials received 200 mg/day tapentadol PR for the treatment of complex regional pain syndrome and post-traumatic pain and 75 mg/day amitriptyline for neuropathic pain. She experienced nausea, vomiting, pyrexia up to 39 °C, tachycardia, restlessness, and tremor approx. 8 h after the first administration of tapentadol. The treating physician suspected a serotonin syndrome which was reported as a serious adverse event probably related to tapentadol; treatment with tapentadol was discontinued and the patient recovered. However, symptoms do not fulfill the Hunter diagnostics criteria [34] and it is thus questionable if a serotonin syndrome was present.\n\nSpontaneous Reports in Safety Database\n\nA total of 151 spontaneous reports were retrieved from the database. None of these cases involved tapentadol dosages above the recommended level. At least one serotonergic drug was co-administered in 109 cases (72.2%); 11.9% of the subjects received two or three serotonergic drugs concomitantly. These included SNRIs (53 cases), SSRIs (46 cases), and tricyclic antidepressants (TCAs; 12 cases). The outcome of 64.9% of all 151 included cases was unknown or not reported, 34.4% were documented as recovered or recovering, and 0.7% were reported as “not recovered”.\n\nOnly four cases fulfilled the Hunter serotonin toxicity criteria [34] and had thus been robustly diagnosed (Table 7). In all four cases, concomitant serotonergic medication was taken which could also have triggered this reaction without tapentadol administration.Table 7 Cases of serotonin syndrome (spontaneous reports)\n\n\tCase 1\tCase 2\tCase 3\tCase 4a [38]\t\nGender\tF\tF\tF\tM\t\nTapentadol dosage\t200 mg bid\t200 mg tid\t25 mg\tunknown\t\nConcomitant serotonergic medication\tVenlafaxine\tAmitriptyline\tDuloxetine\tDuloxetine, amitriptylineb, naloxone, oxycodone\t\nRelationship to tapentadol\tInsufficient documentation\tQuestionable because of the delay of symptoms after tapentadol initiation\tPlausible temporal relation to combined use of both medications\tAlternative explanation: caused by treatment with amitriptyline\t\naContext: suicide attempt\n\nbSelf-medicated\n\nOverall, preclinical findings suggest that a clinically relevant influence of tapentadol on 5-HT leading to the development of serotonin syndrome is unlikely; this has been confirmed in clinical practice with no increased risk identified under tapentadol treatment. Most of the spontaneous reports were not robustly diagnosed, and cases fulfilling the Hunter criteria did not show a definite association of tapentadol with the occurrence of serotonin syndrome.\n\nRespiratory Depression\n\nRespiratory depression is a major clinical concern in the treatment with centrally acting analgesics because of the potentially fatal consequences. Hypoxic and hypercapnic responses are both affected; effects are dose-dependent and vary according to the mechanism of action of the administered opioid. Respiratory depression is mainly due to activation of µ- and δ-receptor subtypes and involves respiratory-related neurons in the brainstem [39, 40].\n\nPreclinical Data\n\nPreclinical data have been published by Tzschentke et al. [27]. Spontaneous respiratory frequency was dose-dependently reduced in conscious rats receiving a 4.64–14.7 mg tapentadol/kg i.v. bolus injection. Using plethysmography, respiratory minute volume was reduced by i.v. tapentadol at 18 mg/kg but not at 2 and 6 mg/kg in rat. Lower potency than morphine was observed for tapentadol in the inhibition of CO2-induced stimulation of respiratory frequency and in the increase in arterial pCO2 in rats. Daily tapentadol or morphine treatment resulted in complete tolerance to the respiratory depression effect within 22 days.\n\nSearch Results\n\nClinical Trial Data\n\nThe clinical database contained 20 ADRs, none of them serious: “respiratory depression” (12 cases), “hypoventilation” (3), “hypopnea” (2), “breath sounds abnormal” (2), and “respiratory rate decreased” (1). The majority (85%) were mild or moderate in intensity and three ADRs were considered severe by the investigator. Dose at onset of event was available for 80% of the cases and ranged from 50 to 500 mg tapentadol/day. Fifteen cases were resolved; one case was not resolved at the end of the trial. The outcome was unknown in four cases. Three ADRs (severe respiratory depression, two with mild hypoventilation) led to study withdrawal.\n\nThe NIT database only contained one case of respiratory depression (moderate intensity) under tapentadol PR treatment (100 mg/day) for an 86-year-old female patient. The ADR was considered possibly related to tapentadol by the treating physician; tapentadol was discontinued and the patient recovered.\n\nSpontaneous Reports in Safety Database\n\nA total of 64 spontaneous reports of respiratory depression were retrieved from the database. Nine subjects (14%) were administered tapentadol dosages above the recommended levels. Twenty-eight subjects (43.8%) concomitantly received centrally depressant medications [benzodiazepine, Z-drugs (zolpidem, zopiclone, zaleplon), strong opioids, or a combination of those]. The medical history of 11 subjects included risk factors of respiratory depression such as alcohol use, asthma, chronic obstructive pulmonary disease (COPD), sleep apnea, brain neoplasm, or neoplasm close to respiratory organs. Three fatal cases were reported; all patients had concomitantly taken opioid analgesics or benzodiazepines. One of the patients had the additional risk factors obesity, sleep apnea, asthma, and COPD [41]; another was a cancer patient. The third patient had pulmonary edema and a peritonsillar abscess; infectious mononucleosis was stated as cause of death.\n\nOverall, respiratory depression rarely occurred under tapentadol treatment. In clinical trials, courses were mostly mild or moderate without severe outcome. In most spontaneous cases, other confounding factors were present (concomitant CNS medications, risk factors of respiratory depression).\n\nConvulsion\n\nConvulsions are a known effect of medications with opioid activity. They can be caused by multiple mechanisms; MOR agonists probably inhibit hippocampal gamma-aminobutyric acid release by interneurons leading to excitatory effects [42]. Results from seizure induction in a mice model suggest that inhibition of neuronal monoamine reuptake is not a major contributor [43]. Commonly used opioid analgesics (codeine, dextromethorphan, hydrocodone, hydromorphone, meperidine, (−)-methadone, morphine, oxycodone, d-propoxyphene, and tramadol) induced dose-related seizures in mice at sufficiently high doses [43]. In pain management, convulsions are only observed for most opioids at doses far exceeding requirements for analgesia [42]. However, incidences of first-time idiopathic seizures under opioid analgesic treatment have been reported [44].\n\nPreclinical Data\n\nClinical signs of toxicity in acute toxicity studies in rats and mice after i.v. and p.o. administration included hyperexcitability, irregular respiratory activity, and convulsions [27]. In repeat-dose toxicity studies, single convulsion episodes occurred at tapentadol doses which showed distinct toxicity including deaths in dogs and in pregnant rats at severe intravenous materno-toxic doses [45].\n\nSearch Results\n\nClinical Trial Data\n\nThere were no reports of convulsion in the ICT database of phase 2, 3, and 4 prospective trials. It should be noted that subjects with a seizure disorder had been excluded from clinical trials. Convulsion was also not documented in the NIT database.\n\nSpontaneous Reports in Safety Database\n\nA total of 117 spontaneous reports of convulsion were retrieved from the database. There was no confirmed administration of tapentadol dosages exceeding the recommended levels. In one case, an overdose was suspected (dosage unknown); single intake exceeded 150 mg tapentadol in two cases (200 and 250 mg).\n\nTwenty-three subjects (19.7%) had a medical history of convulsion risk factors such as alcohol abuse, brain injury/surgery, history of seizures/epilepsy, or a combination of those. Tapentadol was discontinued in 10 of these cases. Five subjects continued with the medication; recovery was reported for two of them. Information about continuation/discontinuation of tapentadol was not available for eight subjects.\n\nOverall, post-marketing tapentadol exposure including administration to subjects with a medical history of convulsion risk factors (excluded in clinical trials) did not identify a risk beyond the existing knowledge. The occurrence of convulsions under tapentadol treatment is low, and this adverse drug reaction has been listed as rare.\n\nDiscussion\n\nThis review presents the most comprehensive analysis to date of post-marketing safety data of tapentadol relating to the topics overall safety, dose administration above approved dosages, administration during pregnancy, serotonin syndrome, respiratory depression, and convulsion following its administration for a wide range of pain conditions. These data collected from spontaneous reports by healthcare and non-healthcare professionals were put in the context of safety information known from interventional and non-interventional trials as well as preclinical findings. It should, however, be noted that underreporting as well as the typically incomplete case information in the spontaneous setting is an important limitation of this research.\n\nClinical trials have shown good tolerability of tapentadol in pain management for a treatment period of up to 2 years [9]; the most frequently observed adverse events (more than 10% of trial subjects) were nausea, dizziness, constipation, headache, and somnolence [46]. Head-to-head comparisons with the classical opioids oxycodone and oxycodone/naloxone have demonstrated a better tolerability profile for tapentadol, in particular regarding gastrointestinal side effects [46–48] which is likely due to the NRI contribution to the analgesic effect of tapentadol allowing for reduced µ-opioid receptor activation to reach efficacy comparable to classical strong opioid analgesics.\n\nOpioid typical gastrointestinal and CNS-related side effects were the most common ADRs stated in post-marketing spontaneous reports, whereas noradrenergic side effects did not seem to be prominent. Nausea and dizziness accounted for 4.9% and 3.6% of all included ADRs, respectively. The collected data are in line with the clinical trial results; they did not reveal major risks and thus do not change the overall safety profile identified for tapentadol.\n\nMany elderly patients are affected by (often chronic) pain. When treating these patients, frequent comorbidities requiring a number of different medications (polypharmacy) and thus increasing the risk of drug–drug interactions and side effects need to be considered in the choice of pain medication. From pharmacokinetic studies during the development of tapentadol it was known that tapentadol has a low potential for pharmacokinetic drug–drug interaction and clinically relevant interactions are unlikely to occur [6, 7]. In our comparison of elderly and younger subjects (< 65 years of age) in the clinical and post-marketing databases, gastrointestinal and CNS-related drug reactions were the most commonly observed adverse effects in both groups. Clinical comparisons to oxycodone showed significantly better gastrointestinal tolerability in elderly patients for tapentadol both for the IR and PR formulations [47, 49]. Overall, tapentadol was well tolerated in elderly patients, no new risks were identified for this age group and we can only speculate that the observed differences concerning constipation, confusional state, nausea, and headache are more likely age-related than tapentadol related.\n\nPain treatment with all analgesics and in particular with substances with an opioid mechanism of action has shown that not all patients respond equally to treatment: some patients might require dose adaptations or a switch to a different analgesic to achieve or maintain pain relief. Classically, this is reflected in spontaneous ADR reports of lack of efficacy. For tapentadol treatment, “drug ineffectiveness” was documented in 6.9% of the spontaneously reported cases.\n\nIn clinical practice, many of the reported cases of tapentadol intake exceeding the recommended dosage occurred during pain treatment in order to achieve stronger analgesia; in some cases, abuse and suicide attempts were the reason for a higher tapentadol intake, mostly in combination with other medications. In some cases, exact dosing information was not available; overall, dosages did not greatly exceed recommended tapentadol dosages for many patients. Medical consequences of higher than recommended dosages during routine clinical practice were mainly gastrointestinal, psychiatric, and nervous system disorders (documented in the NIT database); in the spontaneous report database, somnolence (1.4%), coma (1.5%), and respiratory depression (1.4%) were also noted. None of the 16 reported fatalities could be clearly attributed to a higher than recommended tapentadol intake. The data collected from tapentadol usage above the currently recommended dosages did not provide evidence for an increased risk for tapentadol use outside the therapeutic window.\n\nData about the safety of prenatal tapentadol exposure are limited, as pregnant subjects were excluded from clinical trials for ethical reasons and generally did not receive the medication in routine clinical practice because of recommendations to only use tapentadol in pregnancy “if the potential benefit justifies the potential risk to the fetus” [26]. The available clinical and post-marketing data show mostly healthy, normal term babies and no incidence of birth defects following exposure to tapentadol. It should, however, be noted that pregnancy outcome was not reported for the majority of post-marketing cases which limits further conclusions about the potential risk.\n\nBecause of the preclinical findings, serotonin syndrome is a theoretical risk of tapentadol treatment; the isolated reports of serotonin syndrome in a temporal connection of the combined use of tapentadol and serotonergic substances are therefore included in the product information [26]. The diagnosis of serotonin syndrome requires a typical constellation of symptoms (clonus, agitation, diaphoresis, tremor, hyperreflexia, hypertonia, and temperature greater than 38 °C) [34]. Some of these clinical features are unspecific, others belong to the side effect spectrum of tapentadol, and it is challenging to reach the correct diagnosis. Physicians might mistakenly diagnose the occurrence of some of these symptoms in a patient as serotonin syndrome even if the typical constellation of symptoms is not present [32]. This could be triggered by the list of possible symptoms described in the product information [26, 50]. The diagnosis of probable serotonin syndrome presented by Walczyk and colleagues [38] (listed in our publication as case 4 in Table 7), for example, was questioned in two letters to the editor [51, 52]. In the authors’ opinion, symptoms were more consistent with an opioid overdose and opioid withdrawal after naloxone reversal, and evidence that serotonin syndrome occurred was deemed insufficient. Of the 151 post-marketing cases collected in the safety database, only four fulfilled the Hunter diagnostic criteria (for case 4 (Table 7) from the literature [38], this diagnosis was questioned by another author group [51]), and could be robustly diagnosed. These cases did not show a definite association of tapentadol with the occurrence of serotonin syndrome. It should be noted that many of the 151 reports, however, lacked information about symptoms and thus precluded a reasonable evaluation.\n\nThere were no cases of serotonin syndrome in our ICT database and the diagnosis of the one case documented in the NIT database is questionable. A retrospective analysis of safety data from 11 randomized, double-blind, placebo-controlled acute and chronic pain phase 3 trials (including both IR and PR tapentadol formulations) investigated potential pharmacodynamic interactions with concomitant use of tapentadol and SSRIs and/or SNRIs [53]. Adverse event incidences were compared for tapentadol + SSRI/SNRI (n = 208) and placebo + SSRI/SNRI (n = 137). The observed treatment emergent adverse events (TEAEs) were mostly expected from tapentadol product labeling. The analysis did not identify new clinically relevant adverse drugs interactions associated with concomitant use of tapentadol and SSRI/SNRIs. Analyses of data from nine phase 2/3 tapentadol IR trials (2178 subjects) and from nine phase 2/3 tapentadol PR trials (3613 subjects) also did not identify any cases of serotonin syndrome reported as an adverse event [54].\n\nRespiratory depression is an ADR of medications with an opioid mechanism of action. It was rarely reported in clinical tapentadol trials and resulted in trial discontinuation in 15% of the cases. Courses were mostly mild or moderate without severe outcome. Occurrence in spontaneous reporting was also low; in most spontaneous cases, other confounding factors were present (concomitant CNS medications, risk factors of respiratory depression). A recent trial comparing tapentadol IR and oxycodone IR observed greater respiratory depression under oxycodone than under tapentadol at equianalgesic doses [55]. The authors suggest that differences in respiratory effect may be attributed to the difference of the two medications in their affinity for the µ-opioid receptor.\n\nClinical tapentadol trials did not permit the inclusion of subjects with a seizure disorder; the administration of tapentadol to patients at risk is therefore not recommended. However, post-marketing exposure including patients at risk of seizures did not identify a risk beyond the existing knowledge. The number of cases with a medical history of convulsion risk factors was small though, potentially because of the warning in the product information [26]. Any interpretation of this result is therefore limited.\n\nConclusions\n\nOn the basis of the presented descriptive analysis of post-marketing data, the first years of routine clinical practice experience with tapentadol have confirmed the tolerability profile demonstrated in clinical trials; no new major risks were identified. It should be noted that the limitations of the spontaneous data analyzed are underreporting of adverse reactions and the mostly incomplete information in spontaneous reports. The reporting of expected side effects such as respiratory depression and convulsion was low. The available data did not confirm the theoretical risk of serotonin syndrome. The evaluation of reports on administration of higher than recommended tapentadol doses did not reveal any unexpected side effects. Tapentadol shows a favorable overall safety profile in the treatment of acute and chronic pain.\n\nElectronic supplementary material\n\nBelow is the link to the electronic supplementary material. Supplementary material 1 (PDF 61 kb)\n\nAcknowledgements\n\nThe authors would like to thank the patients, investigators, and study teams involved in the studies included in the ICT and NIT databases as well as all healthcare practitioners and consumers reporting tapentadol safety events. They would also like to thank Jérôme Rapion for statistical analyses, Reinhard-Michael Reichert for the programming of safety data retrievals from the global safety database, and Thomas Tzschentke and Corinne van Dorp for their comments on the preclinical manuscript sections.\n\nFunding\n\nAll analyses, article processing charges, and the open access fee were funded by Grünenthal GmbH. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.\n\nMedical Writing and/or Editorial Assistance\n\nMedical writing support was provided by Elke Grosselindemann and Birgit Brett of Brett Medical Writing. This support was funded by Grünenthal GmbH.\n\nAuthorship\n\nAll named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.\n\nDisclosures\n\nAriane Stollenwerk is an employee of Grünenthal GmbH. Melanie Sohns is an employee of Grünenthal GmbH. Fabian Heisig is an employee of Grünenthal GmbH. Christian Elling is an employee of Grünenthal GmbH. Detlef von Zabern was an employee of Grünenthal GmbH at the time of authorship definition. Detlef von Zabern is now a partner of medwiss-extern.\n\nCompliance with Ethics Guidelines\n\nThis article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.\n\nData Availability\n\nThe datasets generated during and/or analyzed during the current study are not publicly available because of data privacy but are available from the corresponding author on reasonable request.\n\nOpen Access\n\nThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.\n\nEnhanced content\n\nTo view enhanced content for this article go to http://www.medengine.com/Redeem/CDFCF06013CC81E4.\n==== Refs\nReferences\n\n1. Kress HG Tapentadol and its two mechanisms of action: is there a new pharmacological class of centrally-acting analgesics on the horizon? Eur J Pain 2010 14 781 783 10.1016/j.ejpain.2010.06.017 20659810\n2. Tzschentke TM Christoph T Kögel BY The mu-opioid receptor agonist/noradrenaline reuptake inhibition (MOR-NRI) concept in analgesia: the case of tapentadol CNS Drugs 2014 28 319 329 10.1007/s40263-014-0151-9 24578192\n3. Schröder W Tzschentke TM Terlinden R Synergistic interaction between the two mechanisms of action of tapentadol in analgesia J Pharmacol Exp Ther 2011 337 312 320 10.1124/jpet.110.175042 21262850\n4. Terlinden R Kogel BY Englberger W Tzschentke TM In vitro and in vivo characterization of tapentadol metabolites Methods Find Exp Clin Pharmacol 2010 32 31 38 10.1358/mf.2010.32.1.1434165 20383344\n5. Terlinden R Ossig J Fliegert F Lange C Göhler K Absorption, metabolism, and excretion of 14C-labeled tapentadol HCl in healthy male subjects Eur J Drug Metab Pharmacokinet 2007 32 163 169 10.1007/BF03190478 18062408\n6. Kneip C Terlinden R Beier H Chen G Investigations into the drug-drug interaction potential of tapentadol in human liver microsomes and fresh human hepatocytes Drug Metab Lett 2008 2 67 75 10.2174/187231208783478434 19356073\n7. Smit JW Oh C Rengelshausen J Effects of acetaminophen, naproxen, and acetylsalicylic acid on tapentadol pharmacokinetics: results of two randomized, open-label, cross-over, drug-drug interaction studies Pharmacotherapy 2010 30 25 34 10.1592/phco.30.1.25 20030470\n8. Xiao JP Li AL Feng BM Ye Y Wang GJ Efficacy and safety of tapentadol immediate release assessment in treatment of moderate to severe pain: a systematic review and meta-analysis Pain Med 2016 26814244\n9. Baron R Eberhart L Kern KU Tapentadol prolonged release for chronic pain—a review of clinical trials and five years of routine clinical practice data Pain Pract 2016\n10. Daniels SE Upmalis D Okamoto A Lange C Haeussler J A randomized, double-blind, phase III study comparing multiple doses of tapentadol IR, oxycodone IR, and placebo for postoperative (bunionectomy) pain Curr Med Res Opin 2009 25 765 776 10.1185/03007990902728183 19203298\n11. Daniels S Casson E Stegmann JU A randomized, double-blind, placebo-controlled phase 3 study of the relative efficacy and tolerability of tapentadol IR and oxycodone IR for acute pain Curr Med Res Opin 2009 25 1551 1561 10.1185/03007990902952825 19445652\n12. Vorsanger GJ Klopfer AM Xiang J Benson CJ Moskovitz BL Rosenthal NR Immediate-release tapentadol or oxycodone for treatment of acute postoperative pain after elective arthroscopic shoulder surgery: a randomized, phase IIIb study J Opioid Manag 2013 9 281 296 24353022\n13. Hartrick C Van Hove I Stegmann JU Oh C Upmalis D Efficacy and tolerability of tapentadol immediate release and oxycodone HCl immediate release in patients awaiting primary joint replacement surgery for end-stage joint disease: a 10-day, phase III, randomized, double-blind, active- and placebo-controlled study Clin Ther 2009 31 260 271 10.1016/j.clinthera.2009.02.009 19302899\n14. Hale M Upmalis D Okamoto A Lange C Rauschkolb C Tolerability of tapentadol immediate release in patients with lower back pain or osteoarthritis of the hip or knee over 90 days: a randomized, double-blind study Curr Med Res Opin 2009 25 1095 1104 10.1185/03007990902816970 19301989\n15. Afilalo M Etropolski MS Kuperwasser B Efficacy and safety of tapentadol extended release compared with oxycodone controlled release for the management of moderate to severe chronic pin related to osteoarthritis of the knee Clin Drug Investig 2010 30 489 505 10.2165/11533440-000000000-00000 20586515\n16. Wild JE Grond S Kuperwasser B Long-term safety and tolerability of tapentadol extended release for the management of chronic low back pain or osteoarthritis pain Pain Pract 2010 10 416 427 10.1111/j.1533-2500.2010.00397.x 20602712\n17. Buynak R Shapiro DY Okamoto A Efficacy and safety of tapentadol extended release for the management of chronic low back pain: results of a prospective, randomized, double-blind, placebo- and active-controlled phase III study Expert Opin Pharmacother 2010 11 1787 1804 10.1517/14656566.2010.497720 20578811\n18. Baron R Martin-Mola E Müller M Dubois C Falke D Steigerwald I Effectiveness and safety of tapentadol prolonged release (PR) versus a combination of tapentadol PR and pregabalin for the management of severe, chronic low back pain with a neuropathic component: a randomized, double-blind, phase 3b study Pain Pract 2015 15 455 470 10.1111/papr.12200 24738609\n19. Baron R Likar R Martin-Mola E Effectiveness of tapentadol prolonged release (PR) compared with oxycodone/naloxone PR for the management of severe chronic low back pain with a neuropathic component: a randomized, controlled, open-label, phase 3b/4 study Pain Pract 2016 16 580 599 10.1111/papr.12308 26095455\n20. Schwartz S Etropolski M Shapiro DY Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebo-controlled trial Curr Med Res Opin 2011 27 151 162 10.1185/03007995.2010.537589 21162697\n21. Vinik AI Shapiro DY Rauschkolb C A randomized withdrawal, placebo-controlled study evaluating the efficacy and tolerability of tapentadol extended release in patients with chronic, painful diabetic peripheral neuropathy Diabetes Care 2014 37 2302 2309 10.2337/dc13-2291 24848284\n22. Imanaka K Tominaga Y Etropolski M Efficacy and safety of oral tapentadol extended release in Japanese and Korean patients with moderate to severe, chronic malignant tumor-related pain Curr Med Res Opin 2013 29 1399 1409 10.1185/03007995.2013.831816 23937387\n23. Kress HG Koch ED Kosturski H Tapentadol prolonged release for managing moderate to severe, chronic malignant tumor-related pain Pain Physician 2014 17 329 343 25054392\n24. Buynak R Rappaport SA Rod K Long-term safety and efficacy of tapentadol extended release following up to 2 years of treatment in patients with moderate to severe, chronic pain: results of an open-label extension trial Clin Ther 2015 37 2420 2438 10.1016/j.clinthera.2015.08.014 26428249\n25. Electronic Medicines Compendium. Palexia film coated tablets. https://www.medicines.org.uk/emc/medicine/28375. Accessed Feb 15, 2017.\n26. Electronic Medicines Compendium. Palexia SR prolonged release tablets. https://www.medicines.org.uk/emc/medicine/28373. Accessed Sept 19, 2016.\n27. Tzschentke TM De Vry J Terlinden R Tapentadol hydrochloride. Analgesic mu-opioid receptor agonist noradrenaline reuptake inhibitor Drugs Future 2006 31 1053 1061 10.1358/dof.2006.031.12.1047744\n28. Desai RJ Huybrechts KF Hernandez-Diaz S Exposure to prescription opioid analgesics in utero and risk of neonatal abstinence syndrome: population based cohort study BMJ 2015 350 h2102 10.1136/bmj.h2102 25975601\n29. Yadzy MM Desai RJ Brogly SB Prescription opioids in pregnancy and birth outcomes: a review of the literature J Pediatr Genet 2015 4 56 70 10.1055/s-0035-1556740 26998394\n30. Lassen D Ennis ZN Damkier P First-trimester pregnancy exposure to venlafaxine or duloxetine and risk of major congenital malformations: a systematic review Basic Clin Pharmacol Toxicol 2016 118 32 36 10.1111/bcpt.12497 26435496\n31. Bellantuono C Vargas M Mandarelli G Nardi B Martini MG The safety of serotonin-noradrenaline reuptake inhibitors (SNRIs) in pregnancy and breastfeeding: a comprehensive review Hum Psychopharmacol 2015 30 143 151 10.1002/hup.2473 25784291\n32. Gillman PK Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity Br J Anaesth 2005 95 434 441 10.1093/bja/aei210 16051647\n33. Sun-Edelstein C Tepper SJ Shapiro RE Drug-induced serotonin syndrome: a review Expert Opin Drug Saf 2008 7 587 596 10.1517/14740338.7.5.587 18759711\n34. Dunkley EJC Isbister GK Sibbritt D Dawson AH Whyte IM The Hunter serotonin toxicity criteria: simple and accurate diagnostic decision rules for serotonin toxicity Q J Med 2003 96 635 642 10.1093/qjmed/hcg109\n35. Tzschentke TM Christoph T Kögel B (−)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel µ-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties J Pharmacol Expert Ther 2007 323 265 276 10.1124/jpet.107.126052\n36. Bloms-Funke P Dremencov E Cremers TI Tzschentke TM Tramadol increases extracellular levels of serotonin and noradrenaline as measured by in vivo microdialysis in the ventral hippocampus of freely-moving rats Neurosci Lett 2011 490 191 195 10.1016/j.neulet.2010.12.049 21195741\n37. Schröder W, De Vry J, Tzschentke TM, Jahnel U, Christoph T. Differential contribution of opioid and noradrenergic mechanisms of tapentadol in rat models of nociceptive and neuropathic pain. Eur J Pain. 2010:814–21.\n38. Walczyk H Liu CH Alafris A Cohen H Probable tapentadol-associated serotonin syndrome after overdose Hosp Pharm 2016 51 320 327 10.1310/hpj5104-320 27303080\n39. Pattinson KTS Opioids and the control of respiration Br J Anaesth 2008 100 747 758 10.1093/bja/aen094 18456641\n40. Lalley PM Opioidergic and dopaminergic modulation of respiration Respir Physiol Neurobiol 2008 164 160 167 10.1016/j.resp.2008.02.004 18394974\n41. Larson SJ Pestaner J Prashar SK Bayard C Zarwell LW Pierre-Louis M Postmortem distribution of tapentadol and n-desmethyltapentadol J Anal Toxicol 2012 36 440 443 10.1093/jat/bks041 22543979\n42. Gutstein HB Akil H Brunton L Opioid analgesics Goodman and Gilman’s. The pharmacological basis of therapeutics 2006 11 Pennsylvania McGraw-Hill 547 590\n43. Raffa RB Stone DJ Unexceptional seizure potential of tramadol or its enantiomers or metabolites in mice J Pharmacol Exp Ther 2008 325 500 506 10.1124/jpet.108.137273 18292293\n44. Gasse C Derby L Vasilakis-Scaramozza C Jick H Incidence of first-time idiopathic seizures in users of tramadol Pharmacotherapy 2000 20 629 634 10.1592/phco.20.7.629.35174 10853617\n45. Food and Drug Administration. Nucynta summary basis for approval. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022304s000_PharmR_P5.pdf. Accessed June 15, 2017.\n46. Etropolski M Kuperwasser B Flügel M Safety and tolerability of tapentadol extended release in moderate to severe chronic osteoarthritis or low back pain management: pooled analysis of randomized controlled trials Adv Ther 2014 31 604 620 10.1007/s12325-014-0128-6 24985410\n47. Vorsanger G Xiang J Biondi D Post hoc analyses of data from a 90-day clinical trial evaluating the tolerability and efficacy of tapentadol immediate release and oxycodone immediate release for the relief of moderate to severe pain in elderly and nonelderly patients Pain Res Manag 2011 16 245 251 10.1155/2011/323985 22059194\n48. Baron R Jansen JP Binder A Tolerability, safety, and quality of life with tapentadol prolonged release (PR) compared with oxycodone/naloxone PR in patients with severe chronic low back pain with a neuropathic component: a randomized, controlled, open-label, phase 3b/4 trial Pain Pract 2016 16 600 619 10.1111/papr.12361 26554630\n49. Biondi DM Xiang J Häufel T Etropolski M Moskovitz B Tolerability and efficacy of tapentadol extended release in elderly patients ≥ 75 years of age with chronic osteoarthritis knee or low back pain J Opioid Manag 2015 11 393 403 10.5055/jom.2015.0289 26535967\n50. Janssen Pharmaceuticals. NUCYNTA ER-tapentadol hydrochloride tablet, film coated, extended release. https://www.nucynta.com/sites/default/files/pdf/nucyntaer-pi_0.pdf. Accessed Mar 6, 2017.\n51. Mullins ME Dribben WH Comment on tapentadol and serotonin syndrome Hosp Pharm 2017 52 246 247 10.1310/hpj5204-246 28515499\n52. Russo M Santarelli D Isbister G Comment on “probable tapentadol-associated serotonon syndrome after overdose” Hosp Pharm 2017 52 248 10.1310/hpj5204-248 28515500\n53. Brett V Sikes C Xiang J Oh C Biondi D Post hoc analysis of pooled safety data from eleven phase 3 clinical trials to identify potential pharmacodynamic drug interactions between tapentadol and SSRIs/SNRIs J Pharm Pract 2012 25 265\n54. Schmidt P. Safety information on serotonin syndrome for tapentadol IR and tapentadol ER administration (Abstract poster 212). http://www.painmed.org/2016posters/abstract-212/. Accessed Sept 26, 2016.\n55. van der Schrier R, Jonkman K, van Velzen M, et al. An experimental study comparing the respiratory effects of tapentadol and oxycodone in healthy volunteers. Br J Anaesth 2017;119(6):1169.\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "35(1)",
"journal": "Advances in therapy",
"keywords": "Acute pain; Analgesia; Chronic pain; Pain; Routine clinical practice; Safety profile; Tapentadol; Tolerability",
"medline_ta": "Adv Ther",
"mesh_terms": "D000701:Analgesics, Opioid; D059350:Chronic Pain; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D010146:Pain; D011358:Product Surveillance, Postmarketing; D012131:Respiratory Insufficiency; D012640:Seizures; D020230:Serotonin Syndrome; D000077432:Tapentadol",
"nlm_unique_id": "8611864",
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"pages": "12-30",
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"pubdate": "2018-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
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"title": "Review of Post-Marketing Safety Data on Tapentadol, a Centrally Acting Analgesic.",
"title_normalized": "review of post marketing safety data on tapentadol a centrally acting analgesic"
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"abstract": "A 14-year-old girl with a history of complex congenital heart disease in end-stage heart failure and with cyclic vomiting was admitted to our hospice program in 2012. Before hospice enrollment, she had required intermittent infusions of dexmedetomidine to abort cyclic vomiting episodes after cardiac catheterization procedures. Following a hospital admission in November 2013, she was discharged home in the care of our hospice on a continuous dexmedetomidine infusion. She remained on this infusion at varying doses (range of 0.1-0.38 mcg/kg/hour) for nearly three years, until her death in September 2016. This report describes the palliative use of dexmedetomidine in this patient and difficulties related to the use of this medication during the course of her care.",
"affiliations": "Division of Palliative Care, Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.;Division of Palliative Care, Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.;Division of Palliative Care, Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.;Division of Palliative Care, Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.;Division of Cardiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.",
"authors": "Thienprayoon|Rachel|R|;Meyer|Mark|M|;Flint|Hilary|H|;Weidner|Norbert|N|;Hirsch|Russel|R|",
"chemical_list": "D006993:Hypnotics and Sedatives; D020927:Dexmedetomidine",
"country": "United States",
"delete": false,
"doi": "10.1089/jpm.2018.0516",
"fulltext": null,
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"issn_linking": "1557-7740",
"issue": "22(10)",
"journal": "Journal of palliative medicine",
"keywords": "cyclic vomiting; dexmedetomidine; home-based hospice and palliative care; pediatric hospice care; pediatric palliative care",
"medline_ta": "J Palliat Med",
"mesh_terms": "D000293:Adolescent; D020927:Dexmedetomidine; D005260:Female; D006330:Heart Defects, Congenital; D006699:Home Care Services; D017051:Hospice Care; D006801:Humans; D006993:Hypnotics and Sedatives; D010166:Palliative Care; D014839:Vomiting",
"nlm_unique_id": "9808462",
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"pages": "1289-1292",
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"pmid": "31058565",
"pubdate": "2019-10",
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"references": null,
"title": "Use of Continuous Dexmedetomidine at Home for Nearly Three Years in a Young Woman with End-Stage Cyanotic Congenital Heart Disease and Cyclic Vomiting.",
"title_normalized": "use of continuous dexmedetomidine at home for nearly three years in a young woman with end stage cyanotic congenital heart disease and cyclic vomiting"
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"abstract": "To assess the incidence, predictive factors, and prognosis of acyclovir-induced nephrotoxicity. We conducted a historical prospective cohort study of patients treated with intravenous acyclovir in North Denmark Region from 2009 to 2016. Information on baseline demographics, co-morbidities, plasma creatinine, and treatment was obtained from the medical records. The primary outcome was an increase of ≥ 40 μmol/L in plasma creatinine level from baseline. We included 276 patients treated with intravenous acyclovir of which 29 (10.5%) met the primary outcome. In 14 cases, the treating physician considered acyclovir the main reason for nephrotoxicity, whereas a potential competing cause of renal impairment was present among the 15 remaining patients. Hypertension was the only predictive factor associated with nephrotoxicity (risk ratio (RR), 2.77; 95% confidence interval (CI), 1.41-5.46), while having no co-morbidities was protective (RR, 0.32; CI, 0.16-0.63). In all cases, the nephrotoxicity was reversible following rehydration and dose reduction or discontinuation of the drug. However, the normalized plasma creatinine upon treatment was significantly higher between cases with acyclovir-induced nephrotoxicity than cases with a potential competing cause (median [interquartile range (IQR)], 93.5 μmol/L [85-108] vs 75 μmol/L [66.5-88]; p = 0.019). Acyclovir-induced, reversible nephrotoxicity was observed in 5.1-10.5% of patients. It is difficult to predict who will develop acyclovir-induced nephrotoxicity; it may occur late in treatment and hypertension was the only independent predictive factor, while the absence of co-morbidities was protective. Ensuring hydration, frequent evaluations of renal function, and corresponding dose adjustment of intravenous acyclovir treatment seem prudent.",
"affiliations": "Department of Infectious Diseases, Aalborg University Hospital, Hobrovej 18-22, DK-9000, Aalborg, Denmark. r.richelsen@rn.dk.;Department of Infectious Diseases, Aalborg University Hospital, Hobrovej 18-22, DK-9000, Aalborg, Denmark.;Department of Infectious Diseases, Aalborg University Hospital, Hobrovej 18-22, DK-9000, Aalborg, Denmark.",
"authors": "Richelsen|Rasmus K B|RKB|http://orcid.org/0000-0002-6447-7815;Jensen|Signe B|SB|;Nielsen|Henrik|H|",
"chemical_list": "D000998:Antiviral Agents; D003404:Creatinine; D000212:Acyclovir",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10096-018-3332-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0934-9723",
"issue": "37(10)",
"journal": "European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology",
"keywords": "Acute kidney injury; Acyclovir; Herpes encephalitis; Nephrotoxicity",
"medline_ta": "Eur J Clin Microbiol Infect Dis",
"mesh_terms": "D058186:Acute Kidney Injury; D000212:Acyclovir; D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D015331:Cohort Studies; D003404:Creatinine; D003718:Denmark; D005260:Female; D006801:Humans; D006973:Hypertension; D015994:Incidence; D007674:Kidney Diseases; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors",
"nlm_unique_id": "8804297",
"other_id": null,
"pages": "1965-1971",
"pmc": null,
"pmid": "30083888",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28509218;16715038;1288525;22005269;28002877;21867467;6285709;3376977;8416680;6285711;10225250;26985083;12185472;3881542;7947045",
"title": "Incidence and predictors of intravenous acyclovir-induced nephrotoxicity.",
"title_normalized": "incidence and predictors of intravenous acyclovir induced nephrotoxicity"
} | [
{
"companynumb": "DK-GLAXOSMITHKLINE-DK2018150118",
"fulfillexpeditecriteria": "1",
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"patient": {
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"activesubstancename": "ACYCLOVIR"
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... |
{
"abstract": "A schizophrenic patient showed rhabdomyolysis with idiopathic transaminitis. The intermixed pattern of intrahepatic and extrahepatic alanine aminotransferase (ALT) elevation is associated with respective clinical-therapeutic events. Aminotransferases play a role as surrogate biomarkers of \"liver metabolic functioning\" beyond the obsolete classical concept associating ALT elevation only with liver cellular damage.",
"affiliations": "Department of Psychiatry Minamihama Hospital Niigata Japan.;Department of Psychiatry Minamihama Hospital Niigata Japan.",
"authors": "Suzuki|Yoshifumi|Y|;Kawashima|Yoshiaki|Y|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.546",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.546CCR3546Case ReportCase ReportsIntrahepatic and extrahepatic aminotransferase elevation associated with clinical‐therapeutic events in a schizophrenic patient Y. Suzuki & Y. KawashimaSuzuki Yoshifumi \n1\nKawashima Yoshiaki \n1\n1 Department of PsychiatryMinamihama HospitalNiigataJapan* Correspondence\n\nYoshifumi Suzuki, Department of Psychiatry, Minamihama Hospital, Niigata, Japan. Tel: +81‐025‐255‐2121; Fax: +81‐025‐255‐3582;\n\nE‐mail: yosuzu@circus.ocn.ne.jp\n29 3 2016 5 2016 4 5 10.1111/ccr3.2016.4.issue-5469 472 18 8 2015 26 11 2015 03 3 2016 © 2016 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Key Clinical Message\nA schizophrenic patient showed rhabdomyolysis with idiopathic transaminitis. The intermixed pattern of intrahepatic and extrahepatic alanine aminotransferase (ALT) elevation is associated with respective clinical‐therapeutic events. Aminotransferases play a role as surrogate biomarkers of “liver metabolic functioning” beyond the obsolete classical concept associating ALT elevation only with liver cellular damage.\n\nAlanine aminotransferaseaspartate aminotransferaserhabdomyolysisschizophrenia source-schema-version-number2.0component-idccr3546cover-dateMay 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.8.8 mode:remove_FC converted:04.05.2016\n\nClinical Case Reports \n2016 ; 4 (5 ): 469 –472\n==== Body\nIntroduction\nRhabdomyolysis, a syndrome of skeletal muscle cell damage, engenders the release of toxic intracellular materials into systemic circulation 1. The pathogenesis of rhabdomyolysis is based on an increase in free ionized calcium in the cytoplasm 1. Prompt diagnosis requires routine monitoring of serum creatine kinase (CK) activity in a patient with a suggestive history or clinical features 1.\n\nSerum concentrations of alanine (ALT) and aspartate (AST) aminotransferases have been regarded as markers of liver injury 2. Measurement of ALT and AST enzymatic activity is still most commonly done to evaluate putative liver injury 2. Blood concentrations of ALT and AST reflect liver cell membrane damage, with subsequent leakage of intracellular enzymes into circulation, especially the cytosolic ones 2. Transaminases are reliable predictors of individual components including type 2 diabetes and decreased hepatic insulin sensitivity, coronary heart disease, atherothrombotic risk profile, and overall risk of cardiovascular and metabolic disease 2. Therefore, routine testing of aminotransferases ALT and AST is now regarded as an indicator of “liver metabolic function” 2.\n\nCase History and Examination\nA 40‐year‐old man diagnosed with schizophrenia at the age of 17 had functioned stably in his community for more than two decades. A psychiatric clinic had prescribed haloperidol 3 mg and biperiden 1 mg for him. He had no known diagnosis of chronic liver disease. He denied using any non‐prescription or herbal supplement. His family history was negative for liver disease and genetic myopathy. We rejected the possibility of polydipsia by history using information from his mother. Three days before admission, his condition worsened suddenly. He was admitted to our hospital because of auditory hallucinations, delusions, and chaotic and aggressive behavior. For 2 weeks, he had not taken medicines but had worked intensely. Then, aggravation of psychotic symptoms occurred. When admitted, he presented abnormal behavior, agitation, self‐talking, self‐laughing, and aggression in the quiet room. He refused meals and beverages. At 165.8 cm height, his weight was 58.5 kg, implying his body mass index (BMI) as 21.3 kg/m2. Physical examination revealed 147/105 mmHg blood pressure, 113 beats/min heart rate, and 36.3 °C body temperature. Skin and mucous were not dry. He had no evidence of rigidity or muscle tenderness, or of hepatomegaly. Other system examination results were unremarkable. Baseline tests such as those of serum electrolytes, urine examination, thyroid hormones, chest X‐ray, brain CT, and electrocardiography all yielded normal results. Results of the main initial laboratory evaluations are presented in the Table 1: serum CK, 6622 IU/L; serum AST, 208 IU/L; ALT, 68 IU/L; and serum myoglobin, 1644 ng/mL. On the 2nd day, he was diagnosed with rhabdomyolysis. Intravenous infusion containing 35 mmol/L sodium chloride with 20 mmol/L potassium chloride (Solita T3) was started at a rate of 100 mL/h, accompanied by restriction of oral fluids under physical restraint. Antipsychotics were indicated as causing neuroleptic malignant syndrome 3. Therefore, we were unable to prescribe it to the patient because of elevated concentration of serum creatine kinase. Continued intravenous infusion caused positive balances and urine production. The individual value curve for CK, AST, ALT, alkaline phosphatase (ALP), and γ‐glutamyl transferase (GGT) during hospitalization is shown in the Fig. 1. Actually, CK fell rapidly on the 4th day, although AST and ALT started to increase rapidly and mutually in parallel. The respective values of CK, AST, ALT, ALP, and GGT on the 8th day were 715, 388, 582, 212, and 43 IU/L. The AST/ALT ratio was 0.67. He had no symptoms or other stigmata of liver disease. Blood liver function tests were normal: total bilirubin, 1.02 mg/dL; cholinesterase, 221 IU/L; hepaplastin test, 73%; and international normalized ratio (INR) of 1.36. Viral serology tests for hepatitis B and C were negative (Table 1). On the 15th day, AST and ALT decreased rapidly. On the 15th day, risperidone therapy, at a dose of 4 mg/day, was started to treat his hallucinations and his chaotic and aggressive behavior. On the 19th day, his mental state was stabilized. His behavior improved. Therefore, intravenous infusion was discontinued. Meals were started. On the 22nd day, CK was normal, but ALP, ALT, AST, and GGT were elevated as shown in the Fig. 1. Subsequently, we changed to slow‐release paliperidone 6 mg/day to treat his hallucinations and because of difficulty swallowing risperidone. From the 28th day, because his liver damage was suspected to have occurred as an adverse effect of risperidone therapy, blonanserin 8 mg/day was used instead. His liver function data subsequently returned to a normal range by the 43rd day. He was discharged in a stable condition with normal serum aminotransferases on the 67th day. His psychiatric condition and his health condition have remained stable.\n\nTable 1 Selected laboratory parameters\n\n\tNormal range\t1st day\t8th day\t22nd day\t43rd day\t62nd day\t\nCreatine kinase (CK)\t43–272 IU/L\t6622\t715\t87\t46\t38\t\nAspartate aminotransferase (AST)\t8–40 IU/L\t208\t388\t106\t13\t18\t\nAlanine aminotransferase (ALT)\t5–35 IU/L\t68\t582\t189\t29\t26\t\nLactate dehydrogenase (LDH)\t102–204 IU/L\t562\t513\t295\t147\t141\t\nAlkaline phosphatase (ALP)\t100–324 IU/L\t209\t212\t433\t286\t274\t\n\nγ‐glutamyl transferase (GGT)\t16–86 IU/L\t27\t43\t150\t63\t64\t\nCholinesterase (ChE)\t237–495 IU/L\t–a\n\t221\t–\t–\t–\t\nInternational normalized ratio (INR)\t1.0–1.4\t–\t1.36\t–\t–\t–\t\nAmmonia (NH3)\t12–66 μg/dL\t–\t54\t–\t–\t–\t\nHepaplastin test (HPT)\t70–130%\t–\t73\t–\t–\t–\t\nMyoglobin\t0–60 ng/mL\t1644\t168\t–\t–\t–\t\nTotal bilirubin\t0.2–1.2 mg/dL\t–\t1.02\t–\t–\t–\t\nDirect bilirubin\t0–0.4 mg/dL\t–\t0.51\t–\t–\t–\t\nUrea nitrogen\t8–20 mg/dL\t18.5\t12.9\t7.3\t10.2\t11.7\t\nCreatinine\t0.6–1.1 mg/dL\t1.09\t0.85\t0.67\t0.73\t0.85\t\nSodium\t135–148 mmol/L\t144\t135\t141\t140\t139\t\nPotassium\t3.5–5 mmol/L\t3.6\t4.4\t3.9\t4.1\t4.2\t\nHepatitis B antigen\tNegative\tNegative\t–\t–\t–\t–\t\nHepatitis C antibody\tNegative\tNegative\t–\t–\t–\t–\t\nC‐reactive protein\t0–0.3 mg/dL\t0.58\t0.96\t0.59\t–\t–\t\nRed blood cell count\t400–540 × 104/μL\t454\t452\t419\t382\t429\t\nHemoglobin\t13–17 g/dL\t13.8\t13.9\t12.8\t11.8\t13.2\t\nHematocrit\t35–45%\t40.6\t39.6\t37.0\t34.5\t38.5\t\nWhite blood cell count\t3500–9100/μL\t8870\t5590\t7970\t4030\t4550\t\na Not determined.\n\nJohn Wiley & Sons, LtdFigure 1 Time course changes of serum enzymes in the patient: green line, creatine kinase (CK); blue line, aspartate transaminase (AST); red line, alanine aminotransferase (ALT); yellow line, γ‐glutamyl transferase (GGT); and black line, alkaline phosphatase (ALP).\n\nDiscussion\nResults underscore two important clinical issues. The schizophrenic patient showed sudden onset of rhabdomyolysis. The intermixed pattern of intrahepatic and extrahepatic causes of ALT elevation is associated with respective clinical‐therapeutic events.\n\nFirst, the patient suddenly developed rhabdomyolysis. Psychiatric patients with rhabdomyolysis often are asymptomatic 1. The patient presented with rhabdomyolysis that was biochemically proven by an elevated CK (6622 IU/L) and AST (208 IU/L)/ALT (68 IU/L) ratio >3, which, taken together with a normal ALP and GGT indicate an extrahepatic source of transaminitis. The most common causes of rhabdomyolysis are illicit drugs, medical drugs, muscular diseases, trauma, neuroleptic malignant syndrome, seizure, and immobility 4. His past medical, medication, and family histories, respectively, rule out potential drug abuse, behavioral peculiarities such as psychogenic polydipsia and polyphagia, and genetic myopathy. Systemic bacterial infection is unlikely in the absence of inflammation of the blood chemistry tests. Unfortunately, we failed to ascertain what occurred with this patient immediately before admission. Because excessive physical activity is a major cause of rhabdomyolysis in psychiatric patients 1, somewhat elevated CK concentration might result from his excessive physical activity and concurrent interruption of routine medication.\n\nSecond, the intermixed pattern of intrahepatic and extrahepatic causes of ALT elevation is associated with respective clinical‐therapeutic events. Given shorter half‐lives of CK and AST and the resuscitative measures undertaken for treating rhabdomyolysis 2, 4, 5, 6, 7, serum concentrations of CK and AST improved more rapidly than ALT during the first few days, as shown in the Table 1 and Fig. 1. Antipsychotic therapy started immediately after admission can be expected to cause liver dysfunction, which might explain the hepatotoxic pattern of overlapped elevation of ALT more than AST on days 4–8 of hospitalization that might be completely unrelated to rhabdomyolysis. This hypothesis is supported by a concomitant elevation of ALP and GGT (liver function biomarkers) and a continuous decrease in CK (rhabdomyolysis marker), as shown in the Fig. 1 and Table 1. Consequently, this allegedly unusual and mysterious elevation of transaminases that is believed to result from psychotic rhabdomyolysis might reflect intermixed patterns of intrahepatic and extrahepatic causes of ALT elevation associated with respective clinical‐therapeutic events.\n\nTwo isoforms of ALT are ALT1 and ALT2. Actually, ALT1 and ALT2 appear to have not only different tissue sources but also cellular localization, suggesting dissimilar biological roles in the pathogenesis of acute or chronic liver disease 2. ALT1 is encoded by a gene of GPT1 located in chromosome 8 (8p24.3), but ALT2 is encoded by a different gene of GPT2 located in chromosome 16 (16q12.1) 2. ALT1, which is expressed primarily in liver 8, and ALT2, which is expressed primarily in muscular tissue 9, cannot be discriminated using current biochemical tests measuring serum ALT 2. Recently, most activity in circulation is found to be attributed to ALT1 10. Furthermore, elevation of ALT concentrations does not necessarily indicate hepatocellular damage 11. If two isoforms of ALT were applicable in clinical practice, then it might stimulate further insight into how these conflicting observations of seemingly unrelated clinical and biochemical events are explainable and reconciled.\n\nIn conclusion, facts associated with this case support the emerging evidence that aminotransferases are surrogate biomarkers of “liver metabolic function” beyond the classical concept of liver cellular damage because their enzymatic activity might actually reflect key aspects of the physiology and pathophysiology of the liver function 2.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report.\n\nConflict of Interest\nNone declared.\n\nAcknowledgment\nWe acknowledge Dr. H. Matsukura for critical reading of the manuscript.\n==== Refs\nReferences\n1 \n\nSuzuki , Y. \n, \nF. \nShibuya \n, \nK. \nToyooka \n, \nY. \nKawashima \n, \nY. \nSuzuki \n, and \nM. \nGotoh \n. 2015 \nClinical spectrum of psychiatric patients with rhabdomyolysis . J. Psychiatr. Intensive Care \n11 :36 –42 .\n2 \n\nSookoian , S. \n, and \nC. J. \nPirola \n. 2015 \nLiver enzymes, metabolomics and genome‐wide association studies: from systems biology to the personalized medicine . World J. Gastroenterol. \n21 :711 –725 .25624707 \n3 \n\nSeitz , D. P. \n, and \nS. S. \nGill \n. 2009 \nNeuroleptic malignant syndrome complicating antipsychotic treatment of delirium or agitation in medical and surgical patients: case reports and a review of the literature . Psychosomatics \n50 :8 –15 .19213967 \n4 \n\nMelli , G. \n, \nV. \nChaudhry \n, and \nD. R. \nCornblath \n. 2005 \nRhabdomyolysis: an evaluation of 475 hospitalized patients . Medicine \n84 :377 –385 .16267412 \n5 \n\nWeibrecht , K. \n, \nM. \nDayno \n, \nC. \nDarling \n, and \nS. B. \nBird \n. 2010 \nLiver aminotransferases are elevated with rhabdomyolysis in the absence of significant liver injury . J. Med. Toxicol. \n6 :294 –300 .20407858 \n6 \n\nPettersson , J. \n, \nU. \nHindorf \n, \nP. \nPersson \n, \nT. \nBengtsson \n, \nU. \nMalmgvist \n, \nV. \nWerkstrm \n, et al. 2008 \nMuscular exercise can cause highly pathological liver function tests in healthy men . Br. J. Clin. Pharmacol. \n65 :253 –259 .17764474 \n7 \n\nDajani , L. K. \n, \nE. \nPaus \n, and \nD. J. \nWarren \n. 2001 \nDevelopment of a rapid and sensitive immunofluorometric assay for glutathione S‐transferase A . Clin. Chem. \n47 :867 –873 .11325890 \n8 \n\nYang , R. Z. \n, \nG. \nBlaileanu \n, \nB. C. \nHansen \n, \nA. R. \nShuldiner \n, and \nD. W. \nGong \n. 2002 \ncDNA cloning, genomic structure, chromosomal mapping, and functional expression of a novel human alanine aminotransferase . Genomics \n79 :445 –450 .11863375 \n9 \n\nUhlen , M. \n, \nP. \nOksvold \n, \nL. \nFagerberg \n, \nE. \nLundberg \n, \nK. \nJonasson \n, \nM. \nForsberg \n, et al. 2010 \nTowards a knowledge‐based human protein atlas . Nat. Biotechnol. \n28 :1248 –1250 .21139605 \n10 \n\nRafter , I. \n, \nT. \nGråberg \n, \nA. \nKotronen \n, \nL. \nStrömmer \n, \nC. M. \nMattson \n, \nR. W. \nKim \n, et al. 2012 \nIsoform‐specific alanine aminotransferase measurement can distinguish hepatic from extrahepatic injury in humans . Int. J. Mol. Med. \n30 :1241 –1249 .22922605 \n11 \n\nKechagias , S. \n, \nA. \nErnersson \n, \nO. \nDahlqvist \n, \nP. \nLundberg \n, \nT. \nLindström \n, and \nF. H. \nNystrom \n. 2008 \nFast‐food‐based hyper‐alimentation can induce rapid and profound elevation of serum alanine aminotransferase in health subjects . Gut \n57 :649 –654 .18276725\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2050-0904",
"issue": "4(5)",
"journal": "Clinical case reports",
"keywords": "Alanine aminotransferase; aspartate aminotransferase; rhabdomyolysis; schizophrenia",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "469-72",
"pmc": null,
"pmid": "27190609",
"pubdate": "2016-05",
"publication_types": "D002363:Case Reports",
"references": "27190609;20407858;21139605;16267412;11325890;17764474;11863375;25624707;18276725;19213967;22922605",
"title": "Intrahepatic and extrahepatic aminotransferase elevation associated with clinical-therapeutic events in a schizophrenic patient.",
"title_normalized": "intrahepatic and extrahepatic aminotransferase elevation associated with clinical therapeutic events in a schizophrenic patient"
} | [
{
"companynumb": "JP-JNJFOC-20160607908",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "DRESS (drug reaction with eosinophilia and systemic symptoms) is a rare but potentially life-threatening disorder characterized by fever, skin eruption, haematological abnormalities and multi-organ dysfunction after drug exposure. The pathophysiology is thought to be related to interactions between culprit drugs, viral reactivation and T-lymphocytes activation. We report 4 paediatric patients with DRESS who were treated at our centre over the past 12 years. Most cases improved after corticosteroids. Other immunosuppressive medications were attempted in refractory cases with varied outcomes. Patient 3 was the first reported case that involved the use of infliximab, a TNF-α inhibitor, for DRESS. Although clinical efficacy was not observed for this one patient, a previous study demonstrated that patients with DRESS, disease progression and HHV-6 reactivation had elevated pre-treatment TNF- α and IL-6 levels. Further research is needed to explore the role of these cytokines in DRESS.",
"affiliations": "Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, Hong Kong.;Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, Hong Kong.;Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, Hong Kong.;Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, Hong Kong.;Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, Hong Kong.;Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, Hong Kong.",
"authors": "Chua|G T|GT|;Rosa Duque|J S|JS|;Chong|P C Y|PCY|;Lee|P P W|PPW|;Lau|Y L|YL|;Ho|M H K|MHK|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D003879:Dermatologic Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab",
"country": "Italy",
"delete": false,
"doi": "10.23822/EurAnnACI.1764-1489.47",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1764-1489",
"issue": "50(6)",
"journal": "European annals of allergy and clinical immunology",
"keywords": "Chinese; DRESS; Hong Kong; drug reaction with eosinophilia and systemic symptoms; drug-induced hypersensitivity syndrome; paediatric",
"medline_ta": "Eur Ann Allergy Clin Immunol",
"mesh_terms": "D000293:Adolescent; D000305:Adrenal Cortex Hormones; D002675:Child, Preschool; D003879:Dermatologic Agents; D063926:Drug Hypersensitivity Syndrome; D004802:Eosinophilia; D005260:Female; D006723:Hong Kong; D006801:Humans; D000069285:Infliximab; D008297:Male; D012882:Skin Tests; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "101466614",
"other_id": null,
"pages": "273-276",
"pmc": null,
"pmid": "29384118",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Paediatric case series of drug reaction with eosinophilia and systemic symptoms (DRESS): 12-year experience at a single referral centre in Hong Kong and the first reported use of infliximab.",
"title_normalized": "paediatric case series of drug reaction with eosinophilia and systemic symptoms dress 12 year experience at a single referral centre in hong kong and the first reported use of infliximab"
} | [
{
"companynumb": "HK-BAUSCH-BL-2018-032760",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
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