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"abstract": "A previously healthy 62-year-old woman was transferred to the ICU from the medical ward with acute bronchospastic respiratory failure requiring intubation and mechanical ventilation. Four weeks before, the patient was vacationing in Arizona and acquired a mildly productive cough as well as mild dyspnea. She presented to an urgent care facility and was diagnosed with community-acquired pneumonia. She received a 5-day course of azithromycin, with partial improvement of her symptoms. The patient returned home 1 week prior to admission, reporting worsening dyspnea, chest pressure, cough, and fever. The patient was admitted to the medical ward, and treatment for unresolved pneumonia was begun with levofloxacin, an inhaled short-acting beta agonist, and oral prednisone. Despite this treatment, the patient experienced severe respiratory distress with audible wheezing as well as increased work of breathing. She was intubated for acute hypoxemic respiratory failure and transferred to the ICU.",
"affiliations": "Department of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL. Electronic address: peter.hountras@northwestern.edu.;Department of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.",
"authors": "Hountras|Peter|P|;Cajigas|Hector|H|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.chest.2017.04.168",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-3692",
"issue": "152(3)",
"journal": "Chest",
"keywords": null,
"medline_ta": "Chest",
"mesh_terms": "D003047:Coccidioidomycosis; D003422:Critical Care; D005260:Female; D006801:Humans; D008172:Lung Diseases, Fungal; D008875:Middle Aged; D012121:Respiration, Artificial; D012131:Respiratory Insufficiency; D012135:Respiratory Sounds; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0231335",
"other_id": null,
"pages": "e73-e76",
"pmc": null,
"pmid": "28889900",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A 62-Year-Old Woman With Wheezing, Respiratory Failure, and an Abnormal CT Scan.",
"title_normalized": "a 62 year old woman with wheezing respiratory failure and an abnormal ct scan"
} | [
{
"companynumb": "US-CIPLA LTD.-2017US17384",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"drugadditional": "3",
... |
{
"abstract": "Neuregulin 1 (NRG1) fusions, which activate ErbB signaling, are rare oncogenic drivers in multiple tumor types. Afatinib is a pan-ErbB family inhibitor that may be an effective treatment for NRG1 fusion-driven tumors.\n\n\n\nThis report summarizes pertinent details, including best tumor response to treatment, for six patients with metastatic NRG1 fusion-positive tumors treated with afatinib.\n\n\n\nThe six cases include four female and two male patients who ranged in age from 34 to 69 years. Five of the cases are patients with lung cancer, including two patients with invasive mucinous adenocarcinoma and three patients with nonmucinous adenocarcinoma. The sixth case is a patient with colorectal cancer. NRG1 fusion partners for the patients with lung cancer were either CD74 or SDC4. The patient with colorectal cancer harbored a novel POMK-NRG1 fusion and a KRAS mutation. Two patients received afatinib as first- or second-line therapy, three patients received the drug as third- to fifth-line therapy, and one patient received afatinib as fifteenth-line therapy. Best response with afatinib was stable disease in two patients (duration up to 16 months when combined with local therapies) and partial response (PR) of >18 months in three patients, including one with ongoing PR after 27 months. The remaining patient had a PR of 5 months with afatinib 40 mg/day, then another 6 months after an increase to 50 mg/day.\n\n\n\nThis report reviews previously published metastatic NRG1 fusion-positive tumors treated with afatinib and summarizes six previously unpublished cases. The latter include several with a prolonged response to treatment (>18 months), as well as the first report of efficacy in NRG1 fusion-positive colorectal cancer. This adds to the growing body of evidence suggesting that afatinib can be effective in patients with NRG1 fusion-positive tumors.\n\n\n\nNRG1 fusions activate ErbB signaling and have been identified as oncogenic drivers in multiple solid tumor types. Afatinib is a pan-ErbB family inhibitor authorized for the treatment of advanced non-small cell lung cancer that may be effective in NRG1 fusion-driven tumors. This report summarizes six previously unpublished cases of NRG1 fusion-driven cancers treated with afatinib, including five with metastatic lung cancer and one with metastatic colorectal cancer. Several patients showed a prolonged response of >18 months with afatinib treatment. This case series adds to the evidence suggesting a potential role for afatinib in this area of unmet medical need.",
"affiliations": "Assistance Publique Hôpitaux de Paris, Hôpital Tenon and Groupes de recherche clinique Theranoscan and Curamus Sorbonne Université, Paris, France.;Georgetown University Medical Center, Washington, District of Columbia, USA.;Respiratory Department, Louis Pradel Hospital, Hospices Civils de Lyon Cancer Institute, Lyon, France.;Gävle Hospital, Gävle, Sweden.;National Cancer Center Hospital, Tokyo, Japan.;Georgetown University Medical Center, Washington, District of Columbia, USA.;Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), Dresden, Germany.;National Center of Tumor Diseases Heidelberg, Heidelberg University Hospital and German Cancer Research Center, Heidelberg, Germany.;William Osler Health System, University of Toronto, Toronto, Ontario, Canada.;QIAGEN Digital Insights, QIAGEN Inc., Redwood City, California, USA.;Memorial Sloan Kettering Cancer Center, New York, New York, USA.;Fondazione IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Foggia, Italy.;Fondazione IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Foggia, Italy.;Oregon Health and Science University, Portland, Oregon, USA.;Assistance Publique Hôpitaux de Paris, Hôpital Bichat - Claude-Bernard and Université Paris Descartes, Paris, France.;Boehringer Ingelheim International GmbH, Ingelheim, Germany.;Boehringer Ingelheim Regional Center Vienna GmbH & Co KG, Vienna, Austria.;University of British Columbia, BC Cancer, Vancouver, British Columbia, Canada.;University of British Columbia, BC Cancer, Vancouver, British Columbia, Canada.",
"authors": "Cadranel|Jacques|J|;Liu|Stephen V|SV|0000-0002-4852-3914;Duruisseaux|Michaël|M|;Branden|Eva|E|;Goto|Yasushi|Y|;Weinberg|Benjamin A|BA|;Heining|Christoph|C|;Schlenk|Richard F|RF|;Cheema|Parneet|P|;Jones|Martin R|MR|;Drilon|Alexander|A|;Trombetta|Domenico|D|;Muscarella|Lucia Anna|LA|;Tolba|Khaled|K|;Gounant|Valerie|V|;Cseh|Agnieszka|A|;Solca|Flavio|F|;Laskin|Janessa J|JJ|;Renouf|Daniel J|DJ|",
"chemical_list": "C094131:NRG1 protein, human; D020890:Neuregulin-1; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D000077716:Afatinib",
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2020-0379",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "26(1)",
"journal": "The oncologist",
"keywords": "Afatinib; Case series; ErbB-targeted treatment; Gene fusion; NRG1",
"medline_ta": "Oncologist",
"mesh_terms": "D000328:Adult; D000077716:Afatinib; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020890:Neuregulin-1; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "7-16",
"pmc": null,
"pmid": "32852072",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "24469108;30988082;25501131;29466156;29169524;29610121;29802158;29636358;26200269;30568455;24727320;28950338;29515761;28502724;31068372;27626312;23813493;29763625;22888144;28939148;28857077",
"title": "Therapeutic Potential of Afatinib in NRG1 Fusion-Driven Solid Tumors: A Case Series.",
"title_normalized": "therapeutic potential of afatinib in nrg1 fusion driven solid tumors a case series"
} | [
{
"companynumb": "FR-MYLANLABS-2021M1049962",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEMETREXED"
},
"drugadditional": "3",
... |
{
"abstract": "A 36-year-old Thai female who underwent a thymectomy under general anesthesia developed acute abnormal movements in the craniofacial region immediately after awakening with preserved consciousness.\n\n\n\nIntermittent abnormal movements included oculogyric crisis; tongue protrusion; blepharospasm; and oro-mandibular dystonia consisting of risus sardonicus, jaw opening, and right torticollis.\n\n\n\nAn acute dystonic reaction can be a complication of either single or combined general anesthetic agents.",
"affiliations": "Division of Neurology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.;Division of Neurology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.",
"authors": "Jitprapaikulsan|Jiraporn|J|;Srivanitchapoom|Prachaya|P|",
"chemical_list": "D018681:Anesthetics, General; D008738:Methyl Ethers; D000077149:Sevoflurane; D009609:Nitrous Oxide; D005283:Fentanyl",
"country": "England",
"delete": false,
"doi": "10.7916/D8862V0P",
"fulltext": "\n==== Front\nTremor Other Hyperkinet Mov (N Y)Tremor Other Hyperkinet Mov (N Y)TOHMTremor and Other Hyperkinetic Movements2160-8288Columbia University Libraries/Information Services 10.7916/D8862V0PVideo AbstractsAcute Dystonic Reaction Following General Anesthetic Agent Use General Anesthesia-induced Dystonic ReactionJitprapaikulsan Jiraporn 1Srivanitchapoom Prachaya 1*1 Division of Neurology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, ThailandLouis Elan D. Yale University, USA*To whom correspondence should be addressed. E-mail: cloundbuffy@gmail.com2017 14 11 2017 7 51427 9 2017 24 10 2017 © 2017 Jitprapaikulsan et al.2017Jitprapaikulsan et al.This is an open-access article distributed under the terms of the Creative Commons Attribution–Noncommerical–No Derivatives License, which permits the user to copy, distribute, and transmit the work provided that the original author and source are credited; that no commercial use is made of the work; and that the work is not altered or transformed.Background\nA 36-year-old Thai female who underwent a thymectomy under general anesthesia developed acute abnormal movements in the craniofacial region immediately after awakening with preserved consciousness.\n\nPhenomenology\nIntermittent abnormal movements included oculogyric crisis; tongue protrusion; blepharospasm; and oro-mandibular dystonia consisting of risus sardonicus, jaw opening, and right torticollis.\n\nEducational value\nAn acute dystonic reaction can be a complication of either single or combined general anesthetic agents.\n\nAcute dystonic reactiongeneral anesthesiaoculogyric crisis\n==== Body\nCase summary\nA 36-year-old Thai female was recently diagnosed with generalized myasthenia gravis associated with thymoma. Her acetylcholine receptor antibody level was 16.78 nmol/L (normal: <0.45 nmol/L). The patient was treated with oral pyridostigmine and prednisolone and was scheduled for an elective thymectomy. Unfortunately, the patient experienced a myasthenic crisis 3 days before admission for surgery. Physical examination in the emergency department revealed respiratory distress, swallowing difficulty, bilateral ptosis, limited extraocular movement in all directions of the right eye, bilateral facial weakness, and generalized proximal muscle and neck muscle weakness (Medical Research Council [MRC] grade III). The patient was intubated, and intravenous immunoglobulin (IVIg) was administrated. One week after receiving IVIg, the patient could be extubated, and her motor power markedly improved (MRC grade V). The patient subsequently underwent thymectomy under general anesthesia including nitrous oxide, sevoflurane, fentanyl, and thiopental. The operation was uneventful. However, 1 hour after awakening with preserved consciousness, she developed intermittent abnormal movements consisting of oculogyric crisis; tongue protrusion; blepharospasm; and oro-mandibular dystonia comprising risus sardonicus, jaw opening, and right torticollis (Video 1, Segment 1). All abnormal movements occurred spontaneously and involuntarily. No abnormal extremity movements were detected. Physical examination showed that her vital signs and cardiovascular system were normal. Complete blood count and blood chemistry including electrolytes, blood sugar, and thyroid function and kidney function tests were unremarkable. She was diagnosed with an acute dystonic reaction (ADR) due to general anesthetic agents either single or combined (nitrous oxide, sevoflurane, and fentanyl). Because intravenous anticholinergics were unavailable in our hospital, she was given an intravenous benzodiazepine. She was successfully treated with a single 10-mg dose of intravenous diazepam (Video 1, Segment 2). ADR did not recur during her hospital course or at the 1- or 6-month follow-ups.\n\nVideo 1 Segment 1. Phenomenology of the Patient. Immediately after awakening with preserved consciousness, the patient developed intermittent abnormal movements consisting of oculogyric crisis; tongue protrusion; blepharospasm; and oro-mandibular dystonia including risus sardonicus, jaw opening, and right torticollis. All abnormal movements occurred spontaneously and involuntarily. Segment 2: Outcome After Treatment. The symptoms were successfully treated with a single 10-mg dose of intravenous diazepam.\nDiscussion\nWe report an apparent case of ADR in the patient who was exposed to multiple general anesthesia agents. General anesthesia-induced ADR is relatively rare compared to complications following the use of dopamine-blocking agents such as typical and atypical antipsychotics or antiemetics. Propofol has been well described as an ADR-causing anesthetic agent in many reports. However, there are few reports of ADR associated with nitrous oxide,1 sevoflurane,1 and fentanyl,2 which were the agents administered to our patient. The possible mechanism of ADR due to these anesthetic agents may be explained by an imbalance between dopaminergic and cholinergic neurotransmission in the basal ganglia circuit.3 Treatment options are anticholinergics such as diphenhydramine, benztropine, and procyclidine, and benzodiazepines such as diazepam and midazolam. One report proposed that naloxone might be useful for minimizing dystonic symptoms in opioid-induced ADR.2\n\nFunding: None.\n\nFinancial Disclosures: None.\n\nConflicts of interest: The authors report no conflict of interest.\n\nEthics Statement: All patients that appear on video have provided written informed consent; authorization for the videotaping and for publication of the videotape was provided.\n==== Refs\nReferences\n1 Kawana S Toyoshima Y Tobise F Takahashi T Dystonic reaction following general anesthesia in a 2-month-old infant Paediatr Anaesth 2007 17 901 902 doi: http://doi.org/10.1111/j.1460-9592.2007.02250.x \n2 Iselin-Chaves IA Grotzsch H Besson M Burkhard PR Savoldelli GL Naloxone-responsive acute dystonia and parkinsonism following general anaesthesia Anaesthesia 2009 64 1359 1362 doi: http://doi.org/10.1111/j.1365-2044.2009.06068.x 19839983 \n3 Schramm BM Orser BA Dystonic reaction to propofol attenuated by benztropine Anesth Analg 2002 94 1237 1240 doi: http://doi.org/10.1097/00000539-200205000-00034 11973196\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2160-8288",
"issue": "7()",
"journal": "Tremor and other hyperkinetic movements (New York, N.Y.)",
"keywords": "Acute dystonic reaction; general anesthesia; oculogyric crisis",
"medline_ta": "Tremor Other Hyperkinet Mov (N Y)",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000768:Anesthesia, General; D018681:Anesthetics, General; D004421:Dystonia; D005260:Female; D005283:Fentanyl; D006801:Humans; D008738:Methyl Ethers; D009609:Nitrous Oxide; D000077149:Sevoflurane; D013934:Thymectomy",
"nlm_unique_id": "101569493",
"other_id": null,
"pages": "514",
"pmc": null,
"pmid": "29204316",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "11973196;17683413;19839983",
"title": "Acute Dystonic Reaction Following General Anesthetic Agent Use.",
"title_normalized": "acute dystonic reaction following general anesthetic agent use"
} | [
{
"companynumb": "TH-LINDE-TH-LHC-2018228",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NITROUS OXIDE"
},
"drugadditional": "3",
... |
{
"abstract": "The use of synthetic cannabinoids (SC) has been widespread in certain groups of drug users for many years. In the scientific literature many intoxication cases and a number of fatalities after the use of synthetic cannabinoids were reported. In this paper three death cases are described with involvement of the synthetic cannabinoids 5F-PB-22, AB-CHMINACA, and 5F-ADB. The three cases occurred in the eastern region of Germany, which is known as a region of high methamphetamine abuse. All decedents were male, between 25 and 41 years old, and had a known history of drug use. Femoral blood concentrations of the synthetic cannabinoids were measured using a validated LC-MS/MS method. The concentration of 5F-PB-22 in the first case was 0.37ng/mL, the concentration of AB-CHMINACA in the second case was approximately 4.1ng/mL (extrapolated) and the 5F-ADB concentration in the third case was 0.38ng/mL. Compared to other published cases the concentrations in the here presented cases seem to be in the lower range. However, taking into account the scene of death, the results of the forensic autopsy and the full toxicological analysis, the deaths can be explained as a direct consequence of consumption of synthetic cannabinoids, although in case one and two relevant amounts of ethanol were found, and in case three trimipramine and olanzapine were present in non-toxic concentrations. It has to be noted that concentrations of synthetic cannabinoids in femoral blood cannot directly be judged as toxic or lethal due to the possibility of postmortem redistribution and the development of tolerance after frequent use. Therefore, all available information has to be considered carefully before stating SC use as the cause of death.",
"affiliations": "Institute of Forensic Medicine, Forensic Toxicology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Albertstr. 9, D-79104 Freiburg, Germany; Hermann Staudinger Graduate School, University of Freiburg, Hebelstraße 27, 79104 Freiburg, Germany.;Institute of Legal Medicine, Technical University, Dresden, Fetscherstr. 74, D-01307 Dresden, Germany.;Institute of Forensic Medicine, Forensic Toxicology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Albertstr. 9, D-79104 Freiburg, Germany; Hermann Staudinger Graduate School, University of Freiburg, Hebelstraße 27, 79104 Freiburg, Germany.;Institute of Forensic Medicine, Forensic Toxicology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Albertstr. 9, D-79104 Freiburg, Germany. Electronic address: volker.auwaerter@uniklinik-freiburg.de.;Institute of Legal Medicine, Technical University, Dresden, Fetscherstr. 74, D-01307 Dresden, Germany.",
"authors": "Angerer|V|V|;Jacobi|S|S|;Franz|F|F|;Auwärter|V|V|;Pietsch|J|J|",
"chemical_list": "D000067401:Blood Alcohol Content; D002186:Cannabinoids; D015198:Designer Drugs; D007191:Indazoles; D007211:Indoles; D011804:Quinolines; D014633:Valine; C000620621:1-pentyfluoro-1H-indole-3-carboxylic acid 8-quinolinyl ester; C000606289:N-(1-(aminocarbonyl)-2-methylpropyl)-1-(cyclohexylmethyl)-1H-indazole-3-carboxamide; C000616976:5F-ADB cannabinoid",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2017.10.042",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "281()",
"journal": "Forensic science international",
"keywords": "Femoral blood; HPLC-MS/MS; New psychoactive substances; Post mortem toxicology; Synthetic cannabinoids",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000328:Adult; D000067401:Blood Alcohol Content; D001929:Brain Edema; D002186:Cannabinoids; D002851:Chromatography, High Pressure Liquid; D015198:Designer Drugs; D006801:Humans; D007191:Indazoles; D007211:Indoles; D008297:Male; D013058:Mass Spectrometry; D011654:Pulmonary Edema; D011804:Quinolines; D015813:Substance Abuse Detection; D019966:Substance-Related Disorders; D014633:Valine",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "e9-e15",
"pmc": null,
"pmid": "29133010",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Three fatalities associated with the synthetic cannabinoids 5F-ADB, 5F-PB-22, and AB-CHMINACA.",
"title_normalized": "three fatalities associated with the synthetic cannabinoids 5f adb 5f pb 22 and ab chminaca"
} | [
{
"companynumb": "DE-JUBILANT CADISTA PHARMACEUTICALS-2017JUB00429",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TRIMIPRAMINE"
},
"drug... |
{
"abstract": "BACKGROUND\nFumaric acid esters (FAEs) are considered an effective and safe long-term treatment for psoriasis. However, 30-40% of patients need to discontinue FAE treatment due to intolerable adverse events.\n\n\nOBJECTIVE\nTo assess whether the addition of cetirizine, an oral histamine-1 receptor antagonist, to FAEs would reduce the incidence of adverse events.\n\n\nMETHODS\nIn a randomized, double-blind, placebo-controlled trial, patients with psoriasis with a Psoriasis Area and Severity Index ≥ 10 starting an FAE up to a dose of dimethylfumarate 720 mg per day were randomized 1 : 1 to receive either additional cetirizine 10 mg once daily (n = 25) or placebo (n = 25) for 12 weeks. Randomization and treatment allocation were done at our hospital trial pharmacy. Primary outcomes were the incidence of adverse events and the proportion of patients discontinuing treatment.\n\n\nRESULTS\nFifty patients (33 male, 17 female; median age 44 years) were enrolled. Addition of cetirizine did not reduce the incidence of adverse events compared with placebo (84% vs. 84%, P = 1·00). The types of adverse events were not different between the cetirizine and placebo groups, the most common being gastrointestinal complaints (68% vs. 64%) and flushes (60% vs. 48%). The proportion of patients discontinuing treatment was not statistically different between the cetirizine and placebo groups (24% vs. 32%, P = 0·53).\n\n\nCONCLUSIONS\nAddition of oral cetirizine 10 mg once daily to FAE treatment did not reduce adverse events in patients with psoriasis during the first 12 weeks of treatment. The mechanisms underlying FAE-induced gastrointestinal and flushing symptoms likely involve mediators other than histamine.",
"affiliations": "Department of Dermatology, Erasmus Medical Center, Rotterdam, The Netherlands.",
"authors": "Balak|D M W|DM|;Fallah-Arani|S|S|;Venema|C M|CM|;Neumann|H A M|HA|;Thio|H B|HB|",
"chemical_list": "D003879:Dermatologic Agents; D005650:Fumarates; D006633:Histamine Antagonists; D017332:Cetirizine",
"country": "England",
"delete": false,
"doi": "10.1111/bjd.13277",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-0963",
"issue": "172(3)",
"journal": "The British journal of dermatology",
"keywords": null,
"medline_ta": "Br J Dermatol",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D017332:Cetirizine; D003879:Dermatologic Agents; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005650:Fumarates; D006633:Histamine Antagonists; D006801:Humans; D008297:Male; D008875:Middle Aged; D011565:Psoriasis; D016896:Treatment Outcome",
"nlm_unique_id": "0004041",
"other_id": null,
"pages": "754-9",
"pmc": null,
"pmid": "25041291",
"pubdate": "2015-03",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Addition of an oral histamine antagonist to reduce adverse events associated with fumaric acid esters in the treatment of psoriasis: a randomized double-blind placebo-controlled trial.",
"title_normalized": "addition of an oral histamine antagonist to reduce adverse events associated with fumaric acid esters in the treatment of psoriasis a randomized double blind placebo controlled trial"
} | [
{
"companynumb": "NL-JNJFOC-20150320320",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CETIRIZINE HYDROCHLORIDE"
},
"drugadditional": nu... |
{
"abstract": "Brain metastasis affects one third of patients with HER2-positive breast cancer after treatment with trastuzumab. Surgical resection and radiation therapy are often unsuccessful at accomplishing complete control of metastasis. Lapatinib is presumed to cross the blood-brain barrier, and exhibits clinical activities for treatment of HER2-positive breast cancer. A 43-year-old woman was treated for early breast carcinoma with total mastectomy, axillary lymph-node dissection, and adjuvant chemotherapy with cyclophosphamide plus doxorubicin. After the end of adjuvant trastuzumab therapy, she was diagnosed with panhypopituitarism due to pituitary metastasis. Surgical removal and whole brain radiation therapy were performed, but a portion of viable tumor remained. Only taking lapatinib, the size of the metastatic lesion began to shrink. Trastuzumab may have controlled the micro-metastasis of breast cancer, but it was unable to control its progression to the central nervous system. Lapatinib is a possible option for HER2-positive metastatic breast cancer patients with brain metastasis.",
"affiliations": "Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.;Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.;Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea.;Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea ; Division of Medical Oncology, Yonsei University College of Medicine, Seoul, Korea.",
"authors": "Park|Youngmok|Y|;Kim|Hyemin|H|;Kim|Eui-Hyun|EH|;Suh|Chang-Ok|CO|;Lee|Soohyeon|S|",
"chemical_list": "D011799:Quinazolines; D000077341:Lapatinib; D004317:Doxorubicin; D003520:Cyclophosphamide; D018719:Receptor, ErbB-2; D000068878:Trastuzumab",
"country": "Korea (South)",
"delete": false,
"doi": "10.4143/crt.2014.165",
"fulltext": "\n==== Front\nCancer Res TreatCancer Res TreatCRTCancer Research and Treatment : Official Journal of Korean Cancer Association1598-29982005-9256Korean Cancer Association 10.4143/crt.2014.165crt-2014-165Case ReportEffective Treatment of Solitary Pituitary Metastasis with Panhypopituitarism in HER2-Positive Breast Cancer by Lapatinib Park Youngmok MD1Kim Hyemin MD2Kim Eui-Hyun MDPhD3Suh Chang-Ok MDPhD4Lee Soohyeon MDPhD151 Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea2 Department of Pathology, Yonsei University College of Medicine, Seoul, Korea3 Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea4 Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Korea5 Division of Medical Oncology, Yonsei University College of Medicine, Seoul, KoreaCorrespondence: Soohyeon Lee, MD, PhD Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea Tel: 82-2-2228-8127 Fax: 82-2-393-3652 E-mail: socmed0127@gmail.com1 2016 16 2 2015 48 1 403 408 28 6 2014 16 10 2014 Copyright © 2016 by the Korean Cancer Association2016This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Brain metastasis affects one third of patients with HER2-positive breast cancer after treatment with trastuzumab. Surgical resection and radiation therapy are often unsuccessful at accomplishing complete control of metastasis. Lapatinib is presumed to cross the blood-brain barrier, and exhibits clinical activities for treatment of HER2-positive breast cancer. A 43-year-old woman was treated for early breast carcinoma with total mastectomy, axillary lymph-node dissection, and adjuvant chemotherapy with cyclophosphamide plus doxorubicin. After the end of adjuvant trastuzumab therapy, she was diagnosed with panhypopituitarism due to pituitary metastasis. Surgical removal and whole brain radiation therapy were performed, but a portion of viable tumor remained. Only taking lapatinib, the size of the metastatic lesion began to shrink. Trastuzumab may have controlled the micro-metastasis of breast cancer, but it was unable to control its progression to the central nervous system. Lapatinib is a possible option for HER2-positive metastatic breast cancer patients with brain metastasis.\n\nBreast neoplasmsNeoplasm metastasisHypopituitarismHER2\n==== Body\nIntroduction\nOverexpression of human epidermal growth factor receptor 2 (HER2) results in an aggressive form of breast cancer [1]; however, the introduction of trastuzumab has significantly improved the poor prognosis of this population of patients [2]. Although trastuzumab-based regimens are associated with improved control of HER2-positive metastatic breast cancer, one third of trastuzumab-treated patients still develop brain metastasis [3,4]. Trastuzumab is a large monoclonal antibody, therefore, the drug cannot cross the blood-brain barrier [5].\n\nPituitary metastasis is an unusual event of cancer progression, representing only 1% of pituitary lesions [6]. Approximately 30% of pituitary metastasis cases are from primary breast cancer, and less than 10% are symptomatic. Most common signs of pituitary metastasis are diabetes insipidus, hypopituitarism, visual difficulty, and headache [6,7]. There are multiple treatment modalities for pituitary metastasis. Surgical resection, however, is difficult due to tumor vascularity and local invasiveness [8], and radiation therapy is associated with substantial neurocognitive toxicity.\n\nLapatinib, an oral dual tyrosine kinase inhibitor of HER2 [9], has demonstrated activity in combination with capecitabine for treatment of HER2-positive metastatic breast cancer that progresses after treatment with trastuzumab-containing regimens [10-12].\n\nHere, we report on the case of a patient with HER2-positive early breast cancer, who developed solitary pituitary metastasis after treatment with trastuzumab. After incomplete surgery and whole brain radiation therapy, the metastasis was controlled with lapatinib.\n\nCase Report\nA 43-year-old woman presented with polydipsia, general weakness, gait disturbance, somnolence, and headache in September, 2012. She was diagnosed with a stage II breast cancer in April, 2011; a pathology report based on samples taken during total mastectomy with axillary lymph-node dissection showed invasive ductal carcinoma of pT2N0M0, which was estrogen receptor positive (moderate, 10%), progesterone receptor negative, and HER2-positive (2+ by immunohistochemistry and amplification index 5.0 by fluorescence in situ hybridization). Four cycles of adjuvant chemotherapy with cyclophosphamide 600 mg/m2 plus doxorubicin 60 mg/m2 were administered, followed by one year of adjuvant trastuzumab and daily tamoxifen therapy. The patient presented with the same symptoms—polydipsia, general weakness, gait disturbance, somnolence, and headache—1 month after completing the last cycle of adjuvant trastuzumab therapy.\n\nBitemporal hemianopsia was noted after her physical examination. No organomegaly or lymphadenopathy was found. As shown in Table 1, laboratory investigations were in line with the diagnosis of panhypopituitarism. Magnetic resonance imaging (MRI) of the patient’s brain showed an enhancing mass in the sellar and suprasellar regions (Fig. 1A). She started taking hormone replacement therapy (desmopressin acetate 50 μg twice a day, prednisolone 7.5 mg a day, in divided doses every morning and afternoon, and levothyroxine 75 μg a day).\n\nBecause tumor adhesion was suspected from the brain MRI, partial removal of the tumor was performed via transcranial approach. In the surgical field, the right optic nerve was squeezed by the tumor, compressed downward by the suprasellar main mass and upward by the stalk lesion. The tumor was fibrous and adhesive to surrounding vessels and nerves, therefore complete dissection of the margin was difficult. Pathologic reports indicated metastatic carcinoma, which clinically originated from the breast: estrogen receptor positive (30%), progesterone receptor negative, HER2-positive (3+ by immunohistochemistry) (Fig. 2). Whole brain radiation therapy (30 Gy in 12 fractions) was applied (Fig. 1B), followed by weekly paclitaxel chemotherapy, but the patient was unable to finish the second cycle of paclitaxel due to toxicity (grade 3 nausea, somnolence, and loss of memory).\n\nLapatinib (1,250 mg daily) plus capecitabine (2,000 mg/m2 on days 1 through 14 of a 21-day cycle) was started from January 2013. During the third cycle, the patient visited the emergency room with severe septic shock due to gastrointestinal toxicity of lapatinib and capecitabine combination regimen. This was an expected adverse event of the regimen. In addition to poor general condition, her serum sodium level changed rapidly despite treatment with desmopressin as panhypopituitarism originated from the metastatic brain lesion (Fig. 3). In addition, osmotic demyelination syndrome occurred, and her mentality changed from deep stupor to semi-comatose status for 2 months.\n\nIt took more than 3 months of rehabilitation for restoration of the patient’s neurocognitive function; chemotherapy was withheld during this period. Repeated MRIs showed a mild increase in the size of the enhancing lesion in the sella, suprasella, and the right basal ganglia (Fig. 1C). Because a 20% dose reduction of capecitabine still evoked adverse effects (general weakness and electrolyte imbalance), chemotherapy with lapatinib alone was started.\n\nAfter 2 months of lapatinib monotherapy, the follow-up MRI showed a decrease in the size of the enhancing lesion (Fig. 1D). Repeated computed tomography of the patient’s chest, abdomen, and pelvis did not show recurrence of disease in any other extra-cranial locations. The patient continued to suffer from visual loss and hypothalamic dysfunctions, including hypothermia, weight gain, and loss of memory. However, by steadily taking lapatinib, she now maintains a daily activity of 1 to 2 Eastern Cooperative Oncology Group performance score.\n\nDiscussion\nThis is a case involving early recurrence of breast cancer manifested with panhypopituitarism due to metastasis to the pituitary, pituitary stalk, and hypothalamus. The pituitary gland is a rare site of metastasis for all neoplasms (metastasis makes up less than 1% of pituitary tumors), and less than 10% of pituitary metastases are symptomatic [6,7]. Therefore, the clinical history of the patient shows a rare pattern of breast cancer metastasis.\n\nBrain metastasis developed despite previous treatment with trastuzumab in early stage breast cancer. Recent studies have suggested that trastuzumab may not be active in the central nervous system [5], which could be a potential sanctuary site for disease progression in trastuzumab-treated patients with HER2-positive breast cancer. According to previous reports regarding pituitary metastasis from breast cancer, most patients are elderly, and have clinical and/or radiologic evidence of widespread disease, mainly to the lymph nodes, lung and bone, at the time they are diagnosed with pituitary metastasis [13,14]. In this case, trastuzumab may have controlled the micro-metastasis of breast cancer after the initial total mastectomy and lymph-node dissection, however, brain metastasis still occurred. Therefore, the patient experienced solitary central nervous system progression without evidence of extra-cranial lesions.\n\nSurgery and radiation could not completely control the pituitary metastasis of the breast cancer. Metastatic pituitary lesions tend to be firm, diffuse, invasive, vascular, and hemorrhagic; total resection of tumor is difficult [6]. Tumor debulking is beneficial for alleviating local symptoms, especially visual field defect and headache, whereas symptoms such as diplopia and those related to pituitary failure remain unaffected [6]. The patient’s quality of life was significantly affected; she had been required to take hormone replacement therapy every day from the time of diagnosis with pituitary metastasis, and still suffers from loss of memory, hypothermia, weight gain, and complete visual loss.\n\nLapatinib is proven to be as active as first-line treatment of brain metastasis from HER2-positive breast cancer in combination with capecitabine [12]. It has low molecular weight, and therefore is assumed to be able to cross the blood-brain barrier [15]. Lapatinib and capecitabine treatment are sometimes associated with grade 3 and grade 4 toxicity (most commonly, diarrhea and hand-foot syndrome) [12], however, adjustment of regimen can overcome these issues.\n\nWidespread use of trastuzumab for treatment of HER2-positive breast cancer leaves patients with an increased risk of brain metastasis [3,4]. The median survival period after central nervous system progression is about 13 months [3,4]. More follow-up is required; however, even 16 months after the initial diagnosis of brain metastasis, the patient’s brain lesion is well controlled with lapatinib monotherapy. Therefore, we suggest that lapatinib is beneficial for improving the survival and quality of life for patients with HER2-positive brain metastasis.\n\nPituitary metastasis is an uncommon but serious event of cancer progression because it can lead to pituitary insufficiency. Life-long hormone replacement therapy and deteriorated quality of life are inevitable. Lapatinib can be an effective alternative therapy for managing brain metastasis of HER2-positive breast cancer, in cases that cannot be completely controlled by surgery and/or radiation therapy.\n\nConflict of interest relevant to this article was not reported.\n\nFig. 1. Magnetic resonance imaging of metastatic pituitary lesion. (A) At the time of diagnosis, a 35-mm strongly enhancing mass was observed in the sellar and suprasellar regions (September 2012). (B) Even after partial removal of the tumor via craniotomy and whole brain radiation therapy, viable tumor remained (27 mm, November 2012). (C) The size of the enhancing lesion had increased slightly (29 mm) 4 months after discontinuation of lapatinib and capecitabine due to gastrointestinal sepsis (June 2013). (D) After re-starting lapatinib monotherapy, the size of the enhancing mass decreased (25 mm, September 2013).\n\nFig. 2. (A) Histology of invasive ductal carcinoma showing a predominantly trabecular pattern, high nuclear atypia, and high mitotic activity (H&E staining, ×100). (B) Histology of invasive ductal carcinoma metastasis to the brain, showing infiltration of malignant cells to the parenchyma (H&E staining, ×100).\n\nFig. 3. Due to gastrointestinal sepsis, the patient’s serum sodium level changed radically (March to April, 2013), and it was stabilized after the tumor was controlled by lapatinib (November 2013).\n\nTable 1. Blood and urine laboratory results\n\nLaboratory tests\tValue\tNormal value\t\nUrine\t\t\t\n Specific gravity\t1.004\t1.000-1.030\t\n Sodium (mmol/L)\t11\t\t\n Osmolality (mOsm/kg)\t109\t20-1,200\t\n 24-hr urine free cortisol (μg/day)\t39.3 (L)\t58-403\t\nSerum\t\t\t\n Osmolality (mOsm/kg)\t324\t289-308\t\n Sodium (mEq/L)\t159\t135-145\t\n Glucose (mg/dL)\t143\t70-110\t\n Prolactin (ng/mL)\t18.7\t2.74-19.64\t\n Free thyroxine (fT4) (ng/dL)\t0.73\t0.70-1.48\t\n Free triiodothyronine (T3) (ng/dL)\t0.90\t0.58-1.59\t\n Thyroid-stimulating hormone (mIU/mL)\t0.04 (L)\t0.35-4.94\t\n Follicle-stimulating hormone (mlU/mL)\t2.2 (L)\t16.74-113.59\t\n Luteinizing hormone (mlU/mL)\t< 0.2 (L)\t10.87-58.64\t\n Estradiol (pg/mL)\t< 20 (L)\t20-40\t\n Adrenocorticotropic hormone (pg/mL)\t7.67\t7.2-63.3\t\n Cortisol (μg/dL)\t0.9 (L)\t6.7-22.6\t\nL, low.\n==== Refs\nReferences\n1 Slamon DJ Clark GM Wong SG Levin WJ Ullrich A McGuire WL Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene Science 1987 235 177 82 3798106 \n2 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 92 11248153 \n3 Bendell JC Domchek SM Burstein HJ Harris L Younger J Kuter I Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma Cancer 2003 97 2972 7 12784331 \n4 Stemmler HJ Kahlert S Siekiera W Untch M Heinrich B Heinemann V Characteristics of patients with brain metastases receiving trastuzumab for HER2 overexpressing metastatic breast cancer Breast 2006 15 219 25 16026983 \n5 Pestalozzi BC Brignoli S Trastuzumab in CSF J Clin Oncol 2000 18 2349 51 10829059 \n6 Komninos J Vlassopoulou V Protopapa D Korfias S Kontogeorgos G Sakas DE Tumors metastatic to the pituitary gland: case report and literature review J Clin Endocrinol Metab 2004 89 574 80 14764764 \n7 Fassett DR Couldwell WT Metastases to the pituitary gland Neurosurg Focus 2004 16 E8 15191337 \n8 Gsponer J De Tribolet N Deruaz JP Janzer R Uske A Mirimanoff RO Diagnosis, treatment, and outcome of pituitary tumors and other abnormal intrasellar masses. Retrospective analysis of 353 patients Medicine (Baltimore) 1999 78 236 69 10424206 \n9 Rusnak DW Affleck K Cockerill SG Stubberfield C Harris R Page M The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer Cancer Res 2001 61 7196 203 11585755 \n10 Geyer CE Forster J Lindquist D Chan S Romieu CG Pienkowski T Lapatinib plus capecitabine for HER2-positive advanced breast cancer N Engl J Med 2006 355 2733 43 17192538 \n11 Cameron D Casey M Press M Lindquist D Pienkowski T Romieu CG A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses Breast Cancer Res Treat 2008 112 533 43 18188694 \n12 Bachelot T Romieu G Campone M Dieras V Cropet C Dalenc F Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study Lancet Oncol 2013 14 64 71 23122784 \n13 Houck WA Olson KB Horton J Clinical features of tumor metastasis to the pituitary Cancer 1970 26 656 9 5272295 \n14 Max MB Deck MD Rottenberg DA Pituitary metastasis: incidence in cancer patients and clinical differentiation from pituitary adenoma Neurology 1981 31 998 1002 7196526 \n15 Taskar KS Rudraraju V Mittapalli RK Samala R Thorsheim HR Lockman J Lapatinib distribution in HER2 overexpressing experimental brain metastases of breast cancer Pharm Res 2012 29 770 81 22011930\n\n",
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"issue": "48(1)",
"journal": "Cancer research and treatment",
"keywords": "Breast neoplasms; HER2; Hypopituitarism; Neoplasm metastasis",
"medline_ta": "Cancer Res Treat",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006801:Humans; D007018:Hypopituitarism; D000077341:Lapatinib; D010911:Pituitary Neoplasms; D011799:Quinazolines; D018719:Receptor, ErbB-2; D000068878:Trastuzumab; D016896:Treatment Outcome",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Effective Treatment of Solitary Pituitary Metastasis with Panhypopituitarism in HER2-Positive Breast Cancer by Lapatinib.",
"title_normalized": "effective treatment of solitary pituitary metastasis with panhypopituitarism in her2 positive breast cancer by lapatinib"
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"abstract": "This study aimed to evaluate the efficacy and safety of the fludarabine-cyclophosphamide-rituximab regimen for young physically fit patients with chronic lymphocytic leukemia in the \"real-life\" setting. We specifically focused on the impact of dose reduction on patient outcomes. The patient cohort consisted of 128 patients with chronic lymphocytic leukemia (≤ 70 years) treated at 10 Israeli centers with front-line fludarabine-cyclophosphamide-rituximab. We defined reduced chemotherapy as two-thirds or less of the total indicated dose. Patients treated with rituximab were divided into two groups and compared: those who received full dosages of 375 mg/m(2) or 500 mg/m(2), and patients given less than six cycles with either dose. Overall and clinical complete response rates (92.8% and 70.4%), as well as toxicities and overall survival (median not reached at 6 years), were similar to other reported clinical trials, but progression-free survival was shorter (42.5 months). Almost 50% of patients had some dose reduction of chemotherapy, 21% receiving less than two-thirds of the indicated dose, while close to 30% did not complete six cycles of rituximab. Reduced doses of chemotherapy and rituximab were independently associated with shorter progression-free survival (hazard ratio 3.6, P<0.0001 for reduced chemotherapy; hazard ratio 2.5, P=0.003 for incomplete-treatment with rituximab). Achieving a complete response was associated with longer overall survival but was not linked to the given dose of chemoimmunotherapy. In younger physically fit patients, front-line fludarabine-cyclophosphamide-rituximab therapy in the \"real-life\" setting achieves long remissions (albeit shorter than in clinical trials) and prolonged overall survival. However, dose reductions are commonly administered and may impact outcome.",
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"authors": "Herishanu|Yair|Y|;Goldschmidt|Neta|N|;Bairey|Osnat|O|;Ruchlemer|Rosa|R|;Fineman|Riva|R|;Rahimi-Levene|Naomi|N|;Shvidel|Lev|L|;Tadmor|Tamar|T|;Ariel|Aviv|A|;Braester|Andrea|A|;Shapiro|Mika|M|;Joffe|Erel|E|;Polliack|Aaron|A|;|||",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine",
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"delete": false,
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"journal": "Haematologica",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D002869:Chromosome Aberrations; D003520:Cyclophosphamide; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D012189:Retrospective Studies; D000069283:Rituximab; D016019:Survival Analysis; D016896:Treatment Outcome; D014740:Vidarabine; D055815:Young Adult",
"nlm_unique_id": "0417435",
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"references": "11023504;18216293;11304768;11588025;12724482;2784491;8676625;10477712;13703205;15138165;15767648;16649223;16948126;17008537;18411418;19075274;19075280;20194866;20620970;20827108;20888994;21922186;23065520;22966877;24401022;24705492;17635235;17658394;11114313",
"title": "Efficacy and safety of front-line therapy with fludarabine-cyclophosphamide-rituximab regimen for chronic lymphocytic leukemia outside clinical trials: the Israeli CLL Study Group experience.",
"title_normalized": "efficacy and safety of front line therapy with fludarabine cyclophosphamide rituximab regimen for chronic lymphocytic leukemia outside clinical trials the israeli cll study group experience"
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"abstract": "Gamma-aminobutyric acid transaminase (GABA-T) deficiency is an autosomal recessive disorder reported in only three unrelated families. It is caused by mutations in the ABAT gene, which encodes 4-aminobutyrate transaminase, an enzyme of GABA catabolism and mitochondrial nucleoside salvage. We report the case of a boy, deceased at 12 months of age, with early-onset epileptic encephalopathy, severe psychomotor retardation, hypotonia, lower-limb hyporeflexia, central hypoventilation, and rapid increase in weight and, to a lesser rate, length and head circumference. He presented signs of premature pubarche, thermal instability, and water-electrolyte imbalance. Serum total testosterone was elevated (43.3 ng/dl; normal range <16), as well as serum growth hormone (7.7 ng/ml; normal range <1). Brain magnetic resonance imaging (MRI) showed decreased myelination and generalized brain atrophy, later confirmed by post-mortem examination. ABAT gene sequencing was performed post-mortem, identifying a homozygous variant c.888G > T (p.Gln296His),not previously described. In vitro analysis concluded that this variant is pathogenic. The clinical features of this patient are similar to those reported so far in GABA-T deficiency. However, distinct mutations may have a different effect on enzymatic activity, which potentially could lead to a variable clinical outcome. Clinical investigation aiming for a diagnosis should not end with the patient's death, as it may allow a more precise genetic counselling for the family.",
"affiliations": "Centro Hospitalar e Universitário de Coimbra, Praceta Prof. Mota Pinto, 3000-075, Coimbra, Portugal. pjplouro@gmail.com.;Centro Hospitalar e Universitário de Coimbra, Praceta Prof. Mota Pinto, 3000-075, Coimbra, Portugal.;Centro Hospitalar e Universitário de Coimbra, Praceta Prof. Mota Pinto, 3000-075, Coimbra, Portugal.;Centro Hospitalar e Universitário de Coimbra, Praceta Prof. Mota Pinto, 3000-075, Coimbra, Portugal.;Centro Hospitalar e Universitário de Coimbra, Praceta Prof. Mota Pinto, 3000-075, Coimbra, Portugal.;Centro Hospitalar e Universitário de Coimbra, Praceta Prof. Mota Pinto, 3000-075, Coimbra, Portugal.;Centro Hospitalar e Universitário de Coimbra, Praceta Prof. Mota Pinto, 3000-075, Coimbra, Portugal.;Centro Hospitalar e Universitário de Coimbra, Praceta Prof. Mota Pinto, 3000-075, Coimbra, Portugal.;Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.;Centro Hospitalar e Universitário de Coimbra, Praceta Prof. Mota Pinto, 3000-075, Coimbra, Portugal.;Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.;Centro Hospitalar e Universitário de Coimbra, Praceta Prof. Mota Pinto, 3000-075, Coimbra, Portugal.",
"authors": "Louro|Pedro|P|0000-0002-8512-7582;Ramos|Lina|L|;Robalo|Conceição|C|;Cancelinha|Cândida|C|;Dinis|Alexandra|A|;Veiga|Ricardo|R|;Pina|Raquel|R|;Rebelo|Olinda|O|;Pop|Ana|A|;Diogo|Luísa|L|;Salomons|Gajja S|GS|;Garcia|Paula|P|",
"chemical_list": "D000612:4-Aminobutyrate Transaminase",
"country": "United States",
"delete": false,
"doi": "10.1007/s10545-016-9951-z",
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"issn_linking": "0141-8955",
"issue": "39(5)",
"journal": "Journal of inherited metabolic disease",
"keywords": null,
"medline_ta": "J Inherit Metab Dis",
"mesh_terms": "D000612:4-Aminobutyrate Transaminase; D000592:Amino Acid Metabolism, Inborn Errors; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation",
"nlm_unique_id": "7910918",
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"pmid": "27376954",
"pubdate": "2016-09",
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"references": "9733434;20052547;6148708;22268095;2079831;25738457",
"title": "Phenotyping GABA transaminase deficiency: a case description and literature review.",
"title_normalized": "phenotyping gaba transaminase deficiency a case description and literature review"
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"companynumb": "PT-ACCORD-044779",
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"activesubstancename": "LEVETIRACETAM"
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"abstract": "There is no proven treatment for ursodeoxycholic acid (UDCA)-refractory primary biliary cholangitis (PBC) other than obeticholic acid. Although fibrates have been reported to improve biochemical parameters, the long-term effects remain unclear. This study evaluated the effect of fibrate on clinical outcomes of UDCA-refractory PBC.\n\n\n\nPatients whose alkaline phosphatase (ALP) was not normalized with at least 13 mg/kg of UDCA treatment for >1 year were included from two tertiary referral centres. The primary outcome was ALP normalization. Secondary outcomes included the development of cirrhosis and hepatic deterioration. Immortal time bias was adjusted using the Mantel-Byar method.\n\n\n\nA total of 100 UDCA-refractory PBC patients were included: 71 patients received UDCA alone (the UDCA group) and 29 patients received UDCA plus additional fibrate treatment of 160 mg/d fenofibrate or 400 mg/d bezafibrate (the fibrate/UDCA group). During the follow-up period, the probability of ALP normalization was significantly higher in the fibrate/UDCA group (hazard ratio [HR] = 5.00, 95% confidence interval = 2.87-8.27, P < 0.001). Among 58 non-cirrhotic patients (43 in the UDCA group and 15 in the fibrate/UDCA group), 19 patients (44.1%) in the UDCA group and none in the fibrate/UDCA group developed cirrhosis (HR = 0.12, P = 0.04). Hepatic deterioration (Child-Pugh score increase or signs of decompensated cirrhosis) occurred in 17 patients (23.9%) of the UDCA group and none in the fibrate/UDCA group in which the difference was significant (HR = 0.12, P = 0.04).\n\n\n\nIn patients with UDCA-refractory PBC, additional fibrate treatment is associated with a higher probability of ALP normalization and a lower risk of cirrhosis development and hepatic deterioration.",
"affiliations": "Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.;Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.;Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Yonsei University College of Medicine, Yonsei Liver Center, Severance Hospital, Seoul, Korea.;Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.;Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.;Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.;Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Yonsei University College of Medicine, Yonsei Liver Center, Severance Hospital, Seoul, Korea.;Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.;Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.;Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.;Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.;Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.",
"authors": "Chung|Sung Won|SW|0000-0001-7263-6866;Lee|Jeong-Hoon|JH|0000-0002-0315-2080;Kim|Minseok Albert|MA|0000-0003-1850-9406;Leem|Galam|G|;Kim|Sun Woong|SW|;Chang|Young|Y|;Lee|Hyo Young|HY|;Yoon|Jun Sik|JS|;Park|Jun Yong|JY|0000-0001-6324-2224;Lee|Yun Bin|YB|0000-0002-3193-9745;Cho|Eun Ju|EJ|0000-0002-2677-3189;Yu|Su Jong|SJ|;Kim|Yoon Jun|YJ|0000-0003-2358-1170;Yoon|Jung-Hwan|JH|",
"chemical_list": "D002756:Cholagogues and Choleretics; D014580:Ursodeoxycholic Acid; D000469:Alkaline Phosphatase; D011345:Fenofibrate; D001629:Bezafibrate",
"country": "United States",
"delete": false,
"doi": "10.1111/liv.14165",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1478-3223",
"issue": "39(9)",
"journal": "Liver international : official journal of the International Association for the Study of the Liver",
"keywords": "ALP normalization; bezafibrate; cirrhosis; fenofibrate; primary biliary cholangitis",
"medline_ta": "Liver Int",
"mesh_terms": "D000469:Alkaline Phosphatase; D001629:Bezafibrate; D002756:Cholagogues and Choleretics; D004359:Drug Therapy, Combination; D005260:Female; D011345:Fenofibrate; D006801:Humans; D008105:Liver Cirrhosis, Biliary; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D014580:Ursodeoxycholic Acid",
"nlm_unique_id": "101160857",
"other_id": null,
"pages": "1776-1785",
"pmc": null,
"pmid": "31162879",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Additional fibrate treatment in UDCA-refractory PBC patients.",
"title_normalized": "additional fibrate treatment in udca refractory pbc patients"
} | [
{
"companynumb": "KR-ALLERGAN-1924677US",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "URSODIOL"
},
"drugadditional": "3",
"dr... |
{
"abstract": "BACKGROUND\nDue to the growing organ shortage in the Balkans and still underdeveloped cadaver transplantation, we started accepting living expanded criteria renal donors including elderly, marginal and unrelated donors (spouses, etc). The ABO-incompatible renal transplantation was initiated last year. The first two successful cases are presented.\n\n\nMETHODS\nA 40-yr-old mother (blood group A1B) and a 57-yr-old husband (blood group B) were considered as suitable donors for an 18-yr-old daughter (blood group B) and a 52-yr-old wife (blood group O). Both the recipients had a relatively long dialysis treatment before the surgery. The anti-A1 and anti-B titer of isoaglutinins was 1 : 64 in both the recipients before the procedure. A routine laparoscopic splenectomy was performed 40 and 45 days before the transplantation, without any complications. In the 10 days pre-conditioning period, rituximab was administered in a single dose of 375 mg/m2. At the same time four to five plasmaphereses were performed to reduce the isoaglutinins to below 1 : 4. On the last night before the surgery intravenous immunoglobulin (IVIG) in a dose of 0.5 g/kg/bw was administered. Standard induction and maintenance therapy was introduced (Dacllizumab, CyA-Neoral, MMF and steroids) according to the accepted policy in our transplant center. The routine plasmaphereses were performed in the first 2 weeks after transplantation to keep the isoaglutinins titer below 1 : 8.\n\n\nRESULTS\nTen and 6 months after the surgery both recipients are doing well. Their graft function remains stable (actual serum creatinin 140 and 230 microm/L, respectively). In the 1 month protocol biopsy a subclinical cellular and mild vascular rejection occurred, and both recipients were treated by steroid pulse therapy. One to two additional plasmaphereses were performed. The regularly monitored anti-A1 and anti-B isoaglutinins titer was kept below 1 : 8 during a period of follow-up.\n\n\nCONCLUSIONS\nThe first short-term results fully justify the ABO-incompatible living renal transplantation. The authors consider ABO-incompatible transplantation as a safe and promising procedure which may, together with expanded criteria living donors, ameliorate the actual donor shortage in the region.",
"affiliations": "Department of Nephrology, University Clinical Center, Republic of Macedonia. nivanovski@yahoo.com",
"authors": "Ivanovski|Ninoslav|N|;Popov|Zivko|Z|;Masin-Spasovska|Jelka|J|;Dimcevska|Anita Hristova|AH|;Kolevski|Perko|P|",
"chemical_list": "D000017:ABO Blood-Group System; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D016756:Immunoglobulins, Intravenous; D000069283:Rituximab",
"country": "Denmark",
"delete": false,
"doi": "10.1111/j.1399-3089.2006.00294.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0908-665X",
"issue": "13(2)",
"journal": "Xenotransplantation",
"keywords": null,
"medline_ta": "Xenotransplantation",
"mesh_terms": "D000017:ABO Blood-Group System; D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D001787:Blood Group Incompatibility; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016756:Immunoglobulins, Intravenous; D016030:Kidney Transplantation; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D010956:Plasmapheresis; D018843:Republic of North Macedonia; D000069283:Rituximab; D013156:Splenectomy; D019172:Transplantation Conditioning",
"nlm_unique_id": "9438793",
"other_id": null,
"pages": "123-5",
"pmc": null,
"pmid": "16623805",
"pubdate": "2006-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "First two ABO-incompatible living renal transplantations using splenectomy, rituximab, plasmapheresis and IVIG as a preconditioning regimen: a single center experience in the Balkans.",
"title_normalized": "first two abo incompatible living renal transplantations using splenectomy rituximab plasmapheresis and ivig as a preconditioning regimen a single center experience in the balkans"
} | [
{
"companynumb": "NVSC2020MK055909",
"fulfillexpeditecriteria": "1",
"occurcountry": "MK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Hemophagocytic lymphohistiocytosis (HLH) is a disorder of uncontrolled immune activation with distinct clinical features including fever, cytopenia, splenomegaly, and sepsis-like symptoms. In a young adolescent patient a novel germline GATA2 variant (NM_032638.5 (GATA2): c.177C>G, p.Tyr59Ter) was discovered and had resulted in non-tuberculous mycobacterial (NTM) infection and aggressive HLH. Strikingly, impaired degranulation of cytotoxic T-lymphocytes (CTL) and natural killer (NK)-cells was detected in CD107a-analyses. The affected patient was treated with HLA-matched unrelated alloHSCT, and subsequently all hematologic and infectious abnormalities including HLH and NTM resolved. This case supports early alloHSCT in GATA2 deficiencies as curative approach regardless of active NTM infection. Future studies on GATA2 c.177C>G, p.Tyr59*Ter might unravel its potential role in cytotoxic effector cell function and its contribution to HLH pathogenesis.",
"affiliations": "Department of Hematology and Oncology, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany.;Department of Hematology and Oncology, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany.;Department of Hematology and Oncology, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany.;Klinik für Innere Medizin II, Schwarzwald-Baar-Klinikum, Villingen-Schwenningen, Germany.;Medical Clinic, Research Center Borstel, Borstel, Germany.;Clinic for Pediatric Hematology, University Medical Center Eppendorf, Hamburg, Germany.;Hematopathology Lübeck, Lübeck, Germany.;CeGaT and Practice for Human Genetics, Tübingen, Germany.;Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg i.Br., Germany.;Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg i.Br., Germany.;Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg i.Br., Germany.;Department of Rheumatology and Clinical Immunology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg i.Br., Germany.;Department of Hematology and Oncology, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany.",
"authors": "Mika|Thomas|T|;Vangala|Deepak|D|;Eckhardt|Matthias|M|;La Rosée|Paul|P|;Lange|Christoph|C|;Lehmberg|Kai|K|;Wohlschläger|Charlotte|C|;Biskup|Saskia|S|;Fuchs|Ilka|I|;Mann|Jasmin|J|;Ehl|Stephan|S|;Warnatz|Klaus|K|;Schroers|Roland|R|",
"chemical_list": "D015415:Biomarkers; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human",
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fimmu.2021.682934",
"fulltext": "\n==== Front\nFront Immunol\nFront Immunol\nFront. Immunol.\nFrontiers in Immunology\n1664-3224\nFrontiers Media S.A.\n\n10.3389/fimmu.2021.682934\nImmunology\nCase Report\nCase Report: Hemophagocytic Lymphohistiocytosis and Non-Tuberculous Mycobacteriosis Caused by a Novel GATA2 Variant\nMika Thomas 1\n\nVangala Deepak 1\n\nEckhardt Matthias 1\nLa Rosée Paul 2\nLange Christoph 3 4\n\nLehmberg Kai 5\nWohlschläger Charlotte 6\n\nBiskup Saskia 7\nFuchs Ilka 8\nMann Jasmin 8\nEhl Stephan 8\n\nWarnatz Klaus 9 10 *\n\nSchroers Roland 1 *\n\n1 Department of Hematology and Oncology, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany\n2 Klinik für Innere Medizin II, Schwarzwald-Baar-Klinikum, Villingen-Schwenningen, Germany\n3 Medical Clinic, Research Center Borstel, Borstel, Germany\n4 Respiratory Medicine & International Health, University of Lübeck, Lübeck, Germany\n5 Clinic for Pediatric Hematology, University Medical Center Eppendorf, Hamburg, Germany\n6 Hematopathology Lübeck, Lübeck, Germany\n7 CeGaT and Practice for Human Genetics, Tübingen, Germany\n8 Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg i.Br., Germany\n9 Department of Rheumatology and Clinical Immunology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg i.Br., Germany\n10 Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg i.Br., Germany\nEdited by: Catharina Schuetz, University Hospital Carl Gustav Carus, Germany\n\nReviewed by: Anastasios E. Germenis, University of Thessaly, Greece; Alexandra Freeman, National Institutes of Health (NIH), United States\n\n*Correspondence: Roland Schroers, Roland.Schroers@rub.de; Klaus Warnatz, Klaus.Warnatz@uniklinik-freiburg.de\nThis article was submitted to Primary Immunodeficiencies, a section of the journal Frontiers in Immunology\n\n10 5 2021\n2021\n12 68293419 3 2021\n14 4 2021\nCopyright © 2021 Mika, Vangala, Eckhardt, La Rosée, Lange, Lehmberg, Wohlschläger, Biskup, Fuchs, Mann, Ehl, Warnatz and Schroers\n2021\nMika, Vangala, Eckhardt, La Rosée, Lange, Lehmberg, Wohlschläger, Biskup, Fuchs, Mann, Ehl, Warnatz and Schroers\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.\nHemophagocytic lymphohistiocytosis (HLH) is a disorder of uncontrolled immune activation with distinct clinical features including fever, cytopenia, splenomegaly, and sepsis-like symptoms. In a young adolescent patient a novel germline GATA2 variant (NM_032638.5 (GATA2): c.177C>G, p.Tyr59Ter) was discovered and had resulted in non-tuberculous mycobacterial (NTM) infection and aggressive HLH. Strikingly, impaired degranulation of cytotoxic T-lymphocytes (CTL) and natural killer (NK)-cells was detected in CD107a-analyses. The affected patient was treated with HLA-matched unrelated alloHSCT, and subsequently all hematologic and infectious abnormalities including HLH and NTM resolved. This case supports early alloHSCT in GATA2 deficiencies as curative approach regardless of active NTM infection. Future studies on GATA2 c.177C>G, p.Tyr59*Ter might unravel its potential role in cytotoxic effector cell function and its contribution to HLH pathogenesis.\n\nhemophagocytic lymphohistiocytosis\nnon-tuberculous mycobacteriosis\nGATA2\nCD107a\nallogeneic hematopoietic stem cell transplantation\n==== Body\nIntroduction\n\nHemophagocytic lymphohistiocytosis (HLH) is a devastating disorder of uncontrolled immune activation with features resembling systemic inflammatory response syndrome (SIRS). Originally observed in pediatric patients, HLH has been increasingly recognized also in adults. HLH results from aberrantly activated macrophages and cytotoxic T-lymphocytes (CTL). The clinical hallmarks are fever, cytopenia, splenomegaly, and SIRS-like features often including liver-dysfunction. In contrast to children, HLH in adults presents predominantly as acquired (secondary) syndrome triggered by infections, malignancies, or autoimmune disorders (1).\n\nGenetic (primary) HLH is considered to be rare in adults, however, variants in distinctive HLH-associated genes previously have been reported in up to 14% of affected patients (2). Lymphocyte cytotoxicity and natural-killer (NK) cell function are impaired in primary HLH. Accordingly, immunophenotypic and functional analysis of these effector cells together with guided genetic testing are recommended in selected adult patients (1).\n\nGATA binding protein 2 (GATA 2) is a transcription factor and key component in hematopoiesis and stem cell biology. GATA2 variants cause heterogeneous abnormalities including hematologic, immunologic, and dermatologic diseases. In GATA2 deficiency, B-lymphocytopenia, NK-lymphocytopenia, and monocytopenia are striking findings, often accompanied by opportunistic infections such as non-tuberculous mycobacteriosis (NTM). Immunodeficiency as caused by GATA2 variants can be the basis of HLH, as has been described in single cases of severe primary Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections (3, 4).\n\nHere, we describe the medical history and molecular work-up of a young woman with persistent fever, splenomegaly, lymphadenopathy, and pancytopenia. The recognition of an HLH-like disorder was followed by the diagnosis of systemic NTM infection with Mycobacterium avium. Finding a markedly impaired degranulation of CTL and NK-cells as detected in CD107a-analyses, advanced genetic testing was performed and finally revealed a germline heterozygous GATA2 variant (c.177C>G, p.Tyr59*Ter). The resulting GATA2 deficiency was deemed predisposing to poor NTM infection control resulting in persistent immune stimulation with subsequent HLH. This ultimately supported the choice of allogeneic hematopoietic stem cell transplantation (alloHSCT) as successful curative treatment approach in the reported patient.\n\nCase Presentation - Tests and Therapy\n\nIn brief, the 29-year old student presented to her general practitioner with recurrent fever up to 40°C in December 2019. Medically, she and her relatives had an uneventful past. After fever persistence for more than two weeks she was admitted to hospital for an extensive work-up. In clinical and ultrasound examinations, abdominal lymph node enlargements and a marked hepatosplenomegaly were noticed. These findings were confirmed in positron emission computer tomography (PET-CT) scanning ( Figures 1A, B ). Her blood counts showed pancytopenia (WBC 1.5 x 109/l, neutrophils 1.0 x 109/l, lymphocytes 0.35 x 109/l, monocytes 0.01 x 109/l, hemoglobin 76 g/l, platelets 78 x 109/l), and additional lab testing revealed hyperferritinemia (3860 g/l), hypertriglyceridemia (4.56 mmol/l), increased serum levels of aspartate aminotransferase (AST 79 U/l), soluble interleukin-2 receptor (sIL-2R, 2710 U/l), and lactate dehydrogenase (LDH 626 U/L). Although fibrinogen was normal (5.1 g/l), a diagnosis of HLH was made based on HLH-2004 criteria [7/8 fulfilled including impaired NK-cell function, see below; (5)] and an HScore of 239 points [98-99% probability of hemophagocytosis; (6)], respectively.\n\nFigure 1 Positron emission tomography–computed tomography (PET-CT). (A, B) Disseminated lymphadenopathy due to non-tuberculous mycobacterial (NTM) infection (red arrows) and bone-marrow activation and hepatosplenomegaly due to hemophagocytic lymphohistiocytosis (HLH) at diagnosis. (C, D) Control PET-CT following allogeneic hematopoietic transplantation (day +240) and after 12 months of tuberculostatic therapy demonstrating complete remission of NTM-related lymphadenopathy and remission of HLH-associated hematopoietic activation.\n\nAfter ruling out Leishmania spp., HIV, EBV, and CMV infections by serology and PCR (peripheral blood and bone marrow, BM), biopsies of retroperitoneal lymph nodes were taken. Surprisingly, histopathology did not show lymphoma but demonstrated granulomatous lymphadenitis including acid-fast bacteria, which were further classified as Mycobacterium avium by genotyping (MycoDirect 1.7 LCD array, Chipron, Germany). M. avium was also detected in BM and cultured from bronchoalveolar lavage samples, giving the diagnosis of NTM infection triggering HLH. In BM cytology and histopathology no signs of myelodysplasia were identified.\n\nTreatment with amikacin, azithromycin, ethambutol and rifampicin was initiated promptly, however, the fever and other HLH-signs persisted. Only after intensive immunosuppressive therapy including high-dose dexamethasone, ciclosporin A, intravenous immunoglobulins, and repetitive courses of etoposide (75 mg/m2, twice weekly) the HLH-related symptoms could temporarily be ameliorated. The cause for HLH and NTM was further investigated including CTL and NK-cell function analysis in CD107a-assays (7). These indicated significant degranulation impairments in both effector cell types ( Figure 2 ). Perforin expression was normal, and genetic variants in UNC13D, STXBP2, RAB27A, and STX11 were excluded in Sanger sequencing. Subsequently, next generation sequencing (NovaSeq 6000 NGS platform) of genes associated with NTM infections [CYBB, GATA2, IFNGR1/R2, IL12B, IL12RB1/RB2, IL23R, IRF8, ISG15, JAK1, RORC, SPPL2A, STAT1, TYK2; www.CEGAT.de; (8)] was performed. As result, a novel GATA2 variant (c.177C>G, p.Tyr59Ter) in heterozygous form was identified (DNA from peripheral blood and mucosa cells).\n\nFigure 2 CD107a degranulation assay. Degranulation of CD56+ NK-cells (A) and CD8+ CTL (B) was examined as previously published7. In brief, CD107a-expression on cell surfaces was analyzed by flow-cytometry in resting cells (A, B; left dot plot diagrams) and subsequent to 48 h stimulation with interleukin 2 (IL-2) of NK-cells (A, right dot plot diagrams), and phytohemagglutinin (PHA)/IL-2 of CD8+ T-cells (B, right dot plot diagrams), respectively.\n\nConsidering disseminated NTM infection and secondary HLH resulting from primary immunodeficiency due to germline GATA2 deficiency, we aimed for alloHSCT as curative therapy. An HLA-matched unrelated donor (MUD 10/10) was identified, and the patient underwent alloHSCT following reduced-intensity conditioning with fludarabine (150 mg/m²) and treosulfan (30 g/m²) in September 2020. Graft-versus-Host disease (GvHD) prophylaxis consisted of post-transplant cyclophosphamide (100 mg/kg), mycophenolate-mofetil, and ciclosporin. Prior to alloHSCT, the antimycobacterial treatment was switched to azithromycin, clofazimine, and ethambutol. The fever and HLH-signs completely resolved after full hematopoietic engraftment. In the absence of GvHD, ciclosporin was ceased at day +98 post-alloHSCT. Following diagnosis of moderate hepatotoxicity, which appeared drug-related in a liver biopsy, all antibiotics were stopped 6 months after alloHSCT and 1 year after disease onset, respectively. PET-CT scanning at that time demonstrated complete remission of all inflammatory manifestations ( Figures 1C, D ).\n\nDiscussion\n\nHLH is a hyperferritinemic hyperinflammatory syndrome with a common immunologic pathway and inability of the immune system to adequately restrict stimulatory effects towards various triggers (1). In adults, infections and malignancies, primarily lymphomas, are the most frequent initiators of HLH, as has recently been confirmed by our group in a large collaborative analysis (9). Our young adult patient presented with new-onset aggressive HLH requiring straightforward investigation of underlying disorders. Considering her mediterranean origin leishmaniasis was ruled out in addition to infections with HIV and herpesviridae. PET-CT scanning was highly suggestive of malignant lymphoma, but histopathology including molecular diagnostics and culture established the final diagnosis of Mycobacterium avium infection.\n\nWhile secondary HLH has been repeatedly described in relation to typical tuberculosis, occurrence of HLH and NTM such as M. avium remains extremely rare (10). Noteworthy, there is no report on both conditions in the context of primary GATA2 deficiency until today. More often, gene sequence variants associated with adult HLH occur in PRF1, STXBP2, SH2D1A, and UNC13D, respectively (2).\n\nIn our patient, low CD107a-expression on stimulated CTL and NK-cells ( Figure 2 ) was indicative of impaired cytotoxic degranulation. As previously published, quantification of CD107a on surfaces of cytotoxic lymphocytes in standardized robust protocols has a high sensitivity and specificity for the diagnosis of HLH in conjunction with genetic disorders of granule exocytosis (7, 11). However, none of the classic genes associated with exocytosis and primary HLH were mutated in the reported patient.\n\nDisseminated NTM in adolescents and young adults can be caused by acquired autoantibodies against interferon-γ and by primary immune defects due to variants of IL-12RB1, IFNGR1/R2, STAT1LOF, and GATA2, respectively (8). Compatible with MonoMAC-syndrome due to GATA2 deficiency, our patient not only suffered from mycobacterial infection but also presented with monocytopenia, B-lymphopenia (9/μl), and NK-lymphopenia (50/μl) (3, 12, 13).\n\nInterestingly, reduced NK-cell cytotoxicity and specific loss of the CD56bright NK-subset have previously been demonstrated in GATA2 deficiency, but this was linked to impaired differentiation of cytotoxically active NK cells rather than failure of degranulation (14). Our patient repeatedly showed absent CD107a-expression in fresh NK-cells, possibly related to the newly identified GATA2 variant c.177C>G, p.Tyr59*Ter. It is plausible to assume that the severe functional impairment contributed to the NTM infection and the associated HLH. As the family history and GATA2 genetic analysis of first-degree relatives revealed no further affected individuals, the variant of GATA2 was de novo. This genetic variant leads to a premature stop codon and most probably results in nonsense-mediated mRNA decay. Certainly, further unraveling the molecular mechanisms and role of GATA2 in cytotoxic granule exocytosis will be of future interest.\n\nPatients with primary immunodeficiency due to GATA2 variants and NTM infections have poor responses to antimicrobial drugs alone (8, 12). In line with this, the lymphadenitis and HLH were both refractory against combined antimycobacterial and immunosuppressive therapy in our patient. Cure in these situations necessitates alloHSCT as definite treatment (8, 15). AlloHSCT in GATA2 deficiency including MonoMAC-syndrome has been reported in case series and within a prospective clinical trial, describing a disease-free survival rate of 86% following a busulfan/fludarabine-based conditioning regimen (15). In our patient, alloHSCT was challenging because of florid disseminated NTM infection and HLH requiring intensive immunosuppressive therapy. However, short duration of clinical disease and absence of myelodysplasia, myeloid leukemia, and additional infections such as human papilloma virus were favorable. Hence, we chose a reduced-intensity conditioning regimen based on treosulfan/fludarabine and post-transplant cyclophosphamide to facilitate reliable hematopoietic engraftment with acceptable risks of infectious complications and GvHD, respectively.\n\nIn summary, we describe a germline GATA2 variant as the basis of disseminated NTM infection and HLH. The affected patient was successfully treated with HLA-matched unrelated alloHSCT in parallel to prolonged antimicrobial treatment. Subsequent to alloHSCT all hematologic abnormalities and signs of NTM infection and HLH resolved, and the patient experienced full clinical recovery. This case supports early alloHSCT in GATA2 deficiencies as curative approach regardless of active systemic NTM infection. Further studies on the novel GATA2 variant (NM_032638.5 (GATA2): c.177C>G, p.Tyr59Ter, pathogenic) might help understanding the potential role of GATA2 in degranulation of cytotoxic effector cells and HLH pathogenesis.\n\nAccession Gene Database\n\nClinVar accession for the novel GATA2 variant is: https://www.ncbi.nlm.nih.gov/clinvar/variation/1013219/ Variation ID: 1013219 Accession: VCV001013219.1.\n\nData Availability Statement\n\nThe original contributions presented in the study are publicly available. This data can be found here: https://www.ncbi.nlm.nih.gov/clinvar/variation/1013219/.\n\nEthics Statement\n\nThe patient agreed on publication of this study and gave her written informed consent.\n\nAuthor Contributions\n\nTM and RS collected all data and wrote the manuscript. TM, DV, ME, PR, KL, CL, JM, SE, KW, and RS guided and discussed all clinical decisions. CW, SB, and IF performed all diagnostic tests including histopathology, flow-cytometry, and genetic analyses. All authors contributed to the article and approved the submitted version.\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\nAcknowledgments\n\nWe acknowledge support by the DFG Open Access Publication Funds of the Ruhr-Universität Bochum.\n==== Refs\nReferences\n\n1 La Rosée P Horne A Hines M von Bahr Greenwood T Machowicz R Berliner N . Recommendations for the Management of Hemophagocytic Lymphohistiocytosis in Adults. Blood (2019) 133 (23 ):2465–77 10.1182/blood.2018894618.\n2 Zhang K Jordan MB Marsh RA Johnson JA Kissell D Meller J . Hypomorphic Mutations in PRF1, Munc13-4, and STXBP2 are Associated With Adult-Onset Familial HLH. Blood (2011) 118 (22 ):5794–8. 10.1182/blood-2011-07-370148\n3 Suzuki T Takaya S Kunimatsu J Kutsuna S Hayakawa K Shibata H . GATA2 Mutation Underlies Hemophagocytic Lymphohistiocytosis in an Adult With Primary Cytomegalovirus Infection. J Infect Chemother (2020) 26 (2 ):252–6. 10.1016/j.jiac.2019.07.002\n4 Cohen JI Dropulic L Hsu AP Zerbe CS Krogmann T Dowdell K . Association of GATA2 Deficiency With Severe Primary Epstein-Barr Virus (Ebv) Infection and EBV-associated Cancers. Clin Infect Dis (2016) 63 (1 ):41–7. 10.1093/cid/ciw160\n5 Henter JI Horne A Aricó M Egeler RM Filipovich AH Imashuku S . Hlh-2004: Diagnostic and Therapeutic Guidelines for Hemophagocytic Lymphohistiocytosis. Pediatr Blood Cancer (2007) 48 (2 ):124–31. 10.1002/pbc.21039\n6 Fardet L Galicier L Lambotte O Marzac C Aumont C Chahwan D . Development and Validation of the HScore, a Score for the Diagnosis of Reactive Hemophagocytic Syndrome. Arthritis Rheumatol (2014) 66 (9 ):2613–20. 10.1002/art.38690\n7 Bryceson YT Pende D Maul-Pavicic A Gilmour KC Ufheil H Vraetz T . A Prospective Evaluation of Degranulation Assays in the Rapid Diagnosis of Familial Hemophagocytic Syndromes. Blood (2012) 119 (12 ):2754–63. 10.1182/blood-2011-08-374199\n8 Wu UI Holland SM . Host Susceptibility to non-Tuberculous Mycobacterial Infections. Lancet Infect Dis (2015) 15 (8 ):968–80. 10.1016/S1473-3099(15)00089-4\n9 Birndt S Schenk T Heinevetter Brunkhorst FM Maschmeyer G Rothmann F . Hemophagocytic Lymphohistiocytosis in Adults: Collaborative Analysis of 137 Cases of a Nationwide German Registry. J Cancer Res Clin Oncol (2020) 146 (4 ):1065–77. 10.1007/s00432-020-03139-4\n10 Shi W Jiao Y . Nontuberculous Mycobacterium Infection Complicated With Haemophagocytic Syndrome: A Case Report and Literature Review. BMC Infect Dis (2019) 19 (1 ):399. 10.1186/s12879-019-4061-9 31072325\n11 Rubin TS Zhang K Gifford C Lane A Choo S Bleesing JJ . Perforin and CD107a Testing is Superior to NK Cell Function Testing for Screening Patients for Genetic HLH. Blood (2017) 129 (22 ):2993–9. 10.1182/blood-2016-12-753830\n12 Vinh DC Patel SY Uzel G Anderson VL Freeman AF Olivier KN . Autosomal Dominant and Sporadic Monocytopenia With Susceptibility to Mycobacteria, Fungi, Papillomaviruses, and Myelodysplasia. Blood (2010) 115 (8 ):1519–29. 10.1182/blood-2009-03-208629\n13 Hsu AP Sampaio EP Khan J Calvo KR Lemieux JE Patel SY . Mutations in GATA2 are Associated With the Autosomal Dominant and Sporadic Monocytopenia and Mycobacterial Infection (MonoMAC) Syndrome. Blood (2011) 118 (10 ):2653–5 10.1182/blood-2011-05-356352.\n14 Mace EM Hsu AP Monaco-Shawver L Makedonas G Rosen JB Dropulic L . Mutations in GATA2 Cause Human NK Cell Deficiency With Specific Loss of the CD56(bright) Subset. Blood (2013) 121 (14 ):2669–77. 10.1182/blood-2012-09-453969\n15 Parta M Shah NN Baird K Rafei H Calvo KR Hughes T . Allogeneic Hematopoietic Stem Cell Transplantation for GATA2 Deficiency Using a Busulfan-Based Regimen. Biol Blood Marrow Transplant (2018) 24 (6 ):1250–9. 10.1016/j.bbmt.2018.01.030\n\n",
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"title": "Case Report: Hemophagocytic Lymphohistiocytosis and Non-Tuberculous Mycobacteriosis Caused by a Novel GATA2 Variant.",
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"abstract": "Novel 2019 coronavirus (COVID-19) infection usually causes a respiratory disease that may vary in severity from mild symptoms to severe pneumonia with multiple organ failure. Coagulation abnormalities are frequent, and reports suggest that COVID-19 may predispose to venous and arterial thrombotic complications. We report a case of acute lower limb ischemia and resistance to heparin as the onset of COVID-19 disease, preceding the development of respiratory failure. This case highlights that the shift of coagulation profile toward hypercoagulability was associated with the acute ischemic event and influenced the therapy.",
"affiliations": "Department of Anesthesia and Critical Care, ASST Ovest Milanese - Ospedale di Legnano, Legnano, Italy. Electronic address: cristina.mietto@asst-ovestmi.it.;Department of Anesthesia and Critical Care, ASST Ovest Milanese - Ospedale di Legnano, Legnano, Italy.;Vascular Surgery Unit, ASST Ovest Milanese - Ospedale di Legnano, Legnano, Italy.;Vascular Surgery Unit, ASST Ovest Milanese - Ospedale di Legnano, Legnano, Italy.;Department of Anesthesia and Critical Care, ASST Ovest Milanese - Ospedale di Legnano, Legnano, Italy.;Vascular Surgery Unit, ASST Ovest Milanese - Ospedale di Legnano, Legnano, Italy.;Vascular Surgery Unit, ASST Ovest Milanese - Ospedale di Legnano, Legnano, Italy.;Department of Anesthesia and Critical Care, ASST Ovest Milanese - Ospedale di Legnano, Legnano, Italy.",
"authors": "Mietto|Cristina|C|;Salice|Valentina|V|;Ferraris|Matteo|M|;Zuccon|Gianmarco|G|;Valdambrini|Federico|F|;Piazzalunga|Giorgio|G|;Socrate|Anna Maria|AM|;Radrizzani|Danilo|D|",
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"title": "Acute Lower Limb Ischemia as Clinical Presentation of COVID-19 Infection.",
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"abstract": "Renal involvement in patients with the m.3243A>G mutation may result in end-stage renal disease (ESRD) requiring renal replacement therapy. Although kidney transplantations have been performed in a small number of patients, short- and long-term follow-up data are lacking.\nWe describe five patients with the m.3243A<G mutation who received a kidney transplant, including follow-up data up to 13 years. We also summarize all cases (n = 13) of kidney transplantation in m.3243A>G carriers described in the literature.\nProteinuria with or without renal failure was the first clinical presentation of renal involvement in 13 of 18 (72%) patients. Focal segmental glomerulosclerosis (FSGS) was found in 9 of 13 (69%) biopsies. Sixteen of 18 (84%) patients developed hearing loss. All patients were diagnosed with diabetes mellitus, of whom eight (44%) developed the disease after transplantation. All patients with reported follow-up data (13/18) had stable kidney function from 6 months to 13 years of follow-up after transplantation.\nRenal involvement in carriers of the m.3243A>G mutation most commonly leads to proteinuria and FSGS and may lead to ESRD. Proper recognition of the mitochondrial origin of the renal disease in these patients is important for adequate treatment selection and suitable supportive care. This case series and review of the available literature on long-term follow-up after kidney transplantation shows it is feasible for non-mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes phenotype carriers of the m.3243A>G mutation to be considered for kidney transplantation in case of ESRD. These patients should not be excluded from transplant solely for their mitochondrial diagnosis.",
"affiliations": "Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center Amalia Children's Hospital, Nijmegen, The Netherlands.;Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center Amalia Children's Hospital, Nijmegen, The Netherlands.;Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center Amalia Children's Hospital, Nijmegen, The Netherlands.;Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center Amalia Children's Hospital, Nijmegen, The Netherlands.",
"authors": "de Laat|Paul|P|0000-0003-2541-3090;van Engelen|Nienke|N|;Wetzels|Jack F|JF|;Smeitink|Jan A M|JAM|;Janssen|Mirian C H|MCH|",
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"fulltext": "\n==== Front\nClin Kidney JClin Kidney JckjClinical Kidney Journal2048-85052048-8513Oxford University Press 3180729710.1093/ckj/sfz020sfz020Inherited Kidney DiseaseFive non-mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes phenotype adult patients with m.3243A>G mutation after kidney transplantation: follow-up and review of the literature http://orcid.org/0000-0003-2541-3090de Laat Paul 1van Engelen Nienke 1Wetzels Jack F 2Smeitink Jan A M 1Janssen Mirian C H 131 \nDepartment of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center Amalia Children’s Hospital, Nijmegen, The Netherlands2 \nDepartment of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands3 \nDepartment of Internal Medicine, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, The NetherlandsCorrespondence and offprint requests to: Mirian C.H. Janssen; E-mail: mirian.janssen@radboudumc.nl12 2019 21 4 2019 21 4 2019 12 6 840 846 03 9 2018 © The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA.2019This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nBackground\nRenal involvement in patients with the m.3243A>G mutation may result in end-stage renal disease (ESRD) requiring renal replacement therapy. Although kidney transplantations have been performed in a small number of patients, short- and long-term follow-up data are lacking.\n\nMethods\nWe describe five patients with the m.3243A<G mutation who received a kidney transplant, including follow-up data up to 13 years. We also summarize all cases (n = 13) of kidney transplantation in m.3243A>G carriers described in the literature.\n\nResults\nProteinuria with or without renal failure was the first clinical presentation of renal involvement in 13 of 18 (72%) patients. Focal segmental glomerulosclerosis (FSGS) was found in 9 of 13 (69%) biopsies. Sixteen of 18 (84%) patients developed hearing loss. All patients were diagnosed with diabetes mellitus, of whom eight (44%) developed the disease after transplantation. All patients with reported follow-up data (13/18) had stable kidney function from 6 months to 13 years of follow-up after transplantation.\n\nConclusions\nRenal involvement in carriers of the m.3243A>G mutation most commonly leads to proteinuria and FSGS and may lead to ESRD. Proper recognition of the mitochondrial origin of the renal disease in these patients is important for adequate treatment selection and suitable supportive care. This case series and review of the available literature on long-term follow-up after kidney transplantation shows it is feasible for non-mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes phenotype carriers of the m.3243A>G mutation to be considered for kidney transplantation in case of ESRD. These patients should not be excluded from transplant solely for their mitochondrial diagnosis.\n\nencephalomyopathykidney transplantationmitochondrial encephalomyopathylactic acidosis and stroke-like episodes (MELAS) syndromem.3243A>G mutationmaternally inherited diabetes deafness (MIDD)mitochondrial diseasemitochondrial myopathyZonMW PMRare40-41900-98-033\n==== Body\nINTRODUCTION\nSolid organ transplants are rarely performed in adult and paediatric patients with primary mitochondrial disease. It is unclear whether the underlying genetic disease has a significant impact on post-transplant morbidity and mortality.\n\nMitochondria\nMitochondria play an important role in cellular energy supply via the oxidative phosphorylation system (OXPHOS) producing adenosine triphosphate. Mitochondrial dysfunction can result from mutations in either nuclear DNA or mitochondrial DNA (mtDNA). The 37 genes of the mitochondrial genome encode for 22 transfer RNAs (tRNAs), 2 ribosomal RNAs and 13 subunits of the OXPHOS complexes I, III, IV and V. Nuclear genes encode the remaining 75 structural proteins of the OXPHOS [1, 2]. Human mitochondria number per cell varies.\n\nm.3243A>G mutation\nThe acronym MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) was first used in 1984 by Pavlakis et al. [3] to describe a group of patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. In 1990, the adenine to guanine transition at position 3243 of mtDNA (m.3243A>G) in the MT-TL1 gene-encoding tRNALEU(UUR) was found as the molecular basis for this disease [4, 5]. The m.3243A>G mutation in the MT-TL1 gene is the most common cause of MELAS syndrome, therefore the mutation is also known as the MELAS mutation. As this particular mutation—in the literature it is still referred to as the MELAS mutation—causes many different phenotypes, non-mitochondrial experts might get confused and draw inappropriate conclusions by searching literature with the term MELAS instead of m.3243A>G or alternative descriptions. This is exemplified by the fact that the mutation is also associated with diseases and conditions like maternally inherited diabetes deafness (MIDD) [6], hypertrophic cardiomyopathy [7], macular dystrophy [8], focal segmental glomerulosclerosis (FSGS) [9], chronic progressive external ophthalmoplegia [10], gastrointestinal involvement [11], increased risk of obstetric complications [12] and oligosymptomatic variants of MELAS [13].\n\nRenal involvement in the m.3243A>G carriers\nRenal involvement is often seen in patients carrying the m.3243A>G mutation. In children, renal involvement is seen in up to 50% of patients. Proximal tubular dysfunction, including Fanconi syndrome, is the most frequent clinical and pathological finding in biopsies [14]. In general, renal disease is part of a severe multi-organ disease in children with the m.3243A>G mutation, often with a poor prognosis [15]. In adults, ∼30% of the m.3243A>G mutation carriers have renal involvement [16]. The course of renal involvement varies from mild proteinuria to end-stage renal disease (ESRD) requiring renal replacement therapy. Pathological findings correspond with FSGS in ∼79% of patients [17]. Other findings are tubular dysfunction and severe hyaline changes within cytoplasm of smooth muscle cells of afferent arterioles and small arteries [17, 18].\n\nTwo interesting hypotheses have been described about the pathophysiology of the development of renal disease in patients with mitochondrial disease. First, the role of podocytes [17, 19, 20]. These are terminally differentiated cells that are unable to segregate mutant mtDNA between daughter cells so they are unable to undergo regenerative proliferation in response to cell loss. The second hypothesis suggests that vascular changes may contribute to the development of FSGS. The damaged vessel wall is characterized by hyaline changes in the cytoplasm of smooth muscle cells in afferent arterioles and small arteries showing signs of necrosis and apoptosis. In the end, vascular damage results in the loss of renal autoregulation [18]. Dysfunction of mitochondria in smooth muscle and vascular endothelial cells might cause early vascular damage [9].\n\nWhen renal disease occurs, comorbidity includes (sensorineural) hearing loss, cardiomyopathy and diabetes mellitus. In previous literature, patients were misdiagnosed with Alport syndrome although they did not have haematuria [21]. In patients with the m.3243A>G mutation, steroid treatment for proteinuria or nephrotic syndrome is ineffective and may induce or progress the development of myopathy and diabetes [9, 17, 22]. This may be due to the fact that symptoms are caused by mitochondrial alterations and nephron loss of vascular origin. After a period of time, some patients require renal replacement therapy. So far, only 13 patients carrying the m.3243A>G mutation that received a kidney transplant have been described [17, 18, 21, 23–25]. In this article we describe five patients from our Nijmegen cohort of carriers of the m.3243A>G mutation who received a kidney transplant, with special attention on the follow-up. Second, we review the patients in previously reported case reports who received a kidney transplant. Finally, we discuss the effects and possible side effects of kidney transplantation in these patients.\n\nMATERIALS AND METHODS\nPatients\nIn the Radboud Center for Mitochondrial Medicine, patients harboring the m.3243A>G mutation that underwent kidney transplantation were identified. The mitochondrial diagnoses were confirmed by DNA analysis using blood and urine samples. Five unrelated adult patients received a kidney transplant. We describe their cases using information from their medical records.\n\nMutation analysis and quantification of heteroplasmy levels\nHeteroplasmy levels were determined in urinary epithelial cells in all participants using Pyrosequencing technology (Pyrosequencing, Uppsala, Sweden) as described earlier by Lowik et al. [9]. The pyrosequence reaction of the m.3243A>G mutation had a precision of 1.5% and the mutation was detected from a heteroplasmy level of ≥5% [26].\n\nLiterature research\nThe search for available literature on kidney transplantation in patients with the m.3243A>G mutation was performed using online databases (PubMed, Cochrane, Web of Science) using the following keywords: MELAS, MIDD, renal transplantation, kidney transplantation, A3243G, m.3243A>G mutation, renal insufficiency, chronic kidney disease. We also included Medical Subject Headings terms if possible. Additional relevant articles were found using the references from the retrieved articles.\n\nRESULTS\nCase reports\nCase 1\nThe first patient is a 47-year-old female who first presented with renal symptoms during pregnancy at the age of 31 years. A caesarean section was performed due to signs of pre-eclampsia and foetal distress at 27 weeks amenorrhoea. Simultaneously she was diagnosed with nephrotic syndrome. Renal biopsy showed FSGS. The nephrotic syndrome was treated with prednisone, cyclophosphamide and plasmapheresis without any improvement. Four years later the patient was diagnosed with mitochondrial disease due to the m.3243A>G mutation, with a heteroplasmy level in leucocytes of 25%. She developed diabetes, possibly provoked by the high doses of prednisone. Haemodialysis was started at the age of 35 years. Three years later the patient received a kidney transplant from a post-mortem donor. Afterwards she showed no signs of rejection or side effects due to the immunosuppressive medication. Shortly after transplantation, the diabetes became persistent and was hard to regulate properly. Besides the renal complications of the m.3243A>G mutation, the patient also suffers from minor perceptive hearing loss, maculopathy, severe hypercholesterolaemia with intolerance for statins and possibly related sensorimotor axonal polyneuropathy. Recently she developed hypertrophic cardiomyopathy. Eight years after transplantation, kidney function is still stable without any signs of proteinuria. For immunosuppressive therapy, she uses prednisone and mycophenolate mofetil.\n\nCase 2\nThe second case is a 48-year-old male who first presented with proteinuria at the age of 25 years. Seven years later, proteinuria deteriorated and the patient’s creatinine level increased, leading to renal failure. Biopsy was consistent with FSGS. He developed diabetes, which was difficult to manage. At the age of 36 years, the patient received a kidney transplant from his human leucocyte antigen–matched brother. One year post-transplantation, the m.3243A>G mutation was detected, with a heteroplasmy level in leucocytes of 25%. After transplantation and using high doses of prednisone, the patient’s diabetes became insulin-dependent and was even more difficult to manage. Six years after transplantation, he was diagnosed with moderate perceptive hearing loss and started using hearing aids. In the same period, the ophthalmologist found mild cataract and retina pigment epithelial alterations, but no signs of diabetic retinopathy. Ten years after transplantation, the patient is still using cyclosporine and prednisone. He has left ventricle hypertrophy and obstructive sleep apnoea. His kidney function is stable without any signs of proteinuria.\n\nCase 3\nThe third patient is a 41-year-old female. She developed pancreatitis at a young age with recurrent episodes. Kidney dysfunction became apparent at the age of 17 years. Kidney biopsy showed signs of chronic ischaemia. At the age of 20 years, the patient was diagnosed with mitochondrial disease based on a complex I enzyme deficiency in muscle; at that time genetic investigation was not performed. At the age of 27 years, the patient was diagnosed with ESRD. Later that year, at the age of 28 years, she received a kidney transplant from a post-mortem, heart-beating donor. Before leaving the hospital, renal function was normal and there was no sign of proteinuria. Two years after transplantation, cyclosporine was stopped without complications. She is still using prednisone and mycophenolate mofetil as immunosuppressants. Four years after transplantation, the patient started to develop non-insulin-dependent diabetes, but it was not until 8 years post-transplantation that mtDNA investigation confirmed the m.3243A>G mutation at the age of 36 years, with a heteroplasmy level in leucocytes of 35%. The patient’s mother and sister were also diagnosed with the m.3243A>G mutation.\n\nCase 4\nThe fourth patient is a 57-year-old female. As a child, the patient was treated for epilepsy until she was 10 years old. At the age of 31 and 33 years, the patient gave birth to two children. During both pregnancies she suffered from haemolysis, elevated liver enzymes and low platelets syndrome. At the age of 40 years, proteinuria was detected (2.2 g/L). The patient also developed sensorineural hearing loss and started to use hearing aids. In the same year, she also developed diabetes mellitus, which was treated at first with oral medication. At the age of 41 years, renal failure, proteinuria and hypertension were present. Kidney biopsy 3 years later showed immunoglobulin A (IgA) nephropathy and no signs of Alport disease. At the age of 49 years, the renal failure and proteinuria were treated with prednisone, but did not improve, necessitating peritoneal dialysis. Simultaneously the patient’s diabetes became insulin dependent. At the age of 52 years, the patient received a kidney transplant from a postmortem, heart-beating donor. Follow-up after 2 years showed severe left ventricle hypertrophy and diastolic heart failure that remained stable 4 years after transplantation. Four years post-transplantation, the m.3243A>G mutation was found, with a heteroplasmy level in leucocytes of 6%. In the same year, the patient was diagnosed with central scotoma causing visual problems. Currently the kidney function is stable with mild microalbuminuria. She is using prednisone and tacrolimus as immunosuppressants.\n\nCase 5\nThe fifth patient is a 43-year-old female who was diagnosed with diabetes at the age of 13 years. At the age of 21 years, her first pregnancy was complicated by an intrauterine fetal death. At the age of 23 years, a healthy daughter was born with a planned caesarean section. She developed diabetic retinopathy and nephropathy at the age of 28 and 29 years, respectively. The patient suffered from hypertrophic cardiomyopathy, leading to heart failure at the age of 35 years. Two years later, haemodialysis was started. In the same year, the patient received a kidney transplant from her brother complicated by a non-ST segment elevation myocardial infarction acute coronary syndrome 3 days later. One month later, creatinine levels were increasing, showing signs of transplant rejection for which treatment with intravenous methylprednisolone was started. During the treatment, a second acute coronary syndrome occurred. Later she was admitted to the hospital because of sepsis caused by a Staphylococcus aureus infection. After treatment with flucoxacillin, creatinine levels increased and treatment with methylprednisolone was started again. Kidney function was not improving, and for that reason she was treated with anti-thymocyte globulin (ATG) four times. During this treatment, the patient suffered from a third acute coronary syndrome. A year after the ATG treatment, the immunosuppressive treatment was switched from triple therapy to sirolimus and azathioprine. At the age of 40 years, 3 years after transplantation, the m.3243A>G mutation was found as part of a family survey, after her niece was diagnosed with the same mutation. The heteroplasmy level in leucocytes was 16%. Further genetic investigation within the family showed that the patient’s sister and mother of the niece also carried the m.3243A>G mutation. Almost 5 years after transplantation, the patient has stable moderate kidney function (Modification of Diet in Renal Disease estimated glomerular filtration rate 17 mL/min/1.73 m2) without any signs of proteinuria.\n\nSummary of characteristics of all patients\nIn the literature, we found six articles describing cases of patients with the m.3243A>G mutation who received kidney transplantation. The characteristics of our patients and the previously reported cases are summarized in Table 1. All patients successfully received kidney transplantation. We found that proteinuria with or without renal failure was the first clinical presentation of renal involvement in 13 of 18 (72%) patients. FSGS was found in 9 of 13 (69%) biopsies. Sixteen of 18 (89%) patients developed hearing loss. All patients were diagnosed with diabetes mellitus, eight of whom (44%) developed the disease after transplantation. All patients for whom follow-up data were reported (11/18) had stable kidney function at 6 months to 13 years of follow-up.\n\n\nTable 1 A summary of the characteristics of patients who received a renal transplantation\n\nPatient\tAuthor\tSex\tFirst renal symptom (agea)\tBiopsy (agea)\tAgea at RTx (donor)\tHearing loss (agea)\tAgea of onset DM (therapy)\tAgea at diagnosis\tHeteroplasmy (%)b\tPost-transplantationc\t\nCase 1\tThis report\tF\tNS (31)\tFSGS (31)\t38 (PM)\tYes\t35 (OM; IP)\t35\t25/28\t8; KF stable, PR−\t\nCase 2\t This report\tM\tPR (25)\tFSGS (32)\t36 (HLA)\tYes (42)\t32 (OM; IP)\t37\t26/11\t10; KF stable, PR−\t\nCase 3\t This report\tF\tLoss of renal function\tChronic ischaemia (17)\t28 (PM)\tNo\t32 (OM)\t35\t35/44\t 13; KF stable\t\nCase 4\t This report\tF\tPR (40)\tIgA-nephropathy\t52 (PM)\tYes (40)\t41 (I)\t56\t17/31\t4; KF stable, MA+\t\nCase 5\t This report\tF\tNephropathy (29)\t–f\t36 (HLA)\tNo\t13 (I)\t40\t16/31\t5; KF stable, PR−\t\n1\tJansen et al. [21]\tF\tPR + PRF\t–f\t38\tYes\t38 (I)\t–f\t12/ f\t–f\t\n2\tJansen et al. [21]\tF\tPR + PRF\tCLGN (44)\t47\tYes\t48 (D)\t–f\t6/ f\t–f\t\n3\tJansen et al. [21]\tF\tPR + PRF\tFSGS\t25\tYes\t25 (OM)\t–f\t34/ f\t–f\t\n4\tJansen et al. [21]\tF\tPR + PRF\tChronic GS + hyalinized glomeruli\t36\tYes\t34 (OM; IP)\t–f\t18/ f\t–f\t\n5\tGuery [17]\tF\tPR + ESRD (41)\t–f\t43\tYes (36)\t46 (OM)\t–f\t\n\ne\n\n\nf\n\n\t4; SC 63 µmol/L\t\n6\tGuery [17]\tM\tPR (32)\t–f\t39\tYes\t34 (D; IP)\t–f\t\n\ne\n\n\nf\n\n\t–f\t\n7\tGuery [17]\tF\tPR (30)\t–f\t42\tYes (42)\t42 (I)\t–f\t\n\ne\n\n\nf\n\n\t5; SC 92 µmol/L\t\n8\tGuery [17]\tF\tPR (5)\tFSGS (14)\t17\tYes\t17 (I)\t–f\t\n\ne\n\n\nf\n\n\t2; SC 93 µmol/L\t\n9\tDoleris et al. [18]\tF\tPR (18)\tFSGS (21)\t40\tYes (28)\t33 (I)\t–f\t59/ f\t–f\t\n10\tLederer et al. [23]\tM\tNS + PRF (43)d\tFSGS + tubulaire atrophy\t52\tYes (19)\t22 (I)\t57\t–f\t6; SC 1.7 mg/dL\t\n11\tHumeidan et al. [25]\tF\t–f\tFSGS\t33\tYes\t\n\nf\n (D)\t–f\t–f\t–f\t\n12\tSeidowsky et al. [24]\tM\tPRF\tFSGS\t42\tYes (38)\t32 (I)\t43\t10/ f\t4; SC 220 µmol/L, PR 0.55 g/day\t\n13\tSeidoswky et al. [24]\tF\tPRF\tFSGS\t27\tYes (11)\t27 (f)\t25\t40/ f\t0.5; KF stable\t\na Age in years.\n\nb Blood/urine.\n\nc Years after transplantation.\n\nd The patient died at the age of 58 years due to progressive and complicated disease.\n\ne Heteroplasmy in blood reported between 5% and 25%. fData unknown.\n\nF, female; M, male; NS, nephrotic syndrome; PR, proteinuria; PRF, progressive renal failure; IgM-N, IgM nephropathy; CLGN, chronic lobular glomerulonephritis; GS, glomerulosclerosis; PM, post-mortem donor (unrelated); HLA, HLA-matched donor (related); DM, diabetes mellitus; OM, oral medication; IP, insulin post-transplantation; I, insulin; D, diet; KF, kidney function; MA, microalbuminuria; SC, serum creatinine.\n\nDISCUSSION\nWe describe five not yet reported patients with the m.3243A>G mutation who received a kidney transplant. We also summarized 13 cases of patients with the same mitochondrial mutation described in the literature so far, providing an overview of 18 post-kidney transplantation patients carrying the m.3243A>G mutation. While mitochondrial disease patients may have a shortened life expectancy due to progression of their underlying disease, successful kidney transplantation, when feasible, allows for additional years of likely functional survival.\n\nClinical phenotype and follow-up\nMELAS syndrome is one of the possible phenotypic presentations of the m.3243A>G mutation in the MT-TL1 gene and probably one of the most acknowledged. However, in previous reports about the phenotypic expressions in carriers of the m.3243A>G mutation, MELAS syndrome represents only a small proportion of the clinical spectrum [13, 27]. Although all 18 patients described in this article carried the m.3243A>G mutation, none had the typical phenotypic presentation of MELAS syndrome with stroke-like episodes. The phenotypic spectrum of the 18 patients described in this article is clinically heterogeneous. In 72% of patients, proteinuria with or without renal failure was the first renal symptom. All patients developed diabetes, and nearly all developed hearing loss (which combined is known as MIDD). Other symptoms that were present include retinal dystrophy, cardiomyopathy and myopathy. Three of 14 women had obstetric complications, including pre-eclampsia and foetal death. In these cases, the obstetric complications were the first sign of mitochondrial disease, especially the first presentation of renal involvement in the form of proteinuria and hypertension. In general, the classic MELAS phenotype is associated with a poor outcome [28]. This could be seen as a reason to withhold kidney transplant in these patients if they develop ESRD. However, in this study we report on 18 cases of patients carrying the m.3243A>G mutation, with a non-MELAS phenotype, with an average follow-up of 5.6 (range 0.5–13) years after transplantation. This indicates that in a selection of patients carrying the m.3243A>G mutation, kidney transplantation is feasible.\n\nBiopsy\nNine of 13 (69%) patients’ kidney biopsies showed FSGS. Diabetic glomerulopathy was not found at all. In the article of Guery [17], FSGS was diagnosed in 79% of the biopsies. Hirano et al. [29] detected FSGS in 9 of 16 (56%) patients. But the spectrum of possible lesions is more variable, including tubulo-interstitial nephropathy, bilateral enlarged cystic kidneys [17], chronic interstitial nephritis [29], IgA nephropathy [30], neoplasm [22], cystic renal disease [31] and chronic ischaemia in one patient from our own case series.\n\nRelated donors\nFamily members as potential donors should be up for discussion. Two of our patients (Cases 2 and 5) received kidney transplantation from a brother and both patients were diagnosed with the m.3243A>G mutation several years after transplantation. It is recommended to be aware of the diagnosis of mitochondrial disease in case of multisystemic problems, such as renal disease, cardiac failure, diabetes and deafness. The presence of the mutation in potential related donor candidates should be ruled out before transplantation, as the risk of transmission of the mutation in the maternal lineage is very high [26].\n\nAnaesthetics during transplantation\nA recently published study summarized important considerations of the systematic effects of MELAS syndrome for anaesthetics during kidney transplantation surgery [25]. They recommend standard evaluation of electrolyte abnormalities and the possible onset of diabetes, as these are common co-morbidities. Because of the increased risk for cardiomyopathy and conduction abnormalities, they recommend a preoperative electrocardiogram and a low threshold for an echocardiogram. Neuromuscular blockade (such as propofol) should be administered carefully, because reports have described prolonged effects of neuromuscular-blocking agents in patients with mitochondrial diseases [32]. During surgery, patients may be at an increased risk for malignant hyperthermia. Administration of glucose-containing fluids is also recommended to prevent hypoglycaemic and catabolic episodes in response to the stress of surgery.\n\nDiabetes\nIt is not the transplantation itself but the post-transplant therapy with high doses of prednisone that may provoke or progress the development of diabetes in these patients. All 18 patients were diagnosed with diabetes, 8 of whom (44%) developed diabetes following transplantation. The non-insulin-dependent diabetes in four patients became insulin dependent after transplantation. This results in the current use of insulin in 12 of 18 (67%) patients. It should be noted that treatment with metformin is contraindicated in patients with mitochondrial disease because of the elevated risk for lactic acidosis.\n\nRecognition of the m.3243A>G mutation carriers\nStudies have suggested that renal involvement might be the first sign of mitochondrial disease [17, 33]. Recognition of the disease is difficult when only renal symptoms are present. Other symptoms such as deafness and diabetes may lead to the proper diagnosis. However, in some cases they can be misleading, for example, in the case of Alport syndrome. It is important to recognize the possible mitochondrial origin of renal failure in a patient. Possible features that may point to a mitochondrial origin of proteinuria and renal failure are unresponsiveness of nephrotic syndrome to steroid therapy, steroid therapy being complicated by diabetes or the presence of other symptoms frequently seen in carriers of the m.3243A>G mutation. Besides neuromuscular symptoms such as myopathy, dementia, epilepsy and migraines, these also include diabetes, deafness, cardiomyopathy, retinal dystrophy and the presence of these symptoms in (maternal) family members. Either alone or combined, these symptoms should make every doctor consider the possibility of the existence of a mitochondrial disease. In general, we would like to recommend a liberal policy in determining the m.3243A>G mutation in patients with renal failure, in combination with hearing problems, diabetes, neurological involvement and/or cardiac failure.\n\nCONCLUSION\nRenal involvement in carriers of the m.3243A>G mutation most commonly leads to proteinuria and FSGS and may lead to ESRD. Proper recognition of the mitochondrial origin of the renal disease in all patients is important for adequate treatment selection and suitable supportive care. This case series and review of the literature on long-term follow-up after kidney transplantation shows that it is feasible for carriers of the m.3243A>G mutation, with a non-MELAS phenotype, to be considered for kidney transplantation. These patients should not be excluded from transplant solely because of their mitochondrial diagnosis.\n\nFUNDING\nPart of this work was supported by the ZonMW PMRare Grant (40-41900-98-033). \n\nCONFLICT OF INTEREST STATEMENT\nJ.A.M.S. is the founding chief executive officer of Khondrion BV.\n==== Refs\nREFERENCES\n1 \nKoopman WJ , Beyrath J , Fung C-W \net al\nMitochondrial disorders in children: toward development of small-molecule treatment strategies . EMBO Mol Med 2016 ; 8 : 311 –327 26951622 \n2 \nVeltri KL , Espiritu M , Singh G. \nDistinct genomic copy number in mitochondria of different mammalian organs . J Cell Physiol 1990 ; 143 : 160 –164 2318903 \n3 \nPavlakis SG , Phillips PC , DiMauro S \net al\nMitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome . Ann Neurol 1984 ; 16 : 481 –488 6093682 \n4 \nGoto Y , Nonaka I , Horai S. \nA mutation in the tRNALeu(UU) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies . Nature 1990 ; 348 : 651 –653 2102678 \n5 \nKobayashi Y , Momoi MY , Tominaga K \net al\nA point mutation in the mitochondrial tRNALeu(UUR) gene in MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) . Biochem Biophys Res Commun 1990 ; 173 : 816 –822 2268345 \n6 \nvan den Ouweland JMW , Lemkes HHPJ , Ruitenbeek W \net al\nMutation in mitochondrial tRNALeu(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness . Nat Genet 1992 ; 1 : 368 –371 1284550 \n7 \nLev D , Nissenkorn A , Leshinsky-Silver E \net al\nClinical presentations of mitochondrial cardiomyopathies . Pediatr Cardiol 2004 ; 25 : 443 –450 15185043 \n8 \nde Laat P , Smeitink JA , Janssen MC \net al\nMitochondrial retinal dystrophy associated with the m.3243A>G mutation . Ophthalmology 2013 ; 120 : 2684 –2696 23806424 \n9 \nLowik MM , Hol FA , Steenbergen EJ \net al\nMitochondrial tRNALeu(UUR) mutation in a patient with steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis . Nephrol Dial Transplant 2005 ; 20 : 336 –341 15585516 \n10 \nJohns DR. \nMitochondrial DNA and disease . N Engl J Med 1995 ; 333 : 638 –644 7637726 \n11 \nde Laat P , Zweers HE , Knuijt S \net al\nDysphagia, malnutrition and gastrointestinal problems in patients with mitochondrial disease caused by the m3243A>G mutation . Neth J Med 2015 ; 73 : 30 –36 26219939 \n12 \nde Laat P , Fleuren LH , Bekker MN \net al\nObstetric complications in carriers of the m.3243A>G mutation, a retrospective cohort study on maternal and fetal outcome . Mitochondrion 2015 ; 25 : 98 –103 26455484 \n13 \nNesbitt V , Pitceathly RDS , Turnbull DM \net al\nThe UK MRC Mitochondrial Disease Patient Cohort Study: clinical phenotypes associated with the m.3243A>G mutation—implications for diagnosis and management . J Neurol Neurosurg Psychiatry 2013 ; 84 : 936 –938 23355809 \n14 \nMartin-Hernandez E , Garcia-Silva MT , Vara J \net al\nRenal pathology in children with mitochondrial diseases . Pediatr Nephrol 2005 ; 20 : 1299 –1305 15977024 \n15 \nHall AM , Unwin RJ , Hanna MG \net al\nRenal function and mitochondrial cytopathy (MC): more questions than answers? \nQJM \n2008 ; 101 : 755 –766 18487272 \n16 \nGuillausseau PJ , Massin P , Dubois-LaForgue D \net al\nMaternally inherited diabetes and deafness: a multicenter study . Ann Intern Med 2001 ; 134 (9 Pt 1 ): 721 –728 11329229 \n17 \nGuery B. \nThe spectrum of systemic involvement in adults presenting with renal lesion and mitochondrial tRNALeu gene mutation . J Am Soc Nephrol 2003 ; 14 : 2099 –2108 12874464 \n18 \nDoleris LM , Hill GS , Chedin P \net al\nFocal segmental glomerulosclerosis associated with mitochondrial cytopathy . Kidney Int 2000 ; 58 : 1851 –1858 11044204 \n19 \nGucer S , Talim B , Asan E \net al\nFocal segmental glomerulosclerosis associated with mitochondrial cytopathy: report of two cases with special emphasis on podocytes . Pediatr Dev Pathol 2005 ; 8 : 710 –717 16328667 \n20 \nYanagihara C , Oyama A , Tanaka M \net al\nAn autopsy case of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome with chronic renal failure . Intern Med 2001 ; 40 : 662 –665 11506313 \n21 \nJansen JJ , Maassen JA , van der Woude FJ \net al\nMutation in mitochondrial tRNALeu(UUR) gene associated with progressive kidney disease . J Am Soc Nephrol 1997 ; 8 : 1118 –1124 9219161 \n22 \nPiccoli GB , Bonino LD , Campisi P \net al\nChronic kidney disease, severe arterial and arteriolar sclerosis and kidney neoplasia: on the spectrum of kidney involvement in MELAS syndrome . BMC Nephrol 2012 ; 13 : 9 22353239 \n23 \nLederer SR , Klopstock T , Schiffl H. \nMELAS: a mitochondrial disorder in an adult patient with a renal transplant . Wien Klin Wochenschr 2010 ; 122 : 363 –365 20552288 \n24 \nSeidowsky A , Hoffmann M , Glowacki F \net al\nRenal involvement in MELAS syndrome – a series of 5 cases and review of the literature . Clin Nephrol 2013 ; 80 456 –463 22909780 \n25 \nHumeidan ML , Dalia J , Traetow WD. \nAnesthetic considerations for renal transplant surgery in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes syndrome: a case report . J Clin Anesth 2016 ; 34 : 344 –347 27687406 \n26 \nde Laat P , Koene S , Heuvel LP \net al\nInheritance of the m.3243A>G mutation . JIMD Rep 2013 ; 8 : 47 –50 23430519 \n27 \nde Laat P , Koene S , van de Heuvel LPWJ \net al\nClinical features and heteroplasmy in blood, urine and saliva in 34 Dutch families carrying the m.3243A>G mutation . J Inherit Metab Dis 2012 ; 35 : 1059 –1069 22403016 \n28 \nLiu C-H , Chang C-H , Kuo H-C \net al\nPrognosis of symptomatic patients with the A3243G mutation of mitochondrial DNA . J Formos Med Assoc 2012 ; 111 : 489 –494 23021505 \n29 \nHirano M , Konishi K , Arata N \net al\nRenal complications in a patient with A-to-G mutation of mitochondrial DNA at the 3243 position of leucine tRNA . Intern Med 2002 ; 41 : 113 –118 11868597 \n30 \nYamagata K. \nMitochondrial DNA mutations in focal segmental glomerulosclerosis lesions . J Am Soc Nephrol 2002 ; 13 : 1816 –1823 12089377 \n31 \nNiaudet P. \nMitochondrial disorders and the kidney . Arch Dis Child 1998 ; 78 : 387 –390 9623410 \n32 \nSasano N , Fujita Y , So M \net al\nAnesthetic management of a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) during laparotomy . J Anesth 2007 ; 21 : 72 –75 17285419 \n33 \nCheong HI , Chae JH , Kim JS \net al\nHereditary glomerulopathy associated with a mitochondrial tRNALeu gene mutation . Pediatr Nephrol 1999 ; 13 : 477 –480 10452273\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2048-8505",
"issue": "12(6)",
"journal": "Clinical kidney journal",
"keywords": "encephalomyopathy; kidney transplantation; lactic acidosis and stroke-like episodes (MELAS) syndrome; m.3243A>G mutation; maternally inherited diabetes deafness (MIDD); mitochondrial disease; mitochondrial encephalomyopathy; mitochondrial myopathy",
"medline_ta": "Clin Kidney J",
"mesh_terms": null,
"nlm_unique_id": "101579321",
"other_id": null,
"pages": "840-846",
"pmc": null,
"pmid": "31807297",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article",
"references": "9623410;7637726;2102678;6093682;23021505;20552288;12089377;2318903;1284550;16328667;11044204;11506313;26951622;12874464;10452273;22909780;15585516;23806424;23430519;15185043;27687406;22353239;15977024;11868597;18487272;17285419;2268345;26219939;9219161;26455484;22403016;23355809;11329229",
"title": "Five non-mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes phenotype adult patients with m.3243A>G mutation after kidney transplantation: follow-up and review of the literature.",
"title_normalized": "five non mitochondrial myopathy encephalopathy lactic acidosis and stroke like episodes phenotype adult patients with m 3243a g mutation after kidney transplantation follow up and review of the literature"
} | [
{
"companynumb": "NL-MYLANLABS-2020M1026475",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISONE"
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"drugadditional": null,
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{
"abstract": "BACKGROUND\nKaposi's sarcoma (KS) continues to be the most common human immunodeficiency virus (HIV)-associated neoplasm with considerable morbidity and mortality. While lesions normally resolve upon initiation of antiretroviral therapy (ART), recrudescence or unmasking of KS lesions may occur as part of immune reconstitution inflammatory syndrome (IRIS). Treatment of unmasking KS-IRIS is not yet standardised.\n\n\nOBJECTIVE\nTo report the successful treatment of a patient with fulminating mucocutaneous unmasking KS-IRIS by maintaining ART and using pegylated liposomal doxorubicin (PLD).\n\n\nMETHODS\nThe patient, a 39-year-old HIV-positive male with no previous history of KS presented with a 2-week history of cutaneous and oral KS lesions that had disseminated rapidly over the preceding 4 days. The KS lesions appeared 8 weeks after recommencing ART. At the time of this presentation, his CD4+ count was 742 cells/mm(3) with a HIV viral load <400 copies/ml. ART was maintained and treatment with PLD commenced.\n\n\nRESULTS\nDespite the rapid dissemination of KS lesions, virus was undetectable in plasma. In a late-stage vasoformative lesion, immunohistochemistry (IHC) for human herpesvirus 8 (HHV-8) antigen was light and diffuse, with stippled deposits within endothelial cell nuclei. Virus extracted from the lesion was HHV-8 subtype A. The patient responded well to PLD, relapsed a year later, but after further PLD, has remained well for the following 5 years.\n\n\nCONCLUSIONS\nDespite the absence of HHV-8 viraemia, this is clearly a case of unmasking KS-IRIS. It demonstrates that this entity can be successfully treated by maintaining ART and administering PLD.",
"affiliations": "School of Dentistry and Oral Health, Griffith University, Queensland, Australia. d.speicher@griffith.edu.au",
"authors": "Speicher|David J|DJ|;Sehu|Marjoree M|MM|;Johnson|Newell W|NW|;Shaw|David R|DR|",
"chemical_list": "D044966:Anti-Retroviral Agents; D000903:Antibiotics, Antineoplastic; D004279:DNA, Viral; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1386-6532",
"issue": "57(3)",
"journal": "Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology",
"keywords": null,
"medline_ta": "J Clin Virol",
"mesh_terms": "D000328:Adult; D044966:Anti-Retroviral Agents; D000903:Antibiotics, Antineoplastic; D018791:CD4 Lymphocyte Count; D004279:DNA, Viral; D004317:Doxorubicin; D004359:Drug Therapy, Combination; D005838:Genotype; D015658:HIV Infections; D019288:Herpesvirus 8, Human; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D008297:Male; D008969:Molecular Sequence Data; D010949:Plasma; D011092:Polyethylene Glycols; D012514:Sarcoma, Kaposi; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "9815671",
"other_id": null,
"pages": "282-5",
"pmc": null,
"pmid": "23578530",
"pubdate": "2013-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Successful treatment of an HIV-positive patient with unmasking Kaposi's sarcoma immune reconstitution inflammatory syndrome.",
"title_normalized": "successful treatment of an hiv positive patient with unmasking kaposi s sarcoma immune reconstitution inflammatory syndrome"
} | [
{
"companynumb": "AU-GILEAD-2014-0093997",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TENOFOVIR DISOPROXIL FUMARATE"
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{
"abstract": "Statins are widely used for lipid lowering in patients with coronary artery disease (CAD), but increasing evidence indicates an association between statin use and new-onset of diabetes mellitus (NODM). Epicardial adipose tissue (EAT) refers to the visceral fat surrounding the heart, which is associated with metabolic diseases. We sought to determine the association between EAT thickness and NODM in CAD patients treated with high-intensity statins.\n\n\n\nWe conducted a retrospective medical record review of CAD patients treated with high-intensity statins for at least 6 months after percutaneous coronary intervention performed between January 2009 and June 2013 at Seoul National University Bundang Hospital. EAT thickness was measured by echocardiography using standardized methods.\n\n\n\nA total of 321 patients were enrolled, who received high-intensity statins for a mean of 952 days; atorvastatin 40 mg in 204 patients (63.6%), atorvastatin 80 mg in 57 patients (17.8%), and rosuvastatin 20 mg in 60 patients (18.7%). During the follow-up period of 3.9 ± 1.7 years, NODM occurred in 40 patients (12.5%). On Cox proportional-hazard regression analysis, EAT thickness at systole [for each 1 mm: hazard ratio (HR) 1.580; 95% confidence interval (CI) 1.346-1.854; P < 0.001] and prediabetes at baseline (HR 4.321; 95% CI 1.998-9.349; P < 0.001) were the only independent predictors of NODM. Using binary cutoff values derived from the receiver operating characteristic curve analysis, EAT thickness at systole larger than 5.0 mm had an HR of 3.402 (95% CI 1.751-6.611, P < 0.001), sensitivity of 52.5%, and specificity of 80.8% for predicting NODM. Also, patients with EAT thickness ≥ 5 mm and prediabetes at baseline had a 12.0-times higher risk of developing NODM compared to the risk noted in patients with EAT thickness < 5 mm and normal glucose tolerance at baseline.\n\n\n\nEpicardial adipose tissue thickness at systole is a consistent independent predictor of NODM in patients with CAD treated with high-intensity statins. Such predictors may help physicians plan adequate surveillance for early detection of NODM.",
"affiliations": "Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumiro173 Beongil, Bundang, Seongnam, Gyeonggi, 13620, South Korea.;Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.;Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumiro173 Beongil, Bundang, Seongnam, Gyeonggi, 13620, South Korea.;Division of Cardiology, Hallym University Hangang Sacred Heart Hospital, Seoul, South Korea.;Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumiro173 Beongil, Bundang, Seongnam, Gyeonggi, 13620, South Korea.;Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumiro173 Beongil, Bundang, Seongnam, Gyeonggi, 13620, South Korea.;Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumiro173 Beongil, Bundang, Seongnam, Gyeonggi, 13620, South Korea.;Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumiro173 Beongil, Bundang, Seongnam, Gyeonggi, 13620, South Korea.;Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumiro173 Beongil, Bundang, Seongnam, Gyeonggi, 13620, South Korea.;Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumiro173 Beongil, Bundang, Seongnam, Gyeonggi, 13620, South Korea.;Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumiro173 Beongil, Bundang, Seongnam, Gyeonggi, 13620, South Korea. flammeus1@gmail.com.;Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumiro173 Beongil, Bundang, Seongnam, Gyeonggi, 13620, South Korea.;Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumiro173 Beongil, Bundang, Seongnam, Gyeonggi, 13620, South Korea.;Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumiro173 Beongil, Bundang, Seongnam, Gyeonggi, 13620, South Korea.",
"authors": "Kang|Jeehoon|J|;Kim|Young-Chan|YC|;Park|Jin Joo|JJ|;Kim|Sehun|S|;Kang|Si-Hyuck|SH|;Cho|Young Jin|YJ|;Yoon|Yeonyee E|YE|;Oh|Il-Young|IY|;Yoon|Chang-Hwan|CH|;Suh|Jung-Won|JW|;Cho|Young-Seok|YS|0000-0001-9944-9868;Youn|Tae-Jin|TJ|;Chae|In-Ho|IH|;Choi|Dong-Ju|DJ|",
"chemical_list": "D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000068718:Rosuvastatin Calcium; D000069059:Atorvastatin",
"country": "England",
"delete": false,
"doi": "10.1186/s12933-017-0650-3",
"fulltext": "\n==== Front\nCardiovasc DiabetolCardiovasc DiabetolCardiovascular Diabetology1475-2840BioMed Central London 65010.1186/s12933-017-0650-3Original InvestigationIncreased epicardial adipose tissue thickness is a predictor of new-onset diabetes mellitus in patients with coronary artery disease treated with high-intensity statins Kang Jeehoon medikang@gmail.com 12Kim Young-Chan kkim0206@gmail.com 2Park Jin Joo jinjooparkmd@gmail.com 1Kim Sehun mdsehun@gmail.com 3Kang Si-Hyuck eandp303@gmail.com 1Cho Young Jin yino.md@gmail.com 1Yoon Yeonyee E. islandtea@gmail.com 1Oh Il-Young spy510@gmail.com 1Yoon Chang-Hwan changhwanyoon@gmail.com 1Suh Jung-Won suhjw1@gmail.com 1http://orcid.org/0000-0001-9944-9868Cho Young-Seok +82-31-787-7018flammeus1@gmail.com 14Youn Tae-Jin ytjmd@snubh.org 14Chae In-Ho ihchae@snu.ac.kr 14Choi Dong-Ju djchoi@snubh.org 141 0000 0004 0647 3378grid.412480.bDepartment of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumiro173 Beongil, Bundang, Seongnam, Gyeonggi 13620 South Korea 2 0000 0001 0302 820Xgrid.412484.fDepartment of Internal Medicine, Seoul National University Hospital, Seoul, South Korea 3 0000 0004 0647 5322grid.413641.5Division of Cardiology, Hallym University Hangang Sacred Heart Hospital, Seoul, South Korea 4 0000 0004 0470 5905grid.31501.36Seoul National University College of Medicine, Seoul, South Korea 11 1 2018 11 1 2018 2018 17 108 9 2017 23 12 2017 © The Author(s) 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nStatins are widely used for lipid lowering in patients with coronary artery disease (CAD), but increasing evidence indicates an association between statin use and new-onset of diabetes mellitus (NODM). Epicardial adipose tissue (EAT) refers to the visceral fat surrounding the heart, which is associated with metabolic diseases. We sought to determine the association between EAT thickness and NODM in CAD patients treated with high-intensity statins.\n\nMethods\nWe conducted a retrospective medical record review of CAD patients treated with high-intensity statins for at least 6 months after percutaneous coronary intervention performed between January 2009 and June 2013 at Seoul National University Bundang Hospital. EAT thickness was measured by echocardiography using standardized methods.\n\nResults\nA total of 321 patients were enrolled, who received high-intensity statins for a mean of 952 days; atorvastatin 40 mg in 204 patients (63.6%), atorvastatin 80 mg in 57 patients (17.8%), and rosuvastatin 20 mg in 60 patients (18.7%). During the follow-up period of 3.9 ± 1.7 years, NODM occurred in 40 patients (12.5%). On Cox proportional-hazard regression analysis, EAT thickness at systole [for each 1 mm: hazard ratio (HR) 1.580; 95% confidence interval (CI) 1.346–1.854; P < 0.001] and prediabetes at baseline (HR 4.321; 95% CI 1.998–9.349; P < 0.001) were the only independent predictors of NODM. Using binary cutoff values derived from the receiver operating characteristic curve analysis, EAT thickness at systole larger than 5.0 mm had an HR of 3.402 (95% CI 1.751–6.611, P < 0.001), sensitivity of 52.5%, and specificity of 80.8% for predicting NODM. Also, patients with EAT thickness ≥ 5 mm and prediabetes at baseline had a 12.0-times higher risk of developing NODM compared to the risk noted in patients with EAT thickness < 5 mm and normal glucose tolerance at baseline.\n\nConclusion\nEpicardial adipose tissue thickness at systole is a consistent independent predictor of NODM in patients with CAD treated with high-intensity statins. Such predictors may help physicians plan adequate surveillance for early detection of NODM.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s12933-017-0650-3) contains supplementary material, which is available to authorized users.\n\nKeywords\nStatinNew-onset diabetes mellitusEpicardial adipose tissueCoronary artery diseaseEchocardiographyissue-copyright-statement© The Author(s) 2018\n==== Body\nIntroduction\nEpicardial adipose tissue (EAT) refers to the visceral fat surrounding the heart, which can be easily measured in the clinic with standard transthoracic echocardiography [1]. Previous studies have shown the relationship of EAT with metabolic syndrome [2], atherosclerosis [3], glucose intolerance [4] and high blood pressure [5]. Especially in patients with coronary artery disease, EAT can release free fatty acid in the proximity of coronaries arteries, which disturbs vascular homeostasis and endothelial function [6]. Based on various studies, EAT has been suggested to be a promising indicator for the detection of high cardio-metabolic risk [7].\n\nIn patients with high cardiovascular risk, statins have been widely used to lower lipid levels. Although statins are effective in reducing the rate of cardiovascular events and mortality [8], there are consistent concerns regarding the association between statin use and increased rates of diabetes mellitus (DM) [9, 10]. Despite the clinical importance of NODM in patients with cardiovascular disease, previous studies have shown inconsistent results regarding the predictors of statin-associated NODM [11–13].\n\nBecause EAT is a sensitive biomarker of metabolic status, we hypothesized that EAT thickness may be associated with the occurrence of glucose intolerance in patients with coronary artery disease (CAD) treated with high-intensity statin therapy. We also evaluated the clinical utility of EAT thickness as a predictor of NODM in these patients.\n\nMethods\nStudy population\nThe study retrospectively enrolled patients who underwent percutaneous coronary intervention (PCI) between January 2009 and June 2013, received high-intensity statin treatment for at least 6 months, and had at least one baseline echocardiographic evaluation within 3 months after PCI at Seoul National University Bundang Hospital. We excluded patients with DM at baseline or no clinical/laboratory information regarding DM status, patients with a follow-up duration less than 6 months, and patients with a poor echocardiographic image quality for the measurement of EAT thickness (Additional file 1: Figure S1). PCI was performed using standard techniques, and follow-up was performed according to routine clinical guidelines. For each patient, the follow-up duration was calculated based on the prescriptions of high-intensity statins. High-intensity statin therapy, defined as either atorvastatin (40 or 80 mg) or rosuvastatin (20 or 40 mg), had been administered according to the 2013 American College of Cardiology/American Heart Association guidelines [8]. DM was defined as fasting blood glucose levels ≥ 126 mg/dL, glycated hemoglobin levels ≥ 6.5% (48 mmol/mol), and/or the need for oral hypoglycemic agents or insulin. If there was no clear clinical diagnosis, or if a patient had discordant results from two different tests, a second test was searched for confirmation. Prediabetes was defined as fasting blood glucose levels of 100–125 mg/dL or glycated hemoglobin levels of 5.7–6.4% (39–47 mmol/mol) [14].\n\nThe study protocol was approved by the Institutional Review Board of Seoul National University Bundang Hospital and was conducted according to the principles of the Declaration of Helsinki.\n\nMeasurement of EAT thickness\nAll subjects underwent echocardiographic examination performed using commercially available ultrasound machines (Vivid E9, GE Healthcare, Chicago, USA; EPIQ 7, Philips Healthcare, Amsterdam, The Netherlands), and standard examination was performed with the patient in left lateral position. Left ventricular ejection fraction was calculated with the modified biplane Simpson’s method. EAT thickness was measured at the end of systole and diastole on the free wall of the right ventricle in the parasternal long-axis view on standard transthoracic echocardiography, and was defined as an echo-free or hypoechoic area adjacent to the right ventricle (Additional file 1: Figure S2). This method was validated in previous studies and shown to be strongly correlated with various metabolic markers [1, 7]. Only the maximum EAT thickness values were measured. The measurement was performed for two beats, and the average value was retained.\n\nStatistical analysis\nData are presented as numbers and frequencies for categorical variables and as median and interquartile ranges for continuous variables, and were compared using Student’s t-test or the Mann–Whitney U test. To compare the groups, the χ2 test (or the Fisher’s exact test when any expected cell count was < 5 for a 2-by-2 table) was used for categorical variables, and the unpaired Student t-test or one-way analysis of variance was applied for continuous variables.\n\nIn the multivariate analysis performed to identify variables influencing NODM, we used the multivariable Cox proportional hazard model. Candidate variables with P < 0.10 in the univariate analyses, duration of statin treatment, and previously described risk factors of DM [i.e., age, male sex, body mass index (BMI), and hypertension] were included in the model [15, 16]. For the sensitivity analysis of predictors of progression of glucose intolerance, we used the binary logistic model based on multiple variables. Variables included in the logistic regression model were identical to those of the multivariable Cox proportional hazard model. To determine the best cutoff value of EAT thickness that would be included in the predictive model, we performed receiver operating characteristic curve analysis. To determine intraobserver variability, one of the authors (JK) measured EAT thickness at systole and diastole twice at an interval of > 30 days. Agreement was analyzed by means of the Bland–Altman plot (Additional file 1: Figure S3) and by determination of the intraclass correlation coefficient using the two-way mixed model (coefficient for EAT thickness at systole: 0.936 [0.916–0.951]; coefficient for EAT thickness at diastole: 0.943 [0.925–0.956]).\n\nAll statistical tests were two-tailed. A two-sided probability value less than 0.05 was considered to indicate statistical significance. Statistical tests were performed using SPSS version 20 (SPSS Inc., Chicago, IL, USA).\n\nResults\nBaseline characteristics and EAT thickness\nA total of 321 patients were enrolled in this study, according to the flow chart provided in Additional file 1: Figure S1. The mean age was 59.9 years, 74% of patients were male patients, and 64% presented with acute coronary syndrome. The patients received high-intensity statins for a median of 930 days; atorvastatin 40 mg in 204 patients (63.6%), atorvastatin 80 mg in 57 patients (17.8%), and rosuvastatin 20 mg in 60 patients (18.7%; Table 1).Table 1 Baseline characteristics of the total population\n\n\tTotal population\tNODM (+) (n = 40)\tNODM (−) (n = 281)\tP value\t\nDemographic findings\t\n Age (years)\t60 (51, 69)\t60 (51, 72)\t59 (51, 69)\t0.950\t\n Sex (male, %)\t238 (74.1%)\t30 (75.0%)\t208 (74.0%)\t0.895\t\n BMI (kg/m2)\t24.9 (23.2, 27.1)\t25.8 (23.7, 28.0)\t24.8 (23.2, 27.0)\t0.184\t\n BMI > 25 kg/m2\t157 (48.9%)\t23 (57.5%)\t134 (47.7%)\t0.245\t\n Clinical diagnosis (%)\t0.984\t\n Stable angina\t115 (35.8%)\t14 (35.0%)\t101 (35.9%)\t\t\n Unstable angina\t48 (15.0%)\t7 (17.5%)\t41 (14.6%)\t\t\n NSTEMI\t64 (19.9%)\t7 (17.5%)\t57 (20.3%)\t\t\n STEMI\t94 (29.3%)\t12 (30.0%)\t82 (29.2%)\t\t\n Hypertension (%)\t127 (39.6%)\t19 (47.5%)\t108 (38.4%)\t0.273\t\n Current smoking (%)\t84 (26.2%)\t10 (25.0%)\t74 (26.3%)\t0.857\t\n Previous CVA (%)\t11 (3.4%)\t0 (0.0%)\t11 (3.9%)\t0.203\t\n Bronchial asthma (%)\t5 (1.6%)\t1 (2.5%)\t4 (1.4%)\t0.607\t\n COPD (%)\t9 (2.8%)\t2 (5.0%)\t7 (2.5%)\t0.368\t\n Dyslipidemia (%)\t80 (24.8%)\t9 (22.5%)\t71 (25.3%)\t0.705\t\n Prediabetes (%)\t130 (40.5%)\t31 (77.5%)\t99 (35.2%)\t< 0.001\t\nLaboratory findings\t\n WBC (/μL)\t7900 (5970, 10,950)\t7640 (5500, 10,450)\t7900 (6000, 11,040)\t0.589\t\n Hemoglobin (g/dL)\t14.6 (13.5, 15.6)\t15.0 (13.6, 15.8)\t14.5 (13.4, 15.6)\t0.246\t\n Fasting blood glucose (mg/dL)\t92 (84, 103)\t98 (90, 107)\t92 (84, 102)\t0.010\t\n HbA1c (%/mmol/mol)\t5.7 (5.5, 5.9)/38.8 (36.6, 41.0)\t6.0 (5.7, 6.3)/42.1 (39.1, 45.4)\t5.7 (5.4, 5.8)/38.8 (35.5, 39.9)\t< 0.001\t\n Total cholesterol (mg/dL)\t207 (177, 240)\t210 (171, 246)\t207 (179, 240)\t0.774\t\n Triglyceride (mg/dL)\t133 (90, 209)\t145 (99, 214)\t131 (89, 209)\t0.414\t\n HDL-cholesterol (mg/dL)\t42 (37, 50)\t40 (35, 47)\t43 (37, 51)\t0.100\t\n LDL-cholesterol (mg/dL)\t133 (110, 157)\t126 (112, 157)\t133 (108, 157)\t0.979\t\n Serum creatinine (mg/dL)\t0.88 (0.73, 1.01)\t0.84 (0.76-1.00)\t0.98 (0.73, 1.02)\t0.524\t\n hsCRP (mg/dL)\t0.15 (0.10, 0.31)\t0.15 (0.10, 0.25)\t0.15 (0.10, 0.32)\t0.264\t\nEchocardiography\t\n LVEDD (mm)\t48.0 (44.3, 51.9)\t49.0 (45.0, 52.1)\t48.0 (44.0, 51.9)\t0.408\t\n LVESD (mm)\t31.0 (27.0, 35.0)\t32.0 (29.0, 34.6)\t30.3 (26.9, 35.1)\t0.319\t\n LV ejection fraction (%)\t60.0 (53.5, 64.7)\t60.3 (54.9, 66.1)\t59.5 (53.1, 64.5)\t0.246\t\n Left atrium dimension (mm)\t37.1 (33.7, 41.0)\t36.8 (34.1, 40.0)\t37.4 (33.7, 41.0)\t0.624\t\n EAT diastole (mm)\t1.4 (1.0, 2.2)\t2.2 (1.4, 3.5)\t1.2 (1.0, 2.1)\t< 0.001\t\n EAT systole (mm)\t4.0 (3.0, 4.9)\t5.4 (4.2, 7.4)\t3.9 (2.9 4.8)\t< 0.001\t\nBaseline medication\t\n Aspirin\t321 (100%)\t40 (100%)\t281 (100%)\tNA\t\n Clopidogrel\t320 (99.7%)\t40 (100%)\t280 (99.6%)\t0.706\t\n ACE inhibitor or ARB\t275 (85.7%)\t34 (85.0%)\t241 (85.8%)\t0.897\t\n Beta blockers\t246 (76.6%)\t30 (75.0%)\t216 (76.9%)\t0.794\t\n Thiazides\t36 (11.2%)\t4 (10.0%)\t32 (11.4%)\t0.795\t\n Systemic steroid\t30 (9.3%)\t3 (7.5%)\t27 (9.6%)\t0.668\t\nStatin\t0.128\t\n Atorvastatin 40 mg\t204 (63.6%)\t20 (50.0%)\t184 (65.5%)\t\t\n Atorvastatin 80 mg\t57 (17.8%)\t11 (27.5%)\t46 (16.4%)\t\t\n Rosuvastatin 20 mg\t60 (18.7%)\t9 (22.5%)\t51 (18.1%)\t\t\nStatin duration (days)\t\n Total statin duration\t1248 (984, 1800)\t1348 (983, 1827)\t1237 (984, 1800)\t0.293\t\n High intensity statin duration\t930 (541, 1216)\t963 (785, 1322)\t922 (500, 1210)\t0.297\t\nACE angiotensin-converting enzyme, ARB angiotensin-receptor blocker, BMI body mass index, COPD chronic obstructive pulmonary disease, CVA cerebrovascular accident, EAT epicardial adipose tissue, HDL high density lipoprotein, hsCRP high-sensitivity C-reactive protein, ISR in-stent restenosis, LDL low density lipoprotein, LV left ventricular, LVEDD left ventricular end diastolic dimension, LVESD left ventricular end systolic dimension, MI myocardial infarction, NSTEMI non-ST-segment elevation myocardial infarction, STEMI ST-segment elevation myocardial infarction, WBC white blood cell\n\n\n\n\nNew-onset diabetes mellitus occurred in 40 patients (12.5%), with the incidence of NODM increasing gradually over the course of a mean follow-up of 3.9 years. Regarding baseline characteristics, patients with NODM had a higher frequency of baseline prediabetes, and higher levels of fasting blood glucose and HbA1c. Furthermore, among echocardiographic variables, EAT thickness at diastole and systole were significantly larger in the NODM group than in the non-NODM group (Additional file 1: Figure S4), whereas other variables did not show significant difference between the two groups. Regarding the relationship between variables, we found a moderate positive correlation of EAT thickness with HbA1c (Pearson correlation coefficient 0.307, P < 0.001, Additional file 1: Figure S5).\n\nPredictors of NODM\nRegarding factors associated with NODM, univariate Cox regression analysis showed that EAT thickness and prediabetes at baseline were significant predictors of NODM (Table 2), which remained significant after multivariate adjustment for significant covariates (for each 1 mm of EAT thickness at systole: hazard ratio (HR) of 1.580, 95% confidential interval (CI) of 1.346–1.854, P < 0.001; for prediabetes at baseline: HR 4.321, 95% CI 1.998–9.349, P < 0.001; Table 2). Using binary cutoff values derived from the receiver operating characteristic curve analysis, EAT thickness at systole equal to or larger than 5.0 mm showed a sensitivity of 52.5%, and specificity of 80.8% for predicting NODM (Fig. 1). Moreover, the HR for NODM in patients with EAT thickness ≥ 5 mm was 3.402 (95% CI 1.751–6.611, P < 0.001), showing that EAT thickness remained as an independent predictor of NODM after adjusting clinical variables, including prediabetes at baseline.Table 2 Univaraite and multivariate analyses for new-onset diabetes mellitus\n\nFactor\tUnivariate analysis\tMultivariate analysis\t\nHR (95% CI)*\tP value\tHR (95% CI)*\tP value\t\nAge\t0.999 (0.975–1.023)\t0.909\t0.978 (0.950–1.007)\t0.130\t\nMale sex\t1.029 (0.502–2.108)\t0.938\t1.220 (0.539–2.765)\t0.633\t\nBMI\t1.062 (0.956–1.179)\t0.263\t0.996 (0.877–1.131)\t0.996\t\nDiagnosis as acute coronary syndrome\t0.954 (0.497–1.830)\t0.888\t–\t–\t\nHypertension\t1.524 (0.818–2.838)\t0.184\t1.727 (0.872–3.420)\t0.117\t\nCurrent smoking\t1.030 (0.503–2.109)\t0.935\t–\t–\t\nDyslipidemia\t1.114 (0.530–2.341)\t0.775\t–\t–\t\nPrediabetes at baseline\t5.503 (2.619–11.564)\t< 0.001\t4.321 (1.998–9.349)\t< 0.001\t\nAnemia (Hemoglobin < 12 g/dL)\t2.745 (0.377–19.985)\t0.319\t–\t–\t\nTG level (per mg/dL)\t1.001 (0.999–1.004)\t0.309\t–\t–\t\nLDL-cholesterol level (per mg/dL)\t1.002 (0.993–1.011)\t0.703\t–\t–\t\nLV ejection fraction < 40%\t2.153 (0.296–15.672)\t0.449\t–\t–\t\nEAT thickness at diastole (per mm)\t1.625 (1.353–1.950)\t< 0.001\t\t\t\nEAT thickness at systole (per mm)\t1.611 (1.388–1.870)\t< 0.001\t1.580 (1.346–1.854)\t< 0.001\t\nTotal statin duration (per year)\t0.916 (0.716–1.171)\t0.482\t0.876 (0.733–1.048)\t0.147\t\nHigh intensity statin duration\t0.989 (0.804–1.217)\t0.918\t–\t–\t\nBMI body mass index, LV left ventricle, LDL low density lipoprotein, TG triglyceride, EAT epicardial adipose tissue\n\n* The hazard ratio (HR) along with its corresponding 95% confidence interval (CI) and p values are based on Cox proportional hazard analysis\n\n\nFig. 1 The receiver operating characteristic curve for EAT thickness at systole and corresponding area under the curve (AUC) statistics for the risk of NODM\n\n\n\n\nRisk factors of NODM\nWhen we stratified the patients into four groups according to EAT thickness at systole and presence of prediabetes, the incidence of NODM was highest in patients with EAT thickness ≥ 5 mm and prediabetes at baseline (17 out of 40 patients; 42.5%), which was 12.0-fold higher than that in patients with EAT thickness < 5 mm and without prediabetes at baseline (5 out of 153 patients; 3.3%, Fig. 2a). On Kaplan–Meier curve analysis and Cox regression analysis, patients with both risk factors had a significantly higher risk for NODM (Fig. 2b, Table 3). Meanwhile, patients with either one of the risk factors (i.e., those with EAT thickness ≥ 5 mm without prediabetes and those with EAT thickness < 5 mm with prediabetes) had a similar risk for NODM (P = 0.509).Fig. 2 Incidence of new-onset diabetes mellitus (NODM) according to epicardial adipose tissue (EAT) thickness at systole and the presence of prediabetes. a Among the total population, 153 patients had an EAT < 5 mm with no prediabetes at baseline (Group 1), 38 patients had an EAT ≥ 5 mm with no prediabetes at baseline (Group 2), 90 patients had an EAT < 5 mm with prediabetes at baseline (Group 3), and 40 patients had an EAT ≥ 5 mm with prediabetes at baseline (Group 4). Patients with EAT ≥ 5.0 mm and prediabetes at baseline had the highest incidence of NODM. Post-hoc analysis of NODM incidence showed that there were significant differences between all pairs of groups, except between Group 2 and Group 3 (Group 1 vs. Group 2, P = 0.012; Group 1 vs. Group 3, P = 0.001; Group 1 vs. Group 4, P < 0.001; Group 2 vs. Group 3, P = 0.661; Group 2 vs. Group 4, P < 0.001; Group 3 vs. Group 4, P < 0.001). b Kaplan–Meier survival curve showing an incremental increase in risk for NODM, according to the presence of prediabetes at baseline and EAT thickness\n\n\nTable 3 Risk of new-onset diabetes mellitus according to the epicardial adipose tissue thickness and prediabetes\n\n\tHR\t95% CI\tP value\t\nEAT thickness < 5 mm and no prediabetes\tReference\t\nEAT thickness ≥ 5 mm and no prediabetes\t3.481\t0.934–12.972\t0.063\t\nEAT thickness < 5 mm and prediabetes\t5.011\t1.805–13.916\t0.002\t\nEAT thickness ≥ 5 mm and prediabetes\t14.702\t5.336–40.503\t< 0.001\t\nEAT epicardial adipose tissue, HR hazard ratio, CI confidence interval\n\n\n\n\nSensitivity analysis for progression of glucose intolerance\nTo evaluate the association between EAT thickness and gradual impairment in glucose tolerance, we stratified the patients into two groups according to the progression of glucose intolerance (progression vs. no progression; Additional file 2: Table S1). Progression of glucose intolerance was noted in about 40% of the total study population (progression group), among whom 81 patients (25.2%) showed normal glucose tolerance at baseline and developed new-onset prediabetes during the follow-up period. The progression group had more prediabetic patients, higher levels of fasting blood glucose, and marginally longer statin treatment duration. Additionally, analysis of echocardiographic findings revealed larger EAT thickness at systole in the progression group (4.2 [3.2, 5.4] vs. 3.8 [2.9, 4.8] mm, P = 0.014; Additional file 2: Table S2). A logistic regression model including age, sex, BMI, hypertension, statin duration, prediabetes, and EAT thickness at systole showed that EAT thickness was an independent predictor of progression of impaired glucose tolerance (for each 1 mm of EAT thickness at systole: odds ratio of 1.309, 95% CI 1.117–1.534, P = 0.001), and so was prediabetes (odds ratio of 3.265, 95% CI 1.919–5.555, P < 0.001; Additional file 2: Table S3).\n\nDiscussion\nIn this study involving patients who received PCI and were prescribed high-intensity statins for at least 6 months, NODM occurred in 12.5% of patients during a follow-up period of 3.9 years. Baseline EAT thickness at systole and prediabetes at baseline were revealed as two independent predictors for NODM. Patients with EAT thickness ≥ 5 mm and prediabetes at baseline had a 12.0-fold higher risk to develop NODM compared to the risk noted in patients without risk factors. Considering that echocardiography is performed in nearly all CAD patients undergoing PCI, our study provides an easy-to-obtain predictor of NODM in patients who require high-dose statin treatment.\n\nStatins and risk of NODM in cardiovascular disease\nStatins are effective therapeutic agents for prevention of cardiovascular events, and can reduce mortality in patients with coronary heart disease [17]. However, recent studies reported that statin treatment may be associated with an increased risk of NODM. A meta-analysis of 13 trials involving 91,140 individuals showed that statin treatment was associated with a 9% increase in the 4-year risk of NODM [10]. Regarding the dose–effect relationship in statin-associated NODM, some studies have shown a higher risk of incident diabetes in patients on higher-intensity statin therapy [9, 18], while some suggest that there might be difference in the incident diabetes by statin class [19]. Large scale studies focusing on the occurrence of NODM by statin intensity or by statin class should be conducted to give us clear answers on this issue. Our present study found a similar rate of NODM in patients using high-intensity statins during 4 years of follow-up. Regarding previous reports showing that NODM is associated with a substantial risk for mortality [20], further efforts should be allocated to the early prediction and prevention of NODM [21].\n\nBiological relevance of the EAT\nThe EAT is known as the true visceral fat deposit of the heart, lying directly on the epicardial surface of the myocardium within the pericardial sac [22]. Due to its close proximity to the coronary vessels, the EAT exerts profound effect on the local physiology of the myocardium and the coronary vasculature by expressing various cytokines [23]. Additionally, EAT was associated with cardiovascular risks and further development of cardiovascular complications [24]. EAT thickness has also been shown to be related to the metabolic status of the individual. Specifically, Yorgun et al. reported that EAT thickness was significantly increased in patients with metabolic syndrome, and that age and BMI, which are factors related to metabolic syndrome, were the strongest independent predictors of EAT thickness [25]. A recent meta-analysis also showed that EAT thickness was significantly higher in patients with metabolic syndrome [26]. Other studies have explained that the association between metabolic syndrome and EAT thickness may be attributed to the endocrine action of the EAT, which also affects insulin sensitivity [27], designating EAT as a biologically active organ. Conversely, some studies suggested the beneficial effect of EAT by protecting the heart against myocardial stress, hypertension, and local inflammation. EAT may even function as a brown adipose tissue store which can protect adjacent tissues from hypothermia, while showing high degrees of white adipose tissue lipolysis allowing the buffering of high toxic levels of free fatty acids [6]. Additionally, a genetic study explored the EAT transcriptome, unveiling a majority of genes involved in coagulation, endothelial function, phospholipase activity, apoptosis, and immune signaling [28]. Despite these beneficial effects, EAT may shift from being protective to detrimental for obesity and cardiovascular homeostasis [6]. Although the mechanisms that regulate the balance between protective and harmful effects of EAT are not clearly understood, epicardial fat can serve as target for pharmaceutical agents targeting the adipose tissue [29]. Furthermore, the association of EAT and diabetes has been studied in a few studies. Increased EAT thickness was independently associated with the prevalence of diabetes, insulin resistance and cardiac contractile dysfunction in diabetes [30, 31]. In the present study, we found that EAT thickness was closely associated with NODM. Aside from prediabetes, which is a well-known risk factor for DM, EAT thickness was the only other significant predictor of statin-associated NODM.\n\nClinical implications of EAT thickness as a predictor of statin-associated NODM\nPrevious studies have reported conflicting results regarding the potential predictors of NODM. Specifically, the IDEAL study suggested that only patients who already have elevated risk for DM are at increased risk to develop statin-associated DM [32]. Furthermore, the Justification for Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study reported that the risk of statin-associated NODM was independent of baseline glucose levels, whereas Waters et al. reported that the development of NODM can be predicted based on baseline fasting glucose levels and other components of the metabolic syndrome (i.e., triglyceride levels, BMI, and hypertension) [33]. On the other hand, a cohort-based study by Woestijne et al. found that the increase in the risk of type 2 DM with statin therapy was independent of metabolic syndrome or insulin resistance [13]. The discrepancies in these previous observations may be attributed to the differences in the study population, as well as to variable statin dosage and duration.\n\nIn the present study, we limited our study population to patients with CAD who underwent PCI and required strict lipid-lowering therapy and we were able to draw a conclusion based on a relatively homogeneous small sample of patients. Moreover, considering that echocardiography is performed in nearly all CAD patients receiving PCI, our finding that EAT thickness is a predictor of statin-associated NODM may have considerable clinical implication.\n\nDespite the risk of statin-associated NODM, the general consensus is that the positive effects of statins outweigh the negative effects on metabolic control [34]. The TNT study showed that patients at risk of statin-associated NODM also obtained substantial benefit from high-intensity statins [11]. This finding may be related to the traditional effect of statins, which lower blood cholesterol levels, and have favorable pleiotropic effects on endothelial function, oxidative stress and inflammation [35]. Nevertheless, in clinical practice, it remains important to identify factors that can estimate the risk of statin-associated NODM.\n\nLimitations\nSeveral limitations should be noted. The study population was relatively small compared to cohorts investigated in previous studies or randomized controlled trials. Furthermore, we may have introduced selection bias by excluding patients prescribed with high-intensity statins for less than 6 months and those only prescribed with low- or moderate-intensity statin. Moreover, the patients in our study had various patterns of statin usage; specifically, some were not statin-naïve, and had been prescribed low- or moderate-intensity statins before receiving high-intensity statins. We also used a single method to measure EAT thickness. A previous study proposed a method to measure EAT thickness at the anterior interventricular groove, which may be more accurate than our method [36]. However, this measurement was not applicable in our retrospective analysis, because this echocardiographic view was not routinely used in our institute. Furthermore, our study did not include a control arm, which made it impossible to investigate the association between high-dose statin and NODM. However, this was not the purpose of our study, but rather its background. Therefore, the findings of our investigation may be considered as hypothesis-generating, and further large-scale studies are warranted.\n\nAdditional files\n\nAdditional file 1: Figure S1. Selection of Study population. Figure S2. Method of EAT thickness measurement. Representative figure of EAT measurement. EAT thickness was measured at the end of systole and diastole at the free wall of the right ventricle, in the parasternal long axis view. Figure S3. Bland–Altman plot for Intra-observer variability. A Bland–Altman plot proved excellent agreement between the two measurements of EAT thickness at systole within one observer. Figure S4. A scatter plot of EAT thickness and the occurrence of new-onset diabetes mellitus. Figure S5. Linear correlation between HbA1c and EAT thickness.\n\n \nAdditional file 2: Table S1. Changes in glucose tolerance status. Table S2. Baseline clinical characteristics of the total population, grouped by progression of glucose intolerance. Table S3. Multivariate analysis for progression in impairment of glucose tolerance.\n\n \n\n\nAbbreviations\nDMdiabetes mellitus\n\nNODMnew-onset diabetes mellitus\n\nEATepicardial adipose tissue\n\nCADcoronary artery disease\n\nPCIpercutaneous coronary intervention\n\nHRhazard ratio\n\nCIconfidential interval\n\nElectronic supplementary material\n\nThe online version of this article (10.1186/s12933-017-0650-3) contains supplementary material, which is available to authorized users.\n\nAuthors’ contributions\nJK performed analysis/interpretation of data and drafting of manuscript, YCK and SK performed echocardiographic data analysis, JJP, SHK contributed in analysis of data, YJC, YEY, IYO, CHY, JWS contributed in acquisition of patients and data, YSC provided the study conception and drafting of manuscript, TJY, IHC, DJC provided consultation on the study concept and critical revision. All authors read and approved the final manuscript.\n\nAcknowledgements\nNone.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAvailability of data and materials\nThe datasets generated and/or analysed during the current study are not publicly available due regulations of patient information to be released in public, but are available from the corresponding author on reasonable request, after anonymization.\n\nConsent for publication\nAll patients provided informed consent for undergoing the investigations, and for publication.\n\nEthics approval and consent to participate\nThe study protocol was approved by the Institutional Review Board of Seoul National University Bundang Hospital and was conducted according to the principles of the Declaration of Helsinki.\n\nFunding\nNone.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. 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Sironi AM Pingitore A Ghione S De Marchi D Scattini B Positano V Muscelli E Ciociaro D Lombardi M Ferrannini E Early hypertension is associated with reduced regional cardiac function, insulin resistance, epicardial, and visceral fat Hypertension 2008 51 2 282 288 10.1161/HYPERTENSIONAHA.107.098640 18172058 \n6. Gonzalez N Moreno-Villegas Z Gonzalez-Bris A Egido J Lorenzo O Regulation of visceral and epicardial adipose tissue for preventing cardiovascular injuries associated to obesity and diabetes Cardiovasc Diabetol 2017 16 1 44 10.1186/s12933-017-0528-4 28376896 \n7. Iacobellis G Willens HJ Barbaro G Sharma AM Threshold values of high-risk echocardiographic epicardial fat thickness Obesity (Silver Spring) 2008 16 4 887 892 10.1038/oby.2008.6 18379565 \n8. Stone NJ Robinson JG Lichtenstein AH Bairey Merz CN Blum CB Eckel RH Goldberg AC Gordon D Levy D Lloyd-Jones DM 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Circulation 2014 129 25 Suppl 2 S1 S45 10.1161/01.cir.0000437738.63853.7a 24222016 \n9. Dormuth CR Filion KB Paterson JM James MT Teare GF Raymond CB Rahme E Tamim H Lipscombe L Canadian Network for Observational Drug Effect Studies I: higher potency statins and the risk of new diabetes: multicentre, observational study of administrative databases BMJ 2014 348 g3244 10.1136/bmj.g3244 24874977 \n10. Sattar N Preiss D Murray HM Welsh P Buckley BM de Craen AJ Seshasai SR McMurray JJ Freeman DJ Jukema JW Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials Lancet 2010 375 9716 735 742 10.1016/S0140-6736(09)61965-6 20167359 \n11. Deedwania P Barter P Carmena R Fruchart JC Grundy SM Haffner S Kastelein JJ LaRosa JC Schachner H Shepherd J Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: analysis of the treating to new targets study Lancet 2006 368 9539 919 928 10.1016/S0140-6736(06)69292-1 16962881 \n12. Faergeman O Holme I Fayyad R Bhatia S Grundy SM Kastelein JJ LaRosa JC Larsen ML Lindahl C Olsson AG Plasma triglycerides and cardiovascular events in the treating to new targets and incremental decrease in end-points through aggressive lipid lowering trials of statins in patients with coronary artery disease Am J Cardiol 2009 104 4 459 463 10.1016/j.amjcard.2009.04.008 19660594 \n13. van de Woestijne AP van der Graaf Y Westerink J Nathoe HM Visseren FL Effect of statin therapy on incident type 2 diabetes mellitus in patients with clinically manifest vascular disease Am J Cardiol 2015 115 4 441 446 10.1016/j.amjcard.2014.11.021 25554536 \n14. American Diabetes A 2. Classification and diagnosis of diabetes Diabetes Care 2017 40 Suppl 1 S11 S24 10.2337/dc17-S005 27979889 \n15. Kim MJ Lim NK Choi SJ Park HY Hypertension is an independent risk factor for type 2 diabetes: the Korean genome and epidemiology study Hypertens Res 2015 38 11 783 789 10.1038/hr.2015.72 26178151 \n16. Chang SA Smoking and type 2 diabetes mellitus Diabetes Metab J 2012 36 6 399 403 10.4093/dmj.2012.36.6.399 23275932 \n17. Allen Maycock CA Muhlestein JB Horne BD Carlquist JF Bair TL Pearson RR Li Q Anderson JL Intermountain Heart Collaborative S Statin therapy is associated with reduced mortality across all age groups of individuals with significant coronary disease, including very elderly patients J Am Coll Cardiol 2002 40 10 1777 1785 10.1016/S0735-1097(02)02477-4 12446061 \n18. Preiss D Seshasai SR Welsh P Murphy SA Ho JE Waters DD DeMicco DA Barter P Cannon CP Sabatine MS Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis JAMA 2011 305 24 2556 2564 10.1001/jama.2011.860 21693744 \n19. Vallejo-Vaz AJ Kondapally Seshasai SR Kurogi K Michishita I Nozue T Sugiyama S Tsimikas S Yoshida H Ray KK Effect of pitavastatin on glucose, HbA1c and incident diabetes: a meta-analysis of randomized controlled clinical trials in individuals without diabetes Atherosclerosis 2015 241 2 409 418 10.1016/j.atherosclerosis.2015.06.001 26074315 \n20. Barnett KN Ogston SA McMurdo ME Morris AD Evans JM A 12-year follow-up study of all-cause and cardiovascular mortality among 10,532 people newly diagnosed with Type 2 diabetes in Tayside, Scotland Diabet Med 2010 27 10 1124 1129 10.1111/j.1464-5491.2010.03075.x 20854379 \n21. Zucker I Shohat T Dankner R Chodick G New onset diabetes in adulthood is associated with a substantial risk for mortality at all ages: a population based historical cohort study with a decade-long follow-up Cardiovasc Diabetol 2017 16 1 105 10.1186/s12933-017-0583-x 28810857 \n22. Iacobellis G Willens HJ Echocardiographic epicardial fat: a review of research and clinical applications J Am Soc Echocardiogr 2009 22 12 1311 1319 10.1016/j.echo.2009.10.013 19944955 \n23. Christensen RH von Scholten BJ Hansen CS Heywood SE Rosenmeier JB Andersen UB Hovind P Reinhard H Parving HH Pedersen BK Epicardial, pericardial and total cardiac fat and cardiovascular disease in type 2 diabetic patients with elevated urinary albumin excretion rate Eur J Prev Cardiol 2017 24 14 1517 1524 10.1177/2047487317717820 28650207 \n24. Wang Z, Zhang Y, Liu W, Su B. Evaluation of epicardial adipose tissue in patients of type 2 diabetes mellitus by echocardiography and its correlation with intimal medial thickness of carotid artery. Exp Clin Endocrinol Diabetes. 2017;125(9):598–602.\n25. Yorgun H Canpolat U Hazirolan T Ates AH Sunman H Dural M Sahiner L Kaya EB Aytemir K Tokgozoglu L Increased epicardial fat tissue is a marker of metabolic syndrome in adult patients Int J Cardiol 2013 165 2 308 313 10.1016/j.ijcard.2011.08.067 21925747 \n26. Pierdomenico SD Pierdomenico AM Cuccurullo F Iacobellis G Meta-analysis of the relation of echocardiographic epicardial adipose tissue thickness and the metabolic syndrome Am J Cardiol 2013 111 1 73 78 10.1016/j.amjcard.2012.08.044 23040591 \n27. Iacobellis G Leonetti F Epicardial adipose tissue and insulin resistance in obese subjects J Clin Endocrinol Metab 2005 90 11 6300 6302 10.1210/jc.2005-1087 16091479 \n28. McAninch EA Fonseca TL Poggioli R Panos AL Salerno TA Deng Y Li Y Bianco AC Iacobellis G Epicardial adipose tissue has a unique transcriptome modified in severe coronary artery disease Obesity (Silver Spring) 2015 23 6 1267 1278 10.1002/oby.21059 25959145 \n29. Iacobellis G Epicardial fat: a new cardiovascular therapeutic target Curr Opin Pharmacol 2016 27 13 18 10.1016/j.coph.2016.01.004 26848943 \n30. Levelt E Pavlides M Banerjee R Mahmod M Kelly C Sellwood J Ariga R Thomas S Francis J Rodgers C Ectopic and visceral fat deposition in lean and obese patients with type 2 diabetes J Am Coll Cardiol 2016 68 1 53 63 10.1016/j.jacc.2016.03.597 27364051 \n31. Chun H Suh E Byun AR Park HR Shim KW Epicardial fat thickness is associated to type 2 diabetes mellitus in Korean men: a cross-sectional study Cardiovasc Diabetol 2015 14 46 10.1186/s12933-015-0210-7 25935836 \n32. Pedersen TR Faergeman O Kastelein JJ Olsson AG Tikkanen MJ Holme I Larsen ML Bendiksen FS Lindahl C Szarek M High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial JAMA 2005 294 19 2437 2445 10.1001/jama.294.19.2437 16287954 \n33. Waters DD Ho JE DeMicco DA Breazna A Arsenault BJ Wun CC Kastelein JJ Colhoun H Barter P Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials J Am Coll Cardiol 2011 57 14 1535 1545 10.1016/j.jacc.2010.10.047 21453832 \n34. Shah RV Goldfine AB Statins and risk of new-onset diabetes mellitus Circulation 2012 126 18 e282 e284 10.1161/CIRCULATIONAHA.112.122135 23109518 \n35. Zhou Q Liao JK Pleiotropic effects of statins. Basic research and clinical perspectives Circ J 2010 74 5 818 826 10.1253/circj.CJ-10-0110 20424337 \n36. Hirata Y Yamada H Kusunose K Iwase T Nishio S Hayashi S Bando M Amano R Yamaguchi K Soeki T Clinical utility of measuring epicardial adipose tissue thickness with echocardiography using a high-frequency linear probe in patients with coronary artery disease J Am Soc Echocardiogr 2015 28 10 1240 1246 10.1016/j.echo.2015.07.006 26275751\n\n",
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"keywords": "Coronary artery disease; Echocardiography; Epicardial adipose tissue; New-onset diabetes mellitus; Statin",
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"mesh_terms": "D000273:Adipose Tissue; D000368:Aged; D000069059:Atorvastatin; D003324:Coronary Artery Disease; D003920:Diabetes Mellitus; D004452:Echocardiography; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008297:Male; D008875:Middle Aged; D010496:Pericardium; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D012307:Risk Factors; D000068718:Rosuvastatin Calcium; D066106:Seoul; D013997:Time Factors; D016896:Treatment Outcome",
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"title": "Increased epicardial adipose tissue thickness is a predictor of new-onset diabetes mellitus in patients with coronary artery disease treated with high-intensity statins.",
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"abstract": "Microsporum canis is a dermatophyte known to cause superficial skin infections. In immunocompromised patients, it can lead to invasive dermatophytosis. We present a case of biopsy-proven left knee mycetoma caused by M canis in a renal transplant patient. Identification of M canis was achieved via sequencing of the internal transcribed spacer regions. Treatment involved surgical debridement, oral posaconazole, and reduction in immunosuppression. In addition, we provide a review of current literature on invasive M canis infections.",
"affiliations": "Infectious Diseases Unit, The Queen Elizabeth Hospital, Woodville South, South Australia.;Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia.;Plastics Surgery Unit, The Queen Elizabeth Hospital, Woodville South, South Australia.;Plastics Surgery Unit, The Queen Elizabeth Hospital, Woodville South, South Australia.;Plastics Surgery Unit, The Queen Elizabeth Hospital, Woodville South, South Australia.;National Mycology Reference Centre, Microbiology and Infectious Diseases Directorate, SA Pathology, Adelaide, South Australia.;Infectious Diseases Unit, The Queen Elizabeth Hospital, Woodville South, South Australia.",
"authors": "Teo|Teddy S P|TSP|https://orcid.org/0000-0002-1139-7387;Crawford|Lucy C|LC|;Pilch|Wiktor T|WT|;Carney|Bernard|B|;Solanki|Nicholas|N|;Kidd|Sarah E|SE|;Warner|Morgyn S|MS|",
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"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "\nMicrosporum\n; dermatophyte; immunosuppressed; invasive; mycetoma; transplant",
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"mesh_terms": "D003883:Arthrodermataceae; D003881:Dermatomycoses; D006801:Humans; D016030:Kidney Transplantation; D008864:Microsporum; D008271:Mycetoma",
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"title": "Mycetoma caused by Microsporum canis in a patient with renal transplant: A case report and review of the literature.",
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"abstract": "Osteogenesis imperfecta (OI) is a connective tissue disorder that is characterized by low bone density leading to recurrent fractures. The efficacy of the anti-resorption drug denosumab for OI with osteoporosis is still largely unknown. We herein describe the clinical outcomes of eight osteoporotic cases of OI to examine the effects and safety of denosumab. This retrospective, consecutive case series included eight patients respectively aged 42, 40, 14, 22, 3, 51, 37, and 9 years. We measured the bone mineral density (BMD) of the lumbar 1⁻4 spine (L-BMD) and bilateral hips (H-BMD), bone-specific alkaline phosphatase, urinary type I collagen amino-terminal telopeptide, and tartrate-resistant acid phosphatase 5b before and during denosumab therapy. Despite multiple pretreatment fractures in the cohort, no fractures or severe side effects, such as hypocalcemia, were observed during the observational period apart from a fracture in a young pediatric girl. Both L-BMD and H-BMD were increased by denosumab in seven of eight cases. Bone turnover markers were inhibited in most cases by denosumab therapy. Denosumab treatment could generally raise BMD without any adverse effects. The agent therefore represents a good therapeutic option for OI with osteoporosis.",
"affiliations": "Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan. 16m0042e@shinshu-u.ac.jp.;Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan. yxn14@aol.jp.;Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan. takako1119@shinshu-u.ac.jp.;Center for Medical Genetics, Shinshu University Hospital, Matsumoto, Nagano 390-8621, Japan. t_yamaguchi@shinshu-u.ac.jp.;Division of Medical Genetics, Nagano Children's Hospital, Azumino, Nagano 399-8288, Japan. ryojun_takeda@icloud.com.;Department of Pediatrics, Keio University School of Medicine, Tokyo 160-8582, Japan. mtakagi1027@hotmail.com.;Department of Pediatrics, Keio University School of Medicine, Tokyo 160-8582, Japan. thaseg@keio.jp.;Center for Medical Genetics, Shinshu University Hospital, Matsumoto, Nagano 390-8621, Japan. ktomoki@shinshu-u.ac.jp.;Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan. hirokato@shinshu-u.ac.jp.",
"authors": "Kobayashi|Tsukasa|T|;Nakamura|Yukio|Y|;Suzuki|Takako|T|;Yamaguchi|Tomomi|T|;Takeda|Ryojun|R|;Takagi|Masaki|M|;Hasegawa|Tomonobu|T|;Kosho|Tomoki|T|;Kato|Hiroyuki|H|",
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"fulltext": "\n==== Front\nJ Clin MedJ Clin MedjcmJournal of Clinical Medicine2077-0383MDPI 10.3390/jcm7120479jcm-07-00479ArticleEfficacy and Safety of Denosumab Therapy for Osteogenesis Imperfecta Patients with Osteoporosis—Case Series Kobayashi Tsukasa 1https://orcid.org/0000-0002-3911-7180Nakamura Yukio 1*Suzuki Takako 1Yamaguchi Tomomi 2Takeda Ryojun 3Takagi Masaki 4Hasegawa Tomonobu 4Kosho Tomoki 25Kato Hiroyuki 11 Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan; 16m0042e@shinshu-u.ac.jp (T.K.); takako1119@shinshu-u.ac.jp (T.S.); hirokato@shinshu-u.ac.jp (H.K.)2 Center for Medical Genetics, Shinshu University Hospital, Matsumoto, Nagano 390-8621, Japan; t_yamaguchi@shinshu-u.ac.jp (T.Y.); ktomoki@shinshu-u.ac.jp (T.K.)3 Division of Medical Genetics, Nagano Children’s Hospital, Azumino, Nagano 399-8288, Japan; ryojun_takeda@icloud.com4 Department of Pediatrics, Keio University School of Medicine, Tokyo 160-8582, Japan; mtakagi1027@hotmail.com (M.T.); thaseg@keio.jp (T.H.)5 Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan* Correspondence: yxn14@aol.jp; Tel.: +81-263-37-265924 11 2018 12 2018 7 12 47921 10 2018 21 11 2018 © 2018 by the authors.2018Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Osteogenesis imperfecta (OI) is a connective tissue disorder that is characterized by low bone density leading to recurrent fractures. The efficacy of the anti-resorption drug denosumab for OI with osteoporosis is still largely unknown. We herein describe the clinical outcomes of eight osteoporotic cases of OI to examine the effects and safety of denosumab. This retrospective, consecutive case series included eight patients respectively aged 42, 40, 14, 22, 3, 51, 37, and 9 years. We measured the bone mineral density (BMD) of the lumbar 1–4 spine (L-BMD) and bilateral hips (H-BMD), bone-specific alkaline phosphatase, urinary type I collagen amino-terminal telopeptide, and tartrate-resistant acid phosphatase 5b before and during denosumab therapy. Despite multiple pretreatment fractures in the cohort, no fractures or severe side effects, such as hypocalcemia, were observed during the observational period apart from a fracture in a young pediatric girl. Both L-BMD and H-BMD were increased by denosumab in seven of eight cases. Bone turnover markers were inhibited in most cases by denosumab therapy. Denosumab treatment could generally raise BMD without any adverse effects. The agent therefore represents a good therapeutic option for OI with osteoporosis.\n\nbone mineral densitydenosumabfracturesosteogenesis imperfectaosteoporosis\n==== Body\n1. Introduction\nOsteogenesis imperfect (OI) is a connective tissue disorder that is characterized by low bone density, recurrent fractures, and a wide genotypic and phenotypic spectrum of impaired collagen type I production [1]. OI is a rare disorder (1 in 15–20,000 births) and features skeletal fragility and substantial growth deficiency [2]. The clinical classification of OI was established in 1979 [3], which was later revised by van Dijk and Sillence in 2014 [4]. Among OI subtypes, type I is relatively mild and the most common. Type II OI causes death in the perinatal period, while type III induces obvious bone deformities and short stature due to frequent fractures [3,4].\n\nEven in type I OI, it is important to treat bone fragility to reduce the risk of severe fractures that can diminish patient quality of life and activities of daily living. Intravenous bisphosphonate (BP) infusions for OI are the most broadly used medical treatment [5,6]. BPs can decrease long-bone fracture rates, but such injuries remain frequent [7]. In a clinical trial of the BP risedronate for OI, the mean increase in lumbar bone mineral density (L-BMD) at one year was 16.3%, although fractures occurred in 29 (31%) of 94 cases. At two years of therapy, fractures were recorded in 46 (53%) of 87 cases [8]. Thus, new antiresorptive drugs, such as denosumab, and anabolic agents are being investigated for OI with osteoporosis.\n\nDenosumab is a fully human monoclonal antibody against receptor activator of nuclear factor-κB ligand, a mediator of osteoclastogenesis and osteoclast survival [9]. Subcutaneous injections of denosumab have been proposed as an alternative treatment approach for osteoporotic OI. Denosumab decreases bone resorption, increases BMD, and reduces fracture risk in postmenopausal women with osteoporosis [10]. We and others have recently reported that denosumab also improves bone fragility in children with OI and osteoporosis [11,12,13,14]. However, the precise efficacy and adverse effects of denosumab in OI are largely unknown, especially in pediatric cases.\n\nThis study retrospectively investigated eight patients with OI and osteoporosis to clarify the utility and safety of denosumab on bone fragility treatment. \n\n2. Materials and Methods\nSeven consecutive female patients and a male patient diagnosed as having OI began treatment with denosumab for bone fragility. All patients had osteoporosis meeting the revised criteria established by the Japanese Society of Bone and Mineral Research [15], and most had experienced multiple fractures prior to denosumab therapy. Fracture event data were collected at every visit for each patient. The characteristics of the patients are summarized in Table 1. The frequency of fractures prior to treatment was 10 or more times in 6 patients (Patients 1, 2, 3, 4, 6, and 7), a single fracture in Patient 5 (the daughter of Patient 1), and no fracture in Patient 8 (the daughter of Patient 7). Denosumab of 60 mg was injected subcutaneously every 6 months into each patient (i.e., at 0, 6, 12, 18, 24, 30, 33, 39, 42, 49, and 54 months.). We also prescribed vitamin D supplementation tablets (762.5 mg of precipitated calcium carbonate, 200 IU of cholecalciferol, 59.2 mg of magnesium carbonate) twice daily to Patients 2, 3, and 4 and active vitamin D in the form of alfacalcidol to Patient 8 during denosumab administration.\n\n2.1. Analysis of BMD\nAll subjects underwent dual-energy X-ray absorption (DXA) fan-beam bone densitometry (Lunar Prodigy; GE Healthcare Bio-Sciences Corp., Piscataway, NJ) at the lumbar 1–4 levels of the posteroanterior spine (L-BMD) (g/cm2) and total hips (H-BMD) (g/cm2) before and during denosumab administration. Timing period of BMD measurement after the start of denosumab therapy in each patient was approximately unified throughout the study period. \n\n2.2. Analysis of Laboratory Data\nSerum calcium was measured by the Arsenazo reaction and phosphorus was measured by the molybdate reaction. As a bone formation marker, bone alkaline phosphatase (BAP) (μg/L) was measured by a chemiluminescent enzyme immunoassay. As bone resorption markers, urinary N-terminal telopeptide of type-I collagen (NTX) (nmol BCE/ mmol Cr) and tartrate-resistant acid phosphatase 5b (TRACP-5b) (mU/dL) were assessed by an enzyme-linked immunosorbent assay. Values of 1-alpha, 25-dihydroxyvitamin D3 (1,25[OH]2D) (ng/mL) and parathyroid hormone (PTH) (pg/mL) were determined by immunoradiometric assays. After overnight fasting and omission of the first morning samples, serum and urine specimens were collected between 8:30 a.m. and 11:00 a.m. Immunoassays were performed by SRL, Inc. (Tokyo, Japan). BMD and laboratory data were evaluated before, between 2 and 4 months, and at 6, 12, 18, and 24 months of denosumab administration unless otherwise indicated.\n\n2.3. Ethical Approval\nThis investigation was approved by the Institutional Ethical Review Board of Shinshu University School of Medicine, Japan, prior to its initiation. Written informed consent was obtained from all subjects and the mother of the 3-year-old patient. Study methods were carried out in accordance with the approved guidelines.\n\n3. Results\nOI type according to Sillence’s classification was type Ib in Patients 1 and 5, type I similar in Patients 2 and 3, and type Ia in the remaining patients (Table 1), and was characterized by blue sclerae, premature deafness, mild to moderate bone fragility, and normal teeth. Patient 6 suffered from deafness in our cohort.\n\nOne incident of fracture, in Patient 5, was recorded at 11 months after the start of denosumab therapy (Table 1). Both L-BMD and H-BMD became increased in seven of eight cases (Figure 1). Serum albumin-corrected calcium levels during denosumab administration were stable in this cohort, with no hypercalcemia representing rebound inhibition of bone resorption (Table 2). No severe adverse effects were observed in this study.\n\nThe radiological and laboratory findings are summarized in Table 3 and Table 4. BMD generally increased in all patients. In Patients 2, 3, and 8, bone metabolism was strongly inhibited by denosumab treatment and 1,25 (OH)2D was sharply increased at 1 month of administration.\n\nGenetic analysis revealed a missense mutation in the COL1A1 gene encoding the collagen type I alpha 1 chain in Patients 1 and 5, a missense mutation in the COL1A2 gene encoding the collagen type I alpha 2 chain in Patient 4, and a nonsense mutation in the COL1A1 gene in Patients 6, 7, and 8. No mutations were detected by next generation sequencing of OI responsibility gene regions, including COL1A1, COL1A2, SERPINF1, and IFITM5 in Patients 2 and 3. Their detailed clinical and molecular information will be described in another series (Table 1).\n\n4. Case Highlights\nThe changes in BMD (Figure 1), laboratory findings (Figure 2), and bone markers (Figure 3) were plotted for each patient. In Patient 1, BAP, TRACP-5b, and NTX all transiently increased while 1,25 (OH)2D temporarily decreased. In Patient 2, 1,25 (OH)2D became increased at one month and gradually decreased. BAP was decreased for 18 months and increased thereafter. Urinary NTX was mostly maintained and TRACP-5b was decreased at one month. Both L-BMD and H-BMD increased during observation. In Patient 3, 1,25 (OH)2D became increased at one month and gradually decreased. BAP was decreased, while urinary NTX was increased at six and 30 months. TRACP-5b was decreased at one month but fluctuated thereafter. Both L-BMD and H-BMD increased throughout treatment. In Patient 4, serum albumin-corrected calcium fluctuated; 1,25 (OH)2D was increased for three months, and then decreased thereafter. Serum whole PTH was generally increased for 12 months. BAP was continuously decreased. Urinary NTX was decreased at one month, and then gradually increased. TRACP-5b became persistently decreased at one month. L-BMD gradually increased. In Patient 5, serum albumin-corrected calcium was decreased at one month but increased thereafter; 1,25 (OH)2D, whole PTH, BAP, and urinary NTX were persistently decreased. There were no remarkable changes in TRACP-5b. Serum albumin-corrected calcium was mildly increased; 1,25 (OH)2D was increased at one month and decreased thereafter. Serum whole PTH was unaffected for six months but increased at 12 months. BAP decreased for three months and stabilized thereafter. Urinary NTX was decreased at one month, and then fluctuated around baseline. TRACP-5b was greatly decreased. L-BMD was decreased at 12 months, while H-BMD was increased. In patient 6, serum albumin-corrected calcium was decreased but 1,25 (OH)2D was increased at one month. BAP, urinary NTX, and TRACP-5b were decreased for 12 months. L-BMD was decreased at 12 months but H-BMD was increased for 12 months. In Patient 7, 1,25 (OH)2D was mildly increased. Serum whole PTH was increased for three months. BAP was continuously decreased. Urinary NTX and TRACP-5b were markedly decreased at one month. L-BMD and H-BMD increased. In Patient 8, serum albumin-corrected calcium was greatly decreased at one month; 1,25 (OH)2D was markedly increased at one month and decreased thereafter. Serum whole PTH spiked at one month, and then decreased. BAP and urinary NTX were decreased at one month and increased thereafter. TRACP-5b was greatly decreased at one month but then stabilized. L-BMD and H-BMD increased.\n\n5. Discussion\nThis case series including long-term denosumab therapy (over 30 months in five cases) for osteoporotic OI is the first of its kind in Japan. Since Patients 1, 2, 5, 6, and 8 had suffered repeated fractures prior to the start of this study and refused BP therapy due to reflux esophagitis, denosumab was selected as the first therapeutic modality. Patients 3, 4, and 7 had previously been treated with BPs and switched to denosumab due to a poor response. BMD was increased overall, and no fractures were observed in seven of eight patients. Patient 5 experienced a proximal femoral neck fracture during the observation period despite remarkable gains in BMD. Since she was an active 3-year-old girl, the risk of fracture in pediatric cases might be higher than in older OI patients [16]. \n\nAs osteoporosis complicates many cases of OI, adequate and appropriate treatment is required for this condition. The low BMD typically present in OI is considered to be caused by high bone resorption [4]. Most patients with severe clinical OI symptoms are treated with pamidronate, risedronate, and other intravenous BPs [5,6]. However, poor responses to these drugs have been reported [7], necessitating alternative treatments for OI with osteoporosis, especially to prevent fragility fractures. OI-related fractures chiefly occur between childhood and puberty [16]. Patient 3’s height increased from 159 cm to 161 cm at two years of therapy, indicating that her growth was unaffected by denosumab. It was noteworthy that she had suffered multiple fractures in spite of earlier BP administration. The remaining patients had also experienced repeated fractures despite reaching adulthood. Since no fractures were noted for seven of eight patients during denosumab treatment, the drug appears to be effective for OI patients at high fracture risk. \n\nIn our series, BMD increased soon after denosumab administration and remained improved during observation in all cases except Patient 6. She was post-menopausal at denosumab commencement, which might have explained why her L-BMD did not increase but her H-BMD did. The mechanism for this discrepancy is unknown, but may become clear after longer follow-up. Patients 2 and 3 had relatively high baseline BMD values but also repeated fractures prior to treatment. Thus, the modest increases in BMD in our cohort were thought to have partly resulted from originally high BMD. Overall, however, denosumab may improve BMD and decrease fracture risk in OI patients with osteoporosis.\n\nBone formation and bone resorption markers were both generally improved by denosumab in Patients 2 and 3, which was in line with other reports [11,17,18]. Patients 4, 5, 6, 7, and 8 also showed improvements. The causes of elevated BAP and TRACP-5b in Patient 1 are currently unknown. In most cases (Patients 3, 4, 6, 7, and 8), serum albumin-corrected calcium levels were markedly decreased at one month, while serum 1,25 (OH)2D levels were greatly increased at one month. Serum whole PTH was remarkably higher in Patients 3 and 8 at one month of treatment but relatively constant in the remaining cohort. Serum urinary NTX levels were decreased in most cases at one month, although Patient 3 showed a spike at 30 months by yet unknown mechanisms. Taken together, bone formation and bone resorption markers improved, serum albumin-corrected calcium was increased at one month, and serum 1,25(OH)2D and urinary NTX were greatly decreased at 1 month by denosumab administration.\n\nBone metabolism differs between adults and children [9]. L-BMD and H-BMD were both increased in pediatric Patients 5 and 8. In a related report, there was a significant increase in L-BMD percent change after 48 weeks of denosumab with no alterations in mobility parameters or serious adverse events [14]. Thus, denosumab therapy during childhood might be more beneficial since BMD increases tended to be higher than those in the adult OI patients. \n\nWe previously reported on the effects of denosumab on growth in children [11]. Although the observational period was short, this was the first study on the results of denosumab for OI with osteoporosis. In our adolescent Patient 3, no apparent growth disturbance was observed as her height increased from 159 cm at the first administration to 161 cm at two years and she was within the normal age-based height range. The height of Patient 5 was 90.2 cm prior to treatment and 96.3 cm at one year. In Patient 8, it was 111.7 cm prior to therapy and 125.8 cm at one year. These findings support that denosumab can be considered for pediatric cases from the viewpoint of no growth disruption.\n\nThe majority (>90%) of patients with OI have autosomal dominant variants in COL1A1/COL1A2 that lead to defects in type 1 collagen. In our study, mutations in COL1A1/COL1A2 were harbored by 6 of 8 patients. Hoyer-Kuhn et al. also described a heterozygous mutation in the coding region of the interferon-induced transmembrane 5 (IFITM5) (c.-14C > T) gene, an underlying cause of OI type V [14]. Jin et al. reviewed that OI type VI was caused by mutations in serpin peptidase inhibitor, clade F, member 1 (SERPINF1), the gene coding for pigment epithelium-derived factor (PEDF) [19].\n\nIn our cohort, Patients 2 and 3 exhibited no remarkable mutations using a next generation sequencer; there is a possibility that they possessed other gene mutations such as those listed above. \n\nHypocalcemia was absent in all patients during therapy apart from Patient 8 at one month. The reasons for this finding are unknown since denosumab is considered to decrease serum calcium levels in the initial treatment period as a consequence of the inhibition of bone turnover. However, we earlier reported no significant changes in serum calcium in a denosumab monotherapy group and in a denosumab with vitamin D and calcium supplementation group during observation [20]. \n\nPerhaps most strikingly, our cohort had experienced multiple fractures before denosumab treatment, but none were recorded during the administration period in 7 of 8 patients. This suggested that denosumab exerted fracture preventative and BMD increasing effects in OI patients with osteoporosis. Since denosumab discontinuation causes a marked decrease in BMD [21,22], BPs and other alternative treatments are recommended after its cessation. \n\nLimitations\nThe limitations of the current study include its limited size, lack of a control group, lack of 25-Hydroxyvitamin D measurements, short observation period for some patients, and retrospective design. Nonetheless, our case series provides evidence of good BMD response and fracture prevention by denosumab treatment for OI with osteoporosis. \n\n6. Conclusions\nThis study is the first long-term treatment case series of denosumab for osteoporotic OI patients in Japan. Denosumab is well tolerated and provides generally good responses in BMD and bone turnover markers along with possible fracture prevention in OI patients with osteoporosis, and thus represents a good treatment option for such cases.\n\nAcknowledgments\nWe thank Trevor Ralph for his English editorial assistance. \n\nAuthor Contributions\nY.N. directed this study. T.S., R.T., T.H., M.T., and T.K. (Tsukasa Kobayashi) collected patient data. T.Y. performed molecular investigation. T.K. (Tomoki Kosho) and Y.N. wrote the main manuscript. H.K. gave suggestions on this study. All authors reviewed and approved the manuscript. \n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nThe authors declare no conflict of interest. \n\nFigure 1 Changes in bone mineral density (BMD) before and during denosumab administration. (a) In most cases, the percent changes in lumbar 1–4 spine BMD (L-BMD) were positive during the follow-up period. In Patient 6, L-BMD was decreased at 12 months. In Patient 2, L-BMD was decreased until 6 months. (b) In most cases, the percent changes in bilateral hips BMD (H-BMD) were positive during observation. In Patient 4, H-BMD was decreased at 3 and 12 months. In Patient 8, H-BMD was decreased until 3 months. Patient 1: circles connected by a solid line. Patient 2: squares connected by a solid line. Patient 3: squares connected by a dotted line. Patient 4: cross marks connected by a solid line. Patient 5: circles connected by a dotted line. Patient 6: cross marks connected by a hashed line. Patient 7: triangles connected by a dotted line. Patient 8: triangles connected by a solid line. Circles, squares, and triangles represent family members.\n\nFigure 2 Changes in serum albumin-corrected calcium, 1,25 (OH)2D, and whole parathyroid hormone (PTH) levels before and during denosumab administration.(a) Percent changes in serum calcium were not remarkably altered during the follow-up period. Only Patient 6 showed hypocalcemia at 1 month, which returned to baseline values at 3 months of therapy. (b) In Patients 2, 5, 6, and 8, the percent changes in 1,25 (OH)2D were increased at 1 month but returned to baseline values thereafter. In other patients, they were not remarkably changed. (c) Percent changes in whole PTH did not change remarkably during follow-up. Only Patient 6 showed a notable decrease at 1 month, which returned to baseline values at 3 months of therapy. Patient 1: circles connected by a solid line. Patient 2: squares connected by a solid line. Patient 3: squares connected by a dotted line. Patient 4: cross marks connected by a solid line. Patient 5: circles connected by a dotted line. Patient 6: cross marks connected by a hashed line. Patient 7: triangles connected by a dotted line. Patient 8: triangles connected by a solid line. Circles, squares, and triangles represent family members.\n\nFigure 3 Changes in bone turnover markers before and during denosumab administration. (a) Only in Patient 1, the percent changes in bone alkaline phosphatase (BAP) were increased for the first 3 months, and then decreased or slightly increased thereafter. In other patients, they tended to be decreased during the observation period. (b) In Patient 3, the percent changes in urinary NTX were increased during 6 to 24 months, and then sharply increased at 30 months. In other patients, they were mostly constant or slightly inhibited during follow-up. (c) In Patient 1, the percent changes in TRACP-5b were increased at 6, 12, 27, 49, and 54 months. In other patients, they were mostly constant or slightly inhibited during the treatment period. Patient 1: circles connected by a solid line. Patient 2: squares connected by a solid line. Patient 3: squares connected by a dotted line. Patient 4: cross marks connected by a solid line. Patient 5: circles connected by a dotted line. Patient 6: cross marks connected by a hashed line. Patient 7: triangles connected by a dotted line. Patient 8: triangles connected by a solid line. Circles, squares, and triangles represent family members.\n\njcm-07-00479-t001_Table 1Table 1 Patient characteristics.\n\n\n\tAge, Years\nat Study Onset\tGender\tOI Type\tHeight, cm\nat Study Onset\tBMI\nat Study Onset\tPrevious Treatment\tOccurrence of Fracture before Study\tOccurrence of Fracture during Study\tCausative Mutation\tDose, Frequency, and Duration of Denosumab Administration\t\n\nPatient 1\n\t42\tF\tIb\t138\t24.1\tNone\t>10\tNone\tCOL1A1\nc.G769A; p.G257R\t60 mg every 6 months for 54 months\t\n\nPatient 2\n\t40\tF\tI similar\t156\t21.1\tNone\t>10\tNone\tUnidentified\t60 mg every 6 months for 36 months\t\n\nPatient 3\n\t14\tF\tI similar\t159\t22.2\tBP\t>10\tNone\tUnidentified\t60 mg every 6 months for 36 months\t\n\nPatient 4\n\t22\tF\tIa\t134.5\t23.6\tBP\t>10\tNone\tCOL1A1\nc.G1963C; p.G655R\t60 mg every 6 months for 18 months\t\n\nPatient 5\n\t3\tF\tIb\t90.2\t14.8\tNone\t1\t1\tCOL1A1\nc.G769A; p.G257R\t15 mg every 6 months for 18 months\t\n\nPatient 6\n\t51\tF\tIa\t155\t20.8\tNone\t>10\tNone\tCOL1A1\nc.1243C>T; p.R415X\t60 mg every 6 months for 12 months\t\n\nPatient 7\n\t37\tM\tIa\t166\t25.4\tBP\t>10\tNone\tCOL1A1\nc.G607T; p.G203C\t60 mg every 6 months for 4 months\t\n\nPatient 8\n\t9\tF\tIa\t111.7\t15.2\tNone\tNone\tNone\tCOL1A1\nc.607G>T; p.G203C\t30 mg every 6 months for 6 months\t\nF: female, M: male, OI: osteogenesis imperfecta, BMI: body mass index, BP: bisphosphonate. Patient 5 is a daughter of Patient 1, Patient 3 is a daughter of Patient 2, and Patient 8 is a daughter of Patient 7.\n\njcm-07-00479-t002_Table 2Table 2 Patient laboratory data across observation periods for each patient.\n\n\n\tSerum Albumin-Corrected Ca Level (mg/dL)\t\n\n\tBefore (Reference Value: 8.5–10.2)\t1M\t2–4M\t6M\t12M\t18M\t24M\t27M\t30M\t33M\t36M\t39M\t42M\t49M\t54M\t\n\nPatient 1\n\t9.5\t\n\t\n\t9.7\t9.4\t9.1\t9.2\t9.9\t10\t9.6\t9.6\t9.6\t9.6\t9.5\t9.4\t\n\nPatient 2\n\t9.2\t9.2\t9.4\t8.9\t9.0\t9.4\t9.2\t9.4\t9.0\t\n\t9.2\t\n\t\n\t\n\t\n\t\n\nPatient 3\n\t9.6\t9.5\t9.5\t9.4\t9.9\t9.7\t9.7\t9.8\t9.4\t\n\t9.5\t\n\t\n\t\n\t\n\t\n\nPatient 4\n\t9.6\t9.6\t9.4\t9.7\t9.3\t9.4\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 5\n\t10.2\t\n\t10.2\t10.5\t10.6\t11.4\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 6\n\t9.6\t9.6\t9.6\t9.7\t9.7\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 7\n\t9.0\t8.7\t9.1\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 8\n\t9.7\t7.3\t9.6\t9.5\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\n\t\nSerum P (mg/dL)\n\t\n\n\t\nBefore (Reference value: 2.4–4.3)\n\t\n1M\n\t\n2–4M\n\t\n6M\n\t\n12M\n\t\n18M\n\t\n24M\n\t\n27M\n\t\n30M\n\t\n33M\n\t\n36M\n\t\n39M\n\t\n42M\n\t\n49M\n\t\n54M\n\t\n\nPatient 1\n\t3.2\t\n\t4.2\t3.8\t3.8\t3.8\t3.8\t3.3\t4.1\t4.0\t\n\t3.3\t3.0\t3.1\t3.4\t\n\nPatient 2\n\t3.9\t3.2\t3.0\t3.5\t2.7\t3.0\t3.2\t4.1\t3.0\t\n\t3.7\t\n\t\n\t\n\t\n\t\n\nPatient 3\n\t3.8\t3.1\t3.8\t3.5\t3.8\t3.9\t3.5\t4.2\t4.6\t\n\t3.7\t\n\t\n\t\n\t\n\t\n\nPatient 4\n\t4.1\t3.4\t4.2\t3.7\t3.0\t3.7\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 5\n\t5.3\t\n\t5.1\t5.6\t6.0\t5.8\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 6\n\t4.0\t3.7\t4.3\t3.7\t3.8\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 7\n\t2.8\t2.6\t2.3\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 8\n\t6.3\t5.9\t5.0\t5.1\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\n\t\nWhole PTH (pg/dL)\n\t\n\n\t\nBefore (Reference Value: 8.3–38.7)\n\t\n1M\n\t\n2-4M\n\t\n6M\n\t\n12M\n\t\n18M\n\t\n24M\n\t\n27M\n\t\n30M\n\t\n33M\n\t\n36M\n\t\n39M\n\t\n42M\n\t\n49M\n\t\n54M\n\t\n\nPatient 1\n\t40.6\t\n\t35.5\t21\t40.6\t\n\t35.3\t\n\t35.4\t\n\t\n\t\n\t73.5\t29.3\t37.6\t\n\nPatient 2\n\t\n\t17.1\t13.9\t27.4\t19\t19.6\t26.1\t22.3\t17.3\t\n\t16.3\t\n\t\n\t\n\t\n\t\n\nPatient 3\n\t11.8\t21.9\t7.1\t20.2\t13.7\t14\t22.2\t11.7\t15.3\t\n\t21.2\t\n\t\n\t\n\t\n\t\n\nPatient 4\n\t14.8\t12.2\t21.5\t18.5\t27.5\t21.7\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 5\n\t17.3\t\n\t10.4\t12.8\t6.3\t4\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 6\n\t22.8\t24.5\t22.2\t22.5\t30.3\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 7\n\t47.7\t67.3\t43.1\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 8\n\t16.9\t114\t19.2\t22.1\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\nCa: calcium, P: phosphorus, PTH: parathyroid hormone, M: months.\n\njcm-07-00479-t003_Table 3Table 3 Patient bone mineral density across observation periods for each patient.\n\n\n\tL-BMD (g/cm2)\t\n\n\tBefore\t1M\t2–4M\t6M\t12M\t18M\t24M\t27M\t30M\t33M\t36M\t39M\t42M\t49M\t54M\t\n\nPatient 1\n\t0.571\t\n\t\n\t0.707\t0.723\t0.705\t0.705\t0.736\t\n\t0.791\t\n\t0.859\t0.762\t0.754\t0.818\t\n\nPatient 2\n\t1.018\t\n\t\n\t1.002\t1.099\t1.062\t1.082\t\n\t\n\t\n\t1.100\t\n\t\n\t\n\t\n\t\n\nPatient 3\n\t1.070\t\n\t\n\t1.113\t1.154\t1.162\t1.166\t\n\t1.15\t\n\t1.215\t\n\t\n\t\n\t\n\t\n\nPatient 4\n\t0.870\t\n\t0.910\t0.886\t0.908\t0.924\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 5\n\t0.396\t\n\t\n\t0.432\t0.495\t0.521\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 6\n\t0.743\t\n\t0.731\t0.737\t0.693\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 7\n\t1.224\t\n\t1.332\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 8\n\t0.428\t\n\t0.468\t0.559\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\n\t\nL-BMD Z-score\n\t\n\n\t\nBefore\n\t\n1M\n\t\n2–4M\n\t\n6M\n\t\n12M\n\t\n18M\n\t\n24M\n\t\n27M\n\t\n30M\n\t\n33M\n\t\n36M\n\t\n39M\n\t\n42M\n\t\n49M\n\t\n54M\n\t\n\nPatient 1\n\t\n\t\n\t\n\t−3.2\t−3\t−3.1\t−2.9\t−2.4\t\n\t−2.8\t\n\t−2.8\t−2.9\t−2.3\t−2.7\t\n\nPatient 2\n\t−0.8\t\n\t\n\t−1\t−0.6\t−0.4\t−0.6\t\n\t−0.4\t\n\t−0.6\t\n\t\n\t\n\t\n\t\n\nPatient 3\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 4\n\t−1.6\t\n\t−1.7\t−1.9\t−1.8\t−1.6\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 5\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 6\n\t−2.2\t\n\t−2.2\t−2.1\t−2.4\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 7\n\t0.7\t\n\t1.4\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 8\n\t−3.1\t\n\t−2.6\t−1.9\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\n\t\nL-BMD T-score\n\t\n\n\t\nBefore\n\t\n1M\n\t\n2–4M\n\t\n6M\n\t\n12M\n\t\n18M\n\t\n24M\n\t\n27M\n\t\n30M\n\t\n33M\n\t\n36M\n\t\n39M\n\t\n42M\n\t\n49M\n\t\n54M\n\t\n\nPatient 1\n\t\n\t\n\t\n\t−3.4\t−3.2\t−3.4\t−3.1\t−27\t\n\t−2.8\t\n\t−2.8\t−2.9\t−2.4\t−2.8\t\n\nPatient 2\n\t−0.8\t\n\t\n\t−0.9\t−0.4\t−0.2\t−0.6\t\n\t−0.4\t\n\t−0.6\t\n\t\n\t\n\t\n\t\n\nPatient 3\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 4\n\t−2.2\t\n\t−1.7\t−1.9\t−1.8\t−1.6\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 5\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 6\n\t−2.9\t\n\t−3\t−3\t−3.3\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 7\n\t0.7\t\n\t1.4\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 8\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\n\t\nH-BMD (g/cm2\n)\n\t\n\n\t\nBefore\n\t\n1M\n\t\n2–4M\n\t\n6M\n\t\n12M\n\t\n18M\n\t\n24M\n\t\n27M\n\t\n30M\n\t\n33M\n\t\n36M\n\t\n39M\n\t\n42M\n\t\n49M\n\t\n54M\n\t\n\nPatient 1\n\t0.520\t\n\t\n\t0.549\t0.562\t0.595\t0.608\t0.562\t\n\t0.591\t\n\t0.579\t0.558\t0.57\t0.576\t\n\nPatient 2\n\t0.729\t\n\t\n\t0.867\t0.884\t0.879\t0.898\t\n\t\n\t\n\t0.908\t\n\t\n\t\n\t\n\t\n\nPatient 3\n\t0.946\t\n\t\n\t0.964\t0.988\t0.977\t0.993\t\n\t0.996\t\n\t1.027\t\n\t\n\t\n\t\n\t\n\nPatient 4\n\t0.677\t\n\t0.664\t\n\t0.672\t0.711\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 5\n\t0.409\t\n\t\n\t0.370\t0.470\t0.465\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 6\n\t0.654\t\n\t0.661\t0.682\t0.674\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 7\n\t0.979\t\n\t0.997\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 8\n\t0.54\t\n\t0.531\t0.589\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\n\t\nH-BMD Z-score\n\t\n\n\t\nBefore\n\t\n1M\n\t\n2–4M\n\t\n6M\n\t\n12M\n\t\n18M\n\t\n24M\n\t\n27M\n\t\n30M\n\t\n33M\n\t\n36M\n\t\n39M\n\t\n42M\n\t\n49M\n\t\n54M\n\t\n\nPatient 1\n\t\n\t\n\t\n\t−2.95\t−2.85\t−2.85\t−2.85\t−2.6\t\n\t−2.45\t\n\t−2.75\t−2.7\t−2.65\t−2.55\t\n\nPatient 2\n\t−0.55\t\n\t\n\t−0.45\t−0.4\t−0.25\t−0.2\t\n\t−0.15\t\n\t−0.05\t\n\t\n\t\n\t\n\t\n\nPatient 3\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 4\n\t−2\t\n\t−2.25\t−2.25\t−1.9\t−2.25\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 5\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 6\n\t−1.8\t\n\t-1.75\t-1.6\t-1.6\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 7\n\t-0.25\t\n\t-0.15\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 8\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\n\t\nH-BMD T-score\n\t\n\n\t\nBefore\n\t\n1M\n\t\n2–4M\n\t\n6M\n\t\n12M\n\t\n18M\n\t\n24M\n\t\n27M\n\t\n30M\n\t\n33M\n\t\n36M\n\t\n39M\n\t\n42M\n\t\n49M\n\t\n54M\n\t\n\nPatient 1\n\t\n\t\n\t\n\t-3.2\t-3.1\t-3.1\t-3.1\t-2.85\t\n\t-3.15\t\n\t-3.05\t-3\t-2.95\t-2.9\t\n\nPatient 2\n\t−0.65\t\n\t\n\t−0.55\t−0.45\t−0.25\t−0.5\t\n\t−0.4\t\n\t−0.35\t\n\t\n\t\n\t\n\t\n\nPatient 3\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 4\n\t−2.15\t\n\t−2.25\t−2.25\t−1.9\t−2.25\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 5\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 6\n\t−2.35\t\n\t−2.3\t−2.15\t−2.2\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 7\n\t−0.45\t\n\t−0.4\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 8\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\nL-BMD: lumbar 1–4 bone mineral density, H-BMD: bilateral total hip bone mineral density, M: months.\n\njcm-07-00479-t004_Table 4Table 4 Patient laboratory data (bone metabolism markers) across observation periods for each patient.\n\n\n\tBAP (μg/L)\t\n\n\tBefore\n(Reference Value)\t1M\t2–4M\t6M\t12M\t18M\t24M\t27M\t30M\t33M\t36M\t39M\t42M\t49M\t54M\t\n\nPatient 1\n\t7.6\n(2.9–14.5)\t\n\t10.8\t7.9\t7.8\t6.1\t6\t6.7\t6.5\t6.2\t7.6\t7\t5.2\t7.9\t7.9\t\n\nPatient 2\n\t8.4\n(2.9–14.5)\t7.6\t5.8\t5.9\t5.1\t5.1\t7.2\t6.9\t6.8\t\n\t6.6\t\n\t\n\t\n\t\n\t\n\nPatient 3\n\t16.7\n(2.9–14.5)\t11.9\t7.8\t11.5\t8.7\t6.9\t11.5\t5.8\t11.4\t\n\t6.6\t\n\t\n\t\n\t\n\t\n\nPatient 4\n\t14.7\n(2.9–14.5)\t13.4\t7\t7.9\t6.3\t4.9\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 5\n\t62.2\n(2.9–14.5)\t\n\t52.6\t35.6\t43.4\t60.9\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 6\n\t14.2\n(2.9–14.5)\t12\t7.6\t8.5\t8.7\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 7\n\t20.3\n(3.7–20.9)\t11.7\t9.5\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 8\n\t84.4\n(2.9–14.5)\t55.8\t58.8\t74.9\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\n\t\nUrinary NTX (nmol BCE/mmol Cr)\n\t\n\n\t\nBefore (Reference value)\n\t\n1M\n\t\n2–4M\n\t\n6M\n\t\n12M\n\t\n18M\n\t\n24M\n\t\n27M\n\t\n30M\n\t\n33M\n\t\n36M\n\t\n39M\n\t\n42M\n\t\n49M\n\t\n54M\n\t\n\nPatient 1\n\t19.3\n(9.3–54.3)\t18.1\t9.7\t9.9\t29.7\t5.4\t8.5\t18.9\t12\t6.2\t\n\t10.1\t10.1\t38.4\t38.6\t\n\nPatient 2\n\t24.2\n(9.3–54.3)\t4.7\t16.8\t22.8\t12.6\t13.9\t27.9\t10.4\t31.9\t\n\t23.5\t\n\t\n\t\n\t\n\t\n\nPatient 3\n\t32.9\n(9.3–54.3)\t12.9\t18.1\t79.7\t48.4\t44\t52.3\t14.4\t181.2\t\n\t25.8\t\n\t\n\t\n\t\n\t\n\nPatient 4\n\t30.4\n(9.3–54.3)\t15.4\t\n\t\n\t21.3\t24.3\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 5\n\t1562.1\n(9.3–54.3)\t\n\t616.9\t338\t587.3\t612.6\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 6\n\t35.4\n(9.3–54.3)\t13.2\t21\t5\t17.5\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 7\n\t79.8\n(13.0–66.2)\t13.1\t14\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 8\n\t518.2\n(9.3–54.3)\t207.9\t320.3\t601.8\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\n\t\nTRACP-5b (mU/dL\n)\n\t\n\n\t\nBefore\n\n\n(reference value)\n\t\n1M\n\t\n2–4M\n\t\n6M\n\t\n12M\n\t\n18M\n\t\n24M\n\t\n27M\n\t\n30M\n\t\n33M\n\t\n36M\n\t\n39M\n\t\n42M\n\t\n49M\n\t\n54M\n\t\n\nPatient 1\n\t66\n(120–420)\t\n\t62\t106\t133\t70\t61\t112\t69\t71\t\n\t65\t75\t153\t196\t\n\nPatient 2\n\t198\n(120–420)\t48\t62\t83\t59\t72\t144\t72\t149\t\n\t83\t\n\t\n\t\n\t\n\t\n\nPatient 3\n\t414\n(120–420)\t60\t114\t432\t356\t256\t484\t64\t586\t\n\t142\t\n\t\n\t\n\t\n\t\n\nPatient 4\n\t260\n(120–420)\t33\t52\t123\t62\t38\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 5\n\t1500\n(120–420)\t\n\t1500\t1420\t1500\t1500\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 6\n\t319\n(120–420)\t103\t123\t120\t203\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 7\n\t465\n(170–590)\t83\t136\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 8\n\t1500\n(120–420)\t894\t1500\t1500\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\n\t\n1,25 (OH)2D (pg/mL)\n\t\n\n\t\nBefore\n\n\n(Reference Value)\n\t\n1M\n\t\n2–4M\n\t\n6M\n\t\n12M\n\t\n18M\n\t\n24M\n\t\n27M\n\t\n30M\n\t\n33M\n\t\n36M\n\t\n39M\n\t\n42M\n\t\n49M\n\t\n54M\n\t\n\nPatient 1\n\t47.9\n(20.0–60.0)\t\n\t20.3\t55.7\t47.9\t26.1\t52.4\t45.5\t61.4\t85.8\t\n\t49.1\t61.4\t48.9\t31.8\t\n\nPatient 2\n\t49\n(20.0–60.0)\t90.1\t60.3\t55.5\t53.7\t36.8\t52.8\t50.9\t43.3\t\n\t33.1\t\n\t\n\t\n\t\n\t\n\nPatient 3\n\t57.2\n(20.0–70.0)\t131\t54.1\t34.7\t65.6\t47.3\t35.2\t67\t47\t\n\t75.9\t\n\t\n\t\n\t\n\t\n\nPatient 4\n\t45.9\n(20.0–60.0)\t60.6\t64.1\t54.3\t36.8\t68.3\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 5\n\t58.9\n(20.0–70.0)\t\n\t41.3\t29.2\t5.6\t10.7\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 6\n\t30.8\n(20.0–60.0)\t47.1\t35.5\t27.7\t25.7\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 7\n\t69.8\n(20.0–60.0)\t81.6\t83.8\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\nPatient 8\n\t90.7\n(20.0–70.0)\t275\t61.7\t75.2\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\nBAP: bone-specific alkaline phosphatase, NTX: type I collagen amino-terminal telopeptide, TRACP-5b: tartrate-resistant acid phosphatase 5b, 1,25 (OH)2D: 1-alpha, M: months.\n==== Refs\nReferences\n1. Rauch F. Glorieux F.H. Osteogenesis imperfecta Lancet 2004 363 1377 1385 10.1016/S0140-6736(04)16051-0 15110498 \n2. Forlino A. Marini J.C. Osteogenesis imperfecta Lancet 2016 387 1657 1671 10.1016/S0140-6736(15)00728-X 26542481 \n3. Sillence D.O. Senn A. Danks D.M. Genetic heterogeneity in osteogenesis imperfecta J. Med. Genet. 1979 16 101 106 10.1136/jmg.16.2.101 458828 \n4. Van Dijk F.S. Sillence D.O. Osteogenesis imperfecta: Clinical diagnosis, nomenclature and severity assessment Am. J. Med. Genet. A 2014 164 1470 1481 10.1002/ajmg.a.36545 24715559 \n5. Glorieux F.H. Bishop N.J. Plotkin H. Chabot G. Lanoue G. Travers R. Cyclic administration of pamidronate in children with severe osteogenesis imperfecta N. Engl. J. Med. 1998 339 947 952 10.1056/NEJM199810013391402 9753709 \n6. Semler O. Beccard R. Palmisano D. Demant A. Fricke O. Schoenau E. Koerber F. Reshaping of Vertebrae during Treatment with Neridronate or Pamidronate in Children with Osteogenesis Imperfecta Horm. Res. Paediatr. 2011 76 321 327 10.1159/000331128 21952409 \n7. Land C. Rauch F. Travers R. Glorieux F.H. Osteogenesis imperfecta type VI in childhood and adolescence: Effects of cyclical intravenous pamidronate treatment Bone 2007 40 638 644 10.1016/j.bone.2006.10.010 17127117 \n8. Bishop N. Adami S. Ahmed S.F. Antón J. Arundel P. Burren C.P. Devogelaer J.P. Hangartner T. Hosszú E. Lane J.M. Risedronate in children with osteogenesis imperfecta: A randomised, double-blind, placebo-controlled trial Lancet 2013 382 1402 1432 10.1016/S0140-6736(13)61091-0 \n9. Bone H.G. Bolognese M.A. Yuen C.K. Kendler D.L. Wang H. Liu Y. San Martin J. Effects of denosumab on bone mineral density and bone turnover in postmenopausal women J. Clin. Endocrinol. Metab. 2008 93 2149 2157 10.1210/jc.2007-2814 18381571 \n10. Lewiecki E.M. Miller P.D. McClung M.R. Cohen S.B. Bolognese M.A. Liu Y. Wang A. Siddhanti S. Fitzpatrick L.A. AMG 162 Bone Loss Study Group. Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low BMD J. Bone Miner. Res. 2007 22 1832 1841 10.1359/jbmr.070809 17708711 \n11. Uehara M. Nakamura Y. Takahashi J. Kamimura M. Ikegami S. Suzuki T. Uchiyama S. Kosho T. Kato H. Efficacy of denosumab for osteoporosis in three female patients with osteogenesis imperfecta Tohoku J. Med. 2017 242 115 120 10.1620/tjem.242.115 28626166 \n12. Semler O. Netzer C. Hoyer-Kuhn H. Becker J. Eysel P. Schoenau E. First use of the RANKL antibody denosumab in osteogenesis imperfecta type VI J. Musculoskelet. Neuronal Interact. 2012 12 183 188 22947550 \n13. Hoyer-Kuhn H. Netzer C. Koerber F. Schoenau E. Semler O. Two years’ experience with denosumab for children with osteogenesis imparcta type VI Orphanet J. Rare Dis. 2014 9 145 10.1186/s13023-014-0145-1 25257953 \n14. Hoyer-Kuhn H. Franklin J. Allo G. Kron M. Netzer C. Eysel P. Hero B. Schoenau E. Semler O. Safety and efficacy of denosumab in children with osteogenesis imperfect—A first prospective trial J. Musculoskelet. Neuronal Interact. 2016 16 24 32 26944820 \n15. Orimo H. Hayashi Y. Fukunaga M. Sone T. Fujiwara S. Shiraki M. Hagino H. Hosoi T. Ohta H. Yoneda T. Diagnostic criteria of primary osteoporosis: Year 2000 revision Jpn. J. Bone Metab. 2001 16 139 150 10.1007/s007740050038 \n16. Major C.C. Borggren C.L. Devries R.M. Traumatic hand fracture in a patient with osteogenesis imperfecta J. Chiropr. Med. 2008 7 155 160 10.1016/j.jcm.2008.04.003 19646378 \n17. Uehara M. Nakamura Y. Takahashi J. Kamimura M. Isobe F. Yamaguchi T. Kosho T. Uchiyama S. Suzuki T. Kato H. Efficacy of denosumab therapy for neurofibromatosis type 1 with osteoporosis and history of fractures: A case report Ther. Clin. Risk Manag. 2018 14 1243 1246 10.2147/TCRM.S159668 30038498 \n18. Uehara M. Nakamura Y. Takahashi J. Suzuki T. Kato H. Efficacy of denosumab in two cases with multiple-system atrophy and osteoporosis Ther. Clin. Risk Manag. 2018 14 817 822 10.2147/TCRM.S162574 29765223 \n19. Jin Z. Burrage L.C. Jiang M.M. Lee Y.C. Bertin T. Chen Y. Tran A. Gibbs R.A. Jhangiani S. Sutton V.R. Whole-exome sequencing identifies an intronic cryptic splice site in serpinf1 causing osteogenesis imperfecta type VI JBMR Plus 2018 2 235 239 10.1002/jbm4.10044 30283904 \n20. Nakamura Y. Suzuki T. Kamimura M. Murakami K. Ikegami S. Uchiyama S. Kato H. Vitamin D and calcium are required at the time of denosumab administration during osteoporosis treatment Bone Res. 2017 5 17021 10.1038/boneres.2017.21 29021920 \n21. Miller P.D. Bolognese M.A. Lewiecki E.M. McClung M.R. Ding B. Austin M. Liu Y. San Martin J. Amg Bone Loss Study Group. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, and restarting of therapy: A randomized blinded phase 2 clinical trial Bone 2008 43 222 229 10.1016/j.bone.2008.04.007 18539106 \n22. Bone H.G. Bolognese M.A. Yuen C.K. Kendler D.L. Miller P.D. Yang Y.C. Grazette L. San Martin J. Gallagher J.C. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass J. Clin. Endocrinol. Metab. 2011 96 972 980 10.1210/jc.2010-1502 21289258\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2077-0383",
"issue": "7(12)",
"journal": "Journal of clinical medicine",
"keywords": "bone mineral density; denosumab; fractures; osteogenesis imperfecta; osteoporosis",
"medline_ta": "J Clin Med",
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"nlm_unique_id": "101606588",
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"pmid": "30477250",
"pubdate": "2018-11-24",
"publication_types": "D016428:Journal Article",
"references": "15110498;17127117;17708711;18381571;18539106;19646378;21289258;21952409;22947550;23927913;24715559;25257953;26542481;26944820;28626166;29021920;29765223;30038498;30283904;458828;9753709",
"title": "Efficacy and Safety of Denosumab Therapy for Osteogenesis Imperfecta Patients with Osteoporosis-Case Series.",
"title_normalized": "efficacy and safety of denosumab therapy for osteogenesis imperfecta patients with osteoporosis case series"
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"abstract": "A middle-aged man presented 1 day after being discharged from hospital with completing the first course of postoperative chemotherapy. He suffered a sudden persistent high fever and chills. It was noted that he had a history of a total gastrectomy (with D2 lymphadenectomy) 1 month ago. His admission bloods revealed total bilirubin was 142.2 umol/L, indirect bilirubin of 107.6 umol/L and white cell count of 20.05×10(9)/L. A color doppler ultrasound scan confirmed fluid and gas around liver and hilus lienis while the gallbladder cannot be detected. During Computed Tomography (CT) guided puncture positioning technology and setting a three-channel tube, about 400 ml of foul smell hazel turbid liquid was drained out. He was diagnosed as gallbladder perforation and he was underwent conservative treatment consist of drainage, banning diet, total parenteral nutrition and intravenous antibiotics. Then he recovered well within the subsequent 10 days and was discharged.",
"affiliations": "Department of Colorectal Cancer Surgery, Shandong Cancer Hospital and Institute, 440 Jiyan Road, Jinan, 250117, China. sunyanlai@126.com.;Department of Colorectal Cancer Surgery, Shandong Cancer Hospital and Institute, 440 Jiyan Road, Jinan, 250117, China. songwentao676@126.com.;Department of Colorectal Cancer Surgery, Shandong Cancer Hospital and Institute, 440 Jiyan Road, Jinan, 250117, China. houqingsheng676@126.com.;Department of Anesthesiology and Operation, Affiliated Hospital of Shandong Academy of Medical Sciences, 38 Wuyingshan Road, Jinan, 250031, China. l1979jn@126.com.;Department of Colorectal Cancer Surgery, Shandong Cancer Hospital and Institute, 440 Jiyan Road, Jinan, 250117, China. hliangbbb@163.com.",
"authors": "Sun|Yanlai|Y|;Song|Wentao|W|;Hou|Qingsheng|Q|;Li|Jianning|J|;Guo|Hongliang|H|",
"chemical_list": null,
"country": "England",
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"doi": "10.1186/s12957-015-0659-6",
"fulltext": "\n==== Front\nWorld J Surg OncolWorld J Surg OncolWorld Journal of Surgical Oncology1477-7819BioMed Central London 65910.1186/s12957-015-0659-6Case ReportGallbladder perforation: a rare complication of postoperative chemotherapy of gastric cancer Sun Yanlai sunyanlai@126.com Song Wentao songwentao676@126.com Hou Qingsheng houqingsheng676@126.com Li Jianning l1979jn@126.com Guo Hongliang hliangbbb@163.com Department of Colorectal Cancer Surgery, Shandong Cancer Hospital and Institute, 440 Jiyan Road, Jinan, 250117 China Department of Anesthesiology and Operation, Affiliated Hospital of Shandong Academy of Medical Sciences, 38 Wuyingshan Road, Jinan, 250031 China 15 8 2015 15 8 2015 2015 13 24516 5 2015 22 7 2015 © Sun et al. 2015This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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.A middle-aged man presented 1 day after being discharged from hospital with completing the first course of postoperative chemotherapy. He suffered a sudden persistent high fever and chills. It was noted that he had a history of a total gastrectomy (with D2 lymphadenectomy) 1 month ago. His admission bloods revealed total bilirubin was 142.2umol/L , indirect bilirubin of 107.6umol/L and white cell count of 20.05×109/L. A color doppler ultrasound scan confirmed fluid and gas around liver and hilus lienis while the gallbladder cannot be detected. During Computed Tomography (CT) guided puncture positioning technology and setting a three-channel tube, about 400 ml of foul smell hazel turbid liquid was drained out. He was diagnosed as gallbladder perforation and he was underwent conservative treatment consist of drainage, banning diet, total parenteral nutrition and intravenous antibiotics. Then he recovered well within the subsequent 10 days and was discharged.\n\nKeywords\nGallbladder perforationPostoperative chemotherapyGastric cancerComplicationissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nPerforation of the gallbladder is a rare but life-threatening condition, which usually requires immediate surgical intervention [1, 2]. Sometimes perforation of the gallbladder may not be different from uncomplicated acute cholecystitis with high morbidity and mortality rates because of delay in diagnosis [3–4]. Perforation of the gallbladder is an extremely rare but serious complication of postoperative chemotherapy although the progress may mainly facilitated by operation [5–7]. There are no reported cases of these in the literature. There are no similar reported cases in the literature to the best our knowledge. In this article, we describe a case of a perforation of the gallbladder in a patient most likely related to a combination of operation and chemotherapy, which has not been reported yet.\n\nCase presentation\nA 48-year-old man was presented to hospital because of persistent high fever and chills on the first day after completing the first course of chemotherapy. He has a history of a total gastrectomy with D2 lymphadenectomy 1 months ago and one course of postoperative chemotherapy which consisted of Oxaliplatin and S-1(Oxaliplatin 150mg ivdrip d1, S-1 po 40mg bid Day1-14) because of gastric cancer. He has no liver or biliary disease history.\n\nAt the time of admission, his temperature was up to 40 degree and blood pressure was 120/80mmHg. The heart rate and respiratory rate were 86/min and 22/min, respectively. The breath sound of lungs was clear. The whole skin appeared mild jaundice and sclera moderate yellow dye. There was no enlargement phenomenon of superficial lymph nodes. Abdominal examination revealed no pain or tightness. The liver and spleen was unpalpable. Murphy syndrome was negative. Other examination was unremarkable.\n\nInvestigations\nBaseline investigations revealed a aspertate aminotransferase of 97U/L, and the total bilirubin was 142.2umol/L, indirect bilirubin of 107.6umol/L, white cell count of 20.05×109/L. His hepatitis virus examination was negative and renal function, Electrolyte was normal.\n\nDifferential diagnosis\nAn urgent color doppler ultrasound of his upper abdominal was performed which demonstrated right upper abdominal structures disorders as evidenced by the strong echo gas. Parenchyma of Right liver lobe was uneven and the gallbladder cannot be detected. There was a small amount effusion around liver and hilus lienis (Fig. 1).Fig. 1 Color doppler ultrasound investigation. The ultrasound showing fluid around liver and hilus lienis (yellow arrow) and uneven right liver lobe (blue arrow). The gallbladder cannot be detected\n\n\n\nBoth for confirm diagnosis and further treatment, he underwent an emergency CT guided puncture positioning technology and setting a three-channel tube (Fig. 2).Then about 400 ml of foul smell hazel turbid liquid was drained out.Fig. 2 CT scans investigation. CT abdomen/pelvis showing fluid (red arrow) and gas (green arrow) in the liver, gallbladder cannot be detected\n\n\n\nTreatment\nConservative treatment consist of banning diet, total parenteral nutrition and intravenous antibiotics was complemented at the time of admission while records the drainage quantity everyday.\n\nOutcome and follow-up\nHis temperature dropped to 37 degrees,and the jaundice was significantly improved by the first day of conservative treatment. His drainage quantity and liver function tests were noted to be persistently elevated (Table 1). However, blood picture normalised and drainage quantity gradually reduced over the next few days. He was switched to liquid diet by day 5 and continued to recover well. He was discharged 10 days with an outpatient appointment in 8 weeks.Table 1 Progression of liver function tests and drainage quantity after conservative treatment\n\nLiver function tests and drainage quantity\tDay 1\tDay 3\tDay 7\t\ntotal bilirubin(umol/L)\t27.3\t10.9\t9.2\t\nindirect bilirubin(umol/L)\t11.9\t5.1\t4.5\t\nAlkaline phosphatase(U/L)\t113.5\t76.1\t32.7\t\nAlanine transaminase(U/L)\t261.7\t116.0\t49.9\t\ndrainage quantity(ml)\t200\t40\t15\t\n\n\nReview normal every 4 weeks and he had begun the second course of chemotherapy which consisted of oxaliplatin and fluorouracil (oxaliplatin 150mg ivdrip day1, 5-fluorouracil (5-FU) 500mg iv day1, 5-FU 2500mg civ day 2–3).\n\nDiscussion\nPerforation of the gallbladder is one of the rare but severe complications of acute calculous cholecystitis, like empyema, gallstone ileus, cholecystoenteric fistula and emphysematous cholecystits [8]. Acute acalculous cholecystitis is defied as acute cholecystitis without detection of any gallstones. Acute acalculous cholecystitis immediately after gastric operation is also rare [9]. Based on a Danish study, the risk of cholecystitis is 30 % higher in patients with cancer compared with general population [8]. But the data eventually develop to gallbladder perforation in total gastrectomy for cancer can’t be acquired. Perforation of the gallbladder can occur as early as 24 h after the onset of acute cholecystitis, or after a few days to weeks [10]. Ischemic changes of the gallbladder wall triggered by progression of local inflammation lead to perforation, which might explain why perforation occurs in the fundus, the most distant part from the main feeding artery, in more than half of cases [11]. Systemic vascular disorders, such as atherosclerotic cardiovascular disease and diabetes, immunosuppressed states, and malignancy are major risk factors for gallbladder perforation [12].\n\nIt is relatively rare that the gallbladder perforation developed without inflammation, cancer, foreign, stone, or body trauma which makes our study more unique and innovative. Uncommonly, gallbladder perforation may be related to the obstruction of bile duct or the destruction of the gallbladder wall, such as acute cholecystitis, gallstones, parasites, abdominal surgery, gallbladder vascular compression or obstruction. Chemotherapy can lead to gallbladder injury, but, to our knowledge there is no report of postoperative chemotherapy-induced gallbladder perforation.\n\nIn this case, there was no stone shown in the patients with color Doppler ultrasound examination. The following several surgical morbidity factors should be considered.There is a study suggest that the biliary stasis is an important contributing factor in postoperative gallbladder complications [13]. Biliary stasis could cause the chronic cholecystitis and eventually leading to gallbladder perforation.\n\nIt has been reported that the risk of suffering from acute postoperative acalculous cholecystitis was 3.1 % higher in patient with radical gastrectomy compared with patient with simple gastrectomy [14].\n\nA more suggestive cause of postoperative gallbladder perforation may be that the duodenum was excluded from the passage of large volumes of contents, resulting in possible stasis of bile and/or bacterial over growth within its lumen promoting bile inspissation, [15] which increased the pressure of gallbladder and then led to gallbladder inflammation and edema.\n\nIn this case, Gallbladder motility-related hormonal reduce, enteric nervous system function decline and pancreatic fistula may also play important roles in the gallbladder perforation.\n\n\n\nIt’s worth noting that the gallbladder perforation occured on the first day after completing the first course of chemotherapy. Chemo-therapic cholecystitis cases are not rare. In this gallbladder perforation case, chemotherapy-induced gall bladder injury is an important contributing factor.\n\nIn addition to the symptoms and signs, clinical picture and imaging is the first choice method for diagnosis of the disease. CT and ultrasonography are useful in making the diagnosis. Gallbladder wall thickening, peric-holecystic fluid collection, and a streaky omentum or mesentery is common findings of gallbladder perforation. Detection on imaging such as CT scans or color doppler ultrasound can be difficult in small perforations and the findings are usually non-specific that is, pericholecystic fluid/abscess and gallbladder cannot be detected. The presence of extra-luminal gallstones would be a suggestive sign, but it was not seen in this case [16]. In the event of a perforation, the first choice of treatment is urgent surgical intervention. However, conservative treatment which consisted of drainage, absolute diet, total parenteral nutrition and intravenous antibiotics could be given when the patient’s vital signs are stable and there are no symptoms of peritonitis. Avoiding unnecessary fasting and narcotics may be helpful to prevent the incidence of complication. While the presence of stones may increase the likelihood of an attack, preoperative studies undertaken routinely to discover their presence are not justified. A history of attacks of cholecystitis, particularly after previous operations, should be carefully sought.\n\nConclusions\nThis case report is the first presentation of gallbladder perforation associated with operation and chemotherapy. The progression of gallbladder perforation may be mainly facilitated by operation, timing, scheme and dose should be more cautious when postoperative chemotherapy need to be implemented.\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\nAbbreviations\nCTComputed tomography\n\n5-FU5-fluorouracil\n\nYanlai Sun and Wentao Song contributed equally to this work.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nYLS, HLG, WTS and JNL made up the treatment team. YLS, HLG and WTS data acquisition, analysis and interpretation, critical revision; QSH and JNL: data analysis and manuscript writing. All authors read and approved the final manuscript.\n\nAcknowledgements\nThis work was supported by Grants from Science and technology foundation of Shandong Academy of Medical Sciences, NO.2010-10 and NO.2014-04; Science and technology development plan of Jinan, NO.201401253.\n==== Refs\nReference\n1. Sheridan D Qazi A Lisa S Vashisht R Spontaneous acalculous gallbladder perforation BMJ Case Rep 2014 25293685 \n2. Wirsching A Vonlanthen R Lehmann K Gallbladder perforation by absorbable spiral tacker Ann R Coll Surg Engl 2014 96 e22 3 10.1308/003588414X13946184902280 25245719 \n3. Roslyn JJ Thompson JE Jr Darvin H DenBesten L Risk factors for gallbladder perforation Am J Gastroenterol 1987 82 636 40 3605024 \n4. Sood BP Kalra N Gupta S Sidhu R Gulati M Khandelwal N Role of sonography in the diagnosis of gallbladder perforation J Clin Ultrasound 2002 30 270 4 10.1002/jcu.10071 12116106 \n5. Basara I Secil M Spontaneous asymptomatic gallbladder perforation Quant Imaging Med Surg 2014 4 212 3 24914424 \n6. Hanson B Roat J Pocha C Cholecystitis and gallbladder perforation in cirrhotic patients: a clinical dilemma Dig Liver Dis 2014 46 960 1 10.1016/j.dld.2014.05.018 24970015 \n7. Revzin MV Scoutt L Smitaman E Israel GM The gallbladder: uncommon gallbladder conditions and unusual presentations of the common gallbladder pathological processes Abdom Imaging 2015 40 385 99 10.1007/s00261-014-0203-0 25063238 \n8. Bedirli A Sakrak O Sözüer EM Kerek M Güler I Factors effecting the complications in the natural history of acute cholecystitis Hepatogastroenterology 2001 48 1275 8 11677945 \n9. Liu FL Li H Wang XF Shen KT Shen ZB Sun YH Acute acalculous cholecystitis immediately after gastric operation: case report and literatures review World J Gastroenterol 2014 20 30 10642 50 10.3748/wjg.v20.i30.10642 25132787 \n10. Thomsen RW Thomsen HF Nørgaard M Cetin K McLaughlin JK Tarone RE Risk of cholecystitis in patients with cancer: a population-based cohort study in Denmark Cancer 2008 113 3410 9 10.1002/cncr.23961 18951518 \n11. Alvi AR Ajmal S Saleem T Acute free perforation of gall bladder encountered at initial presentation in a 51 years old man: a case report Cases J 2009 2 166 10.1186/1757-1626-2-166 19946477 \n12. Kumkum Singh AS Vidyarthi SH Jindal S CKumar T Spontaneous intrahepatic type II gallbladder perforation: a rare cause of liver abscess – case report J Clin Diagn Res 2013 7 2012 4 24179927 \n13. Takahashi T Yamamura T Utsunomiya J Pathogenesis of acute cholecystitis after gastrectomy Br J Surg 1990 77 536 9 10.1002/bjs.1800770522 2354337 \n14. Wu CC Wu TC Iiu TJ Peng PK Cholelithiasis and cholecystitis after gastrectomy for gastric carcinoma: a comparison of lymphadenectomy of varying extent Hepatogastroenterology 1995 42 867 72 8847037 \n15. Fisher B Finlay IG Vipond MN Duodenal obstruction by gallstone in the absence of cholecystoenteric fistula, an unusual complication of total gastrectomy: report of a case Ann R Coll Surg Engl 1990 91 W1 2 10.1308/147870809X401010 19416577 \n16. Smith EA Dillman JR Elsayes KM Menias CO Bude RO Cross-sectional imaging of acute and chronic gallbladder inflammatory disease AJR Am J Roentgenol 2009 192 188 96 10.2214/AJR.07.3803 19098200\n\n",
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"issn_linking": "1477-7819",
"issue": "13()",
"journal": "World journal of surgical oncology",
"keywords": null,
"medline_ta": "World J Surg Oncol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D004322:Drainage; D005704:Gallbladder; D005705:Gallbladder Diseases; D005743:Gastrectomy; D006801:Humans; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D011379:Prognosis; D012422:Rupture, Spontaneous; D013274:Stomach Neoplasms",
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"references": "25063238;19946477;19416577;11677945;25132787;3605024;2354337;24179927;8847037;25245719;12116106;19098200;18951518;24970015;25293685;24914424",
"title": "Gallbladder perforation: a rare complication of postoperative chemotherapy of gastric cancer.",
"title_normalized": "gallbladder perforation a rare complication of postoperative chemotherapy of gastric cancer"
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"abstract": "In breast cancer, chemotherapy regimens that include infusional 5-fluorouracil (5-FU) lead to high response rates, but require central venous access and pumps. To avoid these inconveniences, we substituted infusional 5-FU with capecitabine. The main objective of this study was to determine the maximum tolerated dose (MTD) of capecitabine when given in combination with fixed doses of epirubicin and cyclophosphamide (100 and 600 mg/m(2) day 1 every (q) 3 weeks) as primary treatment for large operable or locally advanced/inflammatory breast cancer without distant metastasis. Capecitabine was escalated from 750 mg/m(2) twice a day (bid) to 1250 mg/m(2) bid from day 1 to day 14 in four dose levels. Dose escalation was permitted if 0/3 or 1/6 patients experienced dose-limiting toxicity (DLT). A total of 23 patients were included and 117 courses were administered. At dose level 4, 2 of 2 patients presented DLTs defining the MTD. A high rate of capecitabine treatment modification was required with capecitabine 1050 mg/m(2) bid (dose level 3). 19 patients achieved an objective response (83%). In conclusion, we believe that capecitabine 900 mg/m(2) bid (dose level 2) is the recommended dose in combination with epirubicin 100 mg/m(2) and cyclophosphamide 600 mg/m(2). The acceptable toxicity profile and encouraging activity of this regimen warrant further evaluation.",
"affiliations": "Hôpitaux Universitaires de Genève, 30 Boulevard de la Cluse, 1211 14, Geneva, Switzerland. herve.bonnefoi@hcuge.ch",
"authors": "Bonnefoi|H|H|;Biganzoli|L|L|;Mauriac|L|L|;Cufer|T|T|;Schaefer|P|P|;Atalay|G|G|;Piccart|M|M|",
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"title": "An EORTC phase I study of capecitabine (Xeloda) in combination with fixed doses of cyclophosphamide and epirubicin (cex) as primary treatment for large operable or locally advanced/inflammatory breast cancer.",
"title_normalized": "an eortc phase i study of capecitabine xeloda in combination with fixed doses of cyclophosphamide and epirubicin cex as primary treatment for large operable or locally advanced inflammatory breast cancer"
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"abstract": "Most often, urea cycle disorders have been described as acute onset hyperammonemia in the newborn period; however, there is a growing awareness that urea cycle disorders can present at almost any age, frequently in the critical care setting. This article presents three cases of adult-onset hyperammonemia caused by inherited defects in nitrogen processing in the urea cycle, and reviews the diagnosis, management, and pathophysiology of adult-onset urea cycle disorders. Individuals who have milder molecular urea cycle defects can lead a relatively normal life until a severe environmental stress triggers a hyperammonemic crisis. Comorbid conditions such as physical trauma often delay the diagnosis of the urea cycle defect. Prompt recognition and treatment are essential in determining the outcome of these patients.",
"affiliations": "Center for Human Genetic Research, Division of Medical Genetics, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232-0165, USA. marshall.summar@vanderbilt.edu",
"authors": "Summar|Marshall L|ML|;Barr|Frederick|F|;Dawling|Sheila|S|;Smith|Wendy|W|;Lee|Brendan|B|;Singh|Rani H|RH|;Rhead|William J|WJ|;Sniderman King|Lisa|L|;Christman|Brian W|BW|",
"chemical_list": "D014508:Urea",
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"title": "Unmasked adult-onset urea cycle disorders in the critical care setting.",
"title_normalized": "unmasked adult onset urea cycle disorders in the critical care setting"
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"abstract": "Anisocoria may be physiological or seen in fatal conditions, such as intracranial hemorrhage. Newly developing anisocoria may cause confusion and diagnostic difficulty in the emergency department (ED). A 35-year-old female was admitted to the ED with an asthma attack and dyspnea. On examination, the patient was observed to have bilateral rhonchi and was treated with nebulized albuterol (salbutamol) and ipratropium bromide. After the treatment, the dyspnea improved, and mydriasis developed in the left eye (left pupil diameter 9 mm, right 4 mm). An examination revealed that the left pupil was dilated and unreactive to light, but there was no neurological finding. Afterwards, the patient reported that, during the treatment, some aerosol had leaked from the left side of the mask and may have come into contact with her left eye. Given this information, a pilocarpine test was performed, and the patient was diagnosed with pharmacologic anisocoria. The pupil returned to normal within 24 h. Ipratropium bromide is a drug frequently used in patients presenting to the ED with dyspnea. During treatment, nebulized ipratropium may leak from the edge of the facial mask into the ipsilateral eye and may cause mydriasis. A pilocarpine test can be used to differentiate pharmacological anisocoria from other causes, such as third nerve palsy and Adie's pupil. Through the awareness of emergency physicians and the use of the pilocarpine test, a diagnosis can be made without engaging in time-consuming and costly analyses. In addition, this complication can be prevented using masks that better fit the face, as well as protective goggles or eye patches, during treatment.",
"affiliations": "Department of Emergency Medicine, Ümraniye Training and Research Hospital, University of Health Sciences, İstanbul, Turkey. Electronic address: drkokulu@gmail.com.;Department of Emergency Medicine, Ümraniye Training and Research Hospital, University of Health Sciences, İstanbul, Turkey.;Emergency Department, King's College Hospital, London, UK.;Department of Emergency Medicine, Ümraniye Training and Research Hospital, University of Health Sciences, İstanbul, Turkey.;Department of Emergency Medicine, Ümraniye Training and Research Hospital, University of Health Sciences, İstanbul, Turkey.;Department of Emergency Medicine, Ümraniye Training and Research Hospital, University of Health Sciences, İstanbul, Turkey.",
"authors": "Kokulu|Kamil|K|;Öner|Haldun|H|;Özen|Can|C|;Eroğlu|Serkan E|SE|;Altunok|İbrahim|İ|;Akça|H Şeyma|HŞ|",
"chemical_list": "D000336:Aerosols; D001993:Bronchodilator Agents; D010862:Pilocarpine; D009241:Ipratropium",
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"mesh_terms": "D000328:Adult; D000336:Aerosols; D015875:Anisocoria; D001249:Asthma; D001993:Bronchodilator Agents; D005260:Female; D006801:Humans; D009241:Ipratropium; D010862:Pilocarpine",
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"title": "Pharmacologic anisocoria due to nebulized ipratropium bromide: A diagnostic challenge.",
"title_normalized": "pharmacologic anisocoria due to nebulized ipratropium bromide a diagnostic challenge"
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{
"abstract": "A previously infertile woman underwent laparoscopic myomectomy involving opening of the uterine cavity and chromopertubation that showed closed Fallopian tubes during the early implantation stage of an undetected pregnancy. The pregnancy was not terminated, and a child with a complex brain malformation was delivered at 37 weeks of gestation by Cesarean section.",
"affiliations": "Gynecological Endocrinology and Reproductive Medicine, Department of Gynecology and Obstetrics, Ludwig-Maximilians-University Hospital, Maistr. 11, 80337 Munich, Germany.;Prenatal Diagnosis, Department of Obstetrics and Gynecology, Ludwig-Maximilians-University Hospital, Maistr. 11, 80337 Munich, Germany; now: Prenatal Diagnosis Munich, Tegernseer Landstr. 64, 81541 Munich, Germany.;Institute for Clinical Radiology, Ludwig-Maximilians-University Hospital, Munich, Germany.;Department of Pediatric Neurology Ludwig-Maximilians-University Hospital, Munich, Germany.;Gynecological Endocrinology and Reproductive Medicine, Department of Gynecology and Obstetrics, Ludwig-Maximilians-University Hospital, Maistr. 11, 80337 Munich, Germany; Gynecological Endocrinology and Reproductive Medicine, Department of Gynecology and Obstetrics, Ludwig-Maximilians-University Hospital, Marchioninistr. 15, 81377 Munich, Germany.",
"authors": "Mann|C|C|;Karl|K|K|;Ertl-Wagner|B|B|;Weigand|H|H|;Thaler|C J|CJ|",
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"title": "Laparoscopic Chromopertubation, Myomectomy with Opening of the Uterine Cavity and Hysteroscopy during the Early Implantation Phase of an Undetected Pregnancy: Delivery of a Child with a Complex Brain Malformation.",
"title_normalized": "laparoscopic chromopertubation myomectomy with opening of the uterine cavity and hysteroscopy during the early implantation phase of an undetected pregnancy delivery of a child with a complex brain malformation"
} | [
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{
"abstract": "We report a case of nail candidiasis with severe deformities. The patient was a 71-year-old woman who initially consulted our department on April 5, 2006. She had diabetes, chronic rheumatoid arthritis and multiple liver metastasis of unknown origin. She had taken prednisolone for treatment of chronic rheumatoid arthritis for a long period. The initial examination demonstrated deformation of 1/3 of the inner part of the nail plate in both the third and fourth fingers, with apparent hyperkeratosis under the deformed nail plates. KOH-prepared direct microscopy revealed the presence of numerous spores and pseudohyphae. Numerous fungal elements were detected by Grocott staining and PAS staining. Candida albicans was isolated and identified by cultivation on the ATG agar and PCR-RFLP. Fluconazole (100 mg/day) was administered from April 8, 2006. After 14 weeks of treatment her clinical findings had improved, however she died of multiple organ failure on July 25, 2006.",
"affiliations": "Department of Dermatology, Teikyo University School of Medicine, Mizonokuchi Hospital, Kanagawa, Japan.",
"authors": "Kobayashi|Megumi|M|;Soude|Eri|E|;Takahashi|Eri|E|;Sukegawa|Nozomi|N|;Sei|Yoshihiro|Y|;Ito|Yayoi|Y|",
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"medline_ta": "Nihon Ishinkin Gakkai Zasshi",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D002177:Candidiasis; D005260:Female; D015725:Fluconazole; D006801:Humans; D009264:Nails, Malformed; D014009:Onychomycosis",
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"title": "A case of nail candidiasis with severe deformities treated with oral fluconazole.",
"title_normalized": "a case of nail candidiasis with severe deformities treated with oral fluconazole"
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{
"abstract": "The skin is a possible site of extramedullary localization in multiple myeloma (MM) patients; however, the mechanisms involved in this process are poorly understood. We describe the case of a refractory MM patient who developed a cutaneous localization under bortezomib treatment and we further expanded observations in other eight MM patients. We focused on the expression of genes involved in plasma cell skin homing, including CCR10, which was highly expressed. Moreover, we observed a lack of CXCR4 surface expression and the down-regulation of ICAM1/CD54 throughout the progression of the disease, suggesting a possible mechanism driving the escape of MM cells from the bone marrow into the skin.",
"affiliations": "Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Via Gramsci 14, 43126, Parma, Italy.;Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Via Gramsci 14, 43126, Parma, Italy.;Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Via Gramsci 14, 43126, Parma, Italy.;Pathology Unit, \"Azienda Ospedaliero-Universitaria di Parma\", Parma, Italy.;Pathology Unit, \"Azienda Ospedaliero-Universitaria di Parma\", Parma, Italy.;Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Via Gramsci 14, 43126, Parma, Italy.;Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Via Gramsci 14, 43126, Parma, Italy.;Laboratory of Pre-clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy.;Haematopathology Diagnostic Area- Pathology Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.;\"Ematologia e CTMO\", \"Azienda Ospedaliero-Universitaria di Parma\", Parma, Italy.;\"Ematologia e CTMO\", \"Azienda Ospedaliero-Universitaria di Parma\", Parma, Italy.;\"Ematologia e CTMO\", \"Azienda Ospedaliero-Universitaria di Parma\", Parma, Italy.;Department of Oncology and Hemato-Oncology, University of Milano, Milan, Italy.;Haematopathology Diagnostic Area- Pathology Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.;Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Via Gramsci 14, 43126, Parma, Italy.;Myeloma Unit, Department of Clinical and Experimental Medicine, University of Parma, Via Gramsci 14, 43126, Parma, Italy. nicola.giuliani@unipr.it.",
"authors": "Marchica|Valentina|V|;Accardi|Fabrizio|F|;Storti|Paola|P|;Mancini|Cristina|C|;Martella|Eugenia|E|;Dalla Palma|Benedetta|B|;Bolzoni|Marina|M|;Todoerti|Katia|K|;Marcatti|Magda|M|;Schifano|Chiara|C|;Bonomini|Sabrina|S|;Sammarelli|Gabriella|G|;Neri|Antonino|A|;Ponzoni|Maurilio|M|;Aversa|Franco|F|;Giuliani|Nicola|N|http://orcid.org/0000-0003-3457-3774",
"chemical_list": "D000970:Antineoplastic Agents; C527276:CXCR4 protein, human; C573420:ICAM1 protein, human; D019718:Receptors, CXCR4; D018799:Intercellular Adhesion Molecule-1; D000069286:Bortezomib",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-016-2104-1",
"fulltext": null,
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"issn_linking": "0925-5710",
"issue": "105(1)",
"journal": "International journal of hematology",
"keywords": "Bone marrow; Extramedullary disease; Multiple myeloma; Skin homing",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000970:Antineoplastic Agents; D001853:Bone Marrow; D000069286:Bortezomib; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018799:Intercellular Adhesion Molecule-1; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D010950:Plasma Cells; D010954:Plasmacytoma; D019718:Receptors, CXCR4; D012867:Skin; D012878:Skin Neoplasms",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "104-108",
"pmc": null,
"pmid": "27699576",
"pubdate": "2017-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25825255;12707095;16675558;26496024;15860873;22005835;17119115;26032514;18850009;22904142;25212892;12538668;11841427;14523388;11821900;22410751;25681335;16855634;23728080;22689675;21900099;17952614",
"title": "Cutaneous localization in multiple myeloma in the context of bortezomib-based treatment: how do myeloma cells escape from the bone marrow to the skin?",
"title_normalized": "cutaneous localization in multiple myeloma in the context of bortezomib based treatment how do myeloma cells escape from the bone marrow to the skin"
} | [
{
"companynumb": "IT-BAUSCH-BL-2017-008263",
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"abstract": "Immunotherapy-induced pneumonitis is a rare complication with incidence estimated around 3%. This disease is difficult to diagnose and has great morbidity. For this reason, it became a challenge for oncologists and emergencists. We reviewed the case of five patients who used anti-PD1 (program cell death receptor antagonist 1) for antineoplastic treatment and developed treatment-induced pneumonitis. All patients had respiratory problems because of immunotherapy and presence of ground-glass radiologic change. Among all patients, only one had grade 5 pneumonitis, and delaying to begin corticosteroid therapy and worsening in clinical picture led to patient death. Other four patients with symptomatic grade 2 pneumonitis underwent corticosteroid therapy and had improvement in clinical and radiologic picture. Two patients were treated after an episode of pneumonitis, and no new pulmonary complications were observed until the end of this study. Immunotherapy-induced pneumonitis, although uncommon, can be potentially fatal. Medical team has the responsibility to pay attention for most common symptoms of the disease such as cough and dyspnea and conduct an early diagnosis and effective early treatment with corticosteroids.",
"affiliations": "Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.;Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.;Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.;Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.;Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.",
"authors": "Helber|Henrique Alkalay|HA|;Hada|Aline Lury|AL|;Pio|Raquel Baptista|RB|;Moraes|Pedro Henrique Zavarize de|PHZ|;Gomes|Diogo Bugano Diniz|DBD|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000077594:Nivolumab; C582435:pembrolizumab",
"country": "Brazil",
"delete": false,
"doi": "10.1590/S1679-45082018RC4030",
"fulltext": "\n==== Front\nEinstein (Sao Paulo)Einstein (Sao Paulo)EINSEinstein1679-45082317-6385Instituto Israelita de Ensino e Pesquisa Albert Einstein 0050310.1590/S1679-45082018RC4030Case ReportImmunotherapy-induced pneumonitis: cases report Pneumonite induzida por imunoterapia antineoplásica: relato de casos Helber Henrique Alkalay \n1\nHada Aline Lury \n1\nPio Raquel Baptista \n1\nde Moraes Pedro Henrique Zavarize \n1\nGomes Diogo Bugano Diniz \n1\n\n1 Hospital Israelita Albert Einstein, São Paulo, SP, BrazilCorresponding author: Henrique Alkalay Helber, Avenida Albert Einstein, 627/701 − Morumbi, Zip code: 05651-900 − São Paulo, SP, Brazil, Phone: (55 11) 2151-1233, E-mail: henrique.helber@einstein.br2018 15 6 2018 16 2 eRC403021 2 2017 02 8 2017 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.ABSTRACT\nImmunotherapy-induced pneumonitis is a rare complication with incidence estimated around 3%. This disease is difficult to diagnose and has great morbidity. For this reason, it became a challenge for oncologists and emergencists. We reviewed the case of five patients who used anti-PD1 (program cell death receptor antagonist 1) for antineoplastic treatment and developed treatment-induced pneumonitis. All patients had respiratory problems because of immunotherapy and presence of ground-glass radiologic change. Among all patients, only one had grade 5 pneumonitis, and delaying to begin corticosteroid therapy and worsening in clinical picture led to patient death. Other four patients with symptomatic grade 2 pneumonitis underwent corticosteroid therapy and had improvement in clinical and radiologic picture. Two patients were treated after an episode of pneumonitis, and no new pulmonary complications were observed until the end of this study. Immunotherapy-induced pneumonitis, although uncommon, can be potentially fatal. Medical team has the responsibility to pay attention for most common symptoms of the disease such as cough and dyspnea and conduct an early diagnosis and effective early treatment with corticosteroids.\n\nRESUMO\nA pneumonite secundária à imunoterapia é uma complicação rara, com incidência estimada em cerca de 3%. No entanto, trata-se de uma intercorrência de difícil diagnóstico e com grande morbidade, que tem se tornado um desafio para oncologistas e emergencistas. Foram revisados os casos de cinco pacientes que fizeram uso de anti-PD1 (program cell death receptor antagonist 1) para tratamento antineoplásico e que evoluíram com quadro de pneumonite induzida pelo tratamento. Todos os pacientes apresentaram sintomas respiratórios em vigência de tratamento, com imunoterapia e presença de alteração radiológica em vidro fosco. Dentre estes pacientes, apenas um apresentou pneumonite grau 5, com atraso na introdução de corticoidoterapia, indo a óbito em decorrência do quadro. Os outros quatro pacientes apresentaram pneumonite grau 2, sintomática, sendo tratados com corticoidoterapia e evoluindo com melhora clínica e radiológica. Dois pacientes mantiveram o tratamento após o episódio de pneumonite, sem novas complicações pulmonares posteriores, até o momento. A pneumonite induzida por imunoterapia, apesar de ser um evento pouco frequente, pode acarretar grande morbidade, além de ser potencialmente fatal, cabendo à equipe médica ter atenção aos sintomas mais comuns, como tosse e dispneia, para diagnóstico precoce e tratamento efetivo, com uso precoce de corticoide.\n\nKeywords\nPneumonitis/diagnosisImmunotherapyAntiPD1/AntiPDL1Adrenal cortex hormones/adverse effectsCase reportsDescritores\nPneumonite/diagnósticoImunoterapiaAntiPD1/AntiPDL1Corticosteroide/efeitos adversosRelatos de casos\n==== Body\nINTRODUCTION\nImmunotherapy has shown important improvements for treatment of patients with advanced cancer. Programmed cell death protein-1 (PD-1) is a transmembrane T-cell receptor inhibitor. Pembrolizumabe and nivolumabe are monoclonal antibodies that ligate PD-1 receptor and block receptor activation and stimulate lymphocytes activity against tumor cells. Currently in Brazil, pembrolizumabe and nivolumabe are approved for treatment of melanoma, non-small cell lung cancer and renal cancer. However, some studies show promising results with these antibodies to treat several types of solid tumors. Studies including immunotherapy drugs suggest a favorable safety profile with immune-related adverse events that are often transitory, however, sometimes, severe. Among severe effects are diarrhea, skin changes, hepatitis and endocrinopathies. Pneumonitis is a little frequent complication with incidence estimated around 4%. However, this intercurrence is difficult to be diagnosed and present high morbidity.(\n\n1\n\n)\n\n\nFrom June 2015 to November 2016 we reviewed medical records of 69 patients who were treated with anti-PD1 drugs. Of these, 5 developed pneumonitis at Hospital Israelita Albert Einstein (HIAE). This study describes diagnosis and management of these cases, and includes a brief literature review of the subject.\n\nCASE REPORT\nCase 1\nThis was a 69-year-old man diagnosed with metastatic colorectal adenocarcinoma to liver, lung, and skeletal. He underwent previous treatments with schemes based on fluoropyrimidine, platinum, antiangiogenics, and irinotecan and cetuximab, however, the patient's disease had progressed with all these therapies. Treatment was initiated with pembrolizumabe 10mg/kg every 2 weeks, although this medicines use to the patient's disease is not approved in Brazil. After second administration, the patient reported fatigue and dyspnea. Upon physical examination, he had saturation of 83% in an open environment. Chest tomography evidenced infiltrated interstitial to left and bilateral pleural effusion without signs of pulmonary thromboembolism. Blood count showed leukocytosis with 21,580 leukocytes, 69% of them were segmented, 11% rod cells and 3% metamyelocyte. After thoracocentesis, antibiotic therapy with ceftriaxone and clarithromycin was initiated, and oxygen intake with nasal catheter was maintained, however, no improvement was observed. Reassessment of chest computed tomography showed increase of ground-glass infiltrate (Figure 1) that suggested drug reaction (acute interstitial pneumonitis pattern); a lung biopsy was not performed for histological confirmation. Because of worsening in patients’ conscious level and respiratory pattern, after discussion with his family, the sedation was initiated for patient's comfort.\n\nFigure 1 Diffuse bilateral ground-glass infiltrate, suggesting drug reaction\nCase 2\nThis was a 73-year-old man diagnosed with melanoma on his right thigh. He underwent resection and clinical follow-up. After 8 years, he had untreatable metastatic lung melanoma without mutations. The patient was treated with dacarbazine followed by ipilimumab, but disease had progressed. After, we opted to begin pembrolizumab 2mg/kg administration every 3 weeks.\n\nFourteen days after first cycle, the patient had a dry cough but without fever or other symptoms, no changes in blood count was observed. Chest computed tomography showed opacities in ground-glass in both lungs (Figure 2). The hypothesis raised was pembrolizumab-induced pneumonitis, although lung biopsy was not performed for histological confirmation. A treatment with 1mg/kg prednisone associated with antibiotic therapy and the patient had a rapid and important improvement in symptoms. Two months later, a staging computed tomography showed complete resolution of clinical feature (Figure 2). Patient maintained treatment with pembrolizumab, and showed good tolerance.\n\nFigure 2 Computed tomography scan of a patient with immunotherapy-induced pneumonitis\nCase 3\nThis was an 81-year-old man diagnosed with untreatable stage IIIA lung adenocarcinoma without mutation. He underwent surgery followed by radiotherapy and adjuvant chemotherapy with carboplatin and pemetrexed. After 4 months of follow-up, the patient evolved with local recurrence. The affected site was irradiated but no response was seen, therefore, we opted for palliative chemotherapy with carboplatin and paclitaxel. A progression of the disease was also observed. Subsequently, we decided to begin immunotherapy with pembrolizumab 2mg/kg every 3 weeks. After four cycles, the patient had dyspnea and dry cough with oxygen saturation of 80%. Chest tomography showed extensive bilateral pulmonary infiltration (Figure 3), and blood count showed leukocytosis. No lung biopsy was performed to confirm pathology. Corticosteroid therapy was introduced with metilprednisolone 2mg/kg and antibiotic therapy. An important clinical improvement was seen and resolution of findings from controlled computed tomography (Figure 3).\n\nFigure 3 Computed tomography scan of a patient with immunotherapy-induced pneumonitis\nCase 4\nThis was a 54-year-old man diagnosed with pulmonary large-cell neuroendocrine carcinoma located and resected that evolved for metastatic disease. Initially the patient was treated with carboplatin and paclitaxel followed by cisplatin and etoposide, and radiotherapy for controlling specific injuries. The disease progressed to central nervous system and liver. We opted for immunotherapy with pembrolizumab 2mg/kg every 3 weeks.\n\nAfter 5 cycles of treatment, patients’ clinical feature evolved with dyspnea and cough, but no fever. Upon clinical examination his oxygen saturation was 84% in an open environment. In thorax angiotomography the possibility of pulmonary thromboembolism was discarded and it identified opacities in bilateral ground-glass. Thus, we opted for treatment with metilprednisolone 2mg/kg associated with piperaciline-tazobactam 4.5g every 6 hours for the hypothesis of pneumonitis, although no histological confirmation was performed. An important clinical improvement was seen within 24 hours. The controlled computed tomography performed 1 week after treatment showed almost full resolution of pulmonary opacities (Figure 4).\n\nFigure 4 Computed tomography scan of a patient with immunotherapy-induced pneumonitis\nCase 5\nThis was a 70-year-old man with metastatic lung epidermoid carcinoma with multiple liver injuries. The first-line treatment adopted included nivolumab 3mg/kg every 2 weeks, even without these agents approval in Brazil and in the United States considering the patient's status because he had contraindication for platinum-based chemotherapy.\n\nAfter 4 cycles, the patient had mental confusion, dyspnea and dry cough, without fever and oxygen saturation of 74% in an open environment. Blood count result was normal. We performed a chest tomography with appearance of infiltrated areas in ground-glass (Figure 5). The hypothesis raised was pembrolizumab-induced pneumonitis, although the lung biopsy was not performed to confirm the disease. We opted for treatment with methylprednisolone 60mg every 8 hours and also antibiotic therapy. The patient improved clinically within few hours and he was discharged asymptomatic after 3 days of hospitalization.\n\nFigure 5 Nodular opacities in ground-glass, followed by increase of septal interstitial thickness\nDISCUSSION\nWe reviewed five cases of patients who developed immunotherapy-induced pneumonitis. Of these patients, only one had grade 5 pneumonitis and died because of worsening in clinical feature. Other 4 patients had symptomatic grade 3 pneumonitis. These patients were hospitalized and treated with corticosteroids, and had clinical improvement. Two patients were treated after episode of pneumonitis without further lung complications. Other two patients had treatment discontinued. Immunotherapy doses used followed recommendations of their directions, excepted the dose used in case 1 that was based on a specific study that most participants had colorectal neoplasia and that did not have greater incidence of toxicities compared with other studies using a standard-dose.(\n\n2\n\n) Coincidentally or not, the patient from case 1 had worsening in clinical feature and died because of complications in treatment. Another fact to consider is that delayed introduce of corticosteroids – due to fact that pneumonitis hypothesis was initially consider - might contributed to the unfavorable outcome.\n\nMost observed radiologic pattern was ground-glass. Some patients had micronodules and consolidations. All patients were treated with antibiotics therapy and corticosteroids due to the impossibility to exclude associated pulmonary infection. No patient underwent biopsy, therefore, all were treated without pathological confirmation of pneumonitis, a common fact observed in other studies.(\n\n1\n\n–\n\n5\n\n)\n\n\nIncidence of immunotherapy-induced pneumonitis in literature ranged from 2.7% to 5%.(\n\n3\n\n,\n\n4\n\n) There was no difference in incidence of complication in comparison to different anti-PD1 such as nivolumab and pembrolizumab, however, we know that incidence increases when immunotherapies are combined – for example, nivolumab associated with anti-CTLA 4, and ipilimumab.(\n\n3\n\n) Other important observation was the high incidence of any grade pneumonitis occurred among patients with lung as the primary site.(\n\n4\n\n) Although this disease is uncommon, its death rate could reach up to 12%.(\n\n3\n\n) Among radiological patterns observed, opacities in ground-glass were seen in all cases. This result corroborates with other studies in the literature that also show opacities in ground-glass as the most frequent radiological pattern.(\n\n3\n\n) Treatment for pneumonitis is based on stopping all medication associated or not with oral or intravenous corticosteroid therapy, however, the stage of the disease needs to be considered.(\n\n5\n\n) Immunotherapy treatment should be discontinued for grade 2 pneumonitis and definitively discontinued in case of recurrence grade 3, 4 and 4 pneumonitis (Table 1).(\n\n6\n\n)\n\n\nTable 1 Toxicity grade and treatment(\n\n6\n\n)\n\nGrade\tClinical-radiological findings\tManagement\t\n1\tAsymptomatic (only radiological changes)\tObservation\n Consider discontinuation immunotherapy\t\n2\tSymptomatic (with limitation of instrumental daily changes)\tPrednisone 1mg/kg/day (or similar) Discontinuation of immunotherapy drug\t\n3\tSymptomatic (with limitation of self-care) or hypothesis\tDiscontinue of immunotherapy drug\t\n4\tSymptomatic (with limitation of self-care) life threatening\tMethylprednisolone EV 1-2mg/kg/day (or equivalent)\n Consider immunosuppressive drugs in the absence of improvement within 3 to 5 days\t\n5\tDeath\t\t\nIV: intravenous.\n\nCONCLUSION\nEarly diagnosis of pneumonitis in patients undergoing immunotherapy treatment is extremely important because of great morbimortality of this complication and employment growth of this therapy in current oncology practice. This increase in the use has turned a previous rare event into a more frequent one.\n\nThis disease diagnosis is difficult because of the variability of clinical and radiological presentation. Medical team is responsible to identify most common symptoms such as cough and dyspnea to achieve early diagnosis and implement an effective treatment.\n==== Refs\nREFERENCES\n1 Topalian SL Hodi FS Brahmer JR Gettinger SN Smith DC McDermott DF Safety, activity, and immune correlates of anti-PD-1 antibody in cancer N Engl J Med 2012 366 26 2443 2454 22658127 \n2 Le DT Uram JN Wang H Bartlett BR Kemberling H Eyring AD PD-1 Blockade in tumors with mismatch-repair deficiency N Engl J Med 2015 372 26 2509 2520 26028255 \n3 Naidoo J Wang X Woo KM Iyriboz T Halpenny D Cunningham J Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy J Clin Oncol 2017 35 7 709 717 27646942 \n4 Nishino M Giobbie-Hurder A Hatabu H Ramaiya NH Hodi FS Incidence of programmed cell death 1 inhibitor-related pneumonitis in patients with advanced cancer: a systematic review and meta-analysis JAMA Oncol 2016 2 12 1607 1616 Review 27540850 \n5 Nishino M Chambers ES Chong CR Ramaiya NH Gray SW Marcoux JP Anti-PD-1 inhibitor-related pneumonitis in non-small cell lung cancer Cancer Immunol Res 2016 4 4 289 293 26865455 \n6 [Brazilian guidelines for the management of immune-related adverse events associated with checkpoint inhibitors] Braz J Oncol 2017 13 43 1 15 Portugueses\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1679-4508",
"issue": "16(2)",
"journal": "Einstein (Sao Paulo, Brazil)",
"keywords": null,
"medline_ta": "Einstein (Sao Paulo)",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D002277:Carcinoma; D017809:Fatal Outcome; D006801:Humans; D007167:Immunotherapy; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D000077594:Nivolumab; D011014:Pneumonia",
"nlm_unique_id": "101281800",
"other_id": null,
"pages": "eRC4030",
"pmc": null,
"pmid": "29947645",
"pubdate": "2018-06-21",
"publication_types": "D002363:Case Reports",
"references": "27540850;22658127;27646942;26865455;26028255",
"title": "Immunotherapy-induced pneumonitis: cases report.",
"title_normalized": "immunotherapy induced pneumonitis cases report"
} | [
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"companynumb": "BR-009507513-1807BRA008745",
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"activesubstancename": "PEMBROLIZUMAB"
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{
"abstract": "BACKGROUND\nLinear IgA bullous dermatosis (LABD) is an autoimmune subepidermal blistering disease usually with a neutrophil rich inflammatory infiltrate, and characterized by linear IgA deposition at the basement membrane zone (BMZ), and neutrophil predominant dermal inflammation. We report a case of LABD with numerous eosinophils and flame figure formation, a unique histopathologic finding not previously reported. A 69-year-old woman presented with a rapidly progressive, intensely pruritic rash over forearms, breasts, axillae, hips, and thighs. Thelesions were comprised of annular vesicles and bullae with hemorrhagic crusts and erosions. The clinical differential diagnosis included bullous pemphigoid(BP), LABD, and epidermolysis bullosa aquisita (EBA).\n\n\nRESULTS\nA biopsy from a bullous plaque on the wrist revealed a subepidermal blister with neutrophils and numerous eosinophils with flame figure formation.Direct immunofluorescent (DIF) microscopy revealed linear deposition of IgA at the BMZ.\n\n\nCONCLUSIONS\nAlthough unusual, the combined findings supported a diagnosis of LABD. Increased eosinophils may be associated with drug-induced LABD and may explain the numerous eosinophils in our case. It is important to be aware of this finding as the pathology may easily be misdiagnosed as BP, or possibly bullousWells syndrome. This case emphasizes that combined clinical, pathologic, and DIF findings are essential in the diagnosis of bullous dermatoses.",
"affiliations": "Beth Israel Deaconess Medical Center, Department of Pathology, Harvard Medical School, Boston, Massachusetts.",
"authors": "Fulton|E|E|;Jan|F|F|;Zimarowski|M J|MJ|",
"chemical_list": "D007070:Immunoglobulin A; D003622:Dapsone",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "23(11)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000368:Aged; D000465:Algorithms; D003622:Dapsone; D003937:Diagnosis, Differential; D004804:Eosinophils; D005260:Female; D006801:Humans; D007070:Immunoglobulin A; D062027:Linear IgA Bullous Dermatosis; D012867:Skin",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29447641",
"pubdate": "2017-11-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Flame figures in linear IgA bullous dermatosis: a novel histopathologic finding.",
"title_normalized": "flame figures in linear iga bullous dermatosis a novel histopathologic finding"
} | [
{
"companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-18-00487",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"activesubstance": {
"activesubstancename": "METOPROLOL"
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"... |
{
"abstract": "OBJECTIVE\nTo demonstrate the feasibility of a placebo-controlled trial of antipsychotics for delirium in the intensive care unit and to test the hypothesis that antipsychotics would improve days alive without delirium or coma.\n\n\nMETHODS\nRandomized, double-blind, placebo-controlled trial.\n\n\nMETHODS\nSix tertiary care medical centers in the US.\n\n\nMETHODS\nOne hundred one mechanically ventilated medical and surgical intensive care unit patients.\n\n\nMETHODS\nPatients were randomly assigned to receive haloperidol or ziprasidone or placebo every 6 hrs for up to 14 days. Twice each day, frequency of study drug administration was adjusted according to delirium status, level of sedation, and side effects.\n\n\nRESULTS\nThe primary end point was the number of days patients were alive without delirium or coma. During the 21-day study period, patients in the haloperidol group spent a similar number days alive without delirium or coma (median [interquartile range], 14.0 [6.0-18.0] days) as did patients in the ziprasidone (15.0 [9.1-18.0] days) and placebo groups (12.5 [1.2-17.2] days; p = 0.66). No differences were found in secondary clinical outcomes, including ventilator-free days (p = .25), hospital length of stay (p = .68), and mortality (p = .81). Ten (29%) patients in the haloperidol group reported symptoms consistent with akathisia, compared with six (20%) patients in the ziprasidone group and seven (19%) patients in the placebo group (p = .60), and a global measure of extrapyramidal symptoms was similar between treatment groups (p = .46).\n\n\nCONCLUSIONS\nA randomized, placebo-controlled trial of antipsychotics for delirium in mechanically ventilated intensive care unit patients is feasible. Treatment with antipsychotics in this limited pilot trial did not improve the number of days alive without delirium or coma, nor did it increase adverse outcomes. Thus, a large trial is needed to determine whether use of antipsychotics for intensive care unit delirium is appropriate.",
"affiliations": "Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA. timothy.girard@vanderbilt.edu",
"authors": "Girard|Timothy D|TD|;Pandharipande|Pratik P|PP|;Carson|Shannon S|SS|;Schmidt|Gregory A|GA|;Wright|Patrick E|PE|;Canonico|Angelo E|AE|;Pun|Brenda T|BT|;Thompson|Jennifer L|JL|;Shintani|Ayumi K|AK|;Meltzer|Herbert Y|HY|;Bernard|Gordon R|GR|;Dittus|Robert S|RS|;Ely|E Wesley|EW|;|||",
"chemical_list": "D014150:Antipsychotic Agents; D010879:Piperazines; D013844:Thiazoles; C092292:ziprasidone; D006220:Haloperidol",
"country": "United States",
"delete": false,
"doi": "10.1097/ccm.0b013e3181c58715",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-3493",
"issue": "38(2)",
"journal": "Critical care medicine",
"keywords": null,
"medline_ta": "Crit Care Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents; D003693:Delirium; D004311:Double-Blind Method; D005260:Female; D006220:Haloperidol; D006801:Humans; D007362:Intensive Care Units; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D010879:Piperazines; D011183:Postoperative Complications; D011569:Psychiatric Status Rating Scales; D012121:Respiration, Artificial; D013844:Thiazoles; D016896:Treatment Outcome",
"nlm_unique_id": "0355501",
"other_id": null,
"pages": "428-37",
"pmc": null,
"pmid": "20095068",
"pubdate": "2010-02",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": "9812111;12163791;11730446;15082703;10837102;19188334;15942341;10742653;14670738;17102966;15559753;2594878;17919467;16181163;12238737;15071384;14685663;11005704;10053175;14707567;18580517;16394685;2571717;7562537;11797025;1480876;4917967;10928001;11511942;19237884;11867976;11445689;11700159;11304106;15640638;12799407;18073360;19144938;9591913;12421743;11902253",
"title": "Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: the MIND randomized, placebo-controlled trial.",
"title_normalized": "feasibility efficacy and safety of antipsychotics for intensive care unit delirium the mind randomized placebo controlled trial"
} | [
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"companynumb": "US-JNJFOC-20130610126",
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"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
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"drugadditional": null,
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{
"abstract": "To provide outcome data concerning pregnancies exposed to the Interleukin-1 (IL-1) inhibitors prior to conception in both men and women, during pregnancy and breast feeding.\n\n\n\nRetrospective data were collected from members of the International Society for Systemic Autoinflammatory diseases and collated in a single centre. A uniform data collection sheet was used to obtain standardized data including maternal age and diagnosis, type, duration of and response to IL-1 blockade, pregnancy duration, delivery, mode of feeding and neonatal development.\n\n\n\nThere were 31 maternal-exposed pregnancies from seven countries and we report the first data on paternal exposure: six to anakinra and five to canakinumab, with no negative outcomes. We also report the first data on canakinumab-exposed pregnancies: eight pregnancies that resulted in the delivery of seven healthy infants of normal gestational age and birthweight. There were 23 anakinra-exposed pregnancies resulting in the birth of 21 healthy infants, and one baby with unilateral renal agenesis and ectopic neurohypophysis. There were two first trimester miscarriages affecting a mother with active disease. There were no serious neonatal infections. Fourteen infants were breast fed with no complications. There were no reports of developmental delay, with follow-up of up to 10 years (median 18 months).\n\n\n\nThis series substantially increases the published experience of IL-1 blockade and reproduction including the first data on canakinumab and on paternal exposure to these agents. Data are generally reassuring, although the case of renal agenesis is the second reported in an anakinra-exposed pregnancy.",
"affiliations": "National Amyloidosis Centre, University College London Medical School, London, UK.;National Human Genome Research Institute, National Institute of Health, Bethesda, MD, USA.;Division of Rheumatology, Istanbul Faculty of Medicine.;National Amyloidosis Centre, University College London Medical School, London, UK.;National Amyloidosis Centre, University College London Medical School, London, UK.;National Amyloidosis Centre, University College London Medical School, London, UK.;Division of Rheumatology, Department of Internal Medicine, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey.;Division of Rheumatology, Department of Internal Medicine, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey.;Department of Rheumatology, Cork University Hospital, Cork, Ireland.;Department of Rheumatology, Cork University Hospital, Cork, Ireland.;Department of Immunology, Concord Hospital, Sydney, Australia.;Department of Immunology, Concord Hospital, Sydney, Australia.;Department of Paediatric Immunology, University Hospital Carl Gustav Carus, Dresden.;Division of Rheumatology, University of Heidelberg, Heidelberg.;Division of Pediatric Rheumatology, Department of Pediatrics, University Hospital Tuebingen, Germany.;General Internal Medicine, Raboud University, Nijmegen, Netherlands.;Manchester Academic Health Sciences Centre, Royal Manchester Children's Hospital, Manchester, UK.;National Amyloidosis Centre, University College London Medical School, London, UK.;National Amyloidosis Centre, University College London Medical School, London, UK.",
"authors": "Youngstein|Taryn|T|;Hoffmann|Patrycja|P|;Gül|Ahmet|A|;Lane|Thirusha|T|;Williams|Rene|R|;Rowczenio|Dorota M|DM|;Ozdogan|Huri|H|;Ugurlu|Serdal|S|;Ryan|John|J|;Harty|Len|L|;Riminton|Sean|S|;Headley|Alex P|AP|;Roesler|Joachim|J|;Blank|Norbert|N|;Kuemmerle-Deschner|Jasmin B|JB|;Simon|Anna|A|;Woolf|Adrian S|AS|;Hawkins|Philip N|PN|;Lachmann|Helen J|HJ|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; C541220:canakinumab",
"country": "England",
"delete": false,
"doi": "10.1093/rheumatology/kex305",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-0324",
"issue": "56(12)",
"journal": "Rheumatology (Oxford, England)",
"keywords": "CAPS; TRAPS; adult onset stills disease; anakinra; autoinflammatory disease; biologic therapies; canakinumab; familial Mediterranean fever; interleukin-1 inhibitors; pregnancy",
"medline_ta": "Rheumatology (Oxford)",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001327:Autoimmune Diseases; D001724:Birth Weight; D001942:Breast Feeding; D005260:Female; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D008297:Male; D018811:Maternal Exposure; D018812:Paternal Exposure; D011247:Pregnancy; D011256:Pregnancy Outcome; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "100883501",
"other_id": null,
"pages": "2102-2108",
"pmc": null,
"pmid": "28968868",
"pubdate": "2017-12-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "17850284;9755425;16093838;23913417;24924605;26888948;12815153;25223501;19494217;16053904;20074280;25878059;12972465;21750632;25602036",
"title": "International multi-centre study of pregnancy outcomes with interleukin-1 inhibitors.",
"title_normalized": "international multi centre study of pregnancy outcomes with interleukin 1 inhibitors"
} | [
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"abstract": "Patients with high healthcare utilization are at increased risk of polypharmacy and drug interactions. This study investigated the changes in the number of medications, drug interactions and interaction severity in high frequency outpatients with polypharmacy at hospitals and clinics in Taiwan after home pharmaceutical care, to understand the effectiveness of interventions by pharmacists. This was a retrospective observational study. Cases with excessive polypharmacy (10+ drugs) were selected from the Pharmaceutical Care Practice System database of the Taiwan Pharmacist Association in 2017. After the home care intervention, the number of drug types used decreased 1.89-fold (p < 0.001), and the number of medications fell 61.6%. The incidence of drug interaction was 93.82%. In an average case, the incidence of drug interaction after the pharmacist intervention decreased 0.6-fold (p < 0.001). The drug most commonly causing interactions was aspirin, followed by diclofenac; also common were three used in diabetes, two psycholeptics and two beta blockers. Among 22 cases of severe drug interaction, seven resulted in increased risk of extrapyramidal symptoms and neuroleptic malignant syndrome. By analyzing the relationship between the side effects of individual drugs and the pharmacokinetic Tmax, a sequential thermal zone model of adverse drug reactions can be established, the value of which could prompt physicians and pharmacists to intervene in order to prevent adverse events. It is concluded that home pharmaceutical care by pharmacists can significantly reduce the number of medications and interactions in patients with excessive polypharmacy and high healthcare utilization.",
"affiliations": "Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan City 71710, Taiwan. tzchwa@mail.cnu.edu.tw.;Department of Applied Foreign Language, Chia Nan University of Pharmacy and Science, Tainan City 71710, Taiwan. damien@mail.cnu.edu.tw.;Taiwan Pharmacist Association, Taipei City 10452, Taiwan. kupoujen@yahoo.com.tw.;Department of Information Management, Chia Nan University of Pharmacy and Science, Tainan City 71710, Taiwan. hllu2719@gmail.com.;Giraffe Pharmacy, Tainan City 71049, Taiwan. gighv206@gmail.com.;Yong-xiang Pharmacy, Tainan City 70059, Taiwan. bragihsu19840224@gmail.com.",
"authors": "Wang|Tzu-Chueh|TC|;Trezise|Damien|D|;Ku|Pou-Jen|PJ|;Lu|Hai-Lin|HL|;Hsu|Kung-Chuan|KC|;Hsu|Po-Cheng|PC|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/ijerph16122208",
"fulltext": "\n==== Front\nInt J Environ Res Public HealthInt J Environ Res Public HealthijerphInternational Journal of Environmental Research and Public Health1661-78271660-4601MDPI 10.3390/ijerph16122208ijerph-16-02208ArticleEffect of Pharmacist Intervention on a Population in Taiwan with High Healthcare Utilization and Excessive Polypharmacy https://orcid.org/0000-0003-3999-3276Wang Tzu-Chueh 1*Trezise Damien 2Ku Pou-Jen 3Lu Hai-Lin 4https://orcid.org/0000-0002-7541-8976Hsu Kung-Chuan 5Hsu Po-Cheng 61 Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan City 71710, Taiwan2 Department of Applied Foreign Language, Chia Nan University of Pharmacy and Science, Tainan City 71710, Taiwan; damien@mail.cnu.edu.tw3 Taiwan Pharmacist Association, Taipei City 10452, Taiwan; kupoujen@yahoo.com.tw4 Department of Information Management, Chia Nan University of Pharmacy and Science, Tainan City 71710, Taiwan; hllu2719@gmail.com5 Giraffe Pharmacy, Tainan City 71049, Taiwan; gighv206@gmail.com6 Yong-xiang Pharmacy, Tainan City 70059, Taiwan; bragihsu19840224@gmail.com* Correspondence: tzchwa@mail.cnu.edu.tw; Tel.: +886-6-2664911 (ext. 2226)21 6 2019 6 2019 16 12 220818 5 2019 16 6 2019 © 2019 by the authors.2019Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Patients with high healthcare utilization are at increased risk of polypharmacy and drug interactions. This study investigated the changes in the number of medications, drug interactions and interaction severity in high frequency outpatients with polypharmacy at hospitals and clinics in Taiwan after home pharmaceutical care, to understand the effectiveness of interventions by pharmacists. This was a retrospective observational study. Cases with excessive polypharmacy (10+ drugs) were selected from the Pharmaceutical Care Practice System database of the Taiwan Pharmacist Association in 2017. After the home care intervention, the number of drug types used decreased 1.89-fold (p < 0.001), and the number of medications fell 61.6%. The incidence of drug interaction was 93.82%. In an average case, the incidence of drug interaction after the pharmacist intervention decreased 0.6-fold (p < 0.001). The drug most commonly causing interactions was aspirin, followed by diclofenac; also common were three used in diabetes, two psycholeptics and two beta blockers. Among 22 cases of severe drug interaction, seven resulted in increased risk of extrapyramidal symptoms and neuroleptic malignant syndrome. By analyzing the relationship between the side effects of individual drugs and the pharmacokinetic Tmax, a sequential thermal zone model of adverse drug reactions can be established, the value of which could prompt physicians and pharmacists to intervene in order to prevent adverse events. It is concluded that home pharmaceutical care by pharmacists can significantly reduce the number of medications and interactions in patients with excessive polypharmacy and high healthcare utilization.\n\npharmaceutical carepolypharmacydrug interactions\n==== Body\n1. Introduction\nThe National Health Insurance scheme (NHI), introduced in Taiwan in 1995, provides care for all. However, the low copayment, lack of a hierarchical medical and referral system [1], and lack of restrictions on patient visits [2], has resulted in a nearly 17-fold increase in the average number of annual patient visits [3]. Patients with high healthcare utilization not only waste medical resources, but also put themselves at risk of polypharmacy and drug–drug interactions (DDIs) [4,5]. Optimal pharmaceutical care takes place when a pharmacist takes responsibility for the assessment of a condition and the medication prescribed, the development and implementation of therapeutic plans, and the monitoring of treatment efficacy, to ensure that the medications that patients receive are consistent with their indications, are effective, safe, and highly coordinated [6]. In 2007, Article 15 (paragraph eight) of Taiwan’s Pharmacy Act, which concerns functions related to pharmaceutical care, was amended to allow pharmacists to directly provide drug therapy to the general public. In 2010, The Taiwan Medical Association began training pharmacists to implement a home pharmaceutical care plan for sectors of the population with high rates of utilization of healthcare services, enabling pharmacists to provide pharmaceutical care outside of clinical pharmacy services [7].\n\nHome pharmaceutical care in Taiwan is implemented as follows: After cases are selected for this program by the National Health Insurance Administration, the patients continue to attend clinics at their regular medical institutions, but are also visited once a month in their homes by a pharmacist. The aim of these visits is to gain understanding of the patient’s use of medications, and to review the prescriptions given by different medical institutions. If problems are discovered with the medications, the pharmacist will communicate their concerns to the prescribing physician, and the medications will be adjusted accordingly, at the discretion of the physician [8].\n\nPast research on pharmaceutical care in Taiwan has primarily focused on reducing the number of outpatient visits, decreasing the cost of outpatient medical treatment and drugs, decreasing the number of prescriptions written, documenting the cognition and behavior of drug use, and recording service satisfaction. However, such efforts have resulted in little improvement in the number of drug-related problems (DRPs) [3,4,9,10,11,12,13]. In addition, DRP research conducted in other locations may be of little benefit. This is because the characteristics of drug interactions may vary by country, depending on the local conditions, healthcare models, and characteristics of the research community [4,14,15,16,17,18,19,20]. Therefore, the objectives of this study were to investigate the changes in the number of drug types and drug interactions in a population of patients in Taiwan with high healthcare utilization and polypharmacy after home counseling by pharmacists, and to analyze types of drug interactions in order to understand the effectiveness of the pharmacist’s intervention.\n\n2. Materials and Methods\nHigh healthcare utilization is defined in Taiwan as more than 90 outpatient visits in the preceding year (excluding visits to dentists, Chinese medicine practitioners, and those associated with rehabilitation) [21]. The inclusion criterion for cases in this study was based on the standards laid out in the National Health Insurance Administration’s 2017 “National Health Insurance Pharmaceutical Care for Patients with High Healthcare Utilization” project [21]. The period before the pharmacist’s intervention was defined as the data collected at the first visit and the period after the intervention was defined as the data collected at the last visit.\n\nThis was a retrospective observational study, and was approved by the National Cheng Kung University Hospital Institutional Review Board, which waived the requirement for informed consent (IRB No: B-ER-107-142). The procedure for including cases into the study was as follows: Cases with excessive polypharmacy (more than 10 types of drugs used at the same time [22]) were collected from the Pharmaceutical Care Practice System (Hcare) database of the Taiwan Pharmacist Association for 2017, excluding data entry errors and data collected from single visits. Because there is a strong correspondence between incidence of adverse drug reactions and the use of multiple medications, this study focused on these cases of excessive polypharmacy, with the aim of identifying interactive effects between drugs and offering suggestions for improved practice in the future. The Micromedex interaction query system (IBM Watson Health, Greenwood Village, CO) was used to screen drug interactions; statistical analysis was performed using SPSS (SPSS, Inc., Chicago, IL) and Tableau (Tableau Software, Seattle, WA). We analyzed the differences before and after the pharmacist’s intervention in the number of types of drugs taken, the number of drug interactions, and the severity of drug interactions. The formula for the incidence rate of drug interaction was defined as: (1) incidence rate=number of cases with DDIsnumber of cases included in the analysis×100% \n\nThe classification of DDI severity was based on the Micromedex system and literature review. Changes in the number of medications used, and changes in the number of drug interactions were examined using a paired sample t-test, with the standard of significance set at p < 0.05.\n\nWe also analyzed the relationships between the side effects of individual drugs and the times to maximum blood concentration (Tmax) in pharmacokinetics in cases randomly chosen from the database. Under the assumption of a single-dose administration, with medications being taken at the same time, and that the drugs did not interfere with each other’s blood concentrations, the side effects of the drugs were positively correlated with the blood concentration, and an additive effect occurred when drugs had similar side effects.\n\n3. Results\nA total of 469 cases were included in the study. There were 242 male patients (51.6%). The age distribution of cases with potential drug interactions is shown in Table 1. The average age was 70.87 ± 1.03 years and 397 cases (84.7%) were 60 years or older. Among these, 440 cases had drug interactions, for an incidence of drug interactions in patients with polypharmacy and high healthcare utilization of 93.8%.\n\nBefore the pharmacist’s intervention, there were 2874 cases of drug interaction, of which only 22 cases (0.8%) were at the contraindicated level; most drug interactions were (95.9%) at the severe or moderate level. The level of evidence was mostly excellent and good which denoted to 40.2% (Table 2).\n\nThe number of drug types used by patients before the intervention (13.01 ± 3.16) was significantly higher than the number used after the intervention (11.12 ± 5.03) (p < 0.001). In all, 287 cases took fewer types of drugs after the pharmacist intervention, accounting for 61.6% of the total cases and an average reduction in 1.89 types of drugs used per case (Figure 1).\n\nIn addition, the number of drug interactions decreased at all severity levels after the pharmacist intervention. After the intervention, there were 572 fewer drug interactions, a 19.90% reduction. In particular, the level of contraindicated drug interactions decreased 27.27% and severe drug interactions decreased 21.75% (Table 3).\n\nThe number of drug interactions decreased after the pharmacist intervention by an average of 0.6 drug interactions per case (before intervention: M = 3.05, SD = 3.00; after intervention: M = 2.45, SD = 2.87, p < 0.001). A total of 68.76% of cases had a reduced or unchanged number of drug interactions after the pharmacist intervention (Table 4).\n\nThe drug interactions before the pharmacist intervention were further analyzed to select the 10 drugs most involved in drug interactions (Table 5). The results indicated that aspirin with 395 interactions was ranked first, then diclofenac with 298 interactions. Beta blockers, drugs used in diabetes, and psycholeptics were also highly involved in drug interactions.\n\nWe then analyzed the types of contraindicated drug interactions before the pharmacist intervention. In the 22 cases at the contraindicated level, 19 cases had evidence at the level of “general”, 17 cases had non-specified onset and 7 cases had a reported result of an increased risk of extrapyramidal symptoms (EPS) and neuroleptic malignant syndrome (NMS), the most commonly-reported result (Table 6).\n\nWe analyzed the relationship between the side effects of individual drugs and the time to maximum blood concentration (Tmax). We found that the time for this case to suffer serious dizziness ranged 0.7–4 hours after administration, and the probability of occurrence was at least 48.9–68.6% (Figure 2).\n\n4. Discussion\nThis study found that the incidence of drug interaction in a population of patients in Taiwan with high healthcare utilization and excessive polypharmacy was more than 90%. This was much higher than that reported in the relevant literature [4,14,15,16,17,18,19,20]. The reason may be that the types of drugs used in a population with high healthcare utilization are complicated, and we deliberately selected cases with excessive polypharmacy in this study; hence, the remarkably high incidence of drug interaction is unsurprising.\n\nStudies show that the probability of developing DRPs increases with the number of drugs prescribed [23]. Based on this result, DRPs could be significantly reduced if the number of drugs used is reduced. In this study, we found that the drug interaction-related DRPs were significantly reduced by the implementation of home pharmaceutical care by pharmacists, which significantly reduced the number of drug types used in cases with high healthcare utilization. This result demonstrated that home pharmaceutical care can improve drug safety, indicating the specific clinical value of pharmacist intervention.\n\nAlthough the number of medications used by most of the patients decreased after the intervention of the pharmacist, there were still a small number of patients whose number of medications increased. Analysis revealed three major conditions under which this occurred:\n(a) The pharmacist recommended medication for an untreated disease.\n\n(b) The patient’s condition had changed and required an adjustment of medication.\n\n(c) The patient was using medications during an acute phase (such as respiratory infections, urinary tract infections, etc.).\n\n\n\nIn cases with high healthcare utilization, the drugs most commonly causing DDIs were aspirin, diclofenac, drugs used in diabetes, psycholeptics, and beta blocking agents. Among these, aspirin was most likely to interact with metformin and bisoprolol, resulting in a risk of low blood sugar and elevated blood pressure. Diclofenac most often interacted with aspirin and may increase the risk of bleeding. All of these were also among the most used drugs, as reported by the NHI [24]. The best strategy to reduce drug interactions is to use all drug types at the minimum required level [25]. However, the rapidly-aging society of today suffers widely from insomnia, the Three Highs (hypertension, hyperglycemia, hyperlipidemia), degenerative arthritis, and other chronic diseases [26]. In cases where medications are needed to control chronic diseases, medical personnel should exercise caution, particularly pharmacists who are responsible for the regular assessment of a patient’s medications. If the patient has symptoms such as confusion, lethargy, weakness, ambiguity, incontinence, depression or falls, the pharmacist should take the initiative to review all the patient’s medications, identify the drugs that may cause adverse effects, and take the possibility of drug interactions into account [25].\n\nThis study showed that seven of the 22 drug interactions in cases with contraindicated severity (the highest level) had increased risk of EPS and NMS. EPS are drug-induced movement disorders in which the pyramidal tract that controls the movement of the nervous system is blocked by drugs that antagonize dopamine D2 receptors and affect the nigrostriatal dopamine pathway, resulting in extrapyramidal side effects. NMS is a rare but potentially fatal complication caused by the use of antipsychotic drugs or other drugs that affect dopaminergic neurotransmission, with clinical symptoms of hyperthermia, muscle rigidity, consciousness disorder, and autonomic instability. The pharmacist should be alert and promptly intervene in cases with such symptoms after the use of drugs that increase the risk of EPS or NMS.\n\nEven after the pharmacists’ interventions, there were still 16 cases of interactive effects at the level of contraindication. The reasons for this may be:(a) The pharmacist discovered the contraindication and suggested that the prescription be modified, but the physician insisted on maintaining the original prescription.\n\n(b) Although a medication was technically contraindicated, it could actually be used. For example, colchicine is safe for short-term use, but should be discontinued if it reaches toxic concentrations. The pharmacist should pay close attention to the reactions of the case to the medications, and provide counseling on their safe use, in order to prevent adverse reactions, or detect them at an early stage.\n\n\n\nThese reasons cannot be gleaned simply from inspecting the database. In addition, the purpose of this care program for patients with high healthcare utilization is not primarily to directly solve the drug interaction problem, but to reduce the number of visits these patients pay to hospitals, along with the number of medications that they take, and thus indirectly reduce drug interaction effects.\n\nThere are very few studies of the prevalence of different levels of interaction effects. In a 2019 French study of a health insurance database, the prevalence of interaction effects at contraindication levels was found to be 0.2%, which is significantly lower than the rate of 0.76% found in this study. The much higher rate of prevalence in this study may be accounted for by the fact that the sample population consisted of patients with high healthcare utilization of medical services, many of whom used excessive polypharmacy [27]. Patients may use a variety of drugs with similar side effects, which could result in intolerance or serious adverse drug events. By analyzing the relationship between the side effects of individual drugs and the pharmacokinetic Tmax, a sequential thermal zone model of adverse drug reactions can be established, the value of which could prompt physicians and pharmacists to intervene in order to prevent adverse events. Many patients take medications over the long term, increasing their chances of side effects; these chances are again increased as their pill regimen expands. Establishing a polypharmacy risk prediction model could be a possible area of future research.\n\nThe potential for drug interactions is based on the pharmacological effects of the drug and may not occur in every patient who uses the drug [25]. Patients with drug interactions may only require close monitoring without any change or adjustment to their dosage. Even in cases in which the potential drug interaction level is higher than severe, clinicians should still weigh the benefits and disadvantages of prescribing. Therefore, pharmacists should seek to comprehend the condition for individual cases and not arbitrarily submit a dear doctor letter based on guidelines alone, so that clinicians and pharmacists can cooperate fully in patient care.\n\nThis study had some limitations. Firstly, the population investigated were patients with high healthcare utilization and excessive polypharmacy, and the characteristics of drug interaction in this group may not apply to other groups. Secondly, the lack of certain kinds of information in the Hcare database may also limit the usefulness of this study. In future studies, if more dimensions of data can be collected, such as diagnostic codes and lab data, it may be possible to assess whether or not doctors’ prescriptions are evidence based. Thirdly, we used the Micromedex database and certain drugs may not be included (e.g., traditional Chinese medications), resulting in potential underestimation of the number and severity of drug interactions.\n\n5. Conclusions\nThe NHI has established the NHI PharmaCloud System to improve the safety of medical treatment and drug use for patients and to increase the efficiency of health care resource use. When physicians write prescriptions and pharmacists provide medication adjustments and consultations, this system allows them to access the medical history of patients, which may significantly reduce excessive polypharmacy and cut down on medical expenditures [28,29]. However, can robots and computer programs really replace pharmacists and pharmaceutical care? At least at this stage, it is beyond the power of the NHI PharmaCloud System to reduce drug interactions and DRPs. Furthermore, this study has found that receiving pharmaceutical care from a pharmacist not only provides face-to-face interaction, but also results in a reduction in the average number of medications used per patient and associated interactive effects. This is likely to lead to improved safety in patients’ drug use, and is but one example of the importance of pharmacists in improving health care and reducing morbidity and mortality in at-risk populations.\n\nAcknowledgments\nWe would like to express our appreciation to the Taiwan Pharmacists Association for giving us this project, and to all the pharmacists and healthcare professionals who assisted in constructing the database.\n\nAuthor Contributions\nConceptualization, T.-C.W. and P.-J.K.; methodology, T.-C.W., D.T. and H.-L.L.; software, H.-L.L. and K.-C.H.; validation, P.-C.H. and K.-C.H.; formal analysis, P.-C.H. and K.-C.H.; investigation, P.-C.H.; resources, T.-C.W. and P.-J.K.; data curation, H.-L.L. and K.-C.H.; writing—original draft preparation, P.-C.H. and D.T.; writing—review and editing, P.-C.H. and D.T.; visualization, P.-C.H.; supervision, T.-C.W.; project administration, T.-C.W.; funding acquisition, T.-C.W.; all authors have read and approved the final version of the manuscript.\n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nFigure 1 Changes in the number of different types of drugs used after the pharmacist intervention.\n\nFigure 2 A representative case showing the relationship between dizziness and the time to maximum blood concentration (Tmax) of the individual drugs taken.\n\nijerph-16-02208-t001_Table 1Table 1 Age distribution of cases with potential drug interactions.\n\nAge Group (Years)\tNumber of Cases (%)\t\n20–39\t4 (0.9)\t\n40–59\t68 (14.5)\t\n60–79\t295 (62.9)\t\n80–99\t102 (21.7)\t\nTotal\t469 (100)\t\nijerph-16-02208-t002_Table 2Table 2 Analysis of drug interaction before the pharmacist intervention.g\n\nSeverity \tLevel of Evidence \tTotal (%)\t\nExcellent\tGood\tAverage \t\nContraindicated\t2\t1\t19\t22 (0.8)\t\nSevere\t94\t179\t1171\t1444 (50.2)\t\nModerate\t148\t694\t469\t1311 (45.6)\t\nMild\t12\t26\t59\t97 (3.4)\t\nijerph-16-02208-t003_Table 3Table 3 Number of drug interactions before and after the pharmacist intervention.\n\nSeverity\tNumber of Drug Interactions \tPercentage Decrease (%)\t\nBefore Intervention\tAfter Intervention\t\nContraindicated\t22\t16\t27.3\t\nSevere\t1444\t1130\t21.8\t\nModerate\t1311\t1068\t18.5\t\nMild\t97\t88\t9.3\t\nTotal\t2874\t2302\t19.9\t\nijerph-16-02208-t004_Table 4Table 4 Drug interactions reported in the Pharmaceutical Care Practice System database before and after pharmacist intervention on an average per case.\n\nNumber of Drug Interactions\tAverage Count of Drug Interactions\t\nNumber less after intervention\tNumber greater after intervention\tBefore\tAfter\t\n647\t294\t3.05 ± 3.00\t2.45 ± 2.87\t\nijerph-16-02208-t005_Table 5Table 5 The top 10 drugs causing drug interactions.\n\nName of Drug\tDrug Classification\tIncidence Number\t\nAspirin\tAntithrombotic Agents\t395\t\nDiclofenac\tAnti-inflammatory and Antirheumatic Products\t298\t\nBisoprolol\tBeta Blocking Agents\t242\t\nPropranolol\tBeta Blocking Agents\t212\t\nInsulin\tDrugs Used in Diabetes\t157\t\nTramadol\tAnalgesics\t155\t\nGlimepiride\tDrugs Used in Diabetes\t152\t\nZolpidem\tPsycholeptics\t142\t\nAlprazolam\tPsycholeptics\t119\t\nMetformin\tDrugs Used in Diabetes\t118\t\nijerph-16-02208-t006_Table 6Table 6 The results of contraindicated drug interactions before the pharmacist intervention (n = 22).\n\nDrug A\tDrug B\tNumber\tOnset\tInteraction Results\t\nAceclofenac\tKetorolac\t1\tRapid\tIncreased gastrointestinal adverse effects\t\nDicyclomine\tPotassium\t1\tRapid\tIncreased risk of gastrointestinal lesions\t\nOxybutynin\tPotassium\t1\tRapid\tIncreased risk of gastrointestinal lesions\t\nPotassium\tTolterodine\t1\tRapid\tIncreased risk of gastrointestinal lesions\t\nAlprazolam\tItraconazole\t1\tNot Specified\tIncreased concentration and toxicity of alprazolam\t\nAmisulpride\tChlorpromazine\t1\tNot Specified\tIncreased risk of torsades de pointes\t\nBromocriptine\tSulpiride\t1\tNot Specified\tReduced efficacy of both\t\nColchicine\tDiltiazem\t1\tNot Specified\tIncreased blood concentration and toxicity of colchicine\t\nDronedarone\tFamotidine\t1\tNot Specified\tIncreased risk of extended QT-interval \t\nDuloxetine\tRasagiline\t1\tNot Specified\tCaused CNS toxicity or serotonin syndrome\t\nEscitalopram\tRasagiline\t1\tNot Specified\tIncreased risk of serotonin syndrome\t\nLevodopa\tSulpiride\t1\tNot Specified\tReduced efficacy in both\t\nMetoclopramide\tDuloxetine\t1\tNot Specified\tIncreased risk of extrapyramidal reactions (EPS) and neuroleptic malignant syndrome (NMS)\t\nMetoclopramide\tImipramine\t1\tNot Specified\tIncreased risk of EPS and NMS \t\nMetoclopramide\tProchlorperazine\t2\tNot Specified\tIncreased risk of EPS and NMS \t\nMetoclopramide\tQuetiapine\t2\tNot Specified\tIncreased risk of EPS and NMS \t\nMetoclopramide\tSulpiride\t3\tNot Specified\tIncreased risk of EPS and NMS \t\nRopinirole\tSulpiride\t1\tNot Specified\tReduced efficacy of both\t\nColchicine\tErythromycin\t1\tDelayed\tIncreased blood concentration and toxicity of colchicine\n==== Refs\nReferences\n1. National Health Insurance Administration Ministry of Health and Welfare of Taiwan. An Examination of Taiwan’s Health Insurance from the Perspective of the British and American Systems Available online: http://www.nhi.gov.tw/epaper/ItemDetail.aspx?DataID=3337&IsWebData=0&ItemTypeID=3&PapersID=290&PicID (accessed on 6 June 2019) \n2. National Health Insurance Administration Ministry of Health and Welfare 2017–2018 National Health Insurance Annual Report National Health Insurance Administration, Ministry of Health and Welfare Taipei City, Taiwan 2017 \n3. Liu T.-Y. Huang S.-Y. Chang W.-S. Wang J.-H. Outcomes of Home Pharmaceutical Care on Hospital High Users of Medical Resources J. Clin. Pharm. 2017 25 233 245 \n4. Lin C.-L. Yao M.-L. Chen C.-F. Li W.-Y. Pharmaceutical Care in Elderly Frequent Attenders to Ambulatory Health Services J. Taiwan Pharm. 2016 32 120 126 Available online: http://jtp.taiwan-pharma.org.tw/127/120-126.html (accessed on 6 June 2019) \n5. Lin C.-F. Wang C.-Y. Bai C.-H. Polypharmacy, aging and potential drug-drug interactions in outpatients in Taiwan Drugs Aging 2011 28 219 225 10.2165/11586870-000000000-00000 21250763 \n6. Hepler C.D. Strand L.M. Opportunities and responsibilities in pharmaceutical care Am. J. Hosp. Pharm. 1990 47 533 543 10.1093/ajhp/47.3.533 2316538 \n7. Tarn Y.-H. Pharmaceutical Care in Taiwan J. Taiwan Pharm. 2011 27 42 45 Available online: http://jtp.taiwan-pharma.org.tw/108/042-045.html (accessed on 6 June 2019) \n8. Taiwan Pharmacist Association National Standards for Modes of Operation of Pharmaceutical Care Available online: http://hpcare.taiwan-pharma.org.tw/standard.html (accessed on 6 June 2019) \n9. Chen C.-H. Lin T.-Y. Deng S.-T. Effectiveness Analysis of Community Pharmaceutical Care in Elderly People Living Alone J. Taiwan Pharm. 2011 27 61 65 Available online: http://jtp.taiwan-pharma.org.tw/108/061-065.html (accessed on 6 June 2019) \n10. Even R.-M. The Past, Present and Future of Taiwan’s Pharmacy Care J. Taiwan Pharm. 2014 30 2 6 Available online: http://jtp.taiwan-pharma.org.tw/118/001-006.html (accessed on 6 June 2019) \n11. Tan Y.-H. Concept, Process and Management System in Pharmacy Care J. Taiwan Pharm. 2014 30 6 10 Available online: http://jtp.taiwan-pharma.org.tw/119/006-010.html (accessed on 6 June 2019) \n12. Chen S.-Y. Chang C.-W. Tai C.-L. Chung M.-C. The Effectiveness of Executing Program of Home Pharmaceutical Care in Chiayi County J. Taiwan Pharm. 2014 30 148 153 Available online: http://jtp.taiwan-pharma.org.tw/118/148-153.html (accessed on 6 June 2019) \n13. Lin P.-H. Chang H.-W. Liu L.-L. Effects of Pharmaceutical Care Intervention by Pharmacists on High-Risk Patients of Medication J. Taiwan Pharm. 2015 31 114 120 Available online: http://jtp.taiwan-pharma.org.tw/124/114-120.html (accessed on 6 June 2019) \n14. Wu H.-M. Lee P.-Y.S. Incidence and Mechanism of Drug-Drug Interactions Taipei City Med. J. 2004 1 372 379 10.6200/TCMJ.2004.1.3.17 \n15. Yang Y.-P. Bao B.-Y. Pao J.-B. Drug-Drug Interactions in Elder Patients Presenting to an Outpatient Clinic Taipei City Med. J. 2014 11 135 145 10.6200/TCMJ.2014.11.2.03 \n16. Zhao Y. Chen L.-C. Lai S.-C. Wu S.-C. Evaluation Drug-Related Problems of Patients with Polypharmacy Received by Home Nursing Care in a Teaching Hospital J. Clin. Pharm. 2017 25 133 143 10.6168/FJCP.2017.2502.05 \n17. Doucet J. Chassagne P. Trivalle C. Landrin I. Pauty M.D. Kadri N. Ménard J.F. Bercoff E. Drug-drug interactions related to hospital admissions in older adults: A prospective study of 1000 patients J. Am. Geriatr. Soc. 1996 44 944 948 10.1111/j.1532-5415.1996.tb01865.x 8708305 \n18. Goldberg R.M. Mabee J. Chan L. Wong S. Drug-drug and drug-disease interactions in the ED: Analysis of a high-risk population Am. J. Emerg. Med. 1996 14 447 450 10.1016/S0735-6757(96)90147-3 8765105 \n19. Mallet L. Spinewine A. Huang A. The challenge of managing drug interactions in elderly people Lancet 2007 370 185 191 10.1016/S0140-6736(07)61092-7 17630042 \n20. Rodrigues M.C.S. Oliveira C.D. Drug-drug interactions and adverse drug reactions in polypharmacy among older adults: An integrative review Rev. Lat. Am. Enferm. 2016 24 e2800 10.1590/1518-8345.1316.2800 \n21. National Health Insurance Administration Ministry of Health and Welfare of Taiwan. 2017 “National Health Insurance, High-Level Medical Care and Medicinal Care Plan” Available online: https://www.nhi.gov.tw/Resource/bulletin/6757_1050015881-1.pdf (accessed on 6 June 2019) \n22. Masnoon N. Shakib S. Kalisch-Ellett L. Caughey G.E. What is polypharmacy? A systematic review of definitions BMC Geriatr. 2017 17 230 10.1186/s12877-017-0621-2 29017448 \n23. Viktil K.K. Blix H.S. Moger T.A. Reikvam A. Polypharmacy as commonly defined is an indicator of limited value in the assessment of drug-related problems Br. J. Clin. Pharmacol. 2007 63 187 195 10.1111/j.1365-2125.2006.02744.x 16939529 \n24. National Health Insurance Administration, Ministry of Health and Welfare of Taiwan 2016 National Drug Use Available online: https://www.nhi.gov.tw/DL.aspx?sitessn=292&u=LzAwMS9VcGxvYWQvMjkyL3JlbGZpbGUvMC8yMzM0Ni9yZXBvcnQyMDE3MDVfZi5wZGY%3d&n=UkVQT1JUMjAxNzA1X0YucGRm&ico%20=.pdf (accessed on 21 August 2018) \n25. Wang T.-Y. Outcomes Influenced by Drug Interactions J. Long Term Care 2011 15 195 204 Available online: http://www.airitilibrary.com/Publication/alDetailedMesh?DocID=15612546-201112-201202210010-201202210010-24-32 (accessed on 6 June 2019) \n26. The National Health Research Institutes of Taiwan 2013 National Health Interview Survey Results Report The National Health Research Institutes Taipei City, Taiwan 2016 \n27. Létinier L. Cossin S. Mansiaux Y. Arnaud M. Salvo F. Bezin J. Thiessard F. Pariente A. Risk of Drug-Drug Interactions in Out-Hospital Drug Dispensings in France: Results from the DRUG-Drug Interaction Prevalence Study Front. Pharmacol. 2019 10 265 10.3389/fphar.2019.00265 30967779 \n28. National Health Insurance Administration, Ministry of Health and Welfare of Taiwan Health Insurance PharmaCloud System Available online: https://www.nhi.gov.tw/Content_List.aspx?n=8FD3AB971F557AD4&topn=CA428784F9ED78C9 (accessed on 1 May 2018) \n29. National Health Insurance Administration, Ministry of Health and Welfare of Taiwan Health Insurance 21 cloud service EU Available online: https://www.nhi.gov.tw/News_Content.aspx?n=FC05EB85BD57C709&sms=587F1A3D9A03E2AD&s=EFABC8295286B40B (accessed on 26 February 2016)\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1660-4601",
"issue": "16(12)",
"journal": "International journal of environmental research and public health",
"keywords": "drug interactions; pharmaceutical care; polypharmacy",
"medline_ta": "Int J Environ Res Public Health",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004347:Drug Interactions; D005260:Female; D006699:Home Care Services; D006801:Humans; D008297:Male; D008875:Middle Aged; D010045:Outpatients; D010342:Patient Acceptance of Health Care; D010595:Pharmacists; D019338:Polypharmacy; D012189:Retrospective Studies; D013624:Taiwan; D055815:Young Adult",
"nlm_unique_id": "101238455",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31234455",
"pubdate": "2019-06-21",
"publication_types": "D016428:Journal Article",
"references": "17630042;16939529;8708305;2316538;30967779;21250763;8765105;29017448;27598380",
"title": "Effect of Pharmacist Intervention on a Population in Taiwan with High Healthcare Utilization and Excessive Polypharmacy.",
"title_normalized": "effect of pharmacist intervention on a population in taiwan with high healthcare utilization and excessive polypharmacy"
} | [
{
"companynumb": "TW-JNJFOC-20190836004",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXYBUTYNIN CHLORIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Malignant triton tumor (MTT) is a malignant peripheral nerve sheath tumor with rhabdomyoblastic differentiation. The prognosis of patients is poor, and due to its rarity, large case studies are lacking. The aim of this study is to describe the clinical features and identify potential prognostic factors. Two patients with MTT in the head and neck treated at our department are reported. A literature search revealed another 198 published cases. All of these cases then went through a retrospective analysis. The ratio of male-to-female incidence was 1.5:1, and the median age at diagnosis was 29 years. In 41.7% of cases it occurred in patients with neurofibromatosis type 1. The five-year survival of MTT was found to be just 35%. Cox proportional hazards analysis revealed that complete resection (hazard ratio, 0.396; P=0.032) and metastases (hazard ratio, 3.188; P=0.004) were associated with mortality, indicating that complete resection may lead to a longer life span, and that the existence of metastasis suggested a worse prognosis for patients with MTT.",
"affiliations": "Department of Otolaryngology and Head-Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China; Otolaryngology Major Disease Research Key Laboratory of Hunan, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.;Department of Otolaryngology and Head-Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China; Otolaryngology Major Disease Research Key Laboratory of Hunan, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.;Department of Otolaryngology and Head-Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China; Otolaryngology Major Disease Research Key Laboratory of Hunan, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.;Department of Otolaryngology and Head-Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China; Otolaryngology Major Disease Research Key Laboratory of Hunan, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.;Department of Otolaryngology and Head-Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China; Otolaryngology Major Disease Research Key Laboratory of Hunan, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.;Department of Otolaryngology and Head-Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China; Otolaryngology Major Disease Research Key Laboratory of Hunan, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.;Department of Otolaryngology and Head-Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China; Otolaryngology Major Disease Research Key Laboratory of Hunan, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.;Department of Otolaryngology and Head-Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China; Otolaryngology Major Disease Research Key Laboratory of Hunan, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.;Department of Otolaryngology and Head-Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China; Otolaryngology Major Disease Research Key Laboratory of Hunan, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.;Department of Otolaryngology and Head-Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China; Otolaryngology Major Disease Research Key Laboratory of Hunan, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.;Department of Otolaryngology and Head-Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China; Otolaryngology Major Disease Research Key Laboratory of Hunan, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.",
"authors": "Li|Guo|G|;Liu|Chao|C|;Liu|Yong|Y|;Xu|Fang|F|;Su|Zhongwu|Z|;Wang|Yunyun|Y|;Ren|Shuling|S|;Deng|Tengbo|T|;Huang|Donghai|D|;Tian|Yongquan|Y|;Qiu|Yuanzheng|Y|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/ol.2015.3762",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1792-1074",
"issue": "10(6)",
"journal": "Oncology letters",
"keywords": "malignant triton tumor; prognosis; surgery; survival analyses",
"medline_ta": "Oncol Lett",
"mesh_terms": null,
"nlm_unique_id": "101531236",
"other_id": null,
"pages": "3551-3556",
"pmc": null,
"pmid": "26788168",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article",
"references": "1564550;17498335;18636196;6235165;16333835;20671860;12393052;24269170;4198700;16300714;17330850;17670715;19283843;10452514;19944207;21643932;12684619;18325468;19096322;24633363;12850371;21414786;22253011",
"title": "Analysis of clinical features and prognosis of malignant triton tumor: A report of two cases and literature review.",
"title_normalized": "analysis of clinical features and prognosis of malignant triton tumor a report of two cases and literature review"
} | [
{
"companynumb": "PHHY2015JP160696",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TAMOXIFEN"
},
"drugadditional": null,
"druga... |
{
"abstract": "Vancomycin-resistant enterococci are an important cause of healthcare-associated infections and are inherently resistant to many commonly used antibiotics. Linezolid is the only drug currently approved by the US Food and Drug Administration to treat vancomycin-resistant enterococci; however, resistance to this antibiotic appears to be increasing. Although outbreaks of linezolid- and vancomycin-resistant Enterococcus faecium (LR-VRE) in solid organ transplant recipients remain uncommon, they represent a major challenge for infection control and hospital epidemiology.\n\n\n\nWe describe a cluster of 4 LR-VRE infections among a group of liver and multivisceral transplant recipients in a single intensive care unit. Failure of treatment with linezolid in 2 cases led to a review of standard clinical laboratory methods for susceptibility determination. Testing by alternative methods including whole genome sequencing (WGS) and a comprehensive outbreak investigation including sampling of staff members and surfaces was performed.\n\n\n\nReview of laboratory testing methods revealed a limitation in the VITEK 2 system with regard to reporting resistance to linezolid. Linezolid resistance in all cases was confirmed by E-test method. The use of WGS identified a resistant subpopulation with the G2376C mutation in the 23S ribosomal RNA. Sampling of staff members' dominant hands as well as sampling of surfaces in the unit identified no contaminated sources for transmission.\n\n\n\nThis cluster of LR-VRE in transplant recipients highlights the possible shortcomings of standard microbiology laboratory methods and underscores the importance of WGS to identify resistance mechanisms that can inform patient care, as well as infection control and antibiotic stewardship measures.",
"affiliations": "Department of Infection Control and Prevention and Antimicrobial Stewardship Program, Jackson Memorial Hospital, Miami, Florida.;Department of Infection Control and Prevention and Antimicrobial Stewardship Program, Jackson Memorial Hospital, Miami, Florida.;Department of Pharmacy Practice, School of Pharmacy, Presbyterian College, Clinton, South Carolina.;Department of Infection Control and Prevention and Antimicrobial Stewardship Program, Jackson Memorial Hospital, Miami, Florida.;Department of Infection Control and Prevention and Antimicrobial Stewardship Program, Jackson Memorial Hospital, Miami, Florida.;Division of Infectious Diseases, Department of Medicine, University of Miami Miller School of Medicine, Florida.;Division of Infectious Diseases, Department of Medicine, University of Miami Miller School of Medicine, Florida.;Department of Infection Control and Prevention and Antimicrobial Stewardship Program, Jackson Memorial Hospital, Miami, Florida.;Center for Antimicrobial Resistance and Microbial Genomics and Division of Infectious Diseases, McGovern Medical School, University of Texas Health Science Center at Houston, Bogota, Colombia.;Center for Antimicrobial Resistance and Microbial Genomics and Division of Infectious Diseases, McGovern Medical School, University of Texas Health Science Center at Houston, Bogota, Colombia.;Center for Antimicrobial Resistance and Microbial Genomics and Division of Infectious Diseases, McGovern Medical School, University of Texas Health Science Center at Houston, Bogota, Colombia.;Molecular Genetics and Antimicrobial Resistance Unit, International Center for Microbial Genomics, Universidad El Bosque, Bogota, Colombia.;Molecular Genetics and Antimicrobial Resistance Unit, International Center for Microbial Genomics, Universidad El Bosque, Bogota, Colombia.;Department of Infection Control and Prevention and Antimicrobial Stewardship Program, Jackson Memorial Hospital, Miami, Florida.;Department of Infection Control and Prevention and Antimicrobial Stewardship Program, Jackson Memorial Hospital, Miami, Florida.;Department of Infection Control and Prevention and Antimicrobial Stewardship Program, Jackson Memorial Hospital, Miami, Florida.;Department of Pathology and Laboratory Medicine, Department of Surgery, University of Miami Miller School of Medicine, Florida.;Department of Pathology and Laboratory Medicine, Department of Surgery, University of Miami Miller School of Medicine, Florida.;Division of Nephrology, Department of Medicine, Department of Surgery, University of Miami Miller School of Medicine, Florida.;Division of Liver and Gastrointestinal Transplant Surgery, Department of Surgery, University of Miami Miller School of Medicine, Florida.;Division of Liver and Gastrointestinal Transplant Surgery, Department of Surgery, University of Miami Miller School of Medicine, Florida.;Center for Antimicrobial Resistance and Microbial Genomics and Division of Infectious Diseases, McGovern Medical School, University of Texas Health Science Center at Houston, Bogota, Colombia.",
"authors": "Abbo|Lilian|L|;Shukla|Bhavarth S|BS|;Giles|Amber|A|;Aragon|Laura|L|;Jimenez|Adriana|A|;Camargo|Jose F|JF|;Simkins|Jacques|J|;Sposato|Kathleen|K|;Tran|Truc T|TT|;Diaz|Lorena|L|;Reyes|Jinnethe|J|;Rios|Rafael|R|;Carvajal|Lina P|LP|;Cardozo|Javier|J|;Ruiz|Maribel|M|;Rosello|Gemma|G|;Cardona|Armando Perez|AP|;Martinez|Octavio|O|;Guerra|Giselle|G|;Beduschi|Thiago|T|;Vianna|Rodrigo|R|;Arias|Cesar A|CA|",
"chemical_list": "D000900:Anti-Bacterial Agents; D012338:RNA, Ribosomal, 23S; D000069349:Linezolid",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/ciy903",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "69(2)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "\n E faecium\n ; infection control; linezolid resistance; organ transplant; whole genome sequencing",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D000073602:Antimicrobial Stewardship; D019468:Disease Management; D004196:Disease Outbreaks; D024881:Drug Resistance, Bacterial; D016984:Enterococcus faecium; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D017053:Infection Control; D007362:Intensive Care Units; D000069349:Linezolid; D008297:Male; D008875:Middle Aged; D017354:Point Mutation; D012338:RNA, Ribosomal, 23S; D017422:Sequence Analysis, DNA; D066027:Transplant Recipients; D065507:Vancomycin-Resistant Enterococci; D000073336:Whole Genome Sequencing",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "259-265",
"pmc": null,
"pmid": "30339217",
"pubdate": "2019-07-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "1977766;27558178;23221186;26335577;27852447;27006457;9835522;28961986;7699051;26962092;22782487;27645239;22123698;16954275;16007529;19857726;16091044;28989519;26373316;23070165;12234875;25107294;27530756;23893061;28273381;22143525;15034147;24366742;22964255;22238442;16517894",
"title": "Linezolid- and Vancomycin-resistant Enterococcus faecium in Solid Organ Transplant Recipients: Infection Control and Antimicrobial Stewardship Using Whole Genome Sequencing.",
"title_normalized": "linezolid and vancomycin resistant enterococcus faecium in solid organ transplant recipients infection control and antimicrobial stewardship using whole genome sequencing"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2019SP013341",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional"... |
{
"abstract": "The incidence of lung neuroendocrine carcinomas, which originate from lung neuroendocrine cells, is 1.35/100,000, among which mixed neuroendocrine carcinomas are very rare. Because of the heterogeneity and significant differences in sensitivity to treatments, there is no effective treatment, and the prognosis is poor. In this article, we report the diagnosis and treatment of a case of mixed neuroendocrine carcinoma of the lung in our hospital. During the treatment, the patients had significant myelosuppression after initial chemotherapy, but benefited from oral chemotherapy consisting of a combination of capecitabine and temozolomide (CAPTEM). The report was approved by the affiliated Cancer Hospital of Shandong University.",
"affiliations": "Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, People's Republic of China.;Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, People's Republic of China.;Department of Oncology, The Fifth People's Hospital of Dalian, Dalian, People's Republic of China.;Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, People's Republic of China.;Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, People's Republic of China.;Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People's Republic of China.;Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People's Republic of China.",
"authors": "Zhang|Bin|B|;Wang|Di|D|;Zhang|Xia|X|;Cui|Xiaonan|X|;Kong|Li|L|;Li|Minghuan|M|;Yu|Jinming|J|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/OTT.S210699",
"fulltext": "\n==== Front\nOnco Targets TherOnco Targets TherOTTottOncoTargets and therapy1178-6930Dove 21069910.2147/OTT.S210699Case ReportTemozolomide Combined With Capecitabine In The Treatment Of Mixed Neuroendocrine Carcinoma Of The Lung With Poor Tolerance After Repeated Radiochemotherapy: A Case Report And Literature Review Zhang et alZhang et alZhang Bin 12Wang Di 1Zhang Xia 3Cui Xiaonan 1Kong Li 1Li Minghuan 2Yu Jinming 21 Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China2 Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People’s Republic of China3 Department of Oncology, The Fifth People’s Hospital of Dalian, Dalian, People’s Republic of ChinaCorrespondence: Minghuan Li; Jinming Yu Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, No. 440, Yanzhou Road, Jinan250117, People’s Republic of China Tel +86531-87984777Fax +0531-87984079 Email Sy_lmh2001@163.com; sdyujinming@163.com* These authors contributed equally to this work\n\n14 11 2019 2019 12 9663 9668 31 3 2019 08 10 2019 © 2019 Zhang et al.2019Zhang et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Abstract\nThe incidence of lung neuroendocrine carcinomas, which originate from lung neuroendocrine cells, is 1.35/100,000, among which mixed neuroendocrine carcinomas are very rare. Because of the heterogeneity and significant differences in sensitivity to treatments, there is no effective treatment, and the prognosis is poor. In this article, we report the diagnosis and treatment of a case of mixed neuroendocrine carcinoma of the lung in our hospital. During the treatment, the patients had significant myelosuppression after initial chemotherapy, but benefited from oral chemotherapy consisting of a combination of capecitabine and temozolomide (CAPTEM). The report was approved by the affiliated Cancer Hospital of Shandong University.\n\nKeywords\ntemozolomidemixed neuroendocrine carcinomacase reportpoor tolerancelung cancerreview\n==== Body\nCase Report\nThe patient was a 65-year-old male who developed paroxysmal cough without obvious causes in October 2013, with white sticky phlegm, accompanied by chest tightness and persistent back pain. On December 8, 2013, a chest CT showed a space-occupying lesion in the superior lobe of the left lung next to the mediastinum, which was located close to the aorta and showed significant enhancement on enhanced scan, with enlarged mediastinal lymph nodes in regions 1L, 2L and 5, suggesting metastasis. On December 6, 2013, a left lung mass biopsy was performed under CT guidance. The pathology (biopsy of the left upper lung mass) and immunohistochemistry results were consistent with neuroendocrine carcinoma and small-cell carcinoma. Immunohistochemical staining showed Syn+, CgA weak+, CK weak+, TTF-1+, broad-spectrum CK+, CK5/6-, P63 and Ki-67 (70–80%) (Figure 1). Tumour maker determination results were as follows: neuron-specific enolase (NSE) 40.00 ng/mL, cytokeratin-19 fragments (Cyfra21-1) 4.12 ng/mL and carcinoembryonic antigen (CEA) 28.10 ng/mL. There was no obvious abnormality found in bone electroconvulsive therapy (ECT) and cranial MRI examination. The patient was diagnosed with left lung neuroendocrine carcinoma (small-cell type), stage IIIB, cT4N2M0. An EP chemotherapy regimen was administered for four cycles. The first cycle consisted of VP-16 0.1 d1-5, DDP 40 mg d1-3 and q21d. After the first cycle of chemotherapy, degree IV granulocytopenia and degree II thrombocytopenia decreased, with 0.38×10^9/L neutrophils and 73×10^9/L platelets. Second-degree liver function damage occurred with 142 U/L glutamic-pyruvic transaminase and 67 U/L glutamic-oxal(o)acetic transaminase, and bilirubin was within the normal range. Granulocyte colony-stimulating factor (G-CSF) was given to increase the leukocyte count, and hepatoprotective support treatment was provided. The chemotherapy regimen was changed starting in the second cycle. The second to fourth cycles consisted of the following: VP-16 0.1 d1-4, DDP 40 mg d1-3 and q21d. After four cycles of chemotherapy, patient achieved partial response but fourth-degree bone marrow suppression were still present, and chemotherapy was stopped. Since March 14, 2014, the left lung lesion and primary tumour involving the mediastinal lymph node region were treated with radiotherapy consisting of DT 70 Gy/35 times. The treatment efficacy of radiotherapy resulted in almost complete response (CR), and the clinical symptoms disappeared. The patient was then followed up.Figure 1 Patient's imaging pictures.\n\n\n\nOn August 11, 2014, the patient was admitted to the hospital for a follow-up assessment. Preventive brain irradiation was planned, and the CT examination showed no change in the pulmonary lesion. Two enlarged lymph nodes were found in the neck during the physical examination and were approximately 1.5 cm × 1.0 cm in size. A lymph node biopsy showed mixed small-cell carcinoma and large-cell neuroendocrine carcinoma (Figure 1). The left supraclavicular metastatic lymph nodes were treated with radiotherapy, consisting of 60 Gy/30f, and with chemotherapy, consisting of paclitaxel 120 mg d1 and 8+DDP 40 mg d 1–3 for two cycles. The side effects of chemotherapy were first-degree gastrointestinal reactions and second-degree granulocytopenia. Treatment efficacy of cervical lymph nodes after radiotherapy reached CR. In November 2014, the patient complained of pain in the waist. Abdominal CT showed that a soft tissue density nodule with a small diameter of approximately 2.5 cm was visible in the right costophrenic corner, which was close in proximity to the lumbar vertebrae. With the family’s consent, the right costophrenic corner lymph nodes were treated with radiotherapy at DT 54 Gy, and the patient reached PR. In February 2015, the patient complained of chest and back pain and a cough with a small amount of white sticky phlegm, with no chest tightness, chest pain, or haemoptysis. He also had lower back pain with a numerical rating scale (NRS) value of 3 and took acetaminophen tablets himself, resulting in an NRS decrease to 1. On March 18, 2015, a follow-up exam showed an NSE value of 26.57 ng/mL, Cyfra21 of 14.47 ng/mL and CEA of 8.18 ng/mL. CT revealed relapse at the original location and mediastinal lymph node metastasis, with no abnormality in the abdomen or head, and a bone scan showed no bone metastasis. Therefore, the patient was diagnosed with tumour relapse. The patient demonstrated poor tolerance to the previous chemotherapy, showing mainly bone marrow suppression and granulocytosis, and there is no standard treatment regimen for third-line chemotherapy. Thus, the treatment plan for this patient employed combined chemotherapy using oral medicine with low bone marrow toxicity, and the regimen consisted of temozolomide (150 mg/m2 d1-5, PO) and capecitabine (1000 mg/m2 d1-14, PO and q21). The side effects were first-degree digestive tract reactions and second-degree leukopenia. The blood count results were the following: white blood cells, 2.45–4.32×10^9/L; neutrophils, 1.38–2.68×10^9/L; and platelets, 112-167×10^9/L. The symptoms improved after oral administration of medicine to increase the white blood cell count, and the course of chemotherapy was not affected. Evaluation of the patient after two chemotherapy cycles revealed PR; however, CT examination after four cycles of treatment indicated disease progression. After consultation with internal medicine physicians, the patient was treated with pemetrexed 1.0. After one cycle, the symptoms were obviously aggravated. CT and tumour marker analysis suggested disease progression, and the treatment plan was changed to irinotecan combined with a cisplatin regimen for one cycle after exclusion of contraindications of chemotherapy. The exact plan was irinotecan (120 mg d1 and 8) and cisplatin (40 mg d1-3). After chemotherapy, the patient developed granulocytotic fever, abdominal pain, diarrhoea and watery stool, and the patient was treated with drugs to increase the white blood cell count, antibiotics, an antidiarrhoeal drug, nutritional support and other symptomatic and supportive treatments. The patient showed third- and fourth-degree suppression of platelets. Considering that the patient’s general condition was poor, the patient was treated with a platelet transfusion, two transfusions of a therapeutic dose of machine-collected platelets from irradiated B type Rh-positive blood and a transfusion of 200 mL of frozen plasma of virus-inactivated B type Rh-positive blood, and the fever and diarrhoea symptoms were improved. PD was still found in the second evaluation of the treatment efficacy, and due to the patient’s poor general condition, the treatment was changed to single-drug chemotherapy with etoposide. The disease was not controlled, and the patient stopped treatment. The changes of CT, MRI and tumor marker of the patient are shown in Figure 2.Figure 2 The above is the test result of the patient. (A). The figure shows the patient’s chest enhancement CT from 2013-12-8 to 2015-6-8, showing changes in primary lesions and mediastinal lymph node metastasis. (B). The figure shows the changes in tumor markers after the patient started treatment, especially after the application of the CAPTEM program in 2015-3-18, the NES decreased significantly, which suggests the superiority of CAPTEM. (C). CT shows the metastasis of cervical lymph nodes in patients with tumors. (D). In the figure, MRI shows the metastasis of the retroperitoneal lymph nodes in patients with tumors.\n\n\n\nDiscussion\nLung neuroendocrine tumours account for 20% of all primary lung tumours, which are classified by the World Health Organization (WHO) into low-grade malignant typical carcinoid, moderate malignant atypical carcinoid, highly malignant large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC). Mixed LCNEC and SCLC neuroendocrine carcinomas are rare.\n\nLCNEC accounts for 3% of lung cancers and has a strong tendency for metastasis. Early lobectomy can improve survival, but post-operative relapse is common. Most patients lose their surgery opportunity due to mediastinal lymph node metastasis or distant metastasis, and the five-year survival rate is less than 40%. The chemotherapy regimen for LCNEC is still controversial, while some studies noted that LCNEC treatment employing the SCLC chemotherapy regimen, such as etoposide or irinotecan, yielded a better survival rate than that associated with the LCNEC standard chemotherapy regimen. Although the National Comprehensive Cancer Network (NCCN) guidelines are still recommending treatment according to non-small-cell lung cancer (NSCLC), small-sample-size single-arm studies showed that the objective response rate (ORR) could reach 50% if the SCLC protocol is followed.\n\nSCLC accounts for 14% of lung cancers. The median survival time is 8–12 months, and the two-year survival rate is less than 10%. Although SCLC is highly sensitive to initial chemotherapy and radiotherapy, it generally relapses and progresses within six months, and it generally has a poor response to second-line therapies, with a median survival time of only 4–5 months. The treatment efficacy may be highly dependent on the time between initial treatment and relapse. If the interval is less than three months, the efficacy of most drugs and regimens is poor, and if the interval is between three and six months, the expected efficacy rate is 25%. If the interval is more than six months, the original regimen is recommended.1\n\nThis patient was initially diagnosed with a small-cell type of neuroendocrine carcinoma and was administered a first-line EP chemotherapy regimen. The patient showed poor tolerance, with fourth-degree bone marrow suppression appearing in the first cycle. The dose was reduced during the second cycle. Although this reduction affected treatment efficacy, at that time, no long-term effective drugs were available that could increase the white blood cell count as second-level prevention. Therefore, dosage reduction was imperative. Timely introduction of local radiotherapy is also a good choice for patients with intolerable chemotherapy side effects. In SCLC, radiotherapy intervention can improve local control. A phase III randomized controlled study by Jeremic2 showed that patients with ED-SCLC with metastatic lesions reaching CR and chest lesions reaching CR or PR after chemotherapy could significantly benefit from chest radiotherapy. The median survival time was extended by half a year, and the five-year survival rate was 9%. The subsequently initiated multicentre randomized controlled study (CREST) was reported at the American Society of Clinical Oncology (ASCO) and American Society for Radiation Oncology (ASTRO) conferences in 2014. The results showed that thoracic radiation treatment (TRT) reduced the intrathoracic relapse rate by nearly 50% compared with that in the control group and significantly decreased the progression-free survival (PFS) time (HR=0.73). When followed up to two years, the survival of the TRT group was significantly better than that of the control group (13% vs. 3%, p=0.004). In terms of LCNEC, a clinical study3 validated the efficacy of gamma knife radiosurgery (GKRS) for the treatment of LCNEC patients with brain metastasis and reported a one-year neurological death-free rate of 93% and a PFS rate of 87% among 101 patients. Another study4 also found that the median PFS and overall survival improved in LCNEC patients receiving TRT (12.5 vs. 5 months, p=0.02, and 28.3 vs. 5 months, p=0.004, respectively). The above data confirm the positive effects of local radiotherapy.\n\nThere are many choices of treatment plans, including somatostatin synthesis analogues such as octreotide and lanreotide, platinum-type drugs, etoposide, temozolomide, capecitabine and other cytotoxic drugs, which can be used in the treatment of neuroendocrine carcinoma. This patient had very poor tolerance to chemotherapy, and choosing a drug that could be tolerated was the key to successful treatment. For patients with bronchopulmonary or thymic carcinomas with a low or moderate tumour load and obvious symptoms, Temozolomide treatment, either alone or in combination with octreotide or lanreotide, is an option for addressing the tumour load and any associated symptoms.5,6 The CAPTEM combination has been used in neuroendocrine carcinoma. The regimen has high activity and good tolerance and can prolong the survival time of patients with well-differentiated metastatic neuroendocrine tumours.7 A retrospective analysis indicated that the objective remission rate associated with this combined regimen was 70%, and the median PFS was 18 months. Another retrospective study reported that the remission rate of 18 patients was 61%, and one patient had achieved complete pathological remission as demonstrated by surgery.8–10 Cives11 also mentioned that CAPTEM chemotherapy promoted the prolongation of PFS in patients with pancreatic neuroendocrine tumours. In 2018, a meta-analysis of the safety and efficacy of the CAPTEM regimen in the treatment of advanced neuroendocrine tumours12 showed that most of the 384 patients included in the study had a median total survival of more than 12 months, and the median PFS was similar to or slightly higher than that of other therapies, suggesting that CAPTEM is effective and relatively safe in the treatment of advanced neuroendocrine neoplasm (NEN) patients. In this case, the patient had poor tolerance to and obvious bone marrow suppression from the first-line EP regimen, while the degree of bone marrow suppression decreased from fourth degree to second degree after application of the CAPTEM regimen. The CAPTEM regimen not only alleviated side effects but also prolonged the course of chemotherapy and improved the patient’s life quality, which are important advantages of the CAPTEM regimen. The patient obtained nearly 3 months of PFS from the application of this regimen, which is superior than the PFS afforded by other protocols.\n\nIf disease progression relapses after CAPTEM chemotherapy, what treatment method can be used? Recently, immunotherapy has entered the public view. A cytotoxic T lymphocyte-associated protein-4 (CTLA-4) inhibitor, ipilimumab, is the first immune target drug used for SCLC. In the exploratory analysis of phase II clinical trials of combined chemotherapy using ipilimumab,13 it was found that patients with a high expression of antibodies before treatment may benefit from this regimen. A meta-analysis14 indicated that ipilimumab improved the PFS (six months: RR=1.16, P=0.02; one year: RR=1.39, P=0.02) and six-month immune-related PFS (irPFS) (RR=1.60, P=0.004) in 1084 SCLC patients. However, because of the addition of ipilimumab, immune-related toxicity was more obvious in the immuno-chemotherapy group. Another significant breakthrough was the discovery that blocking the binding of programmed death protein 1 (PD-1) to its ligand (PD-L1) could inhibit the immune escape of tumour cells from T cells.15 Schachter16 reported the therapeutic effects of anti-PD-1/PD-L1 drugs on tumours using SCLC as an example disease. Grabowski found that PD-L1 was expressed in 100% of poorly differentiated neuroendocrine carcinomas, and the expression rate of PD-L1 in well-differentiated neuroendocrine tumours was also as high as 50%. The PD-1 inhibitor nivolumab combined with the CTLA-4 inhibitor ipilimumab has become a second-line therapy for advanced SCLCs after chemotherapy.17 The results of the clinical trial CheckMate-032 showed that regardless of the expression level of PD-L1 and whether the cancer was sensitive to the platinum-type chemotherapeutic drugs used in first-line treatments, the effects of immunotherapy were remarkable and could last for a longer period. The two-year survival rate of the combined treatment group reached 30%. However, systematic studies on LCNEC or mixed neuroendocrine carcinoma are lacking, and no related drugs are on the market in China at this time.\n\nTo date, no study has shown the efficacy of targeted therapy in mixed neuroendocrine carcinoma. One possible target is the somatostatin receptor. Somatostatin analogues can effectively control symptoms and prolong survival in LCNEC patients with positive somatostatin imaging.18 Other targets include IGF-1R, the Hh pathway, the Notch pathway, the P13K/AKT/mTOR pathway, the Bcl-2 family of antiapoptotic proteins, PARP and VEGF. Everolimus, an mTOR inhibitor, is also one recommended drug in NCCN guidelines. In a phase 3 RADIANT-4 clinical trial,19 302 patients with advanced, progressive, well-differentiated, nonfunctioning lung or gastrointestinal neuroendocrine tumours were included. The results showed that the median PFS was 11.0 months (95% CI 9.2–13.3) in the treatment group and 3.9 months (3.6–7.4) in the placebo group. At a recent Gastrointestinal Cancers Symposium,20 experts also pointed out that everolimus reduced the risk of disease progression by 40% compared with the placebo group and showed the potential to block cancer cells from growing.\n\nUnfortunately, the patient in this study did not have an opportunity to wait for the development and application of new drugs; however, his case confirmed the efficacy and safety of CAPTEM, which can be used in the treatment of neuroendocrine tumours. We hope that through this article, clinicians will have a better understanding of mixed neuroendocrine carcinoma.\n\nStatement Of Patient’s Family\nThe patient’s next of kin have provided written informed consent for the case details to be published.\n\nDisclosure\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n1. Asamura \nH , Chansky \nK , Crowley \nJ , et al. The international association for the study of lung cancer lung cancer staging project: proposals for the revision of the n descriptors in the forthcoming 8th edition of the TNM classification for lung cancer . J Thorac Oncol . 2015 ;10 :1675 –1684 . doi:10.1097/JTO.0000000000000678 26709477 \n2. Prelaj \nA , Rebuzzi \nSE , Del Bene \nG , et al. Evaluation of the efficacy of cisplatin-etoposide and the role of thoracic radiotherapy and prophylactic cranial irradiation in LCNEC . ERJ Open Res . 2017 ;3 . doi:10.1183/23120541.00128-2016 \n3. Jeremic \nB , Shibamoto \nY , Nikolic \nN , et al. Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer: a randomized study . J Clin Oncol . 1999 ;17 :2092 –2099 . doi:10.1200/JCO.1999.17.7.2092 10561263 \n4. Kawabe \nT , Yamamoto \nM , Sato \nY , et al. Gamma Knife radiosurgery for brain metastases from pulmonary large cell neuroendocrine carcinoma: a Japanese multi-institutional cooperative study (JLGK1401) . J Neurosurg . 2016 ;125 :11 –17 . doi:10.3171/2016.7.GKS161459 27903179 \n5. Cives \nM , Strosberg \nJR . Gastroenteropancreatic neuroendocrine tumors . CA Cancer J Clin . 2018 ;68 :471 –487 . doi:10.3322/caac.v68.6 30295930 \n6. Lu \nY , Zhao \nZ , Wang \nJ , et al. Safety and efficacy of combining capecitabine and temozolomide (CAPTEM) to treat advanced neuroendocrine neoplasms: a meta-analysis . Medicine (Baltimore) . 2018 ;97 :e12784 . doi:10.1097/MD.0000000000012784 30313101 \n7. Chong \nCR , Wirth \nLJ , Nishino \nM , et al. Chemotherapy for locally advanced and metastatic pulmonary carcinoid tumors . Lung Cancer . 2014 ;86 :241 –246 . doi:10.1016/j.lungcan.2014.08.012 25218177 \n8. Crona \nJ , Fanola \nI , Lindholm \nDP , et al. Effect of temozolomide in patients with metastatic bronchial carcinoids . Neuroendocrinology . 2013 ;98 :151 –155 . doi:10.1159/000354760 23969949 \n9. Fine \nRL , Gulati \nAP , Krantz \nBA , et al. Capecitabine and temozolomide (CAPTEM) for metastatic, well-differentiated neuroendocrine cancers: the pancreas center at Columbia University experience . Cancer Chemother Pharmacol . 2013 ;71 :663 –670 . doi:10.1007/s00280-012-2055-z 23370660 \n10. Ekeblad \nS , Sundin \nA , Janson \nET , et al. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors . Clin Cancer Res . 2007 ;13 :2986 –2991 . doi:10.1158/1078-0432.CCR-06-2053 17505000 \n11. Chan \nJA , Stuart \nK , Earle \nCC , et al. Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors . J Clin Oncol . 2012 ;30 :2963 –2968 . doi:10.1200/JCO.2011.40.3147 22778320 \n12. Strosberg \nJR , Fine \nRL , Choi \nJ , et al. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas . Cancer . 2011 ;117 :268 –275 . doi:10.1002/cncr.v117.2 20824724 \n13. Arriola \nE , Wheater \nM , Galea \nI , et al. Outcome and biomarker analysis from a multicenter Phase 2 study of ipilimumab in combination with carboplatin and etoposide as first-line therapy for extensive-stage SCLC . J Thorac Oncol . 2016 ;11 :1511 –1521 . doi:10.1016/j.jtho.2016.05.028 27296105 \n14. Zhang \nH , Shen \nJ , Yi \nL , Zhang \nW , Luo \nP , Zhang \nJ . Efficacy and safety of ipilimumab plus chemotherapy for advanced lung cancer: a systematic review and meta-analysis . J Cancer . 2018 ;9 :4556 –4567 . doi:10.7150/jca.27368 30519362 \n15. Dong \nH , Strome \nSE , Salomao \nDR , et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion . Nat Med . 2002 ;8 :793 –800 . doi:10.1038/nm730 12091876 \n16. Schachter \nJ , Ribas \nA , Long \nGV , et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006) . Lancet . 2017 ;390 :1853 –1862 . doi:10.1016/S0140-6736(17)31601-X 28822576 \n17. Wolchok \nJD , Chiarion-Sileni \nV , Gonzalez \nR , et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma . N Engl J Med . 2017 ;377 :1345 –1356 . doi:10.1056/NEJMoa1709684 28889792 \n18. Filosso \nPL , Ruffini \nE , Oliaro \nA , et al. Large-cell neuroendocrine carcinoma of the lung: a clinicopathologic study of eighteen cases and the efficacy of adjuvant treatment with octreotide . J Thorac Cardiovasc Surg . 2005 ;129 :819 –824 . doi:10.1016/j.jtcvs.2004.05.023 15821649 \n19. Yao \nJC , Fazio \nN , Singh \nS , et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study . Lancet . 2016 ;387 :968 –977 . doi:10.1016/S0140-6736(15)00817-X 26703889 \n20. Singh \nS , Asa \nSL , Dey \nC , et al. Diagnosis and management of gastrointestinal neuroendocrine tumors: an evidence-based Canadian consensus . Cancer Treat Rev . 2016 ;47 :32 –45 . doi:10.1016/j.ctrv.2016.05.003 27236421\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-6930",
"issue": "12()",
"journal": "OncoTargets and therapy",
"keywords": "case report; lung cancer; mixed neuroendocrine carcinoma; poor tolerance; review; temozolomide",
"medline_ta": "Onco Targets Ther",
"mesh_terms": null,
"nlm_unique_id": "101514322",
"other_id": null,
"pages": "9663-9668",
"pmc": null,
"pmid": "32009800",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "30313101;26703889;10561263;17505000;28822576;30295930;27296105;15821649;27236421;27903179;30519362;20824724;23969949;12091876;28889792;22778320;23370660;26709477;28382303;25218177",
"title": "Temozolomide Combined With Capecitabine In The Treatment Of Mixed Neuroendocrine Carcinoma Of The Lung With Poor Tolerance After Repeated Radiochemotherapy: A Case Report And Literature Review.",
"title_normalized": "temozolomide combined with capecitabine in the treatment of mixed neuroendocrine carcinoma of the lung with poor tolerance after repeated radiochemotherapy a case report and literature review"
} | [
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"companynumb": "CN-ACCORD-172332",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
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"activesubstance": {
"activesubstancename": "CISPLATIN"
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{
"abstract": "OBJECTIVE\nCases of Cushing's syndrome (CS) following ocular steroid use have been reported in recent years, albeit rarely.\n\n\nMETHODS\nWe report a case of iatrogenic CS in a child induced by fluorometholone-containing eyedrops. Our patient was referred to our endocrinology clinic due to rapid weight gain. His history revealed that 1.5 months previously he had been started on fluorometholone eyedrops.\n\n\nCONCLUSIONS\nTo the best of our knowledge, no cases of CS have been reported following ocular fluorometholone use. Although eyedrops containing potent glucocorticoids may lead to CS, fluorometholone, a relatively less potent steroid, may also cause the syndrome, as in our case.",
"affiliations": "Department of Pediatrics Istanbul, Haseki Training and Research Hospital, Istanbul, Turkey.;Department of Pediatrics Istanbul, Haseki Training and Research Hospital, Istanbul, Turkey.;Department of Pediatrics Istanbul, Haseki Training and Research Hospital, Istanbul, Turkey.;Department of Pediatrics Istanbul, Haseki Training and Research Hospital, Istanbul, Turkey.;Department of Pediatrics Istanbul, Haseki Training and Research Hospital, Istanbul, Turkey.",
"authors": "Üstyol|A|A|;Kökali|F|F|;Duru|N|N|;Duman|M A|MA|;Elevli|M|M|",
"chemical_list": "D009883:Ophthalmic Solutions; D005469:Fluorometholone",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.12573",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "42(6)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "Cushing's syndrome; ocular steroid; synthetic",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D002675:Child, Preschool; D003480:Cushing Syndrome; D005469:Fluorometholone; D006801:Humans; D008297:Male; D009883:Ophthalmic Solutions",
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "780-782",
"pmc": null,
"pmid": "28627121",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Cushing's syndrome caused by use of synthetic ocular steroid.",
"title_normalized": "cushing s syndrome caused by use of synthetic ocular steroid"
} | [
{
"companynumb": "TR-ALLERGAN-1728327US",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
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"actiondrug": "1",
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"activesubstancename": "FLUOROMETHOLONE"
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{
"abstract": "Nicolau syndrome (NS) is a rare complication that develops after the administration of intramuscular diclofenac sodium. The etiology and surgical treatments of 11 patients with NS were evaluated and studies in the literature were examined. The aim of this study was to compose a basic algorithm for surgical approaches to treat NS.\nEleven patients were evaluated for NS between December 2013 and January 2018. Two patients did not accept treatment, and nine patients underwent surgical debridement of necrotic tissues. The tissue defects of five patients were closed with a fasciocutaneous flap and, in four patients, the defects were repaired primarily.\nNo complications, such as wound infection, wound dehiscence, seroma, or flap necrosis, were encountered. Of the seven patients who received concurrent antibiotic therapy, no patient had any problems at their follow-up (2-30 months). The results were satisfactory from an aesthetic and functional point of view.\nNS was more frequent in women with a high body mass index and high fat in gluteal regions. We considered that any kind of medication could lead to NS. Different methods are discussed for treatment.",
"affiliations": "Department of Plastic, Reconstructive and Aesthetic Surgery, Medical Faculty, Bezmialem Vakıf University, Istanbul, Turkey.;Department of Plastic, Reconstructive and Aesthetic Surgery, Medical Faculty, Bezmialem Vakıf University, Istanbul, Turkey.;Department of Plastic, Reconstructive and Aesthetic Surgery, School of Medicine, Mustafa Kemal University, Serinyol Hatay, Turkey.;Private Practice, Serinyol Hatay, Turkey.;Department of Plastic, Reconstructive and Aesthetic Surgery, Medical Faculty, Bezmialem Vakıf University, Istanbul, Turkey.",
"authors": "Yeniocak|Ali|A|;Kelahmetoğlu|Osman|O|;Özkan|Mustafa|M|;Temel|Metin|M|;Güneren|Ethem|E|",
"chemical_list": null,
"country": "India",
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"doi": "10.4103/JCAS.JCAS_139_19",
"fulltext": "\n==== Front\nJ Cutan Aesthet Surg\nJ Cutan Aesthet Surg\nJCAS\nJournal of Cutaneous and Aesthetic Surgery\n0974-2077 0974-5157 Wolters Kluwer - Medknow India \n\nJCAS-13-154\n10.4103/JCAS.JCAS_139_19\nPractice Points\nA Basic Algorithmic Surgical Approach for Nicolau Syndrome\nYeniocak Ali Kelahmetoğlu Osman Özkan Mustafa 1 Temel Metin 2 Güneren Ethem Department of Plastic, Reconstructive and Aesthetic Surgery, Medical Faculty, Bezmialem Vakıf University, Istanbul, Turkey\n1 Department of Plastic, Reconstructive and Aesthetic Surgery, School of Medicine, Mustafa Kemal University, Serinyol Hatay, Turkey\n2 Private Practice, Serinyol Hatay, Turkey\nAddress for correspondence: Dr. Osman Kelahmetoğlu, Department of Plastic, Reconstructive and Aesthetic Surgery, Bezmialem Vakif University, Adnan Menderes Bulvarı Vatan Caddesi 34093 Fatih, Istanbul, Turkey. E-mail: osmankelahmetoglu@gmail.com\nApr-Jun 2020 \n13 2 154 159\nCopyright: © 2020 Journal of Cutaneous and Aesthetic Surgery2020This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Abstract\nBackground:\nNicolau syndrome (NS) is a rare complication that develops after the administration of intramuscular diclofenac sodium. The etiology and surgical treatments of 11 patients with NS were evaluated and studies in the literature were examined. The aim of this study was to compose a basic algorithm for surgical approaches to treat NS.\n\nMaterials and Methods:\nEleven patients were evaluated for NS between December 2013 and January 2018. Two patients did not accept treatment, and nine patients underwent surgical debridement of necrotic tissues. The tissue defects of five patients were closed with a fasciocutaneous flap and, in four patients, the defects were repaired primarily.\n\nResults:\nNo complications, such as wound infection, wound dehiscence, seroma, or flap necrosis, were encountered. Of the seven patients who received concurrent antibiotic therapy, no patient had any problems at their follow-up (2–30 months). The results were satisfactory from an aesthetic and functional point of view.\n\nConclusion:\nNS was more frequent in women with a high body mass index and high fat in gluteal regions. We considered that any kind of medication could lead to NS. Different methods are discussed for treatment.\n\nKeywords:\nDiclofenac sodiuminjectionintramuscularNicolau syndrome\n==== Body\nINTRODUCTION\nNicolau syndrome (NS), also known as Embolia cutis medicamentosa or livedoid dermatitis, is a complication that occurs subsequent to intramuscular (IM) injection of various drugs. The condition can often be overlooked.[1] It first presents as pain around the injection site and develops as inflammation in the skin, the underlying adipose tissue, and in the muscle.[2]\n\nThe condition has been associated with almost all drug classes, including nonsteroidal anti-inflammatory drugs (NSAIDs),[3] local anesthetic agents,[4] corticosteroids,[56] antibiotics,[789] vitamin B complex, vitamin K,[10] oxytocin,[11] antineoplastics,[121314] antihistamines, and vaccines.[15] The most acute form of the complication occurs after NSAID injections.[1617] In one case, a cold compress applied for local pain management was reported to have increased acute local effects, rapidly leading to necrosis.[18]\n\nAlthough the etiopathogenesis of the condition remains unclear, the most prevalent explanation is accidental penetration of the drug into the intravascular area during IM injection, leading to erythema and a livedoid reticular and/or hemorrhagic wound secondary to arterial thrombosis. The reaction can lead to necrosis and ulceration of the skin, subcutaneous adipose tissue, and muscular tissue.[18]\n\nIM injections are widely administered both in and outside of hospitals. Given that they are not performed by health-care professionals and performed under non-sterile conditions, those performed in nonhospital settings can lead to complications, such as NS. Therefore, it is important to be able to identify and manage NS.\n\nIn this study, we present the treatment results of nine patients who received basic surgical approaches to treat NS.\n\nMATERIALS AND METHODS\nWe retrospectively evaluated 11 patients who were treated or referred to our department for wounds, and eventually diagnosed with NS between December 2013 and January 2018. Patient data on age, gender, height, and weight, etiology/drug and site of the IM injection, and reconstruction techniques for defect closure were recorded. Body mass index (BMI) was calculated, and concomitant diseases and medications were recorded.\n\nRESULTS\nOf the 11 patients (nine female and two males; mean age: 52.5, range: 24–78 years) who were diagnosed with NS, two did not accept treatment. NS had occurred after IM diclofenac sodium injection in eight patients, and after IM ceftriaxone injection in three patients. Seven patients presented with typical postinjection NS lesions in the right gluteal region, and three patients developed lesions in the left gluteal region [Figure 1]. One patient presented with a lesion in bilateral anterior thighs. Initial surgical debridement was performed in all nine of the treated patients. Culture samples were taken from four patients, of which one was reported contaminated. Extended-spectrum β-lactamase-producing Escherichia coli was seen in two wound cultures and Klebsiella pneumoniae was detected in one wound culture. Infected patients were started on antibiotics according to the antibiogram after consulting the infectious disease department. Of the 11 patients, five had diabetes mellitus, six had hypertension, and one had liver cirrhosis. The injections were administered by health-care professionals in eight patients and by their relatives in three patients. All patients reported a history of multiple injections. Negative pressure wound therapy was used for 6–19 days in all seven patients after debridement. Although granulation tissue developed in six patients, one patient required a second debridement procedure. Fasciocutaneous flaps were used in five patients and defects were primarily closed in four patients [Figures 2 and 3]. Patients were discharged on days 2–8 (mean, 3 days). No complications, such as wound infection, wound dehiscence, seroma, or flap necrosis, were encountered in any of the patients. No postoperative complications were observed in any of the nine patients throughout their mean 12-month follow-up period.\n\nFigure 1 Pathognomonic lesion for NS\n\nFigure 2 Case 2. The 64-year-old female patient presented with an eschar wound of approximately 15cm × 15cm in the right gluteal region that developed after an IM diclofenac sodium injection given in an external clinic. Debridement, negative pressure wound therapy were applied, then the site was reconstructed with fasciocutaneous flap\n\nFigure 3 Case 3. The 45-year-old female patient who was receiving IM diclofenac sodium injections for her migraine in her home presented with a partially necrose wound with discharge of approximately 15cm × 8cm in the left gluteal region. Debridement, negative pressure wound therapy were applied, then the site was reconstructed with fasciocutaneous flap\n\nAll nine female patients were obese (BMI 34–47, mean 40.44kg/m2). The BMIs of the two male patients were 30 and 40. The overweight female patients frequently received IM NSAID injections for pain. Demographic data, concomitant diseases, and treatment methods of the patients are given in Table 1.\n\nTable 1 Demographic data, concomitant diseases, and treatment methods of the patients\n\n\tAge\tSex\tLocalization\tEtiology\tTreatment\tBMI\tAdditional disease\t\n1\t46\tFemale\tRight gluteal\tDiclofenac sodium\tFasciocutaneous flap\t35\tHypertension diabetes\t\n2\t64\tFemale\tRight gluteal\tDiclofenac sodium\tFasciocutaneous flap\t41\tHypertension\t\n3\t40\tFemale\tLeft gluteal\tDiclofenac sodium\tNo treatment\t43\t–\t\n4\t62\tFemale\tLeft gluteal\tCeftriaxone\tPrimary repair\t34\tHypertension liver cirrhosis\t\n5\t24\tMale\tRight gluteal\tDiclofenac sodium\tFasciocutaneous flap\t30\t–\t\n6\t62\tFemale\tRight gluteal\tDiclofenac sodium\tNo treatment\t46\tDiabetes\t\n7\t30\tMale\tRight gluteal\tDiclofenac sodium\tPrimary repair\t40\t–\t\n8\t58\tFemale\tRight gluteal\tDiclofenac sodium\tFasciocutaneous flap\t47\tHypertension\t\n9\t45\tFemale\tLeft gluteal\tDiclofenac sodium\tFasciocutaneous flap\t43\tDiabetes\t\n10\t70\tFemale\tRight gluteal\tCeftriaxone\tPrimary repair\t35\tHypertension diabetes\t\n11\t78\tFemale\tBilateral thigh anterior\tAmpicillin/sulbactam\tPrimary repair\t40\tHypertension diabetes\t\nBMI = body mass index\n\nDISCUSSION\nNS was first described by Nicolau in 1925 following IM injections of bismuth salt to treat syphilis.[19] Since then, many drugs have been reported to cause NS. As most of these drugs are routinely used in clinical practice, diagnosis and treatment of NS are important.\n\nThe etiopathogenesis of the condition remains unclear, but it is suggested to be the development of a livedo-like dermatitis secondary to arterial thrombosis as a result of the accidental penetration of the drug into the intravascular area during an IM injection.[617] Navrazhina et al.[20] reported performing a biopsy and tissue culture from a purpura-like NS plaque area that developed after a lumbar puncture. Although the tissue culture failed to grow, the biopsy result was reported as “pauci-inflammatory thrombogenic vasculopathy affecting the capillaries and venules throughout the dermis and subcutaneous fat with endothelial necrosis and sloughing into vascular lumens.” Another theory suggests that perineural, intra-arterial, and periarterial injections cause local pain, and vasospasm secondary to the local pain leads to sympathetic nerve stimulation followed by necrosis in cutaneous, subcutaneous, adipose, and/or muscle tissues.[18] Most cases in the literature are reported to have occurred after a diclofenac sodium injection.[118,21] An IM diclofenac sodium injection was the causative agent in 8 of our 11 patients. The development of NS after injecting NSAIDs suggests that the condition may be associated with the pharmacological characteristics of this drug group. NSAIDs inhibit prostaglandin synthesis by inhibiting cyclooxygenase. Ischemic necrosis develops once prostaglandin is suppressed by the drug and vasospasm is induced.[21] Some studies also indicate that NS has no allergic or immunological origins. There were no findings of NS after the treated patients received IM injections containing the same causative agent.[1822]\n\nAlthough NS is mostly reported to be caused by IM-administered drugs, as compiled in the table given in Nischal et al.,[23] it is also caused by intravenous, intra-articular, and glucocorticoid injections, as well as by subcutaneously and subacromially injected drugs.\n\nAlthough NS is a rare condition, IM injections increase the possibility of occurrence, particularly in obese patients.[22] A mean BMI of 41.28 (high-health risk level) in our female patients and 35 (overweight) in our male patients suggest that weight can be a significant risk factor in the occurrence of NS. Dadaci et al.[24] reported measuring the thickness of the adipose tissue on pelvic tomography images of gluteal injection sites, and concluded that green needles (3.8cm in depth) do not penetrate deep enough to pass the adipose tissue and reach the gluteal region.[24] Adipose tissue thickness was 5.4cm on magnetic resonance imaging. A needle depth of 3.8cm indicates that drugs that have toxic effects, disrupt circulation, and increase the risk of fatty necrosis are injected into the adipose tissue instead of the muscle. Furthermore, as a result of cumulative effects, greater inflammation and tissue necrosis were observed in patients receiving repeated injections. The depth of the subcutaneous tissue also varies depending on gender and weight of the patient. IM injections performed with a standard green needle reach the gluteal region in only 5% of women and 15% of men, and the remainder is injected into subcutaneous tissue.[17] Obesity in all of our female patients could have been a risk for NS. Another risk factor is frequent injections, which was present in all nine of our patients. Vascular problems, particularly in obese patients, have led to the increased administration of IM injections, suggesting that the increased rate of injections, both in hospital and nonhospital settings, could be a risk factor for NS.\n\nIM injections should be duly administered by health-care professionals. Complications can be minimized with Z-track method, which is one of the injection methods.[25]\n\nTreatments for NS remain controversial. Surgical debridement, local flaps, and partial-thickness skin grafts can be used to treat lesions with established necrosis. Analgesics, dressings, and antibiotics are useful as conservative treatment methods for pain management in many cases.[26] Some authors have reported using pentoxifylline to reduce blood viscosity, hyperbaric oxygen to increase oxygenation, fibroblast activity and angiogenesis in the wound, and heparin to reduce vascular occlusion.[520,26] There are also reports of using nifedipine, a calcium channel blocker, for its arterial vasospasm-reducing effects and systemic steroids for their inflammation-suppressing characteristics.[57] There is no standardized treatment for NS; the current aim was to prevent the condition from developing into soft tissue necrosis.[5] In many cases, surgical debridement should be considered to support wound healing and to reduce the risk of infection.[20] In their report of a 9-year-old patient who developed NS on the fingers after a penicillin injection into the deltoid muscle, Memarian et al.[7] described treating the patient with intravenous hydrocortisone, subcutaneous enoxaparin, and local trinitroglycerin. In addition, Alkan et al.[27] reported treating a 4-year-old patient with pentoxifylline and heparinization for NS caused by a penicillin injection, but the treatment was initiated immediately after the injection, before necrosis developed. Surgical debridement was primarily performed in all of our patients as all presented with the typical dark-colored lesion seen in NS. Although the best aesthetic outcomes can be achieved with primary closure, except in large wounds, partial thickness skin grafts will take time to heal if atrophic scarring and hyperpigmentation occur. Flaps are the best option for larger gluteal defects.[28] Kocman et al.[28] reported treating five NS patients with free-style perforator V-Y flaps designed vertically or horizontally according to the long axis of the wound. This provided reduced donor site morbidity and less tension on the recipient site.[28]\n\nPain around the site after injection, followed by erythematous, livedoid, and hemorrhagic formations and, ultimately, cutaneous, subcutaneous, adipose tissue, and muscular tissue necrosis were seen in the reported cases. Necrosis in related dermatomes is pathognomonic for NS.[29]\n\nIn our study, the wounds were primarily closed after surgical debridement in four patients, and a fasciocutaneous flap was used in five patients. In their case series of 17 patients with NS, Dadaci et al.[24] reported treating the wounds with primary closure in 11 patients and reconstructing with local flaps in six patients (four with Limberg flaps and two with V-Y advancement flaps). There are reports of NS cases reconstructed with partial-thickness skin grafts[2023,26] and full-thickness skin grafts[17] after surgical debridement. These cases healed with residual depressed scars. In their study of three patients, Seok-Kwun et al.[26] reported using a partial-thickness skin graft in one, primary closure in one, and bilateral advancement flap in the other case. We designed an algorithmic approach for surgical repair [Figure 4]. Surgical debridement and antibiotics should be given in cases of necrosis and infection. Vacuum treatment may be necessary to mature and granulate wounds that are not infected but are not ready for reconstruction. Skin grafts should be considered in cases where primary closure and faciokutan flap selection are not possible.\n\nFigure 4 An algorithmic approach for surgical repair\n\nCONCLUSION\nNS was more frequent in women with a high BMI and high fat in the gluteal region, particularly those with NS. We considered that any kind of medication could lead to this syndrome. Different treatment methods were discussed and we developed a basic, efficient surgical algorithm for NS.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Park HJ Kim MS Park NH Jung SW Park SI Park CS Sonographic findings in Nicolau syndrome following intramuscular diclofenac injection: a case report J Clin Ultrasound 2011 39 111 3 20848573 \n2 Hamilton B Fowler P Galloway H Popovic N Nicolau syndrome in an athlete following intra-muscular diclofenac injection Acta Orthop Belg 2008 74 860 4 19205337 \n3 Kılıç İ Kaya F Özdemir AT Demirel T Çelik İ Nicolau syndrome due to diclofenac sodium (Voltaren®) injection: a case report J Med Case Rep 2014 8 404 25471251 \n4 García-Vilanova-Comas A Fuster-Diana C Cubells-Parrilla M Pérez-Ferriols MD Pérez-Valles A Roig-Vila JV Nicolau syndrome after lidocaine injection and cold application: a rare complication of breast core needle biopsy Int J Dermatol 2011 50 78 80 21182507 \n5 McKinney C Sharma N Jerath RS Livedoid dermatitis (Nicolau syndrome) following intra-articular glucocorticoid injection J Clin Rheumatol 2014 20 339 40 25160024 \n6 Cherasse A Kahn MF Mistrih R Maillard H Strauss J Tavernier C Nicolau’s syndrome after local glucocorticoid injection Joint Bone Spine 2003 70 390 2 14563471 \n7 Memarian S Gharib B Gharagozlou M Alimadadi H Ahmadinejad Z Ziaee V Nicolau syndrome due to penicillin injection: a report of 3 cases without long-term complication Case Rep Infect Dis 2016 2016 9082158 27882254 \n8 Kim DH Ahn HH Kye YC Choi JE Nicolau syndrome involving whole ipsilateral limb induced by intramuscular administration of gentamycin Indian J Dermatol Venereol Leprol 2014 80 96 \n9 Lee DP Bae GY Lee MW Choi JH Moon KC Koh JK Nicolau syndrome caused by piroxicam Int J Dermatol 2005 44 1069 70 16409285 \n10 Koklu E Sarici SU Altun D Erdeve O Nicolau syndrome induced by intramuscular vitamin K in a premature newborn Eur J Pediatr 2009 168 1541 2 19277707 \n11 Mancano MA Delayed anaphylaxis with methimazole: Nicolau syndrome after oxytocin intramuscular administration anastrazole-induced autoimmune hepatitis amoxicillin- and cephalexin-induced eosinophilic colitis docetaxel-induced supravenous erythematous eruption Hosp Pharm 2016 51 520 3 27559184 \n12 Lobato-Berezo A Martínez-Pérez M Imbernón-Moya A Gallego-Valdés MÁ [Nicolau syndrome after glatiramer acetate injection] Med Clin (Barc) 2015 145 e41 26004272 \n13 Almudimeegh A Le Pelletier F Dupin N Nicolau syndrome secondary to subcutaneous bortezomib injection J Eur Acad Dermatol Venereol 2016 30 348 50 25264810 \n14 Guarneri C Polimeni G Nicolau syndrome following etanercept administration Am J Clin Dermatol 2010 11 51 2 \n15 Nagore E Torrelo A González-Mediero I Zambrano A Livedoid skin necrosis (Nicolau syndrome) due to triple vaccine (DTP) injection Br J Dermatol 1997 137 1030 1 9470941 \n16 Luton K Garcia C Poletti E Koester G Nicolau syndrome: three cases and review Int J Dermatol 2006 45 1326 8 17076716 \n17 Kim KK Nicolau syndrome in patient following diclofenac administration: a case report Ann Dermatol 2011 23 501 3 22148020 \n18 Engin Ş Nicolau syndrome as an avoidable complication J Fam Community Med 2012 19 52 3 \n19 Varga L Asztalos L Nicolau syndrome after ketazon injection Orv Hetil 1990 131 1143 6 2242120 \n20 Navrazhina K Cressey BD Wildman HF Nicolau syndrome after lumbar puncture: a case report in a 22-month-old girl JAAD Case Rep 2017 3 33 5 28116340 \n21 Lie C Leung F Chow SP Nicolau syndrome following intramuscular diclofenac administration: a case report J Orthop Surg (Hong Kong) 2006 14 104 7 16598099 \n22 Noaparast M Mirsharifi R Elyasinia F Parsaei R Kondori H Farifteh S Nicolau syndrome after intramuscular benzathine penicillin injection Iran J Med Sci 2014 39 577 9 25429182 \n23 Nischal KC Basavaraj HB Swaroop MR Agrawal DP Sathyanarayana BD Umashankar NP Nicolau syndrome: an iatrogenic cutaneous necrosis J Cutan Aesthet Surg 2009 2 92 5 20808597 \n24 Dadaci M Altuntas Z Ince B Bilgen F Tufekci O Poyraz N Nicolau syndrome after intramuscular injection of non-steroidal anti-inflammatory drugs (NSAID) Bosn J Basic Med Sci 2015 15 57 60 \n25 McConnell EA Administering a Z-track i.m. injection Nursing 1999 29 26 \n26 Seok-Kwun K Tae-Heon K Keun-Cheol L Nicolau Syndrome after Intramuscular Injection: 3 Cases Arch Plast Surg 2012 39 249 52 22783535 \n27 Alkan BT Demirel G Ormeci T Al S Çakar E Tastekin A Anticoagulant and vasodilator therapy for Nicolau syndrome following intramuscular benzathine penicillin injection in a 4 year old boy Arch Argent Pediatr 2016 114 e184 6 27164354 \n28 Kocman EA Yaşar FN Kose AA Cil Y Karabagli Y Çetin C Freestyle perforator-based fasciocutaneous flap reconstruction in Nicolau syndrome-related tissue necrosis Indian J Surg 2015 77 1187 90 27011533 \n29 Nisbet AC Intramuscular gluteal injections in the increasingly obese population: retrospective study BMJ 2006 332 637 8 16524934\n\n",
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"issue": "13(2)",
"journal": "Journal of cutaneous and aesthetic surgery",
"keywords": "Diclofenac sodium; Nicolau syndrome; injection; intramuscular",
"medline_ta": "J Cutan Aesthet Surg",
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"title": "A Basic Algorithmic Surgical Approach for Nicolau Syndrome.",
"title_normalized": "a basic algorithmic surgical approach for nicolau syndrome"
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"abstract": "We describe a patient with liver metastases from colorectal cancer treated with chemotherapy and hepatic resection, who developed unresectable multifocal liver recurrence and who received liver transplantation using a novel planned technique: heterotopic transplantation of segment 2-3 in the splenic fossa with splenectomy and delayed hepatectomy after regeneration of the transplanted graft. We transplanted a segmental liver graft after in-situ splitting without any impact on the waiting list, as it was previously rejected for pediatric and adult transplantation. The volume of the graft was insufficient to provide liver function to the recipient, so we performed this novel operation. The graft was anastomosed to the splenic vessels after splenectomy, and the native liver portal flow was modulated to enhance graft regeneration, leaving the native recipient liver intact. The volume of the graft doubled during the next 2 weeks and the native liver was removed. After 8 months, the patient lives with a functioning liver in the splenic fossa and without abdominal tumor recurrence. This is the first case reported of a segmental graft transplanted replacing the spleen and modulating the portal flow to favor graft growth, with delayed native hepatectomy.",
"affiliations": "Department of General Surgery and Transplantation, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi University Hospital, Bologna, Italy.;Department of General Surgery and Transplantation, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi University Hospital, Bologna, Italy.;Department of General Surgery and Transplantation, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Department of General Surgery and Transplantation, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Department of General Surgery and Transplantation, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Department of General Surgery and Transplantation, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Department of General Surgery and Transplantation, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Department of General Surgery and Transplantation, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Department of General Surgery and Transplantation, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Department of General Surgery and Transplantation, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Department of General Surgery and Transplantation, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Department of General Surgery and Transplantation, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Department of General Surgery and Transplantation, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Department of General Surgery and Transplantation, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Department of General Surgery and Transplantation, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Department of General Surgery and Transplantation, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Department of General Surgery and Transplantation, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Department of General Surgery and Transplantation, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Emilia-Romagna Transplant Reference Centre, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Department of Pathology, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Department of Medical and Surgical Sciences, Plastic Surgery Unit, S.Orsola-Malpighi Hospital, University of Bologna, Italy.;Department of General Surgery and Transplantation, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.",
"authors": "Ravaioli|Matteo|M|0000-0001-5862-6151;Brandi|Giovanni|G|0000-0003-0013-2858;Siniscalchi|Antonio|A|0000-0002-2014-4680;Renzulli|Matteo|M|0000-0002-1311-5670;Bonatti|Chiara|C|0000-0003-4203-7824;Fallani|Guido|G|0000-0002-5774-7696;Prosperi|Enrico|E|0000-0002-9389-1812;Serenari|Matteo|M|0000-0003-1471-8585;Germinario|Giuliana|G|0000-0002-8019-1956;Del Gaudio|Massimo|M|0000-0003-2754-1627;Zanfi|Chiara|C|0000-0002-7141-7386;Odaldi|Federica|F|0000-0003-2910-2273;Bertuzzo|Valentina Rosa|VR|0000-0002-4339-4877;Pasqualini|Eddi|E|;Maroni|Lorenzo|L|0000-0003-4195-3580;Frascaroli|Giacomo|G|0000-0002-9235-9744;Rossetto|Anna|A|0000-0002-2682-4898;Morelli|Maria Cristina|MC|0000-0002-9742-1981;Vizioli|Luca|L|0000-0003-2278-2181;Serra|Carla|C|0000-0001-5555-0745;Sangiorgi|Gabriela|G|0000-0003-2229-4903;D'Errico|Antonia|A|0000-0003-2747-3732;Contedini|Federico|F|;Cescon|Matteo|M|0000-0003-1715-3794",
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"issue": "21(2)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "clinical research/practice; liver disease; liver transplantation/hepatology; liver transplantation: auxiliary",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000328:Adult; D002648:Child; D006498:Hepatectomy; D006801:Humans; D008099:Liver; D008115:Liver Regeneration; D016031:Liver Transplantation; D009364:Neoplasm Recurrence, Local; D013154:Spleen; D013156:Splenectomy; D016042:Transplantation, Heterotopic",
"nlm_unique_id": "100968638",
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"pages": "870-875",
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"pmid": "32715576",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Heterotopic segmental liver transplantation on splenic vessels after splenectomy with delayed native hepatectomy after graft regeneration: A new technique to enhance liver transplantation.",
"title_normalized": "heterotopic segmental liver transplantation on splenic vessels after splenectomy with delayed native hepatectomy after graft regeneration a new technique to enhance liver transplantation"
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"abstract": "BACKGROUND\nLymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus-associated lymphoproliferative disorder. It most often occurs in patients with immunodeficiency and the clinical course ranges from indolent behavior to that of an aggressive malignancy. Pulmonary, central nervous system and dermatological manifestations are most common. To our knowledge this is the first reported case of LYG related to azathioprine therapy in Crohn disease.\n\n\nMETHODS\nA twenty-six year old Caucasian woman with colonic Crohn disease on maintenance azathioprine therapy presented with right upper quadrant pain and fever. Diagnostic imaging revealed extensive liver, pulmonary and cerebral lesions. A diagnosis of LYG was made based on the pattern of organ involvement and the immunohistochemical features on liver and lung biopsy.\n\n\nCONCLUSIONS\nThiopurine therapy for inflammatory bowel disease is associated with an increased incidence of lymphoproliferative disorders. This report highlights the diagnostic challenges associated with LYG. As long-term thiopurine therapy remains central to the management of inflammatory bowel diseases it is essential that both patients and clinicians are aware of this potential adverse outcome.",
"affiliations": "Division of Gastroenterology and Hepatology, University of Calgary, Foothills Medical Centre, Calgary, Canada. pjbellet@ucalgary.ca.",
"authors": "Connors|William|W|;Griffiths|Cameron|C|;Patel|Jay|J|;Belletrutti|Paul J|PJ|",
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"fulltext": "\n==== Front\nBMC GastroenterolBMC GastroenterolBMC Gastroenterology1471-230XBioMed Central 1471-230X-14-1272502261210.1186/1471-230X-14-127Case ReportLymphomatoid granulomatosis associated with azathioprine therapy in Crohn disease Connors William 1wjaconnors@gmail.comGriffiths Cameron 1Cameron.Griffiths@albertahealthservices.caPatel Jay 2jay.patel@cls.ab.caBelletrutti Paul J 3pjbellet@ucalgary.ca1 Department of Medicine, University of Calgary, Calgary, Canada2 Department of Pathology, Foothills Medical Centre, Calgary, Canada3 Division of Gastroenterology and Hepatology, University of Calgary, Foothills Medical Centre, Calgary, Canada2014 14 7 2014 14 127 127 22 4 2014 26 6 2014 Copyright © 2014 Connors et al.; licensee BioMed Central Ltd.2014Connors et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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\nLymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus-associated lymphoproliferative disorder. It most often occurs in patients with immunodeficiency and the clinical course ranges from indolent behavior to that of an aggressive malignancy. Pulmonary, central nervous system and dermatological manifestations are most common. To our knowledge this is the first reported case of LYG related to azathioprine therapy in Crohn disease.\n\nCase presentation\nA twenty-six year old Caucasian woman with colonic Crohn disease on maintenance azathioprine therapy presented with right upper quadrant pain and fever. Diagnostic imaging revealed extensive liver, pulmonary and cerebral lesions. A diagnosis of LYG was made based on the pattern of organ involvement and the immunohistochemical features on liver and lung biopsy.\n\nConclusions\nThiopurine therapy for inflammatory bowel disease is associated with an increased incidence of lymphoproliferative disorders. This report highlights the diagnostic challenges associated with LYG. As long-term thiopurine therapy remains central to the management of inflammatory bowel diseases it is essential that both patients and clinicians are aware of this potential adverse outcome.\n\nLymphoproliferative disordersCrohn diseaseInflammatory bowel diseaseAzathioprineThiopurines\n==== Body\nBackground\nLymphomatoid granulomatosis (LYG), first described by Liebow et al. in 1972 [1], is a rare Epstein-Barr Virus (EBV)-associated lymphoproliferative disorder. LYG is classically described as primarily extranodal in nature involving the lungs, skin, central nervous system and liver. It is an incompletely understood clinical entity with a median survival of 14 months from the time of diagnosis. Age at first presentation is typically between the fourth and sixth decade with a male to female ratio of two to one. Although it may occur in immunocompetent hosts, there is a strong association with immune deficiency, both humoral and cell mediated. Clinical presentation is often non-specific with pulmonary involvement being most common and manifesting as cough, shortness of breath or chest pain [1-4].\n\nHistopathologically, LYG is characterized as a mixed mononuclear cell infiltrate with atypical large CD20+ B-lymphocytes on the background of reactive CD3+ T- lymphocytes, histiocytes and plasma cells. The infiltrate is angiocentric and typically invades the microvasculature. It is graded from I to III based on both the number of large B-cells and the proportion that stain positively for EBV-encoded small RNA (EBER) by in situ hybridization (ISH) [2]. The presence of these EBER-positive large B-cells and vascular invasion are keys to the diagnosis of LYG. Grade I and II LYG are slowly progressive while grade III LYG is aggressive with poor prognosis and requires treatment with multi-agent immunochemotherapy.\n\nHere we present a case of LYG in a 26-year-old Caucasian female receiving azathioprine maintenance therapy for Crohn disease (CD) who presented with primary gastrointestinal complaints and fever. This report will highlight the diagnostic challenges associated with LYG and describe what we believe to be the first documented case of this rare disease in the setting of azathioprine treatment for CD.\n\nCase presentation\nA 26-year-old Caucasian woman presented with three days of right upper quadrant pain, fever, and malaise. She had a six-year history of Crohn colitis initially treated with high dose mesalamine (4 g daily) then transitioned to azathioprine (2.5 mg/kg) after loss of response. She had been in clinical remission on azathioprine for the preceding 14 months. The patient had not been on any other immune modulating or biologic therapies.\n\nPhysical examination revealed focal right upper quadrant abdominal tenderness but no palpable masses, organomegaly or signs of ascites. Laboratory review revealed new onset pancytopenia (hemoglobin = 119 g/L, neutrophils = 1.4 × 109/L, platelets = 80 x109/L), cholestatic liver enzyme elevation (GGT = 272 U/L, ALP = 342 U/L) and hepatic synthetic impairment (bilirubin = 19 umol/L, INR = 1.8, albumin = 24 g/L). Azathioprine therapy was suspended. Investigations failed to identify a source of infection; however, magnetic resonance (MR) imaging revealed hepatomegaly with periportal, gastrohepatic, and retroperitoneal lymphadenopathy. A clinical diagnosis of azathioprine-associated pancytopenia with a concurrent non-A-E viral hepatitis was favored. She was administered G-CSF and transitioned to oral antibiotics. After clinical improvement, the patient was discharged from hospital with planned repeat MR imaging in one to two months.Six weeks later, she developed progressive abdominal pain, night sweats, and non-positional presyncopal symptoms. The patient did not report diarrhea or GI bleeding. Endoscopic evaluation of the upper GI tract and colon were normal with no evidence of inflammation or active Crohn disease. She had also developed her first outbreak of genital herpes (serologically HSV-2) for which she was started on antiviral therapy. Repeat MR imaging now demonstrated extensive T2 hyperintense lesions distributed throughout her liver and both kidneys (Figure 1A).Over the next weeks in hospital, she experienced progressive abdominal bloating, malaise, dyspnea and night sweats without documented fevers. Computed tomography (CT) of her lungs revealed extensive, peripherally distributed, bilateral ground-glass opacifications (Figure 1B). Bronchoalveolar lavage and transbronchial biopsy were negative for infection or malignancy. A comprehensive infectious diseases work-up was negative; of note serology and PCR viral titers for EBV were negative. HIV serology was negative. Core biopsy of the liver revealed atypical B-lymphocyte proliferation with prominent angiocentricity (Figure 2A). The EBV encoded small RNA (EBER) staining by in situ hybridization was negative (Figure 2B). Thus the liver biopsy was classified by hematopathologist consensus as an “atypical lymphoid infiltrate”. Further work-up with a bone marrow biopsy showed no morphologic abnormalities and was EBER-negative. An MR of the head revealed multiple cerebellar, cortical and subcortical enhancing lesions (Figure 3). As the lesions appeared to be infarcts of different ages across different territories, a vasculitic process was suggested but a subsequent serological work-up was negative.\n\nFigure 1 Diagnostic imaging features of lymphomatoid granulomatosis in our case. A) T2 weighted axial magnetic resonance (MR) image showing hyperintense lesions in the liver. B) CT axial image showing irregular bilateral pulmonary opacities with peripheral predominance and areas of ground-glass changes classic for lymphomatoid granulomatosis.\n\nFigure 2 Histopathology features of lymphomatoid granulomatosis in our case. A) H&E stain of liver core biopsy with a periportal polymorphous infiltrate composed of small lymphocytes, histiocytes, and plasma cells. B) EBV in situ hybridization (EBER) of liver showing no positively stained cells. C) H&E stain of lung wedge biopsy showing an extensive, focally angiocentric, polymorphic infiltrate with geographic tissue necrosis. D) EBER of lung showing scattered positive nuclear staining in the distribution of B-cells (CD20 immunostain not shown).\n\nFigure 3 Central nervous system lesion in our case. T2 weighted MR image showing a large hyperintense lesion in A) right frontal cerebral cortex and B) right cerebellar cortex.\n\nThe patient opted to leave hospital pending consultation opinions on her liver biopsy and one month later returned to hospital with worsening dyspnea, cough and fevers. She underwent video-assisted thoracoscopic surgery (VATS) during which a wedge biopsy of her lung was obtained. In the days prior to surgery she had developed right pleural effusion and lower lobe pneumonia. Cultures from her pleural fluid grew Streptococcus milleri and Prevotella species, therefore she received a six-week course of parenteral antibiotics.Now four months after her initial presentation, the VATS-acquired lung wedge biopsy demonstrated EBER positivity in an atypical CD20+ lymphocyte infiltrate with vascular invasion sufficient to confirm a diagnosis of grade II LYG (Figure 2C, D). Expert pathology opinion from the National Institutes of Health (Bethesda, MD) concurred with the diagnosis. Over this period the patient had several transient episodes of left lower face and tongue paresthesias and repeat brain MRI revealed interval development of new enhancing lesions in both cerebral hemispheres with mild surrounding edema and small internal foci of microhemorrhage.\n\nTreatment was initiated with subcutaneous recombinant interferon-alpha three times weekly titrated up to 10 million units per m2 of body surface area and four weekly doses of rituximab 375 mg/m2. Her treatment course was complicated by neutropenia requiring granulocyte colony stimulating factor (G-CSF), choledocholithiasis requiring cholecystectomy and admission to hospital with recurrent pneumonia. With therapy, all of her systemic lesions have steadily improved. This patient is alive and tolerating ongoing therapy at 12 months follow-up.\n\nOur patient is the first reported case we are aware of with LYG in the context of CD and azathioprine use. Her presentation is atypical for LYG due to her young age, female gender, and the predominance of hepatic involvement preceding other pulmonary and CNS manifestations. In the larger context of LYG, only three percent of cases present with gastrointestinal symptoms; the majority primarily manifest pulmonary symptoms [1-4].\n\nIn our case, the diagnosis of LYG was suspected based on pattern recognition on lung imaging and suggestive liver pathology. The negative EBV staining and lack of necrosis on the liver biopsy sample pointed away from LYG as the diagnosis. After open lung biopsy, however, the classic features of LYG were revealed, namely atypical large B-cells that were EBER-positive, vascular invasion and necrosis. These pathological findings along with the patient’s clinical presentation and pattern of organ involvement clinched the diagnosis of LYG. This case highlights the difficulty of establishing the diagnosis of LYG in many cases due to sampling error and histological heterogeneity in a given patient depending on the site biopsied [5].\n\nThe current literature on LYG in association with CD or azathioprine is limited to two case reports. The first was a 17-year-old female patient with CD who developed LYG (stage III) with nasopharyngeal and pulmonary predominance following six years of 6-mercaptopurine therapy. She received systemic immunochemotherapy and was in clinical remission at four years follow-up [6]. The second was a 69-year-old female who developed LYG (stage III) with central nervous system predominance following ten months of azathioprine therapy for autoimmune hepatitis. Despite initiation of systemic therapy the patient died 34 days after diagnosis due to sepsis and cardio-pulmonary failure [7]. From these two case reports an independent association between the two major features of our case -CD and azathioprine (a thiopurine pro-drug of 6-mercaptopurine)– with the development of LYG can be theorized.\n\nMultiple population-based studies of inflammatory bowel diseases (IBD) have not shown an excess risk of lymphoproliferative disorders (LD) over baseline in part because it is difficult to rule out an effect from the disease itself in the population of patients who require more intensive therapy [8,9]. However, studies evaluating the risk of LD in the setting of CD and thiopurine therapy, summarized in a review by Beaugerie et al[9], support an approximate five-fold therapy specific elevated risk. Along with other smaller retrospective cohort analyses, the CESAME study, a nationwide French prospective observational cohort study of 19,486 patients with IBD, showed an independent association between ongoing thiopurine therapy for IBD and the risk of LD (multivariate-adjusted hazard ratio = 5.28, CI 2.01-13.9, p = 0.0007) [10-12]. It should be noted that the CESAME Study Group concluded the absolute cumulative risk of LD after ten years of thiopurines was less than one percent. This cohort had no patients diagnosed with LYG.\n\nConsistent with the findings in our patient, a comprehensive review of all LYG case series by Katzenstein et al.[4] illustrates the central role of underlying primary or secondary immunodeficiency leading to EBV reactivation. This may result in viral binding of lymphocyte membrane proteins and subsequent viral genome insertion facilitating oncogenesis [4]. Iatrogenic T-cell immunosuppression secondary to thiopurines is consistent with this proposed pathogenesis and was likely the predisposing factor in our case. Crohn disease-related lymphomas have been shown to have a higher prevalence of EBV-related subtypes, and in some EBV-related lymphoproliferative disorders disease remission has been seen with withdrawal of immunosuppression [13].\n\nConclusions\nHere we present the first case in the literature of lymphomatoid granulomatosis in the setting of azathioprine therapy for Crohn disease. LYG is one of several EBV-driven conditions that should be considered when a lymphoproliferative disorder develops in an immunocompromised patient.\n\nThe atypical features in our case underscore the importance of maintaining a high degree of clinical suspicion and diagnostic vigilance when evaluating non-specific abdominal symptoms frequently encountered in CD patients. This case highlights that even limited exposure to such therapy may induce LYG. Future research is needed into the pathogenesis and early detection of this disease to allow both clinicians and patients to make informed decisions and to raise awareness of this uncommon disorder.\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 of this journal.\n\nAbbreviations\nALP: Alkaline phosphatase; CD: Crohn disease; CNS: Central nervous system; CT: Computed tomography; EBV: Epstein-Barr virus; EBER: Epstein-Barr virus encoded small RNA; GGT: Gamma glutamyl transferase; IBD: Inflammatory bowel disease; ISH: In situ hybridization; LD: Lymphoproliferative disorder; LYG: Lymphomatoid granulomatosis; MR: Magnetic resonance.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nWC and CG wrote the manuscript and performed the literature review. JP and PJB conceived of the report, participated in expert review and editing of the final manuscript. All authors read and approved the final manuscript.\n\nPre-publication history\nThe pre-publication history for this paper can be accessed here:\n\nhttp://www.biomedcentral.com/1471-230X/14/127/prepub\n\nAcknowledgments\nWe thank Dr. J.H. MacGregor for assistance with case related diagnostic imaging and Dr. Michelle Geddes for clinical insight and expert opinion from a hematology-oncology perspective.\n==== Refs\nLiebow AA Carrington CR Friedman PJ Lymphomatoid granulomatosis Hum Pathol 1972 3 457 558 4638966 \nJaffe ES Wilson WH Lymphomatoid granulomatosis: pathogenesis, pathology and clinical implications Cancer Surv 1997 30 233 248 9547995 \nFauci AS Haynes BF Costa J Katz P Wolff SM Lymphomatoid granulomatosis. Prospective clinical and therapeutic experience over 10 years N Engl J Med 1982 306 68 74 7053488 \nKatzenstein AL Doxtader E Narendra S Lymphomatoid granulomatosis: insights gained over 4 decades Am J Surg Pathol 2010 34 e35 e48 21107080 \nColby TV Current histological diagnosis of lymphomatoid granulomatosis Mod Pathol 2012 25 S39 S42 22214969 \nDestombe S Bouron-DalSoglio D Rougemont AL Fournet JC Ovetchkine P Champagne J Deslandres C Lymphomatoid granulomatosis: a unique complication of Crohn disease and its treatment in pediatrics J Pediatr Gastroenterol Nutr 2010 50 559 561 20639715 \nKatherine Martin L Porcu P Baiocchi RA Erter JW Chaudhary AR Primary central nervous system lymphomatoid granulomatosis in a patient receiving azathioprine therapy Clin Adv Hematol Oncol 2009 7 65 68 19274043 \nHerrinton LJ Liu L Weng X Lewis JD Hutfless S Allison JE Role of thiopurine and anti-TNF therapy in lymphoma in inflammatory bowel disease Am J Gastroenterol 2011 106 2146 2153 22031357 \nLewis JD Bilker WB Brensinger C Dern JJ Vaughn DJ Strom BL Inflammatory bowel disease is not associated with an increased risk of lymphoma Gastroenterology 2001 121 1080 1087 11677199 \nBeaugerie L Sokol H Seksik P Noncolorectal malignancies in inflammatory bowel disease: more than meets the eye Dig Dis 2009 27 375 381 19786768 \nKandiel A Fraser AG Korelitz BI Brensinger C Lewis JD Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine Gut 2005 54 1121 1125 16009685 \nBeaugerie L Brousse N Bouvier AM Colombel JF Lemann M Cosnes J Hebuterne X Cortot A Bouhnik Y Gendre JP Simon T Maynadie M Hermine O Faivre J Carrat F CESAME Study Group Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study Lancet 2009 374 1617 1625 19837455 \nDayharsh GA Loftus EV JrSandborn WJ Tremaine WJ Zinsmeister AR Witzig TE Macon WR Burgart LJ Epstein-Barr virus-positive lymphoma in patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine Gastroenterology 2002 122 72 77 11781282\n\n",
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"mesh_terms": "D000328:Adult; D001379:Azathioprine; D001932:Brain Neoplasms; D003424:Crohn Disease; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D008113:Liver Neoplasms; D008175:Lung Neoplasms; D008230:Lymphomatoid Granulomatosis; D016609:Neoplasms, Second Primary",
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"title": "Lymphomatoid granulomatosis associated with azathioprine therapy in Crohn disease.",
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"abstract": "Enzalutamide package labeling recommends avoiding concurrent warfarin use due to potential reductions in warfarin concentrations via enzalutamide-associated hepatic enzyme induction. A case of successful management of this interaction via warfarin adjustments is reported.\n\n\nMETHODS\nA 77-year-old Caucasian male, previously relatively stable on warfarin 42-45 mg weekly, reported to clinic after the recent start of enzalutamide and subsequent hospitalization with a subtherapeutic International Normalized Ratio (INR). A 50% increase in weekly warfarin dose resulted in a therapeutic INR. Enzalutamide was temporarily discontinued, and a 33% weekly warfarin dose decrease resulted in two therapeutic INRs.\n\n\nCONCLUSIONS\nThis is the first case to highlight the clinical significance of this interaction, noting that patients taking enzalutamide may require approximately 30%-50% adjustment in their warfarin dosage to maintain a therapeutic INR.",
"affiliations": "Department of Pharmacy, Baptist Health Louisville, Louisville, KY, USA.;Methodist University Hospital, Memphis, TN, USA.;Department of Clinical Pharmacy, University of Tennessee College of Pharmacy, Memphis, TN, USA.;Department of Pharmacy Practice, Wingate University School of Pharmacy, Hendersonville, NC, USA.",
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"title": "Enzalutamide-warfarin interaction necessitating warfarin dosage adjustment: A case report of successful clinical management.",
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"abstract": "BACKGROUND\nPulmonary collapse after intubation is common, and it is caused by a variety of factors.\n\n\nMETHODS\nA 21-year-old man presented at our operation room to undergo an appendectomy. Except for a history of cigarette smoking, his history was negative. Anesthesia was induced with 100% oxygen and sevoflurane, remifentanil infusion, and propofol. Neuromuscular block was obtained with rocuronium. The tip and cuff of a tracheal tube were lubricated with a topical metered-dose of 8% Lidocaine pump spray. After intubation, SPO2 suddenly decreased. The chest x-ray revealed right upper lobe atelectasis. Fiber optic bronchoscopy showed that a large amount of yellow sticky mucus had been secreted into the right main bronchus.\n\n\nCONCLUSIONS\nIn Japan, 8% Lidocaine pump spray contains menthol and ethanol as additives. These additives, particularly menthol, might have led to excessive mucus production, although we did not analyze the mucus secretion.",
"affiliations": "Department of Surgery, Toki General Hospital, Gifu, Japan.;Department of Surgery, Toki General Hospital, Gifu, Japan.;Department of Surgery, Toki General Hospital, Gifu, Japan.;Department of Surgery, Toki General Hospital, Gifu, Japan.;Department of Surgery, Toki General Hospital, Gifu, Japan.;Department of Surgery, Toki General Hospital, Gifu, Japan.;Multidisciplinary Pain Centre, School of Medicine, Aichi Medical University, Aichi, Japan.",
"authors": "Arai|Young-Chang P|YC|;Kawanishi|Jun|J|;Sakakima|Yoshikazu|Y|;Ohmoto|Koichi|K|;Ito|Akihiro|A|;Maruyama|Yuki|Y|;Ikemoto|Tatsunori|T|",
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"fulltext": "\n==== Front\nAnesth Pain MedAnesth Pain Med10.5812/aapm.KowsarAnesthesiology and Pain Medicine2228-75232228-7531Kowsar 10.5812/aapm.33771Case ReportSevere Respiratory Event Initially Thought to be Inadvertent Endobronchial Intubation: Possible Complications From Using of a Topical Metered-Dose of 8% Lidocaine Pump Spray Arai Young-Chang P. 1*Kawanishi Jun 1Sakakima Yoshikazu 1Ohmoto Koichi 1Ito Akihiro 1Maruyama Yuki 1Ikemoto Tatsunori 21 Department of Surgery, Toki General Hospital, Gifu, Japan2 Multidisciplinary Pain Centre, School of Medicine, Aichi Medical University, Aichi, Japan* Corresponding author: Young-Chang P. Arai, Multidisciplinary Pain Centre, School of Medicine, Aichi Medical University, Aichi, Japan. Tel: +81-561623311, Fax: +81-561625004, E-mail: arainon@aichi-med-u.ac.jp16 4 2016 6 2016 6 3 e3377112 10 2015 11 11 2015 09 12 2015 Copyright © 2016, Iranian Society of Regional Anesthesia and Pain Medicine (ISRAPM)2016This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.Introduction\nPulmonary collapse after intubation is common, and it is caused by a variety of factors.\n\nCase Presentation\nA 21-year-old man presented at our operation room to undergo an appendectomy. Except for a history of cigarette smoking, his history was negative. Anesthesia was induced with 100% oxygen and sevoflurane, remifentanil infusion, and propofol. Neuromuscular block was obtained with rocuronium. The tip and cuff of a tracheal tube were lubricated with a topical metered-dose of 8% Lidocaine pump spray. After intubation, SPO2 suddenly decreased. The chest x-ray revealed right upper lobe atelectasis. Fiber optic bronchoscopy showed that a large amount of yellow sticky mucus had been secreted into the right main bronchus.\n\nConclusions\nIn Japan, 8% Lidocaine pump spray contains menthol and ethanol as additives. These additives, particularly menthol, might have led to excessive mucus production, although we did not analyze the mucus secretion.\n\nEndobronchial IntubationSevere Respiratory Event8% Lidocaine Pump Spray\n==== Body\n1. Introduction\nPulmonary collapse after intubation is common and is caused by a variety of factors (1-3). We treated a young healthy male who developed severe hypoxemia and generalized wheezing over both lung fields immediately after intubation. Diagnostic and treatment bronchoscopy showed that a yellow sticky mucus had been secreted into the right main bronchus. Plausible causes are discussed.\n\n2. Case Presentation\nA 21-year-old man, 74 kg in weight and 177 cm in height, presented at our operation room to undergo an appendectomy. Except for a history of pain localized to the right iliac fossa for two days and cigarette smoking (> 1.5 pack/day) for 5 years, his history was negative. He was forced to stop smoking at admission, one day before the operation. There were no previous anesthetics or drug allergies, recent respiratory infection or airway disease. Except for findings related to his appendicitis, his physical examination was unremarkable and his chest abdominal radiograph and computed tomography scans were clear. The SPO2 was above 97% in room air.\n\nWhile the patient was preoxygenated for 3 minutes, routine intraoperative monitoring devices (an electrocardiogram, non-invasive blood pressure monitor, and pulse oximeter) were placed on the subject. Anesthesia was then induced with 100% oxygen and 1.5% sevoflurane, remifentanil infusion at 0.4 mcg/kg/minute, and 150 mg of propofol. Neuromuscular block was obtained with 50 mg of rocuronium. We normally use lidocaine gel for the lubrication of tracheal tube, but there was no lidocaine gel prepared in the operation room; instead, 3 minutes after neuromuscular block, the tip and cuff of an 8.5 mm tracheal tube were lubricated with 3 mL of a topical metered-dose of 8% Lidocaine pump spray. A clear view of the larynx was obtained with a laryngoscope, so the trachea was intubated and the tracheal tube was secured at 21 cm at the lips. On immediate inspection, both side of the chest appeared to inflate; auscultation revealed bilateral normal breathing sounds, and capnography revealed a normal waveform by bag ventilation, so we confirmed that the tube position was appropriate. Thereafter, anesthesia was maintained with 1.5% sevoflurane and oxygen and air (FiO2 = 0.5), remifentanil at 0.4 mcg/kg/minute, and propofol at 100 mg/hour. Mechanical ventilation was set with a tidal volume of 650 mL and a respiratory rate of 12 breaths/minutes.\n\nWithin 3 minutes after intubation, the SPO2 suddenly decreased from 99% to 86%. The inspired oxygen fraction was increased to 1. The peak inspiratory pressure increased up to 30 - 40 cm H2O and the tidal volume decreased to around 200 mL. The left chest was expanding and breathing sounds were vesicular with no wheezing. On the right chest, slight expansion and marked wheezing were observed. The chest X-ray taken at this juncture revealed right upper lobe atelectasis, and the tip of the tracheal tube was found to be 3 cm above the carina. Fiber optic bronchoscopy showed that a large amount of yellow sticky mucus had been secreted into the right main bronchus, so the secretion was removed using a suction port of the bronchoscopy; thereafter, manual ventilation with an O2 bag was applied for 5 minutes for the re-expansion of the collapsed lung. We also administered 125 mg of methylprednisolone intravenously to reduce the secretion of sticky mucus. Since the SPO2 had increased to 95% and the patient was now stable, the operation commenced. Mechanical ventilation was set with a tidal volume of 560 mL, a PEEP of 3 cmH2O, and a respiratory rate of 12 breaths/minutes.\n\nAfter the operation was completed, a chest X-ray revealed right upper lobe atelectasis, and the SPO2 was 96%. Then, fiber optic bronchoscopy showed that a small amount of yellow sticky mucus had been secreted into the right and left main bronchus, so the secretion was removed using a suction port of the bronchoscopy again. Muscle relaxation was reversed with 200 mg of sugammadex, and then sevoflurane, remifentanil, and propofol were discontinued. The patient responded well; the SPO2 was 96%, while spontaneously breathing 100% oxygen without any sign of respiratory distress. We administered 125 mg of methylprednisolone intravenously again for postoperative management. Afterward, the trachea was extubated. Following this, 10 L/minutes of oxygen was applied via a face mask, the SPO2 was maintained above 93%, and the patient did not complain of any discomfort.\n\nOn the following day, computed tomography scans revealed right upper and lower lobe and left lower lobe consolidation (Figure 1A and B), the SPO2 was maintained above 93% with 4 L/min of oxygen applied via a face mask and the patient did not complain of dyspnea. On day 5 following the operation, the patient showed no fever or dyspnea in room air and displayed normal breathing sounds; in addition, computed tomography scans showed an improvement of the lungs (Figure 2A and B).\n\nFigure 1. A, Right Upper Consolidation and B, Right Lower Lobe and Left Lower Lobe Consolidation Immediately After General Anesthesia.\nFigure 2. A, and B, Improvement of The Lungs on Day 5 Following Surgery\n3. Discussion\nPulmonary collapse may be caused by such factors as endobronchial intubation, mucus secretion plug, and bronchospasm (1, 3, 4). The most likely cause is endobronchial intubation, but it is unlikely that the tip of the tracheal tube was beyond the carina in this case because we checked its position via a chest X-ray.\n\nBronchial secretion is known to be a cause of atelectasis, and segmental or lobar collapse results from bronchial obstruction by secretion (3). In our case, fiber optic bronchoscopy showed that a large amount of sticky mucus had been secreted, so we postulated that the sticky mucus might have caused the lobar collapse, thereby reducing the SPO2. It is possible that aspiration occurred. However, the oral cavity was clean at intubation and there were no gastric contents or foreign bodies apart from the sticky secretion shown by the bronchoscopy.\n\nUnfortunately, we did not sample and analyze the removed secretion, so the etiology of the acutely induced airway secretion is not clear. We usually employ lidocaine gel for the lubrication of tracheal tube, but in the present case, the tip and cuff of a 8.5 mm tracheal tube were lubricated with 3 mL of a topical metered-dose of 8% Lidocaine pump spray instead. The dose of 8% Lidocaine pump spray used for the lubrication of the tracheal tube might have triggered excessive mucus production. The aerosolized products used for 8% Lidocaine pump spray in Japan contain menthol and ethanol as additives (5, 6). Menthol and ethanol can irritate airway mucosa (6). For example, they can induce a sore throat. Furthermore, menthol-type cigarette smoking can cause pulmonary disease (7, 8). We thus speculate that these additives, especially menthol, might have led to excessive mucus production, although we did not analyze the mucus secretion in this case. Secretion management in the mechanically ventilated patient includes secretion removal and manual hyperinflation (9), which we think worked effectively in this case.\n\nSmokers tend to require deep general anesthesia not only for its induction but also for maintenance (10). Thus, in the present case, we have to consider the possibility that inadequate anesthetic medication might have induced not only the increased secretion but also severe bronchospasm at first, which could have precipitated atelectasis.\n\nIn conclusion, we have reported a case of severe pulmonary collapse after intubation related to general anesthesia. When sudden hypoxia occurs, the anesthesiologist should check for endotracheal tube malposition and breathing sounds. In such cases, it is helpful to conduct a chest X-ray and diagnostic bronchoscopy.\n\nThe authors would like to express their gratitude to Matthew McLaughlin for assistance as language editor.\n\nAuthors’ Contribution:Young-Chang P. Arai, Jun Kawanishi, Yoshikazu Sakakima, Koichi Ohmoto, Akihiro Ito, and Yuki Maruyama conducted the data acquisition; Tatsunori Ikemoto and Young-Chang P. Arai helped to draft the first and revised manuscripts. All authors read and approved the final manuscript.\n==== Refs\nReferences\n1 Yoo KY Kim SJ Jeong CW Jeong ST Kim YH Lee JU Recurrent attacks of post-intubation right upper lobe atelectasis. Acta Anaesthesiol Taiwan. 2009 47 4 212 5 10.1016/S1875-4597(09)60058-8 20015824 \n2 Magnusson L Spahn DR New concepts of atelectasis during general anaesthesia. Br J Anaesth. 2003 91 1 61 72 12821566 \n3 Igarashi A Amagasa S Oda S Yokoo N Pulmonary atelectasis manifested after induction of anesthesia: a contribution of sinobronchial syndrome? J Anesth. 2007 21 1 66 8 10.1007/s00540-006-0451-4 17285417 \n4 Seto K Goto H Hacker DC Arakawa K Right upper lobe atelectasis after inadvertent right main bronchial intubation. Anesth Analg. 1983 62 9 851 4 6881573 \n5 Maruyama K Sakai H Miyazawa H Toda N Iinuma Y Mochizuki N et al. Sore throat and hoarseness after total intravenous anaesthesia. Br J Anaesth. 2004 92 4 541 3 10.1093/bja/aeh098 14766717 \n6 Maruyama K Sakai H Miyazawa H Iijima K Toda N Kawahara S et al. Laryngotracheal application of lidocaine spray increases the incidence of postoperative sore throat after total intravenous anesthesia. J Anesth. 2004 18 4 237 40 10.1007/s00540-004-0264-2 15549464 \n7 Nakajima M Matsushima T Acute eosinophilic pneumonia following cigarette smoking. Intern Med. 2000 39 10 759 60 11030194 \n8 Miki K Miki M Nakamura Y Suzuki Y Okano Y Ogushi F et al. Early-phase neutrophilia in cigarette smoke-induced acute eosinophilic pneumonia. Intern Med. 2003 42 9 839 45 14518673 \n9 Branson RD Secretion management in the mechanically ventilated patient. Respir Care. 2007 52 10 1328 42 discussion 1342-7 17894902 \n10 Rodrigo C The effects of cigarette smoking on anesthesia. Anesth Prog. 2000 47 4 143 50 11432181\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2228-7523",
"issue": "6(3)",
"journal": "Anesthesiology and pain medicine",
"keywords": "8% Lidocaine Pump Spray; Endobronchial Intubation; Severe Respiratory Event",
"medline_ta": "Anesth Pain Med",
"mesh_terms": null,
"nlm_unique_id": "101585412",
"other_id": null,
"pages": "e33771",
"pmc": null,
"pmid": "27642575",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports",
"references": "15549464;17894902;14766717;11030194;11432181;14518673;17285417;6881573;12821566;20015824",
"title": "Severe Respiratory Event Initially Thought to be Inadvertent Endobronchial Intubation: Possible Complications From Using of a Topical Metered-Dose of 8% Lidocaine Pump Spray.",
"title_normalized": "severe respiratory event initially thought to be inadvertent endobronchial intubation possible complications from using of a topical metered dose of 8 lidocaine pump spray"
} | [
{
"companynumb": "JP-INTERNATIONAL MEDICATION SYSTEMS, LIMITED-1064141",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OXYGEN"
},
"druga... |
{
"abstract": "Tumor lysis syndrome (TLS) is a potential emergent complication of oncologic treatment. TLS is commonly reported in hematological malignancies with rapid cell turnover rates, but is relatively rare in solid tumors. TLS is most frequently a result of cancer treatment in combination with a large tumor burden, but has occasionally been reported to occur spontaneously, especially in cases of advanced or metastatic disease. In this article, we describe the case of a patient with newly diagnosed metastatic melanoma that developed TLS two days after initiation of corticosteroids. In addition, we present a brief literature review of melanoma-associated TLS and review the etiology, diagnosis, and management of TLS.",
"affiliations": "Department of Medical Oncology, Saint Louis University School of Medicine, 1402 S. Grand Blvd, Saint Louis, MO, 63104, USA. meeks@slu.edu.;Department of Gastroenterology and Hepatology, Saint Louis University School of Medicine, Saint Louis, MO, USA.;Department of Pathology, Saint Louis University School of Medicine, Saint Louis, MO, USA.;Department of Medical Oncology, Saint Louis University School of Medicine, 1402 S. Grand Blvd, Saint Louis, MO, 63104, USA.;Department of Medical Oncology, Saint Louis University School of Medicine, 1402 S. Grand Blvd, Saint Louis, MO, 63104, USA.",
"authors": "Meeks|Marshall W|MW|;Hammami|Muhammad B|MB|;Robbins|Katherine J|KJ|;Cheng|Kevin L|KL|;Lionberger|Jack M|JM|",
"chemical_list": "D000305:Adrenal Cortex Hormones",
"country": "United States",
"delete": false,
"doi": "10.1007/s12032-016-0854-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1357-0560",
"issue": "33(12)",
"journal": "Medical oncology (Northwood, London, England)",
"keywords": "Corticosteroids; Melanoma; Oncologic emergency; Tumor lysis syndrome",
"medline_ta": "Med Oncol",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D006801:Humans; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D015275:Tumor Lysis Syndrome",
"nlm_unique_id": "9435512",
"other_id": null,
"pages": "134",
"pmc": null,
"pmid": "27807723",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": "25891305;19570088;19646138;25002953;14984582;15384972;11908861;25167696;10091788;8274754;21561350;11209026;25834806;23673985;26161277",
"title": "Tumor lysis syndrome and metastatic melanoma.",
"title_normalized": "tumor lysis syndrome and metastatic melanoma"
} | [
{
"companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-16-03149",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
... |
{
"abstract": "In the present report, the patient was a 55-year-old woman who had undergone an oophorectomy in October 2016 as surgical intervention for ovarian cancer, followed by 6 courses of TC therapy as postoperative adjuvant therapy. She was diagnosed with recurrent ovarian cancer in August 2017, and we planned anticancer drug treatment considering that the tumor exhibited platinum resistance. However, the platelet count decreased significantly to 2.4×104/μL. Accordingly, she was referred to the hematology department and was diagnosed with idiopathic thrombocytopenic purpura. She was started on oral eltrombopag, and her platelet level recovered to 5.8×104/μL on day 68. Next, gemcitabine plus bevacizumab therapy was initiated. However, as the platelet level again decreased to 1.6×104/μL on day 8, the eltrombopag dose was increased only for 5 days before and after the anticancer drug administration on day 1. Accordingly, after increasing the eltrombopag dose, the anticancer drug treatment was performed without interruptions. Moreover, the gemcitabine dose could be increased. Herein, we report that in patients with platinum-resistant recurrent ovarian cancer complicated with idiopathic thrombocytopenic purpura, increasing the oral hematopoietic stimulant dose for 5 days before and after day 1 had beneficial results in continuing anticancer drug treatment.",
"affiliations": "Dept. of Pharmacy,Takeda Health Foundation, Takeda General Hospital.",
"authors": "Hirayama|Takushi|T|;Kin|Shogo|S|;Ohta|Masatsugu|M|;Saburo|Tsunoda|T|;Kimoto|Shinji|S|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "48(6)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000077216:Carcinoma, Ovarian Epithelial; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010051:Ovarian Neoplasms; D010976:Platelet Count; D016553:Purpura, Thrombocytopenic, Idiopathic",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "821-824",
"pmc": null,
"pmid": "34139731",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Platinum-Resistant Recurrent Ovarian Cancer with Idiopathic Thrombocytopenic Purpura.",
"title_normalized": "a case of platinum resistant recurrent ovarian cancer with idiopathic thrombocytopenic purpura"
} | [
{
"companynumb": "JP-ROCHE-2490725",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "COVID-19, caused by SARS-CoV-2, emerged in late 2019 in Wuhan, China. Its clinical course is variable, as well as the mortality rate, which is higher among people over 65 years of age and persons with underlying conditions. Immunodeficiencies are potential risk factors for severe forms of COVID-19. Furthermore, patients with immunodeficiencies often undergo non-infectious complications, which could bear additional risk. So far, few reports of patients with COVID-19 and humoral immunodeficiencies have been published. Considering the importance of the study of this new viral disease and its potential health impact on patients with immunodeficiency disorders, we present six cases of COVID-19 in patients with impaired humoral immunity. Three were women and three were men. The average age was 48.5 years (range 20-67). Four had been diagnosed with primary antibody deficiency: three had common variable immunodeficiency and one had X-linked agammaglobulinemia. The other two patients had secondary hypogammaglobulinemia, one was associated with thymoma (Good's syndrome), and the other was associated with rituximab treatment. The evolution was favorable in all except the patient with Good's syndrome, who presented a marked decline in clinical status before contracting COVID-19.",
"affiliations": "Unidad de Inmunología e Histocompatibilidad, Hospital Dr. Carlos G. Durand, Buenos Aires, Argentina. E-mail: analauralopez.ra@gmail.com.;Servicio de Alergia e Inmunología, Hospital Británico de Buenos Aires, Argentina.;Unidad de Inmunología e Histocompatibilidad, Hospital Dr. Carlos G. Durand, Buenos Aires, Argentina.;Servicio de Alergia e Inmunología, Hospital Británico de Buenos Aires, Argentina.;Unidad de Inmunología e Histocompatibilidad, Hospital Dr. Carlos G. Durand, Buenos Aires, Argentina.",
"authors": "López|Ana Laura|AL|;Torre|María Gabriela|MG|;Paolini|María Virginia|MV|;Juri|María Cecilia|MC|;Fernández Romero|Diego S|DS|",
"chemical_list": null,
"country": "Argentina",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-7680",
"issue": "81(3)",
"journal": "Medicina",
"keywords": "COVID-19; SARS-CoV-2; primary immunodeficiency ; secondary immunodeficiency",
"medline_ta": "Medicina (B Aires)",
"mesh_terms": "D000328:Adult; D000361:Agammaglobulinemia; D000368:Aged; D000086382:COVID-19; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000081207:Primary Immunodeficiency Diseases; D000086402:SARS-CoV-2; D013945:Thymoma; D013953:Thymus Neoplasms; D055815:Young Adult",
"nlm_unique_id": "0204271",
"other_id": null,
"pages": "478-481",
"pmc": null,
"pmid": "34137714",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "COVID-19 in adults with antibody deficiencies.",
"title_normalized": "covid 19 in adults with antibody deficiencies"
} | [
{
"companynumb": "AR-PFIZER INC-2021874958",
"fulfillexpeditecriteria": "1",
"occurcountry": "AR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Antiepileptic drugs are among the leading causes of drug-induced liver injury (DILI). Due to critical illness, children admitted to intensive care units are more prone to DILI.\nWe attempted to elucidate the association between antiepileptic drug use and the associated factors resulting in DILI in a pediatric intensive care unit of a tertiary care hospital.\nWe carried out an observational retrospective study on children receiving antiepileptic drugs. Details on their demographic characteristics, drugs, serum levels of antiepileptic drugs and liver function tests, and hospital stay were recorded. Council for International Organizations of Medical Sciences definitions were adhered to when defining DILI. LiverTox (https://livertox.nih.gov) and DILIrank were used to assess the risks of hepatotoxicity of the concomitant drugs. Regression models were developed for predicting DILI.\nFive out of 9 patients taking phenobarbitone (55.6%), 9 out of 12 taking phenytoin monotherapy (75%), 7 out of 10 taking phenytoin/phenobarbitone (70%), all 3 receiving phenytoin/phenobarbitone/valproate sodium, and 1 with phenytoin/carbamazepine developed DILI either in the form of hepatocellular injury or liver biochemical test abnormalities. None of the patients had cholestatic or mixed type of liver injury. All the critically ill children received at least 2 concomitant drugs with hepatotoxic potential. Concomitant category B hepatotoxic drugs and toxic drug levels were significantly associated with increased risk of DILI. Similarly, a trend was observed for less-DILI-concern concomitant drug class and toxic drug levels when the drugs were analyzed by DILIrank classification.\nA significant proportion of critically ill children taking antiepileptic drugs experience DILI. Guidelines recommending use of drugs with reduced risk of potential hepatotoxicity for various concomitant disease states in such children admitted to intensive care units receiving antiepileptic drugs are urgently needed.",
"affiliations": "Department of Pharmacology & Therapeutics, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain.;Paediatric Intensive Care Unit, Salmaniya Medical Complex, Ministry of Health, Manama, Bahrain.;Paediatric Intensive Care Unit, Salmaniya Medical Complex, Ministry of Health, Manama, Bahrain.;Paediatric Intensive Care Unit, Salmaniya Medical Complex, Ministry of Health, Manama, Bahrain.",
"authors": "Sridharan|Kannan|K|;Daylami|Amal Al|AA|;Ajjawi|Reema|R|;Ajooz|Husain A M Al|HAMA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.curtheres.2020.100580",
"fulltext": "\n==== Front\nCurr Ther Res Clin Exp\nCurr Ther Res Clin Exp\nCurrent Therapeutic Research, Clinical and Experimental\n0011-393X 1879-0313 Elsevier \n\nS0011-393X(20)30006-0\n10.1016/j.curtheres.2020.100580\n100580\nOriginal Research\nDrug-Induced Liver Injury in Critically Ill Children Taking Antiepileptic Drugs: A Retrospective Study\nSridharan Kannan MD, DMskannandr@gmail.com1⁎ Daylami Amal Al MRCP2 Ajjawi Reema MD2 Ajooz Husain A.M. Al MD2 1 Department of Pharmacology & Therapeutics, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain\n2 Paediatric Intensive Care Unit, Salmaniya Medical Complex, Ministry of Health, Manama, Bahrain\n⁎ Address correspondence to: Kannan Sridharan, MD, DM, Department of Pharmacology & Therapeutics, College of Medicine & Medical Sciences, Arabian Gulf University, Manama, Bahrain. skannandr@gmail.com\n09 3 2020 \n2020 \n09 3 2020 \n92 10058026 11 2019 2 3 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Critically ill children on anti-epileptic drugs often receive multiple concomitant drugs with potential to result in liver injury.\n\n• Antimicrobial drugs followed by drugs for stress ulcer prophylaxis form the major drug classes with the risk of DILI that are concomitantly administered with anti-epileptic drugs in critically ill children.\n\n\n\nBackground\nAntiepileptic drugs are among the leading causes of drug-induced liver injury (DILI). Due to critical illness, children admitted to intensive care units are more prone to DILI.\n\nObjective\nWe attempted to elucidate the association between antiepileptic drug use and the associated factors resulting in DILI in a pediatric intensive care unit of a tertiary care hospital.\n\nMethods\nWe carried out an observational retrospective study on children receiving antiepileptic drugs. Details on their demographic characteristics, drugs, serum levels of antiepileptic drugs and liver function tests, and hospital stay were recorded. Council for International Organizations of Medical Sciences definitions were adhered to when defining DILI. LiverTox (https://livertox.nih.gov) and DILIrank were used to assess the risks of hepatotoxicity of the concomitant drugs. Regression models were developed for predicting DILI.\n\nResults\nFive out of 9 patients taking phenobarbitone (55.6%), 9 out of 12 taking phenytoin monotherapy (75%), 7 out of 10 taking phenytoin/phenobarbitone (70%), all 3 receiving phenytoin/phenobarbitone/valproate sodium, and 1 with phenytoin/carbamazepine developed DILI either in the form of hepatocellular injury or liver biochemical test abnormalities. None of the patients had cholestatic or mixed type of liver injury. All the critically ill children received at least 2 concomitant drugs with hepatotoxic potential. Concomitant category B hepatotoxic drugs and toxic drug levels were significantly associated with increased risk of DILI. Similarly, a trend was observed for less-DILI-concern concomitant drug class and toxic drug levels when the drugs were analyzed by DILIrank classification.\n\nConclusions\nA significant proportion of critically ill children taking antiepileptic drugs experience DILI. Guidelines recommending use of drugs with reduced risk of potential hepatotoxicity for various concomitant disease states in such children admitted to intensive care units receiving antiepileptic drugs are urgently needed.\n\nKeywords\nCarbamazepineDrug-induced liver injuryPhenobarbitonePhenytoinValproate\n==== Body\nIntroduction\nAntiepileptic and anticonvulsant agents are among the commonly used drug classes in intensive care units (ICUs). Antiepileptic drugs (AEDs) are also initiated in ICUs as prophylactic drugs in patients with traumatic brain injury, meningitis, and brain neoplasms.1 Febrile convulsions is a unique indication in children to receive anticonvulsant drugs in pediatric ICUs (PICUs).2 One-tenth of critically ill children were initiated AEDs acutely in ICU settings due to epileptic seizures.3 Almost 53% treated for a seizure attack were reported to have recurrent seizures in a PICU.4\n\nDrug-induced liver injury (DILI) is defined as the xenobiotic-induced hepatic injury resulting in alteration of liver enzymes in the absence of other known causes.5 The majority of antiepileptic agents get metabolized in the liver and form a leading cause of DILI worldwide.6,7 DILI can range between asymptomatic elevations of liver enzymes and hepatic failure.9 Although hepatotoxicity is a common adverse event amongst the conventional AEDs, valproate has more hepatotoxicity than carbamazepine that has more than phenytoin.10 Children are particularly more susceptible to idiosyncratic hepatotoxicity than adults.11 Particularly, children younger than age 2 years are vulnerable to developing DILI following sodium valproate.8 Patients admitted in ICUs are more likely to be observed with abnormal liver enzymes due to several reasons such as acute hepatitis, acute liver failure, and secondary sclerosing cholangitis that are unrelated to antiepileptic agents but rather to their critical illnesses.12 Critically ill patients often have hypoxic, toxic, and inflammatory insults to the hepatocytes that can increase the risk of hepatotoxicity.13 LiverTox (https://livertox.nih.gov) is a database conceptualized by the National Library of Medicine, National Institute of Diabetes and Digestive and Kidney Diseases and the Drug-Induced Liver Injury Network study group to provide evidence-based up-to-date details on DILI for practising clinicians and researchers working on this field.14 Based on the cumulative evidence available for drug-induced hepatotoxicity, LiverTox has classified drugs into categories A, B, C, D, and T.15 Categories A and B have substantial case reports with adequate strength of associating the implicated drugs with liver injury. DILIrank is the largest reference rank dataset on drugs causing DILI, developed by the Food and Drug Administration (FDA) in the year 2016.16 DILIrank classifies 1036 FDA-approved drugs into most-, less-, no-, and ambiguous-DILI-concern drugs. It is vital to understand the hepatotoxic potentials of concomitant drugs administered in ICU setup, particularly in critically ill children receiving categories A and B drugs according to LiverTox or most/less-DILI concerns as per DILIrank classification. We envisaged the present study to assess the changes in liver function tests associated with primary antiepileptic agents belonging to the above categories and the associated factors for DILI in these critically ill children.\n\nMethods\nStudy ethics and population\nThis study was carried out as a retrospective observational study after obtaining approval from our institution's ethics committees. Children admitted into the PICU between January 1, 2016, until December 31, 2018, were included in the study if they were administered any of the antiepileptic or anticonvulsant drugs with at least 1 assessment of serum liver enzyme levels and measurement of serum level of the concerned drug was carried out. Those children diagnosed without any primary liver disorders were included in this study.\n\nStudy procedure\nHospital records of eligible children were examined for the following details: demographic characteristics (eg, age and gender); diagnoses; laboratory investigations (eg, liver enzymes that included serum aspartate amino transferase [AST], alanine amino transferase [ALT], alkaline phosphatase [ALP], and gamma glutamyl transferase [GGT]); drug-related details (eg, dose, frequency, and duration); hospital stay; and outcome status (eg, dead or alive).\n\nDefinitions and classifications used\nDILI has been classified according to the revised criteria by Council for International Organizations of Medical Sciences as follows: hepatocellular injury, ALT ≥2 upper limit of normal (ULN) reference range (RR) and R ≥5; cholestatic injury, ALP ≥2 ULN and R ≤2; mixed injury, ALT ≥3 ULN, ALP ≥2 ULN, and 2<R>5. If ALT and ALP did not meet any of these criteria, it was called liver biochemical test abnormalities.17 The value of R was calculated using the formula (actual ALT/ALT ULN) / (actual ALP/ALP ULN). Our laboratory provides age-specific reference ranges for liver function tests and these values were considered for assessing DILI.\n\nLiverTox classifies the drugs based on the number of published cases with clear association with DILI into category A (≥50 cases); category B (12–49 cases); category C (4–11 cases); category D (1–3 cases), and category E (none). Those drugs that cause DILI only at higher than the recommended doses are categorized as T. Similarly, DILIrank classifies the drugs based on the reported concerns and severity of DILI. Table 1 lists the antiepileptic drugs based on the LiverTox and DILIrank categories. We classified ages of children per FDA classification into the following groups: neonate (birth–1 month), infant (1 month–2 years), children (2–12 years), and adolescents (12–16 years).15Table 1 List of antiepileptic drugs with their potential, degree, and concerns of hepatotoxicity as classified by drug-induced liver toxicity (DILI)rank and LiverTox*.\n\nTable 1Antiepileptic drug\tLiverTox category\tDILIrank classification\t\nRisk of DILI concern\tSeverity class\t\nCarbamazepine\tA\tMost\t7\t\nClonazepam\tD\tLess\t3\t\nDiazepam\tE\tAmbiguous\t4\t\nDivalproex sodium\tNot classified\tMost\t8\t\nEthosuximide\tE\tAmbiguous\t3\t\nFelbamate\tB\tMost\t7\t\nFosphenytoin\tA\tMost\t8\t\nGabapentin\tC\tLess\t3\t\nLacosamide\tNot classified\tAmbiguous\t3\t\nLamotrigine\tB\tMost\t7\t\nLevetiracetam\tC\tLess\t8\t\nLorazepam\tNot classified\tAmbiguous\t3\t\nMidazolam\tNot classified\tNo\t0\t\nOxcarbazepine\tD\tLess\t3\t\nPhenobarbitone\tB\tLess\t3\t\nPhenytoin\tA\tMost\t8\t\nPregabalin\tC\tLess\t0\t\nPrimidone\tNot classified\tNo\t0\t\nTiagabine\tNot classified\tAmbiguous\t3\t\nTopiramate\tC\tLess\t3\t\nValproate sodium\tA\tMost\t8\t\nVigabatrin\tNot classified\tAmbiguous\t2\t\nZonisamide\tD\tLess\t2\t\n⁎ LiverTox (https://livertox.nih.gov), a database conceptualized by the National Library of Medicine, National Institute of Diabetes and Digestive and Kidney Diseases and the Drug-Induced Liver Injury Network study group.\n\n\n\nStatistical analysis\nDescriptive statistics was used for representing demographic characteristics. The χ2 test for independence and Fisher exact probability test were used for the assessment of categorical variables wherever appropriate. Concomitant drugs with potential hepatotoxicity were classified as per LiverTox classification and DILIrank, and were assessed as categorical outcomes. Multivariable logistic regression analysis was used to assess the significance of association between the predictor variables (ie, age group, sex, antiepileptic drug, and number of LiverTox categories A and B drugs) in causing DILI. Only A and B of LiverTox categories were considered because other categories have limited evidence for their association with DILI. A similar regression analysis was carried out for DILIrank categories with the same predictor variables, and only the most- and less-DILI-concern concomitant drugs were included. The effect measures of variables in predicting DILI were expressed as odds ratio (95% CI)]. A P value ≤0.05 was considered significant. SPSS version 26 (IBM SPSS Statistics for Windows, Armonk, NY) was used for performing statistical tests.\n\nResults\nDemographic details\nForty-one patients were identified receiving drugs for seizure disorder out of the total 426 during the study period. Mean (SD) age was 3.9 years (3.8 years); body weight was 15.1 kg (13 kg); and male:female ratio was 26:15. Six had refractory status epilepticus; 5 had septic encephalopathy; 4 each had traumatic brain injury and cerebral palsy; 3 each had hydrocephalus with ventriculo-peritoneal shunt, encephalitis, and congenital heart disease; 2 each were diagnosed with hypoxic ischemic encephalopathy and metabolic disorder; and 1 each had astrocytoma with metastasis, glioblastoma, Treacher syndrome, DiGeorge syndrome, Down syndrome, hemophilia, chronic kidney disease on peritoneal dialysis, leukodystrophy, and metabolic disorder. Mean (SD) hospital stay of the study participants was 12.2 days (9.8 days).\n\nAntiepileptic drug-related details\nEleven patients received phenytoin; 9 received phenobarbitone; 3 were administered valproate sodium; 10 children were administered phenytoin/phenobarbitone; 3 were given phenytoin/phenobarbitone/valproate sodium; and 1 each received phenytoin/valproate sodium, phenobarbitone/valproate and ethosuximide/valproate sodium, phenytoin/carbamazepine, and valproate sodium alone. Newer antiepileptic agents were administered with the aforementioned conventional antiepileptic drugs as follows: levetiracetam (n = 4 with phenytoin and n = 1 each with valproate sodium and phenytoin/phenobarbitone/valproate sodium), topiramate (n = 1 with phenobarbitone), vigabatrin (n = 1 with phenytoin/phenobarbitone), oxcarbazepine/levetiracetam (n = 1 each with phenytoin and phenytoin/phenobarbitone/valproate sodium), and topiramate/lamotrigine (n = 1 with phenobarbitone). A summary of the dose, route, frequency, and duration of the category A and B antiepileptic agents (phenytoin, phenobarbitone, valproate, and carbamazepine) along with the concomitant antiepileptic drugs for the various age groups are described in Table 2.Table 2 Regimen of the categories A/B line antiepileptic agents with concomitant antiepileptic drugs used in the study participants.\n\nTable 2Drugs (n)\tAge group (n)\tMean dose/kg (mg)\tRoute of administration, IV:PO (n)\tMean cumulative dose (mg)\tConcomitant antiepileptic agent (n)\t\nPhenobarbitone (9)\t0–1 mo (3)\t3.28\t2:1\t115\tNA\t\n1 mo–2 y (3)\t2.8\t3:0\t455\tNA\t\n2–12 years (3)\t2.3\t0:3\t586.7\tTopiramate (2); lamotrigine (1)\t\nPhenytoin (12)\t0–1 mo (1)\t2.5\t1:0\t300\tNA\t\n1 mo–2 y (3)\t3.01\t3:0\t750\tLevetiracetam (2); oxcarbazepine (1)\t\n2–12 y (8)\t3.88\t6:2\t1263.9\tLevetiracetam (3)\t\nValproate (2)\t2–12 y (2)\t22.53\t0:2\t6800\tLevetiracetam (1)\t\nPhenytoin/phenobarbitone (10)\t0–1 mo (1)\t2.4/2.4\t0:1\t120/120\tNA\t\n1 mo–2 y (8)\t2.5/2.5\t4:4\t206/428.6\tNA\t\n2–12 y (1)\t2.7/3.1\t1:0\t1780/1610\tVigabatrin (1)\t\nPhenytoin/phenobarbitone/valproate sodium (3)\t2–12 y (3)\t1.8/4.5/7.2\t3:0\t882.5/2360/9513\tLevetiracetam (2); oxcarbazepine (1)\t\nphenobarbitone/Valproate sodium (1)\t2–12 y (1)\t8.7/8.7\t0:1\t250/3000\tNA\t\nPhenytoin/valproate sodium (2)\t2–12 y (2)\t1.6/6.5\t2:0\t500/2200\tLevetiracetam (1)\t\nCarbamazepine/phenytoin (1)\t2 y\t17/10\t0:1\t2660/1680\tNA\t\nValproate/ethosuximide (1)\t2–12 y (1)\t63/39\t0:1\t22,800/10,500\tLevetiracetam (1)\t\nIV = intravenous; NA = no additional; PO; by mouth.\n\n\n\nSerum levels of the antiepileptic drugs\nMean (SD) phenytoin levels amongst the study participants was 56.4 µmol/L (46.6 µmol/L) (RR = 40–80 µmol/L). Eight samples of phenytoin were observed in the toxicity range with the mean (SD) percent difference from the ULN of 37.9% (15.8%). Mean (SD) phenobarbitone serum levels was 149.9 µmol/L (71.2 µmol/L) (RR = 65–172 µmol/L). Similar to phenytoin, 8 samples were in the toxicity range with the mean (SD) percent difference from the ULN being 28.6% (23%). Mean (SD) valproate sodium level was 259.2 µmol/L (174.3 µmol/L) (RR = 350–700 µmol/L) and none were observed to be in the toxicity range.\n\nChanges in the liver enzymes\nLiver functions were checked on daily basis for all the patients on antiepileptic drugs. None of the children had either cholestatic or mixed type of hepatic injury. Similarly, no altered liver functions were observed in patients either receiving valproate alone or in combination with phenytoin, ethosuximide, or phenobarbitone. No significant differences (P = 0.1) were observed in the proportions of patients with hepatocellular injury or liver biochemical test abnormalities between the other antiepileptic drugs (Figure 1). Similarly, none of the patients taking valproate alone or in combination with phenytoin, phenobarbitone, or ethosuximide and phenytoin/carbamazepine showed elevation of GGT, whereas 6 out of 12 (50%) taking phenytoin, 7 out of 9 (77.8%) taking phenobarbitone, 8 out of 10 (80%) taking phenytoin/phenobarbitone, and all the patients who received phenytoin/phenobarbitone/valproate sodium showed such elevations. No statistically significant differences were observed in the aforementioned proportions showing GGT elevations (P = 0.2).Figure 1 Hepatocellular injury and liver biochemical test abnormalities among the study participants. No significant differences were observed in the proportion of patients with any of the types of liver injury between the antiepileptic drugs.\n\nFigure 1\n\nConcomitant drugs with hepatotoxic potential\nSeveral drugs with potential to result in hepatotoxicity were administered concomitantly with antiepileptic drugs (Table 3). Irrespective of age group, there were minimum of 2 and maximum of 15 such drugs in the study population. Due to the number of constraints, statistical analyses for the differences in LiverTox categories were carried out only for phenytoin, phenobarbitone, and phenytoin/phenobarbitone groups; and no significant differences (P values = 0.3, 0.7, and 0.6, respectively) were observed. Assessment of hepatotoxicity potential for the concomitant drug with DILIrank lead to a similar observation as summarized in Table 3. Nearly half of the concomitant drugs with hepatotoxic potential were antimicrobial drugs followed by drugs for stress ulcer prophylaxis (Table 4). However, we also observed certain differences between the LiverTox and DILIrank classifications for certain drugs (Table 5).Table 3 Potential hepatotoxic drugs administered with categories A/B antiepileptic drugs.\n\nTable 3Category A/B antiepileptic drug\tAge group\tConcomitant hepatotoxic drugs\tCategory A/B*\tAntiepileptic drug (n)†\tAge group (n)‡\t\nPhenobarbitone (9)\t0-1 mo (3)\tAmpicillin (C)-2; ranitidine (B)-2; cefotaxime (D)-1; ceftazidime (D)-1; acetazolamide (D)-1; omeprazole (B)-1; cefuroxime (D)-1; ceftriaxone (B)-1; ketamine (B)-1; enoxaparin (D)-1; vancomycin (C)-1; paracetamol (T)-1; meropenem (D)-1\tB-5; C-3; D-6; T-1\tMC,8-1; LC,5-4; LC,4-2; LC,3-5; LC,0-2\t3 (2–6)\t\n1 mo–2 y (3)\tAmpicillin (C)-1; cefotaxime (D)-1; acyclovir (D)-2; vancomycin (C)-2; omeprazole (B)-2; ceftriaxone (B)-1; metronidazole (C)-2; paracetamol (T)-2; amoxicillin-clavulanate (A)-1; meropenem (D)-1\tA-1; B-3; C-5; D-3; T-2\tLC,5-2; LC,4-3; LC,3-4; LC,0-1\t4 (4–5)\t\n2–12 y (3)\tParacetamol (T)-2; amoxicillin-clavulanate (A)-1; lamotrigine (B)-1; topiramate (C)-2; ceftazidime (D)-1; omeprazole (B)-1; clonazepam (D)-1; ranitidine (B)-2; cefotaxime (D)-2; clindamycin (B)-1; cefepime (D)-1; fluconazole (B)-1\tA-1; B-6; C-2; D-5; T-2\tMC,8-1; MC,7-1; LC,5-5; LC,4-1; LC,3-6;\t3 (3–9)\t\nPhenytoin (12)\t0–1 mo (1)\tAmiodarone (A)-1; paracetamol (T)-1; meropenem (D)-1; omeprazole (B)-1; enoxaparin (D)-1; ampicillin (C)-1; cefotaxime (D)-1\tA-1; B-1; C-1; D-3; T-1\tMC,8-1; LC,5-1; LC,4-1; LC,3-3\t6\t\n1 mo–2 y (3)\tParacetamol (T)-3; mebendazole (D)-1; ketamine (B)-1; ranitidine (B)-1; vancomycin (C)-1; fluconazole (B)-1; metronidazole (C)-1; levetiracetam (C)-1; ceftriaxone (B)-3; omeprazole (B)-3; enoxaparin (D)-1; cimetidine (B)-1; baclofen (D)-1; nifedipine (B)-1; ciprofloxacin (B)-1; meropenem (D)-1\tB-12; C-3; D-4; T-3\tMC,8-2; LC,8-1; LC,5-1; LC,4-6; LC,3-6; LC,2-1; LC,0-2\t7 (3–8)\t\n2–12 y (8)\tParacetamol (T)-5; hydroxyurea (C)-1; omeprazole (B)-5; meropenem (D)-5; amoxicillin (B)-1; fluconazole (B)-2; clindamycin (B)-3; levetiracetam (C)-3; ceftriaxone (B)-2; vancomycin (C)-3; acyclovir (D)-1; ranitidine (B)-1; ketamine (B)-1; cefotaxime (D)-2; ondansetron (D)-2; captopril (B)-2; nifedipine (D)-2; acetazolamide (D)-1; cefepime (D)-1; amlodipine (C)-1; labetalol (C)-2; risperidone (C)-1; atenolol (D)-1; trimethoprim-sulfamethoxazole (A)-1; voriconazole (B)-1; etoposide (C)-1; metronidazole (C)-1; ceftazidime (D)-1\tA-1; B-18; C-13; D-9; T-5\tMC,8-6; LC,8-3; LC,7-4; LC,5-4; LC,4-9; LC,3-14; LC,0-4\t4 (3–15)\t\nValproate sodium (2)\t2–12 y (2)\tOmeprazole (B)-2; vancomycin (C)-1; paracetamol (T)-1; levetiracetam (C)-1; ceftriaxone (B)-1; clindamycin (B)-1\tB-4; C-2; T-1\tLC,8-1; LC,4-4; LC,0-1\t3\t\nPhenytoin/phenobarbitone (10)\t0–1 mo (1)\tAmpicillin (C)-1; meropenem (D)-1; omeprazole (B)-1\tB-1; C-1; D-1\tLC,3-2; LC,4-1\t4\t\n1 mo–2 y (8)\tIbuprofen (A)-1; ranitidine (B)-5; atenolol (B)-2; acetazolamide (D)-1; ampicillin (C)-3; ceftazidime (D)-1; meropenem (D)-3; vancomycin (C)-4; paracetamol (T)-2; ceftriaxone (B)-4; acyclovir (D)-2; hydralazine (A)-3; labetalol (C)-2; nifedipine (B)-2; captopril (B)-1; omeprazole (B)-3; cefuroxime (D)-1; labetalol (B)-1; amiodarone (A)-1; ketamine (B)-1; HCTZ (D)-1; cefotaxime (D)-1\tA-5; B-19; C-9; D-10; T-2\tMC,8-6; LC,7-1; LC,5-7; LC,4-9; LC,3-12; LC,2-1; LC,0-5\t6 (3-9)\t\n2–12 y (1)\tClonazepam (D)-1; acetazolamide (D)-1; paracetamol (T)-1; vancomycin (C)-1; fluconazole (B)-1; cefepime (D)-1; omeprazole (B)-1; ciprofloxacin (B)-1; meropenem (D)-1; sildenafil (D)-1; ceftazidime (D)-1\tB-3; C-1; D-6; T-1\tMC,8-2; MC,7-1; LC,3-5; LC,4-1; LC,0-1\t9\t\nPhenytoin/phenobarbitone/valproate (3)\t2–12 y (3)\tMeropenem (D)-2; vancomycin (C)-2; levetiracetam (C)-2; omeprazole (B)-2; ketamine (B)-1; ceftazidime (D)-1; fluconazole (B)-1; nifedipine (B)-1; ranitidine (B)-1; cefepime (D)-1; captopril (B)-1; paracetamol (T)-1; aspirin (T)-1; ceftriaxone (B)-1; acyclovir (D)-1\tB-8; C-4; D-3; T-2\tMC,8-1; LC,8-2; LC,7-1; LC,5-1; LC,3-5; LC,0-3\t7 (6–11)\t\nPhenobarbitone/valproate (1)\t2–12 y (1)\tKetamine (B)-1; labetalol (C)-1; hydralazine (B)-1; ceftriaxone (B)-1; paracetamol (T)-1; acyclovir (D)-1; atenolol (D)-1; amlodipine (C)-1; captopril (D)-1; enalapril (D)-1\tB-3; C-2; D-4; T-1\tMC,8-1; LC,7-2; LC,5-1; LC,4-2; LC,3-1; LC0-1\t8\t\nPhenytoin/valproate sodium (2)\t2–12 y (2)\tAmoxicillin-calvulanate (A)-1; acyclovir (D)-1; ranitidine (B)-2; paracetamol (T)-2; levetiracetam (C)-1; cefotaxime (D)-1\tA-1; B-2; C-1; D-2; T-2\tLC,8-1; LC,5-4\t4.5 (4–5)\t\nCarbamazepine/phenytoin (1)\t2 y\tOmeprazole (B)-1; ceftriaxone (B)-1; clindamycin (B)-1; paracetamol (T)-1; ibuprofen (A)-1; ceftazidime (D)-1; clonazepam (D)-1; ondansetron (D)-1\tA-1; B-3; D-2; T-1\tLC,7-1; LC,4-2; LC,3-4\t8\t\nValproate/ethosuximide (1)\t2–12 y (1)\tClonazepam (D)-1; omeprazole (B)-1; vancomycin (C)-1; clindamycin (B)-1; cefotaxime (D)-1; levetiracetam (C)-1; fluconazole (B)-1\tB-3; C-2; D-2\tMC,8-1; LC,8-1; LC,5-1; LC,4-1; LC,3-2; LC,0-1\t7\t\nDILI = drug-induced liver injury; HCTZ = hydrochlorothiazide; MC = most-DILI concern; LC = less-DILI concern.\n\n⁎ LiverTox (https://livertox.nih.gov), a database conceptualized by the National Library of Medicine, National Institute of Diabetes and Digestive and Kidney Diseases and the Drug-Induced Liver Injury Network study group.\n\n† Severity class classified between 0 and 8 according to Food and Drug Administration.\n\n‡ Excluded the category T because this class of drug is likely to result in DILI only at high doses.\n\nTable 4 Total number of concomitant drugs with potential hepatotoxicity amongst the study cohort.\n\nTable 4Drug class (%)\tDrug\tLiverTox* category\tDILIrank concern; severity class\tNo. of children† (%)\t\nAntimicrobials (56.1)\tAcyclovir\tD\tNot classified\t8 (4.4)\t\nAmoxicillin-clavulanate\tA\tNot classified\t3 (1.7)\t\nAmpicillin\tC\tLC; 3\t8 (4.4)\t\nCefepime\tD\tLC; 3\t4 (2.2)\t\nCefotaxime\tD\tLC; 5\t10 (5.6)\t\nCeftazidime\tD\tLC; 3\t7 (3.9)\t\nCeftriaxone\tB\tLC; 4\t15 (8.3)\t\nClindamycin\tB\tLC; 3\t7 (3.9)\t\nFluconazole\tB\tMC; 8\t7 (3.9)\t\nMeropenem\tD\tLC; 3\t9 (5)\t\nMetronidazole\tC\tLC; 3\t7 (3.9)\t\nVancomycin\tC\tLC; 0\t16 (8.9)\t\nDrugs for SUP (21.1)\tOmeprazole\tB\tLC; 4\t24 (13.3)\t\nRanitidine\tB\tLC; 5\t14 (7.8)\t\nCardiovascular drugs (17.8)\tAtenolol\tD\tLC; 4\t4 (2.2)\t\nCaptopril\tB\tLC; 7\t5 (2.8)\t\nEnoxaparin\tD\tLC; 3\t3 (1.7)\t\nHydralazine\tB\tLC; 3\t4 (2.2)\t\nLabetalol\tC\tMC; 8\t6 (3.3)\t\nNifedipine\tB\tLC; 3\t6 (3.3)\t\nOthers (5)\tAcetazolamide\tD\tMC; 8\t4 (2.2)\t\nKetamine\tB\tLC; 0\t6 (3.3)\t\nOndansetron\tD\tLC; 7\t3 (1.7)\t\nDILI = drug-induced liver injury; LC = Less-DILI concern; MC = Most-DILI concern; SUP = stress ulcer prophylaxis.\n\n⁎ LiverTox (https://livertox.nih.gov), a database conceptualized by the National Library of Medicine, National Institute of Diabetes and Digestive and Kidney Diseases and the Drug-Induced Liver Injury Network study group.\n\n† Total number may exceed the total sample included because each child received multiple drugs.\n\nTable 5 Discrepancies between the LiverTox* and drug-induced liver injury (DILI) rank classifications in classifying certain concomitant drugs in the study participants.\n\nTable 5Drug\tLiverTox category\tDILIrank classification\t\nDILI concern\tSeverity class\t\nAcetazolamide\tD\tMost\t8\t\nAcyclovir\tD\tNot mentioned\t\nAmoxicillin-clavulanate\tA\tOnly amoxicillin has been categorized as less-DILI concern and the severity class is 5. There is no mention for amoxicillin-clavulanate\t\nDivalproex sodium\tNot categorized\tMost\t8\t\nHydralazine\tA\tLess\t3\t\nLabetalol\tC\tMost\t8\t\nTrimethoprim-sulfamethoxazole\tA\tOnly trimethoprim has been categorized as less-DILI concern with the severity class 4. There is no mention for trimethoprim-sulfamethoxazole\t\n⁎ LiverTox (https://livertox.nih.gov), a database conceptualized by the National Library of Medicine, National Institute of Diabetes and Digestive and Kidney Diseases and the Drug-Induced Liver Injury Network study group.\n\n\n\nMultivariable logistic regression analysis\nA multivariable logistic regression model was developed for predicting the risk of hepatocellular injury or liver biochemical test abnormalities compared with children with normal liver enzymes (Table 6). Presence of concomitant category B hepatotoxic drugs (odds ratio = 2; 95% CI, 1–3.3) and toxic drug levels (odds ratio = 10; 95% CI, 1.4–1000) were associated with increased risks of DILI. A similar regression model for DILIrank categories was developed and none of the evaluated factors were observed to be statistically significant (Table 7) although a trend was noted for the number of less-DILI-concern concomitant drugs (P = 0.06) and toxic drug levels (P = 0.09).Table 6 Summary results of multivariable logistic regression analysis for the factors predicting the risk of hepatocellular injury and liver biochemical abnormalities with LiverTox* categories of antiepileptic drugs.\n\nTable 6Predictive factors\tHepatocellular injury/LBA†\t\nCategory A concomitant hepatotoxic drugs\t0.5 [0.2–1.3]; 0.1\t\nCategory B concomitant hepatotoxic drugs\t2 [1–3.3]; 0.05‡\t\nAge group: 0-1 mo§\t5 [0.5–50]; 0.2\t\nAge group: 1 mo–2 y§\t2.5 [0.6–10]; 0.2\t\nMale sex||\t0.4 [0.1–1.7]; 0.2\t\nCategory B antiepileptic drugs¶\t0.5 [0.1–3.3]; 0.5\t\nCategory A/B antiepileptic drugs¶\t2 [0.2–10]; 0.5\t\n2 category A antiepileptic drugs¶\tND\t\n2 category A/B antiepileptic drugs¶\t0.2 [0.01–20]; 0.3\t\nDrug level in the toxic range#\t10 [1.4–1000]; 0.03‡\t\nLBA = liver biochemical test abnormalities; ND = not determined.\n\n⁎ LiverTox (https://livertox.nih.gov), a database conceptualized by the National Library of Medicine, National Institute of Diabetes and Digestive and Kidney Diseases and the Drug-Induced Liver Injury Network study group.\n\n† Values are presented as odds ratio [95% CI]; P value.\n\n‡ Statistically significant.\n\n§ In reference to age group 2–12 y.\n\n|| In reference to female sex.\n\n¶ In reference to category A monotherapy.\n\n# In reference to drug levels in the normal range.\n\nTable 7 Summary results of multivariable logistic regression analysis for the factors predicting the risk of hepatocellular injury and liver biochemical abnormalities with drug-induced liver injury (DILI) rank classification of antiepileptic drugs.\n\nTable 7Predictive factor\tHepatocellular injury/LBA*\t\nMost-DILI-concern concomitant hepatotoxic drugs\t0.7 [0.3–1.7]; 0.5\t\nLess-DILI-concern concomitant hepatotoxic drugs\t1.3 [1–1.7]; 0.06\t\nAge group 0–1 mo†\t3.3 [0.4–50]; 0.2\t\nAge group of 1 mo–2 y†\t2 [0.4–10]; 0.4\t\nMale sex‡\t0.4 [0.1–1.7]; 0.2\t\nAmbiguous/Most-DILI-concern antiepileptic drugs§\tND\t\n2 most/less-DILI-concern antiepileptic drugs§\t0.1 [0.005–3.3]; 0.2\t\nMost/less-DILI-concern antiepileptic drugs§\t0.8 [0.1–5]; 0.8\t\n2 most-DILI-concern antiepileptic drugs§\tND\t\nLess-DILI-concern antiepileptic drugs§\t0.2 [0.04–1.4]; 0.1\t\nDrug level in the toxic range||\t5 [0.7–50]; 0.09\t\nLBA = liver biochemical test abnormalities; ND = not determined.\n\n⁎ Values are presented as odds ratio [95% CI]; P value.\n\n† In reference to age group 2–12 years.\n\n‡ In reference to female sex.\n\n§ In reference to most-DILI-concern antiepileptic monotherapy.\n\n|| In reference to those drug levels in the normal range.\n\n\n\nDiscussion\nWe carried out the present study to assess the incidence and the associated factors for DILI in critically ill children receiving antiepileptic drugs. Five out of 9 patients taking phenobarbitone (55.6%), 9 out of 12 taking phenytoin monotherapy (75%), 7 out of 10 taking phenytoin/phenobarbitone (70%), all 3 receiving phenytoin/phenobarbitone/valproate sodium, and 1 with phenytoin/carbamazepine developed DILI either in the form of hepatocellular injury or liver biochemical test abnormalities. None of the patients had cholestatic or mixed type of liver injuries. Similar number of patients receiving each of the above antiepileptic drug/s also showed elevations of GGT. Minimum 2 drugs with hepatotoxic potential were identified concomitantly with antiepileptic agents. Concomitant category B hepatotoxic drugs and toxic drug levels were associated with significantly increased risks of DILI with antiepileptic drugs. Similarly, a trend was observed for the less-DILI-concern concomitant class of drugs and toxic drug levels per DILIrank classification. Differences might exist between the DILIrank and LiverTox classifications of drugs that needs further exploration.\n\nSepsis and respiratory infections are the most common causes for admissions and consequent mortality in PICUs.16,17 Antimicrobial agents such as third-generation cephalosporins (eg, cefotaxime, ceftriaxone, and ceftazidime), aminopenicillins, aminoglycosides, meropenem, and vancomycin are commonly used in critically ill children in ICUs.18,19 We observed similar antimicrobial agents used in our study participants. With the exception of aminoglycosides, all other groups of antimicrobial drugs have been documented with DILI.15 Surprisingly, antimicrobial agents constitute the major class of drugs causing DILI as well as chronic liver damage according to registry studies.20 Antiepileptic drug classes are the second leading group of implicated in causing DILI.21 Hence, the risk of DILI is certainly higher when such drug combinations are used out of necessity in PICUs. In the present study, we observed that all critically ill children received at least 1 antimicrobial drug with hepatotoxic potential. Similarly, drugs used for stress ulcer prophylaxis (SUP) such as ranitidine and omeprazole are also potentially hepatotoxic and should better be avoided at least when a most-DILI-concern as per DILIrank or category A LiverTox antiepileptic drug is administered to critically ill children. A recent network meta-analysis refuted any therapeutic benefits with all the drug classes that are used for SUP in critically ill adults, but there is dearth of evidence in pediatric populations.22 Sucralfate is as efficacious as proton pump inhibitors and histamine-2 receptor blockers for SUP at least in reducing the overt upper gastrointestinal bleeding.22 Sucralfate is a no-DILI-concern drug according to DILIrank classification and so shall be considered as a safe alternative to other drugs for SUP in critically ill children receiving antiepileptic drugs with greater risks of hepatotoxicity. With regard to the antimicrobial drugs, the choice is limited owing to the development of widespread resistance. On the other hand, most of the recent antiepileptic agents such as levetiracetam, lamotrigine, lacosamide, oxcarbazepine, pregabalin, gabapentin, and vigabatrin are associated with lower risks of DILI, and on considering the framework of similar efficacy to conventional antiepileptic drugs, should be preferred over the first-line antiepileptic drugs in children admitted into ICUs receiving concomitant drugs with hepatotoxic potential. Levetiracetam and lacosamide are also available intravenously and can be alternatives in status epilepticus.23 A systematic review estimated that the efficacy of levetiracetam as an alternative to phenytoin in status epilepticus ranges between 44% and 94%.24 A recent randomized clinical trial in children concluded that levetiracetam is equivalent to phenytoin in status epilepticus.25 Hence, such drugs shall be preferred over the conventional antiepileptic agents in children at high-risk for DILI.\n\nDILI from antiepileptic drugs can be either idiosyncratic or dose-related.26 Idiosyncratic reactions are more common with the aromatic ring containing antiepileptic agents such as carbamazepine, phenytoin, and phenobarbitone and valproate.27 We observed a greater risk of DILI with the antiepileptic drug levels in the toxicity range. Dose-DILI effect relationship has been well elucidated based on the quantum of metabolites especially for valproate sodium.28 Polymorphisms in certain metabolizing enzymes were identified to be associated with antiepileptic agents-induced DILI.29 Future studies should focus on identifying individuals with high-risk alleles predisposing DILI in critically ill patients. It is a great challenge for the treating physicians to maintain conventional antiepileptic agents within a narrow therapeutic window.30 The recent antiepileptic agents have an advantage in this regard and shall be an alternative for children with unstable levels of conventional antiepileptic drugs.\n\nThe study is limited in not following up with the status of liver enzymes in patients after their transfer out from ICU; baseline duration of antiepileptic therapy was not available, and scores for assessing the severity of illness could not be used as complete details required for such scorings were not available from the hospital records.\n\nConclusions\nWe observed significant proportion of critically ill children who are taking antiepileptic drugs experience DILI either in the form of hepatocellular injury or liver biochemical test abnormalities. Guidelines recommending concomitant drugs with less/absent risk of potential hepatotoxicity in children admitted into ICUs sho are receiving antiepileptic agents are the need of the hour.\n\nDeclaration of Competing Interest\nThe authors have indicated that they have no conflicts of interest regarding the content of this article.\n\nAcknowledgment\nThe authors thank the Research Technical Support Team, Ministry of Health, Bahrain, for their approval and continued oversight during the conduct of the study.\n\nDr Kannan Sridharan was responsible for conceptualization of the study, the formal analysis, methodology, project administration, software, and writing the original draft. Dr Kannan Sridharan, Dr Amal Al Daylami, Dr Reema Ajjawi and Dr Husain Al Ajooz performed data curation and were responsible for the investigation, gathering resources, and review and editing of the manuscript.\n==== Refs\nReferences\n1 Vorderwülbecke B.J. Lichtner G. von Dincklage F. Holtkamp M. Acute antiepileptic drug use in intensive care units J Neurol 265 2018 2841 2850 30259177 \n2 Yerram S. Katyal N. Premkumar K. Nattanmai P. Newey C.R. Seizure prophylaxis in the neuroscience intensive care unit J Intensive Care 6 2018 17 29515808 \n3 Sahin S. Yazici M.U. Ayar G. Karalok Z.S. Arhan E.P. Seizures in a Pediatric Intensive Care Unit: A Prospective Study J Trop Pediatr 62 2016 94 100 26892503 \n4 Valencia I. Lozano G. Kothare S.V. Melvin J.J. Khurana D.S. Hardison H.H. Yum S.S. Legido A. Epileptic seizures in the pediatric intensive care unit setting Epileptic Disord 8 2006 277 284 17150441 \n5 Hussein R.R.S. Soliman R.H. Ali A.M.A. Tawfeik M.H. Abdelrahim M.E.A. Effect of antiepileptic drugs on liver enzymes Beni-Suef University Journal of Basic and Applied Sciences 2 2013 14 19 \n6 Devarbhavi H. An Update on Drug-induced Liver Injury J Clin Exp Hepatol 2 2012 247 259 25755441 \n7 Shi Q. Yang X. Greenhaw J.J. Salminen A.T. Russotti G.M. Salminen W.F. Drug-induced liver injury in children: Clinical observations, animal models, and regulatory status Int J Toxicol 36 2017 365 379 28820004 \n8 Alempijevic T. Zec S. Milosavljevic T. Drug-induced liver injury: Do we know everything? World J Hepatol 9 2017 491 502 28443154 \n9 Anderson G.D. Children versus adults: pharmacokinetic and adverse-effect differences Epilepsia 43 2002 53 59 12060006 \n10 Suk K.T. Kim D.J. Drug-induced liver injury: present and future Clin Mol Hepatol 18 2012 249 257 23091804 \n11 Bell L.N. Chalasani N. Epidemiology of idiosyncratic drug-induced liver injury Semin Liver Dis 29 2009 337 347 19826967 \n12 Koch A. Streetz K. Tischendorf J. Trautwein C. Tacke F. Abnormal liver function tests in the intensive care unit] Med Klin Intensivmed Notfmed 108 2013 599 608 24145708 \n13 Lescot T. Karvellas C. Beaussier M. Magder S. Acquired liver injury in the intensive care unit Anesthesiology 117 2012 898 904 22854981 \n14 Yu Y.C. Mao Y.M. Chen C.W. Chen J.J. Chen J. Cong W.M. Ding Y. Duan Z.P. Fu Q.C. Guo X.Y. Hu P. Hu X.Q. Jia J.D. Lai R.T. Li D.L. Liu Y.X. Lu L.G. Ma S.W. Ma X. Nan Y.M. Ren H. Shen T. Wang H. Wang J.Y. Wang T.L. Wang X.J. Wei L. Xie Q. Xie W. Yang C.Q. Yang D.L. Yu Y.Y. Zeng M.D. Zhang L. Zhao X.Y. Zhuang H. Drug-induced Liver Injury (DILI) Study Group Chinese Society of Hepatology (CSH) Chinese Medical Association (CMA) CSH guidelines for the diagnosis and treatment of drug-induced liver injury Hepatol Int. 11 2017 221 241 28405790 \n15 Lisi D.M. Drug-induced liver injury: An overview US Pharm 41 2016 30 34 \n16 Björnsson E.S. Hepatotoxicity by drugs: The most common implicated agents Int J Mol Sci 17 2016 224 26861310 \n17 Paediatric age categories to be used in differentiating between listing on a model essential medicines list for children. World Health Organization. Available at:http://archives.who.int/eml/expcom/children/Items/PositionPaperAgeGroups.pdf(Accessed on 28 April 2019).\n18 Siddiqui N.U. Ashraf Z. Jurair H. Haque A. Mortality patterns among critically ill children in a Pediatric Intensive Care Unit of a developing country Indian J Crit Care Med 19 2015 147 150 25810609 \n19 Ibiebele I. Algert C.S. Bowen J.R. Roberts C.L. Pediatric admissions that include intensive care: a population-based study BMC Health Serv Res 18 2018 264 29631570 \n20 Grohskopf L.A. Huskins W.C. Sinkowitz-Cochran R.L. Levine G.L. Goldmann D.A. Jarvis W.R. Pediatric Prevention Network. Use of antimicrobial agents in United States neonatal and pediatric intensive care patients Pediatr Infect Dis J 24 2005 766 773 16148841 \n21 Blinova E. Lau E. Bitnun A. Cox P. Schwartz S. Atenafu E. Yau Y. Streitenberger L. Parshuram C.S. Marshall J. Seto W. Point prevalence survey of antimicrobial utilization in the cardiac and pediatric critical care unit Pediatr Crit Care Med 14 2013 e280 e288 23823209 \n22 Andrade R.J. Lucena M.I. Kaplowitz N. García-Muņoz B. Borraz Y. Pachkoria K. García-Cortés M. Fernández M.C. Pelaez G. Rodrigo L. Durán J.A. Costa J. Planas R. Barriocanal A. Guarner C. Romero-Gomez M. Muņoz-Yagüe T. Salmerón J. Hidalgo R. Outcome of acute idiosyncratic drug-induced liver injury: Long-term follow-up in a hepatotoxicity registry Hepatology 44 2006 1581 1588 17133470 \n23 Devarbhavi H. Andrade R.J. Drug-induced liver injury due to antimicrobials, central nervous system agents, and nonsteroidal anti-inflammatory drugs Semin Liver Dis 34 2014 145 161 24879980 \n24 Chen M. Suzuki A. Thakkar S. Yu K. Hu C. Tong W. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans Drug Discov Today 21 2016 648 653 26948801 \n25 Vidaurre J. Gedela S. Yarosz S. Antiepileptic Drugs and Liver Disease Pediatr Neurol 77 2017 23 36 29097018 \n26 Sridharan K. Sivaramakrishnan G. Gnanaraj J. Pharmacological interventions for stress ulcer prophylaxis in critically ill patients: a mixed treatment comparison network meta-analysis and a recursive cumulative meta-analysis Expert Opin Pharmacother 19 2018 151 158 29271262 \n27 Zelano J. Kumlien E. Levetiracetam as alternative stage two antiepileptic drug in status epilepticus: a systematic review Seizure 21 2012 233 236 22321334 \n28 Lyttle M.D. Rainford N.E.A. Gamble C. Messahel S. Humphreys A. Hickey H. Woolfall K. Roper L. Noblet J. Lee E.D. Potter S. Tate P. Iyer A. Evans V. Appleton R.E. Paediatric Emergency Research in the United Kingdom & Ireland (PERUKI) collaborative Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial Lancet 2019 Apr 17 pii: S0140-6736(19)30724-X \n29 Bryant A.E. Dreifuss A.E. Hepatotoxicity associated with antiepileptic drug therapy CNS Drugs 4 1995 99 113 \n30 Björnsson E. Hepatotoxicity associated with antiepileptic drugs Acta Neurol Scand 118 2008 281 290 18341684\n\n",
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"journal": "Current therapeutic research, clinical and experimental",
"keywords": "Carbamazepine; Drug-induced liver injury; Phenobarbitone; Phenytoin; Valproate",
"medline_ta": "Curr Ther Res Clin Exp",
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"pages": "100580",
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"pmid": "32280391",
"pubdate": "2020",
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"references": "22854981;24145708;25755441;26948801;29271262;28405790;25810609;18341684;23823209;16148841;17150441;29515808;23091804;22321334;19826967;30259177;31005385;26861310;29097018;17133470;26892503;28443154;28820004;29631570;24879980;12060006",
"title": "Drug-Induced Liver Injury in Critically Ill Children Taking Antiepileptic Drugs: A Retrospective Study.",
"title_normalized": "drug induced liver injury in critically ill children taking antiepileptic drugs a retrospective study"
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"abstract": "OBJECTIVE\nMethotrexate-associated lymphoproliferative disorder (MTX-LPD) is a rare complication that develops in patients treated with methotrexate (MTX).\n\n\nMETHODS\nA 76-year-old male patient had been taking MTX for his rheumatoid arthritis. Computed tomography (CT) revealed masses in the liver, right adrenal gland and T6-T7 vertebra, including an osteolytic lesion. FDG-PET scan showed increased uptake in each lesion. MTX was discontinued, and CT showed complete remission of the tumours after three months. The disease course confirmed MTX-LPD diagnosis.\n\n\nCONCLUSIONS\nBone lesions in LPDs mimic those of metastatic cancer. MTX-LPD should be considered in patients on MTX presenting with mass lesions.",
"affiliations": "Department of Internal Medicine, Hyogo Prefectural Tamba Medical Center, Tamba, Japan.;Department of Internal Medicine, Hyogo Prefectural Tamba Medical Center, Tamba, Japan.;Department of Internal Medicine, Hyogo Prefectural Tamba Medical Center, Tamba, Japan.",
"authors": "Hirata|Chihiro|C|;Kenzaka|Tsuneaki|T|https://orcid.org/0000-0002-3120-6605;Akita|Hozuka|H|",
"chemical_list": null,
"country": "England",
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"doi": "10.1111/jcpt.13415",
"fulltext": "\n==== Front\nJ Clin Pharm Ther\nJ Clin Pharm Ther\n10.1111/(ISSN)1365-2710\nJCPT\nJournal of Clinical Pharmacy and Therapeutics\n0269-4727\n1365-2710\nJohn Wiley and Sons Inc. Hoboken\n\n33768586\n10.1111/jcpt.13415\nJCPT13415\nCase Report\nCase Reports\nMethotrexate‐associated lymphoproliferative disorder with an osteolytic vertebral lesion in an elderly patient with rheumatoid arthritis: A case report\nHIRATA et al.\nHirata Chihiro MD 1\nKenzaka Tsuneaki MD, PhD https://orcid.org/0000-0002-3120-6605\n1 2 smile.kenzaka@jichi.ac.jp\n\nAkita Hozuka MD, PhD 1\n1 Department of Internal Medicine Hyogo Prefectural Tamba Medical Center Tamba Japan\n2 Division of Community Medicine and Career Development Kobe University Graduate School of Medicine Kobe Japan\n* Correspondence\nTsuneaki Kenzaka, Division of Community Medicine and Career Development, Kobe University Graduate School of Medicine, 2‐1‐5, Arata‐cho, Hyogo‐ku, Kobe, Hyogo, 652‐0032, Japan.\nEmail: smile.kenzaka@jichi.ac.jp\n\n25 3 2021\n8 2021\n46 4 10.1111/jcpt.v46.4 11781181\n23 2 2021\n23 1 2021\n10 3 2021\n© 2021 The Authors. Journal of Clinical Pharmacy and Therapeutics published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.\n\nAbstract\n\nWhat is known and objective\n\nMethotrexate‐associated lymphoproliferative disorder (MTX‐LPD) is a rare complication that develops in patients treated with methotrexate (MTX).\n\nCase summary\n\nA 76‐year‐old male patient had been taking MTX for his rheumatoid arthritis. Computed tomography (CT) revealed masses in the liver, right adrenal gland and T6‐T7 vertebra, including an osteolytic lesion. FDG‐PET scan showed increased uptake in each lesion. MTX was discontinued, and CT showed complete remission of the tumours after three months. The disease course confirmed MTX‐LPD diagnosis.\n\nWhat is new and Conclusion\n\nBone lesions in LPDs mimic those of metastatic cancer. MTX‐LPD should be considered in patients on MTX presenting with mass lesions.\n\nBone lesions in LPDs mimic those of metastatic cancer. MTX‐LPD should be considered in patients on MTX presenting with mass lesions.\n\nC‐reactive protein\nelderly\nlymphoproliferative disorder\nmethotrexate\nrheumatoid arthritis\nsource-schema-version-number2.0\ncover-dateAugust 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.5 mode:remove_FC converted:12.08.2021\nFunding information\n\nThis research did not receive any specific grant from funding agencies in the public, commercial or not‐for‐profit sectors.\n==== Body\n1 WHAT IS KNOWN AND OBJECTIVE\n\nMethotrexate (MTX) is an important drug for the treatment of rheumatoid arthritis. It is effective in controlling disease activity and preventing disease‐related damages. Some patients taking MTX experience adverse events, such as severe myelosuppression, interstitial pneumonia and liver injury, during the treatment.1\n\nA previous meta‐analysis of epidemiological studies on rheumatoid arthritis reported a statistically significant association between rheumatoid arthritis and lymphoma.1 MTX‐associated lymphoproliferative disorder (MTX‐LPD) is a lymphoma or lymphoid proliferation that occurs in patients that are immunosuppressed due to MTX administration. It is categorized as one of the “other iatrogenic immunodeficiency‐associated LPDs” by the World Health Organization.2 The first case was reported in 1991;3 since then, cases of MTX‐LPD have been increasingly reported in Japan. Approximately, 50% of patients with MTX‐LPD present only with nodal lesions; however, others have shown extra‐nodal lesions located in the gastrointestinal tract, skin and lungs.1, 4 Although a true causative relationship with the drug is demonstrated by complete or partial regression of LPD shortly after the discontinuation of the drug,1 the mechanisms underlying the occurrence of MTX‐LPD remain unclear. Here, we report a case of MTX‐LPD accompanied by an osteolytic lesion, which was difficult to differentiate from metastatic cancer.\n\n2 CASE SUMMARY\n\nA 76‐year‐old man with a history of rheumatoid arthritis presented to our hospital to evaluate elevated C‐reactive protein level (6.13 mg/dl) detected during a regular check‐up. He had no other complaints and denied experiencing fever, night sweats, weight loss or arthralgia. He had been taking MTX for six years. His recent medication regimen was MTX 10 mg/wk, folate 10 mg/wk, salazosulfapyridine 1,000 mg/d and iguratimod 50 mg/d, and his disease was appropriately controlled with these drugs. He did not smoke or drink alcohol. On physical examination, the vital signs were as follows: blood pressure of 148/55 mm Hg, pulse of 85 beats/min, respiratory rate of 16 breaths/min, O2 saturation of 100% on room air and body temperature of 36.3℃. No evidence of superficial lymphadenopathy was observed, and cardiovascular examination revealed normal findings. His lungs were clear on auscultation, and abdominal examination showed unremarkable findings, including the absence of hepatosplenomegaly. Table 1 presents the laboratory test results. The only notable laboratory test result was the elevated C‐reactive protein level. Other results, including complete blood count, liver and renal function tests, serum albumin level and tumour markers, such as α‐fetoprotein, carcinoembryonic antigen and carbohydrate antigen 19‐9, were normal. Computed tomography (CT) revealed an osteolytic lesion adjacent to the T6‐7 vertebrae, in addition to the masses in the liver and right adrenal gland. All masses were poorly enhanced with contrast, and fluorodeoxyglucose‐positron emission tomography showed increased uptake in each lesion (Figure 1), which were initially thought to be metastatic lesions; this implies that he had only a few months to live. He requested optimal supportive care with no further evaluation. We referred him to his primary physician and advised the discontinuation of MTX, as MTX‐LPD was a possibility.\n\nTABLE 1 Laboratory findings\n\nParameter\tRecorded values\tStandard values\t\nWhite blood cells\t5.59 × 109/L\t4.70–8.70 × 109/L\t\nHaemoglobin\t10.0 g/dl\t13–17 g/dl\t\nPlatelets\t241 × 109/L\t150–350 × 109/L\t\nC‐reactive protein\t5.53 mg/dl\t0–0.3 mg/dl\t\nAlbumin\t3.0 g/dl\t3.9–4.9 g/dl\t\nAlanine transaminase\t20 U/L\t4–44 U/L\t\nLactate dehydrogenase\t232 U/L\t120–230 U/L\t\nBlood urea nitrogen\t12.2 mg/dl\t8.5–20 mg/dl\t\nCreatinine\t0.62 mg/dl\t0.53–1.02 mg/dl\t\nAFP\t6.1 ng/ml\t1.3–8.5 ng/ml\t\nCEA\t2.0 ng/ml\t0.4–5.2 ng/ml\t\nCA19‐9\t6.8 U/ml\t3.2–36.8 U/ml\t\nAbbreviations: AFP, α‐fetoprotein; CA19‐9, carbohydrate antigen 19‐9; CEA, carcinoembryonic antigen.\n\nJohn Wiley & Sons, Ltd\n\nFIGURE 1 Computed tomography (CT) image. CT shows an osteolytic mass lesion adjacent to the T6‐7 vertebrae (A), in addition to the masses in the liver and right adrenal gland (B) (red circles). Fluorodeoxyglucose‐positron emission tomography scan showing increased uptake in each lesion (C, D) (red circles)\n\nSurprisingly, he was in good health at three months after MTX discontinuation, and CT showed complete remission of the tumours (Figure 2). The disease course confirmed the diagnosis of MTX‐LPD. At the time of writing, which was two years since his MTX‐LPD diagnosis, the patient is stable and without recurrence of the disease.\n\nFIGURE 2 CT scans showing complete remission of the tumours at 3 months after methotrexate was discontinued\n\n3 WHAT IS NEW AND CONCLUSION\n\nWe report a case of MTX‐LPD accompanied by an osteolytic lesion. It is extremely rare for MTX‐LPD cases to have a bone lesion. To the best of our knowledge, only two cases of MTX‐LPD with bone involvement have been reported.5, 6 Considering that bone lesions of LPDs are difficult to differentiate from those of metastatic cancer; pathological examination and careful observation after the discontinuation of MTX treatment are needed.\n\nMTX‐LPD is a serious complication in patients treated with MTX. As MTX is an important drug for treating rheumatoid arthritis, MTX‐LPD cases have been increasingly reported in Japan. Although the mechanism underlying the disease is unknown, immunodeficiency resulting from rheumatoid arthritis combined with the immunosuppressive effect of MTX has been implicated in the pathogenesis.4 This patient had been taking iguratimod, MTX and salazosulfapyridine. Iguratimod is a disease‐modifying antirheumatic drug (DMARD) developed in Japan and is considered to elicit immunomodulatory effects by reducing the production of inflammatory cytokines, including interleukin‐1β (Il‐1β), Il‐6, Il‐8, Il‐10, tumour necrosis factor α, and interferon γ, and immunoglobulin by B lymphocytes.7 A combined therapy of iguratimod with other DMARDs is expected to be useful, especially in patients with rheumatoid arthritis who are non‐responsive to MTX therapy alone.8\n\nPatients with rheumatoid arthritis reportedly have a 2.0–5.5‐fold higher risk of developing LPDs than the general population.1, 9\n\nThe clinical symptoms of MTX‐LPD include weight loss, fever and swelling of the superficial lymph nodes. Blood tests reveal high levels of C‐reactive protein, lactate dehydrogenase or soluble‐interleukin 2 receptor.5 MTX‐LPD may affect lymph nodal or extra‐nodal sites, including the pharynx, liver, gastrointestinal tract, kidneys, lungs, skin and soft tissues. Approximately, 40–70% of MTX‐LPD patients with rheumatoid arthritis have extra‐nodal lesions.1 According to a report of 27 cases by Yoshihara, more than half of the cases were located in the extra‐nodal sites.10 However, bone involvement is extremely rare, with only two cases having been reported to date. Oebisu et al. reported a case of MTX‐LPD with a pathological fracture of the femur,5 and Kikuchi reported a case accompanied by a spinal lesion.6 In addition, hepatic lesions rarely develop in patients with MTX‐LPD, with only 11 cases having been reported in the English literature to date.11\n\nIn this case, the patient had a vertebral osteolytic tumour, rendering it difficult to differentiate the tumour from metastatic cancer, thereby leading to an incorrect prognostic prediction. The radiographs of patients with LPDs typically show permeative bone destruction accompanied by extraosseous soft‐tissue masses. It is difficult to differentiate LPDs from metastatic cancer, leukaemia or small round‐cell tumours, such as an Ewing's sarcoma, by radiographic findings.12, 13 Therefore, a thorough pathological examination should be performed. In this case, the patient refused to undergo a biopsy; thus, a diagnosis was established based on the patient's clinical course.\n\nA remarkable response to MTX cessation is helpful for the diagnosis of MTX‐LPD.1 Spontaneous resolution of LPD after the withdrawal of MTX is reported in 20–73% of patients.1 Otherwise, LPDs regrow after the initial regression in some patients and require chemotherapy, such as R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone).9 Our case showed complete remission of all the tumours in the liver, right adrenal gland and T6‐7 vertebra, and the disease course confirmed the diagnosis. Discontinuation of MTX and careful follow‐up can contribute to accurate diagnosis, especially if the patient does not want to undergo a pathological examination, or it is technically difficult to perform a biopsy. When a patient taking MTX presents with mass lesions and development of LPD is suspected, initial cessation of MTX has a diagnostic and therapeutic value.\n\nIn conclusion, our findings indicate that bone lesions in LPDs mimic those of metastatic cancer. Therefore, MTX‐LPD should be considered in patients on MTX who present with mass lesions.\n\nCONFLICT OF INTERESTS\n\nThe authors declare that they have no competing interests.\n\nPATIENT CONSENT STATEMENT\n\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images.\n==== Refs\nREFERENCES\n\n1 HarigaiM. Lymphoproliferative disorders in patients with rheumatoid arthritis in the era of widespread use of methotrexate: a review of the literature and current perspective. Mod Rheumatol. 2018;28 :1‐8.28758827\n2 SwerdlowSH, CampoE, HarrisNL, et al. WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues, 4th edn. Lyon: IARC; 2008:335‐351.\n3 ShirokyJB, FrostA, SkeltonJD, HaegertDG, NewkirkMM, NevilleC. Complications of immunosuppression associated with weekly low dose methotrexate. J Rheumatol. 1991;18 :1172‐1175.1941818\n4 MarietteX, Cazals‐HatemD, WarszawkiJ, et al. Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3‐year prospective study in France. Blood. 2002;99 :3909‐3915.12010788\n5 OebisuN, HoshiM, IeguchiM, et al. Lymphoproliferative disorder with pathological fracture of the femur in a patient with rheumatoid arthritis treated with methotrexate: a case report. Mol Clin Oncol. 2018;9 :187‐191.30101019\n6 KikuchiN, UesugiM, KodaM, et al. Methotrexate‐related lymphproliferative disorder of the lumber spine origin presenting with severe low‐back pain: case report. J Neurosurg Spine. 2018;29 :545‐548.30168781\n7 LuLJ, BaoCD, DaiM, et al. Multicenter, randomized, double‐blind, controlled trial of treatment of active rheumatoid arthritis with T‐614 compared with methotrexate. Arthritis Rheum. 2009;61 :979‐987.19565542\n8 LiJ, BaoJ, ZengJ, et al. Iguratimod: a valuable remedy from Asia Pacific region for ameliorating autoimmune diseases and protecting bone physiology. Bone Res. 2019;7 :27.31646017\n9 HashimotoK, AkagiM. Lymphoproliferative disorder in an elderly rheumatoid arthritis patient after longterm oral methotrexate administration: a case report. Mol Clin Oncol. 2018;9 :293‐296.30155252\n10 YoshiharaR, UefujiA, MurataM, NakagawaN, TanakaY, ShiozawaK. Clinical manifestation of twenty‐seven cases of methotrexate‐associated lymphoproliferative disorders. Clin Rheumatol Rel Res. 2017;29 :164‐172.\n11 OnoR, KumagaeT, UojimaH, et al. Hepatic methotrexate‐associated lymphoproliferative disorders identified by multiple liver tumors: a case report and review of the literature. J Med Case Rep. 2019;13 :196.31242930\n12 BraunsteinEM, WhiteSJ. Non‐Hodgkin lymphoma of bone. Radiology. 1980;135 :59‐63.6892659\n13 GabelGT, SimFH, BeaboutJW, HabermanTM, WoldLE. Non‐Hodgkin's lymphoma of bone. Orthopedics. 1989;12 :1139‐1142.2771830\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0269-4727",
"issue": "46(4)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "C-reactive protein; elderly; lymphoproliferative disorder; methotrexate; rheumatoid arthritis",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": null,
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "1178-1181",
"pmc": null,
"pmid": "33768586",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports",
"references": "12010788;28758827;30101019;30155252;6892659;31242930;2771830;19565542;30168781;1941818;31646017",
"title": "Methotrexate-associated lymphoproliferative disorder with an osteolytic vertebral lesion in an elderly patient with rheumatoid arthritis: A case report.",
"title_normalized": "methotrexate associated lymphoproliferative disorder with an osteolytic vertebral lesion in an elderly patient with rheumatoid arthritis a case report"
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"abstract": "To describe the marked clinical and biological responses of a targeted treatment with anti-interleukin-6 (IL-6)-receptor antibody and Janus kinase (JAK) inhibitors in a patient with a severe, corticoresistant CNS toxicity of immune-checkpoint inhibitor (ICI) therapy.\n\n\n\nA 58-year-old man was admitted for subacute paraparesis, urinary retention, and ascending paresthesia. He was under treatment with ipilimumab and nivolumab for metastatic melanoma. Spine MRI disclosed multiple T2-hyperintense, contrast-enhancing longitudinally extensive lesions. A diagnosis of ICI-related acute transverse myelitis was made.\n\n\n\nICIs were immediately discontinued, and the patient received high-dose glucocorticoids plus 1 session of plasma exchange, but he did not improve. Based on the marked elevation of CSF IL-6 (505 pg/mL), a second-line targeted therapy with anti-IL-6-receptor tocilizumab (8 mg/kg/mo for 3 infusions) plus JAK inhibitor ruxolitinib (50 mg/d) was administered. Patient neurologic status started to improve shortly after, with corresponding radiologic resolution. At 9 months, the patient was able to walk independently, presenting only slight residual disability while remaining in oncologic partial response.\n\n\n\nOur case suggests that some patients with severe, corticoresistant CNS immune-related toxicities of ICIs may benefit from cytokine blockade. Cytokine measurement in serum and CSF might help in selecting patients for personalized treatment strategies.",
"affiliations": "From the AP-HP (A.P., N.V., C.B., G.B., D.P.), GH Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, Paris, France; AP-HP (N.K.), Hôpital Cochin, Department of Dermatology, Paris, France; AP-HP (O.H.), Hôpital Necker, Department of Haematology, Imagine Institute, INSERM U1163, University of Paris, France; AP-HP (N.Z.), GH Pitié-Salpêtrière, Department of Pharmacology, Paris, France; Neurology Unit (G.B.), IRCCS San Raffaele Scientific Institute, Milan, Italy; and OncoNeuroTox Group (D.P.), Center for Patients with Neurological Complications of Oncologic Treatments, GH Pitié-Salpetrière et Hôpital Percy, Paris, France.;From the AP-HP (A.P., N.V., C.B., G.B., D.P.), GH Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, Paris, France; AP-HP (N.K.), Hôpital Cochin, Department of Dermatology, Paris, France; AP-HP (O.H.), Hôpital Necker, Department of Haematology, Imagine Institute, INSERM U1163, University of Paris, France; AP-HP (N.Z.), GH Pitié-Salpêtrière, Department of Pharmacology, Paris, France; Neurology Unit (G.B.), IRCCS San Raffaele Scientific Institute, Milan, Italy; and OncoNeuroTox Group (D.P.), Center for Patients with Neurological Complications of Oncologic Treatments, GH Pitié-Salpetrière et Hôpital Percy, Paris, France.;From the AP-HP (A.P., N.V., C.B., G.B., D.P.), GH Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, Paris, France; AP-HP (N.K.), Hôpital Cochin, Department of Dermatology, Paris, France; AP-HP (O.H.), Hôpital Necker, Department of Haematology, Imagine Institute, INSERM U1163, University of Paris, France; AP-HP (N.Z.), GH Pitié-Salpêtrière, Department of Pharmacology, Paris, France; Neurology Unit (G.B.), IRCCS San Raffaele Scientific Institute, Milan, Italy; and OncoNeuroTox Group (D.P.), Center for Patients with Neurological Complications of Oncologic Treatments, GH Pitié-Salpetrière et Hôpital Percy, Paris, France.;From the AP-HP (A.P., N.V., C.B., G.B., D.P.), GH Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, Paris, France; AP-HP (N.K.), Hôpital Cochin, Department of Dermatology, Paris, France; AP-HP (O.H.), Hôpital Necker, Department of Haematology, Imagine Institute, INSERM U1163, University of Paris, France; AP-HP (N.Z.), GH Pitié-Salpêtrière, Department of Pharmacology, Paris, France; Neurology Unit (G.B.), IRCCS San Raffaele Scientific Institute, Milan, Italy; and OncoNeuroTox Group (D.P.), Center for Patients with Neurological Complications of Oncologic Treatments, GH Pitié-Salpetrière et Hôpital Percy, Paris, France.;From the AP-HP (A.P., N.V., C.B., G.B., D.P.), GH Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, Paris, France; AP-HP (N.K.), Hôpital Cochin, Department of Dermatology, Paris, France; AP-HP (O.H.), Hôpital Necker, Department of Haematology, Imagine Institute, INSERM U1163, University of Paris, France; AP-HP (N.Z.), GH Pitié-Salpêtrière, Department of Pharmacology, Paris, France; Neurology Unit (G.B.), IRCCS San Raffaele Scientific Institute, Milan, Italy; and OncoNeuroTox Group (D.P.), Center for Patients with Neurological Complications of Oncologic Treatments, GH Pitié-Salpetrière et Hôpital Percy, Paris, France.;From the AP-HP (A.P., N.V., C.B., G.B., D.P.), GH Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, Paris, France; AP-HP (N.K.), Hôpital Cochin, Department of Dermatology, Paris, France; AP-HP (O.H.), Hôpital Necker, Department of Haematology, Imagine Institute, INSERM U1163, University of Paris, France; AP-HP (N.Z.), GH Pitié-Salpêtrière, Department of Pharmacology, Paris, France; Neurology Unit (G.B.), IRCCS San Raffaele Scientific Institute, Milan, Italy; and OncoNeuroTox Group (D.P.), Center for Patients with Neurological Complications of Oncologic Treatments, GH Pitié-Salpetrière et Hôpital Percy, Paris, France.;From the AP-HP (A.P., N.V., C.B., G.B., D.P.), GH Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, Paris, France; AP-HP (N.K.), Hôpital Cochin, Department of Dermatology, Paris, France; AP-HP (O.H.), Hôpital Necker, Department of Haematology, Imagine Institute, INSERM U1163, University of Paris, France; AP-HP (N.Z.), GH Pitié-Salpêtrière, Department of Pharmacology, Paris, France; Neurology Unit (G.B.), IRCCS San Raffaele Scientific Institute, Milan, Italy; and OncoNeuroTox Group (D.P.), Center for Patients with Neurological Complications of Oncologic Treatments, GH Pitié-Salpetrière et Hôpital Percy, Paris, France.;From the AP-HP (A.P., N.V., C.B., G.B., D.P.), GH Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, Paris, France; AP-HP (N.K.), Hôpital Cochin, Department of Dermatology, Paris, France; AP-HP (O.H.), Hôpital Necker, Department of Haematology, Imagine Institute, INSERM U1163, University of Paris, France; AP-HP (N.Z.), GH Pitié-Salpêtrière, Department of Pharmacology, Paris, France; Neurology Unit (G.B.), IRCCS San Raffaele Scientific Institute, Milan, Italy; and OncoNeuroTox Group (D.P.), Center for Patients with Neurological Complications of Oncologic Treatments, GH Pitié-Salpetrière et Hôpital Percy, Paris, France. dimitri.psimaras@aphp.fr.",
"authors": "Picca|Alberto|A|;Valyraki|Nefeli|N|;Birzu|Cristina|C|;Kramkimel|Nora|N|;Hermine|Olivier|O|;Zahr|Noel|N|;Berzero|Giulia|G|;Psimaras|Dimitri|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1212/NXI.0000000000001073",
"fulltext": "\n==== Front\nNeurol Neuroimmunol Neuroinflamm\nNeurol Neuroimmunol Neuroinflamm\nnnn\nNEURIMMINFL\nNeurology® Neuroimmunology & Neuroinflammation\n2332-7812\nLippincott Williams & Wilkins Hagerstown, MD\n\n34497101\nNEURIMMINFL2021038799\n10.1212/NXI.0000000000001073\n3\n45\n131\n132\n213\n319\nClinical/Scientific Notes\nAnti–Interleukin-6 and Janus Kinase Inhibitors for Severe Neurologic Toxicity of Checkpoint Inhibitors\nPicca Alberto MD picca.alberto@gmail.com\n\nValyraki Nefeli MD nef.val92@gmail.com\n\nBirzu Cristina MD cristina.birzu89@yahoo.com\n\nKramkimel Nora MD, PhD nora.kramkimel@aphp.fr\n\nHermine Olivier MD, PhD ohermine@gmail.com\n\nZahr Noel PharmD, PhD noel.zahr@aphp.fr\n\nBerzero Giulia MD, PhD *giulia.berzero01@universitadipavia.it\n\nPsimaras Dimitri MD *\nFrom the AP-HP (A.P., N.V., C.B., G.B., D.P.), GH Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, Paris, France; AP-HP (N.K.), Hôpital Cochin, Department of Dermatology, Paris, France; AP-HP (O.H.), Hôpital Necker, Department of Haematology, Imagine Institute, INSERM U1163, University of Paris, France; AP-HP (N.Z.), GH Pitié-Salpêtrière, Department of Pharmacology, Paris, France; Neurology Unit (G.B.), IRCCS San Raffaele Scientific Institute, Milan, Italy; and OncoNeuroTox Group (D.P.), Center for Patients with Neurological Complications of Oncologic Treatments, GH Pitié-Salpetrière et Hôpital Percy, Paris, France.\nCorrespondence Dr. Psimaras dimitri.psimaras@aphp.fr\nGo to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.\n\n* These authors contributed equally to this work.\n\nThe Article Processing Charge was funded by the authors.\n\n11 2021\n8 9 2021\n8 9 2021\n8 6 e107328 2 2021\n15 6 2021\nCopyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.\n2021\nAmerican Academy of Neurology\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.\n\nBackground and Objectives\n\nTo describe the marked clinical and biological responses of a targeted treatment with anti–interleukin-6 (IL-6)–receptor antibody and Janus kinase (JAK) inhibitors in a patient with a severe, corticoresistant CNS toxicity of immune-checkpoint inhibitor (ICI) therapy.\n\nMethods\n\nA 58-year-old man was admitted for subacute paraparesis, urinary retention, and ascending paresthesia. He was under treatment with ipilimumab and nivolumab for metastatic melanoma. Spine MRI disclosed multiple T2-hyperintense, contrast-enhancing longitudinally extensive lesions. A diagnosis of ICI-related acute transverse myelitis was made.\n\nResults\n\nICIs were immediately discontinued, and the patient received high-dose glucocorticoids plus 1 session of plasma exchange, but he did not improve. Based on the marked elevation of CSF IL-6 (505 pg/mL), a second-line targeted therapy with anti-IL-6-receptor tocilizumab (8 mg/kg/mo for 3 infusions) plus JAK inhibitor ruxolitinib (50 mg/d) was administered. Patient neurologic status started to improve shortly after, with corresponding radiologic resolution. At 9 months, the patient was able to walk independently, presenting only slight residual disability while remaining in oncologic partial response.\n\nDiscussion\n\nOur case suggests that some patients with severe, corticoresistant CNS immune-related toxicities of ICIs may benefit from cytokine blockade. Cytokine measurement in serum and CSF might help in selecting patients for personalized treatment strategies.\n\nspecial-propertyvideo\nOPEN-ACCESSTRUE\n==== Body\npmcNeurologic immune-related adverse events (irAEs) of immune-checkpoint inhibitors (ICIs) are uncommon but often severe and potentially life-threatening. High-dose glucocorticoids may be insufficient,1 but optimal treatment in severe and refractory cases remains to be defined.\n\nIn this study, we report the case of a 58-year-old man who started combined treatment with ipilimumab and nivolumab for BRAF–wild-type metastatic melanoma. After the fourth ICI cycle, the patient presented with rapidly progressing paraparesis, urinary retention, and ascending paresthesia, which peaked in 10 days from onset. Neurologic examination showed severe flaccid paraparesis, a dorsal sensory level (T10) with impaired proprioception, and absent deep tendon reflexes. Spine MRI disclosed multiple T2 hyperintensities at C2, C3, C7-T2, T4-T7, and T8-conus levels with associated patchy contrast enhancement (Figure 1, B and C). CSF analysis displayed increased proteins (2.57 g/L) and cell count (112/mm3) with no malignant cells. Screening for anti-aquaporin-4, anti-myelin oligodendrocyte glycoprotein, anti-glutamic acid decarboxylase, and onconeural antibodies (including anti-Hu, anti-Ri, anti-CV2, and anti-amphiphysin) was negative. Cytokine assessment showed a marked elevation of interleukin-6 (IL-6) in the CSF (505 pg/mL, upper normal limit 4 pg/mL) (Figure 1A). After excluding alternative infectious, vascular, and neoplastic causes, a diagnosis of ICI-related acute transverse myelitis was made.\n\nFigure 1 Imaging, Treatment, CSF Monitoring, and Functional Outcome in a Patient With Severe ICI-Related Myelitis\n\n(A) Timeline of patient functional status (as expressed by the modified Rankin Scale [mRS], gray curve), IL-6 levels in CSF (orange dots) and serum (blue dots), and administered treatments. The first CSF analysis at day 10 from symptom onset displayed an inflammatory CSF with markedly increased IL-6 level (515 pg/mL) that rapidly decreased after the first administration of tocilizumab and introduction of oral ruxolitinib (8 pg/mL at day 29 and indetectable at day 50). Follow-up CSF analysis at 3 months (day 107) disclosed a slight rise in CSF inflammatory markers (CSF IL-6: 6 pg/mL; CSF proteins: 1.8 g/L; and CSF cells: 17/mm3) that justified a third administration of IV tocilizumab despite the sustained clinical and radiological improvement. (B and C) Lumbosacral spine MRI at diagnosis displayed a longitudinally extensive lesion with spinal swelling from T8 to the conus in T2-weighted sequences (T2w) (B), with an associated faint parenchymal and leptomeningeal enhancement in postgadolinium T1-weighted images (T1w-Gd) (C). (D and E) Lumbosacral spine MRI 1 week after the introduction of tocilizumab and ruxolitinib, showing a marked reduction of the spinal hyperintensities in T2-weighted images (D) and resolution of the contrast enhancement in postgadolinium T1-weighted images (E). ICI = immune-checkpoint inhibitor; IL-6 = interleukin-6; IVMP = intravenous methylprednisolone; PLEX = plasma exchange; Toci = tocilizumab.\n\nICIs were immediately discontinued, and the patient received IV methylprednisolone (3.5 g over 4 days), followed by oral prednisone tapering (from 100 mg/d) and 1 session of plasma exchange to remove residual circulating ICIs, but the patient did not improve. Based on our recent experience of poor responses to high-dose glucocorticoids and plasma exchanges in ICI-related myelitis1 and on the marked IL-6 elevation in the CSF, a second-line treatment with the anti-IL-6-receptor tocilizumab (8 mg/kg IV every 4 weeks) was started, 14 days after symptom onset. To broaden the inhibition of cytokine signaling, the Janus kinase (JAK) inhibitor ruxolitinib (25 mg orally, twice daily) was initiated (Figure 1A). JAKs are crucial enzymes in downstream signaling of type I and type II cytokine receptors including IL-6R, being required for the activation of mitogen-activated protein kinase, phosphatidylinositol-4,5-bisphosphate-3-kinase, and signal transducer and activator of transcription pathways. Ruxolitinib was also added to prevent a possible initial worsening of inflammation due to the expected transient tocilizumab-induced elevation of IL-6 and consequent signal transduction activation.2\n\nFive days after starting second-line treatment, the patient started improving (Video 1), showing a parallel radiologic amelioration (Figure 1, D and E), a resolution of CSF inflammation, and a dramatic decrease of CSF IL-6 levels (Figure 1A). Measurement of drug levels, 2 weeks after starting second-line treatment, confirmed that both compounds were present in the CSF at therapeutic concentrations (tocilizumab: serum 21 μg/mL, CSF 6 μg/mL and ruxolitinib: serum 138 ng/mL, CSF 12.6 ng/mL). At that time, protein levels in the CSF were 0.55 g/dL, reflecting a very mild blood-brain barrier damage. Tocilizumab was continued for a total of 3 infusions, until a steady decrease of IL-6 in the CSF was observed, whereas ruxolitinib was discontinued after 3 weeks because of grade 3 anemia.\n\n10.1212/001073_Video_1 Video 1 The patient five days after the start of the second-line therapy with tocilizumab plus ruxolitinib, regaining legs movement.Download Supplementary Video 1 via http://dx.doi.org/10.1212/001073_Video_1\n\nAt 3 months from myelitis onset, the patient was able to walk with support (Video 2) and constantly improve with physical therapy. At the last follow-up, 9 months from onset, he could walk independently without limitations of the walking perimeter (Video 3), and he was able to resume his work, although he still had mild sensory ataxia and a bladder and bowel dysfunction. Spinal MRI showed a substantial regression of previously reported abnormalities. Oncologic re-evaluation showed persistent partial response with no progression of his metastatic melanoma, and he remained on simple surveillance.\n\n10.1212/001073_Video_2 Video 2 The patient three months after the start of the second-line therapy, able to walk with aid.Download Supplementary Video 2 via http://dx.doi.org/10.1212/001073_Video_2\n\n10.1212/001073_Video_3 Video 3 The patient at last follow up, nine months after the start of the second-line therapy, able to walk independently.Download Supplementary Video 3 via http://dx.doi.org/10.1212/001073_Video_3\n\nThe present case, recently included in a series of longitudinally extensive myelitis,1 underscores the value of personalized treatment approaches in severe neurologic irAEs, as recently proposed for other irAEs.3,4 In this case, the marked increase of CSF IL-6 suggested the potential value of IL-6-receptor inhibition. Tocilizumab has recently demonstrated its efficacy in patients with ICI-related cerebritis5 and other non-ICI-related CNS inflammatory conditions, such as neuromyelitis optica spectrum disorder (NMOSD).6 Similarly, ruxolitinib was also effective in a patient with severe NMOSD.7 In this study, we demonstrated that both agents reach therapeutic concentrations in the CNS and might be effectively used to treat severe, corticoresistant neurologic irAEs. Nevertheless, we acknowledge the limitations of single-case reporting; we cannot exclude that glucocorticoids and plasma exchange, or a naturally improving course of the disease itself, could have played a role in clinical and biological improvement. Our report is hypothesis generating, and further studies are needed. Cytokine measurement in serum and CSF might help to select patients that would benefit from cytokine blockade.\n\nData Availability\n\nFurther anonymized data will be made available upon reasonable request.\n\nStudy Funding\n\nThe authors report no targeted funding.\n\nDisclosure\n\nThe authors report no disclosures relevant to the manuscript. Go to Neurology.org/NN for full disclosures.\n\nAppendix Authors\n==== Refs\nReferences\n\n1. PiccaA, BerzeroG, BihanK, et al . Longitudinally extensive myelitis associated with immune checkpoint inhibitors. Neurol Neuroimmunol Neuroinflamm. 2021;8 (3 ):e967.33637598\n2. TeacheyDT, LaceySF, ShawPA, et al . Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov. 2016;6 (6 ):664-679.27076371\n3. MartinsF, SykiotisGP, MaillardM, et al . New therapeutic perspectives to manage refractory immune checkpoint-related toxicities. Lancet Oncol. 2019;20 (1 ):e54-e64.30614479\n4. EsfahaniK, ElkriefA, CalabreseC, et al . Moving towards personalized treatments of immune-related adverse events. Nat Rev Clin Oncol. 2020;17 (8 ):504-515.32246128\n5. StroudCR, HegdeA, CherryC, et al . Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade. J Oncol Pharm Pract. 2019;25 (3 ):551-557.29207939\n6. ZhangC, ZhangM, QiuW, et al . Safety and efficacy of tocilizumab versus azathioprine in highly relapsing neuromyelitis optica spectrum disorder (TANGO): an open-label, multicentre, randomised, phase 2 trial. Lancet Neurol. 2020;19 (5 ):391-401.32333897\n7. HodeckerSC, StellmannJP, RosenkranzSC, et al . Ruxolitinib treatment in a patient with neuromyelitis optica: a case report. Neurol Neuroimmunol Neuroinflamm. 2017;4 (2 ):e328.28203617\n\n",
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"title": "Anti-Interleukin-6 and Janus Kinase Inhibitors for Severe Neurologic Toxicity of Checkpoint Inhibitors.",
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"abstract": "Pleuropulmonary blastoma (PPB) is a rare, aggressive mesenchymal tumor of childhood. The Italian Tumori Rari in Età Pediatrica (TREP) Registry was the first in Europe dedicated to prospective data collection on rare pediatric tumors. We analyzed data from an Italian series of patients with PPB, focusing on the role of the TREP Project.\nWe considered patients aged 0-14 with histologically confirmed diagnosis, registered in population-based cancer registries (before 2000) or the TREP Registry (2000 to 2014), and analyzed data on clinical characteristics, treatment, and outcome. Event-free survival (EFS) and overall survival (OS) were estimated. Relevant prognostic factors were identified performing a univariate analysis.\nThirty-seven cases were included (7 type I, 13 type II, 17 type III). The average diagnosis rate rose from 1.10 to 1.73 cases/year after the TREP Project started. All patients underwent surgery, 33 received chemotherapy, and 9 had radiotherapy. The median follow-up was 8.7 years. For type I, II, and III, respectively, the 5-year OS was 85.7% (33.4-97.9), 52.7% (23.4-75.5), and 57.8% (31.1-77.3); the 5-year EFS was 85.7% (33.4-97.9), 52.7% (23.4-75.5), and 52.9% (27.6-73.0). Favorable prognostic factors for EFS were Intergroup Rhabdomyosarcoma Study (IRS) stage I (p = 0.03) and T1 tumor (p = 0.05). A total of 78.3% of patients who had chemotherapy after 2000 received a standardized treatment.\nThe TREP Registry showed an excellent capacity for registering cases of PPB. Patients received homogeneous treatment after the TREP Project started. Long-term outcomes were excellent for type I and unsatisfactory for type II and III. Tumor invasiveness and IRS stage were of prognostic value.",
"affiliations": "Division of Pediatric Hematology and Oncology, Department of Women's and Children's Health, University of Padua, Padua, Italy.;Division of Pediatric Hematology and Oncology, Department of Women's and Children's Health, University of Padua, Padua, Italy.;Division of Pediatric Hematology and Oncology, Ospedale Microcitemico, ASL Cagliari, Cagliari, Italy.;Division of Pediatric Surgery, Department of Women's and Children's Health, University of Padua, Padua, Italy.;Pediatric Oncology Service, Department of Pediatrics, Second University, Naples, Italy.;Hematology/Oncology Department, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, Italy.;Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Bari Faculty of Medicine and Surgery, Bari, Italy.;Division of Pediatric Hematology and Oncology, Department of Women's and Children's Health, University of Padua, Padua, Italy.;Division of Pediatric Hematology and Oncology, Department of Women's and Children's Health, University of Padua, Padua, Italy.;Pediatric Oncology Unit, IRCCS Istituto Nazionale Tumori, Milan, Italy.;Pediatric Oncology Unit, IRCCS Istituto Nazionale Tumori, Milan, Italy.;Division of Pediatric Hematology and Oncology, Department of Women's and Children's Health, University of Padua, Padua, Italy.",
"authors": "Grigoletto|Veronica|V|https://orcid.org/0000-0001-6247-5739;Tagarelli|Arianna|A|;Atzeni|Catia|C|;Cecchetto|Giovanni|G|;Indolfi|Paolo|P|;De Pasquale|Maria Debora|MD|;De Leonardis|Francesco|F|;Coppadoro|Beatrice|B|;Sorbara|Silvia|S|;Chiaravalli|Stefano|S|;Ferrari|Andrea|A|;Bisogno|Gianni|G|",
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"doi": "10.1177/0300891619871344",
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"issue": "106(2)",
"journal": "Tumori",
"keywords": "Pleuropulmonary blastoma; TREP; cancer registry; children; very rare tumors",
"medline_ta": "Tumori",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005060:Europe; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007558:Italy; D008297:Male; D011379:Prognosis; D018202:Pulmonary Blastoma; D012208:Rhabdomyosarcoma",
"nlm_unique_id": "0111356",
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"pages": "126-132",
"pmc": null,
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"pubdate": "2020-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pleuropulmonary blastoma: a report from the TREP (Tumori Rari in Età Pediatrica) Project.",
"title_normalized": "pleuropulmonary blastoma a report from the trep tumori rari in et pediatrica project"
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"abstract": "Gabapentin and pregabalin are widely prescribed to elderly people, but data on their pharmacokinetics, safety, and efficacy in this population are scarce. Neurological adverse effects are common. Atrial fibrillation (AF) associated with their use has been described in several case reports and case series, but the incidence is unknown.\n\n\n\nThe aim of this study was to assess the association between exposure to gabapentin or pregabalin and AF in the elderly.\n\n\n\nPatients ≥ 65 years of age starting treatment with either gabapentin or pregabalin between January 1 and March 31, 2015, free of cardiovascular disease, and who did not receive the alternate study medications were studied. They were compared with patients who initiated treatment with an analgesic opiate or with alprazolam or diazepam. The two primary outcome variables were a first claim of an oral anticoagulant plus an antiarrhythmic drug (OAC + AA), or of an oral anticoagulant or an antiplatelet agent plus an antiarrhythmic drug (OAC/APA + AA), in the 3 months after treatment initiation.\n\n\n\nCompared with opiate analgesics, both gabapentin and pregabalin were associated with an increased risk of initiating OAC/APA + AA. The incidence was 6 of 668 (9.0 per 1000 patients) with gabapentin, versus 12 of 3889 (3.1 per 1000) with opiates, relative risk (RR) 2.91 (95% confidence interval [CI] 1.10-7.73), and for pregabalin it was 6 of 698 (8.6 per 1000) RR 2.79 (95% CI 1.05-7.40). The comparison with alprazolam/diazepam gave similar results. The risks did not vary by age, sex, or co-treatment with NSAIDs, and they increased with dose.\n\n\n\nIn elderly patients free of cardiovascular disease, an association between new exposure to gabapentin or pregabalin and initiating treatment for AF was found. These results should be confirmed in other studies.",
"affiliations": "Gerència de Prestacions Farmacèutiques i Accés al Medicament, Servei Català de la Salut, Travessera de Les Corts 131-159, Edifici Olimpia, 08028, Barcelona, Spain.;Gerència de Prestacions Farmacèutiques i Accés al Medicament, Servei Català de la Salut, Travessera de Les Corts 131-159, Edifici Olimpia, 08028, Barcelona, Spain.;Fundació Institut Català de Farmacologia (FICF), HU Vall d'Hebron, Universitat Autònoma de Barcelona, WHO Collaborating Centre for Research and Training in Pharmacoepidemiology, P Vall d'Hebron 119-129, 08035, Barcelona, Spain.;Gerència de Prestacions Farmacèutiques i Accés al Medicament, Servei Català de la Salut, Travessera de Les Corts 131-159, Edifici Olimpia, 08028, Barcelona, Spain.;Gerència de Prestacions Farmacèutiques i Accés al Medicament, Servei Català de la Salut, Travessera de Les Corts 131-159, Edifici Olimpia, 08028, Barcelona, Spain.;Fundació Institut Català de Farmacologia (FICF), HU Vall d'Hebron, Universitat Autònoma de Barcelona, WHO Collaborating Centre for Research and Training in Pharmacoepidemiology, P Vall d'Hebron 119-129, 08035, Barcelona, Spain. jrl@icf.uab.cat.",
"authors": "Ortiz de Landaluce|Leticia|L|;Carbonell|Pere|P|;Asensio|Carmen|C|;Escoda|Núria|N|;López|Pilar|P|;Laporte|Joan-Ramon|JR|http://orcid.org/0000-0001-9186-0097",
"chemical_list": "D000700:Analgesics; D000069583:Pregabalin; D000077206:Gabapentin",
"country": "New Zealand",
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"doi": "10.1007/s40264-018-0695-6",
"fulltext": "\n==== Front\nDrug SafDrug SafDrug Safety0114-59161179-1942Springer International Publishing Cham 69510.1007/s40264-018-0695-6Original Research ArticleGabapentin and Pregabalin and Risk of Atrial Fibrillation in the Elderly: A Population-Based Cohort Study in an Electronic Prescription Database Ortiz de Landaluce Leticia 1Carbonell Pere 1Asensio Carmen 2Escoda Núria 1López Pilar 1http://orcid.org/0000-0001-9186-0097Laporte Joan-Ramon +34-93 489 41 06jrl@icf.uab.cat 21 0000 0000 9127 6969grid.22061.37Gerència de Prestacions Farmacèutiques i Accés al Medicament, Servei Català de la Salut, Travessera de Les Corts 131-159, Edifici Olimpia, 08028 Barcelona, Spain 2 grid.7080.fFundació Institut Català de Farmacologia (FICF), HU Vall d’Hebron, Universitat Autònoma de Barcelona, WHO Collaborating Centre for Research and Training in Pharmacoepidemiology, P Vall d’Hebron 119-129, 08035 Barcelona, Spain 28 6 2018 28 6 2018 2018 41 12 1325 1331 © The Author(s) 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Introduction\nGabapentin and pregabalin are widely prescribed to elderly people, but data on their pharmacokinetics, safety, and efficacy in this population are scarce. Neurological adverse effects are common. Atrial fibrillation (AF) associated with their use has been described in several case reports and case series, but the incidence is unknown.\n\nObjective\nThe aim of this study was to assess the association between exposure to gabapentin or pregabalin and AF in the elderly.\n\nMethods\nPatients ≥ 65 years of age starting treatment with either gabapentin or pregabalin between January 1 and March 31, 2015, free of cardiovascular disease, and who did not receive the alternate study medications were studied. They were compared with patients who initiated treatment with an analgesic opiate or with alprazolam or diazepam. The two primary outcome variables were a first claim of an oral anticoagulant plus an antiarrhythmic drug (OAC + AA), or of an oral anticoagulant or an antiplatelet agent plus an antiarrhythmic drug (OAC/APA + AA), in the 3 months after treatment initiation.\n\nResults\nCompared with opiate analgesics, both gabapentin and pregabalin were associated with an increased risk of initiating OAC/APA + AA. The incidence was 6 of 668 (9.0 per 1000 patients) with gabapentin, versus 12 of 3889 (3.1 per 1000) with opiates, relative risk (RR) 2.91 (95% confidence interval [CI] 1.10–7.73), and for pregabalin it was 6 of 698 (8.6 per 1000) RR 2.79 (95% CI 1.05–7.40). The comparison with alprazolam/diazepam gave similar results. The risks did not vary by age, sex, or co-treatment with NSAIDs, and they increased with dose.\n\nConclusion\nIn elderly patients free of cardiovascular disease, an association between new exposure to gabapentin or pregabalin and initiating treatment for AF was found. These results should be confirmed in other studies.\n\nElectronic supplementary material\nThe online version of this article (10.1007/s40264-018-0695-6) contains supplementary material, which is available to authorized users.\n\nCatalan Health Service and Fundació Institut Català de Farmacologia.issue-copyright-statement© Springer Nature Switzerland AG 2018\n==== Body\nKey Points\n\nGabapentin and pregabalin are used for various indications, mainly low back pain and other painful conditions. In randomized clinical trials they have shown uncertain efficacy and common neurological adverse effects.\t\nAtrial fibrillation attributed to gabapentin and pregabalin has been described in case reports and in case series.\t\nCompared with alternative drugs for their most common indications, starting treatment with gabapentin or pregabalin was associated with an increased rate of initiation of antithrombotic and antiarrhythmic drugs, suggesting a new diagnosis of atrial fibrillation.\t\nGiven the potential clinical and public health implications of this association, its causal nature should be investigated in studies with individual patients’ data.\t\n\n\n\nIntroduction\nGabapentin and pregabalin are widely and increasingly used for various approved and off-label indications [1, 2], mainly chronic low back pain with or without a neuropathic component, neuropathic pain, and anxiety. Although they are frequently used in the elderly [3–5], there are no published studies on their pharmacokinetics in subjects over the age of 65 years, and evidence of efficacy and safety is unclear [6] and limited to younger adults [7–9].\n\nAtrial fibrillation (AF) attributed to gabapentin and to pregabalin has been described in anecdotal case reports and in case series assembled through spontaneous reporting [10–14]. Atrial fibrillation appeared within the first 3 months of treatment in 70% of cases, > 80% of patients were older than 65 years, and 6% of cases with gabapentin occurred in patients with diabetes mellitus. We examined this association in the Catalan Health Service (CHS) electronic prescription claims database.\n\nMethods\nA retrospective cohort study was performed, based on the CHS prescription claims database. The CHS provides public-funded universal healthcare coverage to the entire population of Catalonia (7.5 million inhabitants), including all prescription drugs. The electronic prescription database contains complete records of all prescriptions from all general practices and outpatient specialty clinics claimed from pharmacies in Catalonia. It includes data on patients’ age, sex, the dispensed medicines, and the date of the dispensing. It does not contain systematic data on indications and clinical diagnoses [15].\n\nIn clinical practice, the most common uses of gabapentin and pregabalin are low back pain and/or sciatica with a generally ill-defined neuropathic component [2], and anxiety. We therefore aimed to compare all patients ≥ 65 years old who initiated treatment with gabapentin or with pregabalin, with patients who initiated treatment with other drugs alternatively used in the same conditions; that is, opiate analgesics for pain, and alprazolam or diazepam for anxiety. Alprazolam and diazepam were chosen because they are the most widely used benzodiazepines for anxiety in Spain [16].\n\nFour cohorts were studied: patients initiating treatment with gabapentin (ATC code N03AX12), with pregabalin (N03AX16), with an opiate analgesic (N02A), or with alprazolam or diazepam (N05BA12 or N05BA02), between January 1 and March 31, 2015 were considered. For each patient, the index date was the date of the first dispensing of the corresponding medication of interest. Previous use of cardiovascular medications was considered as a marker for cardiovascular disease or cardiovascular risk, and also as a potential confounding factor. Therefore, patients who had received a cardiovascular medicine (Group C of the ATC classification) or an antithrombotic agent (oral anticoagulant or antiplatelet agent; groups B01AA, B01AE, and B01AF of the ATC classification) in the 6 months before the index date were excluded.\n\nStart of treatment with any of the study medications was defined as a claimed prescription for a patient who had not been dispensed that medication in the 6 months preceding the index date. The primary analyses were performed in patients who initiated treatment with only one of the study medications (and not with other study medications). Secondary analyses were performed including all patients who initiated treatment with each of the study drugs, including those on concomitant treatment with any of the other study medications (e.g., patients concomitantly on pregabalin and alprazolam, pregabalin and an opiate, etc.). Within each cohort, patients were stratified into three groups: those who started treatment with the medication of interest without a nonsteroidal anti-inflammatory drug (NSAID), those who started with both the medication of interest and an NSAID, and those to whom the medication of interest had been added to an NSAID that had already been dispensed in the 6 months before. The main analyses were performed considering only patients who initiated treatment with any of the medications of interest and not with an NSAID.\n\nThe outcome measure was the proportion of patients claiming a first prescription of medications specifically used in the treatment of AF in the 3 months after the date of the initial dispensing of the study drug. Several outcome variables were selected. The primary co-variables were a first claim of an oral anticoagulant (OAC, groups B01AA, B01AE, and B01AF of the ATC classification) plus an antiarrhythmic drug (AA, ATC code, C01B) (OAC + AA), and a first claim of an OAC or an antiplatelet agent (APA, ATC code, B01AC) plus an antiarrhythmic drug (OAC/APA + AA). Two secondary variables were examined: a first claim of an AA, and a first claim of an OAC or an APA (OAC/APA). The secondary variable OAC/APA, with higher numbers of patients, was used for the analyses stratified by dose, age, and sex.\n\nThe cohorts of users of gabapentin, pregabalin, or any of both were compared with the cohort of opiate users and with that of alprazolam or diazepam users.\n\nFor each outcome variable, relative risks and their corresponding two-sided 95% confidence intervals (CIs) were computed using the VassarStats website for statistical computation (http://vassarstats.net). Stratified analyses were performed by age groups (65–74, 75–84, and ≥ 85 years), by sex, and by co-treatment with NSAIDs. In order to evaluate dose–effect relationships, two dose strata were considered: < 1200 and ≥ 1200 mg per day for gabapentin, and < 150 and ≥ 150 mg per day for pregabalin. The outcome variables with the highest numbers of patients (i.e., OAC/APA + AA and OAC/APA) were used for dose–effect analyses.\n\nEthical approval was not sought, because it is not required for observational studies using anonymized nationwide registries in Catalonia. This study is registered in the European Union Electronic Register of Post-Authorisation Studies (EU PAS Register) with the number EUPAS15048.\n\nResults\nFrom January 1 to March 31 2015, 5402 individuals aged ≥ 65 years initiated treatment with gabapentin, 6053 with pregabalin, 37,500 with opiate analgesics, and 19,849 with alprazolam or diazepam. Fig. S1 of the Electronic Supplementary Material (ESM) shows a flow chart on the selection of the study patients. The cohort of users of alprazolam or diazepam had higher proportions of females and of individuals in the younger age group (65–74 years of age) (Table 1).Table 1 Age and sex distribution and cardiovascular comorbidity of the study cohorts\n\n\tGabapentin\tPregabalin\tAlprazolam\nor diazepam\tOpiatesa\t\nN dispensed, aged ≥ 18 y\t47,104\t63,423\t289.654\t223,614\t\nN aged ≥ 65 y (%)\t25,759 (54.7)\t30,811 (48.6)\t98,323 (33.9)\t129,243 (57.8)\t\nN aged ≥ 65 y initiating treatment\t5402\t6053\t18,119b\t33,343b\t\nAlready on CV medication, n (%)\t4490 (83.1)\t4979 (82.3)\t14,231 (78.5)\t27,653 (83.9)\t\nNaïve to CV medication, n (%)\t912 (16.9)\t1074 (17.7)\t3888 (21.5)\t5690 (17.1)\t\n Units per patient (mean)c\t2.0\t2.6\t1.9\t2.7\t\n Female, %\t65.5\t65.6\t71.2\t68.2\t\n Aged 65–74, %\t60.6\t65.1\t73.5\t62.1\t\n Aged 75–84, %\t29.7\t26.8\t19.8\t27.5\t\n Aged ≥ 84, %\t9.6\t8.1\t6.7\t10.4\t\nCV cardiovascular\n\naIn defined daily doses (DDDs), tramadol made up 52% of total consumption, followed by fentanyl (26%), and other opiates (22%; morphine, oxycodone, tapentadol, etc.)\n\nbPatients who initiated treatment during the study period, free of gabapentin and pregabalin during the first month and in the 6 months before\n\ncDuring the first 3 months of exposure\n\n\n\n\nOut of 5402 patients aged ≥ 65 years initiating treatment with gabapentin, 4490 (83.1%) were already on cardiovascular medications. The corresponding figure for pregabalin was 4979 (82.3%).\n\nIn all four cohorts, the rates of treatment initiation with antithrombotic drugs (OAC/APA) or with OAC/APA plus an antiarrhythmic drug (OAC/APA + AA) in the 3 months after the dispensing of the medications of interest increased considerably with age, and it was higher with gabapentin and pregabalin compared with opiate analgesics or alprazolam/diazepam (Fig. 1). There were no differences between males and females.Fig. 1 Effect of age (y) on the rate of two outcomes in each cohort. OAC/APA + AA oral anticoagulant or antiplatelet drug plus antiarrhythmic drug, OAC/APA oral anticoagulant or antiplatelet drug\n\n\n\nThe incidence rates of initiating OAC/APA + AA were 3.1 per 1000 exposed patients for alprazolam/diazepam, 3.1 for opiate analgesics, 9.0 for gabapentin, and 8.6 for pregabalin (relative risk [RR] 2.91 [95% CI 1.10–7.73] for gabapentin, and RR 2.79 [95% CI 1.05–7.40] for pregabalin, compared with opiate analgesics). The incidence rates of initiating OAC + AA were 1.8 per 1000 patients for opiates, 3.0 for alprazolam/diazepam, 6.0 for gabapentin, and 5.1 for pregabalin. Table 2 shows the risks of the primary and the secondary variables. All the risk estimates were increased, and their magnitudes were similar for gabapentin and pregabalin. However, for the primary variable (OAC + AA) they did not reach statistical significance due to low numbers of patients, both in comparison with opiate analgesics and with alprazolam/diazepam. There were no differences in the risk estimates in the three age strata, nor by sex (Table S1 of the ESM). The results did not vary materially when all patients under the study medications were considered, including those who were concomitantly on more than one study drug (Table S2 of the ESM).Table 2 Use of drugs for atrial fibrillation\n\n\tOAC + AAa\tOAC/APA + AAb\tAAc\tOAC/APAd\t\nCompared with opiate analgesics\t\n Opiates\t1.00 (Reference category)\n(7/3889)\t1.00 (Reference category)\n(12/3889)\t1.00 (Reference category)\n(21/3889)\t1.00 (Reference category)\n(148/3889)\t\n Gabapentin\t3.33 (0.98–11.33)\n(4/668)\t2.91 (1.10–7.73)\n(6/668)\t2.50 (1.15–5.42)\n(9/668)\t2.60 (1.57–2.82)\n(58/668)\t\n Pregabalin\t2.39 (0.62–9.21)\n(3/698)\t2.79 (1.05–7.40)\n(6/698)\t1.86 (0.79–4.35)\n(7/698)\t1.84 (1.36–2.49)\n(53/698)\t\n GP/PGe\t2.85 (1.00–8.10)\n(7/1366)\t2.85 (1.28–6.32)\n(12/1366)\t2.17 (1.14–4.14)\n16/1366)\t1.97 (1.55–2.50)\n(111/1366)\t\nCompared with benzodiazepines\t\n AL/DZf\t1.00 (Reference category)\n(8/2.640)\t1.00 (Reference category)\n(10/2640)\t1.00 (Reference category)\n(12/2640)\t1.00 (Reference category)\n(128/2640)\t\n Gabapentin\t1.96 (0.59–6.50)\n(4/668)\t2.37 (0.86–6.50)\n(6/668)\t2.92 (1.24–6.91)\n(9/668)\t1.79 (1.33–2.41)\n(58/668)\t\n Pregabalin\t1.42 (0.38–5.33)\n(3/698)\t2.27 (0.83–6.22)\n(6/698)\t2.21 (0.87–5.58)\n(7/698)\t1.57 (1.15–2.13)\n(53/698)\t\n GP/PGe\t1.69 (0.61–4.65)\n(7/1366)\t2.32 (1.00–5.35)\n(12/1366)\t2.58 (1.22–5.43)\n(16/1366)\t1.68 (1.31–2.14)\n(111/1366)\t\naOAC + AA: Patients who started treatment with an oral anticoagulant plus an antiarrhythmic drug in the 3 months after treatment initiation with the study drug\n\nbOAC/APA + AA: Patients who started treatment with an oral anticoagulant or an antiplatelet agent plus an antiarrhythmic drug in the 3 months after treatment initiation with the study drug\n\ncAA: Patients who started treatment with an antiarrhythmic drug in the 3 months after treatment initiation with the study drug\n\ndOAC: Patients who started treatment with an oral anticoagulant in the 3 months after treatment initiation with the study drug\n\neGP/PG: gabapentin or pregabalin\n\nfAL/DZ: alprazolam or diazepam\n\n\n\n\nIn each cohort, the results among patients who initiated treatment with the medication of interest added to an NSAID or at the same time as an NSAID were not different from those in patients who were not on NSAIDs (data not shown).\n\nThere were 561 patients treated with gabapentin at doses < 1200 mg per day (84%), and 107 (16%) with ≥ 1200 mg per day. For pregabalin, 579 patients received < 150 mg per day (83%) and 119 (17%) received > 150 mg per day. The relative risks of the variables were twice as high among patients receiving the higher doses, compared with those on lower doses (Table 3).Table 3 Dose of gabapentin and pregabalin and risk of initiating antithrombotic treatment, alone or simultaneously with an antiarrhythmic drug\n\n\tOAC/APAa\tOAC/APA + AAb\t\nCompared with opiates\t\n Gabapentin\t\n < 1200 mg per day\t1.90 (1.37–2.63)\n(44/561)\t2.32 (0.75–7.16)\n(4/561)\t\n ≥ 1200 mg per day\t3.17 (1.90–5.30)\n(14/107)\t6.07 (1.38–26.80)\n(2/107)\t\n All\t2.60 (1.57–2.82)\n(58/668)\t2.92 (1.10–7.75)\n(6/668)\t\n Pregabalin\t\n < 150 mg per day\t1.51 (1.06–2.15)\n(36/579)\t2.24 (0.73–6.94)\n(4/579)\t\n ≥ 150 mg per day\t3.46 (2.17–5.53)\n(17/119)\t5.46 (1.24–24.13)\n(2/119)\t\n All\t1.84 (1.36–2.49)\n(53/698)\t2.79 (1.05–7.42)\n(6/698)\t\n Gabapentin or pregabalin\t\n Low dose\t1.70 (1.31–2.22)\n(80/1140)\t2.28 (0.93–5.56)\n(8/1140)\t\n High dose\t3.33 (2.31–4.78)\n(31/226)\t5.76 (1.87–17.69)\n(4/226)\t\n All\t1.97 (1.55–2.50)\n(111/1366)\t2.85 (1.29–6.34)\n(12/1.366)\t\nCompared with benzodiazepines\t\n Gabapentin\t\n < 1200 mg per day\t1.62 (1.16–2.25)\n(44/561)\t1.89 (0.59–6.00)\n(4/561)\t\n ≥ 1200 mg per day\t2.70 (1.61–4.52)\n(14/107)\t4.86 (1.08–21.90)\n(2/107)\t\n All\t1.79 (1.33–2.41)\n(58/668)\t2.37 (0.86–6.50)\n(6/668)\t\n Pregabalin\t\n < 150 mg per day\t1.21 (0.84–1.73)\n(36/579)\t1.82 (0.57–5.78)\n(4/579)\t\n ≥ 150 mg per day\t2.95 (1.84-4.72)\n(17/119)\t4.45 (0.99–20.10)\n(2/119)\t\n All\t1.73 (1.31–2.28)\n(53/698)\t2.27 (0.83–6.22)\n(6/698)\t\n Gabapentin or pregabalin\t\n Low dose\t1.45 (1.10–1.90)\n(80/1140)\t1.86 (0.74–4.70)\n(8/1140)\t\n High dose\t2.83 (1.96–4.09)\n(31/226)\t4.69 (1.48–14.84)\n(4/226)\t\n All\t1.68 (1.31–2.14)\n(111/1366)\t2.32 (1.00–5.35)\n(12/1366)\t\naOAC/APA: Patients who started treatment with an oral anticoagulant or an antiplatelet agent in the 3 months after treatment initiation with the study drug\n\nbOAC/APA + AA Patients who started treatment with an oral anticoagulant or antiplatelet agent plus antiarrhythmic drug in the 3 months after treatment initiation with the study drug\n\n\n\nDiscussion\nWe found that, compared with users of opiates and of alprazolam or diazepam, users of both gabapentin and pregabalin were at increased risk of initiating treatment with medicines specifically used in the management of AF within 3 months after treatment initiation. The RR estimates were consistent for the primary and secondary variables and across the age, sex, and co-medication strata, and they showed a dose–response trend.\n\nAF associated with gabapentin or pregabalin has not been described in reports of randomized clinical trials (RCTs) or in systematic reviews of RCTs. The reason may be that participants in placebo-controlled RCTs with gabapentin [8] or pregabalin [9] had a mean age of 55 years. In contrast, in a series of patients with AF possibly induced by gabapentin [13] or pregabalin [14], > 80% were older than 60 years.\n\nGabapentin and pregabalin exhibit L-type calcium channel antagonism and attenuate calcium influx, which can explain unwanted electrophysiological effects. Both drugs are eliminated by renal excretion as unchanged drugs, and both Summary of Product Characteristics (SPCs) state that elderly patients may require a dose reduction [17, 18]. However, pharmacokinetic studies in subjects over the age of 65 years have not been reported [7].\n\nOur study covered the whole population, so that representativeness of the study population is not a concern. Patients on cardiovascular medications were excluded and the analyses were restricted to incident users, so that the potential biases and confounding that would have been introduced by the inclusion of patients with high cardiovascular risk and prevalent users were avoided. Patients initiating treatment with gabapentin or with pregabalin were compared with patients initiating treatment with two different alternative therapeutic options in the most common indications of gabapentinoids. The comparison with both opiates and benzodiazepines showed increases of risk in the same direction and of similar magnitudes. The results are biologically plausible, and they were consistent for the primary and the secondary variables and across all age, sex, and NSAID co-treatment strata. A dose–effect trend was found. A material increase in risk with alprazolam or diazepam was not recorded. These features indicate that users of gabapentin and pregabalin are at increased risk of initiating antithrombotic and antiarrhythmic drugs, probably prompted by a diagnosis of AF.\n\nOur study has several limitations. Those which merit more emphasis relate to the lack of clinical details on the participants and to the validity of the outcome variables used. The lack of clinical details precluded describing their clinical course and their prognosis and adjusting for potential clinical confounding factors such as the indication for use and co-morbidities. The outcome variables were surrogate markers of AF. A recent study performed in the French healthcare databases has suggested that the initiation of an oral anticoagulant and an antiarrhythmic drug (OAC + AA) recorded in the national pharmaceutical benefits database (SNIRAM) is the strongest predictor for confirmed AF [19]. In our study, the number of patients initiating OAC + AA was low. However, when patients exposed to either gabapentin or pregabalin were considered, the risk was significantly increased with respect to both opiate analgesics and alprazolam/diazepam. Due to lower numbers of exposed patients, our stratified age, sex, and dose–response analyses were based on the variables OAC/APA and OAC/APA + AA, which may be less specific for AF but included higher numbers of patients. For these reasons, our results should be regarded as hypothesis generating.\n\nIt is generally considered that the use of prescription claims as proxy variables for the clinical conditions under study can limit the validity of the results. However, as an outcome variable, the prescription of an oral antithrombotic and/or an antiarrhythmic agent is at least as hard as an often tentative diagnosis of AF in the medical record. The use of antiarrhythmic drugs without antithrombotic medication, which may reflect prescribing for a patient with AF with a low risk of stroke, was also significantly increased in users of gabapentin or pregabalin.\n\nIf the association between exposure to gabapentinoids and AF is a causal one, its public health impact could be higher than suggested by our data, at least for three reasons. First, although the respective SPCs warn “caution in cardiovascular patients” [17, 18], more than 80% of the new users of gabapentin or pregabalin were already on at least one cardiovascular medication, which is a marker of cardiovascular risk. In order to avoid confounding, we excluded these high-risk patients from the study. Second, in large series of cases reported to the FDA, 70–80% of patients with newly diagnosed AF attributed to gabapentin or pregabalin had developed the condition during the first 3 months of treatment [13, 14], suggesting that additional cases can appear > 3 months after treatment initiation. Third, up to 30% of cases of AF may take time to be diagnosed [20, 21] and many of those who are diagnosed do not receive full anticoagulation initially [22], so that the actual number of cases of AF is probably higher than the number of patients initiating treatment with an antithrombotic drug. Conversely, an episode of AF occurring before the prescription of gabapentin or pregabalin may have been initially overlooked or left untreated, but diagnosed and treated some weeks after the gabapentinoid was prescribed, and this would overestimate the risk.\n\nIn recent years, the consumption of gabapentin and pregabalin has increased steadily [1, 3–5, 23]. Pain appears to be their most common indication [2, 24]. Although their efficacy in neuropathic pain is modest at best, they are widely used for conditions in which the neuropathic component is difficult to establish. In industry-sponsored placebo-controlled RCTs in neuropathic pain, gabapentin was ineffective at doses < 1200 mg per day [8] and pregabalin at doses < 150 mg per day [9]. The best (lowest) number needed to treat for at least a 50% pain relief over baseline with pregabalin was 3.9, but only with a dose of 600 mg daily, which in turn was associated with a withdrawal rate of 19% (mainly due to dizziness and somnolence) [9]. In a recent rigorously conducted placebo-controlled trial, pregabalin at doses of 150–600 mg daily was ineffective to mitigate pain or disability in patients with painful sciatica, and it was associated with a 3-fold increase in the incidence of dizziness [6]. A recent systematic review on gabapentinoids in chronic low back pain concluded that limited evidence shows a significant risk of adverse effects without any demonstrated benefit [25]. In our study, 84% of patients on gabapentin or pregabalin had been prescribed < 1200 mg per day or 150 mg per day, respectively, and the risks of the main outcome variables were already increased with these lower doses.\n\nGabapentin was approved in 1993 as adjunctive therapy for partial complex seizures. Heavy promotion for unapproved indications pushed its sales in the US from US$98 million in 1995 to nearly US$3 billion in 2004 [26]. In that year gabapentin lost its patent, but Pfizer launched pregabalin, not only for epilepsy but also for the wider, softer, and better selling indications of anxiety and neuropathic pain. Gabapentin and pregabalin are being prescribed off-label for painful conditions, mainly low back pain [2], where the neuropathic component is difficult to establish. In 2016 pregabalin reached global sales of US$5435M, and it ranked 12th in the list of global top-selling pharmaceuticals [27]. Between 2012 and 2016, prescriptions of gabapentin increased from 39 to 64 million, and sales of pregabalin increased by more than 2.4-fold in the US [1]. Our results contrast with the fact that after decades of wide and rising clinical use of gabapentin and pregabalin, only a few case reports and case series of AF attributed to these drugs have been described.\n\nConclusion\nIn summary, we found that, despite warnings of caution in the elderly in the respective SPCs, gabapentin and pregabalin were predominantly prescribed to patients with cardiovascular risk, generally at doses too low to be effective. In addition, we found a signal suggesting that in elderly patients free of cardiovascular disease, exposure to gabapentin or to pregabalin may be associated with an increased risk of AF. The incidence might be substantially higher than is stated in the respective SPCs. This association should be confirmed by a review of the company’s postmarketing surveillance data and in studies with validated clinical diagnoses. Meanwhile, given the poor efficacy and benefit/risk ratio of these drugs in their most common indications in clinical practice, prescribers should avoid them, particularly in the elderly and in patients with established or suspected cardiovascular disease or with high cardiovascular risk. In clinical practice, it seems advisable to stop gabapentin or pregabalin in any exposed patient presenting with AF.\n\nElectronic supplementary material\nBelow is the link to the electronic supplementary material.\nSupplementary material 1 (PDF 388 kb)\n\n \n\n\nFunding\nThis work is part of a project on safety of electronic prescribing of the Catalan Health Service and Fundació Institut Català de Farmacologia.\n\nAcknowledgements\nLuisa Ibáñez (FICF), Mònica Sabaté (FICF), and Xavier Vidal (FICF) reviewed the draft paper and formulated comments. Xavier Vidal advised on statistical analysis. Héctor Carmona (FICF) gave support in statistical analyses and manuscript editing. Antoni Gilabert gave institutional support.\n\nConflicts of interest\nLeticia Ortiz, Pere Carbonell, Carmen Asensio, Núria Escoda, Pilar López, and Joan-Ramon Laporte have no conflicts of interest that are directly relevant to the content of this study.\n\nDisclaimer\nThe views expressed are solely those of the authors and do not necessarily represent the position of, nor imply endorsement from, the Catalan Health Service.\n==== Refs\nReferences\n1. Goodman CW Brett AS Gabapentin and pregabalin for pain—is increased prescribing a cause for concern? N Engl J Med 2017 377 411 414 10.1056/NEJMp1704633 28767350 \n2. Härmark Linda van Puijenbroek Eugène Straus Sabine van Grootheest Kees Intensive Monitoring of Pregabalin Drug Safety 2011 34 3 221 231 10.2165/11585030-000000000-00000 21332246 \n3. Ferrer-Argeles P, Rafaniello C, Sabaté M, Ballarin E, Coma A, Zara C, et al. Cross-national comparison of antiepileptic drug use: Catalonia, Denmark and Norway, 2007–2011. Epidemiol Biostat Public Health. 2014;11: e9405-1–e9405-9.\n4. Savica R Beghi E Mazzaglia G Innocenti F Brignoli O Cricelli C Prescribing patterns of antiepileptic drugs in Italy: a nationwide population-based study in the years 2000–2005 Eur J Neurol 2007 14 1317 1321 10.1111/j.1468-1331.2007.01970.x 17903210 \n5. Johansen ME Gabapentinoid use in the United States 2002 through 2015 JAMA Intern Med. 2018 178 292 294 10.1001/jamainternmed.2017.7856 29297045 \n6. Mathieson S Chiro M Maher CG LcLachlan AJ Latimer J Koes BW Trial of pregabalin for acute and chronic sciatica N Engl J Med 2017 376 1111 1120 10.1056/NEJMoa1614292 28328324 \n7. Ben-Menachem E Pregabalin pharmacology and its relevance to clinical practice Epilepsia. 2004 45 Suppl 6 13 18 10.1111/j.0013-9580.2004.455003.x \n8. Wiffen PJ, Derry S, Bell RF, Rice ASC, Tölle T, Phillips T, et al. Gabapentin for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2017;6:CD007938. 10.1002/14651858.cd007938.pub4. http://www.cochrane.org/CD007938/SYMPT_gabapentin-chronic-neuropathic-pain-adults. Accessed 13 June 2018.\n9. Moore RA, Straube S, Wiffen PJ, Derry S, McQuay HJ. Pregabalin for acute and chronic pain in adults. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.:CD007076. 10.1002/14651858.cd007076.pub2. http://www.cochrane.org/CD007076/SYMPT_pregabalin-acute-and-chronic-pain-adults. Accessed 13 June 2018..\n10. Chilkoti G Wadhwa R Saxena A Khurana P Could pregabalin premedication predispose to perioperative atrial fibrillation in patients with sepsis? Saudi J Anaesth. 2014 8 Suppl 1 S115 S116 25538502 \n11. Laville MA de la Gastine B Husson B Le Boisselier R Mosquet B Coquerel A Faut-il se méfier de la prégabaline chez les patients âgés aux antécédents de troubles du rythme cardiaque? La Revue de Médecine Interne. 2008 29 152 154 10.1016/j.revmed.2007.07.009 17976866 \n12. Martinez L, Therasse C, Ginisty S, Eftekhari P. Cardiac events and pregabalin: spontaneous reports notified to the French pharmacovigilance database. 34èmes Journées de Pharmacovigilance, Angers, 22-24 April 2013. Fundamental Clin Pharmacol. 2013;27 [suppl 1]:95 (abstract P 2–086).\n13. eHealthMe, Personalized Health Information. Review: could gabapentin cause atrial fibrillation (Atrial fibrillation/flutter)? http://www.ehealthme.com/ds/gabapentin/atrial+fibrillation. Accessed 10 May 2018.\n14. eHealthMe, Personalized Health Information. Review: could Lyrica cause atrial fibrillation (Atrial fibrillation/flutter)? http://www.ehealthme.com/ds/lyrica/atrial+fibrillation. Accessed 10 May 2018.\n15. Gilabert-Perramon A López-Calahorra P Escoda-Geli N Salvadó-Trias C Receta electrónica en Cataluña (Rec@t): una herramienta de salud Med Clin 2010 134 Suppl 1 49 55 10.1016/S0025-7753(10)70010-5 \n16. CatSalut. Informe mensual de seguiment de la prestació farmacèutica. Facturació de Farmàcia, setembre 2016. http://www.consorci.org/media/upload/arxius/Butlleti/MaterialButlleti/InformeSeguimentFarmacia_Set2016.pdf Accessed 10 May 2018.\n17. Neurontin—Article 30 referral—Annex III. Summary of product characteristics, labelling and package leaflet. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Neurontin_30/WC500009308.pdf Accessed 10 May 2018.\n18. Lyrica: EPAR—Product Information. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000546/WC500046602.pdf Accessed 10 May 2018.\n19. Billionnet C Alla F Bérigaud É Pariente A Maura G Identifying atrial fibrillation in outpatients initiating oral anticoagulants based on medico-administrative data: results from the French national healthcare databases Pharmacoepidemiol Drug Saf 2017 26 535 543 10.1002/pds.4192 28295882 \n20. Schnabel RB Yin X Gona P Larson MG Beiser AS McManus DD 50 year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the Framingham Heart Study: a cohort study Lancet 2015 386 154 162 10.1016/S0140-6736(14)61774-8 25960110 \n21. Svennberg E Engdahl J Al-Khalili F Friberg L Frykman V Rosenqvist M Mass screening for untreated atrial fibrillation. The STROKESTOP study Circulation. 2015 131 2176 2184 10.1161/CIRCULATIONAHA.114.014343 25910800 \n22. Hsu JC Maddox TM Kennedy K Katz DF Marzec LN Lubitz SA Aspirin instead of oral anticoagulant prescription in atrial fibrillation patients at risk for stroke J Am Coll Cardiol 2016 67 2913 2923 10.1016/j.jacc.2016.03.581 27339487 \n23. Fuzier R Serres I Guitton E Lapeyre-Mestre M Montastruc J-L The French Network of Pharmacovigilance Centres. Adverse drug reactions to gabapentin and pregabalin. A review of the French pharmacovigilance database Drug Saf 2013 36 55 62 10.1007/s40264-012-0006-6 23315296 \n24. Jack A Pfizer steps up battle to defend control of pregabalin BMJ 2015 350 h3119 10.1136/bmj.h3119 26055697 \n25. Shanthanna H Gilron I Rajarathinam M AlAmri R Kamath S Thabane L Benefits and safety of gabapentinoids in chronic low back pain: A systematic review and meta-analysis of randomized controlled trials PLoS Med. 2017 14 e1002369 10.1371/journal.pmed.1002369 28809936 \n26. Landefeld CS Steinman MA The Neurontin legacy—Marketing through misinformation and manipulation N Engl J Med 2009 360 103 106 10.1056/NEJMp0808659 19129523 \n27. Top 50 pharmaceutical products by global sales. http://www.pmlive.com/top_pharma_list/Top_50_pharmaceutical_products_by_global_sales. Accessed 10 May 2018.\n\n",
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"mesh_terms": "D000367:Age Factors; D000368:Aged; D000700:Analgesics; D001281:Atrial Fibrillation; D015331:Cohort Studies; D016208:Databases, Factual; D055695:Electronic Prescribing; D005260:Female; D000077206:Gabapentin; D006801:Humans; D008297:Male; D011159:Population Surveillance; D000069583:Pregabalin; D012189:Retrospective Studies; D012307:Risk Factors",
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"title": "Gabapentin and Pregabalin and Risk of Atrial Fibrillation in the Elderly: A Population-Based Cohort Study in an Electronic Prescription Database.",
"title_normalized": "gabapentin and pregabalin and risk of atrial fibrillation in the elderly a population based cohort study in an electronic prescription database"
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"abstract": "A 47-year-old man presented to the emergency department with a rapidly progressive, generalized rash and pustulosis shortly after he had started amoxicillin/clavulanic acid for the treatment of a pulmonary infection. Based on the patient's history and the clinical symptoms, the diagnosis of 'acute generalized exanthematous pustulosis' (AGEP) was suspected. This was confirmed by histopathological examination. The skin abnormalities slowly disappeared after terminating antibiotic medication.",
"affiliations": "Westfriesgasthuis, afd. Spoedeisende Geneeskunde, Hoorn, the Netherlands. c.e.vandrie@amc.uva.nl",
"authors": "van Drie|Christy E|CE|;Kuypers|Maybritt I|MI|",
"chemical_list": "D000900:Anti-Bacterial Agents; D019980:Amoxicillin-Potassium Clavulanate Combination",
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"mesh_terms": "D056150:Acute Generalized Exanthematous Pustulosis; D019980:Amoxicillin-Potassium Clavulanate Combination; D000900:Anti-Bacterial Agents; D006801:Humans; D008297:Male; D008875:Middle Aged",
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"references": null,
"title": "A man with erythema and pustules.",
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"abstract": "Introduction.Staphylococcus caprae is a coagulase-negative staphylococcus that has been reported in several cases as a human pathogen. However, it has rarely been reported as pathogen in native bone. Furthermore, the reported MIC levels noted in the literature for vancomycin were <2 µg ml-1making vancomycin a first line choice for infected patients. Case presentation. We report a case of Staphylococcus caprae causing osteomyelitis of the lumbar spine and bacteraemia and resulting in sepsis and ultimately the demise of a patient despite appropriate prolonged antibiotic therapy. Conclusion.Staphylococcus caprae has been reported as a human pathogen since 1983 when it was discovered. We report a case involving native bone infection which is rare in the absence of mechanical hardware. Furthermore, this strain had an elevated MIC for vancomycin which has not been reported in the literature.",
"affiliations": "Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA.;Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA.;Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA.",
"authors": "Hilliard|Carolyn A|CA|;El Masri|Jad|J|;Goto|Michihiko|M|",
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"country": "England",
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"doi": "10.1099/jmmcr.0.005112",
"fulltext": "\n==== Front\nJMM Case RepJMM Case RepJMMCRJMM Case Reports2053-3721Microbiology Society jmmcr00511210.1099/jmmcr.0.005112Case ReportBoneStaphylococcus caprae bacteraemia and native bone infection complicated by therapeutic failure and elevated MIC: a case report http://jmmcr.microbiologyresearch.orgHilliard Carolyn A. El Masri Jad Goto Michihiko Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA*Correspondence: Carolyn A. Hilliard, carolyn-hilliard@uiowa.edu9 2017 18 9 2017 4 9 e00511226 4 2017 21 8 2017 © 2017 The Authors2017This is an open access article under the terms of the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.Introduction.\nStaphylococcus caprae is a coagulase-negative staphylococcus that has been reported in several cases as a human pathogen. However, it has rarely been reported as pathogen in native bone. Furthermore, the reported MIC levels noted in the literature for vancomycin were <2 µg ml−1making vancomycin a first line choice for infected patients.\n\nCase presentation. We report a case of Staphylococcus caprae causing osteomyelitis of the lumbar spine and bacteraemia and resulting in sepsis and ultimately the demise of a patient despite appropriate prolonged antibiotic therapy.\n\nConclusion.\nStaphylococcus caprae has been reported as a human pathogen since 1983 when it was discovered. We report a case involving native bone infection which is rare in the absence of mechanical hardware. Furthermore, this strain had an elevated MIC for vancomycin which has not been reported in the literature.\n\nStaphylococcus capraetherapeutic failureelevated MICbacteraemianative joint infectionvancomycinOpenAccessEmbargo0\n==== Body\nAbbreviations\nMALDI-TOF, matrix-assisted laser desorption/ionization time-of-flight; MRI, magnetic resonance imaging.\n\nIntroduction\nStaphylococcus caprae is a coagulase-negative staphylococcus that was first described in 1983 after being isolated from goats where it causes mastitis [1–4]. S. caprae typically colonizes human skin, nose and nails and since 1983 it has been reported in several cases as a human pathogen causing peritonitis, meningitis, urinary tract infections, endocarditis, endophthalmitis, prosthetic joint infections, recurrent sepsis, bacteraemia and osteomyelitis [4–9]. Many risk factors for S. caprae have begun to emerge and include immunosuppression, diabetes, chronic renal failure, obesity, open or traumatic fractures and contact with sheep or goats [4, 6]. Importantly, several strains of S. caprae have been noted to produce toxic shock syndrome toxin and carry the gene mecA important for methicillin resistance, and have been noted to form a biofilm in vitro on prostheses or bone thought to be due to the presence of the gene altC in combination with the ica operon [1, 4, 6, 10]. Very few cases of S. caprae bone and joint infection occur in native bone and joints without prostheses, and there are few cases of bacteraemia not associated with line infections. In this case report we present Staphylococcus caprae infection of native vertebrae with resulting bacteraemia and ultimately failure of therapy, and summarize the current case reports of infection with this organism.\n\nCase report\nOur patient was a 69-year-old man with a history of cryptogenic liver cirrhosis (diagnosed 3 months prior to this hospitalization), diabetes mellitus and a history of lumbar spine hemi-laminotomy in 2007. He was admitted to our institution after leaving an outside hospital emergency department for acute worsening of chronic lower back pain, and difficulty ambulating. The patient had been previously diagnosed with L4–L5 discitis with methicillin-susceptible Staphylococcus caprae bacteraemia 3 months prior to admission (drawn at outside hospital, MicroScan panels confirming sensitivity to vancomycin with MIC of <1 µg ml−1) that was treated for 9 weeks total with parenteral antibiotic therapy (initially ertapenem, followed by vancomycin for 6 weeks) at an outside institution. Despite antibiotic therapy, the patient continued to have low back pain, worsening subjective weakness and numbness in his legs and 2 weeks after finishing antibiotics he was unable to walk even with a walker due to pain. Prior to admission, he was evaluated by a neurosurgeon for his chronic back pain in clinic and was thought to have degenerative changes of the spine that were not amenable to surgery.\n\nThe patient reported that the pain was in the lower back, radiating to the lower extremities, chronic with acute worsening over the 5 days preceding the evaluation. On examination, the patient had no fevers and had normal vital signs. He did not have point tenderness on his back, and had 2/5 strength documented in all his extremities, normal sensation and no documentation of gait. Laboratory tests revealed a normal white blood cell count of 9.2 K per mm3, sedimentation rate of 83 mm h−1, and C-reactive protein of 2.5 mg dl−1, with evidence of an acute kidney injury (serum creatinine level: 2.1 mg dl−1 with a normal baseline) and decompensated liver cirrhosis. Magnetic resonance imaging (MRI) of the lumbar spine revealed spinal discitis/osteomyelitis at L4–L5 level with epidural phlegmon resulting in severe canal stenosis at L4–L5 level (Fig. 1). Initially, antibiotics were held as the patient was still haemodynamically stable and a biopsy of affected spine lesion with cultures was desired to establish a microbiological diagnosis.\n\nFig. 1. Lumbar spine MRI (T1 sequence with gadolinium enhancement). Arrow indicates L4–5 discitis/osteomyelitis with epidural extension.\n\nThe patient rapidly developed progressive hepatic failure with severe coagulopathy and acute kidney injury after hospital admission. On hospital day 4, he developed gross haemoptysis with increasing oxygen requirements and was transferred to the medical intensive care unit. Chest x-ray revealed diffuse patchy opacities bilaterally, that were not present on admission. The patient was intubated and a bronchoscopy was performed showing evidence of diffuse alveolar haemorrhage. Blood cultures drawn at the outside hospital emergency department immediately prior to admission were growing Staphylococcus caprae with intermediate resistance to vancomycin documented in the report sent to our hospital (established by Vitek 2 at outside hospital, confirmed by manual MIC testing, although MIC result was 4 µg ml−1 per verbal report). The patient went into shock and was started on vasopressors. He was started on cefazolin for coverage of Staphylococcus caprae at the recommendation of our Infectious Disease specialists, in addition to vancomycin, piperacillin-tazobactam and doxycycline for additional coverage for possible infectious aetiologies for diffuse alveolar haemorrhage. Despite aggressive antimicrobial therapy and supportive care, the patient's haemodynamic status continued to deteriorate and the patient expired on hospital day nine.\n\nAutopsy revealed necrotic and haemorrhagic L4–L5 vertebral bodies and disc spaces, with evidence of bilateral pleural effusions with diffuse alveolar haemorrhage. Tissue cultures from the affected vertebral bodies grew Staphylococcus caprae with MIC of 4 µg ml−1 for vancomycin established with automated microdilution method (Vitek 2; bioMérieux) and confirmed with Etest (bioMérieux).\n\nDiscussion\nStaphylococcus caprae has been noted as a human pathogen since the late 1980s after its discovery in 1983. There are reports in the literature of a variety of infections caused by S. caprae but by far the largest number of infections occur in bone and joint, and of these, the vast majority are in patients with orthopaedic devices in place. S. caprae has been uncommonly reported as a pathogen of native bone and here we report a case of native bone infection as the source of bacteraemia. No prior studies have shown a MIC of 4 µg ml−1 for vancomycin for S. caprae; prior studies publishing MICs are limited but were <2 µg ml−1 and recommended vancomycin as first line therapy against S. caprae [10]. At our institution, doxycycline was a viable alternative and cefazolin was chosen due to the consistent susceptibility of this individual’s S. caprae isolates to oxacillin (cephalosporins are not routinely tested when organism is a species of the genus Staphylococcus). Table 1 lists the three separate cultures of S. caprae during this individual’s clinical course as well as their MIC values. Interestingly, vancomycin began as MIC of 1 µg ml−1and then further MIC values were 4 µg ml−1.\n\nTable 1. Antibiotics tested and their MIC (µg ml−1) values from blood cultures at two outside hospitals and from lumbar spine samples taken at autopsy\nOutside hospital March 2016 (initial, blood):\tOutside hospital July 2016 (blood):\tOur institution July 2016 (lumbar spine):\t\nLevofloxacin <0.5\tLevofloxacin 0.5\t\t\nClindamycin <0.25\tClindamycin 0.25\t\t\nErythromycin <0.25\tErythromycin 1\tErythromycin 0.5\t\nOxacillin <0.25\tOxacillin <0.25\tOxacillin <0.25\t\nTetracycline <1\tTetracycline <1\tTetracycline <1\t\nBactrim <0.5\tBactrim <10\tBactrim <0.5\t\nVancomycin 1\tVancomycin Int (verbal =4)\tVancomycin 4\t\nPenicillin >10 R\t\tRifampin <0.5\t\nCiprofloxacin <1\t\tDoxycycline <0.5\t\nMeropenum <2\t\t\t\nGentamicin <1\t\t\t\nSeveral case reports of infections related to S. caprae are available in the literature. Table 2 lists most of the available case reports. There was also a case report that mentioned a 72-year-old Japanese man with recurrent S. caprae sepsis but this report was only available in Japanese [5]. A different study out of Japan did identify S. caprae in the urine of patients who had received chemotherapy but it was not evident whether it was infectious or not. However, in that report they did note a high incidence of methicillin resistance (11 % of all methicillin-resistant organisms were S. caprae), and that S. caprae totalled 6 % of all coagulase-negative staphylococcal species isolated8]. In 2004, Ross and colleagues published a study in which 10 of 36 neonates in their neonatal intensive care unit were colonized with S. caprae, of which six cases were bacteraemic, one case was a cerebrospinal fluid (CSF) shunt infection and onewas a vascular catheter-associated infection, and it was noted that 13 % of the S. caprae strains recorded carried the mecA gene [3].\n\nTable 2. Summary of case reports involving S. caprae infections\nAuthor and year of case(s)\tPublication type\tSite of infection\tClinical history\t\nVandenesch et al.\n\n1988–1992 [9]\tCase series report\tUTI\t46-year-old s/p medullary decompression for rhabdomyosarcoma \n8-year-old previously healthy female\t\n\t\tEndocarditis\t45-year-old previously healthy female, required mitral valve removal\t\n\t\tBacteremia\t67-year-old s/p ovariectomy for ovarian cancer, from her Port-a-Cath \nNeonate with umbilical catheter and coarctation of the aorta\t\nShuttleworth et al.\n\n1990–1996 [10]\tCase series report\tBone and joint infection\t9 cases, 7 of which were traumatic fractures\t\n\t\tToenail infection\t1 case\t\n\t\tBilateral otitis media\t1 case\t\n\t\tTransplant patients\t3 cases\t\nKanda et al. 1998–2000 [13]\tCase series report\tBacterial otits externa\t2.9 % of 202 cases caused by S. caprae\t\nDevrise et al. and Barelli et al. 1999 [2, 14]\tScientific review articles\tNosocomial infections, varied\t3 of 53 cases were caused by S. caprae\t\nBenedetti et al. 2008 [5]\tCase report\tCSF infection\t47-year-old female with lumbar-sacral s/p spinal analgesia pump implantation, required device removal and 6 weeks IV antibiotics\t\nKato et al. 2010 [8]\tCase report\tBacteremia\tNeutropenic patient after induction chemotherapy for ac, associated with central line\t\nShin et al. 2011 [15]\tCase report\tPeritonitis\t3 patients receiving peritoneal dialysis\t\nHenry et al. 2014 [7]\tCase report\tEndophthalmitis\t24-year-old healthy female after surgery for vitreous floaters\t\nThere are two major studies looking at the incidence of S. caprae bone and joint infections. The first, by d’Ersu et al. [6], was a retrospective study done at Nantes University looking at data between 2004 and 2012. They identified 13 patients with S. caprae bone and joint infections, and in this study four patients had infection of their native bone: two individuals with diabetic foot infections, one with recurrent osteomyelitis and one with chronic osteitis [6].\n\nThe second study was published by Seng et al. [4] and looked at two major hospitals in France between 2006 and 2012, the University of Marseille and the University of Nimes. The University of Marseille had 16 bone and joint infections from 2006 to 2012 caused by S. caprae and the University of Nimes had nine bone and joint infections from 2007 to 2012 caused by S. caprae. In this study, only one patient had infection of a vertebra, and only three patients had no orthopaedic devices present at the time of infection. Most patients required more than two antibiotics with surgical debridement and removal of the orthopaedic device for complete clearance of infection [4].\n\nInterestingly, a study published in 2014 looking at small colony variations in bone and joint infections found that in 76 human samples only two grew S. caprae/Staphylococcus capitis and that distinguishing between the two can be difficult when using the 16S rRNA gene, which is considered the gold standard [11, 12]. Furthermore, in the study of d’Ersu et al. from 2016 they found that a small number of isolates were misidentified by a commercial identification system. MALDI-TOF MS was found to be far superior in identification rates of S. caprae [6].\n\nFor our individual patient, both failure of antibiotic therapy and source control likely contributed to his ultimate clinical outcome. In the available literature it is clear that without removal of infected bone or devices, antibiotic clearance of the infection did not occur. Unfortunately, given his comorbidities and rapid clinical decline, our patient was not a surgical candidate. Additionally, production of toxins by this strain of S. caprae was not tested.\n\nIn conclusion, S. caprae is still an understudied organism of human infection, and it has been determined to carry the mecA gene conferring methicillin resistance making it an important pathogen to be identified early on, especially in patients with significant comorbidities.\n\nFunding information\nThe authors received no specific grant from any funding agency.\n\nConflicts of interest\nThe authors declare that there are no conflicts of interest.\n\nEthical statement\nThe authors complied with institutional ethics policies in the writing of this case report.\n==== Refs\nReferences\n1 Allignet J Aubert S Dyke KG El Solh N Staphylococcus caprae strains carry determinants known to be involved in pathogenicity: a gene encoding an autolysin-binding fibronectin and the ica operon involved in biofilm formation Infect Immun 2001 69 712 718 10.1128/IAI.69.2.712-718.2001 11159959 \n2 Devriese LA Poutrel B Kilpper-Balz R Schleifer KH Staphylococcus gallinarum and Staphylococcus caprae , two new species from animals Int J Syst Bacteriol 1983 33 480 486 10.1099/00207713-33-3-480 \n3 Ross TL Fuss EP Harrington SM Cai M Perl TM Methicillin-resistant Staphylococcus caprae in a neonatal intensive care unit J Clin Microbiol 2005 43 363 367 10.1128/JCM.43.1.363-367.2005 15634995 \n4 Seng P Barbe M Pinelli PO Gouriet F Drancourt M Staphylococcus caprae bone and joint infections: a re-emerging infection? Clin Microbiol Infect 2014 20 O1052 O1058 10.1111/1469-0691.12743 24975594 \n5 Benedetti P Pellizzer G Furlan F Nicolin R Rassu M Staphylococcus caprae meningitis following intraspinal device infection J Med Microbiol 2008 57 904 906 10.1099/jmm.0.2008/000356-0 18566153 \n6 D'Ersu J Aubin GG Mercier P Nicollet P Bémer P Characterization of Staphylococcus caprae clinical isolates involved in human bone and joint infections, compared with goat mastitis isolates J Clin Microbiol 2016 54 106 113 10.1128/JCM.01696-15 26511738 \n7 Henry CR Schwartz SG Flynn HW Endophthalmitis following pars plana vitrectomy for vitreous floaters Clin Ophthalmol 2014 8 1649 10.2147/OPTH.S67855 25210434 \n8 Kato J Mori T Sugita K Murata M Ono Y Central line-associated bacteremia caused by drug-resistant Staphylococcus caprae after chemotherapy for acute myelogenous leukemia Int J Hematol 2010 91 912 913 10.1007/s12185-010-0568-y 20390386 \n9 Vandenesch F Eykyn SJ Bes M Meugnier H Fleurette J Identification and ribotypes of Staphylococcus caprae isolates isolated as human pathogens and from goat milk J Clin Microbiol 1995 33 888 892 7790455 \n10 Shuttleworth R Behme RJ Mcnabb A Colby WD Human isolates of Staphylococcus caprae : association with bone and joint infections J Clin Microbiol 1997 35 2537 2541 9316903 \n11 Tande AJ Osmon DR Greenwood-Quaintance KE Mabry TM Hanssen AD Clinical characteristics and outcomes of prosthetic joint infection caused by small colony variant staphylococci MBio 2014 5 e01910-14 10.1128/mBio.01910-14 25271290 \n12 Zhu W Sieradzki K Albrecht V Mcallister S Lin W Evaluation of the biotyper MALDI-TOF MS system for identification of Staphylococcus species J Microbiol Methods 2015 117 14 17 10.1016/j.mimet.2015.07.014 26183765 \n13 Kanda K Suzuki E Hiramatsu K Oguri T Miura H Identification of a methicillin-resistant strain of Staphylococcus caprae from a human clinical specimen Antimicrob Agents Chemother 1991 35 174 176 10.1128/AAC.35.1.174 2014973 \n14 Barelli C Minto EC Martinez R Darini AL da Costa Darini A Evaluation of the antimicrobial susceptibilities of coagulase-negative staphylococci by E-test Rev Latinoam Microbiol 1999 41 67 72 10932753 \n15 Shin JH Kim SH Jeong HS Oh SH Kim HR Identification of coagulase-negative staphylococci isolated from continuous ambulatory peritoneal dialysis fluid using 16S ribosomal RNA, tuf , and SodA gene sequencing Perit Dial Int 2011 31 340 346 10.3747/pdi.2010.00073 21454395\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2053-3721",
"issue": "4(9)",
"journal": "JMM case reports",
"keywords": "Staphylococcus caprae; bacteraemia; elevated MIC; native joint infection; therapeutic failure; vancomycin",
"medline_ta": "JMM Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101639133",
"other_id": null,
"pages": "e005112",
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"pmid": "29114394",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports",
"references": "9316903;7790455;10932753;15634995;26511738;2014973;21454395;26183765;11159959;24975594;25271290;20390386;18566153;25210434",
"title": "Staphylococcus caprae bacteraemia and native bone infection complicated by therapeutic failure and elevated MIC: a case report.",
"title_normalized": "staphylococcus caprae bacteraemia and native bone infection complicated by therapeutic failure and elevated mic a case report"
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"abstract": "OBJECTIVE\nThe maximum tolerated dose (MTD) and overall safety of sunitinib plus pemetrexed and carboplatin was determined in patients with advanced solid malignancies.\n\n\nMETHODS\nIn this phase I dose-escalation study, patients received oral sunitinib on a continuous daily dosing (CDD) schedule (37.5 mg/day) or Schedule 2/1 (2 weeks on treatment, 1 week off treatment; 37.5 or 50 mg/day). Pemetrexed (400-500 mg/m(2) IV) and carboplatin (AUC = 5 mg·min/ml IV) were administered q3w. At the MTD for the chosen schedule, a cohort of patients with non-small cell lung cancer (NSCLC) or mesothelioma was further evaluated.\n\n\nRESULTS\nTwenty-one patients were enrolled on Schedule 2/1 (expansion cohort included) and 3 patients on the CDD schedule. The MTD on Schedule 2/1 was sunitinib 37.5 mg/day with pemetrexed 500 mg/m(2) and carboplatin AUC = 5 mg·min/ml; MTD on the CDD schedule was not established. Dose-limiting toxicities included grade 3/4 neutropenia, grade 3 thrombocytopenia, and grade 3 hand-foot syndrome. The most common grade 3/4 drug-related non-hematologic adverse events at Schedule 2/1 MTD were fatigue/asthenia and diarrhea (both n = 4). Grade 3/4 hematologic abnormalities included neutropenia (83%) and leukopenia (83%). Pharmacokinetic data revealed no clinically significant drug-drug interactions. Best response at the Schedule 2/1 MTD was stable disease ≥8 weeks in 3/5 evaluable patients (60%).\n\n\nCONCLUSIONS\nWith this combination, in patients with advanced solid malignancies, sunitinib MTD on Schedule 2/1 was 37.5 mg/day. Sunitinib plus pemetrexed and carboplatin were tolerable at the MTD, although sunitinib dose delays and reductions were often required due to myelosuppression.",
"affiliations": "Centre de Lutte Contre le Cancer du CHUM - Hôpital Notre-Dame, 6ième étage (G6162), Pavillon Deschamps, 1560 Sherbrooke Est, Montréal, QC, H2L 4M1, Canada, normand.blais@geoq.com.",
"authors": "Blais|Normand|N|;Camidge|D Ross|DR|;Jonker|Derek J|DJ|;Soulières|Denis|D|;Laurie|Scott A|SA|;Diab|Sami G|SG|;Ruiz-Garcia|Ana|A|;Thall|Aron|A|;Zhang|Ke|K|;Chao|Richard C|RC|;Chow|Laura Q|LQ|",
"chemical_list": "D005971:Glutamates; D007211:Indoles; D011758:Pyrroles; D000068437:Pemetrexed; D006147:Guanine; D016190:Carboplatin; D000077210:Sunitinib",
"country": "United States",
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"doi": "10.1007/s10637-013-0010-4",
"fulltext": "\n==== Front\nInvest New Drugs\nInvest New Drugs\nInvestigational New Drugs\n0167-6997\n1573-0646\nSpringer US New York\n\n23963796\n10\n10.1007/s10637-013-0010-4\nPhase I Studies\nSunitinib combined with pemetrexed and carboplatin in patients with advanced solid malignancies—results of a phase I dose-escalation study\nBlais Normand +1-514-8908000 +1-514-4127572 normand.blais@geoq.com\n\n1\nCamidge D. Ross 2\nJonker Derek J. 3\nSoulières Denis 1\nLaurie Scott A. 3\nDiab Sami G. 4\nRuiz-Garcia Ana 5\nThall Aron 5\nZhang Ke 5\nChao Richard C. 5\nChow Laura Q. 3\n1 Centre de Lutte Contre le Cancer du CHUM – Hôpital Notre-Dame, 6ième étage (G6162), Pavillon Deschamps, 1560 Sherbrooke Est, Montréal, QC H2L 4M1 Canada\n2 University of Colorado Cancer Center, Aurora, CO USA\n3 The Ottawa Hospital Cancer Centre, Ottawa, Canada\n4 Colorado Integrative Cancer Center, Aurora, CO USA\n5 Pfizer Oncology, La Jolla, CA USA\n22 8 2013\n22 8 2013\n2013\n31 6 14871498\n1 8 2013\n2 8 2013\n© The Author(s) 2013\nOpen Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.\nSummary\n\nObjectives The maximum tolerated dose (MTD) and overall safety of sunitinib plus pemetrexed and carboplatin was determined in patients with advanced solid malignancies. Methods In this phase I dose-escalation study, patients received oral sunitinib on a continuous daily dosing (CDD) schedule (37.5 mg/day) or Schedule 2/1 (2 weeks on treatment, 1 week off treatment; 37.5 or 50 mg/day). Pemetrexed (400–500 mg/m2 IV) and carboplatin (AUC = 5 mg·min/ml IV) were administered q3w. At the MTD for the chosen schedule, a cohort of patients with non-small cell lung cancer (NSCLC) or mesothelioma was further evaluated. Results Twenty-one patients were enrolled on Schedule 2/1 (expansion cohort included) and 3 patients on the CDD schedule. The MTD on Schedule 2/1 was sunitinib 37.5 mg/day with pemetrexed 500 mg/m2 and carboplatin AUC = 5 mg·min/ml; MTD on the CDD schedule was not established. Dose-limiting toxicities included grade 3/4 neutropenia, grade 3 thrombocytopenia, and grade 3 hand–foot syndrome. The most common grade 3/4 drug-related non-hematologic adverse events at Schedule 2/1 MTD were fatigue/asthenia and diarrhea (both n = 4). Grade 3/4 hematologic abnormalities included neutropenia (83 %) and leukopenia (83 %). Pharmacokinetic data revealed no clinically significant drug–drug interactions. Best response at the Schedule 2/1 MTD was stable disease ≥8 weeks in 3/5 evaluable patients (60 %). Conclusions With this combination, in patients with advanced solid malignancies, sunitinib MTD on Schedule 2/1 was 37.5 mg/day. Sunitinib plus pemetrexed and carboplatin were tolerable at the MTD, although sunitinib dose delays and reductions were often required due to myelosuppression.\n\nKeywords\n\nSolid tumors\nNon-small cell lung cancer\nSunitinib\nPemetrexed\nCarboplatin\nissue-copyright-statement© Springer Science+Business Media New York 2013\n==== Body\nIntroduction\n\nSunitinib is an oral, multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFRs 1–3) and platelet-derived growth factor receptors (PDGFRs α and β), as well as other receptors [1–6]. VEGF and PDGF are key angiogenic ligands that influence cancer growth, progression, and metastasis [7–10]. Sunitinib is approved multinationally for the treatment of advanced renal cell carcinoma (RCC) and imatinib-resistant or -intolerant gastrointestinal stromal tumors (GISTs) [11]. In a phase II trial, single-agent sunitinib was well tolerated and associated with an encouraging response rate (11.1 %) in patients with previously treated advanced non-small cell lung cancer (NSCLC) [12, 13] and has also shown antitumor activity in patients with other solid malignancies, such as pancreatic neuroendocrine tumor, sarcoma, thyroid cancer, and melanoma [14, 15]. Both intermittent and continuous daily dosing (CDD) schedules of sunitinib have shown similar efficacy and tolerability in patients with RCC, GIST, and NSCLC. The approved dose for RCC and GIST is 50 mg/day administered in 6-week cycles comprising 4 weeks on treatment followed by 2 weeks off treatment (Schedule 4/2), and the approved dose for pancreatic NET is 37.5 mg/day CDD [12, 13, 16–19].\n\nPemetrexed is a chemotherapeutic agent that targets multiple folate pathway enzymes resulting in inhibition of cellular replication. It has clinical activity in a range of solid tumors [20]. While single-agent pemetrexed is approved for second-line or maintenance treatment of patients with non-squamous advanced NSCLC, response rates in the second-line setting remain low (<10 %) and there is a need for treatment combinations with improved efficacy [21, 22]. Pemetrexed in combination with carboplatin is active in multiple tumor types including NSCLC, small-cell lung cancer, and mesothelioma, and has different toxicities than pemetrexed with cisplatin [23–25].\n\nThe addition of antiangiogenic agents to chemotherapy has shown additive or synergistic effects in preclinical models [26–28]. Changes in tumor vasculature initiated by antiangiogenic agents appear to enhance chemotherapy diffusion and delivery, possibly by reducing interstitial pressure and increasing permeability and perfusion [7, 29]. Sunitinib combined with pemetrexed decreased tumor growth in NSCLC NCI-H460 xenograft models [26], although a recent phase II study in patients with advanced NSCLC did not show a benefit for the combination over pemetrexed alone as second-line therapy [30]. Clinical evidence from other antiangiogenic agents, such as the anti-VEGF monoclonal antibody bevacizumab, further support the benefit of combination therapy versus chemotherapy alone in patients with solid tumors including advanced non-squamous NSCLC [31, 32] and colorectal cancer [33].\n\nThe primary objective of this phase I dose-escalation study was to determine the maximum tolerated dose (MTD) and overall safety of sunitinib (on intermittent and CDD schedules) in combination with pemetrexed and carboplatin in patients with advanced solid malignancies.\n\nMethods\n\nStudy population\n\nPatients aged 18 years or older with Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were enrolled. Patients had a histologic or cytopathologic diagnosis of solid malignancy refractory to standard therapy or for which no standard therapy existed, adequate organ function (including bone marrow, kidney, and liver), and a life expectancy of ≥12 weeks. In the expansion cohort, previously treated and/or platinum- refractory/-intolerant patients with recurrent or advanced NSCLC of any histologic subtype and patients with advanced unresectable mesothelioma (pleural or peritoneal; stage 3 or 4) were eligible for enrollment.\n\nPatients were excluded if they had uncontrolled or symptomatic brain metastases; gross hemoptysis (≥5 ml per episode or ≥10 ml per day) within 4 weeks of study start; uncontrolled hypertension (>150/100 mmHg) despite standard antihypertensive agents; or cardiac disease, cerebrovascular accident or pulmonary embolism within 12 months of starting the study. Other exclusion criteria included: National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade 3 hemorrhage within 4 weeks of treatment; ongoing cardiac dysrhythmias of grade ≥2; atrial fibrillation of any grade; prolongation of the QTc interval (>450 ms for males or >470 ms for females); chemotherapy, surgery or radiation therapy less than 4 weeks before study start (except palliative radiotherapy to non-target lesions); known hypersensitivity to carboplatin; or prior treatment with pemetrexed, carboplatin, or sunitinib.\n\nStudy design and treatment\n\nThis open-label, multicenter, phase I trial (NCT00528619) conducted in the US and Canada investigated escalating doses of sunitinib plus pemetrexed and carboplatin in combination in serial patient cohorts. The primary objective was determination of the MTD and overall safety of sunitinib administered in combination with pemetrexed and carboplatin in patients with advanced solid malignancies for which curative therapy was not available. Secondary endpoints included pharmacokinetic (PK) parameters and the preliminary antitumor activity of this combination.\n\nSunitinib (37.5 or 50 mg) was administered orally once daily on either the CDD schedule or Schedule 2/1 (2 weeks on treatment followed by 1 week off treatment). Pemetrexed (400–500 mg/m2 IV) and carboplatin (AUC = 5 mg·min/ml IV) were administered once every 3 weeks (q3w). Planned dose escalation cohorts (Table 1) followed a standard 3+3 design and began with the CDD schedule. The dose levels were based on the previous MTD determinations for sunitinib in combination with pemetrexed (i.e., sunitinib 37.5 mg/day on the CDD schedule and 50 mg/day on Schedule 2/1; pemetrexed 500 mg/m2) [34].Table 1 Drug exposure for sunitinib, pemetrexed, and carboplatin\n\n\tPlanned sunitinib dose (mg)\tPlanned pemetrexed dose (mg/m2)\tPlanned carboplatin dose (AUC mg·min/ml)\tPatients (n)\tNumber of sunitinib cycles started\tMedian no. of sunitinib cycles started (range)\tPatients with sunitinib dose reduced (n)\tNumber of pemetrexed cycles started\tMedian no. of pemetrexed cycles started (range)\tPatients with pemetrexed dose reduced (n)\tNumber of carboplatin cycles started\tMedian no. of carboplatin cycles started (range)\tPatients with carboplatin dose reduced (n)\t\nCDD schedule\t\n Dose level 1B (starting dose)\t37.5\t400\t5\t3\t16\t6.0 (4–6)\t2\t16\t6.0 (4–6)\t1\t16\t6.0 (4–6)\t1\t\n Dose level 2B\t37.5\t500\t5\tN/A\tN/A\tN/A\tN/A\tN/A\tN/A\tN/A\tN/A\tN/A\tN/A\t\n Dose level 3B\t50\t500\t5\tN/A\tN/A\tN/A\tN/A\tN/A\tN/A\tN/A\tN/A\tN/A\tN/A\t\n Total (CDD)\tN/A\tN/A\tN/A\t3\t16\tN/A\t2\t16\tN/A\t1\t16\tN/A\t1\t\nSchedule 2/1\t\n Dose level B1 (starting dose)\t37.5\t400\t5\t3\t11\t3.0 (2–6)\t3\t10\t2.0 (2–6)\t2\t10\t2.0 (2–6)\t2\t\n Dose level B2 (MTD)\t37.5\t500\t5\t6\t26\t5.0 (2–6)\t2\t26\t5.0 (2–6)\t3\t26\t5.0 (2–6)\t3\t\n Expansion cohort\t37.5\t500\t5\t6\t18\t3.5 (1–4)\t4\t20\t3.5 (1–6)\t4\t20\t3.5 (1–6)\t5\t\n Dose level B3\t50\t500\t5\t6\t27\t5.0 (2–6)\t3\t27\t5.0 (2–6)\t5\t27\t5.0 (2–6)\t2\t\n Total (Schedule 2/1)\tN/A\tN/A\tN/A\t21\t82\tN/A\t12\t83\tN/A\t14\t83\tN/A\t12\t\nTotal (CDD + Schedule 2/1)\tN/A\tN/A\tN/A\t24\t98\tN/A\t14\t99\tN/A\t15\t99\tN/A\t13\t\nContinuation data are not included\n\nCDD continuous daily dosing; N/A not applicable\n\nTreatment cycles lasted 3 weeks, and patients received up to six cycles of triple combination treatment. Upon study completion, patients who continued to experience clinical benefit were eligible to enter a continuation study to receive sunitinib either alone or together with any or all components of the original treatment combination, at the investigator’s discretion. Patients with RECIST-defined progressive disease but who were judged as benefiting from treatment were also eligible to enroll into the continuation protocol.\n\nThe MTD was defined as the highest dose at which 0/3 or ≤1/6 patients experienced a dose-limiting toxicity (DLT) during the first 22 days of treatment, with the next higher dose level having at least 2/3 or 2/6 patients with a DLT. DLTs were defined as grade 3 or 4 drug-related toxicities that occurred during the defined time frame or that resulted in a delay in administering cycle 2. Hematologic DLTs were defined as neutropenia (grade ≥3 with grade ≥3 infection; grade 4 lasting ≥7 days or with fever >38.5 °C lasting >24 h), thrombocytopenia (grade ≥3 with bleeding or grade 4 for ≥7 days), or lymphopenia accompanied by an opportunistic infection. Nonhematologic DLTs included grade 3/4 toxicities lasting ≥7 days. Nausea, vomiting, and diarrhea that persisted at grade 3/4 despite maximal medical therapy were also considered DLTs.\n\nDepending on the safety profiles of the CDD schedule and Schedule 2/1, one dosing schedule could be further explored in a separate cohort of up to an additional 10 patients with NSCLC and up to 10 patients with mesothelioma (the expansion cohort) treated at the MTD.\n\nAll patients provided written informed consent. The study was approved by the institutional review board of each participating center and was carried out in accordance with the International Conference on Harmonization Good Clinical Practice guidelines, and applicable local laws and regulatory requirements.\n\nStudy assessments\n\nSafety was evaluated at each patient visit by the assessment of adverse events (AEs; NCI CTCAE version 3.0), laboratory abnormalities, physical examinations, and vital signs. Electrocardiogram profiles were obtained at baseline and cycle 1. The AEs related to each study drug were evaluated to determine the safety of the triple combination.\n\nFull PK profiles for sunitinib, SU12662 (its primary active metabolite), the sum of sunitinib plus SU12662, pemetrexed, and carboplatin (as total and free [unbound] platinum) were obtained from the last 3 patients enrolled in the Schedule 2/1 MTD cohort. Pemetrexed and carboplatin PK samples were collected on cycle 1 day 1 (i.e., in the absence of sunitinib) and cycle 2 day 1 (in the presence of sunitinib). Sunitinib PK samples were collected on cycle 2 day 1. To obtain steady-state values, only patients who received at least 10 consecutive doses of sunitinib prior to sample collection on cycle 2 day 1 were included in the summary. Similarly, for the sunitinib PK data used as reference (historical control, NSCLC patients receiving sunitinib as single therapy) only patients who received at least 10 consecutive doses of sunitinib prior to sample collection were included. Pharmacokinetic parameters were estimated using non-compartmental methods, and included Cmax (maximum plasma concentration), Tmax (time to Cmax), AUC24 (area under the plasma concentration–time curve from time zero to 24 h), AUC∞ (AUC from time zero to infinity), CL (clearance), and t½ (terminal phase half-life).\n\nComputed tomography (CT) or magnetic resonance imaging (MRI) scans were performed at screening, at every even-numbered cycle, whenever disease progression was suspected or to confirm a response, and at the end of treatment/withdrawal from the study. Brain CT or MRI and/or bone scan were performed as clinically indicated. In patients with measurable disease, objective response was determined according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.0) [35].\n\nStatistical methods\n\nDue to the exploratory nature of this study, no confirmatory inferential statistical analyses were planned. Descriptive statistics were used to summarize all patient characteristics, treatment administration/compliance, safety, PK parameters, and antitumor activity.\n\nResults\n\nPatient characteristics\n\nThree patients were enrolled into the CDD and 15 into the Schedule 2/1 dose-escalation cohorts (Table 1). An additional 6 patients with NSCLC (n = 5) and mesothelioma (n = 1) were subsequently enrolled into the expansion cohort on Schedule 2/1 (see below). In the expansion cohort, all 6 patients had undergone previous surgery and 4 had undergone prior radiation therapy. One had received prior systemic treatment (1 regimen). The median duration since first diagnosis was 1.7 months (range, 0.3–5.0) for the patients with NSCLC and 3.5 months for the patient with mesothelioma. In total, these 24 patients received 98 cycles of sunitinib therapy, 99 cycles of pemetrexed therapy, and 99 cycles of carboplatin therapy (Table 1). Patient demographic and baseline characteristics are summarized in Table 2.Table 2 Baseline demographic and disease characteristics\n\n\tCDD schedule (n = 3)\tSchedule 2/1 (n = 21)\t\nSunitinib 37.5 mg + pemetrexed 400 mg/m2 + carboplatin AUC = 5 mg·min/ml (n = 3)\tSunitinib 37.5 mg + pemetrexed 400 mg/m2 + carboplatin AUC = 5 mg·min/ml (n = 3)\tSunitinib 37.5 mg + pemetrexed 500 mg/m2 + carboplatin AUC = 5 mg·min/ml (n = 6)a\tSunitinib 50 mg + pemetrexed 500 mg/m2 + carboplatin AUC = 5 mg·min/ml (n = 6)\tExpansion cohort Sunitinib 37.5 mg + pemetrexed 500 mg/m2 + carboplatin AUC = 5 mg·min/ml (n = 6)\t\nMedian age in years, (range)\t60.0 (51–67)\t54.0 (50–72)\t58.0 (36–67)\t58.0 (21–63)\t60.0 (52–73)\t\nMale/female, n\t2/1\t0/3\t4/2\t2/4\t1/5\t\nECOG PS 0/1, n\t1/2\t1/2\t3/3\t2/4\t4/2\t\nSmoking status (ever smoked), n\t3\t1\t5\t1\t5\t\nPrimary malignancy, n\t\n NSCLCb\t3\t0\t0\t1\t5\t\n Breast cancer\t0\t1\t1\t0\t0\t\n Renal cancer\t0\t0\t2\t1\t0\t\n Otherc\t0\t2\t3\t4\t1\t\nPrior systemic therapy, n\t\n Yes/no\t2/1\t3/0\t4/2\t3/3\t1/5\t\n Number of prior regimens 1 or 2/>2\t1 or 1/0\t2 or 0/1\t2 or 0/2\t1 or 1/1\t1 or 0/0\t\nCDD continuous daily dosing; ECOG PS Eastern Cooperative Oncology Group performance status; NSCLC non-small cell lung cancer\n\naMaximum tolerated dose\n\nbHistologies included: adenocarcinoma, n = 3; bronchioalveolar carcinoma, n = 1; other, n = 1; unknown/not reported, n = 4\n\ncOther carcinomas included: pleural mesothelioma (epithelial and sarcomatoid), prostate cancer, anal cancer, thyroid cancer, endometrial cancer, gastric cancer, esophageal carcinoma, metastatic synovial sarcoma, transitional cell carcinoma, vulval cancer (all n = 1)\n\nSafety\n\nSchedule 2/1\n\nThe MTD on Schedule 2/1 was determined to be sunitinib 37.5 mg/day + pemetrexed 500 mg/m2 + carboplatin AUC = 5 mg·min/ml. At the Schedule 2/1 MTD, one DLT of grade 3 neutropenia was observed (Table 3). In the escalation cohort above this dose (sunitinib 50 mg/day + pemetrexed 500 mg/m2 + carboplatin AUC = 5 mg·min/ml), DLTs of grade 3 thrombocytopenia (n = 1) and grade 4 neutropenia (n = 2) were observed (Table 3).Table 3 Dose-limiting toxicities\n\nSunitinib dose (mg)\tPemetrexed dose (mg/m2)\tCarboplatin dose (AUC mg·min/ml)\tn\tDLT detailsa\t\nSchedule 2/1 (n = 21)\t\n 37.5\t400\t5\t3\t–\t\n 37.5b\t500b\t5b\t6\tGrade 3 neutropenia (n = 1)\t\n 50\t500\t5\t6\tGrade 3 thrombocytopenia (n = 1)\n\nGrade 4 neutropenia (n = 2)\n\n\t\nCDD schedule (n = 3)\t\n 37.5\t400\t5\t3\tGrade 3 hand–foot syndrome (n = 1)\n\nGrade 4 neutropenia (n = 1)\n\n\t\nCDD continuous daily dosing; DLT dose-limiting toxicity\n\naIf a DLT was experienced by only one of the three patients at any dose level, the cohort was expanded to six patients. If none of the additional three patients experienced a DLT, the dose was escalated to the next level. If DLTs occurred in ≥2 patients at any dose level, the dose level was deemed as having exceeded the MTD and the prior, lower dose level was further expanded (if only three patients were previously treated at that dose level). The MTD was defined as the dose level at which no more than one patient in a cohort of six experienced a DLT during the first 22 days of treatment of each schedule\n\nbMaximum tolerated dose (MTD)\n\nIn total, 9/12 patients (75 %) treated at the Schedule 2/1 MTD had at least one sunitinib dose delay, with 1 patient (8 %) having a delay of 3–4 weeks. Additionally, 6 patients (50 %) in this cohort had a sunitinib dose reduction to 25 mg. Six patients discontinued sunitinib at the MTD due to AEs (neutropenia [n = 3], fatigue, diarrhea, and clostridial infection [all n = 1]). The diarrhea was considered by the investigator to be related to sunitinib and pemetrexed, while the neutropenia and fatigue were attributed to all three study treatments. The median number of cycles of sunitinib, pemetrexed, and carboplatin received per patient was 5.0 (range 2–6) in the original Schedule 2/1 MTD cohort (n = 6), and 3.5 (range 1–4) in the expansion cohort (n = 6; Table 1). The dose of sunitinib was reduced to 25 mg in 2 patients (33 %) in the original Schedule 2/1 MTD cohort and 4 patients (67 %) in the expansion cohort (Table 1). Of these 6 patients, four discontinued sunitinib within 12 weeks after dose reduction, while the other two continued for 13–24 weeks. The dose of pemetrexed was reduced to 400 mg/m2 in 3 patients (50 %) in the Schedule 2/1 MTD cohort and 4 patients (67 %) in the expansion cohort. All but one discontinued pemetrexed within 12 weeks after dose reduction. The dose of carboplatin was reduced up to 30 % in 3 patients (50 %) in the Schedule 2/1 MTD cohort and 5 patients (83 %) in the expansion cohort. Of these 8 patients, four discontinued carboplatin within 12 weeks after dose reduction, and the other four continued for 13–24 weeks.\n\nOne patient with NSCLC tolerated 37.5 mg for 3 cycles but was discontinued from the study due to diarrhea related to sunitinib and pemetrexed. One patient with anal cancer received sunitinib 50 mg for 4 cycles but the pemetrexed dose had to be reduced to 375 mg/m2 in Cycles 2 through 4. Another patient with metastatic synovial sarcoma received sunitinib 50 mg for 3 cycles, but the pemetrexed dose had to be reduced to 400 mg/m2 in Cycles 2 and 3.\n\nThe most common treatment-related non-hematologic AEs at the MTD on Schedule 2/1 are shown in Table 4; these events were predominantly mild to moderate in severity. In the original Schedule 2/1 MTD cohort, the most common non-hematologic AEs related to any study drug were fatigue/asthenia and diarrhea (both n = 4; 67 %). Among patients in the expansion cohort, fatigue/asthenia (n = 6; 100 %), nausea, and decreased appetite (each n = 5; 83 %) were most common. Hematologic laboratory abnormalities on Schedule 2/1 at the MTD were grade 3/4 neutropenia, n = 5 (83 %); grade 3 leukopenia, n = 5 (83 %); grade 3 lymphopenia, n = 1 (17 %); grade 3/4 thrombocytopenia, n = 3 (50 %); and grade 3 anemia, n = 3 (50 %). Serious AEs considered related to sunitinib treatment at the MTD included febrile neutropenia (n = 3), neutropenia (DLT), transient ischemic attack, anemia, and diarrhea (each n = 1). No patient at the MTD had more than one serious AE related to sunitinib.Table 4 Treatment-related (sunitinib, pemetrexed or carboplatin) non-hematologic adverse events of special interest or experienced by ≥2 patients treated at the maximum tolerated dose on Schedule 2/1\n\nAdverse event\tSunitinib 37.5 mg + pemetrexed 500 mg/m2 + carboplatin AUC = 5 mg·min/ml (original cohort, n = 6)\tSunitinib 37.5 mg + pemetrexed 500 mg/m2 + carboplatin AUC = 5 mg·min/ml (expansion cohort, n = 6)\t\nGrade 3/4 n (%)\tTotal n (%)\tGrade 3/4 n (%)\tTotal n (%)\t\nFatigue/asthenia\t1 (17)\t4 (67)\t1 (17)\t6 (100)\t\nDecreased appetite\t0\t2 (33)\t1 (17)\t5 (83)\t\nNausea\t0\t1 (17)\t1 (17)\t5 (83)\t\nDiarrhea\t1 (17)\t4 (67)\t1 (17)\t4 (67)\t\nEdema/swellinga\t0\t2 (33)\t0\t4 (67)\t\nDyspepsia\t0\t1 (17)\t0\t3 (50)\t\nDehydration\t0\t0\t2 (33)\t3 (50)\t\nHypertension\t0\t2 (33)\t0\t2 (33)\t\nSkin/subcutaneous tissue disordersb\t0\t2 (33)\t0\t2 (33)\t\nWeight decreased\t0\t1 (17)\t0\t2 (33)\t\nChills\t0\t0\t0\t2 (33)\t\nVomiting\t0\t0\t0\t2 (33)\t\nYellow skin\t0\t0\t0\t2 (33)\t\nHypomagnesemia\t0\t2 (33)\t0\t1 (17)\t\nStomatitis/oral discomfort/related oral syndromesc\t0\t2 (33)\t0\t1 (17)\t\nParesthesia/neuropathyd\t0\t1 (17)\t0\t1 (17)\t\nConstipation\t0\t2 (33)\t0\t0\t\nFlatulence\t0\t2 (33)\t0\t0\t\nJaundice\t0\t2 (33)\t0\t0\t\nNo grade 5 adverse events were reported at the MTD on Schedule 2/1\n\nMTD maximum tolerated dose\n\naEdema/swelling is any event having a preferred term that contains edema or swelling\n\nbSkin/subcutaneous tissue disorders is any event having a preferred term that contains erythema or hyperkeratosis or rash or skin exfoliation or skin hyperpigmentation\n\ncStomatitis/oral discomfort/related oral syndromes is any event having a preferred term equal to aphthous stomatitis, gingival pain, gingival ulceration, gingivitis, glossodynia, glossitis, mouth ulceration, mucosal dryness, mucosal inflammation, mucosal ulceration, oral discomfort, oral mucosal blistering, oral pain, stomatitis, swollen tongue, tongue blistering, tongue edema, or tongue ulceration\n\ndParesthesia/neuropathy is any event having a preferred term that contains paresthesia or neuropathy\n\nCDD schedule\n\nOn the CDD schedule, two DLTs of grade 3 hand–foot syndrome (n = 1) and grade 4 neutropenia (n = 1) were observed with sunitinib 37.5 mg/day + pemetrexed 400 mg/m2 + carboplatin AUC = 5 mg·min/ml (Table 3). Because lower doses of sunitinib, pemetrexed, or carboplatin were considered unlikely to be efficacious, no further dose levels were investigated on the CDD schedule (thus the CDD MTD was not established) and the Schedule 2/1 MTD was selected for the expansion cohort.\n\nOn the CDD schedule, the median number of cycles of sunitinib, pemetrexed, and carboplatin received per patient was 6.0 (4–6), and dose reductions occurred in 2 patients (67 %) for sunitinib, and in 1 patient each for pemetrexed and carboplatin at dose level 1B (Table 1). Three patients on the CDD schedule (100 %) had at least one sunitinib dose delay of 1–3 weeks, and 2 patients had a sunitinib dose reduction to 25 mg. Most treatment-related non-hematologic AEs were grade 1 or 2, with increased lacrimation being the most common (n = 3). Three serious AEs were considered related to sunitinib treatment: anemia, dehydration, and fatigue. Hematologic laboratory abnormalities were grade 4 neutropenia, n = 3 (100 %); grade 3/4 leukopenia, n = 3 (100 %); grade 3 lymphopenia, n = 1 (33 %); grade 3 anemia, n = 2 (67 %); and grade 4 thrombocytopenia, n = 1 (33 %).\n\nAll cohorts\n\nAcross all cohorts there were three deaths (one in the MTD cohort on Schedule 2/1 and two in the sunitinib 50 mg/day + pemetrexed 500 mg/m2 + carboplatin AUC = 5 mg·min/ml cohort on Schedule 2/1). All deaths occurred during follow-up, more than 28 days after the last dose of study medication, and were considered related to the disease under study.\n\nPharmacokinetics\n\nPharmacokinetic data revealed no clinically significant drug–drug interactions with the triple combination of sunitinib, pemetrexed, and carboplatin. The PK profile of sunitinib plus SU12662 in the presence of pemetrexed/carboplatin was compared with historical controls since no data were collected for sunitinib administered alone (Table 5). Samples from the last 3 patients enrolled in the Schedule 2/1 MTD cohort showed that the geometric mean ratios (triple combination relative to sunitinib alone) for sunitinib Cmax and AUC24 were 1.12 and 1.38, respectively. These data suggest that the PK of sunitinib when co-administered with pemetrexed and carboplatin were similar to when it was administered alone. The geometric mean ratios (triple combination relative to pemetrexed/carboplatin alone) for pemetrexed Cmax and AUC∞ were 1.20 and 1.03, respectively; for total platinum Cmax and AUC24 they were 0.97 and 1.00; and for free platinum Cmax and AUC24 they were 0.94 and 0.95 (Table 5). Based on these data, the addition of sunitinib to pemetrexed and carboplatin did not appear to affect the PK of pemetrexed or carboplatin. Individual patient plasma concentration–time profiles are presented in Fig. 1.Table 5 Pharmacokinetic parameters for the sum of sunitinib plus SU12662, pemetrexed, total platinum, and free platinum (carboplatin) at the maximum tolerated dose on Schedule 2/1 (n = 3)\n\nParametera\tSunitinib + SU12662\tPemetrexed\tTotal platinum\tFree platinum\t\nAloneb\tCombined day 1 cycle 2\tPemetrexed + carboplatin day 1 cycle 1\tPemetrexed + carboplatin + sunitinib day 1 cycle 2\tPemetrexed + carboplatin day 1 cycle 1\tPemetrexed + carboplatin + sunitinib day 1 cycle 2\tPemetrexed + carboplatin day 1 cycle 1\tPemetrexed + carboplatin + sunitinib day 1 cycle 2\t\nCmax c (%CV)\t20.3 (31)\t25.8 (47)\t118 (16)\t142 (18)\t15.9 (20)\t15.4 (20)\t15.2 (20)\t14.3 (24)\t\nAUC24 d (%CV)\t347 (27)\t521 (59)\tNR\tNR\t63.7 (11)\t63.4 (2)\tNR\tNR\t\nAUC∞ d (%CV)\tNR\tNR\t261 (29)\t268 (28)\tNR\tNR\t45.7 (17)\t43.3 (11)\t\nTmax (h) (range)\t6 (4.0–10.0)\t8 (6.0–10.0)\t0.17 (0.15–0.17)\t0.17 (0.17–0.23)\t0.53 (0.5–0.9)\t0.75 (0.62–0.75)\t0.53 (0.50–0.90)\t0.75 (0.62–0.75)\t\nCL (L/h/m2) (%CV)\tNR\tNR\t3.65 (23)\t3.55 (24)\tNR\tNR\tNR\tNR\t\nt1/2 (h) (%CV)\tNR\tNR\t2.7 (30)\t2.91 (25)\tNR\tNR\tNR\tNR\t\nAUC 24 area under the plasma concentration–time profile from time zero to 24 h; AUC ∞ AUC from time zero to infinity; C max maximum plasma concentration; CL clearance; N/A not available; NR nonreportable; t 1/2 terminal phase half-life; T max time to Cmax\n\naGeometric means presented, except Tmax where medians presented\n\nbHistorical controls (Study A6181051; Pfizer data on file) since no data were collected for sunitinib administered alone\n\ncUnits: ng/ml for sunitinib + SU12662; μg/ml for pemetrexed total, and free platinum\n\ndUnits: AUC, ng·h/ml for sunitinib + SU12662, μg·h/ml for pemetrexed, total, and free platinum\n\nFig. 1 Individual plasma concentration–time profiles for a the sum of sunitinib plus SU12662 in combination with pemetrexed/carboplatin on day 1 of cycle 2 (n = 3), b pemetrexed (n = 3), c total platinum (n = 3), and d free platinum (n = 3). Pemetrexed and carboplatin are shown alone and in combination with sunitinib at the maximum tolerated dose on Schedule 2/1\n\nAntitumor activity\n\nSchedule 2/1\n\nOf 21 evaluable patients treated on Schedule 2/1, a confirmed partial response was observed in 4 patients (objective response rate [ORR] 19.0 %) and stable disease ≥8 weeks was reported in 9 patients (42.9 %). The patients with a partial response had primary diagnoses of breast cancer (sunitinib 37.5 mg + pemetrexed 400 mg/m2 + carboplatin AUC = 5 mg·min/ml), esophageal carcinoma (sunitinib 37.5 mg + pemetrexed 500 mg/m2 + carboplatin AUC = 5 mg·min/ml), gastric cancer (sunitinib 50 mg + pemetrexed 500 mg/m2 + carboplatin AUC = 5 mg·min/ml), and NSCLC, tumor histology not otherwise specified (NOS; sunitinib 50 mg + pemetrexed 500 mg/m2 + carboplatin AUC = 5 mg·min/ml).\n\nOf 5 patients with NSCLC treated at the Schedule 2/1 MTD who were evaluable based on measurable disease at baseline, three had stable disease ≥8 weeks, one had progressive disease, and in one case the response could not be evaluated (stable disease but <8 weeks for response evaluation) (Table 6). As part of a continuation protocol, sunitinib (25–50 mg/day) was administered to 3 patients with NSCLC upon completion of 6 cycles of sunitinib + pemetrexed + carboplatin in the original study, or at the investigator’s discretion. Best overall responses (taking into account time spent on both the original and continuation protocols) were partial response in 1 patient maintained for 6.9 months and stable disease maintained for 3.5 months and 7.9 months in the other 2 patients. Overall survival times were greater than 10.0, 6.9, and 10.6 months (all 3 patients were alive at last data collection point).Table 6 Responses in patients with NSCLC (all cohorts; n = 8)\n\nPatient\tNSCLC histology\tCohorta\tBest response\tRolled over onto continuation protocol?\tTotal time on treatment (weeks; up to July 2011 for continuation patientsb)\t\n1\tUnknown\tSchedule 2/1, dose level B3\tPartial response\tY\t39.6\t\n2\tOther\tCDD, dose level B1\tStable disease ≥8 weeks\tY\t40\t\n3\tOther\tCDD, dose level B1\tStable disease ≥8 weeks\tN\t20.6\t\n4\tAdenocarcinoma\tSchedule 2/1, MTD (expansion)\tStable disease ≥8 weeks\tY\t20.9\t\n5\tAdenocarcinoma\tSchedule 2/1, MTD (expansion)\tStable disease ≥8 weeks\tN\t21.7\t\n6\tBronchioloalveolar\tSchedule 2/1, MTD (expansion)\tStable disease ≥8 weeks\tN\t8.6\t\n7\tAdenocarcinoma\tSchedule 2/1, MTD (expansion)\tProgressive disease\tN\t8.6\t\n8\tUnknown\tSchedule 2/1, MTD (expansion)\tNot evaluable\tN\t2.1\t\nCDD continuous daily dosing; NSCLC non-small cell lung cancer\n\naDose levels are described in Table 1\n\nbAll rollover patients were still alive at time of data collection\n\nCDD schedule\n\nAll 3 evaluable patients treated with the triple combination on the CDD schedule had stable disease ≥8 weeks as the best confirmed objective response.\n\nDiscussion\n\nData from preclinical tumor models suggest that adding an antiangiogenic agent to chemotherapy may improve efficacy [26–28]. Pemetrexed, sunitinib, and carboplatin are well tolerated individually and in combination, and have demonstrated antitumor activity in a broad range of malignancies, including NSCLC [12, 13, 22, 25]. The combination of pemetrexed and sunitinib has previously been reported to have promising tolerability and the potential for clinical benefit in patients with solid tumors, including NSCLC [34]. However, as noted above, a randomized phase II study of pemetrexed versus sunitinib versus the combination conducted by CALGB suggested that single agent pemetrexed was superior to either arm containing sunitinib [30]. Sunitinib was administered on a 37.5 mg/day CDD schedule and the combination was associated with greater hematologic toxicity than either agent alone.\n\nThis phase I study established the MTD and overall safety of the triple combination of sunitinib plus pemetrexed and carboplatin in patients with advanced solid malignancies. The MTD on Schedule 2/1 was determined to be sunitinib 37.5 mg/day + pemetrexed 500 mg/m2 q3w + carboplatin AUC = 5 mg·min/ml q3w. The MTD cohort was expanded to further explore the feasibility, tolerability, and early activity of this triple combination for the treatment of advanced NSCLC or mesothelioma. The MTD on the CDD schedule was not established, as the first dose level tested on this schedule (sunitinib 37.5 mg/day + pemetrexed 400 mg/m2 q3w + carboplatin AUC = 5 mg·min/ml) was poorly tolerated due to myelosuppression. As preclinical models and data on minimum inhibitory concentrations suggest that the minimum effective dose is in the range of 37.5 mg/day [2], it was not felt that the exploration of a lower dose schedule would lead to clinically significant activity, considering the need to use suboptimal doses of each individual drug and the clinical experience of other groups using sunitinib alone or in combination with other chemotherapy regimens [36, 37]. Although there were no PK interactions, toxicities appeared additive (particularly in the form of myelosuppression), suggesting overlapping pharmacodynamic effects. It should be noted that full PK profiles for sunitinib, SU12662, pemetrexed, and carboplatin were only obtained from the last 3 patients in the Schedule 2/1 MTD cohort. In the investigators’ judgment, the drug was not sufficiently tolerated to proceed with dose escalation and lower doses would not provide a clinical benefit. However, data from these 3 patients were consistent with historical controls from another study in similar patient populations which did not indicate major discrepancies. There is no preclinical evidence suggesting drug–drug interactions, and the pharmacologic profiles of pemetrexed, sunitinib and carboplatin do not predict any elimination interactions when the drugs are used in combination. Sunitinib is metabolized primarily by CYP3A4, which does not play a role in the elimination of carboplatin or pemetrexed. Furthermore, drug–drug interactions at the absorption level can be ruled out as carboplatin and pemetrexed were administered intravenously.\n\nThe Schedule 2/1 MTD was generally tolerable and clinically manageable on both sunitinib treatment schedules, with most non-hematologic toxicities being mild or moderate (grade 1 or 2), and similar to those reported with either single-agent sunitinib or pemetrexed combined with carboplatin in advanced NSCLC [12, 13, 38].\n\nMyelosuppression was a common toxicity on the 2/1 dosing schedule, as anticipated. Sunitinib as a single agent has been associated with myelosuppression in a small proportion of patients [17, 18, 39]. One possible explanation is the inhibition of c-KIT, FLT3, and colony-stimulating factor receptor (c-fms), which may play a role in recovery of blood cells following myelosuppressive chemotherapy [40].\n\nHematologic toxicities such as thrombocytopenia and anemia are common AEs of treatment with carboplatin and pemetrexed monotherapy. In the current study, hematologic toxicities occurred at a greater rate than expected with carboplatin and pemetrexed alone [38, 41]. The DLTs and MTD were determined during the first cycle of treatment; however, the initial tolerability of these doses was not uniformly sustained, as most patients at the Schedule 2/1 MTD required subsequent sunitinib dose delays or reductions (75 % and 50 %, respectively). A median of 5.0 (2–6) cycles of the triple combination was administered in the original Schedule 2/1 MTD cohort, and a median of 3.5 (1–4) cycles was administered in the expansion cohort, which compared favorably with the cycles reported previously for combinations of pemetrexed with platinum agents (a median of 3 cycles of pemetrexed combined with cisplatin or carboplatin has been reported in previously treated patients with NSCLC [42]). Pharmacokinetic analyses revealed no clinically significant drug–drug interactions following co-administration of sunitinib with pemetrexed plus carboplatin.\n\nThe toxicity of the combination was broadly similar to previous reports of sunitinib plus other types of chemotherapy. Myelosuppression, fatigue, and diarrhea occurred frequently and often led to dose adjustments in studies of sunitinib combined with paclitaxel [43, 44], pemetrexed [45], carboplatin/paclitaxel/bevacizumab [37], gemcitabine/cisplatin [40], FOLFIRI [46], or modified FOLFOX6 [47]. Significant toxicities have also been observed with other VEGFR-TKIs combined with chemotherapy. Rates of hematological toxicities and diarrhea were elevated in studies of sorafenib combined with docetaxel/cisplatin [48], gemcitabine/cisplatin [49], or paclitaxel/carboplatin [50]. Similarly, hematologic abnormalities and diarrhea were commonly observed when axitinib was combined with FOLFIRI [51] or docetaxel [52], and the combination of axitinib plus bevacizumab and FOLFOX was reported to markedly raise the incidence of hypertension [51].\n\nIn the current study, the ORR on Schedule 2/1 was 4/21 (19 %). Given the small number of evaluable patients, and that responses were observed in patients with different tumor types, it is not possible to draw a definitive conclusion on the response rate. However, the observed rate compares favorably with the ORR for single-agent pemetrexed (4 % [22]) and carboplatin plus pemetrexed (9 % [39]) observed in larger studies. Of the three patients with NSCLC who entered the continuation study, one patient with NSCLC NOS had a partial response (lasting 6.9 months) and two patients with NSCLC NOS and adenocarcinoma maintained stable disease for 7.9 and 3.5 months, respectively.\n\nIn summary, although the MTD of sunitinib on Schedule 2/1 in combination with pemetrexed and carboplatin was established, dose adjustments were often required as a result of myelosuppression, especially in patients with NSCLC, making it difficult to maintain a pharmacologically active sunitinib dose. Although one response was observed in a patient with NSCLC started at the highest sunitinib dose (50 mg), this dose could not be sustained in this patient group. However, 37.5 mg was better tolerated in patients with other tumor types, and clinical responses were observed in patients with esophageal carcinoma, breast cancer, and gastric carcinoma. Further exploration of this combination in solid tumors is warranted.\n\nWe would like to thank all of the participating patients and their families, as well as the global network of investigators, research nurses, study coordinators, and operations staff.\n\nThis study was sponsored by Pfizer Inc. Medical writing support was provided by Siân Marshall at ACUMED® (Tytherington, UK) and was funded by Pfizer Inc.\n\nConflict of interest\n\nN Blais has received research funding from Pfizer. DR Camidge has served as a paid advisor to Pfizer and Eli Lilly, and has received research funding from Eli Lilly. DJ Jonker has no conflicts to disclose. D Soulières has received honoraria from Pfizer. SA Laurie has served as a paid advisor to Pfizer. SG Diab has no conflicts to disclose. A Ruiz-Garcia, A Thall, K Zhang, and R Chao are employees of Pfizer Oncology and hold stock in Pfizer, the manufacturer of sunitinib. LQ Chow has received research funding from Pfizer.\n==== Refs\nReferences\n\n1. Abrams TJ Lee LB Murray LJ Pryer NK Cherrington JM SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer Mol Cancer Ther 2003 2 471 478 10.4161/cbt.2.5.446 12748309\n2. Chow LQ Eckhardt SG Sunitinib: from rational design to clinical efficacy J Clin Oncol 2007 25 884 896 10.1200/JCO.2006.06.3602 17327610\n3. 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Sharma S Abhyankar V Burgess RE Infante J Trowbridge RC Tarazi J Kim S Tortorici M Chen Y Robles RL A phase I study of axitinib (AG-013736) in combination with bevacizumab plus chemotherapy or chemotherapy alone in patients with metastatic colorectal cancer and other solid tumors Ann Oncol 2010 21 297 304 10.1093/annonc/mdp489 19940012\n52. Rugo HS Stopeck AT Joy AA Chan S Verma S Lluch A Liau KF Kim S Bycott P Rosbrook B Bair AH Soulieres D Randomized, placebo-controlled, double-blind, phase II study of axitinib plus docetaxel versus docetaxel plus placebo in patients with metastatic breast cancer J Clin Oncol 2011 29 2459 2465 10.1200/JCO.2010.31.2975 21555686\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0167-6997",
"issue": "31(6)",
"journal": "Investigational new drugs",
"keywords": null,
"medline_ta": "Invest New Drugs",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002289:Carcinoma, Non-Small-Cell Lung; D004334:Drug Administration Schedule; D005260:Female; D005971:Glutamates; D006147:Guanine; D006801:Humans; D007211:Indoles; D007970:Leukopenia; D008175:Lung Neoplasms; D008297:Male; D020714:Maximum Tolerated Dose; D008654:Mesothelioma; D008875:Middle Aged; D000068437:Pemetrexed; D011758:Pyrroles; D000077210:Sunitinib; D055815:Young Adult",
"nlm_unique_id": "8309330",
"other_id": null,
"pages": "1487-98",
"pmc": null,
"pmid": "23963796",
"pubdate": "2013-12",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "19307503;17868732;21306237;16549838;17691110;14713109;17050869;10804087;21569994;19652072;24419419;11524555;12748309;17167137;15175435;22399619;16103075;18347007;19940012;11208836;20423465;19188680;20032126;12531805;18612155;20212250;20188433;9052396;20458043;18235126;12538485;21735354;21176744;16757724;20096475;19826424;10655437;16258975;19282169;20960028;21555686;17327610;18667090;16849418;21680048;15867359;15117980;20032789;21989766",
"title": "Sunitinib combined with pemetrexed and carboplatin in patients with advanced solid malignancies--results of a phase I dose-escalation study.",
"title_normalized": "sunitinib combined with pemetrexed and carboplatin in patients with advanced solid malignancies results of a phase i dose escalation study"
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"companynumb": "CA-PFIZER INC-2008090733",
"fulfillexpeditecriteria": "1",
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{
"abstract": "Rituximab (RTX) is effective in maintaining remission in patients with nephrotic syndrome (NS), but a standard protocol of RTX administration has not been established.\n\n\n\nThis study was a 2-year multicenter observational study, in which consistent treatments and evaluations were performed. We enrolled pediatric patients with refractory NS between January 2015 and December 2015. RTX infusion was performed four times at 6-month intervals, followed by mizoribine pulse therapy with early discontinuation of calcineurin inhibitor (CNI). Primary endpoints were the relapse-free survival rate and the number of relapses after RTX administration. Secondary endpoints were changes in side effects associated with long-term steroid administration.\n\n\n\nTwenty-two patients were analyzed. The relapse-free survival rate at 1 year and 2 years was 50 and 46%, respectively. Twenty-one patients accomplished our protocol and the frequency of relapse was reduced under the discontinuation of CNI. Although two patients were diagnosed with frequent relapse and/or steroid dependency during the observation period, the frequency of relapse decreased with each rituximab dose. Statistically significant improvements in all steroid complications were observed in the final examination, but no significant improvements were observed from 1 to 2 years after RTX administration. One patient had agranulocytosis, and three patients showed electrocardiographic abnormalities.\n\n\n\nOur protocol was useful and safe for refractory NS. However, RTX administration four times might have been excessive in patients who had no relapse by 1 year after the initial RTX administration. Further investigation of the most appropriate method of RTX administration is required.",
"affiliations": "Department of Pediatrics, Hokkaido University Graduate School of Medicine, North 15, West 7, Sapporo, Hokkaido, 060-8638, Japan.;Department of Pediatrics, Hokkaido University Graduate School of Medicine, North 15, West 7, Sapporo, Hokkaido, 060-8638, Japan. okamon@med.hokudai.ac.jp.;Department of Pediatrics, Hokkaido University Graduate School of Medicine, North 15, West 7, Sapporo, Hokkaido, 060-8638, Japan.;Department of Pediatrics, Hokkaido University Graduate School of Medicine, North 15, West 7, Sapporo, Hokkaido, 060-8638, Japan.;Department of Pediatrics, Hokkaido University Graduate School of Medicine, North 15, West 7, Sapporo, Hokkaido, 060-8638, Japan.;Department of Pediatrics, Obihiro Kyokai Hospital, Obihiro, Japan.;Department of Pediatrics, Nikko Memorial Hospital, Muroran, Japan.;Department of Pediatrics, Oji General Hospital, Tomakomai, Japan.;Department of Pediatrics, Obihiro Kosei Hospital, Obihiro, Japan.;Department of Pediatrics, Kushiro Red Cross Hospital, Kushiro, Japan.;Department of Pediatrics, Hokkaido University Graduate School of Medicine, North 15, West 7, Sapporo, Hokkaido, 060-8638, Japan.",
"authors": "Takahashi|Toshiyuki|T|;Okamoto|Takayuki|T|0000-0002-6029-451X;Sato|Yasuyuki|Y|;Yamazaki|Takeshi|T|;Hayashi|Asako|A|;Aoyagi|Hayato|H|;Ueno|Michihiko|M|;Kobayashi|Norio|N|;Uetake|Kimiaki|K|;Nakanishi|Masanori|M|;Ariga|Tadashi|T|",
"chemical_list": "D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D012263:Ribonucleosides; D000069283:Rituximab; C010052:mizoribine",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00467-018-4063-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0931-041X",
"issue": "34(1)",
"journal": "Pediatric nephrology (Berlin, Germany)",
"keywords": "Calcineurin inhibitor; Children; Mizoribine; Nephrotic syndrome; Repeated administration; Rituximab",
"medline_ta": "Pediatr Nephrol",
"mesh_terms": "D000293:Adolescent; D065095:Calcineurin Inhibitors; D002648:Child; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents; D007262:Infusions, Intravenous; D008297:Male; D009404:Nephrotic Syndrome; D020551:Pulse Therapy, Drug; D012008:Recurrence; D012074:Remission Induction; D012263:Ribonucleosides; D000069283:Rituximab; D016896:Treatment Outcome",
"nlm_unique_id": "8708728",
"other_id": null,
"pages": "87-96",
"pmc": null,
"pmid": "30141179",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": "28487867;17943078;28555464;25121488;24619426;23739238;22332121;24480824;25733089;27422620;21556716;22076431;18250115;26567244;24296765;18050221;21566104;28664242;11896889;23271494;23052656;26585985;27125514;713276;21174219;20798255;16133041;24965823;16030039;25085238;28434126;21810762;23212560;23340857",
"title": "Periodically repeated rituximab administrations in children with refractory nephrotic syndrome: 2-year multicenter observational study.",
"title_normalized": "periodically repeated rituximab administrations in children with refractory nephrotic syndrome 2 year multicenter observational study"
} | [
{
"companynumb": "JP-TEVA-2018-JP-993434",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXCHLORPHENIRAMINE MALEATE"
},
"drugadditional"... |
{
"abstract": "Pustular psoriasis of pregnancy (PPP), also known as impetigo herpetiformis, is a rare condition that affects women in the third trimester of pregnancy through the postpartum period. The relative infrequency of PPP presents both clinical and pathologic challenges in the diagnosis and management of this condition. We report a case of a woman who presented at 32 weeks' gestation with a generalized rash demonstrating clinicopathologic features consistent with PPP. Based on prior reports of adverse maternal-fetal outcomes in PPP, coordinated efforts from our patient's dermatologic and obstetric teams ensured positive outcomes for the patient and the neonate.",
"affiliations": "Department of Dermatology, University of Rochester, New York, USA.;Department of Dermatology, University of Rochester, New York, USA.;Department of Dermatology, University of Rochester, New York, USA.;Department of Dermatology, University of Rochester, New York, USA.;Department of Dermatology, University of Rochester, New York, USA.",
"authors": "Pitch|Michelle|M|;Somers|Kathryn|K|;Scott|Glynis|G|;Tausk|Francisco|F|;Mercurio|Mary G|MG|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0011-4162",
"issue": "101(4)",
"journal": "Cutis",
"keywords": null,
"medline_ta": "Cutis",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D011565:Psoriasis",
"nlm_unique_id": "0006440",
"other_id": null,
"pages": "278-280",
"pmc": null,
"pmid": "29763478",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of pustular psoriasis of pregnancy with positive maternal-fetal outcomes.",
"title_normalized": "a case of pustular psoriasis of pregnancy with positive maternal fetal outcomes"
} | [
{
"companynumb": "US-TEVA-2018-US-974271",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Objective: Hypertension is a serious health problem in Egypt, with prevalence rate of 17% as reported in 2015. Despite receiving treatment, many do not achieve blood pressure (BP) control. The current study aimed to evaluate the efficacy and tolerability of amlodipine/valsartan/hydrochlorothiazide (Aml/Val/HCTZ) single pill combination (SPC) in patients with hypertension from Egypt, who were uncontrolled on any dual therapy.Methods: In this prospective, open label, multicenter, 12-week observational, cohort study, two doses of Aml/Val/HCTZ (5/160/12.5 mg or 10/160/25 mg) SPC were used to evaluate mean change in BP after 12 weeks (primary endpoint). Safety assessments included presence and intensity of ankle edema and other adverse events (AEs).Results: Data were collected from 1080 patients who were treated according to the routine medical practice across 47 centers in Egypt. Significant reduction in systolic and diastolic BP (SBP/DBP) was observed from 165.5 ± 12.83/100.8 ± 7.03 mmHg at baseline to 129.7 ± 8.35/80.6 ± 5.25 mmHg after 12 weeks of treatment (p < .0001). Majority of patients (76.85%) reached the BP goal of <140/90 mmHg. The most commonly reported AE was ankle edema (10.92%).Conclusions: Aml/Val/HCT SPC significantly reduced BP and was well tolerated in Egyptian patients with hypertension not controlled on any previous dual therapy.",
"affiliations": "Faculty of Medicine, Ain Shams University, Cairo, Egypt.;Novartis Pharma S.A.E., Cairo, Egypt.",
"authors": "El-Etriby|Adel Mohamed Kamal|AMK|;Rakha|Sameh|S|",
"chemical_list": "D000068838:Amlodipine, Valsartan Drug Combination; D000959:Antihypertensive Agents; D004338:Drug Combinations; D006852:Hydrochlorothiazide",
"country": "England",
"delete": false,
"doi": "10.1080/03007995.2020.1719394",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-7995",
"issue": "36(4)",
"journal": "Current medical research and opinion",
"keywords": "Compliance; Egypt; efficacy; hypertension; safety; triple therapy",
"medline_ta": "Curr Med Res Opin",
"mesh_terms": "D000328:Adult; D000368:Aged; D000068838:Amlodipine, Valsartan Drug Combination; D000959:Antihypertensive Agents; D004338:Drug Combinations; D004487:Edema; D005260:Female; D006801:Humans; D006852:Hydrochlorothiazide; D006973:Hypertension; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies",
"nlm_unique_id": "0351014",
"other_id": null,
"pages": "537-544",
"pmc": null,
"pmid": "31955630",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Efficacy and safety of amlodipine/valsartan/hydrochlorothiazide single pill combination in Egyptian patients with hypertension uncontrolled on any dual therapy: an observational study.",
"title_normalized": "efficacy and safety of amlodipine valsartan hydrochlorothiazide single pill combination in egyptian patients with hypertension uncontrolled on any dual therapy an observational study"
} | [
{
"companynumb": "NVSC2020EG156364",
"fulfillexpeditecriteria": "1",
"occurcountry": "EG",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMLODIPINE\\HYDROCHLOROTHIAZIDE\\VALSARTAN"
},
"drugad... |
{
"abstract": "As a key member of the innate and adaptive immune response, neutrophils provide insights into the hematopoietic and inflammatory manifestations of inborn errors of immunity (IEI) and the consequences of immunotherapy. The facile recognition of IEI presenting with neutropenia provides an avenue for hematologists to facilitate early diagnosis and expedite biologically rationale care. Moreover, enhancing the understanding of the molecular mechanisms driving neutropenia in IEI-decreased bone marrow reserves, diminished egress from the bone marrow, and decreased survival-offers an opportunity to further dissect the pathophysiology driving neutropenia secondary to iatrogenic immune dysregulation, eg, immune checkpoint inhibitors and chimeric antigen receptor T-cell therapy.",
"affiliations": "Department of Pediatrics, University of Michigan, Ann Arbor, MI.;Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN.",
"authors": "Walkovich|Kelly|K|;Connelly|James A|JA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1182/hematology.2021000285",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1520-4383",
"issue": "2021(1)",
"journal": "Hematology. American Society of Hematology. Education Program",
"keywords": null,
"medline_ta": "Hematology Am Soc Hematol Educ Program",
"mesh_terms": null,
"nlm_unique_id": "100890099",
"other_id": null,
"pages": "504-513",
"pmc": null,
"pmid": "34889406",
"pubdate": "2021-12-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Understanding neutropenia secondary to intrinsic or iatrogenic immune dysregulation.",
"title_normalized": "understanding neutropenia secondary to intrinsic or iatrogenic immune dysregulation"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2022-010376",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IPILIMUMAB"
},
"drugadd... |
{
"abstract": "We report the endovascular stenting of an outflow tract thrombosis in a left ventricular assist device in a patient with relative contraindications to sternotomy and pump exchange. This report highlights the importance of simultaneous prevention of stroke using filter devices in the common carotid arteries.",
"affiliations": "From the *Department of Cardiology, †Department of Medical and Health Sciences, ‡Department of Thoracic and Vascular Surgery, and §Department of Clinical Physiology, Linköping University, Linköping, Sweden.",
"authors": "Hubbert|Laila|L|;Forssell|Claes|C|;Baranowski|Jacek|J|;Lindgren|Bo|B|;Holm|Jonas|J|;Ahn|Henrik|H|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MAT.0000000000000371",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-2916",
"issue": "63(1)",
"journal": "ASAIO journal (American Society for Artificial Internal Organs : 1992)",
"keywords": null,
"medline_ta": "ASAIO J",
"mesh_terms": "D057510:Endovascular Procedures; D006353:Heart-Assist Devices; D006801:Humans; D008297:Male; D008875:Middle Aged; D015607:Stents; D013927:Thrombosis",
"nlm_unique_id": "9204109",
"other_id": null,
"pages": "e3-e5",
"pmc": null,
"pmid": "27014789",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Endovascular Stenting of a LVAD Outflow Graft Thrombosis.",
"title_normalized": "endovascular stenting of a lvad outflow graft thrombosis"
} | [
{
"companynumb": "SE-INGENUS PHARMACEUTICALS NJ, LLC-ING201701-000036",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ASPIRIN\\CARISOPRODOL"
},
... |
{
"abstract": "Necrotizing autoimmune myopathy is characterized by predominant muscle fiber necrosis and regeneration with little or no inflammation. We describe a 58-year-old woman with previous breast cancer and statin use who complained of rapidly progressive weakness of lower limbs without pain, making walking, running and climbing stairs difficult. The creatine kinase level was 2,843 U/L, and muscle biopsy showed a dystrophic pattern. The genetic test for muscular dystrophies was negative and for anti-3-hydroxy-3-methylglutaryl coenzyme A reductase was positive. Intravenous immunoglobulin was administered, which showed mild improvement. Unfortunately, she took a step and collapsed to the floor, which led to the fracture of right femur delaying her improvement. The diagnosis of necrotizing autoimmune myopathy is sometimes delayed due to the atypical pathologic findings on muscle biopsy. As the disease is a severe condition, prompt recognition can lead to a successful outcome. We advise to consider this entity as a differential diagnosis among muscular dystrophies.",
"affiliations": "Laboratory of Neuromuscular Disease, Department of Neurosciences, School of Medicine of ABC, Santo André, São Paulo, Brazil.;Laboratory of Neuromuscular Disease, Department of Neurosciences, School of Medicine of ABC, Santo André, São Paulo, Brazil.;Department of Neurology, School of Medicine of University of São Paulo, São Paulo, Brazil.;Department of Pharmacology, School of Medicine of ABC, Santo André, São Paulo, Brazil.",
"authors": "Carvalho|Alzira Alves de Siqueira|AAS|;da Silva|Vinicius Gomes|VG|;Zanoteli|Edmar|E|;Feder|David|D|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/TCRM.S162931",
"fulltext": "\n==== Front\nTher Clin Risk ManagTher Clin Risk ManagTherapeutics and Clinical Risk ManagementTherapeutics and Clinical Risk Management1176-63361178-203XDove Medical Press 10.2147/TCRM.S162931tcrm-14-903Case ReportMyopathy due to HMGCR antibodies in adult mimicking muscular dystrophy associated with cancer and statin exposure – narrative review of the literature – case report Carvalho Alzira Alves de Siqueira 1da Silva Vinicius Gomes 1Zanoteli Edmar 2Feder David 3\n1 Laboratory of Neuromuscular Disease, Department of Neurosciences, School of Medicine of ABC, Santo André, São Paulo, Brazil\n2 Department of Neurology, School of Medicine of University of São Paulo, São Paulo, Brazil\n3 Department of Pharmacology, School of Medicine of ABC, Santo André, São Paulo, BrazilCorrespondence: Alzira Alves de Siqueira Carvalho, Laboratory of Neuromuscular Disease, Department of Neuroscience, Faculty of Medicine of ABC, Av. Príncipe de Gales, 821, Santo André, São Paulo 09060-650, Brazil, Tel +55 114 993 7299, Email alzirasiqueiracarvalho@gmail.com2018 14 5 2018 14 903 907 © 2018 Carvalho et al. This work is published and licensed by Dove Medical Press Limited2018The 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.Necrotizing autoimmune myopathy is characterized by predominant muscle fiber necrosis and regeneration with little or no inflammation. We describe a 58-year-old woman with previous breast cancer and statin use who complained of rapidly progressive weakness of lower limbs without pain, making walking, running and climbing stairs difficult. The creatine kinase level was 2,843 U/L, and muscle biopsy showed a dystrophic pattern. The genetic test for muscular dystrophies was negative and for anti-3-hydroxy-3-methylglutaryl coenzyme A reductase was positive. Intravenous immunoglobulin was administered, which showed mild improvement. Unfortunately, she took a step and collapsed to the floor, which led to the fracture of right femur delaying her improvement. The diagnosis of necrotizing autoimmune myopathy is sometimes delayed due to the atypical pathologic findings on muscle biopsy. As the disease is a severe condition, prompt recognition can lead to a successful outcome. We advise to consider this entity as a differential diagnosis among muscular dystrophies.\n\nKeywords\nnecrotizing autoimmune myopathyHMGCR antibodymuscular dystrophycancerstatin\n==== Body\nIntroduction\nSince 2003, an international workshop exposed different points of view to improve the classification criteria of different inflammatory myopathies designed by Anthony Amato, allowing us an accurate diagnosis.\n\nAmong the different inflammatory myopathies, a special histologic pattern defined a new subgroup called immune-mediated necrotizing myopathy or necrotizing autoimmune myopathy (NAM), which is characterized by predominant muscle fiber necrosis and regeneration with little or no inflammation.1,2\n\nIt has been known that patients with NAM have specific autoantibodies that are associated with specific clinical phenotypes. Thus, they can be grouped into myositis-specific autoantibodies, myositis-associated autoantibodies, signal recognition particle (SRP) and, more recently, antibodies to 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). Although there are other risk factors recognized for NAM as cancer and, rarely, the HIV infection, prompt recognition of anti-SRP and anti-HMGCR myopathy is very important as the early immuno-suppressive therapy is the treatment of choice often followed by improvement in strength.3,4\n\nCase presentation\nA 58-year-old woman with no previous medical history of neuromuscular disorder was referred to our outpatient clinic in August 2014, complaining of weakness of the right foot for 1 year that progressed after 3 months with weakness of the left foot without pain. The worsening was progressive, making walking, running and climbing stairs difficult within 1 year.\n\nShe had unrelated parents and a familial history that revealed no abnormalities.\n\nA breast neoplasia (invasive ductal carcinoma) was diagnosed in January 2007. She underwent a mastectomy with lymphadenectomy followed by chemotherapy. Currently, the breast neoplasia has been controlled with no complaints.\n\nBetween 2012 and 2014, she had taken 20 mg/day of simvastatin without side effects. She discontinued the medication 3 months after the beginning of symptoms.\n\nIn July 2017, she was diagnosed with colon adenoma without surgery.\n\nHer first assessment revealed muscle weakness, which was proximal–distal in the lower limbs, revealing a distal atrophy. The muscle strength was 4-out of 5 (Medical Researcher Council) in the quadriceps and hamstring muscles and 4 in the gastrocnemius and soleus muscles. The tibialis anterior muscle strength was 5. The upper limbs showed a normal strength of proximal and distal muscles. No facial weakness was detected. Her deep tendon reflexes were preserved. No sensitive abnormalities were present. No retractions were found. No cardiac involvement or respiratory dysfunction was observed.\n\nSerologic tests for autoimmune disorders were all normal. Creatine kinase (CK) was 2,843 U/L (26–140) and aldolase was equivalent to 25.9 U/L (<7.6). Other laboratory findings were within normal limits. The cerebrospinal fluid showed no neoplastic cells.\n\nConduction studies were normal and needle electromyography showed a myogenic pattern with positive waves.\n\nMagnetic resonance imaging of the lower limbs revealed diffuse edema of the right semimembranosus and left semimembranosus and femoral biceps. There was discreet fatty infiltration of the soleus muscle and the medial and lateral heads of both gastrocnemii (Figure 1).\n\nA muscle biopsy of the gastrocnemius was performed, which revealed myopathic changes, including marked variation in fiber size, connective tissue proliferation and necrosis, suggesting a dystrophic pattern. Immunohistochemistry studies, including dysferlin, dystrophin, sarcoglycans, merosin, caveolin-3 and collagen VI, showed normal immunoexpression. Diffuse major histocompatibility complex (MHC) class I overexpression was observed. CD4, CD8 and CD68 were also overexpressed (Figure 1).\n\nBased on these findings, several molecular analyses were performed, including a genetic panel of NGS containing ANO5, DYSF, GAA, SGCB, SGCG, SGCA, SGCD, CAPN3, FKRP and TCAP genes. No mutations were found.\n\nAs the progression continued, it was decided to treat the patient with prednisolone 1 g/day for 5 days, which showed clinical improvement.\n\nAfter 1 year, a new muscle magnetic resonance imaging was done to assess the progression of the weakness, which revealed progressive worsening characterized by muscle atrophy and fatty infiltration of the bilateral semimembranosus and fatty infiltration and edema of the gastrocnemius and soleus muscles (Figure 2).\n\nAs she did not improve, in March 2016, we started treatment with intravenous immunoglobulin (IV Ig). As a result, the patient noticed a slight improvement in the strength of the right foot.\n\nAs all molecular results were negative, anti-SRP and anti-HMGCR antibodies were determined by enzyme-linked immune-sorbent assay (CUSABIO® kit). It was found to be negative for anti-SRP and positive for anti-HMGCR (value=7.516632, cutoff 2.283). A diagnosis of NAM was finally confirmed, but immunoglobulin therapy was stopped due to the fracture.\n\nUnfortunately, in October 2016, she collapsed on the floor. An X-ray revealed a fracture of her right femur. She also suffered from brachial plexus palsy. She underwent surgery and was kept under complete rest for 3 months interrupting IV Ig therapy. Currently, she has started using IV Ig once a month again and is getting better every day despite the limitations resulting from the fall. Currently, she cannot lift her right arm, but is able to walk with assistance.\n\nEthical approval\nWritten informed consent has been provided by the patient to have the case details and any accompanying images published.\n\nDiscussion\nWe report here an adult case of anti-HMGCR antibodies-linked NAM for whom diagnosis was delayed mainly due to pathologic findings, suggesting muscular dystrophy (MD).\n\nThere are a few reports in the literature about cases of anti-HMGCR+ myopathy previously diagnosed as MD.5–7\nTable 1 shows the demographic and clinical characteristics of these patients.\n\nSome points should be highlighted in this case:\nAlthough there were no other family members with muscle disease, the muscle biopsy findings of our patient were reminiscent of hereditary MDs, while the disease progression was faster than it usually occurs in MD.\n\nCareful history and examination of the patient complemented by review of the muscle biopsy showing overexpression of MHC class I associated with absence of facial weakness and extraocular muscle involvement led us to consider the possibility of an autoimmune myopathy, even in the presence of a dystrophic-like pattern on muscle biopsy.\n\nAlthough she was a healthy patient in the point of neurologic view, she had a history of significant comorbidities:\nThe patient had dyslipidemia which had been treated for 2 years with simvastatin 20 mg/day; she discontinued the medication after the onset of muscle symptoms without improvement of muscle strength.\n\nIn 2007, 6 years before the myopathy was diagnosed, she was diagnosed with breast cancer for which she underwent surgery and chemotherapy. They gave satisfactory results that are currently controlled.\n\n\n\n\n\nWe must remember that adults with proximal muscle weakness, elevated CK levels and features of myopathy on electromyography have a broad differential diagnosis that includes autoimmune myopathies, toxic myopathies (statin self-limited side effects, anti-retrovirus), paraneoplastic myopathies and MDs. Distinguishing between immune-mediated myopathies and other etiologies is crucial, because only autoimmune muscle diseases routinely respond to immuno-suppressive therapy.8\n\nAccording to a previous report, weakness in NAM anti-HMGCR in some cases presents an acute onset (within ≤4 weeks), and in a few cases, weakness could evolve slowly (from months to several years), occasionally mimicking MD, the most common and representative myopathy, being part of hereditary or sporadic progressive diseases and characterized by several phenotypic and genetic features.2,6,9\n\nIn relation to autoimmune myopathies, anti-SRP-positive patients have a low incidence of pulmonary fibrosis, skin rash and arthritis as well as muscular involvement. In contrast, anti-HMGCR-positive patients usually present only muscle weakness which difficult to differentiate them from MD patients.9,10\n\nRegardless of the upregulation of MHC class I and the deposition of complement on capillaries and non-necrotic muscle fibers, which may suggest the probability of an immune-mediated process, the possibility of nonimmune-mediated myopathic processes should always be considered in patients who have a necrotizing muscle biopsy.10\n\nAlthough anti-HMGCR myopathy is associated with statin exposure in patients aged 50 years, approximately one-fourth of anti-HMGCR-positive patients develop a similar myopathic process in the absence of statins, including those with self-limited statin intolerance.5,11 Our patient developed the symptoms during statin exposure and showed no improvement after statin withdrawal, maintaining high CK levels.\n\nClinical and epidemiologic data have confirmed the temporal relationship between the onset of myositis and malignancy, and cancer-associated myositis has been defined as a cancer occurring within 3 years of diagnosing myositis.12 In addition, other studies report an increased risk of cancer up to 5 years.13\n\nIn 2016, Allenbach et al examined a large cohort of patients and showed for the first time that patients with NAM and anti-HMGCR antibodies were associated with an increased risk of cancer. Malignancy occurred in 17.3% (9/52) of anti-HMGCR+ patients. The mean duration between the diagnosis of cancer and myopathy was 4.2±4.9 years. Two-thirds of the malignancies occurred within 3 years of or before the diagnosis anti-HMGCR+ myopathy. No specific type of cancer was observed.14\n\nIn the same year, Kadoya et al found that the prevalence of cancer within 3 years of myopathy diagnosis (cancer association) among patients with anti-HMGCR myopathy was 36% (12/33). This occurred in most patients (92%) within 1 year of myopathy diagnosis.15\n\nOn the other hand, previous large-scale studies showed prevalence rates of cancers in patients with anti-HMGCR myopathy ranging from 4% to 26% (irrespective of the temporal association between cancer detection and myopathy diagnosis).15 Our patient had breast cancer 6 years before the beginning of symptoms.\n\nBased on the findings, we considered the possibility of an autoimmune myopathy, which led us to initiate IV Ig that caused a mild improvement in muscle weakness. However, the IV Ig was interrupted because the patient had a fall that caused fracture.\n\nThe poor response to IV Ig may have different explanations:\nWould the HMGCR myopathy be a paraneoplastic manifestation and, therefore, without indication of the immunoglobulin? There are some differences between cancer association and history of cancer, the former highlighting the importance of the successful treatment of malignancy improving the myopathy.\n\nCould the poor response to the immunoglobulin treatment be caused by the fracture, making it impossible for the patient to walk?\n\nCould the patient have a self-limited statin myopathy to NAM anti-HMGCR that typically improves by immuno-suppressive therapy?\n\n\n\nHowever, many questions remain unanswered. The new case studies may clarify these.\n\nIn summary, the diagnosis of NAM is sometimes delayed due to the atypical pathologic findings on muscle biopsy. As the disease is a severe condition, prompt recognition can lead to a successful outcome.\n\nWe advise to consider this entity as a differential diagnosis among MDs.\n\nAcknowledgments\nThe authors gratefully acknowledge the contributions from the staff of Clinical Analysis Laboratory, Faculty of Medicine of ABC. The authors also thank Dr L Avaizoglou for the comments regarding MRI.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Axial muscle MRI of thighs and legs and muscle biopsy findings (gastrocnemius).\n\nNotes: (A–H) MRI of the thighs: axial T1-weighted images (A and B) show mild fatty degeneration of right and left semimembranosus (arrow). Axial fat-suppressed T2-weighted images (C and D) reveal edema of the right semimembranosus and very mild edema of left semimembranosus (arrow) and long head of biceps femoris (arrow head). MRI of the legs: axial T1-weighted images (E and F) show fatty degeneration of medial head of gastrocnemius (arrow) and soleus bilaterally (arrowhead). Axial fat-suppressed T2-weighted images (G and H) reveal mild edema of the medial head of gastrocnemius (arrow) and soleus(arrow head) bilaterally. (I–N) Histological findings: (I) H&E stain: variation in fiber size, connective tissue proliferation and necrosis. (J) Gomori trichrome: connective tissue proliferation. (K–N) Positive immunostaining for MHC class I CD4, CD8 and CD68, respectively. (I–N) 10×; scale bar: 1 μm.\n\nAbbreviations: MHC, major histocompatibility complex; MRI, magnetic resonance imaging.\n\nFigure 2 Axial muscle MRI of thighs and legs.\n\nNotes: Thighs (A–D): diffuse edema of the right semimembranosus and tenuous edema of the left semitendinosus and femoral biceps. Legs (E–H): diffuse edema and discreet fatty infiltration of the soleus muscle and the medial and lateral heads of both gastrocnemii.\n\nAbbreviation: MRI, magnetic resonance imaging.\n\nTable 1 Previous cases reported with anti-HMGCR myopathy simulating dystrophic-like pattern\n\nAuthors\tn\tGender (M/F)\tInitial presentation\tAge of onset\tAge of diagnosis\tCK (first visit)\t\nMohassel et al,5 2017\t1\tM\tDecrease in running\t9 years\t14 years\t8,000\t\nTard et al,6 2017\t1\tF\tAbnormal gait\t5 years\t19 years\t7,576\t\nLiang et al,7 2017\t4\tNO\tMotor delay\t10 months\tNO\t352–918\t\n\t\tNO\tAsymptomatic high CK\t6 years\tNO\t6,391\t\n\t\tNO\tDifficulty in pedaling and climbing stairs\t13 years\tNO\t7,183\t\n\t\tNO\tDifficulty in climbing stairs\t9 years\tNO\t9,570\t\nAbbreviations: CK, creatine kinase; HMGCR, 3-hydroxy-3-methylglutaryl coenzyme A reductase; NO, not obtained.\n==== Refs\nReferences\n1 Hoogendijk JE Amato AA Lecky BR 119th ENMC international workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis. 10–12 October 2003, Naarden, The Netherlands Neuromuscul Disord 2004 14 5 337 345 15099594 \n2 Allenbach Y Drouot L Rigolet A French Myositis Network Anti-HMGCR autoantibodies in European patients with autoimmune necrotizing myopathies: inconstant exposure to statin Medicine (Baltimore) 2014 93 3 150 157 24797170 \n3 Mammen AL Necrotizing myopathies Curr Opin Rheumatol 2014 26 6 679 683 25203117 \n4 Musset L Miyara M Benveniste O Analysis of autoantibodies to 3-hydroxy-3-methylglutaryl-coenzyme A reductase using different technologies J Immunol Res 2014 2014 405956 24741598 \n5 Mohassel P Foley AR Donkervoort S Anti-3-hydroxy-3-methylglutaryl-coenzyme a reductase necrotizing myopathy masquerading as a muscular dystrophy in a child Muscle Nerve 2017 56 6 1177 1181 28066895 \n6 Tard C Tiffreau V Jaillette E Anti-HMGCR antibody–related necrotizing autoimmune myopathy mimicking muscular dystrophy Neuropediatrics 2017 48 6 473 476 28778101 \n7 Liang WC Uruha A Suzuki S Pediatric necrotizing myopathy associated with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies Rheumatology (Oxford) 2017 56 2 287 293 27818386 \n8 Mammen A Statin-associated autoimmune myopathy N Engl J Med 2016 374 7 664 669 26886523 \n9 Suzuki S Hayashi Y Kuwana M Tsuburaya R Suzuki N Nishino I Myopathy associated with antibodies to signal recognition particle Arch Neurol 2012 69 6 728 732 22332183 \n10 Allenbach Y Benveniste O Acquired necrotizing myopathies Curr Opin Neurol 2013 26 5 554 560 23995277 \n11 Mammen AL Chung T Christopher-Stine L Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy Arthritis Rheum 2011 63 3 713 721 21360500 \n12 Landon-Cardinal O Allenbach Y Benveniste O Anti-HMGCR necrotizing autoimmune myopathy leading to identification of cancer relapse Clin Med Rev Case Rep 2017 4 4 164 \n13 Troyanov Y Targoff IN Tremblay JL Goulet JR Raymond Y Senécal JL Novel classification of idiopathic inflammatory myopathies based on overlap syndrome features and autoantibodies: analysis of 100 French Canadian patients Medicine (Baltimore) 2005 84 4 231 249 16010208 \n14 Allenbach Y Keraen J Bouvier A High risk of cancer in autoimmune necrotizing myopathies: usefulness of myositis specific antibody Brain 2016 139 Pt 8 2131 2135 27086869 \n15 Kadoya M Hida A Maeda MH Cancer association as a risk factor for anti-HMGCR antibody-positive myopathy Neurol Neuroimmunol Neuroinflamm 2016 3 6 e290 27761483\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1176-6336",
"issue": "14()",
"journal": "Therapeutics and clinical risk management",
"keywords": "HMGCR antibody; cancer; muscular dystrophy; necrotizing autoimmune myopathy; statin",
"medline_ta": "Ther Clin Risk Manag",
"mesh_terms": null,
"nlm_unique_id": "101253281",
"other_id": null,
"pages": "903-907",
"pmc": null,
"pmid": "29785116",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "27761483;15099594;23995277;27086869;28778101;16010208;27818386;26886523;24741598;22332183;21360500;28066895;24797170;25203117",
"title": "Myopathy due to HMGCR antibodies in adult mimicking muscular dystrophy associated with cancer and statin exposure - narrative review of the literature - case report.",
"title_normalized": "myopathy due to hmgcr antibodies in adult mimicking muscular dystrophy associated with cancer and statin exposure narrative review of the literature case report"
} | [
{
"companynumb": "BR-MYLANLABS-2018M1044503",
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"activesubstancename": "SIMVASTATIN"
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{
"abstract": "Complex regional pain syndrome is a chronic pain condition that may be resistant to many treatment modalities. Ketamine infusions have demonstrated some promising results, though their use may be associated with a number of adverse effects limiting their widespread applicability. Hepatotoxicity and cholangiopathy have been described in chronic ketamine abuse, though rarely in therapeutic use. We report the impact of recurrent short subanesthetic ketamine infusions for the treatment of complex regional pain syndrome resulting in biliary dilation, jaundice, and cholangitis. We recommend that prescribing physicians consider this and monitor liver function tests throughout the treatment period to minimize morbidity.",
"affiliations": "From the Anesthetic Department and Pain Management Unit, St George Hospital Sydney, Kogarah, New South Wales, Australia.",
"authors": "Hewitt|Nathan A|NA|;Cox|Peter|P|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000650",
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"issue": "10(7)",
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"nlm_unique_id": "101714112",
"other_id": null,
"pages": "168-170",
"pmc": null,
"pmid": "29135531",
"pubdate": "2018-04-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Recurrent Subanesthetic Ketamine Infusions for Complex Regional Pain Syndrome Leading to Biliary Dilation, Jaundice, and Cholangitis: A Case Report.",
"title_normalized": "recurrent subanesthetic ketamine infusions for complex regional pain syndrome leading to biliary dilation jaundice and cholangitis a case report"
} | [
{
"companynumb": "AU-MYLANLABS-2019M1022326",
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"activesubstance": {
"activesubstancename": "PANTOPRAZOLE"
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... |
{
"abstract": "The coronavirus disease 2019 pandemic has made us adjust our standards and cope with unpredictable circumstances affecting the whole world, including the medical field. A 2-year-old boy diagnosed with X-linked lymphoproliferative disease type 2 with concomitant positive polymerase chain reaction test for Epstein-Barr virus-DNA was admitted to our transplant ward. His treatment scheme had to be modified at the last moment because of a donor disqualification due to a positive polymerase chain reaction result for severe acute respiratory syndrome coronavirus 2 just before the apheresis. We decided to perform salvage haploidentical bone marrow transplant from the patient's mother because it was the only possible option. Now, in a 5-month observation period after the hematopoietic stem cell transplantation, our patient is in good general condition. His case convinced us to redirect our approach to transplant procedure preparation. Following the European Group of Blood and Marrow Transplantation recommendations, we use cryopreserved apheresis materials to ensure the availability of stem cell products before the start of a conditioning regimen.",
"affiliations": "Department of Pediatric Bone Marrow Transplantation, Oncology, and Hematology, Wroclaw Medical University, Wroclaw, Poland.;Department of Pediatric Bone Marrow Transplantation, Oncology, and Hematology, Wroclaw Medical University, Wroclaw, Poland.;Department of Pediatric Bone Marrow Transplantation, Oncology, and Hematology, Wroclaw Medical University, Wroclaw, Poland.;Department of Pediatric Oncohematology, Medical Faculty University of Rzeszow, Clinical Provincial Hospital No. 2, Rzeszow, Poland.;Clinic of Pediatric Oncology and Hematology, Faculty of Medicine, University of Rzeszow, Rzeszow, Poland.;Department of Pediatric Bone Marrow Transplantation, Oncology, and Hematology, Wroclaw Medical University, Wroclaw, Poland.;Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, Lodz, Poland.;Department of Pediatric Bone Marrow Transplantation, Oncology, and Hematology, Wroclaw Medical University, Wroclaw, Poland. Electronic address: krzysztof.kalwak@gmail.com.",
"authors": "Liszka|Karolina|K|;Marschollek|Pawel|P|;Gul|Katarzyna|K|;Musial|Jakub|J|;Chaber|Radoslaw|R|;Miskiewicz-Bujna|Justyna|J|;Mlynarski|Wojciech|W|;Kalwak|Krzysztof|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2021.04.017",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "53(8)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D016026:Bone Marrow Transplantation; D000086382:COVID-19; D002675:Child, Preschool; D020031:Epstein-Barr Virus Infections; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D004854:Herpesvirus 4, Human; D006801:Humans; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D016879:Salvage Therapy; D013234:Stem Cells; D019172:Transplantation Conditioning; D061349:Unrelated Donors",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2498-2501",
"pmc": null,
"pmid": "34053771",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Salvage Haploidentical Bone Marrow Transplantation in a Child With Hemophagocytic Lymphohistiocytosis, When the Previously Matched Unrelated Donor Tested Positive for SARS-CoV-2 on the Day of Stem Cells Collection.",
"title_normalized": "successful salvage haploidentical bone marrow transplantation in a child with hemophagocytic lymphohistiocytosis when the previously matched unrelated donor tested positive for sars cov 2 on the day of stem cells collection"
} | [
{
"companynumb": "PL-ROCHE-2945029",
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{
"actiondrug": "5",
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"activesubstancename": "ETANERCEPT"
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"drugadditional": "3",
"druga... |
{
"abstract": "OBJECTIVE\nImmune-mediated necrotizing myopathy (IMNM) is a subtype of myositis that is associated with a refractory phenotype and poorer prognosis. The aim of the study was to provide single large center experience of outcomes of intravenous immunoglobulin (IVIg) for patients with IMNM using longitudinally collected data.\n\n\nMETHODS\nThis case series longitudinally evaluated 4 of the 6 myositis core set measures at baseline and at 3 and 6 months after IVIg on 20 adult IMNM patients from 2014 to 2019 at the University of Pittsburgh. We assessed patients for improvement in core set measures, prednisone dose, adverse effects, and by the \"limited\" ACR/EULAR 2016 myositis response criteria. The mean differences in CK and manual muscle testing (MMT-8) were compared using a paired t test. A clinically significant response was defined as a >10% absolute improvement in the MMT-8 and a >50% absolute reduction in serum CK at 6 months of IVIg.\n\n\nRESULTS\nIntravenous immunoglobulin treatment was associated with marked improvement in IMNM patients, with 85% of patient meeting clinically significant response. The median (interquartile range) relative percent improvement in CK level was 96% (85%-98%) and in MMT was 29% (14%-36%) at 6 months.There was a significant reduction in the mean (SD) dose of prednisone at 6 months and had minimal adverse effects. In addition, with IVIg, most (13/14) patients had at least minimal improvement as per ACR/EULAR 2016 myositis response criteria.\n\n\nCONCLUSIONS\nBased on objective, meaningful improvement in MMT-8 and CK as well as marked reduction in prednisone doses with acceptable tolerability, early implementation of IVIg should be considered in adult IMNM.",
"affiliations": "From the Division of Rheumatology and Clinical Immunology, Department of Medicine Departments of Neurology and Pathology (Neuropathology), University of Pittsburgh School of Medicine, Pittsburgh, PA.",
"authors": "Kocoloski|Amanda|A|;Martinez|Silvia|S|;Moghadam-Kia|Siamak|S|;Lacomis|David|D|;Oddis|Chester V|CV|;Ascherman|Dana P|DP|;Aggarwal|Rohit|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/RHU.0000000000001786",
"fulltext": null,
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"issn_linking": "1076-1608",
"issue": null,
"journal": "Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases",
"keywords": null,
"medline_ta": "J Clin Rheumatol",
"mesh_terms": null,
"nlm_unique_id": "9518034",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34581697",
"pubdate": "2021-09-23",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Role of Intravenous Immunoglobulin in Necrotizing Autoimmune Myopathy.",
"title_normalized": "role of intravenous immunoglobulin in necrotizing autoimmune myopathy"
} | [
{
"companynumb": "US-MYLANLABS-2022M1031175",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"activesubstance": {
"activesubstancename": "PREDNISONE"
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... |
{
"abstract": "In ultra-rare bone diseases, information on growth during childhood is sparse. Juvenile Paget disease (JPD) is an ultra-rare disease, characterized by loss of function of osteoprotegerin (OPG). OPG inhibits osteoclast activation via the receptor activator of nuclear factor-κB (RANK) pathway. In JPD, overactive osteoclasts result in inflammatory-like bone disease due to grossly elevated bone resorption. Knowledge on the natural history of JPD, including final height and growth, is limited. Most affected children receive long-term antiresorptive treatment, mostly with bisphosphonates, to contain bone resorption, which may affect growth. In this study, we report the follow-up of height, growth velocity, and skeletal maturation in a 16-year-old female patient with JPD. The patient was treated with cyclic doses of pamidronate starting at 2.5 years of age and with 2 doses of denosumab at the age of 8 years, when pamidronate was paused. In the following years, a sustainable decline in a height z-score and a stunted pubertal growth spurt; despite appropriate maturation of the epiphyseal plates of the left hand, the proximal right humerus and both femora were observed. Whether this reflects the growth pattern in JPD or might be associated to the antiresorptive treatments is unclear, since there is very limited information available on the effect of bisphosphonates and denosumab on growth and the growth plate in pediatric patients. Studies are needed to understand the natural history of an ultra-rare bone disease and to assess the effects of antiresorptive treatment on the growing skeleton.",
"affiliations": "Center for Rare Diseases Ruhr CeSER, Ruhr-University Bochum and Witten/Herdecke University, Bochum, Germany.;Department of Pediatrics II, University Hospital Essen and University of Duisburg-Essen, Essen, Germany.;Technische Universität Dresden, Dresden, Germany.;Institute of Pediatric Radiology, St.-Josef Hospital Bochum, Ruhr-University Bochum, Bochum, Germany.;Department of Pediatrics II, University Hospital Essen and University of Duisburg-Essen, Essen, Germany.;Center for Rare Diseases Ruhr CeSER, Ruhr-University Bochum and Witten/Herdecke University, Bochum, Germany.",
"authors": "Höppner|Jakob|J|;Steff|Katja|K|;Lobert|Felix|F|;Heyer|Christoph M|CM|;Hauffa|Berthold P|BP|;Grasemann|Corinna|C|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000517164",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1663-2818",
"issue": "94(3-4)",
"journal": "Hormone research in paediatrics",
"keywords": "Bisphosphonates; Denosumab; Growth hormone; Height velocity; Juvenile Paget disease; Linear growth; Receptor activator of nuclear factor-κB ligand",
"medline_ta": "Horm Res Paediatr",
"mesh_terms": null,
"nlm_unique_id": "101525157",
"other_id": null,
"pages": "151-158",
"pmc": null,
"pmid": "34261073",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Rhizomelia and Impaired Linear Growth in a Girl with Juvenile Paget Disease: The Natural History of the Condition.",
"title_normalized": "rhizomelia and impaired linear growth in a girl with juvenile paget disease the natural history of the condition"
} | [
{
"companynumb": "DE-AMGEN-DEUSP2012014104",
"fulfillexpeditecriteria": "2",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": "1",
... |
{
"abstract": "INTRODUCTION Escalated BEACOPP (escBEACOPP: bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) significantly improves overall response rates (ORRs) and prolongs progression‑free survival (PFS) in patients with advanced‑stage Hodgkin lymphoma (HL). However, 6 to 8 cycles of escBEACOPP are associated with increased acute toxicity and late complications. OBJECTIVES We aimed to determine the role of early positron emission tomography-computed tomography (PET‑CT) response assessment in a de‑escalation strategy. PATIENTS AND METHODS We retrospectively analyzed 188 consecutive patients with advanced‑stage HL treated at diagnosis. Patients received 2 cycles of escBEACOPP followed by an early PET‑CT response assessment performed after 2 cycles of chemotherapy (PET2). Patients with an active disease continued therapy with escBEACOPP, while those with negative PET2 were de‑escalated to ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). Radiotherapy was allowed in patients with stage IIBX. RESULTS PET2 allowed for de‑escalation of therapy in 141 patients (75%). Their ORR was 92.2%, with a complete remission (CR) rate of 91.5%; 10‑year PFS and overall survival (OS) were 87.2% and 95%, respectively. In the whole cohort, ORR was 87.8% (CR, 85.6%), while the 10‑year PFS and OS were 79.3% and 89.4%, respectively. Hematological and thromboembolic complications were significantly more frequent in patients treated with 6 escBEACOPP cycles, including febrile neutropenia (25 patients, [53.2%] vs 7 [5%]), serious anemia (35 [74.5%] vs 11 [7.8%]), or thrombocytopenia (16 [34%] vs 7 [5%]) (P <0.001 for all comparisons with de‑escalation strategy) as well as pulmonary embolism (3 [6.4%] vs 0) (P = 0.02). CONCLUSIONS The early de‑escalation strategy allows for effective treatment of advanced HL, with a comparable efficacy to that of 6 to 8 cycles of escBEACOPP, but with significantly reduced toxicity.",
"affiliations": "Department of Hematology, Jagiellonian University Medical College, Kraków, Poland;Department of Pulmonary Circulation, Thromboembolic Diseases and Cardiology, Centre of Postgraduate Medical Education, European Health Centre, Otwock, Poland;Department of Medical Education, Jagiellonian University, Kraków, Poland;Department of Allergy and Immunology, Jagiellonian University Medical College, Kraków, Poland;Department of Hematology, Jagiellonian University Medical College, Kraków, Poland;Department of Hematology, Jagiellonian University Medical College, Kraków, Poland;Department of Positron Emission Tomography and Molecular Imaging, Nicolaus Copernicus University, Collegium Medicum, Bydgoszcz, Poland;Department of Endocrinology, Jagiellonian University Medical College, Kraków, Poland;Department of Thoracic and Surgical Oncology, Jagiellonian University Medical College, John Paul II Hospital, Kraków, Poland;Department of Hematology, Jagiellonian University Medical College, Kraków, Poland",
"authors": "Długosz-Danecka|Monika|M|;Szmit|Sebastian|S|;Kocurek|Anna|A|;Koźlik|Paweł|P|;Giza|Agnieszka|A|;Zimowska-Curyło|Dagmara|D|;Małkowski|Bogdan|B|;Sowa-Staszczak|Anna|A|;Kużdżał|Jarosław|J|;Jurczak|Wojciech|W|",
"chemical_list": "D001761:Bleomycin; D011344:Procarbazine; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "Poland",
"delete": false,
"doi": "10.20452/pamw.14786",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0032-3772",
"issue": "129(4)",
"journal": "Polish archives of internal medicine",
"keywords": null,
"medline_ta": "Pol Arch Intern Med",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D003520:Cyclophosphamide; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin; D005047:Etoposide; D005260:Female; D005500:Follow-Up Studies; D006689:Hodgkin Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D000072078:Positron Emission Tomography Computed Tomography; D011241:Prednisone; D011344:Procarbazine; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "101700960",
"other_id": null,
"pages": "259-266",
"pmc": null,
"pmid": "30945698",
"pubdate": "2019-04-30",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Early chemotherapy de-escalation strategy in patients with advanced-stage Hodgkin lymphoma with negative positron emission tomography scan after 2 escalated BEACOPP cycles.",
"title_normalized": "early chemotherapy de escalation strategy in patients with advanced stage hodgkin lymphoma with negative positron emission tomography scan after 2 escalated beacopp cycles"
} | [
{
"companynumb": "PL-JNJFOC-20190528292",
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"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"... |
{
"abstract": "Delirium is a common complication among hospitalized elderly individuals. Systemic analgesics are known precipitating factors for delirium. However, the risk from topical pain agents is not well documented. We report a case of a woman who developed delirium after the application of a lidocaine patch. Although lidocaine patches are generally perceived as safe, clinicians should be aware of delirium as a potential adverse effect, particularly in older patients. This report also highlights the role of a systematic approach of staff education, use of a standardized protocol, and interdisciplinary communication in the identification and management of delirium in acute rehabilitation facilities.",
"affiliations": "Department of Physical Medicine and Rehabilitation, Rutgers New Jersey Medical School, Newark, NJ; Kessler Institute for Rehabilitation, Saddle Brook, NJ(∗).;Department of Physical Medicine and Rehabilitation, Rutgers New Jersey Medical School, Newark, NJ(†).;Department of Physical Medicine and Rehabilitation, Rutgers New Jersey Medical School, Newark, NJ; Kessler Institute for Rehabilitation, Saddle Brook, NJ(‡).;Department of Physical Medicine and Rehabilitation, Rutgers New Jersey Medical School, Newark, NJ; Kessler Institute for Rehabilitation, 1199 Pleasant Valley Way, West Orange, NJ 07052; Kessler Foundation, West Orange, NJ(§). Electronic address: mopark@kessler-rehab.com.",
"authors": "Byun|Eun Kwang|EK|;Berry|Kevin M|KM|;Lee|Anthony|A|;Oh-Park|Mooyeon|M|",
"chemical_list": "D000700:Analgesics; D000779:Anesthetics, Local; D008012:Lidocaine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1934-1482",
"issue": "8(6)",
"journal": "PM & R : the journal of injury, function, and rehabilitation",
"keywords": null,
"medline_ta": "PM R",
"mesh_terms": "D000700:Analgesics; D000779:Anesthetics, Local; D003693:Delirium; D005260:Female; D006801:Humans; D008012:Lidocaine; D010146:Pain",
"nlm_unique_id": "101491319",
"other_id": null,
"pages": "597-601",
"pmc": null,
"pmid": "26772419",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Delirium Associated With Lidocaine Patch Administration: A Case Presentation.",
"title_normalized": "delirium associated with lidocaine patch administration a case presentation"
} | [
{
"companynumb": "US-DENTSPLY-2020SCDP000338",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LIDOCAINE"
},
"drugadditional": null,
... |
{
"abstract": "This report highlights the association of tacrolimus use with acute macular neuroretinopathy (AMN). A 27-year-old woman, a known case of diffuse proliferative membranous glomerulonephritis, developed abnormal body movements, loss of consciousness, and blurring of vision in the left eye, after 3 months of starting tacrolimus. Blood investigations revealed anemia, thrombocytopenia, raised urea and creatinine levels, and raised LDH levels. A diagnosis of tacrolimus induced hemolytic uremic syndrome (HUS) with posterior reversible encephalopathy syndrome (PRES) was made. Ocular examination revealed a reddish-brown petaloid retinal lesion, which was better appreciated on red-free imaging as dark grey area pointing towards the fovea. OCT-A and SD-OCT revealed flow voids in deep retinal plexus, and disruption of ellipsoid and interdigitation zone, respectively, findings consistent with AMN. To the best of our knowledge, it is the first report of association of tacrolimus with AMN.",
"affiliations": "Advanced Eye Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Advanced Eye Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Advanced Eye Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India.",
"authors": "Markan|Ashish|A|;Ayyadurai|Nikitha|N|;Singh|Ramandeep|R|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/09273948.2021.1998549",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0927-3948",
"issue": null,
"journal": "Ocular immunology and inflammation",
"keywords": "Tacrolimus; acute macular neuroretinopathy; hemolytic uremic syndrome; posterior reversible encephalopathy syndrome; thrombotic microangiopathy",
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": null,
"nlm_unique_id": "9312169",
"other_id": null,
"pages": "1-2",
"pmc": null,
"pmid": "34855579",
"pubdate": "2021-12-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Tacrolimus Induced Thrombotic Microangiopathy (TMA) Presenting as Acute Macular Neuroretinopathy.",
"title_normalized": "tacrolimus induced thrombotic microangiopathy tma presenting as acute macular neuroretinopathy"
} | [
{
"companynumb": "IN-Accord-247463",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "1",
"druga... |
{
"abstract": "Recent studies have noted an increased risk of low energy subtrochanteric and femoral shaft fractures termed \"atypical femur fractures\" (AFFs) associated with long-term bisphosphonate use. As such, many clinicians have begun recommending a \"drug holiday\" to reduce the risks associated with long-term bisphosphonate use. We present two cases of AFFs occurring during a 4-year or greater drug holiday following long-term bisphosphonate use. These findings highlight the need to reevaluate optimal bisphosphonate therapy duration, dosage, as well as initiation and duration of a drug holiday with continued monitoring in the prevention of AFFs.",
"affiliations": "Department of Orthopaedic Surgery, Mount Sinai Hospital, 5 East 98th St., 9th Floor, New York, NY, 10029, USA. andrew.lovy@mountsinai.org.;Department of Orthopaedic Surgery, Mount Sinai Hospital, 5 East 98th St., 9th Floor, New York, NY, 10029, USA.;Department of Orthopaedic Surgery, Mount Sinai Hospital, 5 East 98th St., 9th Floor, New York, NY, 10029, USA.;Department of Orthopaedic Surgery, Mount Sinai Hospital, 5 East 98th St., 9th Floor, New York, NY, 10029, USA.;Department of Orthopaedic Surgery, Elmhurst Hospital Center, 79-01 Broadway, Queens, NY, 11373, USA.;Department of Orthopaedic Surgery, Mount Sinai Hospital, 5 East 98th St., 9th Floor, New York, NY, 10029, USA.",
"authors": "Lovy|A J|AJ|;Koehler|S M|SM|;Keswani|A|A|;Joseph|D|D|;Hasija|R|R|;Ghillani|R|R|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates",
"country": "England",
"delete": false,
"doi": "10.1007/s00198-015-3063-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0937-941X",
"issue": "26(6)",
"journal": "Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA",
"keywords": "Atypical femur fractures; Bisphosphonates; Drug holiday; Osteoporosis",
"medline_ta": "Osteoporos Int",
"mesh_terms": "D000368:Aged; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D004334:Drug Administration Schedule; D005260:Female; D005264:Femoral Fractures; D006801:Humans; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal; D058866:Osteoporotic Fractures; D028761:Withholding Treatment",
"nlm_unique_id": "9100105",
"other_id": null,
"pages": "1755-8",
"pmc": null,
"pmid": "25832177",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12590887;24788502;21542743;17663638;24121986;23712442;20886644;20662073;21195812;24120384;18769963;23408697;15324532;22161728;18354114;5641125;22072397;18214569;5875212;17938986;23668401;23858334;9875874;11172164;15028823;18056045;11405286;24733321;20843943;17190893;25184886;20200926",
"title": "Atypical femur fracture during bisphosphonate drug holiday: a case series.",
"title_normalized": "atypical femur fracture during bisphosphonate drug holiday a case series"
} | [
{
"companynumb": "US-APOTEX-2015AP015486",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCHLOROTHIAZIDE"
},
"drugadditional": null,
... |
{
"abstract": "Although much is known about the correlates of heroin overdose, less is known about pharmaceutical opioid (PO) overdose. This study aimed to examine correlates of opioid overdose deaths by opioid and compare correlates between opioids.\n\n\n\nAnalysis of opioid overdose deaths in Australia between 2000-2015, extracted from the National Coronial Information System (NCIS). The NCIS is an online database of deaths reportable to the coroner, and contains coroner's findings, autopsy and toxicology reports. Deaths were categorized into mutually exclusive groups: 1) Heroin deaths; and 2) PO deaths (excluding heroin). PO deaths were examined by individual opioid.\n\n\n\nThere were 10,795 opioid overdose deaths over the study period. Relative to deaths occurring in major cities, deaths in regional/remote areas had 15.2 (95 % CI: 11.5-20.2) times the risk of being attributed to pharmaceutical fentanyl than heroin. Relative to deaths among people without a recorded history of chronic pain, deaths among people with a recorded history of chronic pain had a 1.9-10.7-fold increased risk of the death being attributed to POs than heroin. Deaths among people with a recorded history of substance use problems where the opioid was injected prior to death had 7.2 and 1.7 times the risk of being attributed to methadone and pharmaceutical fentanyl (respectively) than heroin.\n\n\n\nFindings suggest the need to: educate PO consumers about the risks of overdose at the time of prescribing; increase coverage and engagement in opioid dependence treatment (particularly in regional/remote areas); and increase uptake of take-home naloxone to reduce opioid overdose mortality.",
"affiliations": "National Drug and Alcohol Research Centre (NDARC), University of New South Wales, Sydney, NSW, 2052, Australia. Electronic address: a.roxburgh@unsw.edu.au.;National Drug and Alcohol Research Centre (NDARC), University of New South Wales, Sydney, NSW, 2052, Australia; University of Queensland Clinical Centre for Research, University of Queensland, Brisbane, QLD, 4072, Australia; University of Queensland Centre for Youth Substance Abuse Research, University of Queensland, Brisbane, QLD, 4006, Australia; National Addiction Centre, Kings College London, WC2R 2LS, United Kingdom.;National Drug and Alcohol Research Centre (NDARC), University of New South Wales, Sydney, NSW, 2052, Australia.;National Drug and Alcohol Research Centre (NDARC), University of New South Wales, Sydney, NSW, 2052, Australia; School of Population and Global Health, University of Melbourne, VIC, 3010, Australia.",
"authors": "Roxburgh|Amanda|A|;Hall|Wayne D|WD|;Gisev|Natasa|N|;Degenhardt|Louisa|L|",
"chemical_list": "D000701:Analgesics, Opioid; D009270:Naloxone; D014147:Tramadol; D003932:Heroin; D009020:Morphine; D008691:Methadone; D005283:Fentanyl",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.drugalcdep.2019.06.035",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0376-8716",
"issue": "205()",
"journal": "Drug and alcohol dependence",
"keywords": "Fentanyl; Heroin; Morphine; Mortality; Opioid analgesics; Opioid overdose deaths; Oxycodone; Prescription opioids",
"medline_ta": "Drug Alcohol Depend",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000701:Analgesics, Opioid; D001315:Australia; D059350:Chronic Pain; D062787:Drug Overdose; D011307:Drug Prescriptions; D005260:Female; D005283:Fentanyl; D003932:Heroin; D006801:Humans; D008297:Male; D008691:Methadone; D008875:Middle Aged; D009020:Morphine; D009270:Naloxone; D009293:Opioid-Related Disorders; D014147:Tramadol; D055815:Young Adult",
"nlm_unique_id": "7513587",
"other_id": null,
"pages": "107533",
"pmc": null,
"pmid": "31704378",
"pubdate": "2019-12-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Characteristics and circumstances of heroin and pharmaceutical opioid overdose deaths: Comparison across opioids.",
"title_normalized": "characteristics and circumstances of heroin and pharmaceutical opioid overdose deaths comparison across opioids"
} | [
{
"companynumb": "AU-JNJFOC-20191122461",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TRAMADOL HYDROCHLORIDE"
},
"drugadditional": null... |
{
"abstract": "Taxane-based chemotherapy regimens are in widespread use as standard of care treatment for patients with early breast cancer, though rarely its use can be complicated by taxane-induced pneumonitis (TIP). While breast cancer is the most diagnosed cancer in women worldwide, TIP remains under-described in this setting. Key questions relate to its incidence, diagnosis and management, potential predictive biomarkers, and the balance between this life-threatening toxicity and curatively intended treatment. At a single Australian institution, 6 cases of TIP are identified among 132 patients treated with a paclitaxel-containing regimen for early breast cancer (4.55%, 95% confidence interval 1.69-9.63%). This review first outlines the presentation, management, and outcomes for these cases, then answers these questions and proposes an approach to suspected TIP in patients with breast cancer.",
"affiliations": "Department of Medical Oncology, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.;Department of Medical Oncology, Fiona Stanley Hospital, Murdoch, Perth, WA, Australia.;Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead, NSW, Australia.;Department of Medical Oncology, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.;Department of Medical Oncology, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.;St. Vincent's Clinical School, University of New South Wales, Darlinghurst, NSW, Australia.;Department of Medical Oncology, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.",
"authors": "Ardolino|Luke|L|;Lau|Brandon|B|;Wilson|Isabella|I|;Chen|Julia|J|;Borella|Linda|L|;Stone|Emily|E|;Lim|Elgene|E|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2021.701424",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X\nFrontiers Media S.A.\n\n10.3389/fonc.2021.701424\nOncology\nCase Report\nCase Report: Paclitaxel-Induced Pneumonitis in Early Breast Cancer: A Single Institution Experience and Review\nArdolino Luke 1 2 *\n\nLau Brandon 3\nWilson Isabella 4\nChen Julia 1 2\nBorella Linda 1 2 5\nStone Emily 2 5 6\nLim Elgene 1 2\n1 Department of Medical Oncology, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia\n2 St. Vincent’s Clinical School, University of New South Wales, Darlinghurst, NSW, Australia\n3 Department of Medical Oncology, Fiona Stanley Hospital, Murdoch, Perth, WA, Australia\n4 Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead, NSW, Australia\n5 Department of Medical Imaging, St Vincent’s Hospital, Darlinghurst, NSW, Australia\n6 Department of Thoracic Medicine, St Vincent’s Hospital, Darlinghurst, NSW, Australia\nEdited by: Kulmira Nurgali, Victoria University, Australia, Australia\n\nReviewed by: Lawrence Panasci, Segal Cancer Centre, Canada; Liheng Zhou, Shanghai JiaoTong University, China\n\n*Correspondence: Luke Ardolino, Luke.ardolino@svha.org.au; orcid.org/0000-0002-8998-7141\nThis article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Oncology\n\n23 6 2021\n2021\n11 70142428 4 2021\n10 6 2021\nCopyright © 2021 Ardolino, Lau, Wilson, Chen, Borella, Stone and Lim\n2021\nArdolino, Lau, Wilson, Chen, Borella, Stone and Lim\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.\nTaxane-based chemotherapy regimens are in widespread use as standard of care treatment for patients with early breast cancer, though rarely its use can be complicated by taxane-induced pneumonitis (TIP). While breast cancer is the most diagnosed cancer in women worldwide, TIP remains under-described in this setting. Key questions relate to its incidence, diagnosis and management, potential predictive biomarkers, and the balance between this life-threatening toxicity and curatively intended treatment. At a single Australian institution, 6 cases of TIP are identified among 132 patients treated with a paclitaxel-containing regimen for early breast cancer (4.55%, 95% confidence interval 1.69-9.63%). This review first outlines the presentation, management, and outcomes for these cases, then answers these questions and proposes an approach to suspected TIP in patients with breast cancer.\n\nchemotherapy\npneumonitis and pulmonary toxicity\nearly breast cancer\nmanagement of toxicities\nimmunotherapy\n==== Body\nIntroduction\n\nTaxane-induced pneumonitis (TIP) usually occurs within days-weeks following treatment. It is rare and poorly characterised, with incidence cautiously estimated to be 1-5% (1), yet it is critical that it be diagnosed and managed early, as the consequences are potentially fatal. Most published cases are in non-small cell lung cancer (NSCLC) or haematological malignancies and, despite the widespread use of taxanes in breast cancer, there are only a few individual case reports and a small case series in this tumour type.\n\nTaxanes are microtubule toxins used to treat a wide range of malignancies. Commonly used taxanes include docetaxel, cabazitaxel, and paclitaxel. The most common paclitaxel-related toxicities are hypersensitivity reactions, neuropathies and haematological toxicities, most commonly neutropenia (2). More rarely, paclitaxel can induce an interstitial pneumonitis, often resulting in significant clinical deterioration and cessation of further chemotherapy. Nanoparticle-albumin bound paclitaxel (nab-paclitaxel) theoretically carries a reduced risk of hypersensitivity reactions because it lacks many of the solvents found in conventional paclitaxel (3). Interestingly, nab-paclitaxel is associated with lower rates of pneumonitis and a milder clinical course, perhaps leading to underreporting in clinical trials.\n\nTaxane induced pneumonitis (TIP) can occur through a variety of different mechanisms and take a variety of forms. Respiratory symptoms may start at the first treatment and worsen with subsequent exposure or after several cycles. Several clinical entities have been observed: 1) acute diffuse interstitial pneumonia is the most severe and quickly progresses to acute respiratory failure; 2) subacute diffuse interstitial pneumonitis has delayed onset and a less severe clinical course; 3) pulmonary opacities with peripheral eosinophilia are exceedingly rare marked by an indolent course and excess infiltration of eosinophils within lung interstitium and alveoli. Pulmonary fibrosis can occur as a late complication following the initial inflammatory process and may result in chronic respiratory failure (4). Radiological examples of these four sub-types of TIP are presented in Figure 1 . Mechanistically, TIP is thought to be the result of delayed hypersensitivity reaction, suggested by positive leukocyte migration inhibition test to paclitaxel in lymphocytes taken during bronchoalveolar lavage of affected patients (5). Curiously, there have even been cases of TIP following insertion of paclitaxel-containing coronary artery drug eluting stents (DES) (6).\n\nFigure 1 Thoracic HRCT images demonstrating the radiological appearances of the four sub-types of TIP. (A) Pulmonary Fibrosis - Case courtesy of Dr Ian Bickle, Radiopaedia.org, rID: 26493 (B) Acute Diffuse Interstitial Pneumonia - Case courtesy of Radswiki, Radiopaedia.org, rID: 11516 (C) Sub-acute Diffuse Interstitial Pneumonia - Case courtesy of Dr Mark Holland, Radiopaedia.org, rID: 19551 (D) Pulmonary Opacities with peripheral eosinophillia - Case courtesy of Dr Lawrence Josey, Radiopaedia.org, rID: 18019.\n\nPredisposing Factors to TIP\n\nThere are a number of predisposing factors to TIP which should prompt a lower threshold for investigating respiratory symptoms in patients receiving taxanes. These include the following\n\nPre-Existing Interstitial Lung Disease (ILD)\n\nILD includes a group of pulmonary disorders that result in radiological patterns that vary according to underlying histology. High resolution computed tomography (HRCT) is the most sensitive imaging examination to assist with differentiation of types of ILD. HRCT findings primarily reflect interstitial fibrosis and commonly include increased reticular markings, non-dependent ground glass opacities, traction bronchiectasis, and honeycombing. In a retrospective series of 392 Japanese patients with NSCLC treated with 3-weekly docetaxel (60 mg/m2), TIP was observed in 26% of those with pre-existing ILD compared to 4.6% in the overall cohort. Analyses of patients with underlying ILD treated with docetaxel demonstrated an acute exacerbation of the ILD in 14-18% of patients, with half of these exacerbations resulting in death. Resultantly, it is the view of many medical oncologists that baseline ILD is a relative contraindication to taxane chemotherapy (7).\n\nUse of Radiotherapy\n\nThe use of taxanes in combination with either concurrent or sequential radiotherapy (RT) also appears to increase the risk of TIP. However, sequential rather than concurrent administration of thoracic RT with taxane chemotherapy, does appear to negate some of this risk, with an overall lower incidence of pneumonitis (HR = 0.29. [p = 0.003]) (8–10). Additionally, taxane based chemotherapy (especially paclitaxel) does appear to increase the risk of radiation pneumonitis and radiation recall independently of prior TIP, although this risk remains low (11, 12).\n\nCombination Systemic Therapy\n\nThe incidence of TIP is higher when taxanes are combined with other cytotoxic agents (2) and especially with gemcitabine (13, 14). In one case series, 4 of 12 patients (33%) with NSCLC who were treated with the combination of paclitaxel and gemcitabine developed CTCAE ≥ grade 2 pneumonitis (15). In two further case series, ≥ grade 3 pneumonitis was observed in 4 of 39 (10%) and 7 of 63 (11%) patients treated with combination paclitaxel plus gemcitabine or docetaxel plus gemcitabine, respectively (13, 14). Finally, a meta-analysis describing TIP in 5,065 patients receiving docetaxel with gemcitabine (22.1% breast cancer) demonstrated an overall TIP incidence of 2.7% (95% CI 2.26-3.14) for ≥ grade 3 lung toxicity. The lung cancer and breast cancer specific incidence were 4% (95% CI 3.68-4.32) and 0.8% (95% CI 0.68-0.87) respectively. Relative to patients with lung cancer, patients with breast cancer developed severe lung toxicity less frequently (OR = 0.18, 95% CI (0.09, 0.36). Among cases of TIP, mortality was 0.35% in the overall population and in this setting, patients with lung cancer, compared to breast cancer, did not show significantly more fatal lung toxicity (OR = 0.20, 95% CI (0.02, 1.67) (16).\n\nTaxane Dose and Schedule\n\nWhile observational studies have found paclitaxel doses greater than 250mg/m2 to be associated with pneumonitis risk, there was no dose-response relationship seen with lower doses (17). Certainly, the standard schedule of weekly paclitaxel (80mg/m2) used in breast cancer following AC is well below this dose threshold. When compared with 3 weekly paclitaxel therapy (175 mg/m2), weekly dosing may be associated with increased incidence and severity of pneumonitis. Two comparative trials comparing weekly with every-three-week paclitaxel in women with advanced breast cancer, demonstrated rates of grade 3 or higher dyspnoea during therapy of 5-7% versus 3-4% respectively (3, 17). Additionally, in a further phase III trial comparing weekly to three-weekly docetaxel, the overall incidence of TIP was 27% and 6% respectively (7), however, the incidence of lung toxicity of ≥ grade 3 was low in both groups (5% and 3% respectively), similar to paclitaxel. Therefore, although a weekly dosing schedule does appear to increase the incidence of TIP, it is unlikely that there is any significant difference between paclitaxel and docetaxel (18).\n\nManagement of TIP\n\nWhen presented with an acutely breathless and hypoxic patient who has received paclitaxel, the initial assessment and treatment must consider alternative aetiologies including pulmonary embolism, lymphangitis, and infection, in particular atypical infections such as Pneumocystis Carinii which can arise in immunocompromised hosts such as patients undergoing chemotherapy or patients receiving dexamethasone as part of their treatment regimen. Supplemental oxygen and empirical antimicrobials can be provided while awaiting the results of imaging. In patients with radiological features consistent with TIP, such as organising pneumonia (OP) or non-specific interstitial pneumonia (NSIP) patterns, who also have a compatible clinical presentation, bronchoscopy should be considered and bronchoalveolar lavage (BAL) performed. Fluid should be examined for hemosiderin deposition, lipid-laden macrophages, Langerhans cells, and malignant cells. If TIP is suspected, glucocorticoid therapy should be initiated. This is based on case reports and anecdotal observational essays of patients’ respiratory failure being successfully reversed with this treatment (2, 18, 19). The putative mechanism is by suppressing the hypersensitivity reaction driving the pneumonitis (6). While oral prednisone dosed at 0.7mg/kg/day (40-60 mg) is usually adequate to treat TIP, intravenous methyl-prednisone may be required for impending respiratory failure dosed at 1-2mg/kg/day (19, 20). Following clinical recovery, the glucocorticoid should be slowly tapered over 1-2 months.\n\nHere, we report six cases of patients with early-stage breast cancer diagnosed with TIP in the setting of dose-dense AC chemotherapy followed by weekly paclitaxel. To the authors’ knowledge, this represents the largest breast-specific case series in the literature and expands on our current knowledge from previous smaller case studies.\n\nCase Series\n\nBetween 1 March 2018 to 1 March 2021, 132 patients received a paclitaxel-containing chemotherapy regimen for either adjuvant or neoadjuvant treatment of early-stage breast cancer. Six patients were diagnosed with TIP. This provides a point estimate of TIP incidence at our centre of 4.55% (95% confidence interval 1.69-9.63%), similar to what has been previously described (2).\n\nDemographics\n\nThe median age of our cohort was 57, and all patients were prescribed dose-dense doxorubicin (60mg/m2) and cyclophosphamide (600mg/m2) followed by weekly paclitaxel (80mg/m2) for treatment of early-stage breast cancer. Clinicopathological features of the breast cancer diagnoses are described in Table 1 . No patients had pre-existing ILD detectable on baseline computed tomography (CT) staging imaging and all were never-smokers. One had received prior preoperative radiotherapy for a fungating primary breast carcinoma, which was completed 17 weeks prior to developing TIP. Five patients were planned for subsequent adjuvant radiotherapy.\n\nTable 1 Summary of patient’s demographics, diagnosis and management.\n\nCase\tAge\tER status\tHER-2 status\tNodal status\tOnset of symptoms since commencing paclitaxel\tILD on staging CT\tPattern\tDLCO (mL/min/mmHg)/KCO (mL/min/mmHg/L) at time of diagnosis\tReceived anthracycline prior to TIP\tReceived Corticosteroids\tAdjuvant RT following paclitaxel\t\n1\t67\tNegative\tNegative\tNegative\t16 days\tNegative\tNSIP\t15.3 (64%)/\tYes\tYes\tYes\t\n4.4 (77%)\t\n2\t44\tNegative\tNegative\tNegative\t7 days\tNegative\tOP\t13.6 (54%)/\tYes\tNo\tYes\t\n3.5 (66%)\t\n3\t62\tPositive\tNegative\tPositive\t2 days\tNegative\tOP\t16.3 (74%)/\tYes\tYes\tYes\t\n3.5 (73%)\t\n4\t63\tNegative\tPositive\tNegative\t15 days\tNegative\tOP\t15.2 (66%)/\tYes\tYes\tNo\t\n4.5 (71%)\t\n5\t37\tPositive\tPositive\tPositive\t17 days\tNegative\tNSIP\tNot performed\tYes\tNo\tYes\t\n6\t52\tNegative\tPositive\tNegative\t20 days\tNegative\tOP\t17.7 (71%)/\tYes\tYes\tYes\t\n3.92 (81%)\t\nCT, Computerised Tomography; ILD, Interstitial lung disease; NSIP, Non-specific interstitial pneumonia; OP, Organising pneumonia; RT, Radiotherapy; TIP, Taxane induced pneumonitis.\n\nDiagnosis of TIP\n\nThere was a median of 15 days (range 2-20) from the first paclitaxel infusion until development of pneumonitis. All patients developed a dry cough, dyspnoea, and fever (T ≥38°C). Four out of the five patients described additional significant lethargy. All patients were admitted to hospital as inpatients for respiratory support and further diagnostic work up following clinical presentation. All received supplemental oxygen and empirical intravenous antibiotics. Serum C-reactive protein was elevated in all patients, with median 105mg/L (range 26-270), though none had neutrophilia or eosinophilia. All patients had chest radiographs showing diffuse, bilateral interstitial opacities, and two patients had bilateral pleural effusions. All underwent initial CT of the chest, with four patients proceeding to HRCT: all had features of pneumonitis with specific patterns outlined in Table 1 . A radiological example of TIP with NSIP pattern is presented in Figure 2 .\n\nFigure 2 Thoracic HRCT from patient 4, demonstrating interstitial fibrosis, increased reticular markings, ground glass attenuation and traction bronchiectasis at the time of diagnosis (above) and subsequent standard-resolution thoracic CT showing resolution of these changes following 6 weeks of corticosteroids (below).\n\nAll patients underwent pulmonary function testing (PFT), with median diffusing capacity for carbon monoxide (DLCO) of 15.2 mL/min/mmHg (66% predicted; normal 75-140% predicted). In the one case with pre-treatment PFTs available, DLCO decreased from 16.8 mL/min/mmHg (67% predicted) to 13.6 mL/min/mmHg (57% predicted). In the one case with serial PFTs following TIP diagnosis and treatment, there was only marginal improvement in DLCO at 14-week interval: 66% to 69% predicted. All patients underwent bronchoscopy, and had atypical infections such as PJP and malignant cells excluded on brochoalveolar lavage (BAL) evaluation.\n\nManagement of TIP\n\nFour patients received oral corticosteroids at an initial daily dose of 50mg oral prednisone or 8mg of intravenous dexamethasone within 24 hours of clinical diagnosis, followed by prolonged tapering over 4-12 weeks. The two patients who did not receive corticosteroids were offered treatment, but declined due to having a milder clinical course and concerns over developing corticosteroid-related toxicities. All patients, including the two patients who did not receive corticosteroids, received antimicrobial therapies and supportive management. All patients had the paclitaxel discontinued.\n\nDespite the reduced DLCO on PFTs, all women recovered clinically within 6 weeks of presentation. All patients completed their subsequent adjuvant therapy, including radiotherapy, human epidermal growth factor receptor 2 (HER2) directed therapy, and endocrine therapy. For the 4 patients who required adjuvant radiotherapy, this was delayed for a median duration of 37 days (range 28-42) from the last dose of paclitaxel until the demonstration of recovery of PFTs and improvement of the radiological changes.\n\nThe three patients receiving chemotherapy in the neoadjuvant setting proceeded to uncomplicated surgery with a median time to surgery from the last dose of paclitaxel of 34 days (range 27 – 45). At surgery, pathological complete response was reported in all three patients despite an abbreviated course of systemic therapy. At 3 months after TIP diagnosis, all women remained free of respiratory symptoms, oxygen requirement, and functional impairment.\n\nDiscussion\n\nTIP is a relatively rare and potentially fatal toxicity in which early recognition and management is critical. Any patient receiving taxane chemotherapy who presents with a fever and/or dyspnoea should have early thoracic imaging and consideration of bronchoscopy to exclude an atypical infection, followed by the rapid initiation of steroids.\n\nIn our series, the majority of patients had evidence of an OP pattern of lung injury on CT, with bilateral ground glass changes with patchy consolidation with a predominantly sub pleural and/or peri-bronchial distribution, with the minority of patients having an NSIP pattern, consistent with published reports of paclitaxel induced pneumonitis in breast and other cancer subtypes (2, 4, 18). The point estimate of TIP incidence at our centre was 4.55%, which despite being aligned with previous TIP literature, was higher than that expected in a breast cancer specific population. This increased incidence may have been contributed to by all patients in our series receiving dose-dense doxorubicin and cyclophosphamide, prior to paclitaxel. Cyclophosphamide-induced pulmonary injury appears to be rare; the frequency is <1 percent, but is increased with concomitant use of other cytotoxic agents and can result in both early and late-onset pneumonitis (21). Additionally, doxorubicin, despite being far more commonly associated with cumulative cardiac toxicity, several reported cases of pneumonitis and, rarely, organizing pneumonia have been described (22). However, we included 132 consecutive cases of patients with breast cancer receiving paclitaxel in our series, across a year-to-year time point to reduce selection bias. Therefore, as we had a low threshold and defined clinical pathway for investigating patients with suspected TIP, the incidence described here may in fact reflect the true incidence of TIP in patients receiving paclitaxel for breast cancer.\n\nPredictive clinical characteristics are becoming increasingly validated for risk stratification, but besides pre-existing ILD, they rarely contraindicate treatment. Additionally, there are no currently available predictive biomarkers for TIP risk. Pre-existing ILD appears to significantly increase the incidence of TIP (14-18%), with half of these exacerbations resulting in death (23). Therefore, pre-existing ILD is should be considered to be a relative contraindication to taxane chemotherapy. Guidelines do not however recommend routine screening for baseline lung disease or to investigate asymptomatic patients for sub-clinical TIP during treatment with taxane chemotherapy.\n\nA diagnosis of TIP is highly likely to result in compromised chemotherapy and a delay of planned subsequent curative treatment. This is especially the case with chemotherapy becoming increasingly used in the preoperative setting for triple negative and HER2 positive breast cancer subtypes. Additionally, as patients require resolution of their respiratory dysfunction in order to be fit for surgery, a dilemma that may arise regarding how long surgery can safely be delayed in the absence of systemic therapy while the breast cancer remains in situ. Multidisciplinary coordination between the oncologist, respiratory physician and surgeon in critical. While taxane-based chemotherapy (especially paclitaxel) increases the risk of radiation pneumonitis and radiation recall independently of prior TIP, this risk remains low (18, 21). Therefore, TIP should not contraindicate subsequent adjuvant breast radiotherapy, and when indicated and where a safe lung dose can be achieved, adjuvant radiotherapy should be completed as planned. Similarly, TIP does not contraindicate planned subsequent non-taxane based systemic therapies including HER2 or endocrine directed therapies. However, once diagnosed, we do not recommend rechallenging with taxanes. This remains a particular challenge, especially in patients with high-risk disease where treatment intensity is important in reducing risk of disease recurrence. Further investigation and validation of alternative treatment regimens and rechallenge strategies remains desirable.\n\nNab-paclitaxel theoretically carries a reduced risk of hypersensitivity reactions, including pneumonitis compared with conventional paclitaxel. Additionally, its use is becoming increasingly validated in the treatment of breast cancer, especially in the neoadjuvant and metastatic setting (24, 25). One case report has described successful treatment with nab-paclitaxel in a patient with NSCLC and pre-existing ILD (26). Additionally, with other rare chemotherapy toxicities such as doxorubicin-induced pancreatitis, successful rechallenge with PEGylated doxorubicin has demonstrated success (27). Further experience is needed to guide whether nab-paclitaxel may represent a legitimate candidate for rechallenge following TIP. If validated, this strategy may permit the completion of curatively intended therapy in patients experiencing TIP who are at high risk of developing metastatic disease. However, we cannot recommend this strategy without further safety data.\n\nFinally, the rise of checkpoint inhibitor immunotherapy in the treatment of early triple-negative breast cancer adds a potential confounder. The phase 3 study KEYNOTE-522 investigated pembrolizumab versus placebo in 1174 women treated with anthracycline, cyclophosphamide, paclitaxel, and carboplatin. Paclitaxel and pembrolizumab were initiated concurrently in the study. Despite exposure to two drugs each individually associated with lung toxicity, the rate of pneumonitis of any grade was 1.3% regardless of treatment arm (28). Similarly, the phase 3 study IMpassion031 used atezolizumab versus placebo in 333 women treated with doxorubicin, cyclophosphamide, and nab-paclitaxel; the rate of any-grade pneumonitis was low at 1% in both arms (29). While there was no signal for synergistic lung toxicity in these chemo-immunotherapy combinations, the life-threatening nature of this potential side effect warrants rapid assessment of such patients presenting with respiratory decline.\n\nConclusion\n\nTIP is potentially life-threatening and affects up to one in twenty patients receiving curatively intended chemotherapy for breast cancer. Therefore, we recommend a low threshold for performing chest CT in patients receiving paclitaxel who present with dyspnoea or hypoxia. Additionally, if TIP is suspected, glucocorticoid therapy should be initiated promptly and slowly titrated with the resolution of symptoms over a period of 4-6 weeks. TIP should not contraindicate adjuvant breast radiotherapy (RT) or subsequent HER2 or endocrine directed therapies, which should proceed as planned. Finally, at present, we do not recommend rechallenging with taxane chemotherapy following TIP. However, an unanswered question remains, regarding optimal further management of patients at high-risk for developing metastatic disease. Therefore, further investigation and validation of alternative treatment regimens and rechallenge strategies remains desirable.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.\n\nEthics Statement\n\nWritten informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nThe authors confirm contribution to the paper as follows: study conception and design: LA and EL. Data collection: LA and IW. Analysis and interpretation: LA, BL, IW, JC, LB, ES, and EL. Draft manuscript preparation: LA, BL, and EL. All authors contributed to the article and approved the submitted version.\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\nAcknowledgments\n\nEL has received support from the national breast cancer foundation (grant number - EC17-02) and Love your sister.\n==== Refs\nReferences\n\n1 Vahid B Marik PE . Pulmonary Complications of Novel Antineoplastic Agents for Solid Tumors. Chest (2008) 133 (2 ):528–38. 10.1378/chest.07-0851\n2 Bielopolski D Evron E Moreh-Rahav O Landes M Stemmer SF Salamon F . Paclitaxel-Induced Pneumonitis in Patients With Breast Cancer: Case Series and Review of the Literature. J Chemother (2017) 29 (2 ):113–7. 10.1179/1973947815Y.0000000029\n3 Socinski MA Bondarenko I Karaseva NA Makhson AM Vynnychenko I Okamoto I . Weekly Nab-Paclitaxel in Combination With Carboplatin Versus Solvent-Based Paclitaxel Plus Carboplatin as First-Line Therapy in Patients With Advanced Non-Small-Cell Lung Cancer: Final Results of a Phase III Trial. J Clin Oncol (2012) 30 (17 ):2055–62. 10.1200/JCO.2011.39.5848\n4 Camus P King TE Jr . Interstitial Lung Disease From Drugs, Biologics, and Radiation. In: Schwarz MI , editor. Interstitial Lung Disease, 5th. USA, Shelton: People’s Medical Publishing House (2011). p.637.\n5 Fujimori K Yokoyama A Kurita Y Uno K Saijo N . Paclitaxel-Induced Cell-Mediated Hypersensitivity Pneumonitis. Diagnosis Using Leukocyte Migration Test, Bronchoalveolar Lavage and Transbronchial Lung Biopsy. Oncology (1998) 55 (4 ):340–4. 10.1159/000011873\n6 Fujimaki T Kato K Fukuda S Watanabe K Mori T Hibino T . Acute Interstitial Pneumonitis After Implantation of Paclitaxel-Eluting Stents: A Report of Two Fatal Cases. Int J Cardiol (2011) 148 (2 ):e21. 10.1016/j.ijcard.2009.01.069 19239975\n7 Chen YM Shih JF Perng RP Tsai CM Whang-Peng J . A Randomized Trial of Different Docetaxel Schedules in Non-Small Cell Lung Cancer Patients Who Failed Previous Platinum-Based Chemotherapy. Chest (2006) 129 (4 ):1031–8. 10.1378/chest.129.4.1031\n8 Yu TK Whitman GJ Thames HD Buzdar AU Strom EA Perkins GH . Clinically Relevant Pneumonitis After Sequential Paclitaxel-Based Chemotherapy and Radiotherapy in Breast Cancer Patients. J Natl Cancer Inst (2004) 96 (22 ):1676–81. 10.1093/jnci/djh315\n9 Wang S Liao Z Wei X Liu HH Tucker SL Hu C . Association Between Systemic Chemotherapy Before Chemoradiation and Increased Risk of Treatment-Related Pneumonitis in Esophageal Cancer Patients Treated With Definitive Chemoradiotherapy. J Thorac Oncol (2008) 3 (3 ):277–82. 10.1097/JTO.0b013e3181653ca6\n10 Beal K Hudis C Norton L Wagman R McCormick B . Radiation Pneumonitis in Breast Cancer Patients Treated With Taxanes: Does Sequential Radiation Therapy Lower the Risk? Breast J (2005) 11 (5 ):317–20. 10.1111/j.1075-122X.2005.21696.x\n11 Voduc K Tyldesley S Chia S . Risk of Radiation Pneumonitis in Breast Cancer Patients Treated With Adjuvant Taxanes and Radiation. J Clin Oncol (2004) 22 (14 ):624–4. 10.1200/jco.2004.22.90140.624\n12 Parashar B Edwards A Mehta R Pasmantier M Wernicke AG Sabbas A . Chemotherapy Significantly Increases the Risk of Radiation Pneumonitis in Radiation Therapy of Advanced Lung Cancer. Am J Clin Oncol (2011) 34 (2 ):160–4. 10.1097/COC.0b013e3181d6b40f\n13 Harries M Moss C Perren T Gore M Hall G Everard M . A Phase II Feasibility Study of Carboplatin Followed by Sequential Weekly Paclitaxel and Gemcitabine as First-Line Treatment for Ovarian Cancer. Br J Cancer (2004) 91 (4 ):627–32. 10.1038/sj.bjc.6602000\n14 Available at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf (Accessed on January 14, 2021).\n15 Binder D Hübner RH Temmesfeld-Wollbrück B Schlattmann P . Pulmonary Toxicity Among Cancer Patients Treated With a Combination of Docetaxel and Gemcitabine: A Meta-Analysis of Clinical Trials. Cancer Chemother Pharmacol (2011) 68 (6 ):1575–83. 10.1007/s00280-011-1648-2\n16 Sparano JA Wang M Martino S Jones V Perez EA Saphner T . Weekly Paclitaxel in the Adjuvant Treatment of Breast Cancer. N.Engl.J Med (2008) 358 (16 ):1663–71. 10.1056/NEJMoa0707056\n17 Seidman AD Berry D Cirrincione C Harris L Muss H Marcom PK . Randomized Phase III Trial of Weekly Compared With Every-3-weeks Paclitaxel for Metastatic Breast Cancer, With Trastuzumab for All HER-2 Overexpressors and Random Assignment to Trastuzumab or Not in HER-2 Nonoverexpressors: Final Results of Cancer and Leukemia Group B Protocol 9840. J Clin Oncol (2008) 26 (10 ):1642–9. 10.1200/JCO.2007.11.6699\n18 Genestreti G Di Battista M Trisolini R Denicolò F Valli M Lazzari-Agli LA . A Commentary on Interstitial Pneumonitis Induced by Docetaxel: Clinical Cases and Systematic Review of the Literature. Tumori (2015) 101 (3 ):e92–5. 10.5301/tj.5000275\n19 Ostoros G Pretz A Fillinger J Soltesz I Dome B . Fatal Pulmonary Fibrosis Induced by Paclitaxel: A Case Report and Review of the Literature. Int J Gynecol Cancer (2006) 16 (Suppl 1 ):391–3. 10.1111/j.1525-1438.2006.00222.x\n20 Delaunay M Prévot G Collot S Guilleminault L Didier A Mazières J . Management of Pulmonary Toxicity Associated With Immune Checkpoint Inhibitors. Eur Respir Rev (2019) 28 (154 ):190012. 10.1183/16000617.0012-2019 31694838\n21 Twohig KJ Matthay RA . Pulmonary Effects of Cytotoxic Agents Other Than Bleomycin. Clin Chest Med (1990) 11 :31. 10.1016/S0272-5231(21)00670-5 1691069\n22 Jacobs C Slade M Lavery B . Doxorubicin and BOOP. A Possible Near Fatal Association. Clin Oncol (R Coll Radiol) (2002) 14 :262. 10.1053/clon.2002.0071 12109837\n23 Kanaji N Tadokoro A Kita N Murota M Ishii T Takagi T . Impact of Idiopathic Pulmonary Fibrosis on Advanced non-Small Cell Lung Cancer Survival. J Cancer Res Clin Oncol (2016) 142 (8 ):1855–65. 10.1007/s00432-016-2199-z\n24 Brufsky A . nab-Paclitaxel for the Treatment of Breast Cancer: An Update Across Treatment Settings. Exp Hematol Oncol (2017) 6 :7. 10.1186/s40164-017-0066-5 28344858\n25 Li Y Lu X Lin Q Li W . Is Nab-Paclitaxel Better Than Conventional Taxanes as Neoadjuvant Therapy for Breast Cancer? A Meta-Analysis. J Int Med Res (2020) 48 (8 ):300060520943473. 10.1177/0300060520943473 32762463\n26 Azuma Y Tamiya M Shiroyama T Osa A Takeoka S Morishita N . Nanoparticle Albumin-bound Paclitaxel+Carboplatin Therapy for Small Cell Lung Cancer Combined With Squamous Cell Carcinoma and Interstitial Lung Disease. Intern Med (2015) 54 (22 ):2911–3. 10.2169/internalmedicine.54.3243\n27 Ardolino L Moylan E . Pegylated Liposomal Doxorubicin Rechallenge Following Doxorubicin-Induced Pancreatitis. Curr Problems Cancer: Case Rep (2020) 14 (1 ):100001. 10.1016/j.cpccr.2020.100001\n28 Schmid P Cortes J Pusztai L McArthur H Kümmel S Bergh J . Keynote-522 Investigators. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med (2020) 382 (9 ):810–21. 10.1056/NEJMoa1910549\n29 Mittendorf EA Zhang H Barrios CH Saji S Jung KH Hegg R . Neoadjuvant Atezolizumab in Combination With Sequential Nab-Paclitaxel and Anthracycline-Based Chemotherapy Versus Placebo and Chemotherapy in Patients With Early-Stage Triple-Negative Breast Cancer (Impassion031): A Randomised, Double-Blind, Phase 3 Trial. Lancet (2020) 396 (10257 ):1090–100. 10.1016/S0140-6736(20)31953-X\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "11()",
"journal": "Frontiers in oncology",
"keywords": "chemotherapy; early breast cancer; immunotherapy; management of toxicities; pneumonitis and pulmonary toxicity",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
"other_id": null,
"pages": "701424",
"pmc": null,
"pmid": "34249762",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "31694838;21547571;15547180;16515630;18420499;16608954;27350261;16174151;18375893;32762463;32101663;9663424;15238984;25978147;1691069;20498591;32966830;28344858;19239975;18317071;22547591;26568008;12109837;18252919;25908033",
"title": "Case Report: Paclitaxel-Induced Pneumonitis in Early Breast Cancer: A Single Institution Experience and Review.",
"title_normalized": "case report paclitaxel induced pneumonitis in early breast cancer a single institution experience and review"
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"activesubstancename": "CYCLOPHOSPHAMIDE"
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{
"abstract": "Activating variants of the MAPK pathway have been found in some Langerhans cell histiocytosis (LCH) lesions. Inhibition of the MAPK pathway with trametinib (MEK inhibitor) has been shown to induce responses in LCH patients. Two adolescent males with LCH driven by BRAF p.N486_P490del have received trametinib for >1 year with no reactivation in one and partial response in another (including stable lung disease). A third male with neonatal LCH and MAP2K1p.K57_G61del had a complete response to trametinib with no active disease after 22 months. All patients continue on trametinib monotherapy with tolerable skin and creatine phosphokinase toxicity.",
"affiliations": "Cancer and Blood Disorders, Children's Minnesota, Minneapolis, Minnesota.;Cancer and Blood Disorders, Children's Minnesota, Minneapolis, Minnesota.;Pathology and Laboratory Medicine, Children's Minnesota, Minneapolis, Minnesota.;Cancer and Blood Disorders, Children's Minnesota, Minneapolis, Minnesota.;Cancer and Blood Disorders, Children's Minnesota, Minneapolis, Minnesota.;Cancer and Blood Disorders, Children's Minnesota, Minneapolis, Minnesota.",
"authors": "Messinger|Yoav H|YH|0000-0001-7990-1802;Bostrom|Bruce C|BC|0000-0001-7974-1271;Olson|Damon R|DR|;Gossai|Nathan P|NP|;Miller|Lane H|LH|0000-0003-1995-9492;Richards|Michael K|MK|",
"chemical_list": "D000970:Antineoplastic Agents; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.28712",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "67(12)",
"journal": "Pediatric blood & cancer",
"keywords": "Langerhans cell histiocytosis; MAPK pathway variants; trametinib",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents; D017353:Gene Deletion; D006646:Histiocytosis, Langerhans-Cell; D006801:Humans; D048369:MAP Kinase Kinase 1; D008297:Male; D009154:Mutation; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf; D011728:Pyridones; D011744:Pyrimidinones; D055815:Young Adult",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e28712",
"pmc": null,
"pmid": "32991018",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Langerhans cell histiocytosis with BRAF p.N486_P490del or MAP2K1 p.K57_G61del treated by the MEK inhibitor trametinib.",
"title_normalized": "langerhans cell histiocytosis with braf p n486 p490del or map2k1 p k57 g61del treated by the mek inhibitor trametinib"
} | [
{
"companynumb": "NVSC2020US266331",
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"occurcountry": "US",
"patient": {
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{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "TRAMETINIB"
},
"drugadditional": null,
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{
"abstract": "Many poisoned patients may only require a period of observation after their exposure. There are limited data describing the use of observation units for managing poisoned adult and pediatric patients. We performed a retrospective review of all patients reported to the ToxIC Case Registry between January 1, 2012 and December 31, 2013. Eligible patients included those who received a bedside consultation by a medical toxicologist and whose care was provided in an observation unit, or those who were admitted under the care of a medical toxicologist in an observation unit. A total of 15,562 poisonings were reported to the registry during the study period, of which 340 (2.2 %) involved patients who were cared for in an observation unit. Of these patients, 22.1 % were 18 years of age or younger, and the remaining 77.9 % were greater than 18 years of age. The most common reason for exposure was the intentional ingestion of a pharmaceutical agent in both adult (30.2 %) and pediatric patients (36.0 %). Alcohols (ethanol) (24.9 %), opioids (20.0 %), and sedative-hypnotics (17.7 %) were the most common agent classes involved in adult patient exposures. The most common agent classes involved in pediatric exposures were antidepressants (12.0 %), anticonvulsants (10.7 %), and envenomations (10.7 %). In adult patients, the most common signs and symptoms involved the nervous system (52.0 %), a toxidrome (17.0 %), or a major vital sign abnormality (14.7 %). In pediatric patients, the most common signs and symptoms involved the nervous system (53.3 %), a toxidrome (21.3 %), or a major vital sign abnormality (17.3 %). The results of this study demonstrate that a wide variety of poisoned patients have been cared for in an observation unit in consultation with a board-certified medical toxicologist. Patterns for the reasons for exposure, agents responsible for the exposure, and toxicological treatments will continue to evolve. Further study is needed to identify better those poisoned patients who can be appropriately managed in an observation unit.",
"affiliations": "Department of Emergency Medicine, Michigan State University College of Human Medicine, Secchia Center, 15 Michigan Ave NE, Grand Rapids, MI, 49503, USA. bryan.judge@spectrumhealth.org.;Department of Emergency Medicine, Michigan State University College of Human Medicine, Secchia Center, 15 Michigan Ave NE, Grand Rapids, MI, 49503, USA.;Spectrum Health Toxicology Services, 1840 Wealthy St. SE, Grand Rapids, MI, 49506, USA.;Department of Emergency Medicine, Michigan State University College of Human Medicine, Secchia Center, 15 Michigan Ave NE, Grand Rapids, MI, 49503, USA.;University of Texas Southwestern Medical Center, Dallas, TX, USA.",
"authors": "Judge|Bryan S|BS|;Ouellette|Lindsey M|LM|;VandenBerg|Melissa|M|;Riley|Brad D|BD|;Wax|Paul M|PM|;|||",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s13181-015-0498-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-9039",
"issue": "12(1)",
"journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology",
"keywords": "Medical toxicology; Observation units; Overdose; Poisonings; Registry; Toxicology",
"medline_ta": "J Med Toxicol",
"mesh_terms": "D006757:Hospital Units; D006801:Humans; D011041:Poisoning; D012017:Referral and Consultation; D012042:Registries; D012189:Retrospective Studies; D013997:Time Factors; D014116:Toxicology; D016896:Treatment Outcome; D057832:Watchful Waiting",
"nlm_unique_id": "101284598",
"other_id": null,
"pages": "111-20",
"pmc": null,
"pmid": "26275996",
"pubdate": "2016-03",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "3334800;7755208;11214392;11214396;14655230;19191210;21956161;15867018;9382660;24359283;15765325;17490788;23114240;2803351;24499641;23019185;20726217",
"title": "Utilization of Observation Units for the Care of Poisoned Patients: Trends from the Toxicology Investigators Consortium Case Registry.",
"title_normalized": "utilization of observation units for the care of poisoned patients trends from the toxicology investigators consortium case registry"
} | [
{
"companynumb": "US-ABBVIE-15P-163-1453321-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRAMADOL HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "BACKGROUND\nChemotherapeutic regimens for elderly patients with metastatic colorectal cancer (mCRC), such as bevacizumab combined with 5-fluorouracil (5-FU) and leucovorin, often exclude oxaliplatin and irinotecan owing to the risk of toxicity. However, treatment with infusional 5-fluorouracil and leucovorin requires percutaneous port-catheter placement and other precautions, causing unnecessary stress for patients as well as healthcare workers.\n\n\nMETHODS\nWe conducted a phase II study to evaluate the efficacy and safety of bevacizumab plus S-1 in elderly patients with previously untreated mCRC. Bevacizumab was given intravenously every two weeks, and S-1 was administered orally on days 1-28 of a 42-day cycle. The primary end-point was progression-free survival (PFS). The secondary end-points were time to treatment failure, response rate (RR), overall survival (OS), treatment completion status and safety.\n\n\nRESULTS\nFrom October 2007 through March 2010, 56 patients were enroled. The median PFS was 9.9months, the median OS was 25.0months, and the RR was 57%. The main adverse events of grade 3 or higher were hypertension (11%), diarrhoea (9%) and neutropenia (7%).\n\n\nCONCLUSIONS\nOur results suggest that combination chemotherapy with S-1 and bevacizumab can be administered safely and continuously on an outpatient basis and is therapeutically effective in elderly patients with mCRC.",
"affiliations": "Cancer Chemotherapy Center, Osaka Medical College Hospital, 2-7 Daigakumachi, Takatsuki, Osaka 569-8686, Japan. Electronic address: ctc004@poh.osaka-med.ac.jp.;Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi 464-8681, Japan.;Department of Medical Oncology, Kochi Health Sciences Hospital, 2125-1 Ike, Kochi 781-8555, Japan.;Department of Medical Oncology, Tochigi Cancer Center, Utsunomiya, 4-9-13 Yonan, Utsunomiya, Tochigi 320-0834, Japan.;Department of Gastrointestinal Oncology/Gastroenterology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.;Department of Surgical Oncology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Gifu 501-1194, Japan.;Department of Medical Oncology, Oita University Faculty of Medicine, 1-1, Idaigaoka, Hasamacho, Yufu, Oita 879-5543, Japan.;Department of Gastroenterology, Saku Central Hospital, 197 Usuda, Saku, Nagano 384-0393, Japan.;Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi 464-8681, Japan.;Department of Surgical Oncology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Gifu 501-1194, Japan.;Department of Gastrointestinal Oncology/Gastroenterology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.",
"authors": "Yoshida|M|M|;Muro|K|K|;Tsuji|A|A|;Hamamoto|Y|Y|;Yoshino|T|T|;Yoshida|K|K|;Shirao|K|K|;Miyata|Y|Y|;Takahari|D|D|;Takahashi|T|T|;Ohtsu|A|A|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D000068258:Bevacizumab; D010094:Oxonic Acid",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-8049",
"issue": "51(8)",
"journal": "European journal of cancer (Oxford, England : 1990)",
"keywords": "Bevacizumab; Colorectal cancer; Elderly; S-1",
"medline_ta": "Eur J Cancer",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D002277:Carcinoma; D015179:Colorectal Neoplasms; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D010094:Oxonic Acid; D016019:Survival Analysis; D005641:Tegafur; D016896:Treatment Outcome",
"nlm_unique_id": "9005373",
"other_id": null,
"pages": "935-41",
"pmc": null,
"pmid": "25837882",
"pubdate": "2015-05",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Combination chemotherapy with bevacizumab and S-1 for elderly patients with metastatic colorectal cancer (BASIC trial).",
"title_normalized": "combination chemotherapy with bevacizumab and s 1 for elderly patients with metastatic colorectal cancer basic trial"
} | [
{
"companynumb": "JP-ROCHE-1589556",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"drugadditional": null,
"drug... |
{
"abstract": "Objectives: Z-Drugs (ZDs) have been developed to limit benzodiazepines (BZDs) abuse for sleep disorders. Data on the liver toxicity of zolpidem (ZLM) are lacking or anecdotal. The authors evaluated the presence of drug-induced liver injury (DILI) among a cohort of high-dose ZLM abusers. Methods: Retrospective study analyzing clinical records of 1112 consecutive patients admitted for BZDs detoxification from 2003 to 2018. Inclusion criteria: age >18 y.o.; ZLM abuse/dependence; high-dose ZDs abuse. Exclusion criteria: missing lab data; lack of informed consent. Main outcome was the presence of DILI measured as elevation of ALT/AST levels >250 U/l. Results: A total of 107 patients met the eligibility criteria. Liver enzymes alterations were present in 9.3% (95% CI 4.6-16.5%); one patient (0.9%, 95% CI 0.0-2.8%) showed DILI criteria. BMI significantly influenced transaminases levels. No correlations between duration nor doses of ZLM abuse and transaminases levels were found. Conclusion: The present study shows a very low prevalence of DILI among high-dose ZLM abusers. The prevalence of hypertransaminasemia was in line with general population. On one hand ZLM has a substantially safe liver profile but on the other hand ZLM abuse and dependence, especially at very high doses, represents an emerging problem.",
"affiliations": "a Addiction Unit, Department of Medicine, Verona University Hospital , Verona , Italy.;b Department of Medical Sciences, IRCCS Casa Sollievo della Sofferenza Hospital , San Giovanni Rotondo , Italy.;a Addiction Unit, Department of Medicine, Verona University Hospital , Verona , Italy.;a Addiction Unit, Department of Medicine, Verona University Hospital , Verona , Italy.;a Addiction Unit, Department of Medicine, Verona University Hospital , Verona , Italy.;b Department of Medical Sciences, IRCCS Casa Sollievo della Sofferenza Hospital , San Giovanni Rotondo , Italy.;c Department of Internal Medicine and Gastroenterology, Catholic University of Rome , Rome , Italy.;c Department of Internal Medicine and Gastroenterology, Catholic University of Rome , Rome , Italy.",
"authors": "Lugoboni|Fabio|F|https://orcid.org/0000-0002-1434-4432;Mirijello|Antonio|A|https://orcid.org/0000-0003-3932-3803;Morbioli|Laura|L|https://orcid.org/0000-0002-9764-3779;Faccini|Marco|M|;Casari|Rebecca|R|;De Cosmo|Salvatore|S|https://orcid.org/0000-0001-8787-8286;Gasbarrini|Antonio|A|https://orcid.org/0000-0002-6230-1779;Addolorato|Giovanni|G|https://orcid.org/0000-0002-1522-9946",
"chemical_list": "D000068776:Sleep Aids, Pharmaceutical; D000077334:Zolpidem; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase",
"country": "England",
"delete": false,
"doi": "10.1080/14740338.2019.1628216",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1474-0338",
"issue": "18(8)",
"journal": "Expert opinion on drug safety",
"keywords": "DILI; HDU; Z-Drugs; abuse; dependence",
"medline_ta": "Expert Opin Drug Saf",
"mesh_terms": "D000328:Adult; D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D056486:Chemical and Drug Induced Liver Injury; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D012189:Retrospective Studies; D000068776:Sleep Aids, Pharmaceutical; D019966:Substance-Related Disorders; D000077334:Zolpidem",
"nlm_unique_id": "101163027",
"other_id": null,
"pages": "753-758",
"pmc": null,
"pmid": "31177863",
"pubdate": "2019-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Zolpidem high-dose abuse: what about the liver? Results from a series of 107 patients.",
"title_normalized": "zolpidem high dose abuse what about the liver results from a series of 107 patients"
} | [
{
"companynumb": "IT-BAUSCH-BL-2019-023660",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIAZEPAM"
},
"drugadditional": "3",
... |
{
"abstract": "A 50-year-old woman was referred to rheumatology for new onset polyarthralgia and headache. She had a history of metastatic lung adenocarcinoma and was started on treatment with the programmed death 1 receptor (PD-1) antagonist pembrolizumab 2 months prior. Examination revealed left temporal artery tenderness and hand synovitis. Investigations revealed enlarged temporal artery on ultrasound imaging. On steroid treatment, she had resolution of symptoms, but due to significant steroid side effects required methotrexate and her PD-1 antagonist therapy was continued in consultation with her oncologist. Her malignant disease has remained stable, and she has improved functional status.",
"affiliations": "Rheumatology & Immunology, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.;Rheumatology & Immunology, Ohio State University Wexner Medical Center, Columbus, Ohio, USA jisna.paul@osumc.edu.",
"authors": "Couette|Nina|N|;Paul|Jisna|J|http://orcid.org/0000-0002-8038-2138",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-246443",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(11)",
"journal": "BMJ case reports",
"keywords": "lung cancer (oncology); vasculitis",
"medline_ta": "BMJ Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34844970",
"pubdate": "2021-11-29",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Giant cell arteritis associated with PD-1 inhibition.",
"title_normalized": "giant cell arteritis associated with pd 1 inhibition"
} | [
{
"companynumb": "US-TEVA-2022-US-1997448",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nAutologous stem cell transplantation is the gold standard for eligible newly diagnosed multiple myeloma patients. Patients are usually hospitalized for administration of mobilization chemotherapy. We aimed to assess safety and efficacy of mobilization therapy with low-dose (2 g/m2 ) and intermediate-dose (3-4 g/m2 ) cyclophosphamide administered as outpatient.\n\n\nMETHODS\nA total of 176 consecutive newly diagnosed transplant-eligible myeloma patients receiving outpatient mobilization were retrospectively evaluated. Induction therapy was mainly performed with new drugs (91%).\n\n\nRESULTS\nChemotherapy was very well tolerated with 16.6% of patients having all-grade adverse events (AEs) and only 1.2% having severe AEs. The most frequently reported AEs were nausea and vomiting grade 1-2 (6.8%). Only 5.7% of patients required hospitalization for AEs. Stem cell collection was successful in 93.1% of patients, with a median CD34+ harvest of 8.7 × 106 /kg. Target for 2 autologous stem cell transplantation (at least 6 CD34+ × 106 /kg) was reached by 76.3% of patients. Administration of plerixafor on demand was necessary in 12.1% of patients.\n\n\nCONCLUSIONS\nOutpatient mobilization with low- and intermediate-dose cyclophosphamide appears an efficient and safe procedure, with minimal and manageable AEs and low rate of hospitalization.",
"affiliations": "Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Bio-statistical Unit, Regina Elena National Cancer Institute IRCCS, Rome, Italy.;Hematology Unit, ASST Papa Giovanni XXIII, Bergamo, Italy.;Transfusion Medicine and Cell Therapy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Hematology Unit, ASST Papa Giovanni XXIII, Bergamo, Italy.;Transfusion Medicine and Cell Therapy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Hematology Unit, ASST Papa Giovanni XXIII, Bergamo, Italy.;Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.",
"authors": "Pompa|Alessandra|A|;Pettine|Loredana|L|;Giannarelli|Diana|D|;Paris|Laura|L|;Torretta|Lorella|L|;Cavallaro|Francesca|F|;Levati|Giorgia Virginia|GV|;Stefanoni|Paola|P|;Mocellin|Cristina|C|;Galli|Monica|M|;Baldini|Luca|L|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/ejh.13693",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "107(5)",
"journal": "European journal of haematology",
"keywords": "mobilization chemotherapy; multiple myeloma; outpatient; safety",
"medline_ta": "Eur J Haematol",
"mesh_terms": null,
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "566-572",
"pmc": null,
"pmid": "34297879",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Safety of outpatient stem cell mobilization with low- or intermediate-dose cyclophosphamide in newly diagnosed multiple myeloma patients.",
"title_normalized": "safety of outpatient stem cell mobilization with low or intermediate dose cyclophosphamide in newly diagnosed multiple myeloma patients"
} | [
{
"companynumb": "IT-AMGEN-ITASP2022012963",
"fulfillexpeditecriteria": "2",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARFILZOMIB"
},
"drugadditional": "4",
... |
{
"abstract": "To date, a recognized treatment for refractory membranous nephropathy (MN) has not been established. Recently, several reports have indicated the efficacy of rituximab as a novel treatment option. However, only a few published accounts exist of rituximab therapy for idiopathic MN (IMN) in the Asian population. We present the cases of three IMN patients who were treated with single-dose rituximab after they showed no response to conventional therapies, including corticosteroids, cyclosporine, cyclophosphamide, mizoribine, and mycophenolate mofetil. Although one case showed no response, a complete or incomplete remission was achieved in the other two cases. Rituximab may therefore be a beneficial treatment option for IMN.",
"affiliations": "Department of Nephrology, Internal Medicine Nagoya University Graduate School of Medicine, Japan.;Department of Nephrology, Internal Medicine Nagoya University Graduate School of Medicine, Japan.;Department of Nephrology, Internal Medicine Nagoya University Graduate School of Medicine, Japan.;Department of Nephrology, Internal Medicine Nagoya University Graduate School of Medicine, Japan.;Department of Nephrology, Internal Medicine Nagoya University Graduate School of Medicine, Japan.;Department of Nephrology, Internal Medicine Nagoya University Graduate School of Medicine, Japan.;Department of Nephrology, Internal Medicine Nagoya University Graduate School of Medicine, Japan.;Department of Nephrology, Internal Medicine Nagoya University Graduate School of Medicine, Japan.;Department of Nephrology, Internal Medicine Nagoya University Graduate School of Medicine, Japan.;Department of Nephrology, Internal Medicine Nagoya University Graduate School of Medicine, Japan.;Department of Nephrology, Internal Medicine Nagoya University Graduate School of Medicine, Japan.",
"authors": "Katsuno|Takayuki|T|;Ozaki|Takenori|T|;Kim|Hangsoo|H|;Kato|Noritoshi|N|;Suzuki|Yasuhiro|Y|;Akiyama|Shinichi|S|;Ishimoto|Takuji|T|;Kosugi|Tomoki|T|;Tsuboi|Naotake|N|;Ito|Yasuhiko|Y|;Maruyama|Shoichi|S|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D012263:Ribonucleosides; D000069283:Rituximab; D016572:Cyclosporine; D003520:Cyclophosphamide; D009173:Mycophenolic Acid",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.56.7908",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2867435710.2169/internalmedicine.56.7908Case ReportSingle-dose Rituximab Therapy for Refractory Idiopathic Membranous Nephropathy: A Single-center Experience Katsuno Takayuki 1Ozaki Takenori 1Kim Hangsoo 1Kato Noritoshi 1Suzuki Yasuhiro 1Akiyama Shinichi 1Ishimoto Takuji 1Kosugi Tomoki 1Tsuboi Naotake 1Ito Yasuhiko 1Maruyama Shoichi 1\n1 Department of Nephrology, Internal Medicine Nagoya University Graduate School of Medicine, JapanCorrespondence to Dr. Takayuki Katsuno, katsu11@med.nagoya-u.ac.jp\n\n1 7 2017 56 13 1679 1686 26 6 2016 4 10 2016 Copyright © 2017 by The Japanese Society of Internal Medicine2017The 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/).To date, a recognized treatment for refractory membranous nephropathy (MN) has not been established. Recently, several reports have indicated the efficacy of rituximab as a novel treatment option. However, only a few published accounts exist of rituximab therapy for idiopathic MN (IMN) in the Asian population. We present the cases of three IMN patients who were treated with single-dose rituximab after they showed no response to conventional therapies, including corticosteroids, cyclosporine, cyclophosphamide, mizoribine, and mycophenolate mofetil. Although one case showed no response, a complete or incomplete remission was achieved in the other two cases. Rituximab may therefore be a beneficial treatment option for IMN. \n\nrituximabmembranous nephropathynephrotic syndrome\n==== Body\nIntroduction\nMembranous nephropathy (MN) is a common cause of nephrotic syndrome (NS) in adults. Although several diseases such as viral infections, autoimmune diseases, certain drugs, and malignancies may cause secondary MN, most cases of MN are idiopathic MN (IMN) (1). Beck et al. identified the M-type phospholipase A2 receptor (PLA2R) as a major antigenic target in IMN (2). IMN is considered to be an organ-specific autoimmune disease. Previous studies report that approximately 50% of IMN patients with NS develop renal dysfunction; the ten-year renal survival rate is from 49% to 63% (3). Conventional therapies, consisting of corticosteroids and immunosuppressive agents, may be associated with significant adverse side effects and are not effective in all patients. Rituximab, a monoclonal antibody targeting the CD20 antigen of the B lymphocyte, has been reported to induce complete or partial remission (CR or PR) in patients with IMN since its first use in 2002 (4-10). To date, only a few cases of IMN have been treated with rituximab in Japan; thus, its efficacy in the Asian population has not been confirmed. In this case report, we present the cases of three adult Japanese patients with refractory IMN who were treated with rituximab.\n\nCase Reports\nCase 1\nA 24-year-old man was admitted to another hospital because of newly developed peripheral edema. A urinalysis showed proteinuria with the excretion of 7.74 g/g creatinine, and laboratory tests revealed severe hypoproteinemia. The serum total protein and albumin levels were 3.9 g/dL and 0.9 g/dL, respectively. The patient was diagnosed with NS. The patient's renal function was normal (serum creatinine 0.94 mg/dL). He had been diagnosed with Stevens-Johnson syndrome nine years previously. His family history was otherwise unremarkable.\n\nImmediately after hospitalization a renal biopsy was performed to obtain an accurate diagnosis. The sample contained 30 glomeruli, none of which showed global sclerosis. Light microscopy revealed a focal increase in mesangial matrix and mild mesangial hypercellularity in the glomeruli. Endocapillary cell proliferation was also detected in several glomeruli. The capillary walls displayed diffuse thickening. Immunofluorescence staining revealed high concentrations of IgG and C3 along the capillary walls. Staining for IgG subclasses revealed a strong IgG1 signal and weaker signals for IgG2 and IgG3; IgG4 staining was entirely negative. Electron microscopy revealed subepithelial deposits along the glomerular basement membrane (GBM). The renal pathological findings showed MN. The results of a serological workup for the hepatitis B surface antigen, hepatitis C antibody, anti-nuclear antibody, anti-neutrophil cytoplasmic antibody (ANCA), anti-GBM antibody, and rheumatoid factor were all negative. Serum immunoelectrophoresis showed no monoclonal proteins. Hypocomplementemia was not observed. A careful examination excluded the presence of malignant neoplasms.\n\nInitially, the patient was treated with angiotensin II receptor blocker (ARB), anticoagulant, prednisolone (PSL; 60 mg/day), and cyclosporine (CyA; 150 mg/day). Six weeks later, the patient condition was still nephrotic. The treatment was then complemented by low-density lipoprotein apheresis (LDL-A). CyA was stopped, and intravenous cyclophosphamide (IVCY) therapy was subsequently started. The total amount of IVCY was 1,700 mg. However, after four months of treatment, no clinical or laboratory improvement was detected and the patient was transferred to our institution.\n\nOn admission, the patient had a blood pressure of 110/58 mmHg and a body weight of 55.4 kg. A physical examination revealed no edema of the limbs. A urinalysis showed proteinuria with the excretion of 7.34 g/g creatinine. The laboratory tests revealed a normal serum creatinine concentration of 0.69 mg/dL and a markedly decreased serum total protein concentration of 4.0 g/dL with a serum albumin concentration of 1.2 g/dL. Anti-PLA2R antibodies were not detected.\n\nIn view of his resistance to previous immunosuppressive therapies and his persistently severe nephrotic state, we administered single-dose rituximab (500 mg) at two weeks after his admission to our hospital. The premedication was diphenhydramine hydrochloride (30 mg) and acetaminophen (400 mg). The infusion was well tolerated. The PSL dosage was 25 mg/day and no immunosuppressive drugs were administered at the start of rituximab treatment. Six months after the injection of rituximab, the patient's urinary protein excretion was markedly reduced to 0.57 g/g creatinine with a serum albumin concentration of 3.6 g/dL. After the effectiveness of rituximab treatment was confirmed, a second 500 mg infusion of rituximab was administered. The levels of circulating CD19+ B cells were fully depleted from the time of the first rituximab injection to the present time (to date, the patient has been followed for 15 months). At the patient's last follow-up examination, urinary protein excretion was 0.17 g/g creatinine, the serum creatinine concentration was 0.72 mg/dL, and the serum albumin concentration was 4 g/dL. A CR was achieved and maintained (Figure). The PSL dose was gradually tapered to 3 mg/day and no immunosuppression agents were used. No adverse events were observed over the course of rituximab treatment.\n\nFigure. The clinical course of Cases 1 to 3. (A) Case 1. Single-dose rituximab (500 mg) was administered. Six months after the first injection, the same dose of rituximab was administered again. The patient’s urinary protein excretion was significantly decreased, and a complete remission was achieved at 11 months after the initiation of rituximab therapy. CD19+B cells were fully depleted throughout the observation period after the first rituximab treatment. (B) Case 2. Single-dose rituximab (630 mg) was administered. The patient’s urinary protein excretion gradually decreased. At one year after rituximab treatment, an incomplete remission was achieved. Although the patient’s urinary protein excretion increased again, nephrotic syndrome was not observed. CD19+B cells were fully depleted for 26 months after the administration of rituximab. (C) Case 3. Single-dose rituximab (600 mg) was administered. In this case, rituximab therapy was ineffective. The patient’s renal function progressively deteriorated, and peritoneal dialysis was initiated at 16 months after rituximab induction therapy. The CD19+B cells were fully depleted; however, they increased again at five months after the initiation of rituximab treatment. uPCR: urinary protein creatinine ratio, Cre: creatinine, Alb: albumin\n\nCase 2\nA 73-year-old man with a medical history of hypertension and hyperuricemia was admitted to another hospital for severe pedal edema and a weight gain of 5 kg. A urinalysis revealed the presence of massive protein and red blood cells in the urine. The urinary protein excretion was 10.40 g/g creatinine. The serum creatinine level was 1.74 mg/dL, and the serum total protein and albumin concentrations were 5.0 g/dL and 1.9 g/dL respectively. The patient was diagnosed with NS. His family history was otherwise unremarkable.\n\nTwo weeks after admission, a kidney biopsy was performed to make a histological diagnosis. Using light microscopy, 11 glomeruli were observed, one showed global sclerosis. Thickening of the GBM was observed. Mesangial proliferation, endocapillary hypercellularity, and extracapillary proliferation were not observed. Tubular atrophy and interstitial fibrosis were moderate with the patchy infiltration of mononuclear cells. Immunofluorescence staining revealed that the capillary walls were positive for IgG and C3. Staining for IgG subclasses showed intense IgG1 and IgG4 signals and a weaker IgG2 and IgG3 signals. The electron microscopic examination of the biopsy specimens revealed finely granular electron-dense materials along the GBM. The renal histological findings demonstrated MN. The results of serological tests for hepatitis B surface antigen, hepatitis C antibody, ANCA, anti-GBM antibody, and rheumatoid factor were all negative. The patient was positive for anti-nuclear antibodies; however, the presence of autoimmune disease was denied. Serum and urine immunoelectrophoresis showed no monoclonal bands. The serum complement titers were within the normal limits. Malignancy was excluded as the cause of secondary MN.\n\nInitially, the patient was treated with PSL (15 mg/day) and CyA (75 mg/day). Eleven weeks later, his condition deteriorated. The serum creatinine levels elevated to 2.43 mg/dL, while his severe hypoalbuminemia showed no improvement (2.0 g/dL). High urinary protein excretion level was still observed (8.40 g/g creatinine). The patient was therefore referred to our hospital. At the first visit, his urinary protein excretion was 11.97 g/g creatinine. The laboratory investigations revealed a serum creatinine level of 2.34 mg/dL, a serum total protein level of 4.5 g/dL and a serum albumin level of 1.3 g/dL. He was admitted to our hospital and the PSL dosage was increased to 40 mg/day, with the addition of mizoribine (MZR; 100 mg/day). The MZR dosage was increased to 200 mg/day according to the blood concentration. However, these treatments were not effective. We therefore selected rituximab treatment for refractory IMN.\n\nHe was readmitted ten weeks after the first visit to our hospital. On admission, the patient had a blood pressure of 117/77 mmHg and a body weight of 64.0 kg. A physical examination revealed bilateral edema of the lower extremities. A urinalysis showed proteinuria with the excretion of 7.73 g/g creatinine. The laboratory tests revealed an elevated serum creatinine concentration of 3.59 mg/dL and a markedly decreased serum total protein level of 4.0 g/dL with a serum albumin level of 1.1 g/dL. No anti-PLA2R antibodies were detected. The administration of CyA and MZR was halted prior to the initiation of rituximab treatment. Only PSL was continued at a dose of 20 mg/day. Single-dose rituximab (375 mg/m2) was administered after premedication with diphenhydramine hydrochloride (30 mg) and acetaminophen (400 mg). The infusion was well tolerated. Several days after the injection of rituximab, the patient complained of odynophagia. The patient was diagnosed with an esophagus infection caused by herpes simplex virus and treatment with acyclovir was initiated. The circulating CD19+ B cells were fully depleted after the injection of rituximab. At 12 months after rituximab therapy, the patient's urinary protein excretion decreased to 2.16 g/g creatinine and an incomplete remission (ICR) II was achieved. At 18 months, the urinary protein excretion was significantly decreased to 0.75 g/g creatinine and an ICR I was achieved. The serum albumin level had markedly increased to 4.1 g/dL. To date, the patient has been followed for 33 months. The serum albumin levels have been maintained at over 3.0 g/dL and a quantitative analysis of the urinary protein showed that it had increased to 4-6 g/g creatinine. NS was not observed and the serum creatinine levels remained stable (range 1.91-2.18 mg/dL) (Figure). The dosage of PSL was gradually tapered to 4 mg/day and no immunosuppression agents were used.\n\nCase 3\nA 37-year-old man was admitted to our institution to undergo treatment for refractory NS. Twelve years previously, he had been admitted to another hospital for leg edema and an increase in body weight. His urinary protein excretion was 12.66 g/day. His serum creatinine level was 0.8 mg/dL, and his serum total protein and albumin levels were 3.5 g/dL and 1.7 g/dL, respectively. The patient was diagnosed with NS. His medical history was otherwise unremarkable. Interestingly, his father was also diagnosed with NS.\n\nOne month after his hospital admission, a kidney biopsy was performed. On light microscopy, ten glomeruli were observed, none of which showed global sclerosis. The capillary walls showed irregular thickening. Immunofluorescence staining revealed that the capillary walls were strongly positive for IgG and C3 and mildly positive for IgA, IgM, C4. Electron microscopy revealed subepithelial deposits. The histological diagnosis was MN. Tests for hepatitis B and C, anti-nuclear antibody and ANCA were all negative. Serum and urine monoclonal proteins were not detected. The serum complement titers were normal. Malignancy was excluded based on a clinical examination.\n\nAlthough the patient was initially treated with angiotensin-converting enzyme inhibitor (ACE-I), PSL (60 mg/day) and CyA (200 mg/day), remission was not achieved. LDL-A was performed, but no therapeutic effect was confirmed. Despite the addition of MZR (150 mg/day), the nephrotic state continued. At 9 years after the onset of the disease, his renal dysfunction became apparent.\n\nThus, the patient consulted our hospital. At the first visit, his urinary protein excretion was 4.71 g/g creatinine. The laboratory investigations revealed a serum creatinine level of 1.46 mg/dL, a serum total protein level of 4.3 g/dL and a serum albumin level of 2.4 g/dL. MZR was stopped and the patient was switched to mycophenolate mofetil [MMF; 1,000 mg/day (temporarily, increased to 1,500 mg/day)], but the patient was unresponsive to the treatment. As a result of the unsuccessful treatment regimens, the patient was admitted for rituximab therapy at one year after the initial medical examination at our hospital.\n\nOn admission, the patient had a blood pressure of 148/92 mmHg and a body weight of 71.3 kg. A physical examination revealed bilateral pedal edema. A urinalysis showed proteinuria with the excretion of 10.44 g/g creatinine. The laboratory tests revealed an elevated serum creatinine concentration of 2.38 mg/dL and a decreased serum total protein level of 4.4 g/dL with a serum albumin level of 2.8 g/dL. Anti-PLA2R antibodies were detected. MMF was stopped prior to rituximab treatment. Only PSL (5 mg/day) was continued. Single-dose rituximab (375 mg/m2) was administered after premedication with diphenhydramine hydrochloride (30 mg) and acetaminophen (400 mg). The infusion was well tolerated. Despite rituximab therapy, nephrotic range proteinuria with hypoalbuminemia continued and the patient's renal function gradually deteriorated. On account of the ineffectiveness, PSL was also stopped. Sixteen months after the administration of rituximab, the patient presented with end-stage renal disease (Figure). Finally, peritoneal dialysis was initiated. No adverse events were observed over the course of rituximab treatment.\n\nDiscussion\nWe reported three cases of refractory IMN that were treated with rituximab. The baseline patient characteristics are shown in Table 1. Written informed consent was obtained from the patients for the administration of rituximab. The patients provided their informed consent for the publication of this case report.\n\nTable 1. Main Clinical and Laboratory Characteristics of Individual Patients at Baseline.\n\nCharacteristics\tCase 1\tCase 2\tCase 3\t\nAge (years)\t24\t73\t37\t\nGender (male/female)\tmale\tmale\tmale\t\nDisease duration (months)\t4\t6\t150\t\nClinical parameters\t\t\t\t\nBody weight (kg)\t55.4\t64.0\t71.3\t\nSystolic blood pressure (mmHg)\t110\t117\t148\t\nDiastolic blood pressure (mmHg)\t58\t77\t92\t\nLaboratory parameters\t\t\t\t\nTotal protein (g/dL)\t4.0\t4.0\t4.4\t\nSerum albumin (g/dL)\t1.2\t1.1\t2.8\t\nSerum creatinine (mg/dL)\t0.69\t3.59\t2.38\t\neGFR (mL/min/1.73m2)\t118.4\t14.0\t26.7\t\nTotal cholesterol (mg/dL)\t259\t369\t246\t\nUrinary protein excretion (g/gCre)\t7.34\t7.73\t10.44\t\nanti-PLA2R antibody\tnegative\tnegative\tpositive\t\nTreatment before rituximab\t\t\t\t\nPSL (mg/day)\t25\t20\t5\t\nCyA (mg/day)\tunused\t25\tunused\t\nMMF (mg/day)\tunused\tunused\t1,000\t\nMZR (mg/day)\tunused\t200\tunused\t\nFormer immunosuppressive drug\tCyA, IVCY\tnothing\tCyA, MZR\t\nRAS inhibitor agent\tlosartan 25mg\tunused\tunused\t\neGFR: estimated glomerular filtration rate, Cre: creatinine, PLA2R: phospholipase A2 receptor, PSL: prednisolone, CyA: cyclosporine, IVCY: intravenous cyclophosphamide, MMF: mycophenolate mofetil, MZR: mizoribine, RAS: renin-angiotensin system\n\nRecently, rituximab has been demonstrated as a potential treatment option for IMN. A summary of the clinical manifestations and therapeutic processes of previous representative reports is shown in Table 2. Remuzzi et al. treated eight patients who had IMN with persistent nephrotic syndrome (4). Six patients achieved a 50% reduction in their urinary protein excretion from baseline. In two patients, the proteinuria decreased to under 1 g/24 h at 20 weeks. This was the first report to provide evidence that rituximab treatment was associated with a significant reduction in urinary protein excretion in IMN patients. Thereafter, Ruggenenti et al. evaluated the one year outcome (5). Fervenza et al. conducted a prospective pilot trial of rituximab treatment in 15 patients with refractory IMN (6). Within the 12-month observation period, a CR was achieved in two patients and a PR was achieved in six patients. Furthermore, Fervenza et al. conducted a 2-year study of rituximab therapy for IMN (7). By the end of 24 months, a CR was achieved in four patients and a PR was achieved in 12 patients. Ruggenenti et al. described the treatment of 100 consecutive IMN patients with persistent nephrotic syndrome with rituximab (8). During a median follow-up period of 29 months after the administration of rituximab, 65 patients achieved a CR or PR. The median time to remission was 7.1 months. The remission rates were equal in patients with or without a history of immunosuppressive treatment. Cravedi et al. compared first-line rituximab therapy and second-line therapy for IMN and indicated the efficacy of rituximab treatment for the patients who failed to respond to previous immunosuppression (9). During follow-up, two patients in the second-line therapy group and three reference patients achieved a CR and five patients in each cohort achieved a PR.\n\nTable 2. Treatment Courses and Outcomes of Rituximab Therapy for Idiopathic Membranous Nephropathy (Summary of Reported Articles).\n\nReference\tN\tAge (year)\tClinical presentation\tTreatment before rituximab\tProteinuria before rituximab (g/24h)\tSerum creatinine before rituximab (mg/dL)\tRituximab treatment dose\tObservation period\tComplete remission (definition per study)\tPartial remission (definition per study)\t\n4\t8\t52 (range 24-75)\tpersistent NS\tfull-dose ACE-I for 29.7 months\t8.6 ± 1.5*\t1.4 ± 0.3*\t375 mg/m2 every 4 weeks\t20 weeks\t2/8 (UP ≤1g/24h)\t3/8 (UP >1g/24h and ≤3.5g/24h)\t\n5\t8\t52 (range 24-75)\tpersistent NS\tfull-dose ACE-I for 29.7 months\t8.6 ± 1.5*\t1.4 ± 0.3*\t375 mg/m2 every 4 weeks\t12 momths\t2/8 (UP ≤0.5g/24h)\t4/8 (UP ≤3.5g/24h or 50% reduction versus basal)\t\n10\t12\t57± 13*\tpersistent NS\tACE-I at least 6 months\t10.3 ± 8.9*\t1.4 ± 0.5*\t375 mg/m2×1 (n=11), 375 mg/m2×2 (n=1) B cell-driven protocol; When ≥5 B cells/mm3 were detected in the circulation after the first administration, patients received a second infusion.\t12 momths\t2/12 (UP <0.3g/24h)\t6/12 (UP <3g/24h with a >50% reduction)\t\n6\t15\t47± 8*\tpersistent NS\tRAS-I at least 4 months (n=15), Steroids alone (n=2), Steroids+cytotoxic agents (n=2), Steroids+CyA (n=2), Steroids+MMF (n=1)\t13.0 ± 5.7*\t1.4 ± 0.5*\t1g×2, on days 1 and 15; repeated at 6 month if proteinuria>3 g/24h and CD19+B cells>15/μL\t12 momths\t2/15 (UP <0.3g/24h)\t6/15 (UP ≤3g/24h with a >50% reduction)\t\n9\t11\t48.6± 13.9*\tpersistent NS\tRAS-I at least 6 months (n=11), Steroids alone (n=2), Steroids+alkylating agents (n=6), Steroids+CyA (n=2), CyA alone (n=1)\t10.9 (range 6.6-18.6)\t1.3 ± 0.5*\t375 mg/m2 every 4 weeks (n=5) 375 mg/m2×1 or 2 (n=6) B cell-driven protocol; When ≥5 B cells/mm3 were detected in the circulation after the first administration, patients received a second infusion.\t24 momths\t2/11 (UP <0.3g/24h)\t5/11 (UP <3.5g/24h with a >50% reduction)\t\n7\t20\t48.6± 12.9*\tpersistent NS\tRAS-I at least 4 months (n=20), Steroids alone (n=1), CyA alone (n=3), Steroids+CyA (n=1), Steroids+CY followed by MMF (n=2), Steroids+CY followed by CyA (n=1), Steroids+CY followed by CyA followed by MMF (n=2), Steroids+CY followed by MMF followed by Tac (n=1)\t11.9 ± 4.9*\t1.5 ± 0.5*\t375 mg/m2 every 4 weeks; re-treated at month 6 regardless of their clinical status.\t24 momths\t4/20 (UP ≤0.3g/24h)\t12/20 (UP≤3.5 g/24h and a 50% reduction in peak proteinuria with serum albumin >3g/dL)\t\n8\t100\t51.5± 5.9*\tpersistent NS\tfull-dose ACE-I at least 6 months (n=100) 32 patients had been exposed to 55 courses of different immunosuppressive regimens (Steroids alone, CyA alone, Steroids+alkylating agents, Steroids+CyA, adrenocorticotrophic hormone)\t9.1 (range 5.8-12.8)\t1.2 (range 0.97-1.7)\t375 mg/m2 every 4 weeks (up to October 2005), 375 mg/m2×1 patients received a second rituximab infusion only when >5 circulating B cells per mm3 were detected the morning after completion of the first rituximab administration.\t29 momths (range 6-121)\t27/100 (UP <0.3g/24h)\t38/100 (UP <3g/24h with a >50% reduction)\t\n* Variables expressed as mean ± standard deviation, NS: nephrotic syndrome, UP: urinary protein, ACE-I: angiotensin-converting enzyme inhibitor, RAS-I: renin-angiotensin system inhibitor, CyA: cyclosporine, CY: cyclophosphamide, MMF: mycophenolate mofetil, Tac: tacrolimus\n\nIn this case report, three patients who did not respond to corticosteroid and immunosuppressive agents, such as CyA, cyclophosphamide (CY), MZR, and MMF, received rituximab treatment as a second-line therapy. The clinical course of each patient is presented in Table 3. The remission statuses are defined according to the criteria established by Japanese Society of Nephrology (11). A CR was defined as proteinuria <0.3 g/day. An ICR was defined as resolution of NS but continuing proteinuria, and was divided into two grades: ICR I: (urinary protein: <1.0 g/day) and ICR II (urinary protein: 1.0-3.5 g/day). No response (NR) was defined as the persistence of nephrotic-range proteinuria (≥3.5 g/day).\n\nThe effects of therapy should be evaluated by 24-hour urine collection. If the collection of 24-hour urine is impossible, the ratio of urinary protein and urinary creatinine (g/g creatinine) in a spot urine test can be used.\n\nTable 3. Clinical Course of 3 Cases with Rituximab Treatment for Idiopathic Membranous Nephropathy.\n\nCase\tDose of rituximab\tBaseline uPCR(g/gCre)\t3 months uPCR(g/gCre)\t6 months uPCR(g/gCre)\t12 months uPCR(g/gCre)\t18 momths uPCR(g/gCre)\tLast visit uPCR(g/gCre)\tFollow-up months\tResponse to rituximab therapy\tMaintenance treatment after rituximab\t\n1\t500 mg×2\t7.34\t0.91\t0.57\t0.29\tnot reached\t0.17\t15\tCR\tPSL 3 mg\t\n2\t630 mg×1\t7.73\t15.50\t9.87\t2.16\t0.75\t6.61\t33\tICR I\tPSL 4 mg\t\n3\t600 mg×1\t10.44\t9.59\t8.39\t12.88\t14.30\tno data\t29\tNR\t(-)\t\nuPCR: urinary protein creatinine ratio, PSL: prednisolone, CR: complete remission, ICR: incomplete remission, NR: no response\n\nIn Cases 1 and 2, rituximab treatment was effective in treating refractory IMN as a second-line therapy. The patient from the first case achieved and maintained a CR at 15 months following the infusion of rituximab. The patient from the second case achieved a transient ICR I and his proteinuria subsequently increased again. However, his serum albumin levels have been maintained at >3.0 g/dL and NS was not observed for a long time period. The patient's renal function improved (serum creatinine level of 3.59 mg/dL before rituximab treatment and 1.91 mg/dL at last visit). He had no edema and his dosage of PSL could be significantly decreased. For these reasons, rituximab therapy was considered to have been beneficial in the second case. Considering his age and the side effect of infection, rituximab treatment was not repeated.\n\nCase 3 showed no response to a single infusion of rituximab. Cravedi et al. conducted a prospective matched-cohort study that compared the administration of single-dose rituximab (375 mg/m2) with the standard protocol of four weekly rituximab (375 mg/m2) doses in the treatment of nephrotic IMN (10). At 12 months, in the single-dose rituximab group, 2 of 12 patients achieved a CR and 6 achieved a PR. Similarly, in the standard protocol group, two of 24 patients achieved a CR and 14 achieved PR. The administration of single-dose rituximab was as effective as the standard four-dose therapy in achieving a remission from IMN.\n\nThe circulating CD20+ B cells were already fully depleted after the first administration of rituximab and remained below the normal range throughout the whole observation period. Single-dose rituximab treatment could avoid unnecessary re-exposure to rituximab and minimize the medical costs. In addition, a reduction of rituximab dose may limit the production of antichimeric antibodies, which increase the risk for infusion reactions and interrupt retreatment for disease reactivation.\n\nFor these reasons, we treated IMN with a single dose of rituximab. In 2009, there was a significant breakthrough regarding IMN. Beck et al. identified the M-type PLA2R as the primary antigen in IMN (2). Beck et al. performed an assay to detect the anti-PLA2R antibody in two distinct cohorts of IMN patients who were treated with rituximab (12). At baseline, 25 of 35 (71%) patients had the anti-PLA2R antibody. At 12 months after rituximab therapy, these antibodies decreased in 17 (68%) patients. In the patients who reacted serologically, 59% and 88% achieved a CR or PR at 12 and 24 months, respectively. A reduction of the anti-PLA2R antibody titer was associated with decreased urinary protein excretion and preceded changes in proteinuria. Ruggenenti et al. evaluated the correlation between the levels of anti-PLA2R antibodies and the clinical course of IMN patients who were treated with rituximab (13). Eighty-four of the 132 IMN patients achieved the combined end points (CR or PR) within a median follow-up of 30.8 months. At baseline, 101 patients were screened for anti-PLA2R antibodies. The autoantibody could be detected in 81 of the 101 patients. The proportion of patients who entered remission was comparable in the patients with or without detectable anti-PLA2R antibody at baseline. Within the cohort of the 81 participants with antibody levels that were detectable at baseline, the probability of attaining the combined end points was 81.5%, 59.3% and 37.0% in the patients with the lowest (14-86 RU/mL), middle (87-204 RU/mL) and highest (>204 RU/mL) tertiles of antibody titer, respectively. The titer levels of anti-PLA2R antibodies at baseline were associated with the clinical outcome.\n\nThe anti-PLA2R antibody level was measured in all of our cases. Two patients (Cases 1 and 2) who attained remission were negative for the antibody. Rituximab suppresses the production of autoantibodies by means of B lymphocyte depletion and affects autoimmunity in IMN. Prunotto et al. detected specific anti-aldose reductase and anti-manganese superoxide dismutase (SOD2) IgG4 in the serum of IMN patients (14). There is the possibility that these patients may possess another autoantibody aside from anti-PLA2R. On the other hand, in the patient from the third case, in whom anti-PLA2R antibodies were detected, no therapeutic effect of rituximab was observed and his renal function gradually deteriorated. Thus, the anti-PLA2R antibody titer at baseline might have been very high.\n\nRuggenenti et al. evaluated the relevance of renal histological findings to therapeutic response in IMN patients who received rituximab (15). Tubular atrophy and interstitial fibrosis were significantly associated with poor treatment efficacy. In our cases, the therapeutic effect of rituximab was dissimilar. There are several possible explanations for the differences among the three cases. Case 1 showed the best response to rituximab therapy. In Cases 2 and 3, the serum creatinine levels had already been elevated at the initiation of rituximab treatment, whereas the creatinine level was normal in Case 1, the renal function might have influenced the treatment outcome. In particular, the patient from Case 2 had a medical history of hypertension. The bilateral kidneys were atrophic; thus, the presence of nephrosclerosis was suggested. Another explanation is that disease duration was associated with the outcome. In Case 3, rituximab treatment was started at 12 years after the onset of disease. The progression of tubulointerstitial damage may produce poor outcomes; thus, the initiation of rituximab at an early stage of IMN is critical.\n\nBomback et al. conducted a systematic review assessing the effects of rituximab treatment for IMN (16). This systematic review showed that several studies had reported adverse effects. Most of these side effects were mild, transient, and thought to be a reaction to the infusion. A small number of bacterial or viral infections were noted after the rituximab administration. However, no serious cases were reported. Laryngospasm and lung neoplasms were described as serious adverse events. In a prospective cohort study (8), 11 serious adverse events, which included eight cardiovascular events and three cancers, were reported, and four patients died. No treatment-related events, such as infection and myelotoxicity, were observed. In the present study, one elderly patient developed a herpes simplex viral infection shortly after the infusion of rituximab.\n\nIMN is thought to be associated with a more favorable prognosis in Japanese individuals than in Caucasians. Shiiki et al. reported the results of a retrospective investigation of the prognosis and risk factors for renal survival in Japanese IMN patients with NS (17). Seven hundred ninety-five of the 949 (83.8%) patients achieved a CR or ICR, and 154 (16.2%) patients had persistent NS during the average follow-up period of 83.3 months. The patients who received conventional immunosuppressive therapy showed a significant improvement in their renal survival rates. However, massive proteinuria was a significant risk factor for end-stage renal disease. What kind of IMN patients are suitable for rituximab therapy? Although we indicated the efficacy of rituximab as a second-line therapy for IMN patients with NS, it is not clear whether rituximab treatment is superior to conventional therapies as an initial therapy for IMN. Currently, multicenter randomized trials comparing rituximab therapy with conventional immunosuppressive therapy for the treatment of IMN are ongoing (18,19).\n\nIn summary, rituximab may prove to be a beneficial treatment option for Japanese IMN patients who are refractory to immunosuppressive agents. However, our report only included a small patient population and the follow-up periods were relatively short. In relation to rituximab therapy for IMN, the appropriate dose, the number of times that it should be administered, and the appropriate treatment period remain unclear. Furthermore, the safety of the drug and the long-term therapeutic effects are unknown. We expect that future investigations will disclose the long-term efficacy and safety of rituximab therapy for IMN.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nAcknowledgement\nThe authors express our special appreciation to Dr Y. Sato, Dr A. Tanaka, Dr F. Kamiya for their efforts. We also thank excellent technical assistance to N. Asano, Y. Sawa and N. Suzuki. This work was supported by a Grant-in-Aid for Progressive Renal Diseases Research, Research on intractable disease, from the Ministry of Health, Labour and Welfare of Japan.\n==== Refs\n1. \nBeck LH Jr, Salant DJ \nMembranous nephropathy: recent travels and new roads ahead . Kidney Int \n77 : 765 -770 , 2010 .20182413 \n2. \nBeck LH Jr, Bonegio RG , Lambeau G , et al \nM-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy . N Engl J Med \n361 : 11 -21 , 2009 .19571279 \n3. \ndu Buf-Vereijken PW , Branten AJ , Wetzels JF \nIdiopathic membranous nephropathy: outline and rationale of a treatment strategy . Am J Kidney Dis \n46 : 1012 -1029 , 2005 .16310567 \n4. \nRemuzzi G , Chiurchiu C , Abbate M , Brusegan V , Bontempelli M , Ruggenenti P \nRituximab for idiopathic membranous nephropathy . Lancet \n360 : 923 -924 , 2002 .12354476 \n5. \nRuggenenti P , Chiurchiu C , Brusegan V , et al \nRituximab in idiopathic membranous nephropathy: a one-year prospective study . J Am Soc Nephrol \n14 : 1851 -1857 , 2003 .12819245 \n6. \nFervenza FC , Cosio FG , Erickson SB , et al \nRituximab treatment of idiopathic membranous nephropathy . Kidney Int \n73 : 117 -125 , 2008 .17943078 \n7. \nFervenza FC , Abraham RS , Erickson SB , et al ; Mayo Nephrology Collaborative Group \nRituximab therapy in idiopathic membranous nephropathy: a 2-year study . Clin J Am Soc Nephrol \n5 : 2188 -2198 , 2010 .20705965 \n8. \nRuggenenti P , Cravedi P , Chianca A , et al \nRituximab in idiopathic membranous nephropathy . J Am Soc Nephrol \n23 : 1416 -1425 , 2012 .22822077 \n9. \nCravedi P , Sghirlanzoni MC , Marasà M , Salerno A , Remuzzi G , Ruggenenti P \nEfficacy and safety of rituximab second-line therapy for membranous nephropathy: a prospective, matched-cohort study . Am J Nephrol \n33 : 461 -468 , 2011 .21508634 \n10. \nCravedi P , Ruggenenti P , Sghirlanzoni MC , Remuzzi G \nTitrating rituximab to circulating B cells to optimize lymphocytolytic therapy in idiopathic membranous nephropathy . Clin J Am Soc Nephrol \n2 : 932 -937 , 2007 .17702725 \n11. \nNishi S , Ubara Y , Utsunomiya Y , et al \nEvidence-based clinical practice guidelines for nephrotic syndrome 2014 . Clin Exp Nephrol \n20 : 342 -370 , 2016 .27099136 \n12. \nBeck LH Jr, Fervenza FC , Beck DM , et al \nRituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy . J Am Soc Nephrol \n22 : 1543 -1550 , 2011 .21784898 \n13. \nRuggenenti P , Debiec H , Ruggiero B , et al \nAnti-phospholipase A2 receptor antibody titer predicts post-rituximab outcome of membranous nephropathy . J Am Soc Nephrol \n26 : 2545 -2558 , 2015 .25804280 \n14. \nPrunotto M , Carnevali ML , Candiano G , et al \nAutoimmunity in membranous nephropathy targets aldose reductase and SOD2 . J Am Soc Nephrol \n21 : 507 -519 , 2010 .20150532 \n15. \nRuggenenti P , Chiurchiu C , Abbate M , et al \nRituximab for idiopathic membranous nephropathy: who can benefit? \nClin J Am Soc Nephrol \n1 : 738 -748 , 2006 .17699281 \n16. \nBomback AS , Derebail VK , McGregor JG , Kshirsagar AV , Falk RJ , Nachman PH \nRituximab therapy for membranous nephropathy: a systematic review . Clin J Am Soc Nephrol \n4 : 734 -744 , 2009 .19279120 \n17. \nShiiki H , Saito T , Nishitani Y , et al ; Research Group on Progressive Renal Diseases in Japan \nPrognosis and risk factors for idiopathic membranous nephropathy with nephrotic syndrome in Japan . Kidney Int \n65 : 1400 -1407 , 2004 .15086481 \n18. \nFervenza FC , Canetta PA , Barbour SJ , et al ; Mentor Consortium group \nA multicenter randomized controlled trial of rituximab versus cyclosporine in the treatment of idiopathic membranous nephropathy (MENTOR) . Nephron \n3 : 159 -168 , 2015 .\n19. \nRojas-Rivera J , Fernández-Juárez G , Ortiz A , et al \nA European multicentre and open-label controlled randomized trial to evaluate the efficacy of Sequential treatment with TAcrolimus-Rituximab versus steroids plus cyclophosphamide in patients with primary MEmbranous Nephropathy: the STARMEN study . Clin Kidney J \n5 : 503 -510 , 2015 .\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "56(13)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "membranous nephropathy; nephrotic syndrome; rituximab",
"medline_ta": "Intern Med",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000368:Aged; D044466:Asians; D003520:Cyclophosphamide; D016572:Cyclosporine; D015433:Glomerulonephritis, Membranous; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D009173:Mycophenolic Acid; D012263:Ribonucleosides; D000069283:Rituximab",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1679-1686",
"pmc": null,
"pmid": "28674357",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20182413;20150532;17943078;17702725;15086481;19571279;12354476;12819245;22822077;25804280;19279120;21508634;27099136;26413273;17699281;26087670;21784898;16310567;20705965",
"title": "Single-dose Rituximab Therapy for Refractory Idiopathic Membranous Nephropathy: A Single-center Experience.",
"title_normalized": "single dose rituximab therapy for refractory idiopathic membranous nephropathy a single center experience"
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"companynumb": "PHHY2017JP106308",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
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"actiondrug": "5",
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"activesubstancename": "CYCLOSPORINE"
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"abstract": "Epstein-Barr virus (EBV)-related neurologic complications have a diverse presentation in transplant recipients, creating diagnostic and therapeutic challenges for clinicians. In this case series, we report unique manifestations of EBV related neurologic complications following solid organ transplant and highlight pitfalls in management.\n\n\n\nA retrospective search of the electronic medical record of all patients from January 2015 to December 2020 who underwent solid organ transplantation and had central nervous system complications as determined by ICD-10 codes were included. Three patients with unique manifestation of EBV-related neurologic complications after liver transplantation were identified. The first was a 52-year-old man with a live-donor liver transplant 11 years prior for Budd-Chiari syndrome presented with several weeks of headache and several lesions on brain MRI; he was diagnosed with primary central nervous system post-transplant lymphoproliferative disorder. The second patient was a 63-year-old man with a deceased-donor liver transplant 16 years prior for alpha-1-antitrypsin deficiency and was found to have a stroke; he was diagnosed with EBV encephalitis. The final patient was a 75-year-old woman with a deceased-donor liver transplant six years prior for primary biliary cirrhosis who presented with four months of gait instability; she was diagnosed with EBV myelitis. A review of the literature was performed to supplement description of the different diseases.\n\n\n\nEBV-related central nervous infection in post-transplant patients can manifest in a variety of neurologic syndromes, which can be challenging to diagnose. Careful correlation of clinical, pathologic, and radiologic findings and a high index of suspicion are crucial in identification and appropriate management.",
"affiliations": "Department of Neurology, University of Cincinnati, 260 Stetson, Suite 2300, Cincinnati, OH, 45267, USA. mridha@neomed.edu.;Division of Neurology, Lahey Hospital and Medical Center, 41 Mall Road, Burlington, MA, 01805, USA.;Division of Neurology, Lahey Hospital and Medical Center, 41 Mall Road, Burlington, MA, 01805, USA.;Division of Neurology, Lahey Hospital and Medical Center, 41 Mall Road, Burlington, MA, 01805, USA.;Division of Neurology, Lahey Hospital and Medical Center, 41 Mall Road, Burlington, MA, 01805, USA.;Division of Neurology, Lahey Hospital and Medical Center, 41 Mall Road, Burlington, MA, 01805, USA.;Division of Neurology, Lahey Hospital and Medical Center, 41 Mall Road, Burlington, MA, 01805, USA.;Concord Hospital Neurology Associates, 246 Pleasant Street, Concord, NH, 03301, USA.",
"authors": "Ridha|Mohamed|M|0000-0002-0814-0222;Jones|Dylan G|DG|;Lerner|David P|DP|;Vytopil|Michal|M|;Voetsch|Barbara|B|;Burns|Joseph D|JD|;Ramineni|Anil|A|;Raibagkar|Pooja|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12985-021-01629-6",
"fulltext": "\n==== Front\nVirol J\nVirol J\nVirology Journal\n1743-422X\nBioMed Central London\n\n1629\n10.1186/s12985-021-01629-6\nCase Report\nThe spectrum of Epstein-Barr virus infections of the central nervous system after organ transplantation\nhttp://orcid.org/0000-0002-0814-0222\nRidha Mohamed mridha@neomed.edu\n\n1\nJones Dylan G. 23\nLerner David P. 23\nVytopil Michal 23\nVoetsch Barbara 23\nBurns Joseph D. 23\nRamineni Anil 23\nRaibagkar Pooja 4\n1 grid.24827.3b 0000 0001 2179 9593 Department of Neurology, University of Cincinnati, 260 Stetson, Suite 2300, Cincinnati, OH 45267 USA\n2 grid.415731.5 0000 0001 0725 1353 Division of Neurology, Lahey Hospital and Medical Center, 41 Mall Road, Burlington, MA 01805 USA\n3 grid.67033.31 0000 0000 8934 4045 Department of Neurology, Tufts University School of Medicine, 800 Washington Street, Boston, MA 02111 USA\n4 grid.414687.8 0000 0004 0438 964X Concord Hospital Neurology Associates, 246 Pleasant Street, Concord, NH 03301 USA\n6 8 2021\n6 8 2021\n2021\n18 16218 5 2021\n26 7 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nEpstein-Barr virus (EBV)-related neurologic complications have a diverse presentation in transplant recipients, creating diagnostic and therapeutic challenges for clinicians. In this case series, we report unique manifestations of EBV related neurologic complications following solid organ transplant and highlight pitfalls in management.\n\nCase presentations\n\nA retrospective search of the electronic medical record of all patients from January 2015 to December 2020 who underwent solid organ transplantation and had central nervous system complications as determined by ICD-10 codes were included. Three patients with unique manifestation of EBV-related neurologic complications after liver transplantation were identified. The first was a 52-year-old man with a live-donor liver transplant 11 years prior for Budd-Chiari syndrome presented with several weeks of headache and several lesions on brain MRI; he was diagnosed with primary central nervous system post-transplant lymphoproliferative disorder. The second patient was a 63-year-old man with a deceased-donor liver transplant 16 years prior for alpha-1-antitrypsin deficiency and was found to have a stroke; he was diagnosed with EBV encephalitis. The final patient was a 75-year-old woman with a deceased-donor liver transplant six years prior for primary biliary cirrhosis who presented with four months of gait instability; she was diagnosed with EBV myelitis. A review of the literature was performed to supplement description of the different diseases.\n\nConclusions\n\nEBV-related central nervous infection in post-transplant patients can manifest in a variety of neurologic syndromes, which can be challenging to diagnose. Careful correlation of clinical, pathologic, and radiologic findings and a high index of suspicion are crucial in identification and appropriate management.\n\nKeywords\n\nEpstein-Barr virus\nPost-transplant lymphoproliferative disorder\nCentral nervous system\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nWith the advent of organ transplantation and modern immunosuppressive therapy, clinicians frequently encounter unique manifestations of infectious diseases, owing to the interplay of the infectious agent and the altered immune response. Of these manifestations, neurologic presentations may arise inconspicuously but can be devastating.\n\nEpstein-Barr virus (EBV) is capable of causing a diverse range of neurologic maladies [1, 2]. Cell-mediated immunity is the primary defense against EBV-infected B-cells. However, due to immunosuppressive regimens, organ transplant recipients are at increased risk. Treatment of these EBV-related complications, including those involving the central nervous system (CNS), presents a diagnostic challenge due to their protean manifestations as well as a therapeutic dilemma, balancing the risks of organ rejection with the need for immune reconstitution. The increase in prevalence of organ transplantation and development of potential future therapies in EBV post-transplant lymphoproliferative disorders including prophylactic chemo- or antiviral drugs and cytotoxic T-lymphocyte therapy necessitate clinicians to be aware of these disorders when caring for this high-risk population [3].\n\nThe aim of this case-series is to illustrate the CNS manifestations of EBV infection after organ transplantation and review the challenges and approach to diagnosis and management.\n\nMethods\n\nThe study was conducted at Lahey Hospital and Medical Center (LHMC) in Burlington, Massachusetts. LHMC is an academic tertiary care center with a high-volume liver transplantation program.\n\nWe performed a single-center, retrospective review of all patients between January, 2015 and December, 2020 who underwent solid organ transplantation and had CNS complications. During the study period, there were a total of 768 solid organ transplants with 516 liver transplants and 252 kidney transplants [4]. Cases were ascertained utilizing Epic SlicerDicer search of all patients admitted during this time period, including only those with international classification of disease (ICD)-10 codes consistent with organ transplantation and CNS or EBV infection (supporting information). All cases and images were reviewed and verified by two neurologists (MR and PR) to confirm accurate case adjudication. The Institutional Review Board approved this study and a waiver of informed consent was granted.\n\nCase presentations\n\nCase 1: Primary central nervous system post-transplant lymphoproliferative disorder\n\nA 52-year-old man with a live-donor liver transplant 11 years prior for Budd-Chiari syndrome presented with several weeks of headache and diplopia. Immunosuppression consisted of tacrolimus (Table 1). Neurologic exam identified right abducens and right facial nerve palsies.Table 1 Clinical characteristics of cases with central nervous system EBV infection\n\nPatient (age/sex)\tLiver allograft type\tYears from transplant\tPresenting symptoms (EBV syndrome)\tImmunosuppression regimen\t\n52/M\tLive-donor\t11\tRelapsing headache, nausea/vomiting, double vision, facial numbness (PTLD)\tTacrolimus\t\n63/M\tDead-donor\t16\tEncephalopathy, fall, hyperglycemia (encephalitis)\tMycophenolate mofetil, rapamycin\t\n75/F\tDead-donor\t6\tParaparesis, numbness, urinary dysfunction, falls (myelitis)\tTacrolimus, mycophenolate mofetil\t\nEBV, Epstein-Barr virus; F, female; M, male\n\nMagnetic resonance imaging (MRI) of the brain and spinal cord revealed T2 hyperintensity involving portions of the cervical cord, brainstem, and left centrum-semiovale with leptomeningeal and right facial nerve enhancement (Fig. 1).Fig. 1 Primary CNS post-transplant lymphoproliferative disorder radiography. Initial brain MRI showing fluid attenuation inversion recovery (FLAIR) hyperintensities within the dorsal pons (A) and throughout the medulla (B) with foci of susceptibility within the pons (C). MRI of the cervical spine with T1 fat saturation sequence showing contrast enhancement of the upper cervical cord (D, arrow) with leptomeningeal enhancement. MRI one month later when the patient presented with left hemisensory symptoms showing multiple FLAIR hyperintense lesions in the pons (E), midbrain and bilateral temporal lobes (F), and left parietal lobe (G). Additionally, contrast enhancement within the middle cerebellar peduncles was seen (H)\n\nA thorough investigation for infectious, inflammatory, and neoplastic etiologies was performed (Table 2). EBV polymerase chain reaction (PCR) of the cerebral spinal fluid (CSF) was positive. EBV serology was positive for viral capsid antigen (VCA) IgG and early antigen (EA) IgG, but VCA IgM and Epstein-Barr nuclear antigen (EBNA) were negative, indicative of either late primary infection or prior infection.Table 2 Summary of testing and outcomes of cases\n\nDiagnosis\tCase 1: post-transplant lymphoproliferative disorder (PTLD)\tCase 2: EBV encephalitis\tCase 3: EBV myelitis\t\nEBV serology\tEBNA IgG −\n\nEBV VCA IgM −\n\nEBV VCA IgG +\n\nEBV EA IgG +\n\n\tNot performed\tEBNA IgG +\n\nEBV VCA IgM ± b\n\nEBV VCA IgG + \n\nEBV EA IgG + \n\n\t\nEBV CSF PCR\tPositive\tPositive (quantitative EBV PCR: 383,000 copies/mL)\tPositive\t\nCSF profilea\tWBC 12; lymphocytes 81% (occasional plasmacytoid and atypical cells)\n\n < 1 RBC\n\nProtein 36\n\nGlucose 53\n\n\tWBC 171; lymphocytes 95%\n\nRBC 234\n\nProtein 169\n\nGlucose 63\n\n\tWBC 23; lymphocytes 95%\n\n < 1 RBC\n\nProtein 60\n\nGlucose 55\n\n\t\nOther serum testing\tCBC, CMP\n\nCalifornia virus, East Equine encephalitis, St. Louis encephalitis, West Equine encephalitis\n\nTreponemal antibody\n\nANA\n\nHIV\n\nQuantiFERON\n\nAnaplasma, Ehrlichia\n\nLyme\n\nAspergillus galactomannan\n\nAnti-aquaporin-4 IgG\n\nAnti-MOG IgG\n\nC-reactive protein\n\nVitamin B12\n\n\tCBC, CMP\n\nTreponemal antibody\n\nHIV\n\nQuantiFERON\n\nLyme\n\n\tCBC, CMP\n\nVitamin B12\n\nMethylmalonic acid\n\nCopper\n\nVitamin E\n\nZinc\n\nHIV\n\nLyme\n\nTreponemal antibody\n\nANA\n\nACE\n\nANCA\n\nAnti-aquaporin-4 IgG\n\nAnti-MOG IgG\n\n\t\nOther CSF testing\tHerpes simplex virus I/II PCR\n\nListeria\n\nCryptococcal antigen\n\nVaricella zoster PCR\n\nToxoplasma PCR\n\nTropherma whipple\n\nMycoplasma\n\nHistoplasma\n\nCytomegalovirus PCR\n\nEnterovirus PCR\n\nJC virus PCR\n\nHHV-6 PCR\n\nOligoclonal bands\n\nCytology\n\nFlow cytometry\n\n\tHerpes simplex virus I/II PCR\n\nCryptococcal antigen\n\nVaricella zoster PCR\n\nCytomegalovirus PCR\n\nCytology\n\nFlow cytometry\n\nUniversal bacterial and fungal PCR\n\n\tHerpes simplex virus I/II PCR\n\nCryptococcal antigen\n\nVaricella zoster PCR\n\nCytomegalovirus PCR paraneoplastic panel\n\nVDRL\n\noligoclonal bands\n\nWest-Nile virus PCR\n\nHHV-6 PCR\n\n\t\nTreatment\t1. rituximab, prednisone, methotrexate\n\n2. IV ganciclovir then po valganciclovir; tacrolimus held\n\n\tMycophenolate mofetil held, tacrolimus continued; IV acyclovir then transitioned to IV ganciclovir\tMycophenolate held, tacrolimus continued; IV solumedrol\t\nOutcome\tSignificant improvement 20 weeks after presentation with residual radiographic lesions\tDeceased\tComplete recovery 5 months later\t\nACE, angiotensin converting enzyme; ANCA, antineutrophil cytoplasmic antibodies; ANA, antinuclear antibody; CBC, complete blood cell count; CMP, complete metabolic panel; CSF, cerebral spinal fluid; EA, early antigen; EBER, Epstein-Barr encoding region; EBNA, Epstein-Barr nuclear antigen; EBV, Epstein-Barr virus; HHV-6, Human Herpesvirus 6; HIV, human immunodeficiency virus; IV, intravenous; JC virus, John Cunningham virus; LMP1, latent membrane protein 1; MOG, myelin oligodendrocyte glycoprotein; RBC, red blood cell count; VCA, viral capsid antigen; VDRL, venereal disease research laboratory; WBC, white blood cell count\n\naLab reference values: WBC < 10 cells/μL, RBC < 1 cells/μL, lymphocytes 40–80%, protein 15–45 mg/dL, glucose 40–70 mg/dL)\n\nb+/−Means borderline/equivocal\n\nPathology from stereotactic biopsy of a left temporal lobe lesion showed perivascular polymorphic inflammatory infiltrate, including B- and T-cells. Immunohistochemical stains revealed CD20 positive B-cells, CD3 positive T cells, CD68 positive microglial nodules, plasma cells, and scattered EBV-encoded small RNAs (EBER) positive cells (Fig. 2). Latent membrane protein 1 (LMP1) was negative. These results were initially interpreted as Primary CNS Post-transplant Lymphoproliferative Disorder (PCNS-PTLD). Tacrolimus was withheld, and the patient was treated with rituximab, prednisone, and methotrexate. A subsequent opinion of the pathology changed the diagnosis in favor of EBV encephalitis, prompting initiation of ganciclovir and withholding chemotherapy. The neurologic exam and repeat imaging improved over the course of this hospitalization; tacrolimus was resumed. He was readmitted a month later with new left hemisensory loss. Brain MRI demonstrated new expansile T2 hyperintense lesions (Fig. 1). Tacrolimus was again discontinued, and valganciclovir was initiated.Fig. 2 Primary CNS post-transplant lymphoproliferative disorder pathology. Pathology showed perivascular polymorphic inflammatory infiltrate, as well as numerous plasma cells and eosinophils (A–C). Panel B is an enhanced image of the boxed area in A. Immunohistochemical staining was positive for scattered EBER positive cells (D). Also positive for CD20 positive B-cells, CD3 positive T cells, polytypic plasma cells (not pictured)\n\nAfter 2 weeks, he developed leukopenia (white blood cell count of 1.71 K/μL (reference 4.00–11.00 K/μL)) with severe neutropenia (absolute neutrophilic count 0.13 K/μL (reference 1.50–7.70 K/μL)) attributed to antiviral therapy. MRI brain again revealed progressive lesion enlargement. Given the longitudinal clinical, radiographic, and pathologic course, the diagnosis was revised to PCNS-PTLD. All immunosuppression and antiviral therapy were held. SubsequentMRI after one month showed regression of the lesions. At follow-up 6 months later, he remained clinically stable without relapse.\n\nCase 2: EBV encephalitis\n\nA 63-year-old man with a deceased-donor liver transplant 16 years prior for alpha-1-antitrypsin deficiency presented to the emergency department after a fall.\n\nImmunosuppression consisted of mycophenolate mofetil and sirolimus (Table 1). Physical examination identified right hemisensory loss. Brain MRI revealed an acute left insular infarct (Fig. 3). Over the initial three days of his hospitalization, he developed bilateral abducens, left facial, and right oculomotor cranial nerve palsies. Repeat MRI with contrast demonstrated new cortical infarcts and enhancement of the left facial, left trigeminal, and right oculomotor nerves (Fig. 3). Investigations (Table 2) were notable for a positive CSF EBV PCR with 383,000 copies/mL.Fig. 3 EBV encephalitis. MRI of the brain revealed a small area of diffusion restriction along the posterior left insula, consistent with an acute infarct (A); multiple cranial enhancement including the right oculomotor nerve (B, arrow), left facial and vestibulocochlear nerve complex (C, arrow), and left trigeminal nerve (not pictured). There were also new areas of restricted diffusion in the left frontal operculum and posterior left temporal lobe white matter (D, arrow). Two weeks later, MRI of the brain showed multiple areas of non-enhancing FLAIR hyperintensity in the bilateral temporal lobes (E, F)\n\nMycophenolate mofetil was discontinued, sirolimus was continued, and ganciclovir was initiated. The patient became progressively obtunded over several days. MRI one week later indicated disease progression with new infarcts (Fig. 3). The patient was transitioned to hospice and died.\n\nCase 3: EBV myelitis\n\nA 75-year-old woman with a deceased-donor liver transplant 6 years prior for primary biliary cirrhosis presented with four months of progressive weakness and gait instability.\n\nImmunosuppression consisted of tacrolimus and mycophenolate mofetil (Table 1). On examination, she had paraparesis, diminished proprioception, brisk reflexes in all limbs, and bilateral Babinski sign.\n\nSpinal MRI demonstrated a longitudinal extensive T2 hyperintensity of the dorsal columns (C1–C7) with enhancement (Fig. 4). Investigations (Table 2) were remarkable for a positive CSF EBV PCR. EBV serology detected elevated VCA IgG, EBNA IgG, and EA IgG with borderline VCA IgM., indicating a chronic infection or viral reactivation.Fig. 4 EBV myelitis. MRI of the spinal cord in axial (A) and sagittal (B) views revealed a longitudinal extensive area of T2 hyperintensity involving the dorsal cervical spinal cord from C1–C7 (arrows)\n\nShe was treated with methylprednisolone. Mycophenolate mofetil was discontinued with continuation of tacrolimus. At five-month follow-up, she had mild residual paraparesis but was able to ambulate with support. Repeat MRI revealed resolution of the lesion.\n\nDiscussion\n\nVirology\n\nEBV is a DNA virus of the herpesvirus family with a tropism for B-lymphocytes. The life cycle consists of two forms—the latent and lytic phases. The latent phase results in activation, proliferation, and somatic hypermutation of infected B-cells. The phase is characterized by viral expression of proteins EBER and LMP-1. LMP-1 binds to the CD40 receptor on B-cells and prevents cellular apoptosis. These immortalized B-cells establish a viral cache. In the lytic phase, the virus replicates, destroys host cells, and infects other B-cells [1]. Remission is achieved by the control of latent-infected B-cells, primarily by the response of cytotoxic T-cells. Compromise of T-cell mediated immunity results in the loss of the ability to control dormant, immortalized, infected B-cells, causing a neoplastic proliferation in PTLD. This is analogous to pathogenesis of primary CNS lymphoma in AIDS [1].\n\nIn contrast to PTLD, EBV encephalitis and myelitis are manifestations of the lytic phase of the viral cycle. It is hypothesized that the neuronal damage is due to the infiltrative process of infected B-cells and the reactive immunologic cascade rather than a primary infection of neural cells [1].\n\nPCNS-PTLD\n\nEpidemiology and risk factors\n\nPTLD was initially described in 1970 and is defined by the World Health Organization as lymphoid proliferation or lymphoma occurring in patients who have undergone organ transplantation and are maintained on immunosuppressive regimens [5]. PTLD is the second most common malignancy in the post-transplant population, with approximately 15% of cases involving CNS [5, 6]. Risk factors include type of organ transplanted, greater degree of immunosuppression, EBV status of host and donor, and younger host age. Intestine and lung transplantations have the highest rate of PTLD (20%), whereas kidney and liver transplants have a lower rates (1–3%) [5, 7–10]. Seronegative hosts and EBV positive donors have increased risk likely due to the introduction of an EBV-infected graft into a naïve host [5].\n\nPresentation\n\nCNS involvement in PTLD is commonly accompanied by involvement of other organ systems; however, PCNS-PTLD may occur without evidence of systemic involvement. Incidence is highest at six months to one year post-transplant, but PCNS-PTLD may develop several years after the transplant (median 4.4 years) [5]. Presentations include increased intracranial pressure, headache, seizure, and focal neurologic deficits [5–8]. Intraocular spread may occur as well, and a slit-lamp exam is recommended.\n\nInvestigation modalities\n\nDue to the immunosuppressed status of the patients and the non-specific MRI findings, a thorough evaluation of vascular, infectious, and other neoplastic etiologies such as cerebral abscess, posterior reversable encephalopathy syndrome (PRES), stroke, cerebral venous sinus thrombosis, demyelination, infectious encephalitis, autoimmune encephalitis, glioblastoma, and metastatic disease must be undertaken by treating physicians [11]. A summary of relevant testing is highlighted in Table 2.\n\nBrain and spinal cord MRI with contrast is the imaging modality of choice. Radiographically, lesions are commonly multifocal with preferential involvement of periventricular structures with or without meningeal enhancement or hemorrhage. Lesions are typically contrast enhancing with variable patterns (homogenous, ring, or heterogeneous) [5, 11].\n\nThe CSF profile is non-specific with minimal pleocytosis and increased protein. Cytology may show malignant cells, and flow cytometry can sometimes detect a monoclonal population [12]. CSF testing alone is usually insufficient for diagnosis; tissue biopsy is needed in most cases.\n\nPathologic diagnosis requires the detection of latent viral proteins EBER and LMP-1 utilizing in-situ hybridization or immunohistochemistry. As in our case, it may be diagnostically challenging to differentiate EBV encephalitis from PCNS-PTLD. The pathogenies of CNS-PTLD is not binary and the disease itself exists as a continuum from early lesions which resemble reactive lymphoplasmacytic proliferation to the polymorphic subtype with mixed lymphoid and plasma cells to monomorphic PTLD with malignant lymphoid cells of single clonality [3, 10]. Furthermore, it is recognized that PTLD lesions demonstrate a mixed molecular pattern of latent and lytic EBV gene expression [13]. Thus, early CNS-PTLD presents a true diagnostic dilemma since these lesions have a histologic appearance that is difficult to distinguish from encephalitis and detection of latent EBV proteins may be scant as in our case.\n\nTreatment and prognosis\n\nThe goal of therapy requires balancing control of the malignancy and preservation of graft function. It is typically recommended that the initial step be either reduction or complete withdrawal of immunosuppression [5, 10, 12]. Antiviral therapies that target thymidine kinase such as ganciclovir are ineffective since the enzymatic expression does not occur in the latent phase of the viral cycle. Immune reconstitution is typically insufficient and concurrent anti-neoplastic interventions are required. Rituximab is a preferred first-line agent given tolerability, limited toxicity, and high response rate. Other therapies include whole-brain radiation, methotrexate, and autologous or allogenic EBV-specific cytotoxic T-lymphocyte infusions [5, 6, 8–10, 12]. Response to first line therapy is the strongest predicotrs of survival, and with treatment median survival ranges from 26 to 47 months [5, 6, 8]. Current areas of investigation include prophylactic antiviral or anti-CD20 for high risk patients and the utilitity of adoptive immunotherapy in refractory disease [3].\n\nNon-PTLD manifestation of EBV in the CNS\n\nPresentation\n\nPresentation of EBV encephalitis, myelitis, and encephalomyelitis bears semblance to other viral infections of the CNS. Infection may be heralded by prodromal systemic manifestations of infectious mononucleosis or neurologic manifestation may be the initial symptomatology [1]. A diverse array of neurologic deficits have been described with EBV encephalitis [2]. Moreover, EBV encephalitis may trigger para-infectious acute disseminated encephalomyelitis or, as in our case, vasculitis resulting in cerebral infarcts [1, 2].\n\nInvestigation modalities\n\nIt is imperative that a detailed investigation be undertaken for other bacterial, viral, parasitic, and fungal etiologies in an immunocompromised patient after transplantation [14]. Other viral etiologies that may mimic EBV encephalitis or myelitis include Human herpesvirus 6, Herpes simplex virus, Varicella zoster virus, Cytomegalovirus, Human T-cell leukemia virus-1, West Nile Virus, Poliomyelitis, Powassan encephalitis, and Enterovirus A71. Other atypical neurologic infections that may be seen in the immunocompromised population include syphilis, toxoplamosmosis, tuberculosis, nocardia, cryptococcus, lyme disease, invasive fungal infections, listeriosis, whipple’s disease, and mycoplasma. Nutritional causes include vitamin B12, vitamin E, and copper deficiency. Vascular etiologies such as stroke or PRES may occur after transplant. All longitudinally extensive myelitis should entertain neuromyelitis optica, sarcoidosis, and anti-MOG encephalomyelitis in the differential. Acute disseminated encephalomyelitis may be a seen as a para-infectious, immune-mediated phenomenon after a primary EBV infection [15, 16]. Table 2 highlights relevant investigational testing.\n\nCSF studies demonstrate a variable degree of lymphocytic pleocytosis with increased protein and normal glucose. While PCR detection of the virus is utilized for diagnosis of EBV encephalitis and myelitis a positive EBV PCR may reflect incidental reactivation [17]. Conversely, there may be false negative CSF EBV PCR [18]. Corresponding viral serologies to the viral capsid (IgG and IgM), EBNA, and EA may be helpful in supporting the presence of an acute or subacute EBV infection.\n\nBrain MRI with contrast in EBV encephalitis may range from completely normal to multifocal areas of T2 hyperintensity in the parenchyma, diffusion restriction, or contrast-enhancement of the meninges and cranial nerves [1, 2, 19, 20]. In organ transplant recipients, EBV encephalitis has been reported to present as a tumor-like lesion [19].\n\nFor EBV myelitis, a complete spine MRI with contrast is the imaging modality of choice. There is no known pathognomonic finding, although there are reports of longitudinally extensive lesions with or without contrast enhancement [18].\n\nThe histologic findings in EBV encephalitis consist of predominantly perivascular lymphocytic infiltrates of microglia, macrophages, T-cells, and infected B-cells. The infected B-cells may show some clonality, lymphoblastoid-appearance, and increased mitotic figures, making the distinction between malignancy and infection difficult [1, 21].\n\nTreatment and prognosis\n\nThe most crucial step is reduction of immunosuppression to restore the T-cell mediated immune response. There is limited evidence for the use of antiviral agents; however, their use should be strongly considered, especially in severe presentations. Intravenous ganciclovir or parenteral valganciclovir are preferred given their known activity against EBV replication in-vitro [2, 22, 23]. In organ transplant patients, valganciclovir and immunoglobulin therapy have been reported to be effective in EBV encephalitis, but valganciclovir may cause myelosuppression with prolonged use [23]. The optimal duration of treatment is unknown and is usually made based upon clinical response. Steroids are not routinely administered, and the decision should be made at the discretion of the physician.\n\nIn immunocompetent patients with EBV encephalitis, the mortality rate is approximately 10%, with most patients having good outcomes without long-term deficits [20, 24]. However, in post-transplant populations outcomes are unknown.\n\nConclusions\n\nEBV-related complications of the CNS after organ transplantation have a diverse spectrum of infectious to neoplastic manifestations. The presentation can be highly variable often leading to diagnostic delay or an incorrect initial diagnosis. Overlap between EBV encephalitis and PCNS-PTLD exists, creating an especially challenging diagnostic dilemma. A multidisciplinary approach and individualized treatment plan are fundamental for successful treatment.\n\nAbbreviations\n\nACE Angiotensin converting enzyme\n\nANCA Antineutrophil cytoplasmic antibodies\n\nANA Antinuclear antibody\n\nCBC Complete blood cell count\n\nCMP Complete metabolic panel\n\nCSF Cerebral spinal fluid\n\nEA Early antigen\n\nEBER Epstein-Barr encoding region\n\nEBNA Epstein-Barr nuclear antigen\n\nEBV Epstein-Barr virus\n\nHHV-6 Human herpesvirus 6\n\nHIV Human immunodeficiency virus\n\nIV Intravenous\n\nJC virus John Cunningham virus\n\nLMP1 Latent membrane protein 1\n\nMOG Myelin oligodendrocyte glycoprotein\n\nPCNS-PTLD Primary central nervous system post-transplant lymphoproliferative\n\nRBC Red blood cell count\n\nVCA Viral capsid antigen\n\nVDRL Venereal disease research laboratory\n\nWBC White blood cell count\n\nAcknowledgements\n\nThe authors would like to acknowledge Claudia Chaves, MD, and Matthew Tilem, MD for their judicious care of the patients discussed in the article during critical periods of their illness and Christine Thomas, MD, and Elaine Jaffe, MD for their pathology consultation and diagnosis.\n\nAuthors' contributions\n\nPR conceived of the study, coordinated effors, and contributed to revisions. MR and DJ drafted the manuscript, helped in study coordination, and revision. DL assisted with data collection and revision. MV, BV, JB, and AR were involved in manuscript revision. All authors read and approved the final manuscript.\n\nFunding\n\nNo funding was used in the production of this paper.\n\nAvailabilitiy of data and materials\n\nData sharing is not applicable to this article as no datasets were generated or analysed during the current study.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThe Lahey Hospital and Medical Center Institutional Review Board approved this study and a waiver of informed consent was granted.\n\nConsent for publication\n\nWritten informed consent was waived by the Ethics Comittede due to the retrospective nature of the study. No identifiable patient information was included.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Tselis AC Epstein-Barr virus infections of the nervous system Handb Clin Neurol 2014 123 285 305 10.1016/B978-0-444-53488-0.00013-4 25015491\n2. Fujimoto H Asaoka K Imaizumi T Ayabe M Shoji H Kaji M Epstein-Barr virus infections of the central nervous system Intern Med Tokyo Jpn 2003 42 1 33 40 10.2169/internalmedicine.42.33\n3. Allen UD Preiksaitis JK Post-transplant lymphoproliferative disorders, Epstein-Barr virus infection, and disease in solid organ transplantation: guidelines from the American Society of Transplantation Infectious Diseases Community of Practice Clin Transplant 2019 33 9 e13652 10.1111/ctr.13652 31230381\n4. Center - OPTN. Organ Procurement and Transplantation Network. Accessed July 5, 2021. https://optn.transplant.hrsa.gov/data/view-data-reports/center-data/#.\n5. Cavaliere R, Petroni G, Lopes MB, Schiff D, The International Primary Central Nervous System Lymphoma Collaborative Group. Primary central nervous system post-transplantation lymphoproliferative disorder: an international primary central nervous system lymphoma collaborative group report. Cancer. 2010;116(4):863–870. 10.1002/cncr.24834.\n6. Lake W, Chang JE, Kennedy T, Morgan A, Salamat S, Başkaya MK. A case series of primary central nervous system posttransplantation lymphoproliferative disorder: imaging and clinical characteristics. Neurosurgery. 2013;72(6):960–970; discussion 970. 10.1227/NEU.0b013e31828cf619.\n7. Castellano-Sanchez AA Li S Qian J Lagoo A Weir E Brat DJ Primary central nervous system posttransplant lymphoproliferative disorders Am J Clin Pathol 2004 121 2 246 253 10.1309/N82C-TQ1J-0XEV-EFQB 14983939\n8. Evens AM Choquet S Kroll-Desrosiers AR Primary CNS posttransplant lymphoproliferative disease (PTLD): an international report of 84 cases in the modern era Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg 2013 13 6 1512 1522 10.1111/ajt.12211\n9. Petrara MR Giunco S Serraino D Dolcetti R De Rossi A Post-transplant lymphoproliferative disorders: from epidemiology to pathogenesis-driven treatment Cancer Lett 2015 369 1 37 44 10.1016/j.canlet.2015.08.007 26279520\n10. Heslop HE How I treat EBV lymphoproliferation Blood 2009 114 19 4002 4008 10.1182/blood-2009-07-143545 19724053\n11. White ML Moore DW Zhang Y Mark KD Greiner TC Bierman PJ Primary central nervous system post-transplant lymphoproliferative disorders: the spectrum of imaging appearances and differential Insights Imaging 2019 10.1186/s13244-019-0726-6 30972513\n12. Kittan NA Beier F Kurz K Isolated cerebral manifestation of Epstein-Barr virus-associated post-transplant lymphoproliferative disorder after allogeneic hematopoietic stem cell transplantation: a case of clinical and diagnostic challenges Transpl Infect Dis Off J Transplant Soc 2011 13 5 524 530 10.1111/j.1399-3062.2011.00621.x\n13. Montone KT Hodinka RL Salhany KE Lavi E Rostami A Tomaszewski JE Identification of Epstein-Barr virus lytic activity in post-transplantation lymphoproliferative disease Mod Pathol Off J US Can Acad Pathol Inc 1996 9 6 621 630\n14. Pruitt A Central nervous system infections complicating immunosuppression and transplantation Contin Lifelong Learn Neurol 2018 24 1370 1396 10.1212/CON.0000000000000653\n15. Bahadori HR Williams VC Turner RP Acute disseminated encephalomyelitis following infectious mononucleosis J Child Neurol 2007 22 3 324 328 10.1177/0883073807300534 17621505\n16. Mohsen H Abu Zeinah GF Elsotouhy AH Mohamed K Acute disseminated encephalomyelitis following infectious mononucleosis in a toddler BMJ Case Rep 2013 10.1136/bcr-2013-010048 24038324\n17. Weinberg A Bloch KC Li S Tang Y-W Palmer M Tyler KL Dual Infections of the central nervous system with Epstein-Barr virus J Infect Dis 2005 191 2 234 237 10.1086/426402 15609233\n18. Caldas C Bernicker E Nogare AD Luby JP Case report: transverse myelitis associated with Epstein-Barr virus infection Am J Med Sci 1994 307 1 45 48 10.1097/00000441-199401000-00009 8291507\n19. Khalil M Enzinger C Wallner-Blazek M Epstein-Barr virus encephalitis presenting with a tumor-like lesion in an immunosuppressed transplant recipient J Neurovirol 2008 14 6 574 578 10.1080/13550280802345715 18991070\n20. Abul-Kasim K Palm L Maly P Sundgren PC The neuroanatomic localization of Epstein-Barr virus encephalitis may be a predictive factor for its clinical outcome: a case report and review of 100 cases in 28 reports J Child Neurol 2009 24 6 720 726 10.1177/0883073808327842 19151367\n21. Schellinger PD Sommer C Leithäuser F Epstein-Barr virus meningoencephalitis with a lymphoma-like response in an immunocompetent host Ann Neurol 1999 45 5 659 662 10.1002/1531-8249(199905)45:5<659::aid-ana16>3.0.co;2-9 10319890\n22. Zarlasht F Salehi M Abu-Hishmeh M Khan M Encephalitis treatment - a case report with long-term follow-up of EBV PCR in cerebrospinal fluid Int J Gen Med 2017 10 371 373 10.2147/IJGM.S143335 29123419\n23. Lau JSY Low ZM Abbott I Epstein-Barr virus encephalitis in solid organ transplantation New Microbiol 2017 40 3 212 217 28513810\n24. Dyachenko P Smiianova O Kurhanskaya V Oleshko A Dyachenko A Epstein-barr virus-associated encephalitis in a case-series of more than 40 patients Wiadomosci Lek Wars Pol 1960 2018 71 6 1224 1230\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1743-422X",
"issue": "18(1)",
"journal": "Virology journal",
"keywords": "Central nervous system; Epstein-Barr virus; Post-transplant lymphoproliferative disorder",
"medline_ta": "Virol J",
"mesh_terms": null,
"nlm_unique_id": "101231645",
"other_id": null,
"pages": "162",
"pmc": null,
"pmid": "34362398",
"pubdate": "2021-08-06",
"publication_types": "D016428:Journal Article",
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"title": "The spectrum of Epstein-Barr virus infections of the central nervous system after organ transplantation.",
"title_normalized": "the spectrum of epstein barr virus infections of the central nervous system after organ transplantation"
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"abstract": "BACKGROUND\nGiven the tolerability of nPG in first-line therapy, we desired to evaluate the response and toxicity profiles of second-line gemcitabine with nab-paclitaxel (nPG) following FOLFIRINOX. Methods: We retrospectively identified 30 patients who received first-line FOLFIRINOX for unresectable or metastatic pancreatic adenocarcinoma followed by second-line nPG. Response was evaluated by RECIST criteria and carbohydrate antigen 19-9 (CA19-9) change.\n\n\nRESULTS\nMedian age was 63 years with 77% percent having metastatic disease. Nineteen patients (63%) achieved PR based on CA19-9. Median overall survival (OS) with nPG was 12.4 months (mo) and median progression-free survival (PFS) was 3.7 mo. Median PFS and OS for patients with at least stable CA19-9 were 4.7 and 13.9 mo since initiation of nPG. Patients with an increased CA19-9 level during nPG had a shorter median PFS (1.4 mo) and OS (5.3 mo). A significant PFS difference was demonstrated in patients with at least stable disease as the best RECIST response versus in those with progressive disease (5.4 vs. 1.9 mo, P<0.001). Grade 3/4 adverse events include thrombocytopenia (33%), anemia (23%), nausea (17%), lymphopenia (7%), infectious complications (6%), diarrhea (3%), and neuropathy (3%).\n\n\nCONCLUSIONS\nThis study demonstrates a clinical benefit of second-line nPG. The study also suggests a possible use of CA19-9 to predict response to therapy.",
"affiliations": "Department of Hematology and Oncology, University of Pittsburgh, Pennsylvania, USA.;Developmental Therapeutics Program of Department of Hematology and Oncology, Northwestern University, Illinois, USA.;Department of Radiology, University of Pittsburgh, Pennsylvania, USA.;Department of Pathology, University of Pittsburgh, Pennsylvania, USA.;Department of Hematology and Oncology, University of Pittsburgh, Pennsylvania, USA.;Division of Gastrointestinal Surgical Oncology, University of Pittsburgh, Pennsylvania, USA.;Department of Biostatistics, University of Pittsburgh, Pennsylvania, USA.;Department of Hematology and Oncology, University of Pittsburgh, Pennsylvania, USA.",
"authors": "Nguyen|Khanh T|KT|;Kalyan|Aparna|A|;Beasley|H Scott|HS|;Singhi|Aatur D|AD|;Sun|Weijing|W|;Zeh|Herbert J|HJ|;Normolle|Daniel|D|;Bahary|Nathan|N|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/jgo.2017.01.23",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2078-6891",
"issue": "8(3)",
"journal": "Journal of gastrointestinal oncology",
"keywords": "FOLFIRINOX; Pancreatic cancer; carbohydrate antigen 19-9 (CA19-9); gemcitabine; nab-paclitaxel",
"medline_ta": "J Gastrointest Oncol",
"mesh_terms": null,
"nlm_unique_id": "101557751",
"other_id": null,
"pages": "556-565",
"pmc": null,
"pmid": "28736642",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article",
"references": "15999098;16175188;16782929;16899980;17452677;20162463;20565421;21561347;21565490;22786786;22811878;23127528;23247983;23444312;24131140;24294507;24840647;24938522;25092157;25638248;26372701;26451276;26802160;28982109",
"title": "Gemcitabine/nab-paclitaxel as second-line therapy following FOLFIRINOX in metastatic/advanced pancreatic cancer-retrospective analysis of response.",
"title_normalized": "gemcitabine nab paclitaxel as second line therapy following folfirinox in metastatic advanced pancreatic cancer retrospective analysis of response"
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"abstract": "The use of sodium polystyrene sulfonate (SPS) for the treatment of hyperkalemia lacks sufficient efficacy data in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD); however, use remains widespread. Recent evidence suggests that this population may be at risk for serious gastrointestinal adverse effects with SPS. Methods. We conducted a single-center retrospective cohort study. Adult patients with CKD Stages 4, 5, or ESRD maintained on renal replacement therapy with serum potassium >5 mEq/L and receipt of SPS were screened for inclusion. Our primary outcome was decrease in potassium within 24 h post-30 g oral SPS suspended in 33% sorbitol. Secondary outcomes included decrease in potassium within 24 h from 15 or 30 g SPS doses and gastrointestinal adverse events.\nOf 596 records, 114 were included for analysis. At the first serum potassium level within 24 h post-30 g oral SPS the median potassium decrease was 0.8 mEq/L [interquartile range (IQR) 0.4-1.1; P < 0.001]. At the first potassium level within 24 h post-15 or 30 g SPS, the median potassium decrease was 0.7 mEq/L (IQR 0.4-1.0; P < 0.001]. Post-SPS potassium levels occurred 14-16 h post-SPS. Gastrointestinal side effects occurred within 30 days of SPS in 5% of patients, although only two cases were classified as possibly associated.\nThe use of single-dose SPS monotherapy resulted in a significant decrease in serum potassium levels within 24 h in patients with CKD Stage 4, 5, or ESRD. However, it remains unclear if SPS is associated with an increased risk of gastrointestinal injury in this population.",
"affiliations": "Department of Pharmacy, University of Kentucky HealthCare, Lexington, KY, USA.;Department of Pharmacy, Rush University Medical Center, Chicago, IL, USA.;Department of Pharmacy, Boston Medical Center, Boston, MA, USA.;Division of Nephrology, Rush University Medical Center, Chicago, IL, USA.;Department of Pharmacy, Rush University Medical Center, Chicago, IL, USA.",
"authors": "Hunt|Taylor V|TV|;DeMott|Joshua M|JM|;Ackerbauer|Kimberly A|KA|;Whittier|William L|WL|;Peksa|Gary D|GD|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ckj/sfy063",
"fulltext": "\n==== Front\nClin Kidney JClin Kidney JckjClinical Kidney Journal2048-85052048-8513Oxford University Press 10.1093/ckj/sfy063sfy063CKDSingle-dose sodium polystyrene sulfonate for hyperkalemia in chronic kidney disease or end-stage renal disease Hunt Taylor V 1DeMott Joshua M 2Ackerbauer Kimberly A 3Whittier William L 4Peksa Gary D 251 Department of Pharmacy, University of Kentucky HealthCare, Lexington, KY, USA2 Department of Pharmacy, Rush University Medical Center, Chicago, IL, USA3 Department of Pharmacy, Boston Medical Center, Boston, MA, USA4 Division of Nephrology, Rush University Medical Center, Chicago, IL, USA5 Department of Emergency Medicine, Rush University Medical Center, Chicago, IL, USACorrespondence and offprint requests to: Gary D. Peksa; E-mail: Gary_d_peksa@rush.edu6 2019 19 7 2018 19 7 2018 12 3 408 413 07 3 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA.2018This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nBackground\nThe use of sodium polystyrene sulfonate (SPS) for the treatment of hyperkalemia lacks sufficient efficacy data in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD); however, use remains widespread. Recent evidence suggests that this population may be at risk for serious gastrointestinal adverse effects with SPS.\n\n\nMethods. We conducted a single-center retrospective cohort study. Adult patients with CKD Stages 4, 5, or ESRD maintained on renal replacement therapy with serum potassium >5 mEq/L and receipt of SPS were screened for inclusion. Our primary outcome was decrease in potassium within 24 h post-30 g oral SPS suspended in 33% sorbitol. Secondary outcomes included decrease in potassium within 24 h from 15 or 30 g SPS doses and gastrointestinal adverse events.\n\nResults\nOf 596 records, 114 were included for analysis. At the first serum potassium level within 24 h post-30 g oral SPS the median potassium decrease was 0.8 mEq/L [interquartile range (IQR) 0.4–1.1; P < 0.001]. At the first potassium level within 24 h post-15 or 30 g SPS, the median potassium decrease was 0.7 mEq/L (IQR 0.4–1.0; P < 0.001]. Post-SPS potassium levels occurred 14–16 h post-SPS. Gastrointestinal side effects occurred within 30 days of SPS in 5% of patients, although only two cases were classified as possibly associated.\n\nConclusions\nThe use of single-dose SPS monotherapy resulted in a significant decrease in serum potassium levels within 24 h in patients with CKD Stage 4, 5, or ESRD. However, it remains unclear if SPS is associated with an increased risk of gastrointestinal injury in this population.\n\nchronic kidney diseaseend-stage renal diseasehyperkalemiasodium polystyrene sulfonate\n==== Body\nINTRODUCTION\nChronic kidney disease (CKD) is a condition that affects more than 20 million people in the USA. In Europe, prevalence varies between 3.3% to 17.3% and in China 6.7% to 18.3% [1, 2]. As kidney function deteriorates, the body’s ability to excrete potassium begins to decline, placing those with CKD or end-stage renal disease (ESRD) at a higher risk of hyperkalemia [1, 3, 4]. Current guidelines recommend medical management directed at cardiac stabilization, intracellular shift of serum potassium and potassium removal [4]. Although not a first-line agent for treatment of hyperkalemia, multiple guidelines endorse the use of sodium polystyrene sulfonate (SPS) [5–7].\n\nSPS is a cation exchange resin approved by the Food and Drug Administration (FDA) in the late 1950s for the treatment of hyperkalemia. This therapy functions through an exchange process where cross-linked reactive sulfonate groups exchange bound sodium for potassium in the large bowel as the resin passes through the gastrointestinal tract [8, 9]. In 2009, the FDA issued a warning recommending against the use of SPS and concomitant sorbitol due to case reports of adverse events associated with the combination [10–12]. In a later statement, the FDA further advised against the use of SPS in patients with abnormal bowel function, patients at risk for developing constipation or impaction, and patients who develop constipation after SPS use [13]. It has been suggested that patients with CKD or ESRD may be at higher risk for intestinal injury [10, 12, 14].\n\nSince SPS’s development, many of the studies evaluating the efficacy of SPS therapy have not included patients with CKD and ESRD, did not account for confounding factors that affect potassium levels, or contained only a small number of patients [15–17]. Despite having risks and minimal data on efficacy, SPS use remains widespread. Therefore, the aim of this study is to evaluate the effects of single-dose SPS monotherapy for the treatment of acute hyperkalemia in patients with CKD or ESRD.\n\nMATERIALS AND METHODS\nStudy design and setting\nThis study was a single-center, retrospective cohort of adult inpatients treated with SPS suspended in 33% sorbitol between 1 January 2010 and 30 September 2016. The study institution was a 664-bed large academic medical center. The protocol was approved by the study site’s Institutional Review Board (16092610-IRB03).\n\nParticipants\nPatients were included if they received a single dose of oral SPS suspended in 33% sorbitol, were 18 years or older, and had CKD Stage 4 or 5 based upon Kidney Disease: Improving Global Outcomes (KDIGO) classification or ESRD maintained on renal replacement therapy (RRT) [3]. In addition, patients were required to have a baseline serum potassium level >5 mEq/L. Patients were excluded if they received any concomitant therapies for the treatment of hyperkalemia between their pre- and post-SPS serum potassium levels. These therapies included insulin, intravenous sodium bicarbonate, inhaled beta-agonists, diuretics, intravenous fluids >2 L and RRT. Patients were also excluded if laboratory values (potassium at evaluated time points or baseline serum creatinine) were missing, if prior to admission medication information was missing, they were pregnant or found to have acute kidney injury (AKI) based upon KDIGO classification [an increase in serum creatinine by ≥1.5 times baseline (50% increase within 7 days), an increase in serum creatinine by ≥0.3 mg/dL within 48 h, or urine volume <0.5 mL/kg/h for 6 h) at the time of treatment] [4].\n\nData sources/measurement\nElectronic medical records were utilized to abstract clinical data. A patient list was generated based on patients that were prescribed oral SPS suspended in 33% sorbitol while admitted to the study institution. Variables extracted were baseline demographic data (age, gender and race), serum creatinine, location/unit in hospital where the patient received treatment with oral SPS therapy, dose of oral SPS administered, pre- and post-SPS potassium values, prior to admission and concomitant medications known to cause hyperkalemia (angiotensin-converting inhibitors, angiotensin receptor blockers, potassium sparing diuretics, sulfamethoxazole-trimethoprim, potassium supplements, cyclosporine and tacrolimus), time to post-SPS potassium values, gastrointestinal adverse events and inpatient mortality. Renal function was calculated utilizing the Modification of Diet in Renal Disease Study (MDRD) equation [18]. Gastrointestinal adverse events were extracted from provider documented notes. If an electrocardiogram (ECG) was available on the day of SPS therapy, the presence of ECG changes consistent with hyperkalemia was documented. Charlson Comorbidity Indices were calculated and reported [19]. Pre-SPS dose serum potassium levels were obtained within a 12-h period prior to SPS administration. For those with multiple serum potassium levels prior to SPS administration, the level closest to SPS administration was used. Post-SPS dose serum potassium levels were reviewed 12–24 h after the administration of SPS. For those with multiple serum potassium levels within the acceptable time frame, the level closest to 12 h post-SPS was used. For patients who received multiple doses of SPS during the same admission, only their first dose of SPS was included within the analysis.\n\nStudy endpoints\nThe primary endpoint of the study was decrease in serum potassium after a 30 g oral SPS dose, measured as the difference between potassium before SPS administration and the first recheck following SPS administration. Secondary endpoints included the decrease in serum potassium after 15 or 30 g oral SPS doses, incidence of normokalemia within 24 h (defined as serum potassium between 3.5 and 5 mEq/L), incidence of hypokalemia within 24 h (defined as serum potassium <3.5 mEq/L), gastrointestinal adverse events associated with SPS therapy within 30 days (defined as gastrointestinal ulceration, gastrointestinal stenosis, rectal hemorrhage, intestinal necrosis, intestinal colitis or perforation) and mortality prior to hospital discharge. Adverse effects were assessed using the World Health Organization - Uppsala Monitoring Centre (WHO-UMC) causality assessment system [20].\n\nStatistical methods\nAnalyses were performed using Statistical Package for the Social Sciences (SPSS, Inc., Armonk, NY), version 23.0. Using a t-test to detect a difference between two dependent means for the primary endpoint of potassium levels at different time points with an estimated mean difference of 0.15 and a medium effect size of 0.3, a 90% power with an alpha level of 0.05 would require a sample size of 119 patients. After assessing for normality, the primary endpoint and all secondary endpoints evaluating median difference in serum potassium were analyzed using a Wilcoxon signed-rank test. Secondary incident endpoints were analyzed using descriptive statistics. A P < 0.05 was considered statistically significant.\n\nRESULTS\nParticipants\nA total of 596 patients were reviewed for inclusion into the study. After screening for eligibility (Figure 1), 61 patients received 30 g oral SPS and 53 patients received 15 g oral SPS. No other SPS doses were utilized during the pre-specified time frame that met inclusion requirements. The majority of patients were African American (62%), female (52%) and classified as having ESRD requiring RRT (56%) (Table 1). Eighty-six (75%) patients were admitted through the emergency department with 61 (54%) of these patients going on to receive treatment on a medicine or surgical unit. Of the 48 patients with documented ECGs on the day of SPS therapy, 17 (15%) had ECG changes. Thirty-six (32%) patients were prescribed a medication prior to admission that can cause hyperkalemia, 30 (83%) of which were angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Fifteen patients (13%) continued medications that can cause hyperkalemia between the pre- and post-SPS potassium.\n\nFIGURE 1 Patient screening. eGFR, estimated glomerular filtration rate; K+, potassium.\n\nTable 1 Baseline characteristics\n\nCharacteristic\tPatients (n = 114)\t\nAge (years)\t66 (56–77)\t\nFemale\t59 (52)\t\nRace or ethnic group\t\n Caucasian\t16 (14)\t\n African American\t71 (62)\t\n Asian American\t2 (1.8)\t\n Hispanic/Latino\t25 (22)\t\nCKD staging\t\n Stage 4 (eGFR 15–29 mL/min)\t34 (30)\t\n Stage 5 (eGFR <15 mL/min)\t16 (14)\t\n ESRD on RRT\t64 (56)\t\nCharlson Comorbidity Index\t7 (5–8)\t\nECG changesa\t17 (15)\t\nLocation/unit in hospital\t\n Medicine/surgery\t61 (54)\t\n ICU\t17 (15)\t\n Emergency department\t27 (24)\t\n Hematology/oncology\t3 (2.6)\t\n Rehabilitation\t5 (4.4)\t\n Psychiatry\t1 (0.9)\t\nMedications prior to admission\t\n Medications causing hyperkalemiab\t36 (32)\t\n Angiotensin-converting enzyme inhibitors\t17 (15)\t\n Angiotensin receptor blockers\t13 (11)\t\n Otherc\t13 (11)\t\nMedications given between pre- and post-potassium\t\n Medications causing hyperkalemia\t15 (13)\t\n Angiotensin-converting enzyme inhibitors\t4 (4)\t\n Angiotensin receptor blockers\t6 (5)\t\n Tacrolimus\t5 (4)\t\neGFR, estimated glomerular filtration rate; ICU, intensive care unit.\n\nAll values reported as median (IQR) or n (%).\n\na Sixty-eight patients did not have an ECG done at the time of treatment.\n\nb Patients may have had multiple medications (percentages are not additive).\n\nc Other included sulfamethoxazole–trimethoprim (n = 1), cyclosporine or tacrolimus (n = 8), potassium supplement (n = 1) and potassium-sparing diuretics (n = 4).\n\nOutcomes\nPrimary endpoint\nThe median decrease in serum potassium after a 30 g oral SPS dose (n = 61) was 0.8 mEq/L [interquartile range (IQR 0.4–1.1 mEq/L; P < 0.001] (Table 2, Figure 2). Post-SPS serum potassium levels were reviewed 14 h (IQR 10–18 h) post-30 g oral SPS therapy.\n\nFIGURE 2 Efficacy. Serum potassium pre- and post-SPS therapy by dose. Data are presented as box-and-whisker plots, in which the horizontal lines within the rectangles indicate the 50th percentile. The top and bottom of the rectangles indicate the 75th and 25th percentiles, respectively. The lines above and below the rectangles indicate Q1 or Q3 + (1.5 × IQR), respectively.\n\nTable 2. Efficacy outcomes by SPS dose\n\n\tPre-SPS potassium (mEq/L)\tPost-SPS potassium (mEq/L)\tDifference (mEq/L)\tTime to post-SPS potassium (h)\tP\t\nCKD 4, 5, and ESRD 30 g oral SPS (n = 61)\t 5.7 (5.5–5.8)\t 4.9 (4.7–5.2)\t 0.8 (0.4–1.1)\t 14 (10–18)\t <0.001\t\n 15 g oral SPS (n = 53)\t5.6 (5.5–5.7)\t5.1 (4.8–5.4)\t0.5 (0.2–0.9)\t16 (12–19)\t<0.001\t\n 15 or 30 g oral SPS (n = 114)\t5.6 (5.5–5.8)\t5.0 (4.7–5.3)\t0.7 (0.4–1.0)\t15 (11–19)\t<0.001\t\nESRD only\t\n 15 or 30 g oral SPS (n = 64)\t5.7 (5.5–5.8)\t5.1 (4.8–5.4)\t0.5 (0.1–0.9)\t15 (10–18)\t<0.001\t\nAll values reported as median (IQR).\n\nSecondary endpoints\nThe median decrease in serum potassium after a 15 g oral SPS dose (n = 53) was 0.5 mEq/L (IQR 0.2—0.9 mEq/L; P < 0.001), and after a 15 or 30 g oral SPS dose (n = 114) was 0.7 mEq/L (IQR 0.4—1.0 mEq/L; P < 0.001). The decrease in potassium remained significant [0.5 mEq/L (IQR 0.1–0.9 mEq/L); P < 0.001] when examining only ESRD patients (n = 64). Normokalemia occurred post-SPS therapy in 64 (56%) patients. Hypokalemia was not seen in any patients after SPS. Serious gastrointestinal adverse events occurred within 30 days of SPS therapy in six patients (5%), five patients (4%) experienced gastrointestinal ulceration and one patient (0.9%) experienced rectal hemorrhaging (Table 3), however, only two patients had the WHO-UMC causality assessment of possibility related, with the other four being unlikely related to SPS. Inpatient mortality occurred in five patients (4%), although none of the cases was thought to be related to hyperkalemia or the adverse effects of SPS.\n\nTable 3. Adverse events\n\nPatient\tAdverse event summary\tWHO-UMC classification20\t\nPatient #1\tGI ulceration occurred beyond 30 days\tUnlikely\t\nPatient #2\tPresented with nausea, vomiting and abdominal pain prior to SPS therapy. Developed BRBPR 2 days after. EGD revealed large old ulcer and colonoscopy revealed ischemic colitis and possible mesenteric ischemia\tPossible\t\nPatient #3\tDeveloped perforated duodenal ulcer within 14 days of SPS. Other risk factors included recent admission for DAH, possible vasculitis and treatment with high-dose steroids\tPossible\t\nPatient #4\tPresented with dark stools and hematemesis within 14 days of SPS. EGD showed AVMs. Colonoscopy showed moderate to severe diverticulosis\tUnlikely\t\nPatient #5\tHad abdominal pain prior to SPS. EGD two days after SPS revealed gastric ulcer\tUnlikely\t\nPatient #6\tHad abdominal pain prior to SPS. Had BRBPR within 30 days. No colonoscopy performed\tUnlikely\t\nGI, gastrointestinal; EGD, esophagogastroduodenoscopy; BRBPR, bright red blood per rectum; AVM, arteriovenous malformation; DAH, diffuse alveolar hemorrhage.\n\nDISCUSSION\nThis was the largest study to date evaluating the efficacy and safety of single-dose SPS monotherapy for the treatment of hyperkalemia in patients with CKD Stages 4, 5 or ESRD on RRT. The results of this study demonstrated that SPS therapy was effective at lowering serum potassium levels in patients with severe renal insufficiency with a median reduction of 0.8 mEq/L when using a 30-g oral dose suspended in 33% sorbitol.\n\nMany of the prior studies evaluating the efficacy of SPS therapy excluded those with renal insufficiency and ESRD, or did not account for confounding factors (such as concomitant therapies) that affect potassium levels [7, 15, 16, 21, 22]. A study published by Mistry et al. in 2016 found a dose-dependent reduction in serum potassium following single-dose SPS monotherapy in hospitalized patients with renal insufficiency [15]. A mean difference of 0.69 mEq/L following 30 g oral SPS and 0.91 mEq/L following 60 g oral SPS (P < 0.05) was found 12 h post-SPS therapy. However, ESRD patients who required chronic hemodialysis (HD) were excluded from the study and the remainder of the patients included had a mean creatinine clearance (CrCl) classified as CKD Grade 3 or less [15]. Similarly, a large retrospective study by Hagan et al. evaluated single-dose SPS (average dose 32.4 g) and found a potassium decrease of 0.93 mEq/L. Although this study did include patients with CKD and ESRD, they also included patients with normal renal function and a high percentage of patients received other therapies for hyperkalemia known to cause a reduction in potassium such as insulin, albuterol, sodium bicarbonate and diuretics [16].\n\nOf prospective randomized controlled trials including patients with CKD, a prior study involving 33 outpatients with hyperkalemia found a mean serum potassium decrease of 1.25 ± 0.56 mEq/L (P < 0.001) compared with placebo in patients who were given oral SPS therapy for seven consecutive days [17]. Although this study was well designed and included patients with CKD (12.5% CKD Stage 3, 62.5% CKD Stage 4 and 25% CKD Stage 5), the results were after 7 days of SPS and patients on RRT were excluded. Our study evaluated only patients with CKD Stage 4, 5, or ESRD on RRT and limited confounders by excluding patients that had received other therapies for hyperkalemia, making our observed potassium lowering effect more specific to therapy with only single-dose SPS.\n\nDespite minimizing confounders in our study, there is evidence that colonic potassium secretion is already increased in patients with CKD and ESRD without the use of medications [23, 24]. Although this process is currently poorly understood, it could account for some of the decreases in serum potassium when resins or resins plus cathartics are utilized. Studies have evaluated the effectiveness of laxatives for decreasing serum potassium levels in patients with ESRD in an attempt to prove this hypothesis, but there have been mixed results depending on the laxative used [25, 26]. Our preparation of SPS included a cathartic (sorbitol) and this should be taken into account when evaluating the results of our study.\n\nThe results in our study were not without safety concerns. Out of the 114 patients evaluated, six patients (5%) experienced a severe gastrointestinal adverse event within 30 days of SPS therapy. However, only two cases were classified as possibly associated with SPS use and in these two cases, the events could have also been reasonably explained by other causes. Historically, the incidence of SPS-mediated gastrointestinal injury is estimated to be between 0.14% and 1.8%; however, a systematic review by Harel et al. identified 58 cases of SPS bowel-related gastrointestinal adverse events and 91% of the cases included in the review had a history of AKI, CKD or ESRD, concluding that patients with renal insufficiency may be at higher risk than previously described [10, 27, 28]. Despite these cases, many countries still continue to use potassium resins like SPS in a significant percentage of ESRD patients (e.g. up to 42% of ESRD patients in France) with no clear association on mortality or gastrointestinal injury [29].\n\nThis study also had limitations. Patients within this study, on average, had mild hyperkalemia with a median pre-SPS serum potassium level of 5.7 mEq/L. With the exclusion of any concomitant hyperkalemia treatments, many patients with more severe hyperkalemia were inherently excluded. Although this leads to less generalizability for application to more severe hyperkalemia cases, this study was the largest to date that did not include any hyperkalemia therapies other than single-dose SPS. Furthermore, a large number of patients who were screened for eligibility were excluded due to receiving SPS therapy and being started on RRT prior to any post-SPS potassium values. This also may have led to a bias towards less severe cases of hyperkalemia, but will be useful in the future for evaluating the need for SPS therapy in patients at our institution who are already scheduled to receive RRT.\n\nAdditional limitations included the single-center retrospective study design and absence of a placebo control group. By lacking a placebo for comparator, the decrease in potassium cannot be solely attributed to SPS and despite excluding patients who received medications that may decrease serum potassium, a portion of the observed decrease may be attributable to natural patient elimination. In addition, not all factors known to affect potassium balance could be reliably collected and factors such as diet, receipt of dextrose-containing fluids and blood glucose levels could have affected the results. There were also 36 patients that were prescribed medications known to cause hyperkalemia prior to admission and 21 of these patients did not receive these medications during the study time points, and holding these medications during the time between pre- and post-SPS potassium may have confounded the results in a percentage (∼18%) of the patients. However, ESRD patients with reduced intrinsic potassium elimination also experienced a significant decrease in potassium after SPS monotherapy, supporting the hypothesis that the decrease in potassium is at least partially related to SPS. In addition, given the emergent need for treatment in patients with hyperkalemia, most medical centers would be unlikely to withhold treatment by giving placebo and our results represent usual treatment. Next, adverse events that occurred could only be reported if patients presented to our health care system for follow-up care, potentially leading to underreported safety data. Finally, there are no known racial disparities in SPS effectiveness; however, this study included a large proportion of African American patients (62%) and may not be generalizable to other populations.\n\nIn conclusion, the use of single-dose SPS monotherapy resulted in a significant decrease in serum potassium levels within 24 h in patients with CKD Stages 4, 5, or ESRD, irrespective of dose. However, it remains unclear if SPS is associated with an increased risk of gastrointestinal injury in this population.\n\nCONFLICT OF INTEREST STATEMENT\nThe authors received no financial support for the research, authorship, and/or publication of this article and have no actual or potential conflicts of interest to declare.\n==== Refs\nREFERENCES\n1 Centers for Disease Control and Prevention. Chronic kidney disease surveillance system – United States. https://nccd.cdc.gov/ckd/ (4 April 2018, date last accessed)\n2 \nBruck K , Stel VS , Gambaro G \net al\nCKD prevalence varies across the European general population . J Am Soc Nephrol 2016 ; 27 : 2135 –2147 26701975 \n3 \nKDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease . Kidney Int Suppl 2013 ; 3 : 91 –111 \n4 \nKDIGO clinical practice guideline for acute kidney injury . Kidney Int Suppl 2012 ; 2 : 6 \n5 \nAlfonzo A , Soar J , MacTier R. Clinical practice guidelines: treatment of acute hyperkalaemia in adults. UK Renal Association, 2014 \nhttps://renal.org/wp-content/uploads/2017/06/hyperkalaemia-guideline-1.pdf (10 August 2016, date last accessed)\n6 \nHollander-Rodriguez JC , Calvert JF Jr. \nHyperkalemia . Am Fam Physician 2006 ; 73 : 283 –290 16445274 \n7 \nFordjour KN , Walton T , Doran JJ. \nManagement of hyperkalemia in hospitalized patients . Am J Med Sci 2014 ; 347 : 93 –100 23255245 \n8 \nAhee P , Crowe AV. \nThe management of hyperkalaemia in the emergency department . J Accid Emerg Med 2000 ; 17 : 188 –191 10819381 \n9 Kayexalate [package insert]. Laval, Quebec: Sanofi-Aventis. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/011287s022lbl.pdf (10 August 2016 , date last accessed)\n10 \nHarel Z , Harel S , Shah PS \net al\nGastrointestinal adverse events with sodium polystyrene sulfonate (Kayexalate) use: a systematic review . Am J Med 2013 ; 126 : 264.e9 –e24 \n11 \nJacob SS , Parameswaran A , Parameswaran SA \net al\nColitis induced by sodium polystyrene sulfonate in sorbitol: a report of six cases . Indian J Gastroenterol 2016 ; 35 : 139 –142 27033844 \n12 \nMcGowan CE , Saha S , Chu G \net al\nIntestinal necrosis due to sodium polystyrene sulfonate (kayexalate) in sorbitol . South Med J 2009 ; 102 : 493 –497 19373153 \n13 US Food and Drug Administration. Safety: Kayexalate (sodium polystyrene sulfonate) powder. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm186845.htm9/12/2016 (12 August 2016, date last accessed)\n14 \nChelcun JL , Sable RA , Friedman K. \nColonic ulceration in a patient with renal disease and hyperkalemia . JAAPA 2012 ; 25 : 34 , 37–38\n15 \nMistry M , Shea A , Giguere P \net al\nEvaluation of sodium polystyrene sulfonate dosing strategies in the inpatient management of hyperkalemia . Ann Pharmacother 2016 ; 50 : 455 –462 27048188 \n16 \nHagan AE , Farrington CA , Wall GC \net al\nSodium polystyrene sulfonate for the treatment of acute hyperkalemia: a retrospective study . Clin Nephrol 2016 ; 85 : 38 –43 26587776 \n17 \nLepage L , Dufour A-C , Doiron J \net al\nRandomized clinical trial of sodium polystyrene sulfonate for the treatment of mild hyperkalemia in CKD . Clin J Am Soc Nephrol 2015 ; 10 : 2136 –2142 26576619 \n18 \nLevey AS , Bosch JP , Lewis JB \net al\nA more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group . Ann Intern Med 1999 ; 130 : 461 –470 10075613 \n19 \nCharlson ME , Pompei P , Ales KL \net al\nA new method of classifying prognostic comorbidity in longitudinal studies: development and validation . J Chronic Dis 1987 ; 40 : 373 –383 3558716 \n20 The use of the WHO–UMC system for standardised case causality assessment. http://www.who.int/medicines/areas/quality_safety/safety_efficacy/WHOcausality_assessment.pdf (24 April 2018, date last accessed)\n21 \nJoshi P , Beaulieu J , Shemin D. \nThe effect of a single dose of sodium polystyrene sulfonate (SPS) and sorbitol in hyperkalemic patients with kidney disease . J Am Soc Nephrol 2008 ; 19 : 355A \n22 \nKessler C , Ng J , Valdez K \net al\nThe use of sodium polysterene sulfonate in the inpatient management of hyperkalemia . J Hosp Med 2011 ; 6 : 136 –140 21387549 \n23 \nMathialahan T , Maclennan KA , Sandle LN \net al\nEnhanced large intestinal potassium permeability in end-stage renal disease . J Pathol 2005 ; 206 : 46 –51 15772943 \n24 \nSorensen MV , Matos JE , Praetorius HA \net al\nColonic potassium handling . Pflugers Arch 2010 ; 459 : 645 –656 20143237 \n25 \nMathialahan T , Sandle G. \nDietary potassium and laxatives and regulators of colonic potassium secretion in end-stage renal disease . Nephrol Dial Transplant 2003 ; 18 : 341 –347 12543890 \n26 \nEmmett M , Hootkins R , Fine K \net al\nEffects of three laxatives and a cation exchange resin on fecal sodium and potassium excretion . Gastroenterology 1995 ; 108 : 752 –760 7875477 \n27 \nGerstman BB , Kirkman R , Platt R. \nIntestinal necrosis associated with postoperative orally administered sodium polystyrene sulfonate in sorbitol . Am J Kidney Dis 1992 ; 20 : 159 –161 1496969 \n28 \nWatson MA , Baker TP , Nguyen A \net al\nAssociation of prescription of oral sodium polystyrene sulfonate with sorbitol in an inpatient setting with colonic necrosis: a retrospective cohort study . Am J Kidney Dis 2012 ; 60 : 409 –416 22683337 \n29 \nJadoul M , Karaboyas A , Goodkin DA \net al\nPotassium-binding resins: associations with serum chemistries and interdialytic weight gain in hemodialysis patients . Am J Nephrol 2014 ; 39 : 252 –259 24642479\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2048-8505",
"issue": "12(3)",
"journal": "Clinical kidney journal",
"keywords": "chronic kidney disease; end-stage renal disease; hyperkalemia; sodium polystyrene sulfonate",
"medline_ta": "Clin Kidney J",
"mesh_terms": null,
"nlm_unique_id": "101579321",
"other_id": null,
"pages": "408-413",
"pmc": null,
"pmid": "31198541",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article",
"references": "10075613;10819381;12543890;1496969;15772943;16445274;19373153;20143237;21387549;22683337;23115868;23255245;23321430;24642479;26576619;26587776;26701975;27033844;27048188;3558716;7875477",
"title": "Single-dose sodium polystyrene sulfonate for hyperkalemia in chronic kidney disease or end-stage renal disease.",
"title_normalized": "single dose sodium polystyrene sulfonate for hyperkalemia in chronic kidney disease or end stage renal disease"
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"abstract": "Low-dose methotrexate is a well-tolerated and inexpensive systemic immunosuppressive agent used commonly in dermatology. However, several adverse events such as pancytopenia, pneumonitis, mucositis, and cutaneous ulcerations may develop during acute toxicity with dose-dependent or idiosyncratic mechanisms. Risk factors for methotrexate toxicity include advanced age, hypoalbuminemia, renal dysfunction, and concomitant drugs increasing the level of methotrexate in the body. We present a case of methotrexate toxicity presenting with classical features along with mucocutaneous side-effects, such as ulceration of psoriatic plaques and acral erythema, following a single dose of methotrexate.",
"affiliations": "Department of Dermatology, Dr Ram Manohar Lohia Hospital, New Delhi, India.;Department of Dermatology, Dr Ram Manohar Lohia Hospital, New Delhi, India.;Department of Pathology, Dr Ram Manohar Lohia Hospital, New Delhi, India.;Department of Dermatology, Dr Ram Manohar Lohia Hospital, New Delhi, India.",
"authors": "Gupta|Aastha|A|;Sardana|Kabir|K|;Bhardwaj|Minakshi|M|;Singh|Ajeet|A|",
"chemical_list": null,
"country": "India",
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"doi": "10.4103/idoj.IDOJ_316_17",
"fulltext": "\n==== Front\nIndian Dermatol Online JIndian Dermatol Online JIDOJIndian Dermatology Online Journal2229-51782249-5673Medknow Publications & Media Pvt Ltd India IDOJ-9-32810.4103/idoj.IDOJ_316_17Case ReportMethotrexate Cutaneous Toxicity following a Single Dose of 10 mg in a Case of Chronic Plaque Psoriasis: A Possible Idiosyncratic Reaction Gupta Aastha Sardana Kabir Bhardwaj Minakshi 1Singh Ajeet Department of Dermatology, Dr Ram Manohar Lohia Hospital, New Delhi, India1 Department of Pathology, Dr Ram Manohar Lohia Hospital, New Delhi, IndiaAddress for correspondence: Dr. Aastha Gupta, Department of Dermatology, Dr Ram Manohar Lohia Hospital, New Delhi - 110001, India. E-mail: aasthagupta11@gmail.comSep-Oct 2018 9 5 328 330 11 2017 2 2018 Copyright: © 2018 Indian Dermatology Online Journal2018This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Low-dose methotrexate is a well-tolerated and inexpensive systemic immunosuppressive agent used commonly in dermatology. However, several adverse events such as pancytopenia, pneumonitis, mucositis, and cutaneous ulcerations may develop during acute toxicity with dose-dependent or idiosyncratic mechanisms. Risk factors for methotrexate toxicity include advanced age, hypoalbuminemia, renal dysfunction, and concomitant drugs increasing the level of methotrexate in the body. We present a case of methotrexate toxicity presenting with classical features along with mucocutaneous side-effects, such as ulceration of psoriatic plaques and acral erythema, following a single dose of methotrexate.\n\nKeywords:\nCutaneous ulcerationlow-dose methotrexatemethotrexate toxicity\n==== Body\nIntroduction\nMethotrexate remains one of the most commonly prescribed systemic immunosuppressive agents in dermatology owing to its efficacy and low cost. Although uncommon and rarely reported, mucocutaneous side-effects such as ulceration of psoriatic plaques and mucositis can be seen with low-dose methotrexate therapy.[1] These toxic events are usually dose-dependent but may be idiosyncratic in nature. Here, we present a case of with cutaneous ulcerations, acral erythema, and severe pancytopenia following the administration of a single dose of methotrexate.\n\nCase Report\nA 60-year-old male, a known case of chronic plaque psoriasis for 10 years, presented with exacerbation of the disease (impending erythroderma) and pain in sacroiliac joints, left knee joint, both ankle joints, and small joints of hand for 15 days. The patient had hypertension which was controlled on tab. amlodipine 5 mg OD. The patient had received topical steroids and calcipotriol and systemic PUVA therapy 3 years back for his skin disease. On clinical examination, he had well-defined erythematous indurated plaques covered with silvery white scales involving the scalp and body, sparing the palms and soles, with a Psoriasis Area and Severity Index (PASI) of 25.5. The patient was febrile and had cough and difficulty in swallowing, and was diagnosed with as pharyngitis, and initiated on tab. amoxycillin-clavulanic acid 625 mg TDS, tab. paracetamol 500 mg SOS, and tab. ibuprofen 400 mg BD. The complete blood count prior to methotrexate administration was within normal limits with Hb – 10.2 g/dl, red blood cell count – 3.4 million/mm3, WBC count – 10,800/mm3, and platelet count – 4.4 lakh/mm3. Serum biochemistry including serum albumin, kidney, and liver function tests were within normal limits. Urine analysis, chest X-ray, and electrocardiogram (ECG) were normal. After taking a medicine consultation, the patient was initiated on methotrexate 10 mg orally once every week. Three days later, the patient started complaining of nausea, vomiting, abdominal pain, and loss of appetite. Clinical examination revealed ulcerated painful psoriatic plaques present over the neck, chest, abdomen, and back [Figure 1] along with a burning sensation and painful erythematous macules and desquamation of skin present symmetrically on the palm and soles [Figure 2]. Oral mucosa examination showed stomatitis. Laboratory studies showed Hb – 7.8 g/dl, red blood cell count – 2.8 million/mm3, WBC count – 4800/mm3, platelet count – 80,000/mm3. Biochemistry screen showed elevated liver enzymes with SGOT – 168 IU/L, SGPT – 89 IU/L, and alkaline phosphatase – 471 IU/L. Other investigations were normal. Skin biopsy done from the ulcerated plaque is depicted in Figure 3. Using Naranjo Adverse Drug Reaction Probability Scale and WHO-UMC causality criteria, a probable relationship was found between these cutaneous adverse effects and methotrexate therapy in this patient.[23] Based on the clinical and laboratory findings, a diagnosis of methotrexate toxicity was made. Methotrexate therapy was withheld and the patient was initiated on leucovorin rescue (Inj. leucovorin calcium 15 mg 6 hourly for 3 days) and Inj. pantoprazole 40 mg i.v. BD. Skin care consisted of cleaning the lesions with povidone-iodine followed by application of bland emollients and 2% mupirocin cream. Patient's general condition improved and lesions began to heal in 7 days.\n\nFigure 1 Ulceration of the psoriatic plaques present over the neck\n\nFigure 2 Painful erythematous macules with desquamation of the skin present on the palms and soles\n\nFigure 3 Skin biopsy from ulcerated plaque showing ulcerated epidermis and parakeratotic keratin along with necrotic debris and fibrinosuppurative exudate and perivascular inflammatory infiltrate in dermis. (H and E, ×100)\n\nDiscussion\nLow-dose methotrexate (7.5 mg to 25 mg/week) used in dermatology is usually well tolerated with mild adverse effects appearing within 48 hours after a weekly dose. However, several idiosyncratic or dose-dependent toxicities have been noted including pancytopenia, hepatotoxicity, severe mucositis, central nervous system complications, and pneumonitis. Of these, bone marrow toxicity has been reported to develop even after a single low dose of methotrexate.[4]\n\nCutaneous manifestations of methotrexate toxicity include dose-related mucositis, photosensitivity, and idiosyncratic immune reactions such as erythema multiforme, Stevens–Johnson syndrome, and toxic epidermal necrolysis. Methotrexate-induced cutaneous ulceration occurs in two patterns: in type 1, there is superficial ulceration of the existing psoriatic plaques and in type 2, ulceration involves nonpsoriatic skin. It develops because of increased susceptibility of the rapidly multiplying keratinocytes within the psoriatic plaques to the effects of folate-antagonism. Interestingly, it has been seen more frequently in patients on low-dose treatment than in high-dose chemotherapy regimens.[5] Jariwala et al. reported that the skin ulceration with methotrexate therapy can develop either at initiation of therapy or as a presenting feature of methotrexate toxicity during longstanding treatment.[6] Acral erythema or palmar plantar erythrodysesthesia is a side effect of high-dose chemotherapy, presenting clinically as dysaesthesia and tingling over the palms and soles followed by the development of symmetrical, well-defined, painful erythema, which may progress to bullae formation and desquamation.[7] Although the pathogenesis remains unclear, the most widely accepted hypothesis is direct cytotoxicity by chemotherapeutic agents on epidermal cells. The acral involvement in our case was suggestive of this reaction, which has not been noted with low-dose methotrexate used for dermatological diseases in the past.[89]\n\nOur patient presented with signs of methotrexate toxicity (nausea, mucositis, cutaneous ulcerations, acral erythema, elevated liver enzymes, and pancytopenia) which developed after a single dose of methotrexate. Though acute toxicity with methotrexate has been reported previously with low-dose therapy, to our knowledge, mucocutaneous signs of methotrexate toxicity such as ulceration of psoriatic plaques and acral erythema have not been reported previously with a single low dose (10 mg) of methotrexate. Several risk factors have been implicated for the development of these severe adverse drug reactions [Table 1] including incorrect dosing, which is, taking methotrexate daily instead of weekly. However, because the patient developed toxicity during inpatient hospital treatment, the drug intake was supervised, ruling out any overdosing. In our case, it was probably the concomitant administration of nonsteroidal anti-inflammatory drugs (NSAIDS) and penicillin antibiotics and old age that may have played a role.[1011]\n\nTable 1 Risk factors for the development of methotrexate toxicity\n\nBecause the patient had not received methotrexate in the past and developed acute toxicity with a single low dose of methotrexate, it was possibly due to an idiosyncratic mechanism, which is dependent on an individual's genotype and the consequent metabolism of the drug.[12] Our case highlights the mucocutaneous signs of methotrexate toxicity, with a single low dose of methotrexate, and reiterates that, in predisposed individuals, even the first dose may cause toxicity.\n\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nReferences\n1 Souza CFD Suarez OMZ Silva TFM Gorenstein AC Quintella LP Avelleira JC Ulcerations due to methotrexate toxicity in a psoriasis patient An Bras Dermatol 2016 91 375 7 27438211 \n2 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 \n3 The use of the WHO-UMC system for standardised case causality assessment Last accessed on 2018 Jan 29 Available from: http://www.WHO-UMC.org/graphics/4409.pdf \n4 Agarwal V Chauhan S Singh R Sachdev A D'Cruz S Tahlan A Pancytopenia with the first dose of methotrexate in a patient with psoriatic arthritis J Indian Rheumatol Assoc 2005 13 60 1 \n5 Weidmann A Foulkes AC Kirkham N Reynolds NJ Methotrexate toxicity during treatment of chronic plaque psoriasis: A case report and review of the literature Dermatol Ther 2014 4 145 56 \n6 Jariwala P Kumar V Kothari K Thakkar S Umrigar DD Acute methotrexate toxicity: A fatal condition in two cases of psoriasis Case Rep Dermatol Med 2014 2014 946716 25276442 \n7 Hueso L1 Sanmartín O Nagore E Botella-Estrada R Requena C Llombart B Chemotherapy-induced acral erythema: A clinical and histopathologic study of 44 cases Actas Dermosifiliogr 2008 99 281 90 18394404 \n8 Kuruvila S Dalal M Sivanesan B Bullous variant of acral erythema due to methotrexate Indian J Dermatol Venereol Leprol 2006 72 440 2 17179620 \n9 Werchniak AE Chaffee S Dinulos JG Methotrexate-induced bullous acral erythema in a child J Am Acad Dermatol 2005 52 S93 5 15858519 \n10 Yélamos O Català A Vilarrasa E Roé E Puig L Acute severe methotrexate toxicity in patients with psoriasis: A case series and discussion Dermatology 2014 229 306 9 25401478 \n11 Hsu MC Chen CC Low-dose methotrexate-induced ulcerated psoriatic plaques: A rare case JAAD Case Rep 2015 1 264 27051748 \n12 Carretero-Hernández G Methotrexate in Psoriasis: Do We Need to Give a Test Dose.? Actas Dermosifiliogr 2012 103 1 4\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2229-5178",
"issue": "9(5)",
"journal": "Indian dermatology online journal",
"keywords": "Cutaneous ulceration; low-dose methotrexate; methotrexate toxicity",
"medline_ta": "Indian Dermatol Online J",
"mesh_terms": null,
"nlm_unique_id": "101586880",
"other_id": null,
"pages": "328-330",
"pmc": null,
"pmid": "30258802",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "25276442;22093543;18394404;25401478;27438211;24942326;7249508;15858519;17179620;27051748",
"title": "Methotrexate Cutaneous Toxicity following a Single Dose of 10 mg in a Case of Chronic Plaque Psoriasis: A Possible Idiosyncratic Reaction.",
"title_normalized": "methotrexate cutaneous toxicity following a single dose of 10 mg in a case of chronic plaque psoriasis a possible idiosyncratic reaction"
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"companynumb": "IN-ACCORD-073252",
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"activesubstancename": "ACETAMINOPHEN"
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{
"abstract": "Uterine arteriovenous malformations (AVM) are rare and can be classified as either congenital or acquired. Acquired AVMs may result from trauma, uterine instrumentation, infection or gestational trophoblastic disease. The majority of acquired AVMs are encountered in women of reproductive age with a history of at least one pregnancy. Traditional therapies of AVMs include medical management of symptomatic bleeding, blood transfusions, uterine artery embolization (UAE) or hysterectomy. In this retrospective case series, we report our experience with AVM and UAE in five symptomatic women of reproductive age who wished to preserve fertility. Patients were 18-32 years old, and had 1-3 previous pregnancies prior to initial presentation. All patients were followed until their deliveries. All five patients delivered live births. Three of the five patients required two embolization procedures and one of these women required a subsequent hysterectomy. Two deliveries were at term and had normal weight babies and normal placenta. One woman had cerclage placed and developed chorioamnionitis at 34 weeks but had a normal placenta. Two pregnancies were induced <37 weeks for pre-eclampsia/b intrauterine growth restriction ± abnormal umbilical artery dopplers. The low birthweight were both <2000 g. Both placentas showed accelerated maturity and infarcts. All estimated blood losses were recorded as <500 cc. In conclusion, UAE may not be as effective at managing AVM as previously thought and should be questioned as an initial therapy in symptomatic women of reproductive age desiring fertility preservation.",
"affiliations": "The Fertility Clinic, London Health Sciences Center, Victoria Hospital, London, Ontario, Canada Department of Obstetrics and Gynecology, Western University, London, Ontario, Canada Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada angelos.vilos@lhsc.on.ca.;The Fertility Clinic, London Health Sciences Center, Victoria Hospital, London, Ontario, Canada Department of Obstetrics and Gynecology, Western University, London, Ontario, Canada Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.;The Fertility Clinic, London Health Sciences Center, Victoria Hospital, London, Ontario, Canada Department of Obstetrics and Gynecology, Western University, London, Ontario, Canada Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.;The Fertility Clinic, London Health Sciences Center, Victoria Hospital, London, Ontario, Canada Department of Obstetrics and Gynecology, Western University, London, Ontario, Canada Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.;Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada St. Joseph's Health Care, London, Ontario, Canada Department of Radiology, Western University, London, Ontario, Canada.;Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada St. Joseph's Health Care, London, Ontario, Canada Department of Radiology, Western University, London, Ontario, Canada.",
"authors": "Vilos|Angelos G|AG|;Vilos|George A|GA|;Hollett-Caines|Jackie|J|;Rajakumar|Chandrew|C|;Garvin|Greg|G|;Kozak|Roman|R|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/humrep/dev097",
"fulltext": null,
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"issn_linking": "0268-1161",
"issue": "30(7)",
"journal": "Human reproduction (Oxford, England)",
"keywords": "arteriovenous malformation; menorrhagia; pregnancy outcomes; uterine artery embolization",
"medline_ta": "Hum Reprod",
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"title": "Uterine artery embolization for uterine arteriovenous malformation in five women desiring fertility: pregnancy outcomes.",
"title_normalized": "uterine artery embolization for uterine arteriovenous malformation in five women desiring fertility pregnancy outcomes"
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"abstract": "Delamanid, recently available for the treatment of multidrug-resistant tuberculosis (MDR TB), has had limited use outside clinical trials. We present the early treatment results for 53 patients from 7 countries who received a delamanid-containing treatment for MDR TB. Results show good tolerability and treatment response at 6 months.",
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"authors": "Hewison|Cathy|C|;Ferlazzo|Gabriella|G|;Avaliani|Zaza|Z|;Hayrapetyan|Armen|A|;Jonckheere|Sylvie|S|;Khaidarkhanova|Zarema|Z|;Mohr|Erika|E|;Sinha|Animesh|A|;Skrahina|Alena|A|;Vambe|Debrah|D|;Vasilyeva|Irina|I|;Lachenal|Nathalie|N|;Varaine|Francis|F|",
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"fulltext": "\n==== Front\nEmerg Infect Dis\nEmerging Infect. Dis\nEID\nEmerging Infectious Diseases\n1080-6040\n1080-6059\nCenters for Disease Control and Prevention\n\n17-0468\n10.3201/eid2310.170468\nResearch Letter\nResearch Letter\nSix-Month Response to Delamanid Treatment in MDR TB Patients\nSix-Month Response to Delamanid Treatment in MDR TB Patients\nSix-Month Response to Delamanid Treatment in MDR TB Patients\nHewison Cathy\nFerlazzo Gabriella\nAvaliani Zaza\nHayrapetyan Armen\nJonckheere Sylvie\nKhaidarkhanova Zarema\nMohr Erika\nSinha Animesh\nSkrahina Alena\nVambe Debrah\nVasilyeva Irina\nLachenal Nathalie\nVaraine Francis\nMédecins Sans Frontières, Paris, France (C. Hewison, F. Varaine);\nMédecins Sans Frontières, Cape Town, South Africa (G. Ferlazzo, E. Mohr);\nNational Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia (Z. Avaliani);\nNational Tuberculosis Control Centre Ministry of Health, Yerevan, Armenia (A. Hayrapetyan);\nMédecins Sans Frontières, Johannesburg, South Africa (S. Jonckheere);\nRepublican Tuberculosis Dispensary, Grozny, Chechnya, Russian Federation (Z. Khaidarkhanova);\nMédecins Sans Frontières, Minsk, Belarus (A. Sinha);\nRepublican Research and Practical Centre for Pulmonology and Tuberculosis, Minsk (A. Skrahina);\nSwaziland National Tuberculosis Control Program, Mbabane, Swaziland (D. Vambe);\nResearch Institute of Phthisiopulmonology of I.M. Sechenov First MSMU, Moscow, Russian Federation (I. Vasilyeva);\nMédecins Sans Frontières, Geneva, Switzerland (N. Lachenal)\nAddress for correspondence: Cathy Hewison, Medical Department, Médecins Sans Frontières, Paris, France, 8 rue Saint Sabin, Paris, 75011, France; email: cathy.hewison@paris.msf.org\n10 2017\n23 10 17461748\nDelamanid, recently available for the treatment of multidrug-resistant tuberculosis (MDR TB), has had limited use outside clinical trials. We present the early treatment results for 53 patients from 7 countries who received a delamanid-containing treatment for MDR TB. Results show good tolerability and treatment response at 6 months.\n\nKeywords:\n\nTuberculosis\nmultidrug resistance\ndelamanid\ndrug therapy\ncombination\nantitubercular agents\nbacteria\nantimicrobial resistance\nMDR TB\nArmenia\nBelarus\nGeorgia\nIndia\nRussia\nSouth Africa\nSwaziland\n==== Body\nOutcomes of conventional 18–24-month regimens for multidrug-resistant tuberculosis (MDR TB) (1,2) and extensively drug-resistant tuberculosis (XDR TB) (3,4) are notoriously poor. Two recently marketed drugs, delamanid (5–7) and bedaquiline (8), represent hope for better outcomes. Médecins Sans Frontières (MSF) supported national TB programs to introduce delamanid according to World Health Organization recommendations (9) for patients lacking 4 effective second-line drugs in the regimen or at high risk for poor treatment outcomes. Delamanid was preferred over bedaquiline to treat TB in patients with hepatitis C (because of less potential hepatic toxicity with delamanid), patients who are taking antiretroviral drugs (because delamanid produces fewer interactions), or patients previously exposed to bedaquiline (and who had previous treatment failure) or clofazimine (because of potential cross resistance with bedaquiline). We present interim treatment response and safety data for patients treated with delamanid within MSF-supported programs.\n\nThis retrospective study comprises all patients started on MDR TB regimens containing delamanid in MSF-supported sites before March 1, 2016. Routine programmatic data were collected on site. Information on serious adverse events (SAEs) was retrieved from a central pharmacovigilance database. The study was approved by the relevant health ministries and meets the criteria of the MSF Ethics Review Board for exemption from ethics review.\n\nWe defined culture conversion as 2 consecutive negative culture results 1 month apart for culture-positive patients at start of delamanid treatment. We defined patients as having a favorable interim treatment response at 6 months if they completed 24 weeks of delamanid and culture converted or remained culture negative; we classified patients who did not meet these criteria as having an unfavorable interim treatment response. We used unadjusted bivariate odds ratios with 95% CIs to express the magnitude and precision of associations between outcomes and risk factors (the small number of records precluded a multivariable analysis). We defined SAEs as deaths irrespective of cause, hospitalizations, events leading to disability or congenital malformation, and events considered life threatening or otherwise medically noteworthy.\n\nDuring February 6, 2015–February 29, 2016, a total of 53 patients from 7 countries (Technical Appendix Table 1) started a delamanid-containing regimen (Table). Of these, 46 (86.8%) received delamanid through a compassionate-use program. Most patients had been treated previously with second-line drugs (48/53, 90.6%), experienced MDR TB treatment failures (32/53, 60.4%), exhibited resistance to second-line TB drugs (41/51, 80.4%), or had extensive pulmonary disease (40/45, 88.9%). Almost all patients (52/53, 98.1%) received delamanid for an indication of <4 effective drugs in the regimen.\n\nA total of 31 SAEs were reported in 14 patients (26.4%); most common were hepatotoxicity (5), electrolyte imbalance (5), and QT prolongation (3). The most frequent contributing factors reported were TB disease (6), hepatitis C infection (6), and non–anti-TB drugs, including antiretroviral drugs (ARVs) (8). A possible relation to any TB drug was reported in 80.6% (25/31) of events, including a possible relation to delamanid in 58.6% (18/31). Causes of the 7 reported deaths were advanced TB (2), encephalitis in an untreated HIV patient (1), traumatic pneumothorax (1), sepsis in an HIV patient (1), respiratory failure related to end-stage hepatitis (1), and sudden death of unknown cause (1); a possible relationship to anti-TB drugs was initially reported in the last 2 cases. In 1 patient with hepatitis C and liver cirrhosis, all drugs were permanently discontinued due to hepatotoxicity. No other permanent discontinuation of delamanid was reported (Technical Appendix Table 2).\n\nOf the patients who were culture positive at delamanid start, 67.6% (25/37) culture converted by 6 months. At 6 months, 73.6% (39/53) of patients had a favorable response, 13.2% (7/53) had died, 7.5% (4/53) remained culture positive, 3.8% (2/53) were lost to follow-up, and 1.9% (1/53) were declared to have a failure in treatment as a result of an SAE. Factors associated with unfavorable response in a univariate analysis were age >35 years (odds ratio [OR] 5.62, 95% CI 1.47–21.57; p = 0.012); hepatitis C infection (OR 7.78, 95% CI 1.45–41.78; p = 0.017); smear positivity at delamanid start (OR 5.21, 95% CI 1.35–20.06; p = 0.016); and serum albumin <34 g/L (OR 7.14, 95% CI 1.6–33.3; p = 0.010) (Technical Appendix Table 3).\n\nThese preliminary results indicate good tolerability and interim treatment response to delamanid at 6 months in a narrow and difficult-to-treat cohort of patients for whom delamanid was preferred to bedaquiline, most of whom had previously failed MDR TB treatment and had extensive disease. Delamanid was used in preference to bedaquiline in this group of patients, despite the programmatic availability of bedaquiline, which may explain the frequency of adverse events in relation to hepatitis C and HIV co-infection, comorbidities that influence this choice, further supporting the need for essential monitoring and treatment of hepatitis C and HIV in MDR TB patients. Limitations of this study include its small numbers and retrospective nature, and data on delamanid treatment outcomes and safety in programmatic conditions with larger indications deserve further studies.\n\nTable Demographic, clinical, and bacteriological characteristics at baseline of 53 patients starting a delamanid-containing MDR TB treatment regimen*\n\nVariable\tNo. (%) patients or median (IQR)\t\nSex\t\t\n M\t36 (67.9)\t\n F\t17 (32.1)\t\nAge at delamanid start, y\t29.5 (20.0–43.0)\t\n 14–17\t11 (20.8)\t\nHIV co-infected, n = 48\t8 (16.7)\t\nHCV co-infected, n = 42\t8 (19.0)\t\nMalnutrition,† n = 51\t21 (41.2)\t\nSerum albumin at delamanid start, g/L, n = 46\t37.6 (32.0–37.6)\t\nWHO case definition\t\t\n New case\t4 (7.5)\t\n Relapse\t5 (9.4)\t\n Treatment after being lost to follow-up\t5 (9.4)\t\n Treatment after failure\t32 (60.4)\t\n Other\t7 (13.5)\t\nPreviously treated\t49 (92.4)\t\n With first-line drugs only\t1 (2.1)\t\n With second-line drugs\t48 (97.9)\t\n MDR TB confirmed\t51 (96.2)\t\nDrug resistance subgroups among confirmed MDR TB\t\n MDR TB only‡\t10 (19.6)\t\n Pre–XDR TB FQ\t6 (11.8)\t\n Pre–XDR TB Inj\t8 (15.7)\t\n XDR TB\t27 (52.9)\t\nRadiograph features\t\t\n Bilateral, n = 45\t35 (77.8)\t\n Cavities, n = 43\t26 (60.5)\t\n Bilateral or cavity, n = 45\t40 (88.9)\t\nCulture positive at delamanid start\t37 (69.8)\t\n*HCV, hepatitis C virus serology; HIV, human immunodeficiency virus; MDR TB, multidrug-resistant tuberculosis; pre–XDR TB FQ, MDR TB with fluoroquinolone resistance; pre–XDR TB Inj, MDR TB with resistance to injectable drugs; WHO, World Health Organization; XDR TB, extensively drug-resistant tuberculosis. \n†Malnutrition: either BMI <18.5 kg2/cm, mid-upper arm circumference \n<16cm, or weight <50 kg in 3 patients from South Africa without height measurement. \n‡Without resistance to fluoroquinolone or injectable drugs.\t\n\nTechnical Appendix\n\nThe pharmacovigilance system of reporting serious adverse drug effects and additional patient information for study of delamanid-containing multidrug-resistant tuberculosis treatment regimen.\n\nAcknowledgments\n\nThe authors thank Nana Kiria, Lusine Yeghiazaryan, Virginia de Azevedo, and the MSF-TB working group: Krzysztof Herboczek, Alex Telnov, Mathieu Bastard, Helena Huerga, and Jay Achar.\n\nC.H., N.L., and F.V. report grants from UNITAID, outside the submitted work. MSF received a donation of delamanid from Otsuka Company.\n\nDr. Hewison is a medical doctor working with Médecins Sans Frontières since 1997, a tuberculosis advisor in the medical department of MSF since 2005, and chair of the endTB medical committee. Her primary research interest is all aspects of diagnosis and treatment of MDR TB, particularly the effectiveness and safety of new anti-TB drugs.\n\nSuggested citation for this article: Hewison C, Ferlazzo G, Avaliani Z, Hayrapetyan A, Jonckheere S, Khaidarkhanova Z, et al. Six-month response to delamanid treatment in MDR TB patients. Emerg Infect Dis. 2017 Oct [date cited]. https://doi.org/10.3201/eid2310.170468\n==== Refs\nReferences\n\n1. World Health Organization. Global Tuberculosis Report 2016 [cited 2017 Jul 20]. http://apps.who.int/iris/bitstream/10665/250441/1/9789241565394-eng.pdf\n2. Ahuja SD, Ashkin D, Avendano M, Banerjee R, Bauer M, Bayona JN, et al. ; Collaborative Group for Meta-Analysis of Individual Patient Data in MDR TB. Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients. PLoS Med. 2012;9 :e1001300. 10.1371/journal.pmed.1001300 22952439\n3. Falzon D, Gandhi N, Migliori GB, Sotgiu G, Cox HS, Holtz TH, et al. ; Collaborative Group for Meta-Analysis of Individual Patient Data in MDR TB. Resistance to fluoroquinolones and second-line injectable drugs: impact on multidrug-resistant TB outcomes. Eur Respir J. 2013;42 :156–68. 10.1183/09031936.00134712 23100499\n4. Bonnet M, Bastard M, du Cros P, Khamraev A, Kimenye K, Khurkhumal S, et al. Identification of patients who could benefit from bedaquiline or delamanid: a multisite MDR TB cohort study. Int J Tuberc Lung Dis. 2016;20 :177–86. 10.5588/ijtld.15.0962 26792469\n5. European Medicines Agency. Deltyba (delamanid) [cited 2017 Jan 6]. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002552/human_med_001699.jsp&mid=WC0b01ac058001d124\n6. Gler MT, Skripconoka V, Sanchez-Garavito E, Xiao H, Cabrera-Rivero JL, Vargas-Vasquez DE, et al. Delamanid for multidrug-resistant pulmonary tuberculosis. N Engl J Med. 2012;366 :2151–60. 10.1056/NEJMoa1112433 22670901\n7. Skripconoka V, Danilovits M, Pehme L, Tomson T, Skenders G, Kummik T, et al. Delamanid improves outcomes and reduces mortality in multidrug-resistant tuberculosis. Eur Respir J. 2013;41 :1393–400. 10.1183/09031936.00125812 23018916\n8. European Medicines Agency. Sirturo (bedaquiline) [cited 2017 Jan 6]. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002614/human_med_001730.jsp&mid=WC0b01ac058001d124\n9. World Health Organization. Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis. 2014 [cited 2017 Jul 20]. http://apps.who.int/iris/bitstream/10665/130918/1/9789241548809_eng.pdf?ua=1&ua=1\n\n",
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"keywords": "Armenia; Belarus; Georgia; India; MDR TB; Russia; South Africa; Swaziland; Tuberculosis; antimicrobial resistance; antitubercular agents; bacteria; combination; delamanid; drug therapy; multidrug resistance",
"medline_ta": "Emerg Infect Dis",
"mesh_terms": "D000293:Adolescent; D000995:Antitubercular Agents; D005260:Female; D015658:HIV Infections; D006526:Hepatitis C; D006801:Humans; D008297:Male; D009593:Nitroimidazoles; D010080:Oxazoles; D012189:Retrospective Studies; D018088:Tuberculosis, Multidrug-Resistant",
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"title": "Six-Month Response to Delamanid Treatment in MDR TB Patients.",
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"abstract": "Cryptococcus gattii was recognized as an emerging infection in the Pacific Northwest in 2004. Out of 62 total infections in Oregon since the outbreak, 11 were in solid organ transplant (SOT) recipients. SOT recipients were more likely to have disseminated disease and higher mortality than normal hosts, who mostly had isolated mass lesions. The median time from transplantation to C. gattii diagnosis was 17.8 months. The primary sites of infection were lung (n = 4), central nervous system (n = 3), or both (n = 4). The Oregon-endemic strain, VGII (subtypes IIa and IIc) was present in 10 of 11 patients; the median fluconazole minimum inhibitory concentration (MIC) was 12 μg/mL (range 2-32 μg/mL) for this strain. We found C. gattii infection among organ transplant recipients was disseminated at diagnosis, had low cerebrospinal fluid cryptococcal antigen titers, and was associated with an elevated fluconazole MIC and high attributable mortality.",
"affiliations": "Division of Infectious Diseases, Portland Veterans Affairs Medical Center, Portland, Oregon, USA.;Division of Infectious Diseases, Oregon Health and Science University, Portland, Oregon, USA.;Oregon Health Authority, Public Health Division, Acute and Communicable Disease Prevention, Portland, Oregon, USA.;Division of Infectious Diseases, Oregon Health and Science University, Portland, Oregon, USA.;Mycotic Diseases Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.;Division of Infectious Diseases, Portland Veterans Affairs Medical Center, Portland, Oregon, USA.;Oregon Health Authority, Public Health Division, Acute and Communicable Disease Prevention, Portland, Oregon, USA.",
"authors": "Forrest|G N|GN|;Bhalla|P|P|;DeBess|E E|EE|;Winthrop|K L|KL|;Lockhart|S R|SR|;Mohammadi|J|J|;Cieslak|P R|PR|",
"chemical_list": "D000946:Antigens, Fungal; D015725:Fluconazole",
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"issue": "17(3)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "Cryptococcus gattii; antifungals; immunosuppression; organ transplantation",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000946:Antigens, Fungal; D003453:Cryptococcosis; D056285:Cryptococcus gattii; D004196:Disease Outbreaks; D005260:Female; D015725:Fluconazole; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009922:Oregon; D016377:Organ Transplantation; D012189:Retrospective Studies; D066027:Transplant Recipients",
"nlm_unique_id": "100883688",
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"title": "Cryptococcus gattii infection in solid organ transplant recipients: description of Oregon outbreak cases.",
"title_normalized": "cryptococcus gattii infection in solid organ transplant recipients description of oregon outbreak cases"
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"abstract": "ICON3 trial results have suggested that CAP and carboplatin-taxol regimens as first-line treatment of advanced ovarian cancer (AOC) yield similar survival. We explored the impact of increased dose of cyclophosphamide in a modified CAP regimen on the disease-free survival (DFS) and overall survival (OS) of AOC patients. From February 1994 to June 1997, 164 patients were randomised to receive six cycles every 3 weeks of either standard CEP (S) combining cyclophosphamide (C), 500 mg m(-2), epirubicin (E) 50 mg m(-2), and cisplatin (P) 75 mg m(-2) or intensive CEP (I) with E and P at the same doses, but with (C) 1800 mg m(-2) and filgrastim 5 mug kg(-1) per day x 10 days. Response was evaluated at second-look surgery. Patient characteristics were well balanced. Except for grade 3-4 neutropaenia (S: 54%, I: 38% of cycles), Arm1 presented a significantly more important toxicity: infection requiring antibiotics, grade 3-4 thrombocytopaenia, anaemia, nausea-vomiting, diarrhoea, mucositis. Median follow-up was 84 months. DFS (15.9 vs 14.8 months) and OS (33 vs 30 months) were not significantly different between S and I (P>0.05). Increasing cyclophosphamide dose by more than 3 times with filgrastim support in the modified CAP regimen CEP induces more toxicity but not better efficacy in AOC.",
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"chemical_list": "D016179:Granulocyte Colony-Stimulating Factor; D003520:Cyclophosphamide; D016190:Carboplatin; D002945:Cisplatin",
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"fulltext": "\n==== Front\nBr J Cancer\nBr J Cancer\nBritish Journal of Cancer\n0007-0920\n1532-1827\nNature Publishing Group\n\n6604026\n10.1038/sj.bjc.6604026\n17923867\nClinical Study\nIntensified dose of cyclophosphamide with G-CSF support versus standard dose combined with platinum in first-line treatment of advanced ovarian cancer a randomised study from the GINECO group\nTreatment of advanced ovarian cancer\nRay-Coquard I 1*\nParaiso D 2\nGuastalla J-P 1\nLeduc B 3\nGuichard F 4\nMartin C 5\nChauvenet L 6\nHaddad-Guichard Z 7\nLepillé D 8\nOrfeuvre H 9\nGautier H 10\nCastera D 11\nPujade-Lauraine É 6\nfor the GINECO group\n1 Centre Léon Bérard, EA 4129 sis, 28 rue Laënnec, Lyon 69008, France\n2 Centre hospitalier de l'Agglomération Montargeoise, 658 Rue des Bourgoins, Amilly 45200, France\n3 Centre hospitalier, bd du Dr Verlhac, Brive la Gaillarde 19100, France\n4 Polyclinique Bordeaux-nord, 15 rue Claude Boucher, Bordeaux 33300, France\n5 Centre hospitalier, 1 avenue de Tresum, Annecy 74000, France\n6 Hôtel-Dieu, Place du Parvis de Notre-Dame, Paris 75004, France\n7 Centre hospitalier, 7 quai Hôpital, Chalon-sur-Saône 71100, France\n8 Clinique Pasteur, 58 bd Pasteur, Evreux 27000, France\n9 Hôpital Fleyriat, 900 route de Paris, Bourg en Bresse 01000, France\n10 CMC de Bligny, 91640 Briis sous Forges, Hôpital Privé d'Antony, 1 rue Velpeau, Antony 92160, France\n11 Clinique Saint-Pierre, rue Jean Galia, Perpignan 66000, France\n* E-mail: ray@lyon.fnclcc.fr\n05 11 2007\n09 10 2007\n97 9 12001205\n23 05 2007\n13 08 2007\n04 09 2007\nCopyright © 2007 Cancer Research UK\n2007\nCancer Research UK\nhttps://creativecommons.org/licenses/by/4.0/ This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.\nICON3 trial results have suggested that CAP and carboplatin–taxol regimens as first-line treatment of advanced ovarian cancer (AOC) yield similar survival. We explored the impact of increased dose of cyclophosphamide in a modified CAP regimen on the disease-free survival (DFS) and overall survival (OS) of AOC patients. From February 1994 to June 1997, 164 patients were randomised to receive six cycles every 3 weeks of either standard CEP (S) combining cyclophosphamide (C), 500 mg m−2, epirubicin (E) 50 mg m−2, and cisplatin (P) 75 mg m−2 or intensive CEP (I) with E and P at the same doses, but with (C) 1800 mg m−2 and filgrastim 5 μg kg−1 per day × 10 days. Response was evaluated at second-look surgery. Patient characteristics were well balanced. Except for grade 3–4 neutropaenia (S: 54%, I: 38% of cycles), Arm1 presented a significantly more important toxicity: infection requiring antibiotics, grade 3–4 thrombocytopaenia, anaemia, nausea-vomiting, diarrhoea, mucositis. Median follow-up was 84 months. DFS (15.9 vs 14.8 months) and OS (33 vs 30 months) were not significantly different between S and I (P>0.05). Increasing cyclophosphamide dose by more than 3 times with filgrastim support in the modified CAP regimen CEP induces more toxicity but not better efficacy in AOC.\n\nadvanced ovarian cancer\ncyclophosphamide\nhigh-dose chemotherapy\nepirubicin\nrandomised trial\n==== Body\npmcAdvanced ovarian cancer (AOC) is considered one of the most chemotherapy-sensitive epithelial malignant tumours (Ozols and Young, 1991; Trimble et al, 1994). First-line regimens with a platinum salt used alone or in combination (McGuire et al, 1996; Muggia et al, 2000) induce objective response in more than half of the patients. However, a majority ultimately relapse after a median interval which rarely exceeds 18 months (McGuire et al, 1996) suggesting the need of new therapeutic regimens.\n\nIn the 1990s, the combination of cisplatin and paclitaxel was established as first-line therapy for AOC patients after two large phase III trials had demonstrated the superiority of this combination over the then standard regimen of cyclophosphamide and cisplatin (McGuire et al, 1996; Piccart et al, 2000). A number of studies have evaluated the combination of paclitaxel and carboplatin as an alternative to the paclitaxel–cisplatin regimen (Neijt et al, 2000; Bookman et al, 2003; Ozols et al, 2003). They have shown that the carboplatin combination is associated with a lower incidence of non-haematologic toxicities (particularly neurotoxicity) and better quality of life, whereas no significant difference in progression-free survival (PFS) and overall survival (OS) was detected. From these findings, the International Consensus Conference in Ovarian cancer, held in Baden-Baden in 2004, concluded that carboplatin–paclitaxel was the first-line standard for AOC treatment.\n\nThis consensus however has been challenged by the results of two randomised trials comparing platinum–paclitaxel to alternative regimens. The GOG 132 study compared cisplatin alone (100 mg m−2), paclitaxel alone (200 mg m−2 over 24 h), and the combination of the two agents (paclitaxel 135 mg m−2 followed by cisplatin 75 mg m−2) in 614 women with stage III or IV disease (Muggia et al, 2000). There were no PFS or OS differences between the combination arm and the cisplatin-alone arm. The ICON3 trial enrolled 2074 patients with stage I through stage IV ovarian cancer who were randomised to receive carboplatin (dosed to AUC 6) in combination with paclitaxel (175 mg m−2 over 3 h), or a control of carboplatin (dosed to AUC 6) alone or the combination of cyclophosphamide (500 mg m−2), doxorubicin (50 mg m−2), and cisplatin (50 mg m−2) (CAP regimen) (ICON, 2002) no significant OS or PFS differences were between the groups. These data suggest that, at least in certain circumstances, platinum used as a single agent or in combination within a CAP regimen might be as effective as the standard paclitaxel–platinum doublet.\n\nOne approach to improve the results of chemotherapy in the first-line setting would be to optimise platinum-based regimens by increasing drug dose intensity. However, most prospective trials exploring an increase of platinum dose intensity in AOC have given negative results, suggesting that no significant benefit could be obtained with doses over 75–100 mg m−2 for cisplatin and AUC 5–7.5 for carboplatin (Levin et al, 1993).\n\nOne alternative option would be to explore the impact of increasing cyclophosphamide doses within a platinum-based regimen. The dose-limiting factor of cyclophosphamide is haematological toxicity, particularly neutropaenia. Severe neutropaenia can be improved by the administration of granulocytecolony stimulating factors (G-CSF), allowing to increase cyclophosphamide dose to a magnitude not attainable by platinum compounds because of their non-haematological or platelet dose-limiting toxicity.\n\nThese observations prompted the GINECO group to test the efficacy of chemotherapy using intensified doses of cyclophosphamide in combination with cisplatin and epirubicin against the same chemotherapy with standard doses of each drug.\n\nPATIENTS AND METHODS\n\nStudy design\n\nThis study was an open, comparative, multicentric, phase III study. The primary end point was to determine the impact of increased doses of cyclophosphamide supported by filgrastim in a modified CAP regimen (CEP) on the OS of International Federation of Gynaecology and Obstetrics (FIGO) stage III–IV epithelial AOC patients. Secondary end points included evaluation of disease-free survival (DFS), patterns of recurrence, response rate, and toxicity.\n\nPatient selection\n\nEligible patients included patients with histologically documented, chemotherapy-naïve ovarian epithelial carcinoma. Other requirements included: age 18–70 years, World Health Organization (WHO) performance status ⩽2, FIGO stage III or IV, satisfactory haematological, renal, cardiac and hepatic functions, and initiation of chemotherapy within 4 weeks after initial laparotomy. Exclusion criteria were previous malignant tumour (except for treated basal cell skin cancer or in situ cervical cancer), history of nervous or psychiatric disorder that would preclude informed consent or compliance, infection, or severe disease including intestinal occlusion, bilirubin level >1.25 times upper normal limit, transaminases >2.5 times upper normal limit except for patients with liver metastases, white blood cell count <3.5 × 109 per l, granulocyte count <2.0 × 109 per l, platelet count <100 × 109 per l, serum creatinine >120 μmol l−1, symptomatic cardiomyopathy or cerebral metastasis. All patients gave written informed consent approved from regulatory authorities and ethics committees before taking part in the study.\n\nPatients were stratified according to stage and size of the residual lesion after initial surgery: stage III and microscopic residuals, or stage III and <2 cm residuals, or stage III and >2 cm residuals, or stage IV. They were randomly assigned to receive either intensified or standard chemotherapy.\n\nPre-treatment and treatment evaluation\n\nThoracic radiography and computed tomographic scans of the abdomen and the pelvis were performed after surgery (if realised) within 4 weeks before entry into the study. Medical history, clinical examination, performance status assessment, electrocardiogram, ventricular ejection fraction (VEF) and blood tests (complete blood cell count, serum creatinine, bilirubin, transaminases, alkaline phosphatases, and CA-125) were performed within 2 weeks. Blood cell and platelet counts were repeated weekly. Physical examination, serum CA-125 level, WHO grade toxicity assessment and blood tests were performed on day 1 of each cycle. Radiological examinations, to document the status of the disease at baseline, and serum CA-125 levels were repeated systematically at the end of the program and whenever necessary. For patients with clinical and tumour marker complete responses, treatment was followed by a second-look laparotomy.\n\nTreatment\n\nTreatment schedule\n\nEligible patients were randomised to receive six cycles of either standard CEP (S) or intensive CEP (I).\n\nIn the standard treatment arm (S) patients received at day 1 of each cycle: cyclophosphamide (ENDOXAN®) 500 mg m−2 administered as a 30-min intravenous infusion, followed by epirubicin (FARMORUBICINE®) 50 mg m−2 as a bolus infusion, and cisplatin (CISPLATYL®) 75 mg m−2 diluted in 500 ml of normal saline delivered as a 30-min intravenous infusion. Hydration with isotonic solution (3 l on day 1) was systematically realised for each cycle. In the intensified treatment arm (I) patient received, at day 1 of each cycle, a combination of cyclophosphamide (ENDOXAN) 1800 mg m−2 administered as a 30-min intravenous infusion after hyperhydration, followed by epirubicin (FARMORUBICINE) 50 mg m−2 and cisplatin CISPLATYL) 75 mg m−2. Hydration with isotonic solution (3 l on day 1) was systematically realised for each cycle, but mesna rescue was not forecasted. Filgrastim (NEUPOGEN®) 5 μg kg−1 per day was administered from day 2 to day 11 of each cycle in the intensified arm. Filgrastim was not proposed in the standard arm, reduction of dose should be considered before.\n\nCycles were repeated every 3 weeks. A number of six cycles was planned, up to a maximum of nine cycles. All patients received prophylactic anti-emetic therapy with 5HT3 inhibitors.\n\nToxicity and dosage modification guidelines\n\nToxicity was evaluated according to the WHO criteria (Perry, 1992). When patients experienced febrile neutropaenia, prolonged grade 4 neutropaenia (>7 days) or grade 4 thrombopaenia, doses of cyclophosphamide were reduced by 20% in the subsequent cycles. Doses of cisplatin were also reduced by 20% in case of grade 2 neurotoxicity. Doses of epirubicin and cyclophosphamide were also reduced by 20% in case of grade 2 stomatitis. A similar dose reduction of the three drugs was necessary in case of any grade 3 non-haematological toxicity, except digestive toxicity. Chemotherapy was stopped in case of symptomatic heart failure and creatinine serum level >150 μmol l−1.\n\nFollow-up\n\nAfter treatment, patients were followed every 3 months during 3 years, then every 6 months up to 5 years, and every year thereafter. Routine evaluations at each follow-up visit included physical examination and serum CA-125 level.\n\nEfficacy criteria\n\nPFS was measured from the date of protocol entry to the date of first progression or death or to the date of last contact for patients who are alive and progression-free. OS was defined as the time from random assignment to death or last contact.\n\nClinical response was evaluated according to the WHO criteria. Those patients who were in complete clinical and serological response at the end of chemotherapy were submitted to a second-look laparotomy. Complete pathological response was defined as the absence of macroscopic and microscopic tumour lesion. Partial pathological response was defined as the persistence of microscopic lesions at second-look laparotomy in patients with residual macroscopic lesions after initial surgery, or a reduction of macroscopic lesions according to the WHO criteria.\n\nStatistical analysis\n\nThe study was designed to detect a difference of 15% in OS at 2 years from an expected 2-year OS of 50% in the standard arm. With a statistical power of 0.90 and a type I error of 0.05, this difference would require the inclusion of 195 patients in each arm. Statistical analysis was performed using SPSS® 9.0 software (SPSS Inc., Chicago, IL, USA 1999) and P-values less than 0.05 (two-sided test) were considered statistically significant. Patients who withdrew before completion of the study treatment or who were declared ineligible (n=9) were excluded from the primary analyses of toxicity and second look. Frequency tables and summary statistics (e.g., mean and median) were used to describe the distributions of patient characteristics and toxicity. Parametric and χ2 tests were used to test for significant differences in patient characteristics and toxicity between treatment arms. The Kaplan–Meier method was used to estimate the distributions of DFS and OS (Kaplan, 1958). Cox proportional hazards models were used to explore the associations of patient characteristics (e.g. stage and residual tumour) with patient outcome (e.g. survival) (Mantel, 1959). The score statistic was used to test for a significant difference in patient outcome on the basis of a single covariate (e.g. sex). The likelihood ratio test was used to test for the significance of a single covariate in the presence of (or adjusting for) other covariates.\n\nRESULTS\n\nEnrolment began in February 1994 and was stopped in June 1996 with a lower than expected accrual of 164 patients. The main reason for this low accrual was the approval of paclitaxel in first line in the course of study enrolment. Of the 164 accrued patients, 155 were eligible and assessable, 5 had non-epithelial ovarian cancer (S (2), I (3)), 1 (I) had cardiac failure at study entry and 3 withdrew their consent before treatment (S (1), I (2)).\n\nPatient characteristics are summarised in Table 1. The two treatment arms were well matched with respect to demographics and disease characteristics. Interestingly, like in other published series (Hoskins et al, 1994) less than 50% of included patients benefited of optimal debulking surgery.\n\nOverall and progression-free survival\n\nThe primary end point of the study (OS at 2 years) was 66% for the standard arm and 64% for the intensified arm (P=0.7). The median survival duration was 31.1 months (range 27.2–35.0) for the whole cohort. It was 32.5 months (CI 95% 27.3–37.7) for patients in the standard arm, and 30 months (CI 95% 24.7–35.7) for patients in the intensified arm (P=0.6) (Figure 1). Median PFS for patients receiving the standard treatment was 15.9 months (CI 95% 12.3–19.5) vs 14.8 months (CI 95% 11.8–17.8) for patients in the intensified treatment arm (P=0.55) (Figure 2).\n\nIn a univariate analysis, PFS was correlated to presence of residual lesions after initial surgery (no or microscopic lesion vs less than 2 cm vs more than 2 cm) (P=0.005) and to initial FIGO stage (P=0.05), but not to age at diagnosis, histological subtype, treatment arm, or performance status. Multivariate Cox model analysis showed that only residual lesion size after initial surgery was a significant independent prognostic factor for PFS, with a median of 33.7 months for patients without macroscopic residual lesion and 14.9 months for patients with macroscopic residual lesions (P=0.003).\n\nRegarding OS, the univariate analysis identified significant prognostic values for FIGO stage (P=0.02), residual lesion size (P=0.016), and performance status (P=0.015), but not for age (P=0.34), treatment arm (P=0.61), or histological subtype (P=0.21). In a Cox model analysis, only residual lesion size after initial surgery remained statistically significantly correlated to OS (P=0.024) with a median survival of 46.2 months for patients without macroscopic residual lesion and 30.4 months for patients with macroscopic residual lesions.\n\nPathological response\n\nAmong the 155 patients assessable for clinical and tumour marker response, only 114 (74%) had a second-look laparotomy. The reasons why second-look laparotomy was not performed in the other 41 patients are detailed in Table 2; reasons were equally distributed between the two arms.\n\nOf the 114 patients who had a second-look laparotomy, 25 out of 63 (39%) in the standard group and 12 out of 51 (23%) in the intensified group achieved a pathological complete response (pCR) (P=0.46). Also, no statistical difference was noted between the two groups of patients; the intensified arm resulted in less pCR and more macroscopic residual disease. However, no information in the database provided any basis for formulating hypotheses or postulating causes, such as dose reduction, treatment delay, or patients or initial surgical characteristics.\n\nToxicity\n\nA total of 830 courses were administered (447 in S and 383 in I). The ratio of the delivered dose to the planned dose was cisplatin (S (0.99), I (0.98)), epirubicin (S (0.99), I (0.98)) and cyclophosphamide (S (0.99), I (0.94)). A total of 65 patients (78%) in the standard arm and 56 (77%) in the intensive arm received the six planned courses. No patient in either arm received more than six cycles. A dose reduction in one of the drugs was performed in 31 (15%) cycles: 20% dose reduction in 11 (5%) cycles, and 40% dose reduction in 20 (10%) cycles. In 30 out of 31 cases, dose reduction was decided because of haematotoxicity.\n\nChemotherapy was stopped in 34 patients, 17 in each arm. Causes of early treatment stop were as follows: Standard arm: toxic death [1], progressive disease [4], nausea/vomiting [1], hypersensitivity [1], elevated creatinine [1], haematological toxicity [2], others [7].\n\nIntensive arm: toxic death [2], progressive disease [3], cardiac arrhythmia [1], elevated creatinine [1], elevated alkaline phosphatases [1], haematological toxicity [1], fatigue [1], others [7].\n\nMain WHO grade 3–4 toxicities are shown in Table 3. Compared to standard treatment, patients receiving intensive treatment and filgrastim support experienced a lower rate of grade 3 out of 4 neutropaenia but more frequent severe thrombopaenia and anaemia. The rate of severe infection and mucositis was significantly superior in patients receiving intensified treatment.\n\nGrade 2 peripheral neuropathy was observed in 2 out of 82 patients of group S (2%) and in 3 out of 73 patients of group I (4%); no grade 3 was observed. Grade 2 alopecia was observed in 74 patients of group S (90%) and 69 patients of group I (95%). Grade 2 serum creatinine elevation was observed in one patient of group S (1%) and three patients of group I (4%).\n\nDISCUSSION\n\nA total of 164 AOC patients were randomised to receive six cycles of CEP regimen every 3 weeks, with either standard cyclophosphamide dose (500 mg m−2), or intensive dose (1800 mg m−2) with filgrastim support.\n\nToxicity was higher, with more frequent severe thrombopaenia and anaemia, in the intensive than that in the standard treatment arms. Despite a lower rate of severe neutropaenia, more severe infections and mucositis were reported in patients receiving intensive cyclophosphamide. Interestingly, this increased toxicity was not associated with increased mortality and did not compromise the total drug dose or number of cycles. Thus, increasing doses of cyclophosphamide up to over 3 times, the standard dose is possible in patients with ovarian cancer within a first-line CEP regimen.\n\nHowever, patients treated with the CEP regimen derived no benefit from this higher cyclophosphamide dose. PFS and OS rates were not superior for patients treated in the intensive arm compared to those in the standard arm. One of the limitations to these results is the small size of the patient sample studied. Nevertheless, it is very unlikely that a larger cohort would have allowed proving a superior efficacy of intensified cyclophosphamide dose compared to standard dose. None of the efficacy criteria tested indicated a superiority of the intensive arm over the standard. The rates of complete pathological response at second-look laparotomy, PFS and OS were all slightly inferior in patients treated with intensive cyclophosphamide. A possible explanation could be derived from the fact that the intensified arm resulted in less pCR and more macroscopic residual disease; however, this was an intriguing finding.\n\nThis study addressed two important issues for the management of first-line chemotherapy in ovarian cancer patients: the impact of high-dose therapy and the role of cyclophosphamide. The recent results of high-dose chemotherapy, including high-dose cyclophosphamide supported by peripheral blood stem cell transplantation, have yielded disappointing results in the first-line treatment of ovarian cancer. H Curé and the GINECO group have shown no benefit of high-dose carboplatin–cyclophosphamide over standard dose used as consolidation therapy in patients responding to first-line chemotherapy (Cure et al, 2004). Recently, Lederman et al (2005) reported the results of a phase III study of multi-cycle high-dose chemotherapy vs standard platinum-based chemotherapy in predominately optimally debulked stage IIB to IV epithelial ovarian cancer. Their data did not show a short-term benefit of the high-dose arm. There is currently no evidence of a benefit of intensive chemotherapy in ovarian cancer.\n\nThe results of the present study may contribute to the debate on the role of cyclophosphamide in the first-line setting. Before the introduction of paclitaxel in first-line, platinum combinations were considered more effective than single-agent platinum when the drug was used at the same dose (AOCT, 1991). The association of cyclophosphamide and cisplatin was adopted at that time as a standard and served as a control in the first two trials exploring the impact of paclitaxel–cisplatin combinations. However, the benefit of platinum combinations compared to single-agent platinum has long been debated; the analysis published by the Advanced Ovarian Cancer Trialists Group showed that the difference between the two regimens was at the limit of significance (ORR 0.85; CI 95%: 0.72–1.00) (AOCT, 1991). In addition, the ICON2 trial conducted in a large population of AOC patients failed to demonstrate an outcome advantage for patients treated with the CAP regimen compared to carboplatin monotherapy (ICON, 1998). The debate was revisited after the results of the four randomised trials exploring the role of paclitaxel in combination with platinum. Two of these trials used cyclophosphamide plus cisplatin as control and reported an advantage for the paclitaxel combination. In contrast, the other two trials using single-agent platinum as control did not show any benefit of the platinum–paclitaxel combination over platinum alone. From the analysis of these four trials, it has been hypothesised that a detrimental role of cyclophosphamide might explain the discordant results observed (Buyse et al, 2003). Our current data are not in favour of this negative impact of cyclophosphamide on patient survival for doses at least three-fold higher than standard doses, but all doses of cyclophosphamide may still impact negatively on the efficacy of cisplatin. Cisplatin dose was 75 mg m−2 in both arms of the study.\n\nIn conclusion, this is the only published study evaluating the dose intensity of cyclophosphamide and the two treatment arms have shown no significant difference in terms of second-look findings, complete pathological response, PFS, and OS. Our data do not support an increase of cyclophosphamide dose in a modified CAP regimen (CEP) for the first-line treatment of advanced AOC.\n\nThe authors thank Nathalie Le Fur and Christiane Puléo for data management and M-Dominique Reynaud for editing assistance.\n\nFigure 1 Median survival duration was 32.5 months for patients in the standard arm and 30 months for patients in the intensified arm (P=0.6).\n\nFigure 2 Median PFS for patients receiving the standard treatment was 15.9 months vs 14.8 months for patients in the intensified treatment arm (P=0.55).\n\nTable 1 Patient characteristics\n\n \tCEP\t \t\n \tStandard (S)\tIntensive (I)\tP\t\nPatient number (%)\t85 (100%)\t79 (100%)\t \t\nMedian age (range), in years\t60 (23–70)\t59 (23–70)\t0.46\t\n \t \t \t \t\nWHO performance status\t \t \t0.66\t\n 0\t24 (28%)\t17 (22%)\t \t\n 1\t48 (56%)\t50 (63%)\t \t\n 2\t13 (16%)\t12 (15%)\t \t\n \t \t \t \t\nFIGO stage\t \t \t0.43\t\n IIIA+B\t22 (26%)\t22 (28%)\t \t\n IIIC\t44 (52%)\t42 (53%)\t \t\n IV\t19 (22%)\t15 (19%)\t \t\nPresence of ascites\t31 (36%)\t39 (49%)\t0.15\t\n \t \t \t \t\nHistologic type\t \t \t0.72\t\n Serous\t59 (69%)\t53 (67%)\t \t\n Endometrioid\t10 (12%)\t6 (8%)\t \t\n Others\t16 (19%)\t20 (25%)\t \t\n \t \t \t \t\nHistologic grade\t \t \t0.81\t\n 1\t19 (22%)\t16 (20%)\t \t\n 2\t23 (27%)\t22 (28%)\t \t\n 3\t20 (24%)\t22 (28%)\t \t\n Unknown\t23 (27%)\t19 (24%)\t \t\n \t \t \t \t\nSize of residual lesion after surgery\t \t \t0.77\t\n Microscopic\t12 (15%)\t8 (10%)\t \t\n <2 cm\t26 (30%)\t25 (32%)\t \t\n ⩾2 cm\t47 (55%)\t46 (58%)\t \t\nAbbreviation: FIGO=International Federation of Gynaecology and Obstetrics.\n\nTable 2 Second-look laparotomy (SLL)\n\n \tNo. of evaluable patients (n=155)\t\n \tStandard (S) n=82\tIntensive (I) n=73\t\nSLL (n=114)\t63 (77%)\t51 (70%)\t\n Findings\t\n pCR\t25 (39%)\t12 (23%)\t\n Microscopic\t11 (17%)\t12 (24%)\t\n <2 cm\t16 (25%)\t15 (29%)\t\n >2 cm\t11 (18%)\t12 (24%)\t\n \t \t \t\nNot done (n=41)\t19 (23)\t22 (30)\t\n Reasons\t\n Stable/progressive disease\t4 (21%)\t3 (14%)\t\n Early stopping due to toxicity\t6 (32%)\t7 (32%)\t\n Patient refusal\t1 (5%)\t3 (14%)\t\n Others\t8 (42%)\t9 (41%)\t\nAbbreviation: pCR=pathological complete response.\n\nTable 3 WHO grade 3 out of 4 toxicities\n\n \t% of patients\t \t\n \tStandard (S) n=82\tIntensive (I) n=73\tP\t\nLeucopaenia\t33 (40%)\t40 (55%)\t0.07\t\nNeutropaenia\t53 (65%)\t37 (51%)\t0.07\t\nAnaemia\t17 (21%)\t31 (42%)\t0.003\t\nThrombocytopaenia\t10 (12%)\t24 (33%)\t0.001\t\nNausea-vomiting\t25 (30%)\t24 (33%)\t0.74\t\nDiarrhoea\t0\t3 (4%)\t0.06\t\nConstipation\t1 (1%)\t3 (4%)\t0.25\t\nMucositis\t0\t1 (2%)\t0.28\t\nInfections\t2 (2%)\t11 (15%)\t0.004\t\n\nAuthorship section\n\nIsabelle Ray-Coquard, investigator, analysis of data, and writer, Désiré Paraiso analysis of data, Jean-Paul Guastalla concept and investigator, B Leduc investigator, F Guichard investigator, C Martin investigor, L Chauvenet investigator, Z Haddad-Guichard investigator, D Lepillé investigator, H Orfeuvre investigator, H Gautier investigator, D Castera investigator, Éric Pujade-Lauraine concept, analysis of data, and writing.\n\nPresented in part at the annual meeting of ASCO, San Francisco, May 2001.\n==== Refs\nAOCT Group (1991) Chemotherapy in advanced ovarian cancer: an overview of randomised clinical trials. Advanced Ovarian cancer trialists group. BMJ 303 : 884–8931834291\nBookman MA, Greer BE, Ozols RF (2003) Optimal therapy of advanced ovarian cancer: carboplatin and paclitaxel vs. cisplatin and paclitaxel (GOG 158) and an update on GOG0 182-ICON5. Int J Gynecol Cancer 13 : 735–77414675308\nBuyse M, Burzykowski T, Parmar M, Torri V, Omura G, Colombo N, Williams C, Conte P, Vermorken J, International Collaborative Ovarian Neoplasm Collaborators (2003) Ovarian cancer meta-analysis project. Using the expected survival to explain differences between the results of randomized trials: a case in advanced ovarian cancer. J Clin Oncol 21 : 1682–168712721242\nCure H, Battista RN, Guastalla J, Fabbro M, Tubiana N, Bourgeois H, Pujade-Lauraine E (2004) Phase III randomized trial of high-dose chemotherapy (HDC) and peripheral blood stem cell (PBSC) support as consolidation in patients (pts) with advanced ovarian cancer (AOC): 5-year follow-up of a GINECO/FNCLCC/SFGM-TC study. J Clin Oncol, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition) 22 : 14S [5006]\nHoskins WJ, McGuire WP, Brady MF, Homesley HD, Creasman WT, Berman M, Ball H, Berek JS (1994) The effect of diameter of largest residual disease on survival after primary cytoreductive surgery in patients with suboptimal residual epithelial ovarian carcinoma. Am J Obstet Gynecol 170 : 974–9798166218\nInternational Collaborative Ovarian Neoplasm Group (1998) ICON2: randomised trial of single-agent carboplatin against three-drug combination of CAP (cyclophosphamide, doxorubicin, and cisplatin) in women with ovarian cancer. ICON collaborators. International collaborative ovarian neoplasm study. Lancet 352 : 1571–15769843101\nInternational Collaborative Ovarian Neoplasm Group (2002) Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial. 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Baltimore: Williams & Wilkins Inc\nPiccart MJ, Bertelsen K, James K, Cassidy J, Mangioni C, Simonsen E, Stuart G, Kaye S, Vergote I, Blom R, Grimshaw R, Atkinson RJ, Swenerton KD, Trope C, Nardi M, Kaern J, Tumolo S, Timmers P, Roy JA, Lhoas F, Lindvall B, Bacon M, Birt A, Andersen JE, Zee B, Paul J, Baron B, Pecorelli S (2000) Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin–cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst 92 : 699–70810793106\nTrimble EL, Arbuck SG, McGuire WP (1994) Options for primary chemotherapy of epithelial ovarian cancer: taxanes. Gynecol Oncol 55 : S114–S1217835794\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0007-0920",
"issue": "97(9)",
"journal": "British journal of cancer",
"keywords": null,
"medline_ta": "Br J Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D018269:Carcinoma, Endometrioid; D002945:Cisplatin; D003520:Cyclophosphamide; D018284:Cystadenocarcinoma, Serous; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "0370635",
"other_id": null,
"pages": "1200-5",
"pmc": null,
"pmid": "17923867",
"pubdate": "2007-11-05",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "8166218;8411257;10963636;2042062;10793106;1834291;12241653;12860964;7835794;13655060;12721242;10623700;14675308;7494563;9843101",
"title": "Intensified dose of cyclophosphamide with G-CSF support versus standard dose combined with platinum in first-line treatment of advanced ovarian cancer a randomised study from the GINECO group.",
"title_normalized": "intensified dose of cyclophosphamide with g csf support versus standard dose combined with platinum in first line treatment of advanced ovarian cancer a randomised study from the gineco group"
} | [
{
"companynumb": "FR-PFIZER INC-2020136034",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAlthough lenalidomide maintenance therapy has demonstrated improved outcomes after autologous hematopoietic stem cell transplantation (auto-HCT) for patients with multiple myeloma (MM), the impact of the duration of this therapy is not clearly known.\n\n\nMETHODS\nThis study retrospectively analyzed all MM patients who were placed on maintenance lenalidomide after auto-HCT between January 2007 and December 2013. Progression-free survival (PFS) and overall survival (OS) were analyzed in multivariate Cox proportional hazards regression models that included the duration of maintenance as a time-dependent covariate.\n\n\nRESULTS\nOf the 464 patients identified, 46% initiated therapy early (<4 months after auto-HCT). The median PFS and OS were 38 and 78 months, respectively. Improvements in PFS (hazard ratio [HR], 0.13; 95% confidence interval [CI], 0.04-0.38; P < .001) and OS (HR, 0.09; 95% CI, 0.03-0.26; P < .001) were seen for those on maintenance for >2 years versus those on maintenance for ≤2 years. For those on maintenance for >3 versus those on maintenance for ≤3 years, this trend continued with improvements seen in PFS (HR, 0.02; 95% CI, 0.00-0.44; P = .012) and OS (HR, 0.05; 95% CI, 0.00-0.83; P = .037). The incidence of second primary malignancies (SPMs) in the entire cohort was 3%. No differences were seen in survival between early and late initiators of maintenance lenalidomide.\n\n\nCONCLUSIONS\nA longer duration of maintenance therapy was associated with longer survival. The incidence of SPMs was low, and they were not associated with the duration of maintenance. The timing of the initiation of maintenance had no effect on survival. Cancer 2016;122:3831-3837. © 2016 American Cancer Society.",
"affiliations": "Internal Medicine Residency Program, The University of Texas Health Science Center at Houston, Houston, Texas.;Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.",
"authors": "Mian|Idrees|I|;Milton|Denái R|DR|;Shah|Nina|N|;Nieto|Yago|Y|;Popat|Uday R|UR|;Kebriaei|Partow|P|;Parmar|Simrit|S|;Oran|Betul|B|;Shah|Jatin J|JJ|;Manasanch|Elisabet E|EE|;Orlowski|Robert Z|RZ|;Shpall|Elizabeth J|EJ|;Champlin|Richard E|RE|;Qazilbash|Muzaffar H|MH|;Bashir|Qaiser|Q|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D013792:Thalidomide; D000077269:Lenalidomide",
"country": "United States",
"delete": false,
"doi": "10.1002/cncr.30366",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-543X",
"issue": "122(24)",
"journal": "Cancer",
"keywords": "maintenance lenalidomide; myeloma; prolonged duration; stem cell transplantation",
"medline_ta": "Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D018572:Disease-Free Survival; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D012189:Retrospective Studies; D013792:Thalidomide; D014182:Transplantation, Autologous",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "3831-3837",
"pmc": null,
"pmid": "27680710",
"pubdate": "2016-12-15",
"publication_types": "D016428:Journal Article",
"references": "26282661;24525201;23603914;22674807;23288300;25754350;20479421;22571201;22571200;25769794;22021371;24525202;25184862;24248686;22150057;16855634;23977334;22571202",
"title": "Prolonged survival with a longer duration of maintenance lenalidomide after autologous hematopoietic stem cell transplantation for multiple myeloma.",
"title_normalized": "prolonged survival with a longer duration of maintenance lenalidomide after autologous hematopoietic stem cell transplantation for multiple myeloma"
} | [
{
"companynumb": "US-CELGENEUS-USA-2016102300",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Objectives Prader-Willi Syndrome (PWS) is characterised by hyperphagia often leading to obesity; a known risk factor for insulin resistance and type 2 (T2) diabetes. We present a prepubertal girl with PWS who developed diabetes. Case presentation Our case was diagnosed with PWS in infancy following investigation for profound central hypotonia and feeding difficulties. She commenced growth hormone (GH) aged 8 years for short stature and treatment improved linear growth. At age 12 years, she presented with polydipsia, polyuria and vulvovaginitis. She was overweight (BMI SDS +1.43). Diabetes was diagnosed (Blood glucose = 24.2 mmol/L, HbA1c = 121 mmol/mol or 13.2%). She was not acidotic and had negative blood ketones. Autoantibodies typical of type 1 diabetes were negative. She was initially treated with basal bolus insulin regime. GH was discontinued 3 months later due to concerns regarding GH-induced insulin resistance. Off GH, insulin requirements reduced to zero, allowing Metformin monotherapy. However off GH, she reported significant lethargy with static growth and increased weight. Combinations of Metformin with differing insulin regimes did not improve glucose levels. Liraglutide (GLP-1 agonist) and Metformin did not improve glucose levels nor her weight. Liraglutide and Empaglifozin (SGLT-2 inhibitor) therapy used in combination were well tolerated and demonstrated rapid normalisation of blood glucose and improvement in her HbA1c to within target (48 mmol/mol) which was sustained after 6 months of treatment. Conclusions Newer treatments for type 2 diabetes (e. g. GLP-1 agonists or SGLT-2 inhibitors) offer potential treatment options for those with diabetes and PWS when conventional treatments are ineffective.",
"affiliations": "Department of Paediatric Endocrinology, Bristol Royal Hospital for Children, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.;Department of Paediatrics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.;Department of Paediatric Endocrinology, Bristol Royal Hospital for Children, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.;Department of Paediatrics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.;Department of Paediatric Endocrinology, Bristol Royal Hospital for Children, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.",
"authors": "Candler|Toby|T|https://orcid.org/0000-0002-4587-8744;McGregor|David|D|;Narayan|Kruthika|K|;Moudiotis|Chris|C|;Burren|Christine P|CP|",
"chemical_list": "D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; C570240:empagliflozin",
"country": "Germany",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0334-018X",
"issue": "33(7)",
"journal": "Journal of pediatric endocrinology & metabolism : JPEM",
"keywords": "Prader-Willi syndrome; SGLT-2 inhibitors; children and adolescents; incretin therapies",
"medline_ta": "J Pediatr Endocrinol Metab",
"mesh_terms": "D000293:Adolescent; D001559:Benzhydryl Compounds; D001786:Blood Glucose; D002648:Child; D003920:Diabetes Mellitus; D004359:Drug Therapy, Combination; D005260:Female; D052216:Glucagon-Like Peptide 1; D005960:Glucosides; D006801:Humans; D000069450:Liraglutide; D011218:Prader-Willi Syndrome; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D016896:Treatment Outcome",
"nlm_unique_id": "9508900",
"other_id": null,
"pages": "951-955",
"pmc": null,
"pmid": "32447330",
"pubdate": "2020-07-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Improvement in glycaemic parameters using SGLT-2 inhibitor and GLP-1 agonist in combination in an adolescent with diabetes mellitus and Prader-Willi syndrome: a case report.",
"title_normalized": "improvement in glycaemic parameters using sglt 2 inhibitor and glp 1 agonist in combination in an adolescent with diabetes mellitus and prader willi syndrome a case report"
} | [
{
"companynumb": "GB-ALKEM LABORATORIES LIMITED-GB-ALKEM-2020-02473",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "INSULIN GLARGINE"
},
... |
{
"abstract": "Our objective is to describe a chronic myeloid leukemia patient with a severe liver toxicity likely due to a drug-drug interaction between imatinib and sertraline. The patient started treatment with sertraline three months after starting imatinib. From the beginning of sertraline treatment, the patient developed vomiting, and five weeks later she developed a severe hepatic failure and was admitted to the hospital. The Naranjo nomogram showed a probable correlation between this adverse effect and the interaction between imatinib and sertraline. This interaction is extremely rare and the mechanism of action is not clear; it could be a mix of pharmacokinetic and pharmacodynamic processes. To our knowledge, this is the first case in medical literature of a severe liver toxicity due to an interaction between imatinib and sertraline. This interaction is also not described in the main secondary data sources, such as Lexicomp® and Micromedex®. However, due to the severity of this event, the hepatic function should be carefully monitored in patients treated with imatinib and sertraline.",
"affiliations": "1 Hematology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;2 Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.;4 Unidad de Hematología y Oncología Médica, Hospital Morales-Meseguer, IMIB-Murcia, Murcia, Spain.;1 Hematology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;1 Hematology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;5 Unidad de Hematología y Oncología Médica, Hospital Morales-Meseguer, Centro Regional de Hemodonación, IMIB-Murcia, Murcia, Spain.",
"authors": "Osorio|Santiago|S|;Escudero-Vilaplana|Vicente|V|http://orcid.org/0000-0003-4417-8321;Reguilón-Gallego|Laura|L|;Gómez-Centurión|Ignacio|I|;Díez|José Luis|JL|;Ferrer-Marín|Francisca|F|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1078155217735689",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": null,
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Drug–drug interaction; hepatotoxicity; imatinib; safety; sertraline",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": null,
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1078155217735689",
"pmc": null,
"pmid": "29065786",
"pubdate": "2017-01-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Severe liver toxicity in a chronic myeloid leukemia patient probably induced by a drug interaction between imatinib and sertraline.",
"title_normalized": "severe liver toxicity in a chronic myeloid leukemia patient probably induced by a drug interaction between imatinib and sertraline"
} | [
{
"companynumb": "ES-TEVA-2017-ES-829875",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METOCLOPRAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Pneumatosis cystoides intestinalis (PCI) is a relatively rare condition in which gas is found as a linear or cystic form in the submucosa or subserosa of bowel wall. PCI is usually found incidentally on an imaging study. Treatment is usually conservative including oxygen and antibiotics therapy. So far, etiology and pathogenesis of PCI remain uncertain. PCI is associated with various medical conditions including various pulmonary diseases, connective tissue diseases, and endoscopic procedures. However, there are only few reports on lactulose causing PCI in patients with cirrhosis. Oral lactulose or enema is one of the main treatment modalities in hepatic encephalopathy. Here, we report a case of PCI which was found during the treatment with lactulose therapy in a patient with liver cirrhosis and hepatic encephalopathy.",
"affiliations": "Naju Central Hospital, and Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.",
"authors": "Lee|Jeong-Soo|JS|;Joo|So-Young|SY|;Park|Chang-Hwan|CH|;Park|Seon-Young|SY|;Park|Hyeong-Cheon|HC|;Kim|Hyun Soo|HS|;Choi|Sung Kyu|SK|;Rew|Jong Sun|JS|",
"chemical_list": "D005765:Gastrointestinal Agents; D007792:Lactulose",
"country": "Korea (South)",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1598-9992",
"issue": "50(1)",
"journal": "The Korean journal of gastroenterology = Taehan Sohwagi Hakhoe chi",
"keywords": null,
"medline_ta": "Korean J Gastroenterol",
"mesh_terms": "D005765:Gastrointestinal Agents; D006801:Humans; D007792:Lactulose; D008103:Liver Cirrhosis; D008297:Male; D008875:Middle Aged; D011006:Pneumatosis Cystoides Intestinalis; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101189416",
"other_id": null,
"pages": "56-60",
"pmc": null,
"pmid": "18172360",
"pubdate": "2007-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of pneumatosis cystoides intestinalis in a cirrhosis patient.",
"title_normalized": "a case of pneumatosis cystoides intestinalis in a cirrhosis patient"
} | [
{
"companynumb": "VISTAPHARM, INC.-VER201801-000303",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LACTULOSE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nThough technically feasible, free tissue transfer carries the risk of perioperative morbidity and mortality in elderly patients. To minimize the operative treatment time and complication rates, we choose the rectus abdominis muscle (RAM) flap.\n\n\nMETHODS\nBetween 2012 and 2017, 34 patients (mean age: 74±7 years, range: 65-89 years) with comorbidities underwent defect reconstruction with a free RAM flap. Recipient-sites were: lower extremity (65%), trunk (18%), upper extremity (12%), and head and neck (6%).\n\n\nRESULTS\nThe ASA status was 2 in 11 patients, 3 in 21 patients, and 4 in 2 patients. Twenty patients (59%) received additional vascular surgery. Three patients (9%) underwent simultaneous restoration of fractures. The mean operative time (OT) was 325±75 min. There was no total flap loss. Partial flap loss occurred in one patient (3%). The incidence of surgical and medical complications was 32% and 38%: 11 patients experienced a total of 22 surgical complications, of which 15 were major (requiring additional surgery) and 7 minor (conservative treatment). One patient died postoperatively because of progressive respiratory failure. Prolonged OT was highly associated with hematoma formation requiring re-operation (p = 0.01). ASA status was a significant predictor for postoperative critical care monitoring (p = 0.03). Reconstruction was successful in 31 out of 34 patients (91%) during a mean follow-up time of 17.7 ± 8.8 months (range: 2-51 months).\n\n\nCONCLUSIONS\nThe free RAM flap has proven as a reliable and efficient tool in the armamentarium of reconstructive microvascular surgeons with some advantages in the treatment of multimorbid patients older than 65 years.",
"affiliations": "Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, Hand and Plastic Surgery, University of Heidelberg, Ludwig-Guttmann-Strasse 13, 67071 Heidelberg, Germany.;Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, Hand and Plastic Surgery, University of Heidelberg, Ludwig-Guttmann-Strasse 13, 67071 Heidelberg, Germany.;Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, Hand and Plastic Surgery, University of Heidelberg, Ludwig-Guttmann-Strasse 13, 67071 Heidelberg, Germany.;Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, Hand and Plastic Surgery, University of Heidelberg, Ludwig-Guttmann-Strasse 13, 67071 Heidelberg, Germany.;Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, Hand and Plastic Surgery, University of Heidelberg, Ludwig-Guttmann-Strasse 13, 67071 Heidelberg, Germany.;Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, Hand and Plastic Surgery, University of Heidelberg, Ludwig-Guttmann-Strasse 13, 67071 Heidelberg, Germany.;Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, Hand and Plastic Surgery, University of Heidelberg, Ludwig-Guttmann-Strasse 13, 67071 Heidelberg, Germany. Electronic address: amir.bigdeli@bgu-ludwigshafen.de.",
"authors": "Thomas|Benjamin|B|;Gazyakan|Emre|E|;Falkner|Florian|F|;Schmidt|Volker J|VJ|;Hirche|Christoph|C|;Kneser|Ulrich|U|;Bigdeli|Amir K|AK|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.bjps.2019.01.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1748-6815",
"issue": "72(4)",
"journal": "Journal of plastic, reconstructive & aesthetic surgery : JPRAS",
"keywords": "Elderly; Multimorbid; Rectus abdominis muscle flap",
"medline_ta": "J Plast Reconstr Aesthet Surg",
"mesh_terms": "D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D058752:Free Tissue Flaps; D006801:Humans; D008297:Male; D019651:Reconstructive Surgical Procedures; D017568:Rectus Abdominis; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "101264239",
"other_id": null,
"pages": "555-564",
"pmc": null,
"pmid": "30770213",
"pubdate": "2019-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Free tissue transfer with the free rectus abdominis flap in high-risk patients above 65 years: A retrospective cohort study.",
"title_normalized": "free tissue transfer with the free rectus abdominis flap in high risk patients above 65 years a retrospective cohort study"
} | [
{
"companynumb": "DE-TEVA-2019-DE-1047243",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "3",
... |
{
"abstract": "Ingestion of sulfonylureas is life-threatening in toddlers and children due to its strong and prolonged hypoglycemic effect. The authors present a 15-mo-old boy with accidental ingestion of Glipizide who presented with encephalopathy, seizure and severe hypoglycemia. The management included parenteral dextrose and octreotide administration to maintain euglycemia, followed by complete neurological recovery within 24 h. Sulphonylurea intoxication should be considered in previously healthy toddlers and children presenting with hypoglycemia especially if any caregiver is on sulfonylurea drugs.",
"affiliations": "Department of Pediatrics, Advanced Pediatrics Center, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India.;Department of Pediatrics, Advanced Pediatrics Center, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India.;Department of Pediatrics, Advanced Pediatrics Center, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India.;Department of Pediatrics, Advanced Pediatrics Center, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India.;Department of Pediatrics, Advanced Pediatrics Center, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India. mjshree@hotmail.com.;Department of Pediatrics, Advanced Pediatrics Center, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India.",
"authors": "Kumar|Suresh|S|;Choudhary|Abhijit|A|;Ali|Mahammad|M|;Gupta|Vipul|V|;Muralidharan|Jayashree|J|;Singhi|Sunit C|SC|",
"chemical_list": "D005765:Gastrointestinal Agents; D007004:Hypoglycemic Agents; D005947:Glucose; D015282:Octreotide; D005913:Glipizide",
"country": "India",
"delete": false,
"doi": "10.1007/s12098-016-2249-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0019-5456",
"issue": "84(2)",
"journal": "Indian journal of pediatrics",
"keywords": "Dextrose; Hypoglycemia; Octreotide; Sulfonylurea",
"medline_ta": "Indian J Pediatr",
"mesh_terms": "D005765:Gastrointestinal Agents; D005913:Glipizide; D005947:Glucose; D006801:Humans; D007004:Hypoglycemic Agents; D007223:Infant; D008297:Male; D015282:Octreotide",
"nlm_unique_id": "0417442",
"other_id": null,
"pages": "147-149",
"pmc": null,
"pmid": "27796819",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19142176;15200348;20352540;22165864;21606145;21878825;16909651;17015284;23827165;9255206",
"title": "Sulfonylurea Poisoning in a Healthy Toddler.",
"title_normalized": "sulfonylurea poisoning in a healthy toddler"
} | [
{
"companynumb": "IN-MYLANLABS-2017M1010366",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GLIPIZIDE"
},
"drugadditional": null,
... |
{
"abstract": "Anaplastic lymphoma kinase (ALK) gene fusions occur in 3%-7% of non-small-cell lung cancer (NSCLC) cases. Ceritinib, a once-daily, oral ALK inhibitor, has activity against crizotinib-resistant and crizotinib-naïve NSCLC, including brain metastases. Ceritinib (Zykadia™) was granted accelerated approval by the US Food and Drug Administration in 2014 for treating crizotinib-resistant ALK-positive NSCLC. Adverse events (AEs), particularly gastrointestinal (GI) AEs, are commonly experienced at the recommended dose of 750 mg/d and ∼38% of patients require dose interruption or reduction for GI AEs. This case study details our experience with the use of proactive GI AE management regimens in patients treated with ceritinib (750 mg/d) across two study sites. Proactive Regimens A and B were implemented in patients with metastatic ALK-positive NSCLC treated with ceritinib to manage drug-related GI AEs. Regimen A comprised ondansetron and diphenoxylate/atropine or loperamide, taken 30 minutes prior to ceritinib dose. Regimen B included dicyclomine (taken with the first ceritinib dose), ondansetron (taken 30 minutes prior to ceritinib dose for the first seven doses), and loperamide (taken as needed with the onset of diarrhea). The proactive medications were tapered off depending on patient tolerability to ceritinib. Nine patient cases are presented. Starting Regimens A or B before the first dose of ceritinib, or as soon as GI symptoms were encountered, prevented the need for dose reduction due to GI toxicity in eight of the nine patients. Using these regimens, 78% of patients were able to remain on 750 mg/d fasting. Two patients received 23 months and 16 months of therapy and remain on ceritinib 750 mg/d and 600 mg/d, respectively. Although not currently recommended or implemented in clinical studies, based on the patients evaluated here, upfront or proactive treatment plans that address AEs early on can allow the majority of patients to remain on the approved 750 mg/d ceritinib dose.",
"affiliations": "Section of Medical Oncology, Highlands Oncology Group, Fayetteville, AR, USA.;Department of Medicine, Medical Oncology Division, University of Washington School of Medicine, Seattle, WA, USA.",
"authors": "Schaefer|Eric S|ES|;Baik|Christina|C|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/CMAR.S96471",
"fulltext": "\n==== Front\nCancer Manag ResCancer Manag ResCancer Management and ResearchCancer Management and Research1179-1322Dove Medical Press 10.2147/CMAR.S96471cmar-8-033Original ResearchProactive management strategies for potential gastrointestinal adverse reactions with ceritinib in patients with advanced ALK-positive non-small-cell lung cancer Schaefer Eric S 1Baik Christina 21 Section of Medical Oncology, Highlands Oncology Group, Fayetteville, AR, USA2 Department of Medicine, Medical Oncology Division, University of Washington School of Medicine, Seattle, WA, USACorrespondence: Eric S Schaefer, Section of Medical Oncology, Highlands Oncology Group, 3232 N Northhills Boulevard, Fayetteville, AR 72703, USA, Tel +1 479 601 3145, Email eschaefer@hogonc.com2016 24 3 2016 8 33 38 © 2016 Schaefer and Baik. This work is published and licensed by Dove Medical Press Limited2016The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Anaplastic lymphoma kinase (ALK) gene fusions occur in 3%–7% of non-small-cell lung cancer (NSCLC) cases. Ceritinib, a once-daily, oral ALK inhibitor, has activity against crizotinib-resistant and crizotinib-naïve NSCLC, including brain metastases. Ceritinib (Zykadia™) was granted accelerated approval by the US Food and Drug Administration in 2014 for treating crizotinib-resistant ALK-positive NSCLC. Adverse events (AEs), particularly gastrointestinal (GI) AEs, are commonly experienced at the recommended dose of 750 mg/d and ∼38% of patients require dose interruption or reduction for GI AEs. This case study details our experience with the use of proactive GI AE management regimens in patients treated with ceritinib (750 mg/d) across two study sites. Proactive Regimens A and B were implemented in patients with metastatic ALK-positive NSCLC treated with ceritinib to manage drug-related GI AEs. Regimen A comprised ondansetron and diphenoxylate/atropine or loperamide, taken 30 minutes prior to ceritinib dose. Regimen B included dicyclomine (taken with the first ceritinib dose), ondansetron (taken 30 minutes prior to ceritinib dose for the first seven doses), and loperamide (taken as needed with the onset of diarrhea). The proactive medications were tapered off depending on patient tolerability to ceritinib. Nine patient cases are presented. Starting Regimens A or B before the first dose of ceritinib, or as soon as GI symptoms were encountered, prevented the need for dose reduction due to GI toxicity in eight of the nine patients. Using these regimens, 78% of patients were able to remain on 750 mg/d fasting. Two patients received 23 months and 16 months of therapy and remain on ceritinib 750 mg/d and 600 mg/d, respectively. Although not currently recommended or implemented in clinical studies, based on the patients evaluated here, upfront or proactive treatment plans that address AEs early on can allow the majority of patients to remain on the approved 750 mg/d ceritinib dose.\n\nVideo abstract\n\n\n\nKeywords\ncase studiestolerabilityantidiarrhealantiemeticGI symptoms\n==== Body\nIntroduction\nAnaplastic lymphoma kinase (ALK) gene fusions and mutations are implicated in the pathogenesis of several human cancers.1 The fusion of echinoderm microtubule-associated protein-like 4 (EML4) with ALK is the most frequent of known ALK rearrangements resulting in constitutive oncogenic ALK activation. ALK gene rearrangement occurs in 3%–7% of non-small-cell lung cancer (NSCLC) cases,2,3 with higher prevalence in younger patients with adenocarcinoma who are never- or light smokers.4\n\nThe ALK protein is thus a therapeutic target for the treatment of ALK-rearranged (ALK-positive) NSCLC, and a number of ALK inhibitors are currently under clinical development. Crizotinib (XALKORI®), an oral first-in-class dual ALK and c-MET inhibitor, was approved by the US Food and Drug Administration (FDA) in 2011 to treat metastatic ALK-positive NSCLC in any line, having demonstrated clinical efficacy.5 In clinical trials, crizotinib achieved an overall response rate (ORR) of 60% and a median progression-free survival (PFS) of 8–10 months.6,7 However, patients ultimately acquire resistance within 1–2 years of therapy, resulting in disease progression, thus limiting its long-term application.8,9\n\nNext-generation ALK inhibitors that overcome crizotinib resistance have been developed. Ceritinib (ZYKADIA™) is a once-daily oral, small-molecule, ATP-competitive ALK inhibitor that is 20 times more potent against ALK than crizotinib in preclinical studies, with activity against common secondary ALK mutations that confer resistance to crizotinib.10 Ceritinib was granted accelerated approval by the US FDA in 2014 for treating metastatic, ALK-positive NSCLC that has progressed on or is intolerant to crizotinib, based on response rate and duration of response.11 In a Phase I study, 246 ALK inhibitor-treated and ALK inhibitor-naïve patients with NSCLC achieved ORRs of 56% and 72%, respectively, with a median duration of response of 9.7 months. Median PFS was 6.9 months in prior ALK inhibitor-treated patients and 18.4 months in ALK inhibitor-naïve patients.12 Ceritinib dosed at 750 mg/d also demonstrated antitumor activity in patients with ALK-positive NSCLC, including brain metastases, with durable intracranial responses (overall intracranial response rate [OIRR]: 34.5%) observed in either previously untreated (OIRR: 60.0%) or crizotinib-treated patients (OIRR: 29.2%).13\n\nCeritinib is recommended at a dose of 750 mg/d, administered orally on an empty stomach (not within 2 hours of a meal).14 A food effect study14 in healthy volunteers found that dosing with a high-fat meal increases ceritinib systemic exposure (peak plasma levels) by 43%, compared with the fasted state. Adverse events (AEs) are commonly experienced at this dose level and ∼60% of patients initiating treatment at 750 mg/d require at least one dose reduction, with a median time to first dose reduction of 7 weeks. The majority of patients (96%; 14% severe cases) in the Phase I study experienced gastrointestinal (GI) AEs, including diarrhea, nausea, vomiting, and abdominal pain, when taking the recommended ceritinib dose. In clinical studies, GI AEs are one of the most common reasons for dose modification (38% of patients).14\n\nCurrent recommendations for the management of GI AEs are reactive and include 1) symptomatic treatment with antiemetic or antidiarrheal therapy or 2) treatment interruption and dose reduction in severe cases.14 Maintaining the prescribed dose is important for preserving efficacious systemic drug exposure. During crizotinib therapy, most relapses in patients with ALK-positive NSCLC occur in the brain15,16; therefore, the dose of ceritinib – and consequent systemic and intracranial exposure – may affect the central nervous system (CNS) concentration, which is critical for the control of CNS metastases. As such, upfront proactive treatment regimens to address nausea (eg, ondansetron [Zofran]), diarrhea (eg, loperamide [Imodium]), and abdominal pain (eg, dicyclomine [Bentyl]) could be implemented in clinics to help ensure optimum ceritinib exposure and efficacy. Here, we report a case series of nine patients treated with ceritinib (750 mg/d) for whom proactive GI AE management strategies were implemented.\n\nPatients and methods\nAll patients had metastatic ALK positive NSCLC and were participants in ceritinib clinical trials. The study protocols allowed investigators to use both reactive and proactive medications to help deal with the normal GI side effects (NCT01283516, NCT01947608, NCT01685060, and NCT01828112). All clinical studies involved were conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Conference on Harmonization. All protocols were approved by relevant Institutional Review Boards and Ethics Committees. Written informed consent was obtained from all the patients before screening. All patients were initially dosed orally with ceritinib (750 mg/d) fasting. Patients were encouraged to maintain dosage at the same time of day for the duration of the study.\n\nProactive regimens\nBetween the two study sites, two proactive regimens were implemented in patients with metastatic ALK-positive NSCLC treated with ceritinib to manage drug-related GI AEs (Figure 1). The use of these regimens was consistent with the protocol recommendations. Regimen A comprised ondansetron 8 mg, along with either diphenoxylate and atropine 2.5 mg or loperamide 2 mg, to be taken orally 30 minutes prior to the ceritinib dose. Additional agents were administered for persistent symptoms. Regimen B included dicyclomine 20 mg twice daily (to be taken orally starting with the first ceritinib dose), ondansetron 8 mg (to be taken orally 30 minutes prior to ceritinib dose for the first seven doses), and loperamide 2 mg (to be taken orally as needed with the onset of diarrhea; two tablets at onset and one tablet with every loose stool). If diarrhea persisted with loperamide, then diphenoxylate and atropine (Lomotil) 2.5 mg was prescribed, to be taken every 6 hours as needed. For both regimens, the proactive medications were tapered off, depending on clinically judged patient tolerability to ceritinib. For instance, for Regimen A, if patients reported lack of nausea but ongoing diarrhea, prophylactic antidiarrheal medication was continued, while antinausea medication use was changed from prophylactic to as-needed (PRN) basis. For Regimen B, patients remained on the prophylactic regimen for two cycles. After two cycles, the following were recommended:\nStop the dicyclomine at Week 1 of Cycle 3. If Grade 1 cramping occurs, use PRN, and restart dose if Grade 2 or greater.\n\nStop the ondansetron at Week 2 of Cycle 3. If Grade 1 nausea or vomiting is seen, use PRN, and restart dose if Grade 2 or greater.\n\nStop the loperamide at Week 3 of Cycle 3. If Grade 1 diarrhea occurs, use PRN, and restart if Grade 2 or greater. Safety and tolerability of ceritinib in patients were monitored according to the Common Terminology Criteria for Adverse Events v4.03.\n\n\n\nResult\nPatient characteristics and treatment\nA total of nine patients were included in this series. These patients were enrolled into ceritinib clinical trials across two sites and were treated by the authors, between October 2012 and March 2014. Table 1 provides an overview of patient characteristics, treatment history, and proactive management strategies. Ceritinib was the second to fifth line of treatment for these patients. Eight of nine patients had previously received crizotinib and had discontinued due to disease progression or intolerance. All patients were dosed at 750 mg/d and provided upfront with a GI AE treatment regimen to proactively address the AEs that are experienced by the majority of patients taking ceritinib. Preventive regimens were also used to potentially avoid remote AE management for patients traveling long distances to clinical study sites. Patients 1–4 were started on the two-drug proactive Regimen A, while Patients 5–9 received the three-drug Regimen B. Preventive treatment was initiated at the start of ceritinib therapy.\n\nTreatment outcome\nIn eight of the nine patients starting Regimens A and B prior to initiation of ceritinib therapy, dose reductions due to GI toxicity were not required (Table 1). Patient 3 required dose reduction to 600 mg/d due to grade 3 transaminitis. Patient 4 discontinued therapy due to GI toxicities despite receiving proactive treatment. Patient 5 had a 1-week ceritinib dose interruption due to elevated creatinine levels but resumed treatment at the recommended 750 mg/d dose. In a Phase I study,12 31% of patients experienced grade 1–2 constipation while on ceritinib 750 mg/d. Two patients on Regimen A experienced intermittent constipation, suspected to be due to the use of antidiarrheal medication. Proactive regimens were tapered off in two patients on Regimen A (Patients 1 and 3) and three patients on Regimen B (Patients 5, 7, and 8) as tolerability to ceritinib increased. Proactive treatment was continued in patients who experienced persistence of diarrhea/nausea in either regimen.\n\nUsing these proactive regimens, seven of the nine (78%) patients were able to remain on ceritinib 750 mg/d fasting, with a dose reduction rate for GI side effects of 12.5% (one out of the eight patients) when accounting for the one patient whose dose was reduced due to transaminitis. Patients 3 and 7 received 16 months and 23 months of therapy and remain on ceritinib to date at 600 mg/d and 750 mg/d, respectively. All other patients discontinued ceritinib due to progressive disease, comorbidity, or intolerance.\n\nDiscussion\nCeritinib is recommended at an oral, once-daily dose of 750 mg/d based on clinical efficacy results from the Phase I dose-escalation study.11 The current prescribing information recommends ceritinib dose interruption and modification for patients experiencing intolerable nausea, vomiting, or diarrhea despite optimal antiemetic or antidiarrheal therapy.14 In the case series presented herein, only one patient discontinued ceritinib treatment due to GI-related toxicity. A majority of patients were able to remain on ceritinib at 750 mg/d within the prescribing guidelines (ie, without food) and without the need for dose reductions or interruptions due to GI AEs.\n\nPreclinical studies have shown that ceritinib crosses the blood–brain barrier in non-tumor-bearing rats, and in the Phase I study, patients with ALK-positive NSCLC and documented brain metastases who received ceritinib 750 mg/d had an intracranial antitumor response rate of 34.5%.13\n\nThis study was limited by the relatively small number of patients treated at our institutions and a lack of comparator patients who did not receive the proactive regimen. Nonetheless, considering that 38% of patients on ceritinib require dose modification due to GI AEs,14 on the basis of the nine patients evaluated here, implementation of proactive drug treatment plans, such as Regimens A and B, may significantly increase the number of patients who remain on 750 mg daily.\n\nGI AEs experienced on tyrosine kinase inhibitor therapy can be distressing for patients and if persistent, may affect their quality of life.17 In our experience, the initial 1–2 weeks of treatment are often the most difficult time for patients, and therefore addressing potential AEs at this stage may help prevent deviations from the recommended 750 mg daily dose. Adherence to therapy is a pertinent issue for cancer patients, and it is estimated that up to 80% of patients do not take oral antineoplastic agents according to their prescription.18 These two regimens allow for the initiation of supportive care with the first dose and are then tapered off based upon symptoms, to minimize the duration of needed treatment. Patient education has been reported to increase patient adherence to oral anticancer agents.18 Therefore, preparing patients and physicians to expect adverse reactions is valuable; dispensing the supportive medication prior to leaving the office and taking the first dose is essential; and presenting proactive AE treatment options upfront as part of a treatment package could help maximize patient drug exposure as they start a new therapy.\n\nAcknowledgments\nThis study was supported by Novartis Pharmaceuticals. We thank the participating patients, their families, research coordinators, and nurses, as well as thanking Maria Alfaradhi from Articulate Science for providing editorial assistance.\n\nDisclosure\n\nCB has received institutional research support from Novartis Pharmaceuticals Corporation. CB and ESS have participated as advisory board members for Novartis Pharmaceuticals Corporation. The authors report no other conflicts of interest in this work.\n\nFigure 1 Schematic representation of proactive regimens A and B.\n\nNotes:\naTaken 30 minutes before ceritinib dose. All agents to be taken orally. Patients were tapered off proactive treatment based on symptoms.\n\nAbbreviations: bid, twice daily; d, dose; PRN, as needed; Q4h, every 4 hours; Q6h, every 6 hours; qd, once daily.\n\nTable 1 Patient characteristics\n\n\tPatient\n\t\n1\t2\t3\t4\t5\t6\t7\t8\t9\t\nAge at enrollment, years\t64\t54\t62\t72\t53\t57\t81\t48\t41\t\nLine of therapy\tThird\tSecond\tFourth\tFifth\tFifth\tThird\tThird\tFourth\tThird\t\nPrevious regimens\t• Carbo/PEM\n• Crizotinib\t• P/Carbo + RT\t• Carbo/PEM\n• P\n• Crizotinib\t• P/Carbo\n• DTX\n• PEM + Bev\n• Crizotinib\t• Erlotinib\n• P/Carbo\n• PEM\n• Crizotinib\t• Carbo/PEM + Bev\n• Crizotinib\t• Carbo/DTX\n• Crizotinib\t• P/Carbo + Bev\n• Crizotinib\n• P/Cis\t• Cis/PEM\n• Crizotinib\t\nOther previous therapies\tWBRT\tChest RT\tWBRT\tChest RT\tNone\tNone\tCraniotomy in Jul 2013; SRS in Jul 2013\tNone\tSRS Apr 2012\t\nReasons for discontinuation of previous therapy\tPD\tPD\tPD\tPD\tPD\tIntolerance\tIntolerance; brain and bone lesions\tBrain metastasis\tPD in brain (LC)\t\nTime on ceritinib treatmenta\t4 months: Nov 2013–Mar 2014\t5 months: Oct 2012–Mar 2013\t>16 months: Mar 2014–Aug 2015 (ongoing with dose reduction to600 mg/d due to Gr 3 transaminitis)\t2 weeks: Nov 2013\t20 months: Jan 2013–Aug 2014\t2 months: Mar 2014–Apr 2014\t>23 months: Aug 2013–Aug 2015 (ongoing at 750 mg/d)\t4 months: Jul 2013–Oct 2013\t2 months: Mar 2014–Apr 2014 (compassionate use – transferred to commercial drug)\t\nReasons for discontinuation of ceritinib\tNew primary malignancy\tComorbidity\tOngoing\tAbdominal cramps, diarrhea\tPD\tPD\tOngoing\tPD in brain\tPD/death\t\nInitial regimen\tRegimen A\t\t\t\tRegimen B\t\t\t\t\t\n\tOndansetron and diphenoxylate/atropine\tOndansetron and loperamide\tOndansetron and diphenoxylate/atropine\tOndansetron and diphenoxylate/atropine\tOndansetron, dicyclomine, and loperamide\t\t\t\t\t\nOther agents added\tNone\tLorazepam, dicyclomine, and dronabinol\tNone\tNone\tDiphenoxylate/atropine for persistent diarrhea\t\t\t\t\t\nNote:\n\na Treated at University of Washington for patients 1–4 and Highlands Oncology Group for patients 5–9.\n\nAbbreviations: Bev, bevacizumab; Carbo, carboplatin; Cis, cisplatin; DTX, docetaxel; Gr, grade; LC, leptomeningeal carcinomatosis; P, paclitaxel; PD, progressive disease; PEM, pemetrexed; RT, radiotherapy; SRS, stereotactic radiosurgery; WBRT, whole-brain radiotherapy.\n==== Refs\nReferences\n1 Barreca A Lasorsa E Riera L European T-Cell Lymphoma Study Group Anaplastic lymphoma kinase in human cancer J Mol Endocrinol 2011 47 1 R11 R23 21502284 \n2 Soda M Choi YL Enomoto M Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer Nature 2007 448 7153 561 566 17625570 \n3 Wong DW Leung EL So KK University of Hong Kong Lung Cancer Study Group The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS Cancer 2009 115 8 1723 1733 19170230 \n4 Shaw AT Solomon B Targeting anaplastic lymphoma kinase in lung cancer Clin Cancer Res 2011 17 8 2081 2086 21288922 \n5 Xalkori® New York, NY Pfizer Labs, Pfizer Inc.; FDA-approved prescribing information ; LAB-0441-702015 Available from: http://labeling.pfizer.com/showlabeling.aspx?id=676 Accessed February 25, 2016\n6 Shaw AT Kim DW Nakagawa K Crizotinib versus chemotherapy in advanced ALK-positive lung cancer N Engl J Med 2013 368 25 2385 2394 23724913 \n7 Camidge DR Bang YJ Kwak EL Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study Lancet Oncol 2012 13 10 1011 1019 22954507 \n8 Katayama R Shaw AT Khan TM Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers Sci Transl Med 2012 4 120 120ra17 \n9 Doebele RC Pilling AB Aisner DL Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer Clin Cancer Res 2012 18 5 1472 1482 22235099 \n10 Li N Michellys PY Kim S Activity of a potent and selective phase I ALK inhibitor LDK378 in naive and crizotinib-resistant preclinical tumor models Poster presented at: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics November 12–16 2011 San Francisco, CA Abstract B232 \n11 Shaw AT Kim DW Mehra R Ceritinib in ALK-rearranged non-small-cell lung cancer N Engl J Med 2014 370 13 1189 1197 24670165 \n12 Felip E Kim D Mehra R Efficacy and safety of ceritinib in patients with advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC): an update of ASCEND-1 Poster presented at: European Society for Medical Oncology Congress September 26–30 2014 Madrid, Spain Abstract 1295P \n13 Shaw AT Felip E Vansteenkiste JF Evaluation of ceritinib-treated patients (pts) with anaplastic lymphoma kinase rearranged (ALK+) non-small cell lung cancer (NSCLC) and brain metastases in the ASCEND-1 study Poster presented at: European Society for Medical Oncology Congress September 26–30 2014 Madrid, Spain Abstract 1293P \n14 Novartis Pharmaceuticals Corporation: Zykadia™ FDA-approved prescribing information; T2015-114/T2015-115 2015 Available from: http://www.pharma.us.novartis.com/product/pi/pdf/zykadia.pdf Accessed February 10, 2016 \n15 Weickhardt AJ Scheier B Burke JM Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer J Thorac Oncol 2012 7 12 1807 1814 23154552 \n16 Shaw AT Yeap BY Solomon BJ Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis Lancet Oncol 2011 12 11 1004 1012 21933749 \n17 Califano R Tariq N Compton S Expert consensus on the management of adverse events from EGFR tyrosine kinase inhibitors in the UK Drugs 2015 75 12 1335 1348 26187773 \n18 Partridge AH Avorn J Wang PS Winer EP Adherence to therapy with oral antineoplastic agents J Natl Cancer Inst 2002 94 9 652 661 11983753\n\n",
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"issue": "8()",
"journal": "Cancer management and research",
"keywords": "GI symptoms; antidiarrheal; antiemetic; case studies; tolerability",
"medline_ta": "Cancer Manag Res",
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"nlm_unique_id": "101512700",
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"pubdate": "2016",
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"title": "Proactive management strategies for potential gastrointestinal adverse reactions with ceritinib in patients with advanced ALK-positive non-small-cell lung cancer.",
"title_normalized": "proactive management strategies for potential gastrointestinal adverse reactions with ceritinib in patients with advanced alk positive non small cell lung cancer"
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"abstract": "Capecitabine, an oral prodrug of 5-fluorouracil (5-FU) is extensively used to treat many solid tumors, particularly breast and colorectal cancers. Neurotoxicity of capecitabine has been rarely reported as peripheral neuropathy, cerebellar syndrome, and multifocal leukoencephalopathy. Although very little is known about the pathogenetic mechanisms responsible for this toxicity, dihydropyrimidine dehydrogenase (DPD) deficiency has been found in few of these patients. TYMS gene encodes for the human thymidylate synthase, and is considered a candid factor for toxicity and efficacy of 5-FU and capecitabine. However, TYMS polymorphism has been associated previously with capecitabine-induced neurotoxicity. We report here a 31-year-old patient with metastatic colorectal cancer undergoing chemotherapy consisting of oxaliplatin and capecitabine who developed acute cerebellar syndrome during cycle 5. MRI did not show any abnormalities. We performed pharmacogenetic studies related to capecitabine including DPD deficiency and TYMS polymorphism. DPD gene mutation analysis was negative for the IVS14+1G>A mutation in the DPD gene, which accounts for 50% of the DPD deficiency alleles. However, the patient was found to have 3RG/3RC genotype and Del/Del genotype of TYMS 3'-untranslated region. Withdrawal of capecitabine improved his neurotoxicity in 9 days. No re-challenge was given to this patient but he was able to tolerate irinotecan, oxaliplatin, and bevacizumab without any toxicities. To the best of our knowledge, this is the first patient in the literature who developed acute cerebellar syndrome following capecitabine and was found to have mutations of TYMS. Patients on fluoropyrimidines, including capecitabine with new neurological symptoms must be investigated for a rare but real central neurotoxicity. Though the treatment of 5-FU neurotoxicity is supportive care but use of uridine triacetate may be indicated in few patients, especially with overdose.",
"affiliations": "Department of Medicine, Zucker School of Medicine, Northwell Health Cancer Institute, Lake Success, New York, USA.",
"authors": "Saif|Muhammad W|MW|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D000069287:Capecitabine; C000600377:TYMS protein, human; D013940:Thymidylate Synthase",
"country": "England",
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"issn_linking": "0959-4973",
"issue": "30(4)",
"journal": "Anti-cancer drugs",
"keywords": null,
"medline_ta": "Anticancer Drugs",
"mesh_terms": "D000328:Adult; D000964:Antimetabolites, Antineoplastic; D000069287:Capecitabine; D002526:Cerebellar Diseases; D015179:Colorectal Neoplasms; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D013940:Thymidylate Synthase",
"nlm_unique_id": "9100823",
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"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Capecitabine-induced cerebellar toxicity and TYMS pharmacogenetics.",
"title_normalized": "capecitabine induced cerebellar toxicity and tyms pharmacogenetics"
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"abstract": "Five cases are presented with different types of cerebellar lesions which may be encountered in epileptics. Case 1 represents typical postical lesions, Case 2 perinatal anoxic-ischemic damage, Case 3 transneuronal degeneration causing crossed cerebellar atrophy, Case 4 iatrogenic cerebellar atrophy due to Phenytoin toxicity. Case 5 illustrates the interaction of two mechanisms, postictal lobular sclerosis and transneuronal degeneration. It is suggested that by attention to the type and distribution of the cerebellar lesions, to the clinical history and to the distribution of lesions in other parts of the brain the pathogenetic mechanisms can be elucidated in most cases.",
"affiliations": null,
"authors": "Gessaga|E C|EC|;Urich|H|H|",
"chemical_list": "D010672:Phenytoin",
"country": "Germany",
"delete": false,
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"issn_linking": "0722-5091",
"issue": "4(6)",
"journal": "Clinical neuropathology",
"keywords": null,
"medline_ta": "Clin Neuropathol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D001284:Atrophy; D002526:Cerebellar Diseases; D002531:Cerebellum; D004827:Epilepsy; D005260:Female; D006801:Humans; D002534:Hypoxia, Brain; D007223:Infant; D008297:Male; D008875:Middle Aged; D010672:Phenytoin",
"nlm_unique_id": "8214420",
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"pages": "238-45",
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"pubdate": "1985",
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"references": null,
"title": "The cerebellum of epileptics.",
"title_normalized": "the cerebellum of epileptics"
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{
"abstract": "Partial deletions in chromosomes 1p and 19q are found in a subset of astrocytic tumors; however, it remains unclear how these alterations affect their histological features and prognosis. Herein, we present 3 cases of isocitrate dehydrogenase (IDH)-mutant astrocytoma with chromosome 19q13 deletion. In the first case, the primary tumor harbored an IDH1 mutation with chromosome 1p/19q partial deletions, which covered 19q13 and exhibited a durable initial response to radiotherapy and temozolomide (TMZ) treatment. However, the tumor lost the chromosome 1p/19q partial deletions at recurrence and became resistant to TMZ. Histologically, an oligodendroglioma-like feature was found in the primary tumor but not in the recurrent tumor. Capicua transcriptional repressor (CIC), located on 19q13, was less expressed in the primary tumor but was highly expressed in the recurrent tumor. Similar histological findings were observed in 2 other astrocytic tumors with IDH1 or IDH2 mutations. These tumors also had chromosome 19q13 deletion, including the CIC gene, weakly expressed CIC, and oligodendroglioma-like morphology. These tumors recurred at 6 and 32 months, respectively. These findings suggest that IDH-mutant astrocytoma with chromosome 19q13 partial deletion, including the CIC gene, may induce an oligodendroglioma-like phenotype, but the clinical prognosis may not be similar to that of genetically defined oligodendroglioma.",
"affiliations": "From the Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.;From the Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.;From the Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.;From the Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.;From the Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.;Department of Pathology, Yokohama City University Hospital, Yokohama, Japan.;Department of Pathology, Yokohama City University Hospital, Yokohama, Japan.;Department of Pathology, Yokohama City Minato Red Cross Hospital, Yokohama, Japan.;From the Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.;Department of Neurosurgery, Yokohama City Minato Red Cross Hospital, Yokohama, Japan.;Department of Pathology, Yokohama City University Hospital, Yokohama, Japan.;Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan.;From the Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.;From the Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.",
"authors": "Miyake|Yohei|Y|;Fujii|Keita|K|;Nakamaura|Taishi|T|;Ikegaya|Naoki|N|;Matsushita|Yuko|Y|;Gobayashi|Yuko|Y|;Iwashita|Hiromichi|H|;Udaka|Naoko|N|;Kumagai|Jiro|J|;Murata|Hidetoshi|H|;Takemoto|Yasunori|Y|;Yamanaka|Shoji|S|;Ichimura|Koichi|K|;Tateishi|Kensuke|K|;Yamamoto|Tetsuya|T|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/jnen/nlaa161",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3069",
"issue": "80(3)",
"journal": "Journal of neuropathology and experimental neurology",
"keywords": "\n CIC\n ; Chromosome 19q13 deletion; Oligodendroglioma-like astrocytoma",
"medline_ta": "J Neuropathol Exp Neurol",
"mesh_terms": null,
"nlm_unique_id": "2985192R",
"other_id": null,
"pages": "247-253",
"pmc": null,
"pmid": "33432322",
"pubdate": "2021-02-22",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "IDH-Mutant Astrocytoma With Chromosome 19q13 Deletion Manifesting as an Oligodendroglioma-Like Morphology.",
"title_normalized": "idh mutant astrocytoma with chromosome 19q13 deletion manifesting as an oligodendroglioma like morphology"
} | [
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"companynumb": "JP-009507513-1910JPN002258J",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "We present an 8-year-old male with metastatic alveolar rhabdomyosarcoma (ARMS) who developed precipitous cardiopulmonary collapse with severe tumor lysis syndrome (TLS) 48 hr after initiation of chemotherapy. Despite no detectable pulmonary metastases, acute hypoxemic respiratory failure developed, requiring extracorporeal membrane oxygenation (ECMO). Although TLS has been reported in disseminated ARMS, this singular case of life-threatening respiratory deterioration developing after initiation of chemotherapy presented unique therapeutic dilemmas. We review the clinical aspects of this case, including possible mechanisms of respiratory failure, and discuss the role of ECMO utilization in pediatric oncology.",
"affiliations": "Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts.;Department of Anesthesia and Critical Care Medicine, Boston Children's Hospital, Boston, Massachusetts.;Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.;Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.",
"authors": "Sanford|Ethan|E|;Wolbrink|Traci|T|;Mack|Jennifer|J|;Rowe|R Grant|RG|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.25879",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "63(5)",
"journal": "Pediatric blood & cancer",
"keywords": "ECMO; alveolar rhabdomyosarcoma; pediatric cancer; tumor lysis syndrome",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000208:Acute Disease; D002648:Child; D015199:Extracorporeal Membrane Oxygenation; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D011654:Pulmonary Edema; D018232:Rhabdomyosarcoma, Alveolar; D015275:Tumor Lysis Syndrome",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "928-30",
"pmc": null,
"pmid": "26713672",
"pubdate": "2016-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20466114;24326270;19242331;10199309;15730609;18496413;20517638;21357792;21317556;16567173;16421913;25251585;18837429;2196466;26124967;20959787;23944202",
"title": "Severe Tumor Lysis Syndrome and Acute Pulmonary Edema Requiring Extracorporeal Membrane Oxygenation Following Initiation of Chemotherapy for Metastatic Alveolar Rhabdomyosarcoma.",
"title_normalized": "severe tumor lysis syndrome and acute pulmonary edema requiring extracorporeal membrane oxygenation following initiation of chemotherapy for metastatic alveolar rhabdomyosarcoma"
} | [
{
"companynumb": "US-ACTAVIS-2016-08574",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "4",
"activesubstance": {
"activesubstancename": "IRINOTECAN HYDROCHLORIDE"
},
"drugadditional": nu... |
{
"abstract": "Local anesthetic systemic toxicity (LAST) is a life-threatening complication that may follow application of LAs through various routes. Despite increasing usage of LA techniques in a large number of health-care settings, contemporary awareness of LAST and understanding of its management are inadequate.\nWe report two cases who suffered LAST following brachial plexus block for surgery on the upper extremity. The first patient received an ultrasound-guided supraclavicular block with 300 mg lidocaine (6 mg/kg) and 50 mg ropivacaine (1 mg/kg) in 25 mL without epinephrine, and the second patient received an ultrasound guided interscalene block with 200 mg lidocaine (4.5 mg/kg) and 45 mg ropivacaine (1 mg/kg) supplemented with epinephrine 1:200,000. Both patients presented with symptoms of central nervous and respiratory system depression, the first roughly 10 minutes after injection, and the second immediately after withdrawal of the needle. In both cases, thorough recovery was obtained using lipid-emulsion therapy.\nThe complication of LAST following ultrasound-guided brachial plexus block could be treated successfully applying the American Society of Regional Anesthesia and Pain Medicineprotocol of intravenous administration of lipid emulsion.",
"affiliations": "Center of Emergency, Critical Care Medicine, and Clinical Toxicology, Military Hospital 103, Vietnam Military Medical University, Hanoi, Vietnam.;Department of Cardiothoracic Surgery, Military Hospital 103, Vietnam Military Medical University, Hanoi, Vietnam.;Center of Emergency, Critical Care Medicine, and Clinical Toxicology, Military Hospital 103, Vietnam Military Medical University, Hanoi, Vietnam.;Department of Anesthesia and Pain Medicine, Military Hospital 103, Vietnam Military Medical University, Hanoi, Vietnam.;Department of Anesthesia and Pain Medicine, Military Hospital 103, Vietnam Military Medical University, Hanoi, Vietnam.;Faculty of Medicine, Vietnam Military Medical University, Hanoi, Vietnam.;Department of Anesthesia and Pain Medicine, Military Hospital 103, Vietnam Military Medical University, Hanoi, Vietnam.;Department of Pharmacy, Military Hospital 103, Vietnam Military Medical University, Hanoi, Vietnam.;Center of Anesthesia and Surgical Intensive Care, Vietduc University Hospital, Hanoi, Vietnam.;Anesthesia and Pain Medicine, Cho Ray Hospital, Ho Chi Minh City, Vietnam.",
"authors": "Kien|Nguyen Trung|NT|;Giang|Nguyen Truong|NT|;Van Manh|Bui|B|;Cuong|Nguyen Manh|NM|;Van Dinh|Ngo|N|;Pho|Dinh Cong|DC|;The Anh|Vu|V|;Khanh|Dao Thi|DT|;Quang Thuy|Luu|L|;Van Dong|Pham|P|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/IMCRJ.S207317",
"fulltext": "\n==== Front\nInt Med Case Rep JInt Med Case Rep JIMCRJimcrjInternational Medical Case Reports Journal1179-142XDove 20731710.2147/IMCRJ.S207317Case SeriesSuccessful intralipid-emulsion treatment of local anesthetic systemic toxicity following ultrasound-guided brachial plexus block: case report Kien et alKien et alKien Nguyen Trung 1Giang Nguyen Truong 2Van Manh Bui 1Cuong Nguyen Manh 3Van Dinh Ngo 3Pho Dinh Cong 4The Anh Vu 3Khanh Dao Thi 5Quang Thuy Luu 6Van Dong Pham 71 Center of Emergency, Critical Care Medicine, and Clinical Toxicology, Military Hospital 103, Vietnam Military Medical University, Hanoi, Vietnam2 Department of Cardiothoracic Surgery, Military Hospital 103, Vietnam Military Medical University, Hanoi, Vietnam3 Department of Anesthesia and Pain Medicine, Military Hospital 103, Vietnam Military Medical University, Hanoi, Vietnam4 Faculty of Medicine, Vietnam Military Medical University, Hanoi, Vietnam5 Department of Pharmacy, Military Hospital 103, Vietnam Military Medical University, Hanoi, Vietnam6 Center of Anesthesia and Surgical Intensive Care, Vietduc University Hospital, Hanoi, Vietnam7 Anesthesia and Pain Medicine, Cho Ray Hospital, Ho Chi Minh City, VietnamCorrespondence: Pham Van Dong Anesthesia and Pain Medicine, Cho Ray Hospital, 201 Nguyen Chi Thanh Road, Ward 12, District 5, Ho Chi Minh City700000, VietnamTel +84 90 391 9391 Email pvdongbvcr@gmail.com28 6 2019 2019 12 193 197 01 3 2019 01 6 2019 © 2019 Kien et al.2019Kien et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Background\nLocal anesthetic systemic toxicity (LAST) is a life-threatening complication that may follow application of LAs through various routes. Despite increasing usage of LA techniques in a large number of health-care settings, contemporary awareness of LAST and understanding of its management are inadequate.\n\nCase presentation\nWe report two cases who suffered LAST following brachial plexus block for surgery on the upper extremity. The first patient received an ultrasound-guided supraclavicular block with 300 mg lidocaine (6 mg/kg) and 50 mg ropivacaine (1 mg/kg) in 25 mL without epinephrine, and the second patient received an ultrasound guided interscalene block with 200 mg lidocaine (4.5 mg/kg) and 45 mg ropivacaine (1 mg/kg) supplemented with epinephrine 1:200,000. Both patients presented with symptoms of central nervous and respiratory system depression, the first roughly 10 minutes after injection, and the second immediately after withdrawal of the needle. In both cases, thorough recovery was obtained using lipid-emulsion therapy.\n\nConclusion\nThe complication of LAST following ultrasound-guided brachial plexus block could be treated successfully applying the American Society of Regional Anesthesia and Pain Medicineprotocol of intravenous administration of lipid emulsion.\n\nKeywords\nlocal anesthetic system toxicitylipid emulsion\n==== Body\nBackground\nThe first documented cases of local anesthetic systemic toxicity (LAST) were about 100 years ago, with the report of 40 deaths related to LAs by the American Medical Association in 1928.1 Current data have revealed that the primary mechanism of LAST is multifactorial, with varied cellular consequenses in the cardiovascular system and central nervous system (CNS). Several cohort studies from 1993 to 1997 indicated that the incidence of LAST for epidural anaesthesia was about 1.2–11 per 10,000 cases,2 while incidence after peripheral nerve blockade varied from 2.5 to 9.8 per 10,000.3,4,5 The year 2006 witnessed the first human patient to be sucessfully resuscitated from LAST by lipid emulsion.6 Thereafter, there have been some clinical reports confirming reversal of LAST by lipid emulsion in adults and children.7,8\n\nCase presentation\nCase one\nIn June 2016, a 73-year-old male patient with a body-mass index (BMI) of aproximately 18.5, was admitted to Millitary Hospital 103 with right-hand injury because of a labor accident requiring an emergency surgery for wound debridement and reconstruction of index- and middle-finger amputation under supraclavicular block. Biochemical laboratory values and blood formulae were within normal ranges, except for mildly elevated serum AST and ALT levels of 122 U/L and 117 U/L, respectively. Intravenous access was obtained, 2 L/min oxygen by face mask provided, and routine hemodynamic monitoring performed. On physical examination, the patient's vital signs were steady.\n\nAfter conscious sedation with intravenous 100 µg fentanyl and 20 mg propofol, an ultrasound-guided supraclavicular brachial plexus block was performed with 300 mg lidocaine (6 mg/kg) and 50 mg ropivacaine (1 mg/kg) in 25 mL. Aspiration every 2–5 mL was negative. Verbal communication was sustained during the procedure to monitor mental status and reduce the risk of intraneural injection.\n\nAbout 3 minutes after the block, the patient felt numbness in his arm. Motor block assessed by Bromage score indicated level 2. Roughly 10 minutes after withdrawal ofg the needle, the patient became confused, unconscious, and then apneic. SpO2 decreased from 100% to 50%. Supported ventilation via face mask with 100% oxygen was applied for 5 minutes, and SpO2 recovered to a normal range of 98%–100%. Hemodynamics were stable throughout this period. Spontaneous breathing returned to a rate of 18 per minute, but the patient was still unconscious and did not respond to verbal commands or deep pain stimulation anymore. Pupils were a normal size and replied adequately to light.\n\nAt 20 minutes after loss of consciousness, intravenous 10% lipid-emulsion therapy was initiated with a bolus dose of 3 mL/kg (150 mL) for 1 minute. Immediately after completion of the bolus dose, the patient opened his eyes, responded well to verbal commands, and achieved full recovery. We did not use continuous infusion of lipid emulsion, and the surgical procedure continued for 64 minutes under brachial plexus anesthesia. The patient was transferred to the postoperative care unit with normal hemodynamic and respiratory parameters. He was discharged after 7 days of treatment.\n\nCase two\nIn March 2018, a 32-year-old female patient was admitted to Military Hospital 103 for treatment of an osteoma in the upper head of the left humerus. She had undergone seven operations before, and was scheduled to undergo left glenohumeral joint-replacement procedure. The old surgical site was still swollen and secreting purulent exudate. The patient had an asthenic body habitus with a BMI of 18.5 (1.55 m and 45 kg). ThLaboratory values related to cardiac and pulmonary function were within normal physiological limits. Vital parameters were observed continuously on a Nihon Kohden monitor, oxygen was given via face mask at a rate of 5 L/min, and an 18 G intravenous needle was placed. Her mental status was normal. Vital signs immediately before anesthesia indicated heart rate (HR) 84 beats/minute, blood pressure (BP) 125/55 mmHg, and SpO2 100%.\n\nAn interscalene block was performed under ultrasound guidance. Lidocaine (200 mg) and 45 mg ropivacaine with epinephrine 1:200,000 were administered after ensuring that the tip of the needle was indeed within the plexus cover on the ultrasound screen and there was no blood aspiration in the syringe. While the last 5 mL of anesthetic was being injected, the patient suddenly felt dizzy and reported a metallic taste with perioral and tongue numbness. The anesthesiologist aspirated a small amount of blood in the syringe, stopped the injection, and withdrew the needle. The patient showed clouding of consciousness and slowing response to verbal commands. Vital signs at this time were HR 88 beats/minute, BP 127/60 mmHg, and SpO2 100%. Around 30–40 seconds after stopping injection, HR increased to 140 beats/minute, BP increased to 201/130 mmHg, SpO2 maintained 100%. Two minutes after stopping the injection, the patient lost consciousness completely, breathed very slowly, and was provided ventilation support via face mask and manual resuscitator. The monitor showed that hemodynamic values had returned to the patient’s baseline: HR 89 beats/minute, BP 119/74 mmHg, and SpO2 100%. The cardiac rhythm was sinus, and she remained stable.\n\nTen minutes after LA administration, the patient was given an intravenous injection of 20% lipid emulsion 70 mL for 1 min (3 mg/kg), followed by an infusion of 150 mL for 15 minutes. After the bolus dose of lipid emulsion, the patient regained consciousness, responded well to verbal commands, and was oriented to name and age. After a further 20 minutes, the patient was completely conscious, communicated well, and was fully oriented. Her left upper extremity continued to manifest signs of effective sensory and motor brachial plexus blockade: 2/5 motor strength (movement possible, but not against gravity). She continued to report perioral and tongue numbness. After 2 hours, 20 minutes, patient was transferred to the inpatient ward, where we continued to observe her progression. After 48 hours, the patient had achieved complete recovery and there were no sequelae.\n\nDiscussion\nThe typical manifestation of LAST often originates with prodromal symptoms, such as dizziness, tinnitus, perioral numbness, agitation, and confusion. These may be followed by CNS derangements, such as excitation (eg, confusion, muscle twitching, or seizure), depression (eg, drowsiness, obtundation, coma, or apnea), cardiovascular derangements, such as hypertension, tachycardia, bradycardia, asystole, or ventricular arrhythmias, or a combination thereof. In our first case, the symptoms of CNS dysfunction appeared without any prodromal signs, whereas the second one followed the classical progression in which CNS toxicity was preceded by altered sensoria (dizziness, metallic taste, perioral and tongue numbness). The differential diagnosis for these symptoms may comprise drug allergy, pulmonary embolism, cardiovascular crisis, and LAST. The typical symptoms of type 1 anaphylaxis include urticaria, bronchoconstriction, hypotension, nausea, and vomiting. Neither patient presented with any of these signs. In addition, the incidence of allergic reaction to amide LAs is extremely low, and thus a diagnosis of drug allergy may be ruled out. Pulmonary embolism is typically characterized by pain, altered mental status, tachypnea, normoxia, tachycardia, and hypertension. Although our two patients exhibited some changes in perceptual condition and some cardiovascular signs, their physical and laboratory examinations showed no risk factors or evidence of pulmonary embolism. Unconsciousness and apnea in the first patient is unlikely to have been a result of the fentanyl or propofol that was administered for sedation, because verbal contact was maintained during the procedure and his symptoms did not begin until >10 minutes after the procedure had been completed. Given the nature and progression of their symptoms associated with brachial plexus blockade, we established a diagnosis of LAST in both cases.\n\nRecent data have demonstrated that atypical types account for about 40% of LAST,9 and in 68%–77% of cases CNS toxicity, presenting as seizures or coma, is the most prevalent attribute.10,11 It is clearly evident that the two patients presented with CNS symptoms (altered mental status followed by unconsciousness). It is noteworthy that the short-lived increase in HR (140 beats/minute from a baseline of 88 beats/minute) and BP (201/130 mmHg from a baseline of 127/60 mmHg) in the second patient was likely related to the effect of epinephrine used as an indicator of inadvertent intravascular injection, rather than the presentation of cardiovascular toxicity. The majority of LAST events take place immediately following injection of LAs.2 However, recent data have also revealed that delayed onset may happen at a variety of time points up to several hours following commencement of an administration. Whether LAST presents with an early or delayed onset depends on the mechanism that leads to the event. LAs thatreach the circulation via systemic absorption from surrounding tissue often result in postponed presentation, whereas accidental intravascular injection leads to rapid exhibition.12 This mechanism may explain why the onset duration for LAST in the first case was 10 minutes, while the event happened immediately in the second case.\n\nThe risk factors of toxicity include the type and dose of LA, injection around a vessel-rich region, preexisting pulmonary, cardiac, and nervous system vulnerability, extremes of age, needle or catheter placement without imaging devices, and small or limited muscle mass.12 Precautions employed in our two cases to minimize the occurence of LAST included use of ultrasound guidance, aspiration before injecting to detect intravascular needle placement, use of epinephrine as an indicator for accidental intravascular injection, and optimizing the dose according to patient weight. In the first patient, however, 6 mg/kg lidocaine and 1 mg/kg ropivacaine without epinephrine was a significantly high dose, especially for a 73-year-old and 18.5 BMI patient with modest muscle mass. Skeletal muscle plays an important role as a depot for systemically absorbed LAs.13 Similarly, although the dose:weight ratio of anesthetics in the second patient was not really high (approximately 4.5 mg/kg lidocaine and 1 mg/kg ropivacaine with epinephrine), the risk was still substantial for such a diminutive patient. According to Felice and Schumann,14 the maximum dose of lidocaine is 6–8 mg/kg. However, the emergence of LAST may be related more to plasma concentration than the total amount of drug injected.15 Symptoms of toxicity may occur at concentrations of 6 µg/mL, convulsions may be seen at 10 µg/mL, and cardiovascular collapse at levels of 30 µg/mL.16 We lacked the laboratory support to examine these patients’ serum LA concentration.\n\nIt is easily recognized that the main reason for the toxicity in the second patient was the unintended intravascular administration of anesthetics. Although performing regional anesthesia under ultrasound guidance offers several potential advantages, including the use of smaller volumes of LAs and direct visualization of the drug’s spread, thus reducing the risk of inadvertent intravascular injection of LAs,17–19 incomplete visualization of the needle or movement during injection may still result in intravascular injection. Evidence for intravascular injection in this case were aspiration of blood during injection of the last 5 mL of anesthetics, the immediate symptoms experienced by the patient, and the elevation of HR and systolic BP 30–40 seconds after injection. A rise in HR of at least 10 beats/minute or an increase in systolic BP of at least 15 mmHg may imply an intravascular injection. The increase in HR and BP cannot have been a cardiovascular effect of LAST, because it existed for a very short time, there was no other dysrhythmia, and electrocardiogramphy showed a continuous sinus rhythm.\n\nPresently, seizure control, advanced cardiac life support, and prompt lipid-emulsion therapy are the three pillars in the algorithm of treatment for LAST. Seizure activity can be treated effectively by intravenous benzodiazepines or barbiturates (eg, phenobarbital). Supplemental oxygen is necessary for any patient undergoing LAST, but for severe cases with hemodynamically unstable arrhythmia, apnea, or cardiac arrest, immediate invasive airway management or circulatory support should be considered. The goals are to guarantee adequate ventilation and sufficient organ perfusion, especially of the heart, brain, and kidneys, with well oxygenated bloodand to prevent progression of acidosis until commencement of lipid-emulsion therapy.16 Our two patients did not have seizures or cardiovascular dysfunction, so seizure management and advanced cardiac life support were unnecessary. They were provided supplemental oxygen at a rate of 5 L/min and given ventilation support via facial mask and manual resuscitator as needed.\n\nWeinberg recommended that lipid infusion should be initiated as early as possible and vasopressor drugs not be used as it may worsen acidosis and precipitate arrhythmia.16 According to the American Society of Regional Anesthesia and Pain Medicine,20 20% lipid-emulsion therapy should include a bolus over 2–3 minutes of 100 mL for patients >70 kg or 1.5 mL/kg if the patient is <70 kg (ideal body weight). Following the bolus, it recommends an infusion of 200–250 mL over 15–20 minutes if patient is >70 kg or 0.25 mL/kg/min if the patient is <70 kg, to be continued for at least 10 minutes after circulatory stability has been attained. If circulatory stability is not attained, consider rebolus or increasing infusion to 0.5 mL/kg/min. Because the 20% commercial product was not available, we utilized an equivalent dose of 10% emulsion with 3 mL/kg (150 mL) bolus, with prompt resolution of signs and symptoms of toxicity. In the second patient, the initial dose of lipid emulsion was given after 10 minutes with a bolus injection of 70 mL 20% lipid emulsion for 1 minute and then continuous intravenous injection of 150 mL for 15 minutes, with a similarly prompt recovery. The rapid effect of lipid emulsion can be explained by its multifactorial mechanism, where lipid employs a scavenging effect (also known as the “lipid sink”) in which a large lipid phase in the serum is able to extract LAs from the plasma. There is also a direct metabolic effect in which mitochondrial lipid metabolism is impeded,21 thus lowering tissue acidosis and reducing carbon dioxide production. It has a role in activating calcium and potassium channels as well.\n\nConclusion\nUltrasound-guided peripheral nerve block carries a risk of LAST. We recommend following the American Society of Regional Anesthesia and Pain Medicine protocol of lipid-emulsion therapy as soon as possible if there are any changes in CNS or cardiovascular function related to usage of LAs.\n\nAcknowledgments\nWe would like to express our very great appreciation to Dr Phillip Geiger, who revised this manuscript.\n\nEthics approval and consent to participate\nThe case reports received approval for publication from the Ethics Committee of 103 Military Hospital.\n\nConsent for publication\nWritten informed consent for publication of the clinical details and clinical images was obtained from the patients.\n\nDisclosure\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n1. Weinberg \nGL . Lipid infusion therapy: translation to clinical practice . Anesth Analg . 2008 ;106 :1340 –1342 . doi:10.1213/ane.0b013e31816a6c09 18420841 \n2. Mulfoy \nMF . Systemic toxicity and cardiotoxicity from local anesthetics: incidence and preventive measures . Reg Anesth Pain Med . 2002 ;27 :556 –561 .12430104 \n3. Auroy \nY , Benhamou \nD , Bargues \nL , et al. Major complications of regional anesthesia in France: the SOS regional anesthesia hotline service . Anesthesiology . 2002 ;97 :1274 –1280 .12411815 \n4. Barrington \nMJ , Watts \nSA , Gledhill \nSR , et al. Preliminary results of the Australasian Regional Anaesthesia Collaboration: a prospective audit of more than 7000 peripheral nerve and plexus blocks for neurologic and other complications . Reg Anesth Pain Med . 2009 ;34 :534 –541 .19916206 \n5. Barrington \nMJ , K \nR . Ultrasound guidance reduces the risk of local anesthetic systemic toxicity following peripheral nerve blockade . Reg Anesth Pain Med . 2013 ;38 :289 –297 . doi:10.1097/AAP.0b013e318292669b 23788067 \n6. Rosenblatt \nMA , Abel \nM , Gw \nF . Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest . Anesthesiology . 2006 ;105 :217 –218 .16810015 \n7. Cave \nG , Harvey \nM , Willers \nJ . LIPAEMIC report: results of clinical use of intravenous lipid emulsion in drug toxicity reported to an online lipid registry . J Med Toxicol . 2014 ;10 :133 –142 . doi:10.1007/s13181-013-0375-y 24414252 \n8. Presley \nJD , Pa. \nC . Intravenous lipid emulsion to reverse acute drug toxicity in pediatric patients . Ann Pharmacother . 2013 ;47 :735 –743 . doi:10.1345/aph.1R666 23613099 \n9. Neal \nJM , Bernards \nCM , Butterworth \nJF . ASRA practice advisory on local anesthetic systemic toxicity . Reg Anesth Pain Med . 2010 ;35 :152 –161 . doi:10.1097/AAP.0b013e3181d22fcd 20216033 \n10. El-Boghdadly \nK , Kj. \nC . Local anesthetic systemic toxicity: continuing professionaln development . Can J Anaesth . 2016 ;63 :330 –349 . doi:10.1007/s12630-015-0564-z 26830640 \n11. Gitman \nM , Mj. \nB . Local anesthetic systemic toxicity: a review of recent case reports and registries . Reg Anesth Pain Med . 2018 ;43 :124 –130 . doi:10.1097/AAP.0000000000000721 29303925 \n12. Sekimoto \nK , Tobe \nM , Saito. \nS . Local anesthetic toxicity: acute and chronic management . Acute Med Surg . 2017 ;4 :152 –160 . doi:10.1002/ams2.265 29123854 \n13. Fettiplace \nMR , Pichurko \nA , Ripper \nR . Cardiac depression induced by cocaine or cocaethylene is alleviated by lipid emulsion more effectively than by sulfobutylether-B-cyclodextrin . Acad Emerg Med . 2015 ;22 :508 –517 . doi:10.1111/acem.12657 25908403 \n14. Felice \nK , Schumann \nH . Intravenous lipid emulsion for local anesthetic toxicity: a review of the literature . J Med Toxicol . 2008 ;4 :184 –191 . doi:10.1007/bf03161199 18821493 \n15. Robert \nK , Stoetling \nMD , Hillier \nSC . Pharmacology and Physiology in Anesthetic Practice . 4th ed. Philadelphia: Lippincott Williams and Wilkins ; 2006 :179 –207 .\n16. Weinberg \nGL . Treatment of local anesthetic systemic toxicity . Reg Anesth Pain Med . 2010 ;35 :188 –193 . doi:10.1097/AAP.0b013e3181d246c3 20216036 \n17. Neal \nJM . Ultrasound-guided regional anesthesia and patient safety . Reg Anesth Pain Med . 2010 ;35 :S59 –S67 . doi:10.1097/AAP.0b013e3181ccbc96 20216027 \n18. Orebaugh \nSL , Williams \nBA , Vallejo \nM . Adverse outcomes associated with stimulator-based peripheral nerve blocks with versus without ultrasound visualization . Reg Anesth Pain Med . 2009 ;34 :251 –255 . doi:10.1097/AAP.0b013e3181a3438e 19587625 \n19. Salinas \nFV , Na. \nH . Evidence-based medicine for ultrasound-guided regional anesthesia . Anesthesiol Clin . 2014 ;32 :771 –787 . doi:10.1016/j.anclin.2014.08.001 25453661 \n20. Neal \nJM , Barrington \nMJ , Fettiplace \nMR , et al. The third american society of regional anesthesia and pain medicine practice advisory on local anesthetic systemic toxicity . Reg Anesth Pain Med . 2018 ;43 :113 –123 . doi:10.1097/AAP.0000000000000720 29356773 \n21. Wagner \nM , Zausig \nYA , Ruf \nS , Rudakova \nE , Gruber \nM . Lipid rescue reverses the bupivacaine-induced block of the fast Na+ current (INa) in cardiomyocytes of the rat left ventricle . Anesthesiology . 2014 ;120 :724 –736 . doi:10.1097/ALN.0b013e3182a66d4d 23941864\n\n",
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"keywords": "lipid emulsion; local anesthetic system toxicity",
"medline_ta": "Int Med Case Rep J",
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"title": "Successful intralipid-emulsion treatment of local anesthetic systemic toxicity following ultrasound-guided brachial plexus block: case report.",
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"abstract": "BACKGROUND\nGlioblastoma (GBM) is a highly malignant brain neoplasm with poor survival. Despite its aggressive nature, metastatic spread of GBM is identified only rarely. While the molecular alterations associated with GBM and its subtypes are well-described, there remains a gap in understanding which alterations may predispose towards metastasis. In this report, we present a case of GBM with multi-organ metastases and discuss its genomic alterations.\n\n\nMETHODS\nA 74-year-old woman was diagnosed with left occipital glioblastoma (IDH-wildtype, MGMT-unmethylated), for which she underwent resection, standard chemoradiation, and then stereotactic radiosurgery (SRS) for local recurrence. One month after SRS, work-up for a pathologic hip fracture revealed a left breast mass, lytic lesions involving pelvic bones, and multiple pulmonary and hepatic lesions. Biopsies of the breast and bone lesions both demonstrated metastatic IDH-wildtype GBM. For worsening neurologic symptoms, the patient underwent debulking of a large right temporal lobe recurrence and expired shortly thereafter. Autopsy confirmed metastatic GBM in multiple systemic sites, including bilateral lungs, heart, liver, thyroid, left breast, small bowel, omentum, peritoneal surfaces, visceral surfaces, left pelvic bone, and hilar lymph nodes. Targeted sequencing was performed on tissue samples obtained pre- and postmortem, as well as on cell cultures and an orthotopic mouse xenograft derived from premortem surgical specimens. A BRCA1 mutation (p.I571T) was the only variant found in common among the primary, recurrence, and metastatic specimens, suggesting its likely status as an early driver mutation. Multiple subclonal ARID1A mutations, which promote genomic instability through impairment of DNA mismatch repair, were identified only in the recurrence. Mutational spectrum analysis demonstrated a high percentage of C:G to T:A transitions in the post-treatment samples but not in the primary tumor.\n\n\nCONCLUSIONS\nThis case report examines a rare case of widely metastatic IDH-wildtype GBM with a clonal somatic mutation in BRCA1. Post-treatment recurrent tumor in the brain and in multiple systemic organs exhibited evidence of acquired DNA mismatch repair deficiency, which may be explained by functional loss of ARID1A. We identify a potential role for immune checkpoint and PARP inhibitors in the treatment of metastatic GBM.",
"affiliations": "Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Departments of Neurosurgery and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Department of Neurology, Medicine (Division Hem-Onc), Neurosurgery and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Departments of Neurosurgery and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. raymund.yong@mountsinai.org.",
"authors": "Umphlett|Melissa|M|;Shea|Stephanie|S|;Tome-Garcia|Jessica|J|;Zhang|Yizhou|Y|;Hormigo|Adilia|A|;Fowkes|Mary|M|;Tsankova|Nadejda M|NM|;Yong|Raymund L|RL|http://orcid.org/0000-0002-7585-4153",
"chemical_list": "C112476:ARID1A protein, human; D018906:Antineoplastic Agents, Alkylating; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D000077204:Temozolomide",
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"doi": "10.1186/s12885-020-6540-1",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 654010.1186/s12885-020-6540-1Case ReportWidely metastatic glioblastoma with BRCA1 and ARID1A mutations: a case report Umphlett Melissa 1Shea Stephanie 1Tome-Garcia Jessica 1Zhang Yizhou 2Hormigo Adilia 3Fowkes Mary 1Tsankova Nadejda M. 14http://orcid.org/0000-0002-7585-4153Yong Raymund L. raymund.yong@mountsinai.org 21 0000 0001 0670 2351grid.59734.3cDepartment of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY USA 2 0000 0001 0670 2351grid.59734.3cDepartments of Neurosurgery and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA 3 0000 0001 0670 2351grid.59734.3cDepartment of Neurology, Medicine (Division Hem-Onc), Neurosurgery and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA 4 0000 0001 0670 2351grid.59734.3cDepartment of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY USA 20 1 2020 20 1 2020 2020 20 4713 9 2019 13 1 2020 © The Author(s). 2020Open 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\nGlioblastoma (GBM) is a highly malignant brain neoplasm with poor survival. Despite its aggressive nature, metastatic spread of GBM is identified only rarely. While the molecular alterations associated with GBM and its subtypes are well-described, there remains a gap in understanding which alterations may predispose towards metastasis. In this report, we present a case of GBM with multi-organ metastases and discuss its genomic alterations.\n\nCase presentation\nA 74-year-old woman was diagnosed with left occipital glioblastoma (IDH-wildtype, MGMT-unmethylated), for which she underwent resection, standard chemoradiation, and then stereotactic radiosurgery (SRS) for local recurrence. One month after SRS, work-up for a pathologic hip fracture revealed a left breast mass, lytic lesions involving pelvic bones, and multiple pulmonary and hepatic lesions. Biopsies of the breast and bone lesions both demonstrated metastatic IDH-wildtype GBM. For worsening neurologic symptoms, the patient underwent debulking of a large right temporal lobe recurrence and expired shortly thereafter. Autopsy confirmed metastatic GBM in multiple systemic sites, including bilateral lungs, heart, liver, thyroid, left breast, small bowel, omentum, peritoneal surfaces, visceral surfaces, left pelvic bone, and hilar lymph nodes. Targeted sequencing was performed on tissue samples obtained pre- and postmortem, as well as on cell cultures and an orthotopic mouse xenograft derived from premortem surgical specimens. A BRCA1 mutation (p.I571T) was the only variant found in common among the primary, recurrence, and metastatic specimens, suggesting its likely status as an early driver mutation. Multiple subclonal ARID1A mutations, which promote genomic instability through impairment of DNA mismatch repair, were identified only in the recurrence. Mutational spectrum analysis demonstrated a high percentage of C:G to T:A transitions in the post-treatment samples but not in the primary tumor.\n\nConclusion\nThis case report examines a rare case of widely metastatic IDH-wildtype GBM with a clonal somatic mutation in BRCA1. Post-treatment recurrent tumor in the brain and in multiple systemic organs exhibited evidence of acquired DNA mismatch repair deficiency, which may be explained by functional loss of ARID1A. We identify a potential role for immune checkpoint and PARP inhibitors in the treatment of metastatic GBM.\n\nKeywords\nGlioblastomaMetastasisBRCA1 mutationARID1A mutationMismatch repair deficiencyTemozolomideTreatment resistancehttp://dx.doi.org/10.13039/100000065National Institute of Neurological Disorders and StrokeR01NS106229R03NS104669Tsankova Nadejda M. issue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nGlioblastoma (GBM) is the most common primary brain tumor in adults and universally harbors a poor prognosis due to its aggressive nature [1]. Despite modern improvements in treatment for afflicted patients, the mortality of GBM remains high, with a median overall survival of 10–16.5 months [2]. Although it is commonly associated with widespread infiltration throughout the brain, GBM is only rarely associated with extracranial metastatic disease [3, 4], which occurs at an estimated incidence of less than 2% [5–11]. Widespread multi-organ metastases are rarer still. A literature review of 79 cases of extracranial metastatic GBM found that only 4% of cases examined had greater than four metastatic sites [12]. Furthermore, to our knowledge there are only nine reported cases of high-grade glioma metastases involving skin, soft tissue, or muscle [13].\n\nPossible explanations for the rarity of GBM systemic metastases include underdiagnosis and short patient survival time [14]. Case reports have described the diagnosis of metastatic GBM in recipients of lung, liver, and other organ transplants from deceased donors harboring GBM, indicating that GBM micrometastases may be present at the time of death [14, 15]. Such cases suggest that rates of clinically detected GBM metastases may underestimate the extent to which these malignant tumors are capable of seeding distant organs. The underlying genomic drivers of systemic GBM metastases remain poorly defined. Limited molecular analyses of several reported cases have suggested an association with mutations in TP53 [16]; however, TP53 mutations are also among the most common across all cancer.\n\nRecognizing the importance of identifying unique molecular features that may drive extracranial GBM metastasis, we present a rare case with widespread multi-organ metastases, placing special attention on a comparative analysis of the most frequent genetic alterations found in the primary tumor, its post-treatment brain recurrence, and multiple systemic metastatic sites.\n\nCase presentation\nA 74-year-old female was initially evaluated for a headache and right eye peripheral vision loss. MRI brain with and without contrast was performed, revealing a 5.5 cm heterogeneously T2 hyperintense lesion with thick irregular nodular enhancement in the left parietal-occipital region (Fig. 1). The patient underwent a gross total resection of the mass that was diagnosed as GBM, IDH-wildtype, WHO grade IV, MGMT promoter methylation not detected. Fresh specimen in multiple sectors was processed for tumor culture. Following resection, she received hypofractionated concurrent chemoradiation with temozolomide followed by four cycles of adjuvant temozolomide (TMZ). Six months later, the patient developed multifocal GBM recurrence in the right temporal and frontal lobes, for which she underwent single fraction 18 Gy stereotactic radiosurgery to the right frontal lesion and five fractions of 2250 cGy to the right temporal lesion.\nFig. 1 Primary GBM in the left occipital lobe. Axial T1 gadolinium-enhanced magnetic resonance image performed (a) preoperatively, and (b) 24 h postoperatively\n\n\n\nThree months following SRS, the patient began to experience falls associated with hip pain and difficulty walking. MRI of the right hip demonstrated a pathologic hip fracture, which was thought to be due to metastatic disease from an undiagnosed second primary cancer. The patient then developed altered mental status and right-sided upper motor neuron facial weakness. A full metastatic imaging work-up was performed, revealing a 3.9 cm left breast mass, multiple lytic lesions of the pelvic bones, and multiple pulmonary and hepatic nodules. Core biopsies were obtained from the left breast and the left pubic bone, both of which demonstrated metastatic GBM.\n\nThe patient’s mental status deteriorated as the right temporal recurrence rapidly progressed, and she underwent right temporal craniotomy for debulking of the tumor eleven months after her initial diagnosis of GBM (Fig. 2). Histologically, this secondary tumor was identical to the primary. 2 × 105 freshly dissociated cells from the right temporal recurrence were orthotopically transplanted directly into the striatum of SCID mice with preserved microglial activity (IcrTac:ICR-Prkdcscid strain) to assess the cells’ ability to generate a patient-derived xenograft (PDX). Following surgery, the patient stabilized neurologically, but opted for palliative care and was transferred to hospice where she expired one month later.\nFig. 2 Histopathology of post-treatment recurrence of IDH-wildtype GBM in the temporal lobe.a Gross image of the right temporal lobe with resection cavity (6.0 × 3.5 cm) and residual tumor. b Tumor is histologically compatible with GBM on H&E stain. c Tumor cells are diffusely positive on GFAP stain. d Tumor cells demonstrate positive MIB-1 focally up to 60%. e Tumor cells are negative on reticulin stain. f Tumor cells are negative (wild-type) on IDH1 R132H stain. Micrographs are 10X magnification\n\n\n\nWhile the patient was alive, consent was obtained for a rapid autopsy, which was ultimately performed within four hours of death. Gross and histological evaluation confirmed numerous GBM metastases. The extent of metastatic disease was widespread, including bilateral lungs, heart, liver, thyroid, left breast, small bowel, omentum, peritoneum, left pelvic bone, and hilar lymph nodes (Fig. 3). Notably, there were extensive metastatic lesions involving the abdominal cavity.\nFig. 3 Metastatic GBM lesions involving multiple organs. a Gross photo of “peritoneal glioblastomatosis,” i.e., metastatic GBM studding the surface of the small bowel and omentum. b Metastatic GBM infiltrating breast tissue (H&E stain). c Metastatic GBM infiltrating cardiac muscle (H&E stain). d Metastatic GBM infiltrating thyroid parenchyma (H&E stain). Metastatic GBM infiltrating lung tissue (e H&E stain, and f GFAP stain). Metastatic GBM infiltrating breast tissue (g H&E stain, and h GFAP stain). i Metastatic GBM infiltrating omental tissue (H&E stain). Micrographs are 10X magnification\n\n\n\nThe autopsy revealed residual GBM in the original site of occurrence (left occipital lobe). On histological examination of pre- and post-mortem samples, the metastases appeared identical to the primary tumor and temporal recurrence. All sites demonstrated the classic appearance of GBM on H&E staining, including nuclear atypia, microvascular proliferation, and pseudopalisading necrosis. Sarcomatous transformation was not identified on histological review of the tissue sections, and was confirmed absent by reticulin-staining performed on representative sections from occipital lobe, temporal lobe (Fig. 2e), left breast, heart, lung, liver, lymph nodes, and omentum.\n\nTo evaluate the molecular phenotype of the primary, recurrent, and metastatic lesions, two different next-generation-sequencing (NGS) panels were employed (see Additional file 1). The Ion AmpliSeq Hotspot Cancer NGS Panel v2, covering 50 genes and 207 amplicons, was performed on all pre-mortem (left occipital brain primary, right temporal lobe recurrence, and left breast metastases) and select post-mortem (paratracheal lymph node and omentum) tissue specimens. The Ion Torrent Oncomine Comprehensive Assay v3, covering 161 cancer driver genes, was performed on the remaining post-mortem samples (left occipital lobe, right temporal lobe, left breast, lungs, and liver) collected during rapid autopsy.\n\nThe AmpliSeq panel revealed single nucleotide variants (SNVs) in PIK3CA, SMARCB1, BRAF, and TP53. Notably, five different SNVs were detected for TP53. There were differences in TP53 mutations between the primary tumor, metastases, and among the metastases themselves (Fig. 4). The more comprehensive Oncomine panel revealed only one non-silent SNV common to all specimens: BRCA1 p.I571T. A large number of private mutations were detected in the temporal lobe recurrence, left breast, lung, and liver metastases. Among the extracranial metastatic sites, only the left breast, liver, and omentum specimens were found to share any mutations other than the one identified at BRCA1.\nFig. 4 Comparative analysis of coding SNVs identified in metastatic GBM tissue and derived cultures. BRCA1 p.I571T, an early putative driver mutation found at all time points -- primary resection (black boxes), brain recurrence (red boxes), extracranial metastatic sites (blue boxes) -- is highlighted in red text. Several distinct TP53 SNVs (green text) were identified in the temporal recurrence and multiple metastatic sites, suggesting convergent evolution. Several SNVs (purple text) were shared between metastatic sites, indicating a common ancestral clone. To assist in distinguishing putative driver and passenger mutations, variant frequencies (in brackets) were compared between source tissue (solid boxes) and cultured or xenografted cells (dashed boxes). Asterisks indicate samples sequenced using Ampliseq Cancer Hotspot panel only\n\n\n\nCells cultured from the left occipital primary site at the time of initial diagnosis, and the right temporal site at the time of recurrence, expanded readily in serum-free conditions and were all found to harbor the BRCA1 p.I571T mutation (see Additional file 1). Both mice, orthotopically xenotransplanted with cells from the temporal recurrence, developed fatal malignant gliomas after 5 weeks, confirming the tumor’s aggressive behavior in both human and rodents (Fig. 5). Necropsy analysis of the lungs, intestines, liver, and spleen in these mice did not reveal the presence of any peripheral metastases as seen in the patient. Tumor cells from this aggressive GBM were isolated from the primary PDX and were subsequently propagated in culture and used to generate a reliable PDX model which forms within 3–4 weeks post implantation and, importantly, recapitulates both the rapid growth and the malignant infiltrative spread of human GBM. Mutational hotspot analysis of the PDX confirmed the presence BRCA1 p.I571T in all cells, and multiple inactivating mutations of ARID1A in a significant subpopulation. ARID1A mutations were also identified in the left breast autopsy specimen (Fig. 4).\nFig. 5 Patient-derived xenograft of recurrent temporal lobe GBM in a SCID mouse brain. a Time to fatal xenograft formation for cells derived from the index case (sample ID 302) versus six other consecutive cases of IDH-wildtype GBM not associated with extracranial metastasis. b Micrograph of mouse brain 5 weeks after xenotransplantation into the right striatum of 200,000 GBM cells obtained during resection of the temporal lobe recurrence. Tumor cells are seen infiltrating the contralateral hemisphere via the corpus callosum. HNA, human nuclear antigen. Scale bar = 1000 μm.\n\n\n\nTo investigate whether the relatively high number of SNVs in all secondary sites compared to the primary could have resulted from mismatch repair (MMR) deficiency, we performed a mutational spectrum analysis; results confirmed a high proportion of C:G to T:A transitions, which is typical of the mismatch repair deficiency described in the setting of temozolomide-treated recurrent GBM (Fig. 6). The integrity of the mismatch repair pathway was evaluated using immunohistochemistry. All metastatic specimens exhibited positive staining for anti-MLH1, anti-MSH2, anti-MSH6, and anti-PMS2, indicating microsatellite stability (MSS). MSS was further confirmed with PCR of established microsatellite loci [17] (see Additional file 1). In addition, we evaluated DNA polymerase epsilon (POLE) using PCR, which showed no alterations at mutational hotspots within the coding region of the gene.\nFig. 6 Percentage of all somatic SNVs identified through targeted sequencing (Oncomine Comprehensive Assay version 2) of primary, recurrent, and metastatic GBM specimens that were C:G to T:A transitions\n\n\n\nDiscussion and conclusions\nGBM is known to have aggressive biological behavior with poor survival outcomes [1], as demonstrated in this case of a woman who expired approximately one year after initial diagnosis. At autopsy, in addition to the widespread extracranial metastases, this case had a unique gross finding. In the abdominal cavity, metastatic lesions extensively studded the surfaces of the small bowel, omentum, and peritoneum, mimicking the appearance of peritoneal carcinomatosis; therefore, when secondary to GBM, we propose the term “peritoneal glioblastomatosis” to describe this rare presentation (Fig. 3a).\n\nWhile the molecular variants associated with GBM and its subtypes are well-described [18, 19], there remains a critical gap in understanding which genomic drivers may lead GBM to metastasize. The unusually large number of private SNVs observed in all specimens except the left-occipital primary suggests that a parental clone at the primary site acquired a hypermutator-like phenotype during adjuvant chemoradiation and subsequently seeded the extra-CNS sites, possibly via invasion of the sagittal sinus. The hypermutating subclone also seeded the contralateral temporal lobe – presumably via white matter migration – and was able to expand due to its location outside the primary radiation treatment volume. GBM dissemination via CSF pathways is also a recognized possibility, but in this case less likely to have been a major mechanism given the absence of diffuse leptomeningeal disease or spinal drop metastases.\n\nGliosarcoma is a rare variant of GBM with an increased tendency to metastasize [20], and must be considered in the differential diagnosis in this case. In gliosarcoma, metaplastic transformation of gliomatous tumor gives rise to a sarcomatous component, which is associated with a higher rate of connective tissue invasion and extracranial metastasis [20]. This transformation has been linked to the acquisition of driving TP53 mutations [21]. In our case, sarcomatous histology was not identified in any of the primary or secondary specimens; thus, the pathogenetic mechanism of extracranial spread of GBM in our case is likely distinct from that seen in gliosarcoma. Although numerous TP53 mutations were detected, none were shared between sites, suggesting they arose as a product of genetic instability in a parental clone, rather than as primary drivers of the instability. Consistent with this view, Park et al. detected multiple different TP53 mutations between sites in 2 out of a series of 6 metastatic GBM cases examined. They suggest that this resulted from dissemination of subclones that were dormant in the primary tumor, which then activated and expanded in the metastatic microenvironment [16].\n\nSince it was the only coding alteration common to the primary tumor, recurrence, and metastases, we consider the BRCA1 p.I571T SNV to be the most likely driver of this GBM’s unique metastatic phenotype. Although there is no literature to date describing a role for BRCA1 mutations in GBM pathogenesis, alterations in BRCA2 have been associated with genomic instability in astrocytomas [22], and a BRCA2 inactivating mutation was found in the primary site of a metastatic GBM [23]. Perhaps screening for metastatic disease may be considered when BRCA mutations are found in a primary GBM. Among GBM specimens in The Cancer Genome Atlas (TCGA), BRCA1 and BRCA2 missense mutations are rare, each occurring at a rate of 1.4%. Piccirilli et al. [24] described a series of 11 patients with a history of invasive breast carcinoma who subsequently developed GBM; however, an analysis of BRCA1 or BRCA2 mutational status was not performed. BRCA1 defects are known to dysregulate cell checkpoint pathways and impair the fidelity of the DNA damage response, particularly to double-strand breaks (DSBs) [25]. We speculate that GBM cells with BRCA1 defects might exhibit particularly high levels of genomic instability when exposed to DSB-inducing agents such as RT and temozolomide, increasing the risk of treatment-induced cancer evolution and acquiring new, aggressive phenotypes.\n\nIn GBM and other solid malignancies, a high proportion of acquired C:G to T:A transitions is classically associated with chronic exposure to alkylating agents in the context of a deficiency in one or more components of the DNA mismatch repair machinery. Possible mechanisms include acquired inactivating mutations or epigenetic silencing of the MMR genes MSH6, MSH2, MLH1, and PMS2. Recent studies show that treatment with TMZ of MGMT unmethylated tumors, such as in our case, introduces a strong selective pressure to lose mismatch repair pathway function [26]. Although immunostaining demonstrated intact MMR protein expression in the recurrent and metastatic specimens of our case, mutational hotspot analysis of the PDX derived from the temporal recurrence revealed inactivation of ARID1A, which has recently been shown to promote MMR by interacting with MSH2 [27]. ARID1A mutations are rare in GBM, occurring at a rate of 0.7% in newly diagnosed cases, and may be associated with an aggressive phenotype. Both cases described in TCGA were seen in males under the age of 50, one of whom survived less than 1 year. Thus, our case illustrates the need for caution in the treatment of MGMT unmethylated GBM with TMZ, even if the tumor exhibits microsatellite stability by conventional methods, since other forms of instability may exist.\n\nIn considering alternatives to TMZ, new data suggests that PARP inhibitor therapy may be effective in ARID1A- as well as BRCA-defective tumors [28]. ARID1A-defective tumors may also be particularly good candidates for immune checkpoint blockade due to the potentially large number of immune-activating neoepitopes generated by MMR deficiency [27]. The PARP inhibitors olaparib and BGB-290, among others, are currently being evaluated as radio- and chemosensitizers in both IDH-wildtype and IDH-mutant GBM in early phase clinical trials, but no molecular biomarkers for response have so far emerged [29–31].\n\nIn conclusion, we describe a rare and highly aggressive case of widely metastatic IDH-wildtype GBM with a clonal somatic mutation in BRCA1. Post-treatment recurrent tumor in the brain and in multiple systemic organs exhibited evidence of acquired DNA mismatch repair deficiency, despite retaining intact expression of mismatch repair pathway proteins. This may be explained by loss of ARID1A, which is required for MSH2 function.\n\nSupplementary information\n\nAdditional file 1. Supplementary Methods.\n\n \n\n\nAbbreviations\nGBMGlioblastoma\n\nMMRMismatch repair\n\nMSSMicrosatellite stability\n\nNGSNext-generation sequencing\n\nPDXPatient-derived xenograft\n\nSNVSingle nucleotide variant\n\nTCGAThe Cancer Genome Atlas\n\nTMZTemozolomide\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary information\nSupplementary information accompanies this paper at 10.1186/s12885-020-6540-1.\n\nAcknowledgements\nWe wish to thank Dr. Robert Sebra for generously providing resources for targeted sequencing; Dr. Michael Donovan, principal investigator of the Mount Sinai Cancer Institute Biorepository; Dr. Jane Houldsworth for interpretation of clinical sequencing data; and Dr. Amy Chan for her involvement in the care of the patient.\n\nAuthors’ contributions\nMU, SS, YZ, NMT and RLY were major contributors in writing the manuscript. YZ and RLY generated and interpreted genetic data. MU, SS, and NMT performed and interpreted all histology. JT-G and NMT generated and interpreted mouse xenograft data. MU and MF performed and interpreted the autopsy. AH, NMT, and RLY conceived the project. All authors read and approved the final manuscript.\n\nFunding\nThis study was supported in part by R01NS106229 (N.M.T.) for collection and culture of tumor samples and R03NS104669 (N.M.T.) for generation of mouse xenografts.\n\nAvailability of data and materials\nThe data that support the findings of this study are not publicly available to protect patient privacy, but are available from the corresponding author upon reasonable request.\n\nEthics approval and consent to participate\nThe patient described in this case report consented to participate in the Mount Sinai Cancer Institute Biorepository IRB-approved protocol (study ID# HSM#-00135, Mount Sinai Health System IRB).\n\nConsent for publication\nWritten informed consent for participation in the study and publication was obtained from the patient described in this case report.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Saad AG Sachs J Turner CD Extracranial metastases of glioblastoma in a child: a case report and review of the literature J Pediatr Hematol Oncol 2007 72 157 161 \n2. Rajagopala V El Kamar FG Thayparan R Grossman ML Bone marrow metastases from glioblastoma multiforme – a case report and review of literature J Neuro-Oncol 2005 72 157 161 10.1007/s11060-004-3346-y \n3. Schonsteiner SS Bommer M Haenle MM Rare phenomenon: liver metastases from glioblastoma multiforme J Clin Oncol 2011 29 23 e668 ee71 10.1200/JCO.2011.35.9232 21670450 \n4. Lun M Lok E Gautam S Wu E Wong ET The natural history of extracranial metastasis from glioblastoma multiforme J Neuro-Oncol 2011 105 2 261 273 10.1007/s11060-011-0575-8 \n5. Waite KJ Wharton SB Old SE Burnet NG Systemic metastases of glioblastoma multiforme Clin Oncol 1999 11 205 207 10.1053/clon.1999.9045 \n6. Datta CK Weinstein JD Bland JE Brager PM Stewart MA A case of cervical lymph node metastasis resulting from glioblastoma multiforme W V Med J 1998 94 276 278 9803886 \n7. Fecteau AH Penn I Hanto DW Peritoneal metastasis of intracranial glioblastoma via a ventriculoperitoneal shunt preventing organ retrieval: case report and review of the literature Clin Transpl 1998 12 348 350 \n8. Widjaja A Mix H Gölkel C Uncommon metastasis of a glioblastoma multiforme in liver and spleen Digestion. 2000 61 219 222 10.1159/000007761 10773729 \n9. Yasuhara T Tamiya T Meguro T Glioblastoma with metastasis to spleen - case report Neurol Med Chir 2003 43 452 456 10.2176/nmc.43.452 \n10. Piccirilli M Brunetto GM Rocchi G Giangaspero F Salvati M Extra central nervous system metastases from cerebral glioblastoma multiforme in elderly patients. Clinico-pathological remarks on our series of seven cases and critical review of the literature Tumori 2008 94 40 51 10.1177/030089160809400109 18468334 \n11. Templeton A Hofer S Töpfer M Extraneural spread of glioblastoma - report of two cases Onkologie 2008 31 192 194 10.1159/000118627 18418021 \n12. Kalokhe G Metastatic glioblastoma: case presentations and a review of the literature J Neuro-Oncol 2012 107 21 27 10.1007/s11060-011-0731-1 \n13. Armanios MY Grossman SA Yang SC White B Perry A Burger PC Orens JB Transmission of glioblastoma multiforme following bilateral lung transplantation from an affected donor: case study and review of the literature Neuro-Oncology 2004 6 259 263 10.1215/S1152851703000474 15279719 \n14. Kraft M Land F Braunschweig R Janzer RC Parotid gland metastasis from glioblastoma multiforme: a case report and review of literature Eur Arch Otorhinolarungol 2008 265 709 711 10.1007/s00405-007-0499-2 \n15. Chen H Shah AS Girgis RE Grossman SA Transmission of glioblastoma multiforme after bilateral lung transplantation J Clin Oncol 2008 26 3284 3285 10.1200/JCO.2008.16.3543 18591565 \n16. Park CC Hartmann C Folkerth R Systemic metastasis in glioblastoma may represent the emergence of neoplastic subclones J Neuropathol Exp Neurol 2000 59 1044 1050 10.1093/jnen/59.12.1044 11138924 \n17. Suraweera N Evaluation of tumor microsatellite instability using five quasimonomorphic mononucleotide repeats and pentaplex PCR Gastroenterol 2002 123 6 1804 1811 10.1053/gast.2002.37070 \n18. Fratini V The integrated landscape of driver genomic alterations in glioblastoma Nat Genet 2013 45 1141 1149 10.1038/ng.2734 23917401 \n19. Brenan CW The somatic genomic landscape of glioblastoma Cell 2013 155 462 477 10.1016/j.cell.2013.09.034 24120142 \n20. Ray A Extracranial metastasis of glioblastoma: three illustrative cases and current review of the molecular pathology and management strategies J Molecul Clin Neurooncol 2015 3 479 486 \n21. Pain M Treatment-associated TP53 DNA-binding domain missense mutations in the pathogenesis of secondary gliosarcoma Oncotarget 2017 9 2603 2621 29416795 \n22. Liu J Lu H Ohgaki H Merlo A Shen Z Alterations of BCCIP, a BRCA interactive protein in astrocytomas BMC Cancer 2009 9 268 10.1186/1471-2407-9-268 19653894 \n23. Franceschi S Molecular portrait of a rare case of metastatic glioblastoma: somatic and germline mutations using whole-exome sequencing Neuro-Oncology 2016 18 2 298 300 10.1093/neuonc/nov314 26803811 \n24. Piccirilli M Salvati M Bistazzoni S Frati A Brogna C Giangaspero F Frati R Santoro A Glioblastoma multiforme and breast cancer: report on 11 cases and clinico-pathological remarks Tumori 2005 91 256 260 10.1177/030089160509100309 16206651 \n25. Saha J Davis AJ Unsolved mystery: the role of BRCA1 in DNA end-joining J Radiat Res 2016 57 S1 24 10.1093/jrr/rrw032 \n26. Choi Serah Yu Yao Grimmer Matthew R Wahl Michael Chang Susan M Costello Joseph F Temozolomide-associated hypermutation in gliomas Neuro-Oncology 2018 20 10 1300 1309 10.1093/neuonc/noy016 29452419 \n27. Shen J ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade Nat Med 2018 24 556 562 10.1038/s41591-018-0012-z 29736026 \n28. Shen J ARID1A deficiency impairs the DNA damage checkpoint and sensitizes cells to PARP inhibitors Cancer Discov 2015 5 7 752 767 10.1158/2159-8290.CD-14-0849 26069190 \n29. Lesueur P Lequesne J Grellard JM Phase I/IIa study of concomitant radiotherapy with olaparib and temozolomide in unresectable or partially resectable glioblastoma: OLA-TMZ-RTE-01 trial protocol BMC Cancer 2019 19 1 198 10.1186/s12885-019-5413-y 30832617 \n30. Sistigu Antonella Manic Gwenola Obrist Florine Vitale Ilio Trial watch – inhibiting PARP enzymes for anticancer therapy Molecular & Cellular Oncology 2015 3 2 e1053594 10.1080/23723556.2015.1053594 27308587 \n31. Pain M Wang H Lee E Treatment-associated TP53 DNA-binding domain missense mutations in the pathogenesis of secondary gliosarcoma Oncotarget 2018 9 2 2603 2621 10.18632/oncotarget.23517 29416795\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "20(1)",
"journal": "BMC cancer",
"keywords": "ARID1A mutation; BRCA1 mutation; Glioblastoma; Metastasis; Mismatch repair deficiency; Temozolomide; Treatment resistance",
"medline_ta": "BMC Cancer",
"mesh_terms": "D000368:Aged; D000818:Animals; D018906:Antineoplastic Agents, Alkylating; D019313:BRCA1 Protein; D001932:Brain Neoplasms; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D005260:Female; D005909:Glioblastoma; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D016634:Radiosurgery; D000077204:Temozolomide; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays",
"nlm_unique_id": "100967800",
"other_id": null,
"pages": "47",
"pmc": null,
"pmid": "31959133",
"pubdate": "2020-01-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21512826;27308587;29416795;18591565;10773729;29452419;27170701;21670450;26069190;12454837;17968576;16206651;11138924;10465480;9686330;26803811;15279719;23917401;9803886;14560851;18418021;17356401;21964740;24120142;29736026;30832617;15925996;26137254;19653894;18468334",
"title": "Widely metastatic glioblastoma with BRCA1 and ARID1A mutations: a case report.",
"title_normalized": "widely metastatic glioblastoma with brca1 and arid1a mutations a case report"
} | [
{
"companynumb": "US-CADILA HEALTHCARE LIMITED-US-ZYDUS-048904",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"drugaddi... |
{
"abstract": "Cardiac rhythm and conduction disorders are common in patients with epilepsy and are presumably one of the leading causes of sudden unexpected death. There are only a few published reports on ictal cardiac arrhythmias detected by continuous monitoring, and the majority had a small sample size.\n\n\n\nThe aim of this study was to evaluate the frequency and type of cardiac arrhythmias recorded by an implantable loop recorder in patients with drug-resistant epilepsy.\n\n\n\nWe implanted a subcutaneous loop recorder to 193 patients with drug-resistant epilepsy. Automatic triggers to initiate cardiac rhythm recording were cardiac pauses of >3 seconds and any episodes of bradycardia (≤45 beats/min) or tachycardia (≥150 beats/min). Patients/relatives were instructed to begin peri-ictal rhythm recording by using an external activator device. The follow-up duration was 36 months, with scheduled follow-up visits every 3 months.\n\n\n\nA total of 6494 electrocardiogram traces were recorded during the median follow-up of 36 months (interquartile range 3-36 months). Ictal heart rhythm and rate changes were detected in 143 patients (74%). The most common finding was ictal sinus tachycardia (66.8%). Sinus bradycardia was observed in 13 patients (6.7%). Three patients had clinically relevant cardiac pauses of >6 seconds, requiring permanent pacemaker implantation. Five patients (2.6%) died suddenly.\n\n\n\nIctal heart rhythm and rate changes occur in most of the patients with drug-resistant epilepsy. Clinically relevant cardiac events, related to ictal and postictal periods, are rare. No potentially malignant arrhythmias were detected in patients who died suddenly during the preceding follow-up period.",
"affiliations": "Department of Cardiac Rhythm and Conduction Disturbances, National Medical Research Center for Therapy and Preventive Medicine, Moscow, Russia. Electronic address: sserdiuk@mail.ru.;Department of Cardiac Rhythm and Conduction Disturbances, National Medical Research Center for Therapy and Preventive Medicine, Moscow, Russia.;Department of Neurology, Neurosurgery and Medical Genetics at Pirogov Russian Research Medical University, Moscow, Russia.;Department of Cardiac Rhythm and Conduction Disturbances, National Medical Research Center for Therapy and Preventive Medicine, Moscow, Russia.;National Medical Research Center of Cardiology, Moscow, Russia.;Department of Neurology, Neurosurgery and Medical Genetics at Pirogov Russian Research Medical University, Moscow, Russia.;Department of Cardiac Rhythm and Conduction Disturbances, National Medical Research Center for Therapy and Preventive Medicine, Moscow, Russia.",
"authors": "Serdyuk|Svetlana|S|;Davtyan|Karapet|K|;Burd|Sergey|S|;Drapkina|Oksana|O|;Boytsov|Sergey|S|;Gusev|Evgeniy|E|;Topchyan|Arpi|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.hrthm.2020.09.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1547-5271",
"issue": "18(2)",
"journal": "Heart rhythm",
"keywords": "Cardiac arrhythmias; Cardiac monitoring; Epilepsy; Implantable loop recorder; Seizure; Sudden death",
"medline_ta": "Heart Rhythm",
"mesh_terms": null,
"nlm_unique_id": "101200317",
"other_id": null,
"pages": "221-228",
"pmc": null,
"pmid": "32911052",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Cardiac arrhythmias and sudden unexpected death in epilepsy: Results of long-term monitoring.",
"title_normalized": "cardiac arrhythmias and sudden unexpected death in epilepsy results of long term monitoring"
} | [
{
"companynumb": "RU-UCBSA-2021031822",
"fulfillexpeditecriteria": "1",
"occurcountry": "RU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "3",
... |
{
"abstract": "An allergic anaphylactic reaction is a potentially fatal cascade consisting of an initial sensitization, antigen exposure, crosslinking of immunoglobulin E (IgE) specific for the antigen, activation of mast cells, and release of bioactive substances. Postmortem diagnosis of anaphylaxis is challenging because of the limited availability of antemortem history and minimal macroscopic evidence at autopsy. The elevated activity of a neutral proteinase, such as tryptase, can be a surrogate marker for the activation and degranulation of mast cells. However, it does not directly indicate the involvement of antigen-specific IgE, which has an important role in IgE-mediated allergic anaphylaxis. In the present study, we examined blood from a case of death following infusion of the antibiotic ceftriaxone (CTRX), with a control case for comparison. The aim was to detect IgE specific for CTRX. A pull-down assay with N-hydroxysuccinimide-activated sepharose identified IgE specific for CTRX only in the serum obtained from the case of CTRX exposure, and not in the control case. The specificity of IgE was confirmed by adsorption to an excess of CTRX, which resulted in the signal for IgE disappearing in the pull-down assay. This antigen-specific IgE is a key molecule in the IgE-mediated allergic anaphylaxis and seldom investigated in postmortem examinations. Its detection can provide support for the postmortem diagnosis of allergic anaphylaxis, especially when combined with an antemortem history of allergen exposure and elevated neutral proteinase levels in serum.",
"affiliations": "Division of Legal Medicine, Department of Community Medicine and Social Health Science, Kobe University Graduate School of Medicine, Hyogo, Japan. Electronic address: genring@med.kobe-u.ac.jp.;Division of Legal Medicine, Department of Community Medicine and Social Health Science, Kobe University Graduate School of Medicine, Hyogo, Japan.;Division of Legal Medicine, Department of Community Medicine and Social Health Science, Kobe University Graduate School of Medicine, Hyogo, Japan.;Division of Legal Medicine, Department of Community Medicine and Social Health Science, Kobe University Graduate School of Medicine, Hyogo, Japan.;Division of Legal Medicine, Department of Community Medicine and Social Health Science, Kobe University Graduate School of Medicine, Hyogo, Japan.;Division of Legal Medicine, Department of Community Medicine and Social Health Science, Kobe University Graduate School of Medicine, Hyogo, Japan.",
"authors": "Takahashi|Motonori|M|;Kondo|Takeshi|T|;Morichika|Mai|M|;Kuse|Azumi|A|;Nakagawa|Kanako|K|;Ueno|Yasuhiro|Y|",
"chemical_list": "D000900:Anti-Bacterial Agents; D007073:Immunoglobulin E",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2016.04.025",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "266()",
"journal": "Forensic science international",
"keywords": "Amine coupling; Anaphylaxis; Ceftriaxone; Pull-down assay",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000707:Anaphylaxis; D000900:Anti-Bacterial Agents; D003933:Diagnosis; D006801:Humans; D007073:Immunoglobulin E; D008407:Mast Cells",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "14-17",
"pmc": null,
"pmid": "27161295",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Postmortem detection of antibiotic-specific immunoglobulin E in the case of anaphylactic death.",
"title_normalized": "postmortem detection of antibiotic specific immunoglobulin e in the case of anaphylactic death"
} | [
{
"companynumb": "JP-PFIZER INC-2016258764",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CEFTRIAXONE SODIUM"
},
"drugadditional": null... |
{
"abstract": "The purpose of the study is to demonstrate the characteristics of lymphoproliferative disorders (LPDs) in patients with rheumatoid arthritis (RA) and risk factors for LPD among RA patients concurrently treated with methotrexate (MTX). Among patients who participated in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort study in October 2010, past existence of LPD from patient's report was confirmed through medical charts. Background factors, LPD pathological findings, and the clinical courses of LPD and RA after LPD were assessed. To analyze the risk of MTX-associated LPD among RA patients concurrently treated with MTX, a nested case-control study design was used to select control patients who had received MTX but did not develop LPD by matching calendar date, sex, and age (within 5 years) at a 1:10 ratio. Odds ratios (ORs) with 95% confidence intervals (95% CIs) for occurrence of LPD were analyzed by multivariate analysis. Forty-eight patients experienced LPD among 5757 patients, and 25 (52.1%) of those had lymphoma. LPD regressed in 60.4% of all LPD patients and 24.0% of lymphoma patients. In the 26 cases who developed LPD during MTX treatment, multivariate analysis revealed that 28-joint disease activity score (DAS28) (OR 1.57 [95% CI, 1.12-1.57]; p < 0.01) and lactate dehydrogenase (LDH) level (OR 1.01 [95% CI, 1.00-1.02]; p < 0.01), but not concomitant dose of MTX, were risk factors for LPD. Among RA patients concomitantly treated with MTX, high disease activity, but not MTX dose, was a risk factor for the occurrence of LPD.",
"affiliations": "Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo, 162-0054, Japan.;Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo, 162-0054, Japan. ayakonkj@ior.twmu.ac.jp.;Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo, 162-0054, Japan.;Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo, 162-0054, Japan.;Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo, 162-0054, Japan.;Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo, 162-0054, Japan.;Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo, 162-0054, Japan.;Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo, 162-0054, Japan.;Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo, 162-0054, Japan.;Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo, 162-0054, Japan.",
"authors": "Shimizu|Yoko|Y|;Nakajima|Ayako|A|;Inoue|Eisuke|E|;Shidara|Kumi|K|;Sugimoto|Naoki|N|;Seto|Yohei|Y|;Tanaka|Eiichi|E|;Momohara|Shigeki|S|;Taniguchi|Atsuo|A|;Yamanaka|Hisashi|H|",
"chemical_list": "D018501:Antirheumatic Agents; D008727:Methotrexate",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10067-017-3634-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0770-3198",
"issue": "36(6)",
"journal": "Clinical rheumatology",
"keywords": "Disease activity; Lymphoma; Lymphoproliferative disorders; Methotrexate; Rheumatoid arthritis",
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008223:Lymphoma; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D009365:Neoplasm Regression, Spontaneous; D012307:Risk Factors",
"nlm_unique_id": "8211469",
"other_id": null,
"pages": "1237-1245",
"pmc": null,
"pmid": "28455827",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "20476859;16508929;24498893;25073613;15843454;18368468;23316401;20473757;27550304;17117491;22707613;18461290;1787499;20064207;14673964;19828563;26573205;12139747;26676102;23494713;21036875;24161836;22473917;21933041;21516373;8656264;26545825;23269079;21183450;17437163;26279520;6712287;9665898;20535785;22948700;19026144;25294567",
"title": "Characteristics and risk factors of lymphoproliferative disorders among patients with rheumatoid arthritis concurrently treated with methotrexate: a nested case-control study of the IORRA cohort.",
"title_normalized": "characteristics and risk factors of lymphoproliferative disorders among patients with rheumatoid arthritis concurrently treated with methotrexate a nested case control study of the iorra cohort"
} | [
{
"companynumb": "JP-PFIZER INC-2017202327",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": null... |
{
"abstract": "The development of perifocal edema and tumor bed cyst has been reported after implantation of biodegradable carmustine wafers for the treatment of malignant gliomas. We retrospectively evaluated these changes in a series of patients; 19 consecutive patients with malignant glioma who received carmustine wafer implantation at our hospital from January 2013 through July 2013, and 28 patients who underwent surgery prior to our institution's initiation of carmustine wafer implantation, as historical controls. The volume of the tumor bed cyst and perifocal edema was calculated on MRI acquired at four time points: ⩽72hours after surgery for baseline, and at 1-4, 5-8, and 9-12weeks after surgery. The volume of the tumor bed cyst in the wafer group increased significantly relative to the control group at all time points (p=0.04). Opening of the ventricle was inversely correlated with enlargement of the tumor bed cyst in the wafer group (p=0.04). The change in the volume of perifocal edema in the wafer group was not significantly different (p=0.48), but exhibited a considerable increase in patients with anaplastic oligodendroglioma relative to glioblastoma patients in the wafer group (p=0.01). We demonstrated significant enlargement of the tumor bed cyst volume after carmustine wafer implantation, as well as the development of marked perifocal edema in patients with anaplastic oligodendroglioma.",
"affiliations": "Division of Neurological Surgery, Chiba Cancer Centre, 666-2 Nitonacho, Chuo-ku, Chiba City, Chiba 260-8717, Japan. Electronic address: yhasegawa@chiba-cc.jp.;Division of Neurological Surgery, Chiba Cancer Centre, 666-2 Nitonacho, Chuo-ku, Chiba City, Chiba 260-8717, Japan.;Division of Neurological Surgery, Chiba Cancer Centre, 666-2 Nitonacho, Chuo-ku, Chiba City, Chiba 260-8717, Japan.;Division of Chemotherapy and Cancer Diagnosis, Chiba Cancer Centre, Chuo-ku, Chiba City, Chiba 260-8717, Japan.;Division of Neurological Surgery, Chiba Cancer Centre, 666-2 Nitonacho, Chuo-ku, Chiba City, Chiba 260-8717, Japan.",
"authors": "Hasegawa|Yuzo|Y|;Iuchi|Toshihiko|T|;Sakaida|Tsukasa|T|;Yokoi|Sana|S|;Kawasaki|Koichiro|K|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D002330:Carmustine",
"country": "Scotland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0967-5868",
"issue": "31()",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Brain edema; Carmustine wafer; Cysts; Glioma; MRI",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D000368:Aged; D018906:Antineoplastic Agents, Alkylating; D001929:Brain Edema; D001932:Brain Neoplasms; D002330:Carmustine; D003560:Cysts; D005260:Female; D005910:Glioma; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies",
"nlm_unique_id": "9433352",
"other_id": null,
"pages": "67-71",
"pmc": null,
"pmid": "27430412",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The influence of carmustine wafer implantation on tumor bed cysts and peritumoral brain edema.",
"title_normalized": "the influence of carmustine wafer implantation on tumor bed cysts and peritumoral brain edema"
} | [
{
"companynumb": "JP-MYLANLABS-2017M1020617",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARMUSTINE"
},
"drugadditional": "3",
... |
{
"abstract": "Bipolar and other psychiatric disorders are associated with considerably increased risk of suicidal behaviour, which may include self-poisoning with medication used to treat the disorder. Therefore, choice of medication for treatment should include consideration of toxicity, especially for patients at risk. The aim of this study was to estimate the relative toxicity of specific drugs within two drug categories, antipsychotics and mood stabilizers, using large-scale databases to provide evidence that could assist clinicians in making decisions about prescribing, especially for patients at risk of suicidal behaviour.\n\n\n\nTwo indices were used to assess relative toxicity of mood stabilisers and antipsychotics: case fatality (the ratio between rates of fatal and non-fatal self-poisoning) and fatal toxicity (the ratio between rates of fatal self-poisoning and prescription). Mood stabilisers assessed included lithium [reference], sodium valproate, carbamazepine, and lamotrigine, while antipsychotics included chlorpromazine [reference], clozapine, olanzapine, quetiapine and risperidone. Fatal self-poisoning (suicide) data were provided by the Office for National Statistics (ONS), non-fatal self-poisoning data by the Multicentre Study of Self-harm in England, and information on prescriptions by the Clinical Practice Research Datalink. The primary analysis focussed on deaths due to a single drug. Cases where the drug of interest was listed as the likely primary toxic agent in multiple drug overdoses were also analysed. The study period was 2005-2012.\n\n\n\nThere appeared to be little difference in toxicity between the mood stabilisers, except that based on case fatality where multiple drug poisonings were considered, carbamazepine was over twice as likely to result in death relative to lithium (OR 2.37 95% CI 1.16-4.85). Of the antipsychotics, clozapine was approximately18 times more likely to result in death when taken in overdose than chlorpromazine (single drug case fatality: OR 18.53 95% CI 8.69-39.52). Otherwise, only risperidone differed from chlorpromazine, being less toxic (OR 0.06 95% CI 0.01-0.47).\n\n\n\nThere was little difference in toxicity of the individual mood stabilisers. Clozapine was far more toxic than the other antipsychotics. The findings are relevant to prescribing policy, especially for patients at particular risk of suicidal behaviour.",
"affiliations": "Centre for Suicide Research, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK. anne.ferrey@phc.ox.ac.uk.;Centre for Suicide Research, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.;Centre for Suicide Research, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.;Office for National Statistics, Newport, UK.;Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.;Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.;Centre for Self-harm and Suicide Prevention Research, Derbyshire Healthcare NHS Foundation Trust, Derby, UK.;Centre for Suicide Prevention, University of Manchester, Manchester, UK.;School of Social and Community Medicine, University of Bristol, Bristol, UK.;Centre for Suicide Prevention, University of Manchester, Manchester, UK.;Centre for Suicide Research, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.",
"authors": "Ferrey|Anne E|AE|0000-0002-5644-2735;Geulayov|Galit|G|;Casey|Deborah|D|;Wells|Claudia|C|;Fuller|Alice|A|;Bankhead|Clare|C|;Ness|Jennifer|J|;Clements|Caroline|C|;Gunnell|David|D|;Kapur|Navneet|N|;Hawton|Keith|K|",
"chemical_list": "D014150:Antipsychotic Agents; D014149:Tranquilizing Agents",
"country": "England",
"delete": false,
"doi": "10.1186/s12888-018-1993-3",
"fulltext": "\n==== Front\nBMC PsychiatryBMC PsychiatryBMC Psychiatry1471-244XBioMed Central London 199310.1186/s12888-018-1993-3Research ArticleRelative toxicity of mood stabilisers and antipsychotics: case fatality and fatal toxicity associated with self-poisoning http://orcid.org/0000-0002-5644-2735Ferrey Anne E. anne.ferrey@phc.ox.ac.uk 13Geulayov Galit galit.geulayov@psych.ox.ac.uk 1Casey Deborah deborah.casey@psych.ox.ac.uk 1Wells Claudia claudia.wells@ons.gsi.gov.uk 2Fuller Alice alice.fuller@phc.ox.ac.uk 3Bankhead Clare clare.bankhead@phc.ox.ac.uk 3Ness Jennifer Jennifer.Ness@derbyshcft.nhs.uk 4Clements Caroline caroline.v.clements@manchester.ac.uk 5Gunnell David D.J.Gunnell@bristol.ac.uk 6Kapur Navneet nav.kapur@manchester.ac.uk 5Hawton Keith keith.hawton@psych.ox.ac.uk 11 0000 0004 1936 8948grid.4991.5Centre for Suicide Research, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK 2 0000 0001 2157 6840grid.426100.1Office for National Statistics, Newport, UK 3 0000 0004 1936 8948grid.4991.5Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK 4 0000 0004 0396 1667grid.418388.eCentre for Self-harm and Suicide Prevention Research, Derbyshire Healthcare NHS Foundation Trust, Derby, UK 5 0000000121662407grid.5379.8Centre for Suicide Prevention, University of Manchester, Manchester, UK 6 0000 0004 1936 7603grid.5337.2School of Social and Community Medicine, University of Bristol, Bristol, UK 27 12 2018 27 12 2018 2018 18 3996 6 2018 19 12 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nBipolar and other psychiatric disorders are associated with considerably increased risk of suicidal behaviour, which may include self-poisoning with medication used to treat the disorder. Therefore, choice of medication for treatment should include consideration of toxicity, especially for patients at risk. The aim of this study was to estimate the relative toxicity of specific drugs within two drug categories, antipsychotics and mood stabilizers, using large-scale databases to provide evidence that could assist clinicians in making decisions about prescribing, especially for patients at risk of suicidal behaviour.\n\nMethod\nTwo indices were used to assess relative toxicity of mood stabilisers and antipsychotics: case fatality (the ratio between rates of fatal and non-fatal self-poisoning) and fatal toxicity (the ratio between rates of fatal self-poisoning and prescription). Mood stabilisers assessed included lithium [reference], sodium valproate, carbamazepine, and lamotrigine, while antipsychotics included chlorpromazine [reference], clozapine, olanzapine, quetiapine and risperidone. Fatal self-poisoning (suicide) data were provided by the Office for National Statistics (ONS), non-fatal self-poisoning data by the Multicentre Study of Self-harm in England, and information on prescriptions by the Clinical Practice Research Datalink. The primary analysis focussed on deaths due to a single drug. Cases where the drug of interest was listed as the likely primary toxic agent in multiple drug overdoses were also analysed. The study period was 2005–2012.\n\nResults\nThere appeared to be little difference in toxicity between the mood stabilisers, except that based on case fatality where multiple drug poisonings were considered, carbamazepine was over twice as likely to result in death relative to lithium (OR 2.37 95% CI 1.16–4.85). Of the antipsychotics, clozapine was approximately18 times more likely to result in death when taken in overdose than chlorpromazine (single drug case fatality: OR 18.53 95% CI 8.69–39.52). Otherwise, only risperidone differed from chlorpromazine, being less toxic (OR 0.06 95% CI 0.01–0.47).\n\nConclusions\nThere was little difference in toxicity of the individual mood stabilisers. Clozapine was far more toxic than the other antipsychotics. The findings are relevant to prescribing policy, especially for patients at particular risk of suicidal behaviour.\n\nKeywords\nDrug toxicityMood stabilisersAntipsychoticsSuicideSelf-poisoninghttp://dx.doi.org/10.13039/501100007602Programme Grants for Applied ResearchRP-PG-0610-10026Hawton Keith issue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nMood stabilisers and antipsychotics are used to treat psychiatric disorders such as bipolar disorder and schizophrenia. It is estimated that 5–8% of people with bipolar disorder die by suicide [1]. However, other studies suggest a higher rate [2, 3]. The equivalent figure for schizophrenia is 5% [4]. The method of suicide used by people with these disorders is often self-poisoning [5]. One important consideration when prescribing drugs for these conditions is their relative toxicity in overdose, because if patients self-poison they are likely to use their prescribed medication [6, 7]. Several mood stabilisers are also anticonvulsants used to manage epilepsy. Epilepsy is also associated with an increased risk of suicidal behaviour, including self-poisoning [8]. It is therefore important for clinicians be as well-informed as possible about the relative toxicity of drugs they prescribe for a given condition [9]. Previous work on the use of psychotropic medication in non-fatal self-poisoning in patients in Ireland suggested that more than 10% of the sample ingested antipsychotics, while approximately 7% used mood stabilisers [7]. Most of these drugs had been prescribed to the patient prior to the overdose. Establishing the relative toxicity of mood stabilisers and antipsychotics is important for clinical practice and regulatory agencies. The main aim of this study was to estimate the relative toxicity of specific drugs within two drug categories, antipsychotics and mood stabilisers, using large-scale databases. This will provide evidence that could assist clinicians in making decisions about prescribing, especially for patients at risk of suicidal behaviour.\n\nMethods\nWe investigated the relative toxicity of the mood stabilisers and antipsychotics most often used for fatal and/or non-fatal self-poisoning in the UK. We considered antipsychotics and mood stabilisers together because both are used as treatments for severe mental illnesses. We used two approaches: first, case fatality, in which the number of self-poisoning deaths involving a specific drug is compared to the number of episodes of non-fatal self-poisoning involving this drug [10, 11]; second, fatal toxicity, in which the number of deaths by self-poisoning involving a specific drug is compared to the number of individuals prescribed this drug [12]. We previously used these approaches to investigate the relative toxicity of antidepressants, [11] to highlight the toxicity of co-proxamol, [13] and to examine the relatively toxicity of benzodiazepines [14].\n\nStudy drugs\nThe mood stabilisers investigated in this study were lithium and the anti-convulsants sodium valproate, carbamazepine and lamotrigine. The antipsychotics investigated included chlorpromazine, clozapine, olanzapine, quetiapine and risperidone. The period covered by the study was 2005–2012.\n\nDeaths\nWe obtained information on drug poisoning deaths receiving a verdict of intentional self-poisoning (ICD-10 codes X60–64) or death of undetermined intent (open verdict; ICD-10 codes Y10-Y14), that involved either mood stabilisers or antipsychotics, from the Office of National Statistics based on deaths in individuals aged 15 years and over occurring during 2005–2012 in England registered to the end of 2014. We included open verdicts as this is policy with regard to suicide statistics and research in the UK because a high proportion are thought to be probable suicides [15–17]. Intentional self-poisonings and open verdicts are henceforth termed ‘suicides’. We conducted two analyses. The first included only deaths involving single drugs (in the presence or absence of alcohol), while the second included these deaths together with deaths where the drug under investigation was the first drug recorded by the coroner in multiple drug overdoses, again with or without alcohol. This assumes that the first drug recorded was likely to have been the primary agent involved in the death. Death data were obtained for males and females separately for all drugs.\n\nNon-fatal self-poisoning\nData on non-fatal self-poisoning was obtained from the Multicentre Study of Self-harm in England [18]. The Multicentre Study of Self-harm collects data on all presentations for self-harm to the emergency departments at five general hospitals. These include one hospital in Oxford, three hospitals in Manchester and two hospitals in Derby that merged into one in 2009. Self-harm is defined as intentional self-poisoning or self-injury, irrespective of the motivation or degree of suicidal intent, [19] and self-poisoning includes the intentional ingestion of more than the prescribed amount of any drug. This applies whether or not there is evidence that the act was intended to result in death. Data were collected on gender, age, date and method of self-poisoning, including the specific drugs ingested. Episodes of non-fatal self-poisoning include all non-fatal overdoses involving the mood stabilisers and antipsychotics under investigation, regardless of whether or not other drugs or alcohol were involved.\n\nWe extracted data for all episodes of non-fatal self-poisoning involving individuals aged 15 years and over which included the mood stabiliser or antipsychotic under investigation. The analysis included only episodes of self-harm by individuals who resided in the catchment area of Oxford City, The City of Manchester and Derby Unitary Area at the time of the episode, because reliable mid-year population estimates were available for these areas. Mid-year population estimates were required to calculate rates.\n\nPrescriptions\nWe obtained data on prescriptions of the study drugs for individuals aged 15 years and over from the Clinical Practice Research Datalink (CPRD [20]), which is a governmental research service which provides anonymised primary care records that can be used for public health research. It currently includes data on just under 10% of the UK population. Patients included in the CPRD have been found to broadly represent the UK population in terms of age, sex and ethnicity [21]. Information from the CPRD included the number of patients registered with the general practices appearing in the CPRD database and the number of individuals who were prescribed the specific study medication, by individual year (2005–2012), age and gender.\n\nStatistical analysis\nWe calculated rates of non-fatal self-poisoning based on the number of episodes of non-fatal self-poisoning per 100,000 person-years using mid-year population estimates obtained from ONS for Oxford City, the City of Manchester, and Derby Unitary area for 2005–2012. We calculated rates of suicide by self-poisoning per 100,000 person-years using England’s mid-year population estimates for 2005–2012, which we obtained from the Office for National Statistics (ONS). Prescription rates were calculated as the number of individuals prescribed a specific medication per 100,000 person-years registered with the general practices in the CPRD during 2005–2012. All analyses were carried out using the Poisson distribution with exact 95% CIs.\n\nOur measures of relative toxicity included case fatality and fatal toxicity. Case fatality was calculated by taking the number of deaths by self-poisoning in England during 2005–2012 attributed to a given study drug divided by the number of episodes of non-fatal self-poisoning involving this drug during the equivalent period from the Multicentre Study of Self-harm in England and standardising these ratios to the risk for lithium (for the mood stabilisers) and chlorpromazine (for the antipsychotics). Fatal toxicity was calculated using the number of deaths by self-poisoning in England during 2005–2012 attributed to a drug divided by the number of individuals prescribed this drug during the equivalent period and standardised to the risk for lithium (for the mood stabilisers) and chlorpromazine (for the antipsychotics). We were not able to calculate a fatal toxicity measure for clozapine because this drug is rarely prescribed via GP surgeries. For this drug we therefore relied on case fatality. Lithium and chlorpromazine were selected as reference drugs on the basis of long-term use (these are older drugs with a substantial history of use). Confidence intervals for relative toxicity were calculated using the Poisson distribution.\n\nWe conducted two sets of analyses for each of the toxicity indices (fatal toxicity and case fatality). First, we included only deaths involving single drugs (with or without alcohol). Second, we also included cases of deaths involving multiple drugs where the drug of interest was the first drug recorded by the coroner, on the basis that this drug was likely to have been the main cause of death.\n\nWe also calculated the proportion of individuals for whom alcohol was mentioned in the coroner’s report for each of the drugs investigated. Statistical analyses were carried out using Excel 2013 and Stata 14.1.\n\nEthical approval\nThe monitoring systems for self-harm in Oxford and Derby have approval from local Health /Psychiatric Research Ethics Committees to collect data on self-harm for local and multicentre projects. Self-harm monitoring in Manchester is part of a clinical audit system, and has been ratified by the local Research Ethics Committee. All three monitoring systems are fully compliant with the Data Protection Act of 1998. All centres have approval under Section 251 of the National Health Services (NHS) Act 2006 (formerly Section 60, Health and Social Care Act 2001) to collect patient identifiable information without patient consent.\n\nWe also obtained specific Independent Scientific Advisory Committee (ISAC) approval from the CPRD (protocol number 14_064R2) and also from ONS to obtain mortality data.\n\nResults\nMood Stabilisers\nDuring the eight-year study period (2005–2012) there were 59 suicide deaths in England due to single-drug poisoning with mood stabilisers and a further 37 cases where more than one drug was listed as contributing to the death but the mood stabiliser under investigation was listed first (Table 1). Of these 96 deaths, 55% involved males and 45% females. These were from a total of 3083 poisoning suicide deaths occurring during the study period. Of the 59 deaths, 7% were in people age 15–24, 61% were in people age 25–54, and 32% in people age 55 or older. In 51 cases there was a verdict of intentional self-poisoning and in 45 cases a verdict of undetermined intent.Table 1 Number and rates of suicides involving single-drugs or single and multiple (first-listed) drugs in England and of individuals prescribed each medication, in individuals aged 15 years and over (2005–2012)\n\n\tSingle-drug deaths in England, total n\tSingle-drug deaths in England, death rate per 100,000 person-years (95% CI)\tSingle and first listed drug deaths in England, total n\tSingle and first listed drug deaths in England, Death rate per 100,000 person-years (95% CI)\tPrescriptions, average number per year\tPrescription rate per 100,000 person-years (95% CI)\tNon-fatal self-poisonings in three centres, average number per year\tSelf-poisoning rate per 100,000, per 100,000 person-years (95% CI)\t\nMood Stabilisers\t\n Lithium\t6\t0.002 (0.001–0.004)\t10\t0.003 (0.001–0.005)\t4956\t107.24 (106.18–108.30)\t12\t1.64 (1.32–2.01)\t\n Sodium valproate\t15\t0.004 (0.002–0.007)\t18\t0.005 (0.003–0.008)\t15,433\t333.97 (332.11–335.84)\t32\t4.45 (3.92–5.03)\t\n Carbamazepine\t33\t0.010 (0.007–0.014)\t56\t0.016 (0.012–0.021)\t18,836\t407.62 (405.56–409.68)\t28\t3.87 (3.88–4.42)\t\n Lamotrigine\t5\t0.001 (0.00–0.003)\t12\t0.004 (0.002–0.006)\t7635\t165.22 (163.91–166.54)\t15\t2.02 (1.67–2.43)\t\n Total\t59\t\t96\t\t46,860\t\t87\t\t\nAntipsychotics\t\n Chlorpromazine\t12\t0.004 (0.002–0.006)\t19\t0.006 (0.003–0.009)\t3760\t81.37 (80.46–82.30)\t25\t3.44 (2.97–3.95)\t\n Risperidone\t1\t0.000 (0.00–0.002)\t2\t0.001 (0.00–0.002)\t8302\t179.65 (178.29–181.03)\t34\t4.69 (4.15–5.29)\t\n Quetiapine\t40\t0.012 (0.008–0.016)\t65\t0.019 (0.015–0.024)\t9971\t215.78 (214.28–217.28)\t73\t10.20 (9.39–11.07)\t\n Olanzapine\t55\t0.016 (0.012–0.021)\t78\t0.023 (0.018–0.029)\t10,568\t228.70 (227.16–230.25)\t61\t8.55 (7.81–9.34)\t\n Clozapine\t35\t0.010 (0.007–0.014)\t40\t0.012 (0.008–0.016)\t157\t3.39 (3.21–3.59)\t4\t0.54 (0.36–0.77)\t\n Total\t143\t\t204\t\t32,758\t\t197\t\t\n\n\nDuring the same period, 687 non-fatal self-poisonings with mood stabilisers were identified through the Multicentre Study of Self-harm in England. Data taken from the CPRD (which contains records from approximately 10% of the GP surgeries in England) indicated that there were on average 46,860 prescriptions per year of the mood stabilisers under investigation during the 2005–2012 period (Table 1).\n\nCase fatality indices\nUsing single-drug deaths, carbamazepine appeared to be over twice as likely to result in death when taken in overdose compared to lithium, although the evidence was weak. There was no indication of major differences in toxicity for the other mood stabilizers (Table 2).Table 2 Case fatality indices– number of suicides involving a given drug per non-fatal self-poisoning episode relative to a. lithium and b. chlorpromazine\n\n\tOdds ratio (95% CI)\t\nSingle drug only\tSingle and first listed drug\t\nA. Mood Stabilisers\t\n Lithium\t1.0\t1.0\t\n Sodium Valproate\t0.92 (0.35–2.45)\t0.66 (0.30–1.49)\t\n Carbamazepine\t2.33 (0.94–5.74)\t2.37 (1.16–4.85)\t\n Lamotrigine\t0.68 (0.20–2.28)\t0.97 (0.40–2.35)\t\nB. Antipsychotics\t\n Chlorpromazine\t1.0\t1.0\t\n Risperidone\t0.06 (0.01–0.47)\t0.08 (0.02–0.34)\t\n Quetiapine\t1.12 (0.58–2.18)\t1.15 (0.67–1.97)\t\n Olanzapine\t1.84 (0.97–3.52)\t1.65 (0.97–2.80)\t\n Clozapine\t18.53 (8.69–39.52)\t13.38 (6.88–26.00)\t\n\n\nThe results were similar when we also included cases in which multiple drugs had been consumed in self-poisoning deaths but the drug of interest was listed first, except that the result for carbamazepine was statistically significant. This indicates that overdoses with carbamazepine were more likely to result in death than overdoses with lithium (Table 2).\n\nFatal toxicity indices\nMeasures of fatal toxicity showed a similar pattern of results to those for case fatality, except that the finding for carbamazepine was attenuated and consistent with chance (Table 3). Using additional cases in which the drug of interest was listed first where multiple drugs had been ingested indicated the same pattern.Table 3 Fatal toxicity indices – number of suicides involving a given drug per individuals prescribed this drug relative to a. lithium or b. chlorpromazine\n\n\tOdds ratio (95% CI)\t\nSingle drug only\tSingle plus first listed drug\t\nA. Mood Stabilisers\t\n Lithium\t1.0\t1.0\t\n Sodium Valproate\t0.80 (0.31–2.07)\t0.58 (0.27–1.25)\t\n Carbamazepine\t1.45 (0.61–3.45)\t1.47 (0.75–2.89)\t\n Lamotrigine\t0.54 (0.17–1.77)\t0.78 (0.34–1.80)\t\nB. Antipsychotics\t\n Chlorpromazine\t1.0\t1.0\t\n Risperidone\t0.04 (0.01–0.29)\t0.05 (0.01–0.21)\t\n Quetiapine\t1.26 (0.66–2.40)\t1.29 (0.77–2.15)\t\n Olanzapine\t1.63 (0.87–3.05)\t1.46 (0.89–2.41)\t\n\n\nAntipsychotics\nDuring the study period there were 143 suicide deaths due to single-drug poisoning with major tranquillisers and a further 61 in which there was evidence of multiple-drug ingestion but the drug of interest was listed first. Of these 204 deaths, 66% involved males and 34% females. These were from a total of 3083 suicides involving self-poisoning. In terms of age breakdown, 6% of deaths occurred in people aged 15–24 years, 80% in people aged 25–54 year and 14% of deaths in people 55 years or older. In 91 cases there was a verdict of intentional self-poisoning and in 113 cases an open verdict.\n\nThere were 1631 non-fatal self-poisoning episodes in the Multicentre Study of Self-harm in England in which antipsychotics were ingested. During the equivalent period, 32,758 individuals in the CPRD were prescribed the study antipsychotics yearly.\n\nCase fatality indices\nThe toxicity of risperidone was lower than the reference drug chlorpromazine. Clozapine appeared to be almost 19 times more toxic in overdose than chlorpromazine. Including deaths where the drug of interest was listed first in multiple drug deaths produced a similar pattern of results (Table 2).\n\nFatal toxicity indices\nThe fatal toxicity approach using single-drug data also showed risperidone to have lower toxicity relative to chlorpromazine. Using cases where the drug of interest was listed first in multiple drug deaths produced the same pattern of results (Table 3). As noted earlier, the fatal toxicity approach could not be used for clozapine since complete data on prescribing were not available from the CPRD because most prescriptions are provided by hospitals.\n\nAlcohol\nAlcohol was involved in very few of the deaths. Alcohol was mentioned in the coroner’s report in only five cases (8.5%) of single-drug deaths involving mood stabilisers, and in 22 deaths involving antipsychotics (15.4%). In neither drug group was there any indication of excess alcohol involvement with specific drugs.\n\nDiscussion\nWe have examined the relative toxicity of individual mood stabilisers and antipsychotics using two measures of toxicity – case fatality and fatal toxicity. Both the case fatality and fatal toxicity approaches produced similar results. The more conservative method of including only deaths where one drug was listed on the coroner’s report was confirmed by a secondary analysis in which we also included cases with the involvement of more than one drug, but where the drug of interest was listed first. This second approach was used on the basis that the first drug was likely to have been the main cause of death. This supports the findings, as does the convergence of the results of both the fatal toxicity (not possible for clozapine) and case fatality methods.\n\nMood Stabilisers\nPerhaps the most notable finding regarding the mood stabilisers was that lithium, contrary to a tendency to regard this drug as particularly toxic in overdose [22] did not appear to be more toxic compared to the other mood stabilisers included in this study. This finding, together with increasing evidence that lithium may have specific anti-suicidal effects, should encourage clinicians to consider the use of lithium in patients with recurrent affective disorder, including those at risk of suicide.\n\nThere was some indication to suggest that carbamazepine may be more toxic relative to the other mood stabilisers, although evidence in support of this was shown in only one of the four models assessing the relative toxicity of carbamazepine. Carbamazepine, like most of the other mood stabilisers, is an anticonvulsant. While people with bipolar disorder have an elevated risk of taking prescribed drugs in overdose, [23] it is also important to recognise that risks of both suicide and non-fatal self-poisoning are elevated in people with epilepsy [8, 24]. Although antiepileptic drugs in general may not lead to higher rates of suicidal behaviour, carbamazepine has been found to be associated with increased levels of suicide attempts compared to other anti-epileptics [25] and carbamazepine is related to a higher risk of suicide attempts in bipolar disorder [26]. Carbamazepine also interacts with other drugs, which may increase its toxicity [27].\n\nNeither of the other drugs (sodium valproate or lamotrigine) showed any sign of elevated toxicity relative to the reference drug.\n\nAntipsychotics\nIn this analysis, clozapine was the most toxic of the drugs examined, although only the case fatality approach could be used to assess its relative toxicity because clozapine is prescribed mainly from hospitals. Clozapine is an atypical antipsychotic usually used to treat patients with schizophrenia who have not responded to other antipsychotics [28]. Its use is already tightly regulated in the UK, [29] mainly because of the risk of blood dyscrasia [30]. Clozapine is often used to treat serious psychotic disorders of patients who have not responded to treatment with other drugs; patients who may already be at higher risk of suicide. However, in one major trial clozapine was found to reduce suicidal behaviour in people with schizophrenia who were at high risk of suicide, [31] a result which has support from longitudinal analysis of patient records on and off clozapine. [32] This provides support for the suggestion that suicide prevention could be an additional indication for clozapine. It is approved for this indication in the USA. [33] Nevertheless, the high toxicity of the drug in overdose needs to be considered in management. There should be careful monitoring for possible suicidal ideation and possibly controlled availability of the drug and regular monitoring of mood and suicidal ideation where risk is thought to be elevated.\n\nRisperidone was also found to have lower toxicity than the reference drug chlorpromazine using both case fatality and fatal toxicity approaches, while both olanzapine and quetiapine were not found to be more toxic than the reference drug. These findings should be taken into account when prescribing antipsychotics.\n\nStrengths and limitations\nIn this study we used two methods to evaluate the relative toxicity of mood stabilizers and antipsychotics (case fatality and fatal toxicity), the results of which largely converged. Findings from the primary analysis using only deaths attributed to a single drug were consistent with findings using multiple-drug deaths, where the drug of interest was listed first in the coroner’s report. These analyses were based on several large datasets, including all the deaths in England attributed to self-poisoning between 2005 and 2012. Another strength is the consistent findings between the results of the fatal toxicity and case fatality approaches, although only the latter approach was possible for clozapine.\n\nThere are also several limitations to this work. Perhaps most importantly, our data were taken from different sources. The mortality data were obtained from ONS and covered the entire population of England, prescription data were provided by the CPRD and comprised medical records for just under 10% of the UK population, and data on non-fatal self-poisoning were obtained from the Multicentre Study of Self-harm in England, which covers three cities in England. However, these last two sources provided relatively large datasets and are likely to be reasonably representative of the population as a whole [21].\n\nWe also have limited data on the cause of death. There is no information on dosage of drugs taken in overdose or relative blood levels of drugs (in the cases where multiple drugs were taken). Therefore we cannot draw firm conclusions on drug interactions. However, this was mitigated by using single-drug deaths in our primary analyses. Similarly, we only have information on the reported presence or absence of alcohol in the bloodstream but no information on alcohol levels and hence the contribution of alcohol to deaths. We included deaths of undetermined intent (open verdicts) in line with current UK policy on suicide research. This is because the majority of deaths with this verdict are probable suicides, [16, 15] although it is not possible to be certain about intent in such cases.\n\nData on non-fatal self-poisoning was taken from data collected from emergency departments. It is important to note that self-harm in the community frequently does not result in presentation to an emergency department, although information from studies of young people indicate that hospital presentation is more likely where the method of self-harm is self-poisoning [34, 35]. It should nonetheless be acknowledged that the number of non-fatal poisonings will be an underestimate. Of course, this problem does not affect the relative toxicity findings.\n\nIt is possible that differences in patient groups may have contributed to the observed findings. For example, patients treated with lithium are likely to have bipolar disorder, while those treated with anticonvulsants may have a range of disorders including bipolar, epileptic or borderline personality disorders. The patients in each group may therefore differ in their risk of suicide or self-harm and access to potentially lethal doses of medications. As well, certain drugs prescribed for a given disorder may be a more effective treatment but also more toxic in overdose, meaning that it may be difficult to interpret the risks and benefits using this approach.\n\nConclusions\nThe finding that lithium did not appear to have elevated toxicity when used for self-poisoning and that very few deaths occurred due to lithium ingestion in overdose may suggest the potential value of lithium as an anti-suicidal agent in people with mood disorders. The possible excess toxicity of carbamazepine in overdose compared to the other mood stabilisers should be borne in mind when prescribing, especially in patients with bipolar disorder or epilepsy thought to be at risk of suicidal behaviour.\n\nAmong the antipsychotics, clozapine is clearly far more toxic than other drugs. This adds to the need for very careful management when treating patients who are prescribed this drug, especially if they are considered to be at risk of suicidal behaviour. Risperidone was found to have lower toxicity than the reference drug chlorpromazine.\n\nAbbreviations\nCPRDClinical Practice Research Datalink\n\nGPGeneral practice\n\nICD-1010th revision of the International Statistical Classification of Diseases and Related Health Problems\n\nISACIndependent Scientific Advisory Committee\n\nNHSNational Health Service\n\nONSOffice for National Statistics\n\nOROdds ratio\n\nUKUnited Kingdom\n\nUSAUnited States of America\n\nAcknowledgements\nWe thank Fiona Brand and Liz Bale in Oxford for their assistance with data collection and Muzamal Rehman (Derbyshire Healthcare Foundation Trust) for data processing. We also thank Professor Philip Cowen (University of Oxford) and Orla MacDonald for providing expert advice. We are grateful to Keith Waters (Derbyshire Healthcare Foundation Trust) for his contribution to various aspects of this project and to Professor Jonathan Deeks (University of Birmingham) for providing statistical advice.\n\nFunding\nThis paper summarises independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (Grant Reference Number RP-PG-0610-10026). The Multicentre Study of Self-harm in England is supported by the Department of Health. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.\n\nKH and DG are NIHR Senior Investigators.\n\nAvailability of data and materials\nThe data that support the findings of this study are available from ONS and the CPRD, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of ONS and the CPRD.\n\nAuthors’ contributions\nAEF, GG, KH, NK and DG made substantial contributions to the conception and design of the study and determined the method of data analysis. Data was collected and/or processed by CW, AF, JN, CC and CB. Data was analysed by AEF, GG, DC and CW. AEF, GG and KH were major contributors in writing the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThe monitoring systems for self-harm in Oxford and Derby have approval from local Health /Psychiatric Research Ethics Committees to collect data on self-harm for local and multicentre projects. Self-harm monitoring in Manchester is part of a clinical audit system, and has been ratified by the local Research Ethics Committee. All three monitoring systems are fully compliant with the Data Protection Act of 1998. All centres have approval under Section 251 of the National Health Services (NHS) Act 2006 (formerly Section 60, Health and Social Care Act 2001) to collect patient identifiable information without patient consent.\n\nWe also obtained specific Independent Scientific Advisory Committee (ISAC) approval from the CPRD (protocol number 14_064R2) and also from ONS to obtain mortality data.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Nordentoft M Mortensen P Pedersen C Absolute risk of suicide after first hospital contact in mental disorder Arch Gen Psychiatry 2011 68 10 1058 1064 10.1001/archgenpsychiatry.2011.113 21969462 \n2. Pompili M Gonda X Serafini G Innamorati M Sher L Amore M Epidemiology of suicide in bipolar disorders: a systematic review of the literature Bipolar Disord 2013 15 5 457 490 10.1111/bdi.12087 23755739 \n3. Chesney E Goodwin GM Fazel S Risks of all-cause and suicide mortality in mental disorders: a meta-review World Psychiatry 2014 13 2 153 160 10.1002/wps.20128 24890068 \n4. Harris EC Barraclough B Suicide as an outcome for mental disorders. A meta-analysis Br J Psychiatry 1997 170 3 205 228 10.1192/bjp.170.3.205 9229027 \n5. Ösby U Brandt L Correia N Ekbom A Sparén P Excess mortality in bipolar and unipolar disorder in Sweden Arch Gen Psychiatry 2001 58 9 844 850 10.1001/archpsyc.58.9.844 11545667 \n6. Tournier M Grolleau A Cougnard A Molimard M Verdoux H Factors associated with choice of psychotropic drugs used for intentional drug overdose Eur Arch Psychiatry Clin Neurosci 2009 259 2 86 91 10.1007/s00406-008-0839-2 18806918 \n7. Corcoran P Heavey B Griffin E Perry IJ Arensman E Psychotropic medication involved in intentional drug overdose: implications for treatment Neuropsychiatry 2013 3 3 285 293 10.2217/npy.13.23 \n8. Meyer N, Voysey M, Holmes J, Casey D, Hawton K. Self-harm in people with epilepsy: a retrospective cohort study. Epilepsia. 2014;55(9):1355–65.\n9. Günaydın YK Akıllı NB Dündar ZD Köylü R Sert ET Çekmen B Antiepileptic drug poisoning: three-year experience Toxicol Rep 2015 2 56 62 10.1016/j.toxrep.2014.11.004 28962337 \n10. White N Litovitz T Clancy C Suicidal antidepressant overdoses: a comparative analysis by antidepressant type J Med Toxicol 2008 4 4 238 250 10.1007/BF03161207 19031375 \n11. Hawton K Bergen H Simkin S Cooper J Waters K Gunnell D Toxicity of antidepressants: study of rates of suicide relative to prescribing and non-fatal overdose Br J Psychiatry 2010 196 354 358 10.1192/bjp.bp.109.070219 20435959 \n12. Buckley N McManus P Fatal toxicity of drugs used in the treatment of psychotic illnesses Br J Psychiatry 1998 172 6 461 464 10.1192/bjp.172.6.461 9828983 \n13. Hawton K Simkin S Deeks JJ Co-proxamol and suicide: a study of national mortality statistics and local non-fatal self-poisonings BMJ 2003 326 1006 1008 10.1136/bmj.326.7397.1006 12742920 \n14. Geulayov G Ferrey A Casey D Wells C Fuller A Bankhead C Relative toxicity of benzodiazepines and hypnotics commonly used for self-poisoning: an epidemiological study of fatal toxicity and case fatality J Psychopharmacol 2018 32 6 654 662 10.1177/0269881118754734 29442611 \n15. Gunnell D Bennewith O Simkin S Cooper J Klineberg E Rodway C Time trends in coroners’ use of different verdicts for possible suicides and their impact on officially reported incidence of suicide in England: 1990-2005 Psychol Med 2013 43 7 1415 1422 10.1017/S0033291712002401 23113986 \n16. Linsley KR Schapira K Kelly TP Open verdict v. suicide - importance to research Br J Psychiatry 2001 178 465 468 10.1192/bjp.178.5.465 11331564 \n17. Statistics OfN: Statistical Update on Suicide. In.; 2015.\n18. Hawton K Bergen H Casey D Simkin S Palmer B Cooper J Self-harm in England: a tale of three cities. Multicentre study of self-harm Soc Psychiatry Psychiatr Epidemiol 2007 42 7 513 521 10.1007/s00127-007-0199-7 17516016 \n19. Hawton K Harriss L Hall S Simkin S Bale E Bond A Deliberate self-harm in Oxford, 1990-2000: a time of change in patient characteristics Psychol Med 2003 33 6 987 996 10.1017/S0033291703007943 12946083 \n20. Clinical Practice Research Datalink [https://www.cprd.com, Accessed 05 Feb 2015].\n21. Herrett E Gallagher AM Bhaskaran K Forbes H Mathur R van Staa T Data resource profile: clinical practice research datalink (CPRD) Int J Epidemiol 2015 44 3 827 836 10.1093/ije/dyv098 26050254 \n22. Vodovar D Mégarbane B Prognosis and outcome of severe lithium poisoning J Psychopharmacol 2017 31 9 1274 1277 10.1177/0269881117699168 28918709 \n23. Tondo L Isacsson G Baldessarini RJ Suicidal behaviour in bipolar disorder CNS Drugs 2003 17 7 491 511 10.2165/00023210-200317070-00003 12751919 \n24. Christensen J Vestergaard M Mortensen PB Sidenius P Agerbo E Epilepsy and risk of suicide: a population-based case–control study The Lancet Neurology 2007 6 8 693 698 10.1016/S1474-4422(07)70175-8 17611160 \n25. Gibbons RD Hur K Brown CH Mann JJ Relationship between antiepileptic drugs and suicide attempts in patients with bipolar disorder Arch Gen Psychiatry 2009 66 12 1354 1360 10.1001/archgenpsychiatry.2009.159 19996040 \n26. Caley CF Perriello E Golden J Antiepileptic drugs and suicide-related outcomes in bipolar disorder: a descriptive review of published data Mental Health Clinician 2018 8 3 138 147 10.9740/mhc.2018.05.138 29955559 \n27. I Johannessen S Johannessen Landmark C Antiepileptic drug interactions - principles and clinical implications Curr Neuropharmacol 2010 8 3 254 267 10.2174/157015910792246254 21358975 \n28. Chakos M Lieberman J Hoffman E Bradford D Sheitman B Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials Am J Psychiatry 2001 158 4 518 526 10.1176/appi.ajp.158.4.518 11282684 \n29. Khan AY Preskorn SH Examining concentration-dependent toxicity of clozapine: role of therapeutic drug monitoring J Psychiatr Pract 2005 11 5 289 301 10.1097/00131746-200509000-00003 16184070 \n30. British National Forumulary 66 edn: BMJ Publishing Group; 2014.\n31. Meltzer HY Alphs L Green AI Altamura AC Anand R Bertoldi A Clozapine treatment for suicdality in schizophrenia: international suicide prevention trial (InterSePT) Arch Gen Psychiatry 2003 60 82 91 10.1001/archpsyc.60.1.82 12511175 \n32. Modestin J Dal Pian D Agarwalla P Clozapine diminishes suicidal behavior: a retrospective evaluation of clinical records J Clin Psychiatry 2005 66 4 534 538 10.4088/JCP.v66n0418 15816798 \n33. Kelly DL Wehring HJ Vyas G Current status of clozapine in the United States Shanghai Arch Psychiatry 2012 24 2 110 113 25324612 \n34. Hawton K Rodham K Evans E Harriss L Adolescents who self harm: a comparison of those who go to hospital and those who do not Child Adolesc Mental Health 2009 14 1 24 30 10.1111/j.1475-3588.2008.00485.x \n35. Geulayov G Casey D McDonald KC Foster P Pritchard K Wells C Incidence of suicide, hospital-presenting non-fatal self-harm, and community-occurring non-fatal self-harm in adolescents in England (the iceberg model of self-harm): a retrospective study Lancet Psychiatry 2018 5 2 167 174 10.1016/S2215-0366(17)30478-9 29246453\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-244X",
"issue": "18(1)",
"journal": "BMC psychiatry",
"keywords": "Antipsychotics; Drug toxicity; Mood stabilisers; Self-poisoning; Suicide",
"medline_ta": "BMC Psychiatry",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D062787:Drug Overdose; D004739:England; D005260:Female; D006801:Humans; D054539:Medication Therapy Management; D001523:Mental Disorders; D010818:Practice Patterns, Physicians'; D020379:Risk Adjustment; D016728:Self-Injurious Behavior; D013405:Suicide; D014149:Tranquilizing Agents",
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"pages": "399",
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"pmid": "30587176",
"pubdate": "2018-12-27",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "25324612;11545667;11282684;29955559;26050254;9828983;19996040;12511175;12742920;25052948;16184070;23113986;18806918;17516016;23755739;28918709;19031375;29246453;24890068;28962337;12751919;12946083;17611160;11331564;21358975;9229027;21969462;20435959;15816798;29442611",
"title": "Relative toxicity of mood stabilisers and antipsychotics: case fatality and fatal toxicity associated with self-poisoning.",
"title_normalized": "relative toxicity of mood stabilisers and antipsychotics case fatality and fatal toxicity associated with self poisoning"
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"abstract": "The diagnosis of synchronous colorectal cancer (CRC) is crucial as the management, including the extent of surgical resection, depends on it. There have been numerous studies on the clinicopathological features of synchronous CRC; however, only a few studies have discussed synchronous cancer treatment. The guidelines to best manage the synchronous and metachronous CRC are limited, especially the most appropriate surgical treatment and chemotherapy based on mutational analysis of mismatch repair genes and the carcinoma sequence model. We present a rare case of a metachronous CRC with intact nuclear expression of microsatellite instability markers following a synchronous CRC, and it failed to show any significant response to surgical resection and chemoradiotherapy. A 53-year-old female presented in June 2016 with bleeding per rectum for one month, weight loss, and a recent history of altered bowel habits. The per rectal examination revealed a circumferential growth. Colonoscopy and biopsy yielded multiple polyps throughout the colon and invasive adenocarcinoma in the upper and lower one-third of the rectum. The above features were highly suggestive of synchronous CRC. Serologic studies revealed elevated carcinoembryonic antigen (CEA). Excisional biopsy of mesenteric and retroperitoneal lymph nodes during proctocolectomy and end ileostomy was negative for metastasis, including the other metastatic workup preoperatively-eight months post-resection and adjuvant chemotherapy patient developed metachronous CRC. Mutational analysis showed positivity only for adenomatous polyposis coli (APC) while negative for KRAS, NRAS, and BRAF. Immunohistochemistry (IHC) markers for mismatch repair (MMR) proteins showed intact protein expression. The patient was given multiple chemotherapy cycles throughout her course, including oral capecitabine, XELOX (capecitabine + oxaliplatin), cetuximab-capecitabine, cetuximab-irinotecan, and FOLFIRI (5-fluorouracil [5-FU] + irinotecan + folinic acid)-bevacizumab, as is the standard chemotherapy regimen for these tumors. The diagnosis of metachronous CRC with intensive follow up is crucial. IHC markers for MMR proteins showed intact protein expression ruling out the possibility of microsatellite instability and Lynch Syndrome. The only presence of APC mutation indicates a partial chromosomal instability. During the course, the patient had either stable size of the masses or developed new metastatic growth despite intensive chemotherapeutic regimes. Unfortunately, there are no precise guidelines based on aberrant mutational analysis regarding synchronous and metachronous CRCs management.",
"affiliations": "General Surgery, South Texas Health System, McAllen, USA.;General Surgery, Jawaharlal Nehru Medical College, Aligarh, IND.;Internal Medicine, Kiruba Hospital, Coimbatore, IND.;General Surgery, Ramaiah Medical College and Hospital, Bangalore, IND.;Surgical Oncology, Cape Fear Valley Medical Center, Fayetteville, USA.",
"authors": "Dominic|Jerry Lorren|JL|;Feroz|Shah Huzaifa|SH|;Muralidharan|Abilash|A|;Ahmed|Asma|A|;Thirunavukarasu|Pragatheeshwar|P|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.11308",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.11308\nGastroenterology\nGeneral Surgery\nOncology\nAberrant Partial Chromosomal Instability With Chemotherapeutically Resistant Metachronous Colorectal Cancer Following a Synchronous Primary Colorectal Cancer: A Case Report\nMuacevic Alexander Adler John R Dominic Jerry Lorren 1 Feroz Shah Huzaifa 23 Muralidharan Abilash 4 Ahmed Asma 5 Thirunavukarasu Pragatheeshwar 6 \n1 \nGeneral Surgery, South Texas Health System, McAllen, USA \n\n2 \nGeneral Surgery, Jawaharlal Nehru Medical College, Aligarh, IND \n\n3 \nGeneral Surgery, Larkin Community Hospital, Miami, USA \n\n4 \nInternal Medicine, Kiruba Hospital, Coimbatore, IND \n\n5 \nGeneral Surgery, Ramaiah Medical College and Hospital, Bangalore, IND \n\n6 \nSurgical Oncology, Cape Fear Valley Medical Center, Fayetteville, USA \n\nShah Huzaifa Feroz drhuzaifa@protonmail.com\n3 11 2020 \n11 2020 \n12 11 e113083 11 2020 Copyright © 2020, Dominic et al.2020Dominic et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/43341-aberrant-partial-chromosomal-instability-with-chemotherapeutically-resistant-metachronous-colorectal-cancer-following-a-synchronous-primary-colorectal-cancer-a-case-reportThe diagnosis of synchronous colorectal cancer (CRC) is crucial as the management, including the extent of surgical resection, depends on it. There have been numerous studies on the clinicopathological features of synchronous CRC; however, only a few studies have discussed synchronous cancer treatment. The guidelines to best manage the synchronous and metachronous CRC are limited, especially the most appropriate surgical treatment and chemotherapy based on mutational analysis of mismatch repair genes and the carcinoma sequence model. We present a rare case of a metachronous CRC with intact nuclear expression of microsatellite instability markers following a synchronous CRC, and it failed to show any significant response to surgical resection and chemoradiotherapy.\n\nA 53-year-old female presented in June 2016 with bleeding per rectum for one month, weight loss, and a recent history of altered bowel habits. The per rectal examination revealed a circumferential growth. Colonoscopy and biopsy yielded multiple polyps throughout the colon and invasive adenocarcinoma in the upper and lower one-third of the rectum. The above features were highly suggestive of synchronous CRC. Serologic studies revealed elevated carcinoembryonic antigen (CEA). Excisional biopsy of mesenteric and retroperitoneal lymph nodes during proctocolectomy and end ileostomy was negative for metastasis, including the other metastatic workup preoperatively-eight months post-resection and adjuvant chemotherapy patient developed metachronous CRC. Mutational analysis showed positivity only for adenomatous polyposis coli (APC) while negative for KRAS, NRAS, and BRAF. Immunohistochemistry (IHC) markers for mismatch repair (MMR) proteins showed intact protein expression. The patient was given multiple chemotherapy cycles throughout her course, including oral capecitabine, XELOX (capecitabine + oxaliplatin), cetuximab-capecitabine, cetuximab-irinotecan, and FOLFIRI (5‐fluorouracil [5‐FU] + irinotecan + folinic acid)-bevacizumab, as is the standard chemotherapy regimen for these tumors.\n\nThe diagnosis of metachronous CRC with intensive follow up is crucial. IHC markers for MMR proteins showed intact protein expression ruling out the possibility of microsatellite instability and Lynch Syndrome. The only presence of APC mutation indicates a partial chromosomal instability. During the course, the patient had either stable size of the masses or developed new metastatic growth despite intensive chemotherapeutic regimes. Unfortunately, there are no precise guidelines based on aberrant mutational analysis regarding synchronous and metachronous CRCs management.\n\nprimary colorectal cancermetachronous colorectal cancersynchronous colorectal cancerchromosomal instabilitymicrosatellite instabilitymetastatic colorectal cancerchemotherapeutic resistancecapecitabinecetuximabirinotecanThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nSynchronous colorectal carcinoma (synchronous CRC) is a rare type of colorectal malignancy, defined by the presence of more than one primary colorectal carcinoma at the time of initial presentation [1]. The prevalence of all colorectal cancers ranges from 1.1% to 8.1% [2]. The diagnosis of the synchronous CRC is vital. If disregarded, they can develop into advanced-stage metachronous cancer and usually require re-operation with intensive chemotherapy. A preoperative diagnosis of synchronous colorectal cancer is crucial because it may influence the treatment options concerning the type and extent of surgical resection [3]. There are numerous studies on the clinicopathological characteristics of synchronous cancer. However, very few studies have reviewed the treatment of synchronous cancer. The guidelines to best manage the synchronous CRC are limited, primarily the most appropriate surgical treatment and chemotherapy based on mutational analysis results of mismatch repair genes and the adenoma-carcinoma sequence model.\n\nMetachronous colorectal cancers are defined as primary colorectal cancers developing six months after the previous colorectal surgery for the CRC [4]. Although the incidence of metachronous CRCs is increasing, the management guidelines, including chemotherapy, prognosis, and the impact of synchronicity on the prognosis, also remain understudied.\n\nOur case report presents a rare metachronous CRC following a synchronous CRC. In addition, it exhibits partial chromosomal instability with intact nuclear expression of microsatellite instability markers. Moreover, the CRC failed to show any significant response to surgical resection concomitant with chemoradiotherapy.\n\nCase presentation\nA 53-year-old female presented in June 2016 with bleeding per rectum for one month, 10-pound weight loss over nine months, and a recent history of altered bowel habits. The patient denied nausea, vomiting, abdominal discomfort, fevers, bone pain, night sweats, trauma, intake of blood thinners. Her past medical history and family history were non-significant. On physical examination, the patient was obese. Her vitals were within normal limits, and exhibited mild pallor. The abdomen was soft, obese, non-distended with a mild left lower quadrant tenderness with no abnormal mass in any quadrant or any clinical evidence of cirrhosis. On per rectal examination, the circumferential growth was evident.\n\nThis constellation of symptoms necessitated an extensive workup. The patient underwent colonoscopy and biopsy, which revealed a rectal growth to be grade II-III moderately differentiated adenocarcinoma. In addition, multiple adenomatous polyps with low-grade dysplasia extending from the cecum to descending colon were present.\n\nCT scan of the abdomen revealed multiple colonic polyps throughout the colon and circumferential mass/large polyps in the distal sigmoid colon, rectosigmoid junction, and rectum extending for a length 9-10 cm. The liver was enlarged and showed diffuse-low attenuation consistent with the fatty infiltration with no focal nodule or area of enhancement. No significant lymphadenopathy was apparent. Other workups for metastasis were either negative or normal.\n\nSerum lab profile (including CBC, CMP, coagulation studies, LFT, RFT) was positive only for mild anemia (Hb 11.1). The remainder were negative or normal. The serum tumor marker carcinoembryonic antigen (CEA) was elevated 316.9 ng/mL.\n\nA probable initial diagnosis of familial adenomatous polyposis degenerating into synchronous primary colorectal cancer was made. The surgical team was consulted for further evaluation and management.\n\nIn view of the low rectal cancer, the patient underwent total proctocolectomy with end ileostomy with adjacent lymph node resection in June 2016. The gross specimen revealed more than 200 mostly sessile polyps throughout the colon with an ulcero-proliferated lesion studded in the upper third of the rectum and the largest polyp in the lower third of the rectum. Morphologic review of the slides from ulcero-proliferated lesion demonstrated high-grade/poorly differentiated malignant neoplasm with pleomorphic hyperchromatic nuclei infiltrating the muscularis propria. At the same time, the section from the largest polyp revealed invasive adenocarcinoma infiltrating the submucosa. The histopathology of the resected 29 lymph nodes (22 mesocolic, 7 inferior mesenteric) was negative for any malignancy.\n\nStaging (2010 AJCC TNM Classification System for Colorectal Cancer [5]):\npT2: Tumor invading the muscularis propria in a sample from the distal ulcero-proliferated lesion (12 cm from the distal resection margin)\npT1: Tumor invading submucosa in a sample from the largest polyp (2 cm from the distal resection margin)\npN0: No regional lymph node metastasis\nM0: No distant metastasis by imaging; no evidence of tumor in other sites or organs\n\nGiven the above parameters, an initial diagnosis of stage I primary colorectal cancer (CRC) was made.\n\nIn light of the familial polyposis nature and early colorectal cancer, the patient received adjuvant chemotherapy from July 2016 to September 2016 with oral capecitabine (two cycles of 21 days). Concurrently, she received the 28 fractions of 50.4 cGY radiotherapy.\n\nPositron emission tomography-computed tomography (PET-CT) was subsequently obtained in February 2017, which revealed extensive FDG-avid hepatic, peritoneal and mesenteric metastases (Figures 1, 2, 3).\n\nFigure 1 (a) Contrast-enhanced CT abdomen image shows solitary hepatic metastasis. (b) Corresponding fused PET-CT image shows a metabolically active hypodense lesion of size 16 x 14 mm in segment II/III of the left lobe of the liver (standardized uptake value [SUV] Max = 5.5).\nPET-CT, positron emission tomography-computed tomography.\n\nFigure 2 (a) Contrast-enhanced CT abdomen image shows gastric serosal deposits. (b) Corresponding fused PET-CT image shows gastric serosal deposits. A peritoneal nodule of size 25 x 20 mm is noted abutting the greater curvature of the stomach with mild metabolic activity.\nPET-CT, positron emission tomography-computed tomography.\n\nFigure 3 (a) Contrast-enhanced CT abdomen image shows mesenteric lesions with peritoneal fat stranding. (b) Corresponding fused PET-CT image shows patchy areas of soft tissue thickening in the mesentery adjacent to the ileostomy site with mild increased metabolic activity, measuring ~ 28 x 18 mm (standardized uptake value [SUV] Max = 1.5).\nPET-CT, positron emission tomography-computed tomography.\n\nFurthermore, the genetic analysis of the specimen acquired from the liver biopsy showed strong positivity for APC while negative for BRAF, KRAS, and NRAS (Table 1).\n\nTable 1 PCR amplified DNA sequencing for mutation analysis of the specimen from liver metastasis\n\nPCR Amplified DNA Sequencing for Mutation Analysis\n\t\nResult(s)\n\t\n\nAPC\n\t\nPositive\n\t\n\nBRAF\n\t\nNegative\n\t\n\nKRAS\n\t\n\nNRAS\n\t\nIn light of advanced metastatic disease, six cycles of XELOX regimen chemotherapy was planned in a three-week treatment cycle: IV oxaliplatin 130 mg/m² (day 1) followed by PO capecitabine 1000 mg/m² twice daily (day 1 evening to day 15 morning) with no treatment for seven days. After completion of the five cycles of chemotherapy, a repeat PET-CT was obtained in June 2017 to evaluate his response to treatment. It yielded a resolution of hepatic metastasis in the left lobe; however, the peritoneal and mesenteric deposits remained stable and non-FDG avid. The irregular peritoneal deposits were seen indenting the stomach's posterior body along the greater curvature and measured 2.2 x 1.4 cm (previously 2.5 x 2.0 cm), while the mesenteric deposits measure 2.7 x 1.7 cm (previously 2.8 x1.8 cm) in the largest dimension. During cycle 6 (May 2017), the patient's treatment course was complicated by chemotherapy-induced severe neutropenia on CBC, with no additional symptoms.\n\nIn July 2017, given the mild response and advanced metastatic disease, the patient was further advised 12 cycles of combination chemotherapy regimen (cetuximab-capecitabine) in a two-week cycle (weekly cetuximab (400 mg/m² [over 120 minutes], followed by 250 mg/m² [over 30 minutes]), capecitabine 800 mg/m² twice daily (day 1 through 14, every two weeks)).\n\nFollowing the completion in Jan 2018, the patient was given an additional eight-week cycle of cetuximab-irinotecan (weekly cetuximab (400 mg/m² [over 120 minutes], followed by 250 mg/m² [over 30 minutes]), IV Irinotecan 200 mg/m² [on day 1 every 2 weeks]) until August 2019.\n \nPET-CT obtained in September 2018 revealed new hypermetabolic solitary hepatic metastasis (Figure 4) along with new non-FDG avid parenchymal nodules in the upper lobe of the right lung.\n\nFigure 4 (a) Contrast-enhanced CT abdomen image shows a new solitary hepatic metastasis in the left lobe of the liver. (b) Corresponding fused PET-CT image shows a new metabolically active hypodense lesion of size 20 x 16 mm in the left lobe of the liver.\nPET-CT, positron emission tomography-computed tomography.\n\nA new combination of chemotherapy FOLFIRI and Bevacizumab in a 2 weekly cycle was started in September 2019, considering the new metastatic lesions despite being on cetuximab-irinotecan chemotherapy:\nDay 1: IV irinotecan 180 mg/m² [over 30-90 minutes] with leucovorin 400 mg/m² IV infusion to match the duration of irinotecan infusion, followed by:\nDays 1-2: fluorouracil 400 mg/m² IV push on day 1, then 1,200 mg/m²/day × 2 days (total 2,400mg/m² over 46-48 hours) IV continuous infusion\nDay 1: bevacizumab 5mg/kg IV\n\nPET-CT obtained sequentially revealed:\nOctober 2019: Hypermetabolic metastatic lesions in both lobes of the liver (Figure 5a, b) with mildly FDG avid metastatic nodules in the upper lobe of the right lung.\nJanuary 2020: Stable size (Figure 5c) and activity\nSeptember 2020: Multiple metastatic lesions in various segments of the liver.\n\nFigure 5 (a) PET-CT shows hepatic metastasis in the left lobe of the liver. (b) PET-CT shows hepatic metastasis in the right lobe of the liver. (c) PET-CT shows stable hepatic metastasis in the right lobe of the liver.\nPET-CT, positron emission tomography-computed tomography.\n\nConsidering she was non-responsive to chemotherapy, the surgical team, as per the National Comprehensive Cancer Network (NCCN) guidelines version 4.2020, planned to perform a needle core biopsy from the metastatic lesion in the left lobe of the liver for immunohistochemistry testing, to detect microsatellite instability or mismatch repair, to guide chemotherapeutic regime. The results were typical for each marker (i.e., all four MMR proteins are normally expressed). Additionally, Her-2 testing is also negative (Table 2).\n\nTable 2 Immunohistochemistry (IHC) studies for mismatch repair (MMR) proteins and Her-2/Neu protein.\nImmunohistochemistry (IHC) Markers\tPattern of Expression\t\nMLH1\tIntact protein expression\t\nMSH2\tIntact protein expression\t\nMSH6\tIntact protein expression\t\nPMS2\tIntact protein expression\t\nHer-2/Neu\tNegative\t\nDiscussion\nCRC is the most common gastrointestinal cancer and is the third most common malignancy in the United States and the third leading cause of cancer-related deaths. CRC has both strong environmental associations and genetic risk factors. The incidence rate peaks in the 7th-8th decades (but increases with age starting at 40), with equal incidence in males and females. The incidence and mortality rate has been steadily declining for the past years, due to increased cancer screening and better therapy modalities.\n\nCRC development is a multistep process wherein benign adenomas give rise to carcinomas (Figure 6) [6]. Sequential cellular and molecular events in the mucosal epithelium lead to altered proliferation, cellular accumulation, and glandular disarray, which may result in adenomatous polyps. Further genetic alteration results in a greater degree of cellular atypia and glandular disorganization (dysplasia), which may evolve into a carcinoma. The sequence of adenoma-to-carcinoma is almost always associated with genetic changes, even in sporadic colon cancers. Multiple somatic mutations contributed by environmental insults are associated with polyps and cancers. The genetic contribution in the formation of adenomas, as well as progression to malignancy, include:\n Mutation in proto-oncogenes (K-ras)\n Inactivation of tumor suppressor gene: Stepwise progression of the tumor is associated with inactivation of tumor suppressor gene designated DCC (deleted in colorectal cancer) on chromosome 18q- (responsible for normal cell-cell adhesive interactions) in more than 75% of cases, i.e., 18q deletion is the most common cytogenetic abnormality. While chromosome 17p deletions can cause loss of the p-53 tumor suppressor gene.\n Mutation in genes involved in DNA repair (mismatch repair genes) can cause microsatellite instability (a clinically significant prognostic factor recommended in TNM 2010 staging criteria).\n\nFigure 6 Adenoma–carcinoma sequence model for microsatellite and chromosomal instability in colorectal cancer. This model is likely to be an oversimplification. Still, it represents the clinicopathological changes with genetic abnormalities in the progression of chromosomally unstable colorectal cancer (CRC) (the gatekeeper pathway involving genes that regulate cell growth).\nFrom [7].\n\nSynchronous CRC, as suggested in the previous studies, are more common in the setting of diseases with a precursor lesion such as adenoma as in hereditary nonpolyposis colorectal cancer (HNPCC; Lynch Syndrome), familial adenomatous polyposis, and inflammatory bowel diseases [2]. Typical sites of synchronous CRC are the rectum and sigmoid colon. The lack of KRAS and BRAF mutation and no loss of nuclear expression of mismatch repair proteins (MLH1, MSH2, MSH6, PMS2) indicates a low probability of microsatellite instability. It also ruled out the presence of Lynch syndrome. In contrast to our case, the synchronous CRC is more heeded in the colon's proximal portion, has a higher incidence of mucinous adenocarcinoma, and a higher likelihood of having microsatellite instability [2].\n\nThe diagnosis of synchronous CRC has increased, primarily because of advancements in diagnostic modalities such as colonoscopy and computed tomography (CT) colonography [8]. However, there is much skepticism about the most appropriate surgical treatment. Few authors have suggested that the treatment of synchronous or metachronous CRC is the same as solitary colorectal carcinoma, with the removal of enough bowel and local lymph nodes resection [9]. It is proposed that subtotal colectomy with recto-ileostomy should be performed for patients with distant synchronous lesions, combined with multiple adenomatous polyps or a familial history if they are a surgical candidate [9]. Others suggest extensive surgical resection is required for patients with synchronous colorectal cancer with known predisposing factors such as familial adenomatous polyposis, HNPCC or ulcerative colitis [2]. For other cases, appropriate surgical resection with a colonoscopic examination on follow-up is recommended. Passman et al. [10] suggested a more extensive resection for lesions in adjacent segments. Some authors have recommended multiple resections aimed at retaining the normal colon [11,12]. Likewise, there has been insufficient agreement among surgeons regarding the appropriate surgical treatment for synchronous cancers located in separate segments.\n\nThe patient manifested early metachronous metastases as the metastatic lesions were detected within 12 months after the surgery of the primary CRC. The current National Comprehensive Cancer Network (NCCN) guidelines for unresectable metastatic CRC recommend FOLFIRI (5‐fluorouracil [5‐FU] + irinotecan + folinic acid) or FOLFOX (5‐FU + oxaliplatin + folinic acid) or CAPEOX/XELOX (capecitabine + oxaliplatin), or FOLFOXIRI (5‐FU + oxaliplatin + irinotecan + folinic acid) ± bevacizumab for patients who are appropriate for intensive therapy [13]. The NCCN panel recommends these regimens as uniformly effective cytotoxic treatment options. Little or no clinical difference is discerned when administering intensive therapy as first‐line versus subsequent‐line therapy following less intensive therapy [13-17]. The European Society for Medical Oncology guidelines similarly recommends first‐line backbone chemotherapy of a fluoropyrimidine in various schedules and combinations [18]. FOLFOX and FOLFIRI are currently considered the preferred cytotoxic treatment options for first‐line treatment of mCRC [14, 18].\n\nThe chemotherapy and immunotherapy based on mutational analysis of the specimen for the metachronous metastatic CRC remain understudied. For example, it is clearly understood the absence of KRAS mutation makes the EGFR specific antibody ineffective. So the question arises what chemotherapy or immunotherapy or their combination would be most effective if the patient shows positivity for APC genes while negative for KRAS, NRAS, and BRAF on DNA sequencing, i.e., a patient showing a partial chromosomal instability as per the adenoma-carcinoma sequence model. Concurrently, there are no established guidelines for optimal sequencing of biological or cytotoxic agents in metastatic colorectal cancer (mCRC) [19].\n\nThe prognosis of synchronous CRC compared to solitary CRC also remained dubious. The retrospective analysis performed by Passman et al. [10] showed a similar prognosis between the two. While in multivariate analysis, synchronous CRC was an independent prognostic factor associated with poor overall survival [1,20]. As yet, no biological marker has been recognized that distinguishes synchronous metastases from metachronous metastases [20].\n\nConclusions\nClassifying patients at high risk for developing metachronous colorectal cancer is crucial as it may contribute to more accurate patient information, customized follow-up plans, and adequate management. The chemotherapy proposed for the metachronous CRC also remains widely understudied. Unfortunately, there are no precise guidelines based on mutational analysis regarding the management of metachronous CRC post resection of the synchronous CRC. As such, the selection of a chemotherapeutic agent is based on less studied trials and depends on the patient’s clinical status and the clinician’s expertise. Until now, no data are present in the literature regarding the management of metachronous colorectal malignancy, which showed the partial mutational characteristics of chromosomal instability. This patient’s aberrant mutational analysis in the presence of his elevated serum tumor markers and chemotherapeutic resistance indicates a need for more specific modalities of diagnosis, treatment, and follow-up.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Prognosis of synchronous colorectal carcinoma compared to solitary colorectal carcinoma: a matched pair analysis Eur J Gastroenterol Hepatol He W Zheng C Wang Y 1489 1495 31 2019 31441800 \n2 Synchronous colorectal cancer: clinical, pathological and molecular implications World J Gastroenterol Lam AK Chan SS Leung M 6815 6820 20 2014 24944471 \n3 Synchronous colorectal carcinoma: a risk factor in colorectal cancer surgery Dis Colon Rectum Van Leersum NJ Aalbers AG Snijders HS 460 466 57 April 24608302 \n4 Guidelines for colonoscopy surveillance after cancer resection: a consensus update by the American Cancer Society and US Multi-Society Task Force on Colorectal Cancer CA Cancer J Clin Rex DK Kahi CJ Levin B 160 167 56 2006 16737948 \n5 The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM Ann Surg Oncol Edge SB Compton CC 1471 1474 17 2010 20180029 \n6 Step Up to Surgery 2nd Edition Wolters Kluwer I Lippincott Williams & Wilkins Zaslau S Vaughan RA 115 Philadelphia Michael Tully 2014 https://shop.lww.com/Step-Up-to-Surgery/p/9781451187632 \n7 Genetic prognostic and predictive markers in colorectal cancer Nat Rev Cancer Walther A Johnstone E Swanton C 489 499 Philadelphia Michael Tully 9 2009 19536109 \n8 Epidemiology and prognosis of synchronous colorectal cancers Br J Surg Latournerie M Jooste V Cottet V Lepage C Faivre J Bouvier AM 1528 1533 95 2008 18991301 \n9 Clinical features, diagnosis, treatment and prognosis of multiple primary colorectal carcinoma World J Gastroenterol Wang HZ Huang XF Wang Y Ji JF Gu J 2136 2139 10 2004 15237453 \n10 Synchronous colon primaries have the same prognosis as solitary colon cancers Dis Colon Rectum Passman MA Pommier RF Vetto JT 329 334 39 1996 8603557 \n11 Synchronous carcinoma of the colon and rectum: prognostic and therapeutic implications Am J Surg Adloff M Arnaud JP Bergamaschi R Schloegel M 299 302 157 1989 2537586 \n12 Multiple synchronous colonic anastomoses: are they safe? Colorectal Dis Holubar SD Wolff BG Poola VP Soop M 135 140 12 2010 19207709 \n13 National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Colon Cancer. Version 4.2020 9 2020 2020, June-15 https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf \n14 FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study J Clin Oncol Tournigand C André T Achille E 229 237 22 2004 14657227 \n15 Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000-05): an open-label, randomised, phase 3 trial Lancet Oncol Ducreux M Malka D Mendiboure J 1032 1044 12 2011 21903473 \n16 Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial Lancet Koopman M Antonini NF Douma J 135 142 370 2007 17630036 \n17 Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial Lancet Seymour MT Maughan TS Ledermann JA 143 152 370 2007 17630037 \n18 Guidelines for diagnosis, treatment and follow-up Ann Oncol Van Cutsem E Cervantes A Nordlinger B Arnold D; ESMO Guidelines Working Group. Metastatic colorectal cancer: ESMO Clinical Practice 143 152 25 2014 24356625 \n19 A comprehensive review of sequencing and combination strategies of targeted agents in metastatic colorectal cancer Oncologist Ciombor KK Bekaii-Saab T 25 34 23 2018 29021377 \n20 Managing synchronous liver metastases from colorectal cancer: a multidisciplinary international consensus Cancer Treat Rev Adam R de Gramont A Figueras J 729 741 41 2015 26417845\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "12(11)",
"journal": "Cureus",
"keywords": "capecitabine; cetuximab; chemotherapeutic resistance; chromosomal instability; irinotecan; metachronous colorectal cancer; metastatic colorectal cancer; microsatellite instability; primary colorectal cancer; synchronous colorectal cancer",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e11308",
"pmc": null,
"pmid": "33282585",
"pubdate": "2020-11-03",
"publication_types": "D002363:Case Reports",
"references": "26417845;17630037;17630036;18991301;24608302;25190710;29021377;19207709;24944471;31441800;14657227;8603557;16737948;20180029;2537586;19536109;21903473;15237453",
"title": "Aberrant Partial Chromosomal Instability With Chemotherapeutically Resistant Metachronous Colorectal Cancer Following a Synchronous Primary Colorectal Cancer: A Case Report.",
"title_normalized": "aberrant partial chromosomal instability with chemotherapeutically resistant metachronous colorectal cancer following a synchronous primary colorectal cancer a case report"
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"companynumb": "US-AMGEN-USASP2020204619",
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"activesubstancename": "FLUOROURACIL\\IRINOTECAN\\LEUCOVORIN"
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{
"abstract": "In a series of 1007 consecutively admitted patients, 3 cases of neuroleptic malignant syndrome (NMS) were identified (0.3%). All three patients were affected by mood disorders with congruent psychotic features, had shown catatonia just before the onset of NMS, and had been treated with low neuroleptic doses. All of them presented low serum iron levels. The relationship between NMS and catatonia and possible therapeutic decisions are discussed.",
"affiliations": "Ospedale Santo Spirito, Dipartimento di salute mentale USL RM11, Rome, Italy.",
"authors": "Raja|M|M|;Altavista|M C|MC|;Cavallari|S|S|;Lubich|L|L|",
"chemical_list": "D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D006220:Haloperidol",
"country": "Germany",
"delete": false,
"doi": "10.1007/BF02195723",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0940-1334",
"issue": "243(6)",
"journal": "European archives of psychiatry and clinical neuroscience",
"keywords": null,
"medline_ta": "Eur Arch Psychiatry Clin Neurosci",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D001714:Bipolar Disorder; D002389:Catatonia; D003866:Depressive Disorder; D003987:Dibenzothiazepines; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D017809:Fatal Outcome; D005260:Female; D006220:Haloperidol; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009459:Neuroleptic Malignant Syndrome; D009460:Neurologic Examination; D011618:Psychotic Disorders; D012189:Retrospective Studies",
"nlm_unique_id": "9103030",
"other_id": null,
"pages": "299-303",
"pmc": null,
"pmid": "7913834",
"pubdate": "1994",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11941110;2863986;3224231;2567121;1362369;2572206;1674666;2889378;2873715;2894782;2645794;1672456;1674665;3307984;11941178;3789214;6143410;2877012;2876647;2440291;1976763;1676049;3892294;1363674;2884371;1977485;1677602;3777225;6101595;2673115",
"title": "Neuroleptic malignant syndrome and catatonia. A report of three cases.",
"title_normalized": "neuroleptic malignant syndrome and catatonia a report of three cases"
} | [
{
"companynumb": "IT-JNJFOC-20170804507",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "DIAZEPAM"
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"d... |
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