article dict | reports listlengths 1 3.97k |
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{
"abstract": "OBJECTIVE\nMilitary deployments to the tropics are associated with specific infection risks. To add to the available epidemiological information, infectious disease risks in German military personnel returning from predominantly tropical deployments were assessed.\n\n\nMETHODS\nSince 2006, German soldiers returning from predominantly tropical deployments have been offered the opportunity of returnee screenings at the Department of Tropical Medicine and Infectious Diseases of the Bundeswehr Hospital Hamburg. Case files and diagnostic results recorded between 2006 and 2018 were retrospectively assessed to identify deployment-associated infectious disease risks.\n\n\nRESULTS\nAlong with high enteric colonisation rates with apathogenic protozoa and resistant Enterobacteriaceae, direct or indirect proof of infections among the 764 assessed cases comprised Plasmodium spp (n=37), Giardia duodenalis (n=21), Schistosoma spp (n=14), Yersinia enterocolitica (n=5), Strongyloides stercoralis (n=3), Campylobacter jejuni (n=1), Leishmania spp (n=1) and Salmonella enterica (n=1), as well as latent infections with Mycobacterium tuberculosis complex (n=8). The infections were mainly imported from the African region and Eastern Mediterranean region and high proportions of cases lacked typical symptoms. Reported side effect rates of antimalarial chemoprophylaxis for mefloquine (n=121), atovaquone/proguanil (n=49) and doxycycline (n=6) were 36.3%, 19.3% and 11.8%, respectively, while non-compliance rates were 12.9%, 13.0% and 5.9%, respectively.\n\n\nCONCLUSIONS\nConsiderable rates of infections with sometimes atypical or absent symptoms confirm a need for returnee screenings after tropical deployments. High reported side effect rates for mefloquine support its replacement by atovaquone/proguanil or doxycycline for antimalarial chemoprophylaxis.",
"affiliations": "Department of Tropical Medicine and Infectious Diseases, Bundeswehrkrankenhaus Hamburg, Hamburg, Germany.;Department of Tropical Medicine and Infectious Diseases, Bundeswehrkrankenhaus Hamburg, Hamburg, Germany.;Department of Microbiology and Hospital Hygiene, Bundeswehrzentralkrankenhaus Koblenz, Koblenz, Germany.;Department of Microbiology and Hospital Hygiene, Bundeswehrkrankenhaus Hamburg, Hamburg, Germany Frickmann@bni-hamburg.de.",
"authors": "Schawaller|Marius|M|;Wiemer|D|D|;Hagen|R M|RM|;Frickmann|H|H|http://orcid.org/0000-0002-8967-9528",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bmjmilitary-2020-001575",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2633-3767",
"issue": null,
"journal": "BMJ military health",
"keywords": "diagnostic microbiology; epidemiology; gastrointestinal infections; infectious diseases; molecular diagnostics; tropical medicine",
"medline_ta": "BMJ Mil Health",
"mesh_terms": null,
"nlm_unique_id": "101761581",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33257519",
"pubdate": "2020-11-30",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Infectious diseases in German military personnel after predominantly tropical deployments: a retrospective assessment over 13 years.",
"title_normalized": "infectious diseases in german military personnel after predominantly tropical deployments a retrospective assessment over 13 years"
} | [
{
"companynumb": "DE-GLAXOSMITHKLINE-DE2020GSK251473",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ATOVAQUONE\\PROGUANIL HYDROCHLORIDE"
},
... |
{
"abstract": "A case is presented of mucormycosis in a patient with acute myeloblastic leukemia following liver transplantation for Wilson's disease. A 58-year-old female was admitted to the Department of Haematology with deterioration of her general condition, loss of appetite, tiredness and difficulty with mental contact for a few days. Blood and urine cultures for bacteria and fungus, galactomannan antigen were negative. Whole body computed tomography demonstrated bilateral hilar lymphadenopathy with necrotic lesions: splenomegaly with a hypodensive lesion 13 × 20 × 19 mm and lower pulmonary infiltrates suggested fungal etiology. Magnetic resonance imaging of the brain showed thickened meninges. Finally, mucormycosis was diagnosed. Treatment with amphotericin B lipid complex was started, resulting in an partial improvement of the general condition and decreased level of inflammatory markers. However, the patient's condition continued to deteriorate, with sepsis etiology Escherichia coli, and despite the intensive managements she eventually died.",
"affiliations": "Pomeranian Medical University, Szczecin, Poland.;Pomeranian Medical University, Szczecin, Poland.;Pomeranian Medical University, Szczecin, Poland.;Pomeranian Medical University, Szczecin, Poland.",
"authors": "Łanocha|Aleksandra Anna|AA|;Guzicka-Kazimierczak|Renata|R|;Zdziarska|Barbara|B|;Wawrzynowicz-Syczewska|Marta|M|",
"chemical_list": "D000935:Antifungal Agents; D000666:Amphotericin B",
"country": "Poland",
"delete": false,
"doi": "10.26444/aaem/105533",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1232-1966",
"issue": "26(4)",
"journal": "Annals of agricultural and environmental medicine : AAEM",
"keywords": "Mucormycosis; Willson’s disease; acute myeloblastic leukemia; liver transplantation",
"medline_ta": "Ann Agric Environ Med",
"mesh_terms": "D000666:Amphotericin B; D000935:Antifungal Agents; D017809:Fatal Outcome; D005260:Female; D006527:Hepatolenticular Degeneration; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D016031:Liver Transplantation; D008875:Middle Aged; D009091:Mucormycosis; D011183:Postoperative Complications",
"nlm_unique_id": "9500166",
"other_id": null,
"pages": "665-668",
"pmc": null,
"pmid": "31885243",
"pubdate": "2019-12-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mucormycosis in a patient with acute myeloblastic leukemia following liver transplantation for Wilson's disease.",
"title_normalized": "mucormycosis in a patient with acute myeloblastic leukemia following liver transplantation for wilson s disease"
} | [
{
"companynumb": "PL-MYLANLABS-2020M1028764",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CLADRIBINE"
},
"drugadditional": null,
... |
{
"abstract": "Mental disturbances have been described in patients with Parkinson's Disease (PD). Of these, the common conditions are delirium and psychosis. Delirium has been attributed to change of environment, especially hospital stay and infections; while psychosis is due to drugs like dopamine agonists. This is a case of a 75-year-old male, on levodopa therapy for PD, who presented with delirium and ended up with a cocktail diagnosis: Cryptococcal meningitis, Hashimoto's Encephalopathy (HE), Urinary tract infection with acute renal failure, Uremic encephalopathy and Levodopa induced psychosis. This case report, therefore, highlights the need to look for other causes of delirium in a patient with PD who is on levodopa therapy.",
"affiliations": "Consultant - Physician, Department of Internal Medicine, National Hospital , Calicut, Kerala, India .",
"authors": "Manappallil|Robin George|RG|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.7860/JCDR/2016/22248.9089",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0973-709X",
"issue": "10(12)",
"journal": "Journal of clinical and diagnostic research : JCDR",
"keywords": "Cryptococcal meningitis; Hashimoto’s encephalopathy; Mental disturbances",
"medline_ta": "J Clin Diagn Res",
"mesh_terms": null,
"nlm_unique_id": "101488993",
"other_id": null,
"pages": "OD15-OD16",
"pmc": null,
"pmid": "28208916",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports",
"references": "8528224;8553450;11407265;20943237;11391498;24596591;25957635;16551444;19005879;19092289;1603727;2240918;2073307;20716391;12580699;16885711",
"title": "Delirium in Parkinson's Disease: A Cocktail Diagnosis.",
"title_normalized": "delirium in parkinson s disease a cocktail diagnosis"
} | [
{
"companynumb": "IN-IMPAX LABORATORIES, INC-2016-IPXL-02473",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBIDOPA\\LEVODOPA"
},
"dru... |
{
"abstract": "BACKGROUND\nIndividuals with autistic disorder (autism) frequently exhibit significant irritability marked by severe tantrums, aggression, and self-injury. Despite advances in the treatment of this symptom domain in autism, there remains an ongoing need for more effective and better tolerated pharmacotherapies.\n\n\nOBJECTIVE\nThe aim of this study is to determine the effectiveness and tolerability of paliperidone for irritability in autism.\n\n\nMETHODS\nThis is a prospective, 8-week open-label study of paliperidone in 25 adolescents and young adults with autism. Primary outcome measures included the Clinical Global Impressions-Improvement (CGI-I) Scale and the Irritability subscale of the Aberrant Behavior Checklist (ABC-I). Concomitant medications (except antipsychotics) were permitted if dosages were stable for ≥2 months.\n\n\nRESULTS\nTwenty-one (84 %) of 25 subjects ages 12-21 years (mean 15.3 years) responded to paliperidone, based on a CGI-I Scale score of 1 or 2 (very much or much improved) and ≥25 % improvement on the ABC-I. The mean final dosage of paliperidone was 7.1 mg/day (range 3-12 mg/day). Two subjects discontinued paliperidone prior to study completion (moderate sedation, n = 1; nonresponse, n = 1). Mild-to-moderate extrapyramidal symptoms were recorded in four subjects. A mean weight gain of 2.2 ± 2.6 kg (range -3.6 to +7.9 kg) was recorded. Mean age- and sex-normed body mass index increased from 23.6 to 24.2 (p ≤ 0.001). Mean serum prolactin increased from 5.3 to 41.4 ng/mL (p ≤ 0.0001).\n\n\nCONCLUSIONS\nPaliperidone treatment was associated with significant improvement in irritability and was generally well tolerated. Larger scale, placebo-controlled studies are needed to elucidate the efficacy and tolerability of paliperidone in this population.",
"affiliations": "Section of Child and Adolescent Psychiatry, Department of Psychiatry, Indiana University School of Medicine, Christian Sarkine Autism Treatment Center, James Whitcomb Riley Hospital for Children, 705 Riley Hospital Drive, Indianapolis, IN 46202-5200, USA. kstigler@iupui.edu",
"authors": "Stigler|Kimberly A|KA|;Mullett|Jennifer E|JE|;Erickson|Craig A|CA|;Posey|David J|DJ|;McDougle|Christopher J|CJ|",
"chemical_list": "D014150:Antipsychotic Agents; D007555:Isoxazoles; D011743:Pyrimidines; D000068882:Paliperidone Palmitate",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00213-012-2711-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0033-3158",
"issue": "223(2)",
"journal": "Psychopharmacology",
"keywords": null,
"medline_ta": "Psychopharmacology (Berl)",
"mesh_terms": "D000293:Adolescent; D014150:Antipsychotic Agents; D001321:Autistic Disorder; D002648:Child; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007508:Irritable Mood; D007555:Isoxazoles; D008297:Male; D000068882:Paliperidone Palmitate; D010865:Pilot Projects; D011446:Prospective Studies; D011569:Psychiatric Status Rating Scales; D011743:Pyrimidines; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "7608025",
"other_id": null,
"pages": "237-45",
"pmc": null,
"pmid": "22549762",
"pubdate": "2012-09",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "16926619;9672054;18775367;19948625;19713555;17601495;11132243;21464191;20981764;10832774;17530476;21389140;20568835;17092691;20492853;3993694;18466043;20166801;18854723;12151468;9549957;12959421;15930063;16321731;15492353;19411369;12071395;7814313;19797985;19519261;9136504;17224706;20565430;17466492;20706126",
"title": "Paliperidone for irritability in adolescents and young adults with autistic disorder.",
"title_normalized": "paliperidone for irritability in adolescents and young adults with autistic disorder"
} | [
{
"companynumb": "US-JNJFOC-20121000053",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "A patient undergoing cyclosporine therapy presented with muscle weakness. This was preceded by diarrhea and treated with ciprofloxacin. Rhabdomyolysis was diagnosed clinically and biochemically. This was presumably drug-induced triggered by a combined therapy with cyclosporine, amlodipine, simvastatin and ciprofloxacin. The case presented demonstrates that during therapy with several substances which inhibit the degradation of simvastatin, the additional administration of ciprofloxacin should be considered with extreme caution.",
"affiliations": "Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Deutschland. attaran.masoumeh@mh-hannover.de.;Abteilung Neurologie, Klinikum Braunschweig, Braunschweig, Deutschland.;Zentrum für Innere Medizin, Klinik für Nieren- und Hochdruckerkrankungen, Medizinische Hochschule Hannover, Hannover, Deutschland.;Zentrum für Innere Medizin, Klinik für Nieren- und Hochdruckerkrankungen, Medizinische Hochschule Hannover, Hannover, Deutschland.",
"authors": "Attaran-Bandarabadi|M|M|;Kalbasi Anaraki|P|P|;Gwinner|W|W|;Haller|H|H|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00108-016-0060-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0020-9554",
"issue": "57(8)",
"journal": "Der Internist",
"keywords": "Amlodipine; Ciprofloxacin; Cyclosporin; Rhabdomyolysis; Simvastatin",
"medline_ta": "Internist (Berl)",
"mesh_terms": "D000368:Aged; D003937:Diagnosis, Differential; D004359:Drug Therapy, Combination; D005121:Extremities; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D018908:Muscle Weakness; D012206:Rhabdomyolysis",
"nlm_unique_id": "0264620",
"other_id": null,
"pages": "815-8",
"pmc": null,
"pmid": "27167632",
"pubdate": "2016-08",
"publication_types": "D016428:Journal Article",
"references": "19046720;24946698;23965645;21566311;24379677;23859539;24799748;19571284;25883814;12848784;19729463;16556082;12672737",
"title": "Weakness of the extremities in a 73-year-old male patient.",
"title_normalized": "weakness of the extremities in a 73 year old male patient"
} | [
{
"companynumb": "DE-WEST-WARD PHARMACEUTICALS CORP.-DE-H14001-16-00926",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
... |
{
"abstract": "BACKGROUND\nIn cases of hypertrophic obstructive cardiomyopathy (HOCM), the systolic anterior motion of the mitral valve apparatus results in an obstruction of the left ventricular outflow tract (LVOT), which is known as the SAM [systolic anterior motion] phenomenon. Hypothetically, a pathological obstruction of the LVOT of a different etiology would result in a comparable hemodynamic instability, which would be refractory to inotrope therapy, and may be detectable through echocardiography.\n\n\nMETHODS\nWe observed a severely impaired left ventricular function due to a combination of a thrombotic LVOT obstruction and distinctive mitral regurgitation in a 56-year-old Caucasian, female patient after massive transfusion with aggressive procoagulant therapy. Initially, the patient had to be resuscitated due to cardiac arrest after a long-distance flight. The resuscitation attempts in combination with lysis therapy due to suspected pulmonary artery embolism were initially successful but resulted in traumatic liver injury, hemorrhagic shock and subsequent acute respiratory distress syndrome (ARDS). Oxygenation was stabilized with veno-venous extracorporeal membrane oxygenation (ECMO), but the hemodynamic situation deteriorated further. Transesophageal echocardiography (TEE) showed a massive, dynamic LVOT obstruction. Two thrombi were attached to the anterior leaflet of the mitral valve, resulting in a predominantly systolic obstruction. Unfortunately, the patient died of multiple-organ failure despite another round of lysis therapy and escalation of the ECMO circuit to a veno-venoarterial cannulation for hemodynamic support.\n\n\nCONCLUSIONS\nMassive transfusion with aggressive procoagulant therapy resulted in mitral valve leaflet thrombosis with dynamic, predominantly systolic LVOT obstruction, comparable to the SAM phenomenon. The pathology was only detectable with a TEE investigation.",
"affiliations": "Department of Anesthesiology and Intensive Care Medicine (CVK, CCM) Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13357, Berlin, Germany. vladimir.skrypnikov@charite.de.;Department of Anesthesiology, Intensive Care Medicine, Emergency Medicine and Pain Therapy, Vivantes Klinikum im Friedrichshain, Landsberger Allee 49, 10249, Berlin, Germany.;Department of Anesthesiology and Intensive Care Medicine (CVK, CCM) Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13357, Berlin, Germany.;Department of Anesthesiology and Intensive Care Medicine (CVK, CCM) Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13357, Berlin, Germany.;Department of Anesthesiology and Intensive Care Medicine (CVK, CCM) Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13357, Berlin, Germany.",
"authors": "Skrypnikov|Vladimir|V|;Rosenthal|Christoph|C|;Weber-Carstens|Steffen|S|;Menk|Mario|M|;Russ|Martin|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13256-021-02840-3",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n2840\n10.1186/s13256-021-02840-3\nCase Report\nDynamic thromboembolic left ventricular outflow tract obstruction after aggressive procoagulant treatment in hemorrhagic shock: a case report\nSkrypnikov Vladimir vladimir.skrypnikov@charite.de\n\n13\nRosenthal Christoph christoph.rosenthal@vivantes.de\n\n2\nWeber-Carstens Steffen steffen.weber-carstens@charite.de\n\n1\nMenk Mario mario.menk@charite.de\n\n1\nRuss Martin martin.russ@charite.de\n\n1\n1 grid.7468.d 0000 0001 2248 7639 Department of Anesthesiology and Intensive Care Medicine (CVK, CCM) Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13357 Berlin, Germany\n2 grid.415085.d Department of Anesthesiology, Intensive Care Medicine, Emergency Medicine and Pain Therapy, Vivantes Klinikum im Friedrichshain, Landsberger Allee 49, 10249 Berlin, Germany\n3 grid.6363.0 0000 0001 2218 4662 Department of Anesthesiology and Operative Intensive Care Medicine, Campus Virchow Klinikum Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany\n18 5 2021\n18 5 2021\n2021\n15 2691 2 2021\n31 3 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\nIn cases of hypertrophic obstructive cardiomyopathy (HOCM), the systolic anterior motion of the mitral valve apparatus results in an obstruction of the left ventricular outflow tract (LVOT), which is known as the SAM [systolic anterior motion] phenomenon. Hypothetically, a pathological obstruction of the LVOT of a different etiology would result in a comparable hemodynamic instability, which would be refractory to inotrope therapy, and may be detectable through echocardiography.\n\nCase presentation\n\nWe observed a severely impaired left ventricular function due to a combination of a thrombotic LVOT obstruction and distinctive mitral regurgitation in a 56-year-old Caucasian, female patient after massive transfusion with aggressive procoagulant therapy. Initially, the patient had to be resuscitated due to cardiac arrest after a long-distance flight. The resuscitation attempts in combination with lysis therapy due to suspected pulmonary artery embolism were initially successful but resulted in traumatic liver injury, hemorrhagic shock and subsequent acute respiratory distress syndrome (ARDS). Oxygenation was stabilized with veno-venous extracorporeal membrane oxygenation (ECMO), but the hemodynamic situation deteriorated further. Transesophageal echocardiography (TEE) showed a massive, dynamic LVOT obstruction. Two thrombi were attached to the anterior leaflet of the mitral valve, resulting in a predominantly systolic obstruction. Unfortunately, the patient died of multiple-organ failure despite another round of lysis therapy and escalation of the ECMO circuit to a veno-venoarterial cannulation for hemodynamic support.\n\nConclusion\n\nMassive transfusion with aggressive procoagulant therapy resulted in mitral valve leaflet thrombosis with dynamic, predominantly systolic LVOT obstruction, comparable to the SAM phenomenon. The pathology was only detectable with a TEE investigation.\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1186/s13256-021-02840-3.\n\nKeywords\n\nHemorrhagic shock\nDynamic LVOT obstruction\nSAM phenomenon\nPro-coagulatory therapy\nThrombotic complication\nCharité (3093)Open Access funding enabled and organized by Projekt DEAL.\n\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nDynamic obstruction of the left-ventricular outflow tract is a rare condition. The known common causes of left ventricular outflow tract (LVOT) obstruction include hypertrophic obstructive cardiomyopathy (HOCM), dehydration, sepsis, cardiac surgical treatment after valve repair, and Takotsubo cardiomyopathy [1].\n\nIn the case reported here, the LVOT obstruction was caused by thrombotic formations. The thrombotic structures situated at the mitral valve caused a severe systolic obstruction of the LVOT comparable to the so-called SAM [systolic anterior motion] phenomenon [2]. In this condition, the anterior leaflet (cusp) moves towards the LVOT and obstructs the outflow tract. This leads to the extension of the systolic ejection phase, a decrease in the ejection volume and increased pressure work for the left ventricle. Also, a posterior mitral insufficiency was caused by an insufficient coaptation of the mitral leaflets. This further impaired cardiac output and led to abrupt hypotension and a low cardiac output syndrome. The SAM phenomenon is known in patients with hypertrophic obstructive cardiomyopathy (HOCM) or in the condition of severe volume depletion [3–6]. The condition is a dynamic phenomenon and can—albeit rarely—be a cause of hypotension [7–9].\n\nWe present the case of a rare thrombus formation attached to the mitral valve under procoagulant therapy, massive transfusion and extracorporeal membrane oxygenation (ECMO) therapy despite continued anticoagulation, which resulted in a unique dynamic obstruction of the LVOT similar to a SAM phenomenon.\n\nCase presentation\n\nA 56-year-old woman (Caucasian, married, two children) without preexisting conditions, who had previously performed moderate endurance runs about 2-3 times per week according to her relatives, suffered from acute cardiac arrest at home. Prior to cardiac arrest she had complained of pain in her calf after a long-distance flight. The first rhythm detected by the emergency service crew was pulseless electrical activity. During pre-clinic cardiopulmonary resuscitation, systemic lysis therapy (tenecteplase, 100 mg) was initiated under suspicion of pulmonary embolism. After the return of spontaneous circulation, the patient was transferred to an emergency department. At arrival at the resuscitation area, the patient presented with hemodynamic shock (mean arterial pressure, MAP of 92 mmHg, heart rate 133 beats/minute, epinephrine dosage of 5.5 µg/kg/minute, norepinephrine dosage of 4.5 µg/kg/minute), was intubated, mechanically ventilated and was unresponsive (Glasgow Coma Scale score of 3) without further sedation (the patient had received 15 mg midazolam, 0.5 mg fentanyl during the initial resuscitation). The first computed tomography (CT) scan did not reveal a pulmonary embolism. The treating team assumed that a pulmonary embolism, which was completely lysed, was the most likely explanation for the cardiac arrest based on the typical clinical presentation, case history and good response to lysis therapy. Shortly thereafter, the hemodynamic situation deteriorated again with requirement for massive doses of catecholamines, a pronounced drop in hemoglobin levels and the need for massive transfusion. The CT scan showed a hemoperitoneum due to a traumatic rupture of the liver after resuscitation. An emergency laparotomy was performed, the liver was sutured and the abdomen was packed. During surgery, a prolonged, massive transfusion of packed red blood cells, fresh-frozen plasma and thrombocyte concentrates was necessary. Further, coagulation factors including fibrinogen, antithrombin (AT) and four-factor prothrombin complex concentrate (4F-PCC) were administered (Fig. 1).Fig. 1 Schematic presentation of interventions, hemodynamics, catecholamine therapy, coagulation parameters and substituted clotting preparations over time. Interventions, hemodynamic data, laboratory results and all clotting preparations and blood products which were substituted or transfused during the course of treatment are shown. A representative catecholamine dosage is provided for each day of treatment. CPR cardiopulmonary resuscitation, V-V ECMO veno-venous extracorporeal membrane oxygenation, V-VA ECMO veno-venoarterial extracorporeal membrane oxygenation, MAP mean arterial pressure, bpm beats per minute, INR international normalized ratio of prothrombin time, PTT partial thromboplastin time, AT antithrombin concentration, Plt platelet concentration, TXA tranexamic acid, PCC prothrombin complex concentrate, IU international unit, FFP fresh-frozen plasma, pRBC packed red blood cells\n\nOn the following day, the patient developed an abdominal compartment syndrome with the onset of acute liver failure and the need for a re-laparotomy. She also developed progressive lung failure with highly elevated parameters of mechanical ventilation and poor oxygenation. Therefore, she was transferred to our ECMO center, where veno-venous (V-V) ECMO was implemented.\n\nTransesophageal echocardiography (TEE) revealed severe right-heart stress (severe right ventricular dilatation, RV/LV > 2, decreased septal wall motion, severe tricuspid regurgitation, volume depletion of left ventricle) and beginning right-heart failure. Consequently, V-V ECMO was extended to venous-venoarterial (V-VA) cannulation with a 23 French, 38-cm-long drainage cannula (right femoral vein), 19 French 50-cm-long, venous return cannula (left femoral vein) and 15 French, 15-cm-long arterial return cannula (left femoral artery), that is, with a continuous cardiopulmonary bypass flow. Anticoagulation with an activated partial thromboplastin time (aPTT) above 60 seconds was performed with unfractionated heparin. Further, echocardiography revealed two pronounced, hyperdense thrombotic structures located directly at both leaflets of the mitral valve. The thrombus located at the anterior leaflet measured 0.9 × 1.0 cm and caused an obstruction of the LVOT during systole (Fig. 2, Additional file 1: Video S1, Additional file 3: Video S3).Fig. 2 Midesophageal longaxis view (137°): showing obstructive mass on anterior mitral leaflet ~ 0.9 cm x 1.0 cm in left ventricular outflow tract during systole. The hypodense structure at the mitral valve causes obstruction of the left ventricular outflow tract and significantly reduces left-ventricular ejection volume and cardiac output\n\nVmax in the LVOT was 3.52 m/second (Pmax of 50 mmHg) (Fig. 3). Also, a moderate mitral insufficiency with a vena contracta of 0.6 cm was found (Figs. 4, 5, Additional file 2: Video S2). Of note, both the thrombus and the tip of the anterior mitral leaflet (AMVL, which was enclosed by the thrombus) obstructed the LVOT in a dynamic fashion (Additional file 3: Video S3), which was aggravated during systole and may be comparable to the SAM phenomenon in its hemodynamic consequence. Furthermore, the mitral insufficiency was an indirect indicator of a SAM-like pathology if considered with respect to the systolic motion of the thrombus and the tip of the AMVL.Fig. 3 Transgastric long-axis view at 118°. Continuous-wave Doppler shows 3.5 m/second velocity across left ventricular outflow tract with indicating moderate obstruction\n\nFig. 4. Mid-esophageal long-axis view at 144° showing mitral jet during systole, showing moderate mitral insufficiency\n\nFig. 5. Mid-esophageal view at 50° showing moderate mitral valve regurgitation with vena contracta ~ 0.6 cm\n\nClinically, the patient remained highly unstable, demanding high dosages of catecholamines despite V-VA ECMO support. A new ultima ratio CT scan to rule out other causes of hemodynamic instability showed a previously undescribed central, right pulmonary embolism with almost complete obstruction of the right upper pulmonary artery, as well as numerous small thrombi in several left and right lung segments. In this situation with thromboembolic obstruction of both LVOT and pulmonary arteries, another systemic lysis treatment (alteplase, 30 mg) was initiated as ultima ratio therapy. Echocardiography performed shortly after lysis revealed no remaining mitral thrombi and an unobstructed, free LVOT. In parallel, the catecholamine dosages were decreased substantially, but the patient could not be weaned completely at any point.\n\nNevertheless, the patient developed progressive acute liver failure with increasing lactic acidosis and high demand for glucose substitution, pulmonary failure without improvement in oxygenation or decarboxylation (ECMO gas flow could not be reduced) and renal failure. Finally, the patient died from severe multiple-organ failure despite V-VA ECMO therapy. Postmortem examination revealed the disseminated formation of intravascular thrombi, for instance in the vena femoralis, pulmonary arteries, vena porta hepatis and vena lienalis.\n\nDiscussion and conclusions\n\nTo the best of our knowledge, this is the first report of a dynamic LVOT obstruction as a direct consequence of procoagulant therapy and the subsequent formation of a massive thrombus, which was attached to the anterior leaflet of the mitral valve.\n\nThe condition of hemorrhagic shock is complex, and the imbalance in the coagulation processes can substantially increase the risk of intravascular thrombosis [4]. A differentiated and well-balanced treatment applying both pro- and anti-coagulatory factors (such as heparin, AT) has been shown to be a relevant part of therapy for severe bleeding [5]. In our case, AT levels were far below 20% at intensive care unit (ICU) admission. Thus, we speculate that the excessive substitution of pro-coagulatory factors and the subsequent imbalance of the coagulation system was—at least in part—causative for the thrombotic complications seen in our patient. 4F-PCCs carry an increased prothrombotic potential. In trauma patients, Schöchl et al. described an increased endogenous thrombin potential after administration of 4F-PCC [10]. The benefit of PCC compared to fresh-frozen plasma with its decreased volume load to the patient (especially in pulmonary and cardiac failure) has to be weighed against the increased prothrombotic risk. It would have been ideal to use viscoelastic tests combined with a point-of-care testing (POCT)-based coagulation management algorithm for monitoring of coagulation status and for goal directed coagulation management in this highly dynamic situation to avoid procoagulant overstimulation. Unfortunately, at the time of treatment of this patient, we did not have a well-established POCT-based coagulation management algorithm.\n\nA bacterial endocarditis has to be considered as a differential diagnosis of structures at the mitral valve. However, in the case reported here, no signs of ongoing or florid infections were seen before the critical incident. Also, postmortem examination revealed no evidence for a pre-existing or new endocarditis.\n\nOf importance, low flow situations on ECMO, especially V-A ECMO, such as increased afterload caused by the jet from the return cannula, can cause or aggravate LVOT thrombi. However, in the case presented here, the mitral valve thrombus was detected before the ECMO therapy was escalated to V-VA ECMO. The ECMO circuit (pump, oxygenator, ECMO lines) did not show any thrombus formation. Thus, we think that the combination of massive transfusion with aggressive procoagulant therapy was the major cause of the mitral valve leaflet thrombosis. Nevertheless, phases of reduced flow during hemodynamic decompensation in our patient as well as LV underfilling (during bleeding, surgery and pulmonary embolism) might have contributed to the thrombus formation which was detected with TEE.\n\nOf note, the case confirms the essential role of echocardiography in the diagnosis and treatment of critically ill cardiovascular unstable patients in the ICU [11]. None of the common methods of hemodynamic monitoring such as invasive blood pressure measurement, pulse index contour cardiac output (PiCCO) or pulmonary artery catheterization provides sufficient information on intracardiac pathologies. Echocardiography with evaluation of the LVOT was essential for diagnosis and treatment of the condition in the present case. Even if the thrombi could have been visualized with a CT scan, only the moving real-time images of an ultrasound investigation displayed the systolic obstruction of the LVOT. In our opinion, echocardiography should be regarded as the diagnostic procedure of choice in cardiovascular unstable patients on the ICU whenever possible.\n\nSupplementary Information\n\nAdditional file 1: Video S1. Midesophageal longaxis view at 137°: obstructive mass on anterior mitral leaflet in left ventricular outflow tract during systole.\n\nAdditional file 2: Video S2. Midesophageal longaxis view (137°): obstructive mass anterior mitral leaflet in left ventricular outflow tract during systole (slow motion).\n\nAdditional file 3: Video S3. Mid-esophageal long-axis view (137°): obstructive mass on mitral valve (AMVL) in LVOT during systole (slow motion).\n\nAbbreviations\n\nAMVL Anterior mitral leaflet\n\nARDS Acute respiratory distress syndrome\n\nAT Antithrombin\n\nCT Computed tomography\n\nECMO Extracorporeal membrane oxygenation\n\nHOCM Hypertrophic obstructive cardiomyopathy\n\nLVOT Left ventricular outflow tract\n\nPiCCO Pulse index contour cardiac output\n\nPOCT Point-of-care testing\n\nSAM Systolic anterior motion\n\nTEE Transesophageal echocardiography\n\nV-V Veno-venous\n\nV-VA Venous-venoarterial\n\n4F-PCC Four-factor prothrombin complex concentrate\n\nAcknowledgements\n\nWe have no acknowledgements.\n\nAuthors’ contributions\n\nVS: directed the project, designed and wrote the manuscript, performed the echocardiographic examinations, designed the figures with CR and approved the final version. CR: was significantly involved in the interpretation of coagulation disorders, helped write the article and approved the final version. SWB: was involved in interpreting the results, reviewed the first version of the article and approved the final version. MM: designed the manuscript, edited the reviewed version, aided in interpreting the clinical results with CR, MR and CR, and approved the final version. MR: aided in interpreting the results, revised the first version of manuscript substantially with VS and CR and approved the final manuscript. All authors read and approved the final manuscript.\n\nFunding\n\nOpen Access funding enabled and organized by Projekt DEAL. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sector.\n\nAvailability of supporting data\n\nAll data generated or analyzed during this study are included in this published article and its additional information files.\n\nDeclarations\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nWritten informed consent was obtained from the legal guardian of the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nAll authors declare that they have no competing interests.\n\nThe results presented in this manuscript have not been published before.\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. Slama M Left ventricular outflow tract obstruction in ICU patients Curr Opin Crit Care 2016 22 3 260 266 10.1097/MCC.0000000000000304 27054628\n2. Walker CM Reddy GP Mohammed TL Systolic anterior motion of the mitral valve J Thorac Imaging 2012 27 4 W87 10.1097/RTI.0b013e31825412dd 22847594\n3. Kim S Kim SJ Kim J Dynamic obstruction induced by systolic anterior motion of the mitral valve in a volume-depleted left ventricle: an unexpected cause of acute heart failure in a patient with chronic obstructive pulmonary disease J Thorac Dis 2015 7 9 E365 26623139\n4. Ledgerwood AM Lucas CE A review of studies on the effects of hemorrhagic shock and resuscitation on the coagulation profile J Trauma 2003 54 5 Suppl S68 74 12768106\n5. Wiedermann CJ Kaneider NC A systematic review of antithrombin concentrate use in patients with disseminated intravascular coagulation of severe sepsis Blood Coagul Fibrinol 2006 17 7 521 526 10.1097/01.mbc.0000245302.18010.40\n6. Maron MS Olivotto I Betocchi S Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy N Engl J Med 2003 348 4 295 303 10.1056/NEJMoa021332 12540642\n7. Jiang L Shakil O Montealegre-Gallegos M Systolic anterior motion of the mitral valve and three-dimensional echocardiography J Cardiothorac Vasc Anesth 2015 29 1 149 150 10.1053/j.jvca.2013.05.041 24200494\n8. Sobczyk D Dynamic left ventricular outflow tract obstruction: underestimated cause of hypotension and hemodynamic instability J Ultrason 2014 14 59 421 10.15557/JoU.2014.0044 26674265\n9. Popescu BA Rosca M Schwammenthal E Dynamic obstruction in hypertrophic cardiomyopathy Curr Opin Cardiol 2015 30 5 468 474 10.1097/HCO.0000000000000199 26165376\n10. Schöchl H Endogenous thrombin potential following hemostatic therapy with 4-factor prothrombin complex concentrate: a 7-day observational study of trauma patients Crit Care 2014 18 4 R147 10.1186/cc13982 25008277\n11. Caselli S Martino A Genuini I Pathophysiology of dynamic left ventricular outflow tract obstruction in a critically ill patient Echocardiography 2010 27 10 E122 E124 10.1111/j.1540-8175.2010.01210.x 20553322\n\n",
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"keywords": "Dynamic LVOT obstruction; Hemorrhagic shock; Pro-coagulatory therapy; SAM phenomenon; Thrombotic complication",
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"mesh_terms": "D002312:Cardiomyopathy, Hypertrophic; D005260:Female; D006801:Humans; D008875:Middle Aged; D008943:Mitral Valve; D008944:Mitral Valve Insufficiency; D012771:Shock, Hemorrhagic; D014694:Ventricular Outflow Obstruction",
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"title": "Dynamic thromboembolic left ventricular outflow tract obstruction after aggressive procoagulant treatment in hemorrhagic shock: a case report.",
"title_normalized": "dynamic thromboembolic left ventricular outflow tract obstruction after aggressive procoagulant treatment in hemorrhagic shock a case report"
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"abstract": "We report the case of letrozole-induced radiation recall dermatitis (RRD) in a patient with a remote history of radiation therapy. There is only one previously known case of RRD triggered by letrozole in a patient with a recent (<3 month) history of radiation. Previously, only four other cases of aromatase-inhibitor-induced RRD have been reported. This case is significant for cancer care teams considering personalized treatments. In addition, improved long-term outcomes in cancer patients may lead to increases in and underdiagnoses of RRD. Likewise, RRD is patient specific, exacerbating health concerns, and can be difficult to recognize without proper awareness, documentation, and classification of triggering drugs. The authors hope to address these issues in this report.",
"affiliations": "Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Department of Surgery, Johns Hopkins Hospital, Bayview Campus, Baltimore, MD, USA.;Department of Surgery, Johns Hopkins Hospital, Bayview Campus, Baltimore, MD, USA.;Department of Surgery, Johns Hopkins Hospital, Bayview Campus, Baltimore, MD, USA.;Department of Surgery, Johns Hopkins Hospital, Bayview Campus, Baltimore, MD, USA.;Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. mkerns1@jhmi.edu.",
"authors": "Sweren|Evan|E|http://orcid.org/0000-0001-6664-8174;Aravind|Pathik|P|;Dembinski|Robert|R|;Klein|Catherine|C|;Habibi|Mehran|M|http://orcid.org/0000-0003-2944-4388;Kerns|Michelle L|ML|",
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"fulltext": "\n==== Front\nNPJ Breast Cancer\nNPJ Breast Cancer\nNPJ Breast Cancer\n2374-4677\nNature Publishing Group UK London\n\n271\n10.1038/s41523-021-00271-3\nCase Report\nRadiation recall dermatitis following letrozole administration in patient with a remote history of radiation therapy\nhttp://orcid.org/0000-0001-6664-8174\nSweren Evan 1\nAravind Pathik 2\nDembinski Robert 2\nKlein Catherine 2\nhttp://orcid.org/0000-0003-2944-4388\nHabibi Mehran 2\nKerns Michelle L. mkerns1@jhmi.edu\n\n1\n1 grid.21107.35 0000 0001 2171 9311 Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD USA\n2 grid.411935.b 0000 0001 2192 2723 Department of Surgery, Johns Hopkins Hospital, Bayview Campus, Baltimore, MD USA\n26 5 2021\n26 5 2021\n2021\n7 6221 7 2020\n19 4 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.\nWe report the case of letrozole-induced radiation recall dermatitis (RRD) in a patient with a remote history of radiation therapy. There is only one previously known case of RRD triggered by letrozole in a patient with a recent (<3 month) history of radiation. Previously, only four other cases of aromatase-inhibitor-induced RRD have been reported. This case is significant for cancer care teams considering personalized treatments. In addition, improved long-term outcomes in cancer patients may lead to increases in and underdiagnoses of RRD. Likewise, RRD is patient specific, exacerbating health concerns, and can be difficult to recognize without proper awareness, documentation, and classification of triggering drugs. The authors hope to address these issues in this report.\n\nSubject terms\n\nCancer microenvironment\nBreast cancer\nissue-copyright-statement© The Author(s) 2021\n==== Body\nIntroduction\n\nRadiation recall dermatitis (RRD) is a localized drug-induced inflammatory skin reaction occurring in a previously irradiated site months to years after discontinuation of ionizing radiation exposure. D’Angio et al. first described RRD in 1959 in association with actinomycin-D1. Since then, numerous pharmacological agents have been implicated as potential RRD triggers, with each trigger drug and risk factors being patient specific and unpredictable2,3. Clinical signs of RRD include erythema, pruritus, pain, desquamation, edema, vesiculation, necrosis, ulceration, and hemorrhage and can arise hours to months after initiation and even discontinuation of triggering medicines4. Recognition of RRD is of particular relevance for cancer care teams to avoid misdiagnoses and inappropriate treatments given anticancer medications comprise around 20–30% of RRD cases5. We report the case of letrozole (a selective aromatase inhibitor)-induced RRD in a 78-year-old woman nine years after ionizing radiation exposure, the longest known radiation-RRD gap for letrozole, the second reported case for this drug, and the first exclusively independent of potential ARD confounders6.\n\nResults\n\nCase history and presentation\n\nA 78-year-old woman with cancer at age 58, 69, and 78 presented to the emergency room with fevers, chills, malaise, and painful erythema of the left chest wall. A review of her history indicated that the cancer at age 58 was left-sided ductal carcinoma in situ treated with lumpectomy, followed by 5 years of adjuvant tamoxifen without radiation. The cancer at age 69 was left-sided lobular carcinoma in situ with microinvasion, which was treated with excision of the targeted area and adjuvant intensity modulated radiation therapy (IMRT) at a dose of 42.56 Gy to the whole breast (mixed energy) and an additional 8.1 Gy electron boost to the surgical bed with (12-MeV energy); total cumulative dose was 50.66 Gy. The pathology was microinvasive lobular carcinoma, arising in a background of multifocal lobular carcinoma in situ (LCIS), ER- (0%), PR - (0%), HER-2 negative (1+), Ki-67 10–15%. The LCIS was patchy ER + (5–10%), patchy PR + (5–10%).\n\nMost recently, her cancer at age 78 was a 2.5 cm invasive lobular carcinoma in her left breast that was treated with a simple mastectomy and sentinel lymph node biopsy. The cancer was T2N0Mx, grade 2, ER + (>95%, strong), PR focally + (1–5%), HER-2/neu equivocal by IHC (2+), not amplified by FISH, HER-2: D 17Z1 ratio 0.9, average HER-2 signals per nucleus 2.6. Ki-67 was 50–60%. Four left axillary lymph nodes were negative. Though the patient developed a rash around the incision accompanied with fever and chills following surgery, the rash completely resolved with Augmentin by the second week post operation despite being unresponsive to Bactrim. Letrozole was then started at a dose of 2.5 mg orally.\n\nIn the emergency room, ~2 weeks following the initiation of letrozole, the patient reported a two-day history of fevers, chills, malaise and painful, warm erythema localized to a 20 cm × 10 cm area of the left chest wall. On exam, her surgical incision appeared to be well healed. No fluctuance or induration was appreciated. Laboratory values were remarkable for leukocytosis (WBC 13.41). No imaging was performed. She was diagnosed with cellulitis and treated with a seven-day course of the antibiotic Bactrim. At follow up evaluation, the patient’s fever was found to have resolved, and her WBC had normalized. However, given persistence of cutaneous symptoms, the patient was started on a course of Augmentin as well as treatment with topical Clotrimazole for a possible fungal infection. Her rash continued to darken and became more violaceous in color. After ~2 weeks with no improvement of the skin eruption, despite these interventions, the patient was referred to dermatology for further evaluation.\n\nPhysical examination at her initial presentation to dermatology clinic revealed an irregular, erythematous to violaceous patch with telangiectases involving the left chest wall and extending from the sternum to the left axilla (Fig. 1a). No induration or tenderness was appreciated. There was a striking localization of the discoloration to previously irradiated area nearly 10 years prior. Our patient denied any other trauma to the site other than her recent surgery. Given the clinical history and physical findings, the patient was diagnosed with RRD. Follow up was recommended in 4–6 weeks for a biopsy unless the rash had improved. With the initiation of letrozole, the patient had also developed malaise, nausea, hair thinning, fatigue, and mood disturbances. In light of the occurrence of RRD as well as adverse side effects, the decision was made by the oncology team to cease letrozole treatment. Within 3 days, the patient reported improved feelings of non-cutaneous disturbances. Over 3 months of discontinued letrozole, her RRD has resolved, and the discoloration of the left chest wall has faded with almost no skin involvement (Fig. 1b). Currently, alternative systemic treatments are being considered for this patient.Fig. 1 Letrozole induces radiation recall dermatitis (RRD).\n\na, c Irregular erythematous purpuric patch with telangiectases involving the left chest wall, extending from the sternum to the left axilla at site of previous radiation 3 weeks after initiation of letrozole. b, d Resolution of skin eruption 3 months after discontinuation of letrozole.\n\nDiscussion\n\nRRD is a rare phenomenon with a significant impact on cancer patients, whose exact frequency is unknown due to misdiagnoses and underreporting; it has been suggested to be anywhere from 6 to 8.8%5. Interestingly, the negative effects of radiation on skin have been recognized as a limiting factor in therapeutic radiation exposure levels since the implementation of radiation for clinical benefit in the early 1900s7. This direct cutaneous response to radiation has since been defined as acute radiation dermatitis (ARD), and it can have a similar presentation to RRD, though the former results from direct ionizing nuclear damage and perhaps even acute immune cell activation. In fact, up to 95% of patients can experience skin problems due to radiation treatment8. While, ARD has been defined by some as a reaction occurring within 30–90 days of radiation exposure, it is likely that many case reports for RRD may be confounded by potential overlaps between ARD7–10.\n\nRRD’s specific causes and physiological pathway, however, remain largely unknown. Thus, clinical familiarity and comprehensive repositories of known RRD triggers are of paramount importance.\n\nRRD should be considered in patients presenting with skin changes localized to an area of previous radiation therapy; a biopsy is not needed to confirm the diagnosis and is rarely performed. Triggering drugs may be withdrawn or discontinued, depending on patient preference and severity, to allow for complete resolution of symptoms11. In this case, though grade 1-2 dermatologic (radiation recall) and neurologic (mood swings and depression) CTCAE may be managed to allow for continuation of treatment, the patient requested to discontinue medication and has refused further hormonal therapy at present. She remains disease free as of July 2020 based on 3D mammography and continues to follow up with Oncology.\n\nInterestingly, while a dose dependent relationship seems to exist between radiation exposure and potential for RRD, even in separate anatomical sites that receive concurrent and equivalent radiation exposure doses, RRD may occur asymmetrically and not in all sites2,12,13.\n\nA thorough investigation of our patient’s history of oncological interventions was crucial for the correlation of the patient’s symptoms and clinical signs to recent initiation of letrozole. This case is the second to identify letrozole as the probable trigger of RRD, and it also highlights the significant time gap that can exist between radiation therapy and the development of RRD. Intervals as long as 15 years between completion of radiation and RRD have been suggested since the 1970s, yet there are not sufficient data regarding the mean time of onset14.\n\nOutside of RRD, the differential diagnoses can include more common entities, such as erysipelas, herpes zoster, fungal infection, erysipelatous carcinoma, angiosarcoma, fixed drug reaction, panniculitis, and other radiation reactions2. RRD should be favored in patients with a history of radiation, a recurrent or chronic course despite antibiotic intervention, a lack of laboratory evidence of infection, and recent exposure to known trigger drugs, which our case adds to. Since RRD can present with erythema, warmth, and pain, it is commonly misdiagnosed as cellulitis4,15,16.\n\nTheories pertaining to the pathogenesis of RRD focus on radiation effects on the skin and characteristics of the trigger drug, since many are anticancer agents; however, this may simply reflect a sampling bias given radiation’s critical utility in treating cancer and the fact that even antibiotics can induce RRD3. Some proposed explanations include: depletion of epithelial stem cells and associated cell proliferation impairment, genetic predispositions, increased vascular permeability impacted drug pharmacokinetics, the induced expression of cytokines, and that RRD is a drug hypersensitivity reaction2,17,18. Some of these suggestions gain credence as epithelial tissues, including the lungs, esophagus, and gut, are the typical organs that experience RRD19. Yet, RRD likely results from a confluence of the above factors or undiscovered ones given trigger drug rechallenge may fail to elicit as pronounced and sometimes no RRD, perhaps due to resident tissue memory18.\n\nOur patient’s history definitively correlates letrozole with RRD and extends the known radiation-RRD gap for this drug to up-to nearly 10 years. Significantly, only four other cases of aromatase-inhibitor-induced RRD have been reported, including one for letrozole in a patient with a recent (<3 month) history of radiation (Table 1)6,20–22. Of note, in one of these cases, letrozole did not induce RRD while another aromatase inhibitor did. Our case also stresses how even non-cytoxic medications can induce RRD and the need for further research17. We believe the architectural changes resultant from our patient’s left mastectomy reiterated epithelial tissue’s unique sensitivity to RRD, as well.Table 1 Cases of aromatase inhibitor induced radiation recall dermatitis (RRD).\n\nAuthor (Year)\tAge/Gender\tRadiotherapy Dose (Gy)\tDrug/Dose\tTime\tTreatment\tRRD on Rechallenge\t\n\t\t\t\tRadiation to RRD\tDrug to RRD\t\t\t\nHaydaroglu et al. (2012)\t68/F\t50 + 10 Gy\tAnastrazole/1 mg\t2 mo\t2 mo\tMethylprednisolone aseponate, 10% urea, and fusidic acid creams started; anastrozole discontinued\tNA\t\nFoster et al. (2014)\t74/F\t50.4 + 10 Gy\tLetrozole/2.5 mg\t2 mo\t30 days\tLetrozole withdrawn\tNo\t\naIoannidis et al. (2014)\t58/F\tData not available\tEverolimus + Exemestane/10 mg + 25 mg\t10 yrs\t3 days\tExemestane + everolimus withdrawn; systemic corticosteroids, topical dexpanthenol started\tNo\t\naMarchand et al. (2016)\t74/F\t66 Gy\tExemestane/25 mg\t<1 yr\t27 days\tExemestane discontinued\tNA\t\nPresent case\t78/F\t42.56 + 8.1 Gy\tLetrozole/2.5 mg\t9 yrs\t14 days\tLetrozole discontinued\tNA\t\naThese 2 cases were published as Letters to the Editor.\n\nFortunately, RRD tends to decrease in intensity with each administration of the target drug and resolve with discontinuation of the medication. In some cases of cancer with high rates of recurrence, triggering medication has been continued and RRD has been managed with topical treatments, alone23. In most cases, the drug can be continued with symptomatic treatment including systemic or topical steroids and antihistamines3. For our patient, the adverse drug side effects in addition to the RRD prompted the discontinuation of letrozole, which resulted in gradual fading of skin changes over the period of 3 months. In summary, the authors hope that this case raises awareness of RRD in oncology patients.\n\nMethods\n\nEthics statement\n\nThe patient provided written informed consent to participate in this case report and to the use of their data, including photographs, for publication. IRB approval was not required per Johns Hopkins Medicine institutional guidelines, and all additional relevant ethical considerations were complied with.\n\nData collection\n\nImages were collected at clinical visits at Johns Hopkins Hospital or provided to the care team by the patient.\n\nReporting summary\n\nFurther information on research design is available in the Nature Research Reporting Summary linked to this article.\n\nSupplementary information\n\nReporting Summary\n\nSupplementary information\n\nThe online version contains supplementary material available at 10.1038/s41523-021-00271-3.\n\nAuthor contributions\n\nE.S. and M.L. contributed equally to all aspects of writing and editing. P.A., R.D., C.K. and M.H. collected images, prepared figures, and assisted with revisions.\n\nData availability\n\nAll the data supporting the findings in this case report are contained within the text.\n\nCompeting interests\n\nThe authors declare no competing interests.\n\nPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. D’Angio GJ Farber S Maddock CL Potentiation of x-ray effects by actinomycin D Radiology 1959 73 175 177 10.1148/73.2.175 13813586\n2. Ristic B Radiation recall dermatitis Int J. Dermatol 2004 43 627 631 10.1111/j.1365-4632.2004.02406.x 15357739\n3. Burris HA 3rd Hurtig J Radiation recall with anticancer agents Oncologist 2010 15 1227 1237 10.1634/theoncologist.2009-0090 21045191\n4. Melnyk SM More KF Miles EF Idiopathic radiation recall dermatitis developing nine months after cessation of Cisplatin therapy in treatment of squamous cell carcinoma of the tonsil Case Rep. Oncol. Med 2012 2012 271801 22745919\n5. Barco I Tamoxifen induced radiation recall dermatitis in a breast cancer patient Breast J. 2018 24 662 663 10.1111/tbj.13014 29517150\n6. Foster LM Mahoney ME Harmon MW Allen JW Luh JY Radiation recall reaction with letrozole therapy in breast cancer Clin. Breast Cancer 2014 14 e95 e97 10.1016/j.clbc.2013.12.011 24512859\n7. Kole AJ Kole L Moran MS Acute radiation dermatitis in breast cancer patients: challenges and solutions Breast Cancer (Dove Med Press) 2017 9 313 323 28503074\n8. Hegedus F Mathew LM Schwartz RA Radiation dermatitis: an overview Int J. Dermatol 2017 56 909 914 10.1111/ijd.13371 27496623\n9. Kodym E Frequency of radiation recall dermatitis in adult cancer patients Onkologie 2005 28 18 21 10.1159/000088824\n10. Camidge R Price A Characterizing the phenomenon of radiation recall dermatitis Radiother. Oncol. 2001 59 237 245 10.1016/S0167-8140(01)00328-0 11369064\n11. Moon D Radiation recall dermatitis induced by trastuzumab Breast Cancer 2016 23 159 163 10.1007/s12282-013-0462-6 23543400\n12. Bokemeyer C Paclitaxel-induced radiation recall dermatitis Ann. Oncol. 1996 7 755 756 10.1093/oxfordjournals.annonc.a010730\n13. Yeo W Leung SF Johnson PJ Radiation-recall dermatitis with docetaxel: establishment of a requisite radiation threshold Eur. J. Cancer 1997 33 698 699 10.1016/S0959-8049(96)00461-3 9274459\n14. Burdon J Bell R Sullivan J Henderson M Adriamycin-induced recall phenomenon 15 years after radiotherapy JAMA 1978 239 931 10.1001/jama.1978.03280370027018\n15. Ravishankar A Park SS Olivier KR Corbin KS Gemcitabine-Induced Radiation Recall Myositis: Case Report and Review of the Literature Case Rep. Oncol. 2018 11 168 178 10.1159/000487478 29681817\n16. Tan DH Bunce PE Liles WC Gold WL Gemcitabine-related “pseudocellulitis”: report of 2 cases and review of the literature Clin. Infect. Dis. 2007 45 e72 e76 10.1086/520684 17682983\n17. Azria D Radiation recall: a well recognized but neglected phenomenon Cancer Treat. Rev. 2005 31 555 570 10.1016/j.ctrv.2005.07.008 16168567\n18. Yeo W Johnson PJ Radiation-recall skin disorders associated with the use of antineoplastic drugs. Pathogenesis, prevalence, and management Am. J. Clin. Dermatol 2000 1 113 116 10.2165/00128071-200001020-00006 11702310\n19. Ding X Ji W Li J Zhang X Wang L Radiation recall pneumonitis induced by chemotherapy after thoracic radiotherapy for lung cancer Radiat. Oncol. 2011 6 24 10.1186/1748-717X-6-24 21375774\n20. Ioannidis G Gkogkou P Charalampous P Diamandi M Ioannou R Radiation-recall dermatitis with the everolimus/exemestane combination ten years after adjuvant whole-breast radiotherapy Radiother. Oncol. 2014 112 449 450 10.1016/j.radonc.2014.08.030 25220368\n21. Marchand A Exemestane-induced radiation recall dermatitis and morbilliform rash J. Dermatol 2016 43 575 576 10.1111/1346-8138.13238 26813265\n22. Haydaroglu A Sert F Kazandi AC Unal I Radiation recall reaction with anastrozole treatment in breast cancer Pr. Radiat. Oncol. 2012 2 e65 e68 10.1016/j.prro.2012.03.001\n23. Bourgeois, A., Grisoli, S. B., Soine, E. J. & Rosen, L. B. Tamoxifen-induced radiation recall dermatitis. Dermatol Online J 23 (2017).\n\n",
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"abstract": "Coronavirus is a novel human pathogen causing fulminant respiratory syndrome (COVID-19). Developing an effective and reliable vaccine was emergently pursued to control the dramatic spread of the global pandemic. The standard stages for vaccine development were unprecedentedly accelerated over a few months. We report a case of new-onset refractory status epilepticus (NORSE) after receiving the first dose of the ChAdOx1 nCoV-19 vaccine. We attribute the occurrence of NORSE to the vaccine due to the temporal relationship and the lack of risk factors for epilepsy in the patient. This report adds to the literature a possible rare side effect of a COVID-19 vaccine and contributes to the extremely limited literature on potential neurological side effects of viral vector vaccines. Healthcare providers should be aware of the possibility of post-vaccination epilepsy. The patient had recurrent seizures that were refractory to conventional antiepileptic drug therapy with a dramatic response to immunotherapy with pulse steroids and plasmapheresis. This likely reflects an underlying autoimmune mechanism in the genesis of post-vaccination generalized seizures without fever. Further research is needed to probe and study the exact mechanism at a more molecular level.",
"affiliations": "King Abdulaziz Medical City, Jeddah, Saudi Arabia; King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia; King Abdullah International Medical Research Center, Jeddah, Saudi Arabia. Electronic address: yasseraladdin@yahoo.com.;King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia; King Abdullah International Medical Research Center, Jeddah, Saudi Arabia.",
"authors": "Aladdin|Yasser|Y|;Shirah|Bader|B|",
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"abstract": "Lemierre syndrome was first documented in the literature in 1936, and is defined as septic thrombophlebitis of the internal jugular vein. It is typically a result of oropharyngeal infection causing local soft tissue inflammation, which spreads to vasculature, and promotes formation of septic thrombi within the lumen, persistent bacteremia, and septic emboli. We present the case of a 24-year-old incarcerated man, who presented with leukocytosis and a right-sided tender, swollen neck after undergoing left mandibular molar extraction for an infected tooth. Computed tomography revealed a persistent thrombus in the transverse and sigmoid sinuses bilaterally, extending downwards, into the upper jugular veins. He was started on empiric intravenous vancomycin, zosyn, and heparin, but subsequently demonstrated heparin resistance, and was thus anticoagulated with a lovenox bridge to warfarin. Throughout his hospital course, hemocultures demonstrated no growth, so antibiotic treatment was deescalated to oral metronidazole and ceftriaxone. On discharge, the patient was transitioned to oral amoxicillin and metronidazole for an additional 4 weeks with continuation of anticoagulation with warfarin for a total of 3 to 6 months. This case report details a unique presentation of Lemierre syndrome with bilateral transverse sinus, sigmoid sinus, and internal jugular vein thrombosis that was presumably secondary to an odontogenic infectious focus.",
"affiliations": "Kern Medical, Bakersfield, CA, USA.;Kern Medical, Bakersfield, CA, USA.;Kern Medical, Bakersfield, CA, USA.;Kern Medical, Bakersfield, CA, USA.;Kern Medical, Bakersfield, CA, USA.;Kern Medical, Bakersfield, CA, USA.;Kern Medical, Bakersfield, CA, USA.;Kern Medical, Bakersfield, CA, USA.;Kern Medical, Bakersfield, CA, USA.;Kern Medical, Bakersfield, CA, USA.;Kern Medical, Bakersfield, CA, USA.",
"authors": "Clark|Kiley|K|;Sly|Morgan|M|;Chan|Pearl|P|;Lai|Hobart|H|0000-0002-8246-3871;Ali|Hadi|H|;Contreras|David|D|;Sidhu|Ramanjeet|R|;Bhandohal|Janpreet|J|;Mishra|Sikha|S|;Kuran|Rasha|R|;Polineni|Rahul Dev|RD|",
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"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096\nSAGE Publications Sage CA: Los Angeles, CA\n\n34420414\n10.1177/23247096211040635\n10.1177_23247096211040635\nCase Report\nLemierre Syndrome in a Patient With Splenectomy Secondary to Pyruvate Kinase Deficiency, Complicated by Heparin Resistance\nClark Kiley BS 1\nSly Morgan BA 1\nChan Pearl BA 1\nhttps://orcid.org/0000-0002-8246-3871\nLai Hobart DO 1\nAli Hadi MD 1\nContreras David MD 1\nSidhu Ramanjeet MD 12\nBhandohal Janpreet MD 12\nMishra Sikha MD 12\nKuran Rasha MD 12\nPolineni Rahul Dev MD 12\n1 Kern Medical, Bakersfield, CA, USA\n2 University of California, Los Angeles, CA, USA\nKiley Clark, Department of Medicine, Kern Medical, 1700 Mount Vernon Avenue, Bakersfield, CA 93306, USA. Email: clarkkiley@yahoo.com\n23 8 2021\nJan-Dec 2021\n9 2324709621104063512 7 2021\n28 7 2021\n31 7 2021\n© 2021 American Federation for Medical Research\n2021\nAmerican Federation for Medical Research\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nLemierre syndrome was first documented in the literature in 1936, and is defined as septic thrombophlebitis of the internal jugular vein. It is typically a result of oropharyngeal infection causing local soft tissue inflammation, which spreads to vasculature, and promotes formation of septic thrombi within the lumen, persistent bacteremia, and septic emboli. We present the case of a 24-year-old incarcerated man, who presented with leukocytosis and a right-sided tender, swollen neck after undergoing left mandibular molar extraction for an infected tooth. Computed tomography revealed a persistent thrombus in the transverse and sigmoid sinuses bilaterally, extending downwards, into the upper jugular veins. He was started on empiric intravenous vancomycin, zosyn, and heparin, but subsequently demonstrated heparin resistance, and was thus anticoagulated with a lovenox bridge to warfarin. Throughout his hospital course, hemocultures demonstrated no growth, so antibiotic treatment was deescalated to oral metronidazole and ceftriaxone. On discharge, the patient was transitioned to oral amoxicillin and metronidazole for an additional 4 weeks with continuation of anticoagulation with warfarin for a total of 3 to 6 months. This case report details a unique presentation of Lemierre syndrome with bilateral transverse sinus, sigmoid sinus, and internal jugular vein thrombosis that was presumably secondary to an odontogenic infectious focus.\n\nLemierre\nsplenectomy\npyruvate kinase\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nLemierre syndrome (LS), also commonly referred to as human necrobacillosis and postanginal septicemia,1 was first discovered in 1936.2 LS is characterized by an oropharyngeal infection, with resulting metastatic septic emboli and internal jugular vein thrombosis.3 The organism most commonly implicated (81% of cases) in the infection is the gram-negative oral flora anaerobe Fusobacterium necrophorum.4 Symptoms typically correlate with the primary infection site and generally include local pain and sore throat (present in more than 80% of cases), fever, trismus, nausea, and odynophagia.5\n\nThe highest incidence of LS is found in young, healthy adults, with 70% of cases occurring in patients aged between 16 and 25 years.5 However, since the advent of antibiotics, LS has been commonly referred to as “the forgotten disease.”6 Infection most commonly originates from the head and neck, with greater than 85% of cases being secondary to tonsillitis or pharyngitis.1 Less commonly, odontogenic infections and mastoiditis account for 2% and 3% of LS cases, respectively.5 The original publication on LS in 1936 described 18 out of 20 cases resulting in death.5 With use of modern day antibiotics, mortality rates range from 4% to 12%.5 The purpose of this case report is to document a rare and unique presentation of LS that presumably resulted secondary to an infectious odontogenic source.\n\nCase\n\nA 24-year-old incarcerated man with a history of pyruvate kinase deficiency requiring splenectomy presented to the emergency department with complaints of left lower tooth pain, right-sided neck pain, and swelling. He was diagnosed with odontogenic infection with reactive lymphadenopathy and discharged on clindamycin for 7 days. He then underwent a left-sided mandibular molar extraction and was given an additional 3 days of antibiotics. He returned to the emergency department 1 day post tooth extraction complaining of headache, right-sided neck pain, and swelling that was exacerbated with chewing, as well as a slightly muffled voice. In addition, he had tenderness to palpation of the right sternocleidomastoid muscle, which was erythematous and warm to touch. He remained afebrile throughout his hospital course, but had significant leukocytosis of 22.8 × 109/L on admission that peaked at 36.0 × 109/L. Patient also had significant thrombocytosis with an elevation as high as 1.29 × 1010/L.\n\nPhysical examination findings were significant for a left mandibular molar tender to palpation without surrounding gingival erythema, in duration, or fluctuance, right tonsillar grade 3 enlargement, without erythema or exudates, and left tonsillar grade 2 enlargement without erythema or exudates. Of note, the sublingual and submental regions were soft, without induration, and bilateral tympanic membranes were without air-fluid levels, bulging membranes, or erythema. He exhibited a slightly muffled voice due to the swelling. A week into his hospital stay, he began complaining of new-onset mild pain behind his right eye on extreme rightward gaze. Throughout the hospital course, the patient did not exhibit signs of respiratory distress such as tripoding or intercostal retractions, or signs of meningeal irritation.\n\nA computed tomography (CT) scan of the neck/soft tissue with contrast demonstrated soft tissue thickening surrounding the thrombosed right jugular vein. Right-sided cervical adenopathy in both the suprahyoid and infrahyoid neck was present. There was no evidence of any frank abscesses. Notably, there was thrombosis extending from the right sigmoid sinus down into the right jugular vein in the mid neck. CT angiogram of the brain and neck with contrast demonstrated partial obstruction of the right transverse sinus with complete obstruction of the right sigmoid sinus and jugular vein (Figure 1). There was nonvisualization of the entire right jugular vein (Figure 1). Magnetic resonance imaging of the brain without and with contrast as well as magnetic resonance venography of the head with contrast demonstrated some dilatation of the right superior ophthalmic vein with diminished flow in the cavernous sinuses bilaterally. There was prominent collateral venous flow extending from the orbital regions down to the facial veins bilaterally. There was significant inflammatory signal in the right mastoid and middle ear. The most diagnostically significant finding was persistent thrombosis in the transverse and sigmoid sinuses bilaterally, extending down to the upper jugular veins (Figures 2 and 3).\n\nFigure 1. Computed tomography angiography of the brain and neck with contrast demonstrated complete obstruction and nonvisualization of the entire right jugular vein. Yellow arrows indicate location of right and left jugular veins.\n\nFigure 2. Magnetic resonance imaging of the brain with contrast: T1- and T2-weighted images demonstrate occlusion of the right sigmoid sinus indicated by yellow arrow.\n\nFigure 3. Magnetic resonance imaging of the brain without contrast: T1- and T2-weighted images demonstrate occlusion of the right sigmoid sinus indicated by yellow arrow.\n\nOn admission, the patient was started on heparin drip of 18 units/kg/h. As partial thromboplastin time (PTT) level remained subtherapeutic, heparin drip was incrementally increased over the subsequent 4 days. On hospital day 4, the patient was receiving 38 units/kg/h, totaling 72 960 U 24 h−1, and multiple heparin boluses but PTT continued to be subtherapeutic. At this point, the patient was diagnosed with heparin resistance, which is defined as requiring 35 000 U 24 h−1 to prolong the PTT,7 and the patient was switched to warfarin, bridged with lovenox. The patient reached the goal international normalized ratio of 2 to 3 after 7 days. He was discharged on warfarin 5 mg with a goal of 3 to 6 months of anticoagulation.\n\nTo address the leukocytosis at the time of admission, the patient was started on empiric IV vancomycin and zosyn. Blood cultures were negative for any growth, but the patient was empirically treated for F necrophorum given concern for LS. While in the hospital, the patient completed a 2-week course of IV metronidazole and ceftriaxone before being transitioned to oral metronidazole and amoxicillin for an additional 4 weeks.\n\nOn discharge, the patient’s thrombocytosis persisted, leukocytosis had decreased to 12.8 × 109/L and the only symptom that remained was a mild headache.\n\nDiscussion\n\nLS had a mortality rate of 90% when data were first published in 1936.5 With modern antibiotics, mortality rate ranges from 4% to 12%.5 Interestingly, there were many reported cases in the early 1900s, but the number of reported cases dropped from the years of 1955 to the 1980s.5 Riordan hypothesizes that this may have been due to the popularity of using antibiotics to treat infections of the oropharynx during this time.5,8 Of note, there has been an increase in the reported incidence of LS in the last 30 years, possibly explained by an increase in antibiotic resistance and/or more hesitancy to use antibiotics for treatment of oropharyngeal infections.5\n\nAlthough the criteria to provide a definitive diagnosis of LS is still contentious, the most agreed upon criteria for diagnosis are the following findings: recent pharyngeal illness, complicated by septic emboli, as well as either thrombosis of the internal jugular vein or findings of F necrophorum in blood cultures.6 The case presented in this article met only 2 of these criteria: recent odontogenic infection, and extensive thrombosis of the bilateral upper internal jugular veins, transverse sinuses, and sigmoid sinuses. We believe that the dramatic leukocytosis and lack of hemoculture growth in our patient could be explained by containment of infection within the thrombus.\n\nA systematic review found that 95% of cases of LS were diagnosed with CT scans.6 CT is favorable in that it is cheaper and available in most hospitals compared with magnetic resonance imaging. Ultrasound may also play a role in imaging, but is limited due to its low sensitivity for newly formed thrombosis, as well as impaired visualization of deeper tissues and structures.6\n\nDue to the rarity of LS cases, a clear consensus on the role of anticoagulation and antibacterial treatment has yet to be established. A review by Riordan8 suggests that carbapenems, a combination of penicillin/B-lactamase inhibitor, or metronidazole are the best candidates for the treatment of LS. Armstrong and colleagues9 reported that in the literature, the most frequently used agent was metronidazole. The popularity of metronidazole use in treatment of LS is explained by its high oral availability, its activity against all strains of Fusobacterium spp, and its penetration into tissues.8 In addition, the literature also suggests treating LS with metronidazole in combination with a penicillin to cover oral streptococci.8 Riordan details in his review that most cases should undergo IV therapy for 2 to 3 weeks, with transition to 3 to 4 weeks of oral therapy for a total treatment of 6 weeks duration.8\n\nThe role of anticoagulation in the treatment of LS remains to be elucidated. However, anticoagulation is more frequently used in patients who have received 2 to 3 days of antimicrobial therapy with no signs of improvement, underlying thrombophilia, progression of thrombosis, or retrograde extension of cavernous sinus thrombosis.10 A study by Jaremko and colleagues11 suggests that anticoagulation likely decreases the risk of clot extension, and has the potential to shorten recovery times.8 If anticoagulation therapy is clinically indicated, optimal duration is unclear and has been reported to range from 4 weeks to 6 months.10 In our case, imaging demonstrated extensive thrombosis involving the transverse and sigmoid sinuses bilaterally extending down to the upper jugular veins (Figures 2 and 3). Due to the large size of this thrombus, in addition to the patient’s inherent hypercoagulable state, we opted to treat with anticoagulation, as suggested by the limited literature.\n\nReview of the literature suggests that hypercoagulability may be a predisposing risk factor for the development of LS. Hope and colleagues detailed a case of LS with reduced antithrombin 3 levels.8,12 Klinge and coleagues presented a case of thrombosis of the internal jugular vein (IJV) and sigmoid sinus in a patient with Factor 5 Leiden mutation.8,13 Another case series reported 7 children with mastoiditis and sinus thrombosis, of which 5 had accompanying prothrombotic disorders.8,14 However, a case series of 9 pediatric cases of septic jugular venous thrombosis secondary to oropharyngeal infection reported that 7 children had thrombophilia including 3 with APLA, 4 with raised factor VIII levels, and 1 with factor V Leiden. Six months later, APLA was no longer present in 2 patients, and factor VIII levels returned to normal, suggesting that these thrombophilic conditions were a possible result of the acute inflammatory state rather than true persistent thrombophilia.8,15 Due to the rarity of LS, 1 person per million per year, it is less likely to be a random association between LS and hypercoagulable states, but instead that hypercoagulability may serve as a risk factor for development of LS.16 In addition, an analysis of 712 patients with LS found that there was a substantial risk of new thromboembolic complications after initial infection.17 Our case favors the hypothesis that an intrinsic prothrombotic state, such as in our case of hemolytic anemia and splenectomy, may be a risk factor for the development of LS.\n\nThis case is unique in that the patient was in a hypercoagulable state prior to developing LS. His chronic hemolytic anemia requiring splenectomy secondary to pyruvate kinase deficiency explains his baseline thrombocytosis. Both chronic hemolytic anemia and thrombocytosis place this patient in a hypercoagulable state due to endothelial damage. In patients with normal platelet counts who have undergone splenectomy, there is evidence of increased platelet adhesiveness.18 Although rare, a case report documented that a patient with pyruvate kinase deficiency began having recurrent thrombosis post-splenectomy.18 We hypothesize that both the infectious odontogenic foci, and the tissue damage incurred during tooth extraction further exacerbated our patient’s persistent hypercoagulability, thus predisposing him to venous thrombosis.\n\nConclusion\n\nIn conclusion, we present a rare case of possible LS that originated from an odontogenic source in a patient with intrinsic hypercoagulable state due to hemolytic anemia and asplenia. The role of anticoagulation in the treatment of LS is still debatable, but somewhat supported in cases of progressive thrombosis and hypercoagulable states. It is our hope that adding to the scarce literature on LS will aid in creating definitive diagnostic guidelines and treatment regimens for future cases.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Ethical approval to report this case was obtained from Kern Medical Institutional Review Board (21012).\n\nInformed Consent: Written informed consent was obtained from the patient for their anonymized information to be published in this article.\n\nORCID iD: Hobart Lai https://orcid.org/0000-0002-8246-3871\n==== Refs\nReferences\n\n1 Lee WS Jean SS Chen FL Hseih SM Hsueh PR. Lemierre’s syndrome: a forgotten and re-emerging infection. J Microbiol Immunol Infect. 2020;53 :513-517. doi:10.1016/j.jmii.2020.03.027 32303484\n2 Lemierre A. On certain septicemias due to anaerobic organisms. Lancet. 1936;227 :701-703.\n3 Gore MR. Lemierre syndrome : a meta-analysis. Int Arch Otorhinolaryngol. 2020;24 :379-385. doi:10.1055/s-0039-3402433\n4 Escalona IJ Carandell AD Centenero SAH , et al . Lemierre syndrome associated with dental infections. Report of one case and review of the literature. Med Oral Patol Oral Cir Bucal. 2007;12 :394-396.\n5 Noy D Rachmiel A Levy-Faber D Emodi O. Lemierre’s syndrome from odontogenic infection: review of the literature and case description. Ann Maxillofac Surg. 2015;5 :219-225.26981474\n6 Johannesen K Bodtger U. Lemierre’s syndrome: current perspectives on diagnosis and management. Infect Drug Resist. 2016;9 :221-227. doi:10.1371/journal.pmed.1000097 27695351\n7 Anderson JAM Saenko EL. Heparin resistance. Br J Anaesth. 2002;88 :467-469. doi:10.1093/bja/88.4.467 12066718\n8 Riordan T. Human infection with Fusobacterium necrophorum (Necrobacillosis), with a focus on Lemierre’s syndrome. Clin Microbiol Rev. 2007;20 :622-659. doi:10.1128/CMR.00011-07 17934077\n9 Armstrong AW Spooner K Sanders JW. Lemierre’s syndrome. Curr Infect Dis Rep. 2000;2 :168-173.11095853\n10 Phua CK Chadachan VM Acharya R. Lemierre syndrome—should we anticoagulate? A case report and review of the literature. Int J Angiol. 2013;22 :137-142. doi:10.1055/s-0033-1336828 24436600\n11 Jaremko JL Kirton A Brenner JL. A 12-year-old girl with pharyngitis, meningitis and sinovenous thrombosis. CMAJ. 2003;169 :811-812.14557322\n12 Hope A Bleach N Ghiacy S. Lemierre’s syndrome as a consequence of acute supraglottitis. J Laryngol Otol. 2002;116 :216-218.11893267\n13 Klinge L Vester U Schaper J Hoyer PF. Severe Fusobacteria infections (Lemierre syndrome) in two boys. Eur J Pediatr. 2002;161 :616-618.12424589\n14 Oestreicher-Kedem Y Raveh E Kornreich L Yaniv I Tamary H. Prothrombotic factors in children with otitis media and sinus thrombosis. Laryngoscope. 2004;114 :90-95.14710001\n15 Goldenberg NA Knapp-Clevenger R Hays T Manco-Johnson MJ. Lemierre’s and Lemierre’s-like syndromes in children: survival and thrombogenic outcomes. Pediatrics. 2005;116 :e543-e548.\n16 Lakshminarayana PH Woodske ME. A unique case of Lemierre syndrome associated with thrombophilia in an adult and the role of anticoagulation. Case Rep Med. 2010;2010 :982494. doi:10.1155/2010/982494 20953325\n17 Valerio L Zane F Sacco C , et al . Patients with Lemierre syndrome have a high risk of new thromboembolic complications, clinical sequelae and death: an analysis of 712 cases. J Intern Med. 2021;289 :325-339. doi:10.1111/joim.13114 32445216\n18 Chou R Deloughery TG. Recurrent thromboembolic disease following splenectomy for pyruvate kinase deficiency. Am J Hematol. 2001;67 :197-199. doi:10.1002/ajh.1107 11391719\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2324-7096",
"issue": "9()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "Lemierre; pyruvate kinase; splenectomy",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D000328:Adult; D000746:Anemia, Hemolytic, Congenital Nonspherocytic; D006493:Heparin; D006801:Humans; D057831:Lemierre Syndrome; D008297:Male; D011770:Pyruvate Kinase; D015323:Pyruvate Metabolism, Inborn Errors; D013156:Splenectomy; D055815:Young Adult",
"nlm_unique_id": "101624758",
"other_id": null,
"pages": "23247096211040635",
"pmc": null,
"pmid": "34420414",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "32303484;27695351;11391719;11095853;26981474;17767106;14557322;14710001;11893267;12066718;20953325;16147971;32754251;12424589;17934077;32445216;24436600",
"title": "Lemierre Syndrome in a Patient With Splenectomy Secondary to Pyruvate Kinase Deficiency, Complicated by Heparin Resistance.",
"title_normalized": "lemierre syndrome in a patient with splenectomy secondary to pyruvate kinase deficiency complicated by heparin resistance"
} | [
{
"companynumb": "US-MYLANLABS-2021M1097434",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "We describe a case of airway fire in an 83-year-old, critically ill patient. The fire occurred during a surgical tracheostomy under general anaesthesia, following ignition of the tracheal tube by diathermy. After debridement of the burnt tissue and treatment with intravenous antibiotics and glucocorticoids, the patient's respiratory function worsened initially. The patient eventually recovered without long-term sequelae and was discharged from the intensive care unit. The circumstances of this and other similar incidents are reviewed, as are the suggested methods for preventing this frightening occurrence.",
"affiliations": "Department of Anaesthesia and Intensive Care, The Cardiothoracic Centre, Liverpool, UK.",
"authors": "Rogers|S A|SA|;Mills|K G|KG|;Tufail|Z|Z|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1046/j.1365-2044.2001.1317/az1174.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-2409",
"issue": "56(5)",
"journal": "Anaesthesia",
"keywords": null,
"medline_ta": "Anaesthesia",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D002059:Burns, Inhalation; D003422:Critical Care; D003972:Diathermy; D005390:Fires; D006801:Humans; D007431:Intraoperative Complications; D008297:Male; D014139:Tracheostomy; D016896:Treatment Outcome",
"nlm_unique_id": "0370524",
"other_id": null,
"pages": "441-3",
"pmc": null,
"pmid": "11350329",
"pubdate": "2001-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Airway fire due to diathermy during tracheostomy in an intensive care patient.",
"title_normalized": "airway fire due to diathermy during tracheostomy in an intensive care patient"
} | [
{
"companynumb": "GB-LINDE-GB-LHC-2018054",
"fulfillexpeditecriteria": "2",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OXYGEN"
},
"drugadditional": null,
"... |
{
"abstract": "Denosumab-related osteonecrosis of the jaws (DRONJ) is a recently described entity that shares many common clinical and radiological features with bisphosphonate-related osteonecrosis of the jaws (BRONJ). The aim of the present study is to report a case of DRONJ affecting the anterior mandible of a 58-year-old male treated with denosumab to prevent skeletal-related events associated with prostate cancer. Conservative surgery in conjunction with antibiotic therapy and discontinuation of denosumab use were effective in managing the condition and the patient remains free of clinical and radiological changes after a 38 month follow-up.",
"affiliations": "Resident, Oral and Maxillofacial Surgery, Pedro Ernesto University Hospital, State University of Rio de Janeiro, Brazil.;Resident, Oral and Maxillofacial Surgery, Pedro Ernesto University Hospital, State University of Rio de Janeiro, Brazil.;Adjunct Professor, Oral and Maxillofacial Surgery, Pedro Ernesto University Hospital, State University of Rio de Janeiro, Brazil.;Associate Professor, Oral Pathology, School of Dentistry, State University of Rio de Janeiro, Brazil.",
"authors": "de Souza Póvoa|Raphaela Capella|RC|;Marlierè|Daniel Amaral Alves|DA|;da Silveira|Henrique Martins|HM|;Pires|Fábio Ramoa|FR|",
"chemical_list": "D000900:Anti-Bacterial Agents; D050071:Bone Density Conservation Agents; D000069448:Denosumab",
"country": "United States",
"delete": false,
"doi": "10.1111/scd.12168",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0275-1879",
"issue": "36(4)",
"journal": "Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry",
"keywords": "denosumab; jaw; mandible; osteonecrosis; receptor activator of nuclear factor kappa-B ligand (RANKL)",
"medline_ta": "Spec Care Dentist",
"mesh_terms": "D000900:Anti-Bacterial Agents; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D050071:Bone Density Conservation Agents; D003131:Combined Modality Therapy; D000069448:Denosumab; D006801:Humans; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "8103755",
"other_id": null,
"pages": "231-6",
"pmc": null,
"pmid": "26859582",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Denosumab-related osteonecrosis of the jaws: successful management with a conservative surgical approach.",
"title_normalized": "denosumab related osteonecrosis of the jaws successful management with a conservative surgical approach"
} | [
{
"companynumb": "BR-AMGEN-BRASP2016090909",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GOSERELIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe purpose of this study was to investigate the effect of sertraline (SRT) in children and adolescents with obsessive-compulsive disorder (OCD) who did not respond to two consecutive courses of cognitive-behavior therapy (CBT).\n\n\nMETHODS\nObservational study with 11 participants (males, n=6), 7-17 years of age with Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) primary OCD. All had received 14 plus 10 sessions of CBT over the course of 218-532 days (mean=342.2, SD=85.5). Outcome measures were mean reduction of the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) total score and adequate clinical response (CY-BOCS<16). All participants received SRT (maximum dose 200 mg/day). The study was a part of the Nordic Long-Term OCD Treatment Study (NordLOTS).\n\n\nRESULTS\nParticipants were treated with SRT over 72-300 days (mean=164.2, SD=68.3). The mean CY-BOCS score was reduced from 21.5 (SD=2.6) to 17.5 (SD=3.3). Only three participants obtained adequate clinical response (27.2%), and only two obtained >25% CY-BOCS total score reduction (close to 50%).\n\n\nCONCLUSIONS\nA clinical response in approximately one third of the participants suggests that SRT treatment might be beneficial to a minority of patients who have consistently failed CBT.",
"affiliations": "1 Center for Child and Adolescent Mental Health , Eastern and Southern Norway, Oslo, Norway .;2 Norwegian University of Science and Technology, Faculty of Medicine, Regional Center for Child and Youth Mental Health and Child Welfare , Trondheim, Norway .;1 Center for Child and Adolescent Mental Health , Eastern and Southern Norway, Oslo, Norway .",
"authors": "Skarphedinsson|Gudmundur|G|;Weidle|Bernhard|B|;Ivarsson|Tord|T|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D020280:Sertraline",
"country": "United States",
"delete": false,
"doi": "10.1089/cap.2015.0041",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1044-5463",
"issue": "25(7)",
"journal": "Journal of child and adolescent psychopharmacology",
"keywords": null,
"medline_ta": "J Child Adolesc Psychopharmacol",
"mesh_terms": "D000293:Adolescent; D002648:Child; D015928:Cognitive Behavioral Therapy; D005260:Female; D006801:Humans; D008297:Male; D009771:Obsessive-Compulsive Disorder; D011569:Psychiatric Status Rating Scales; D017367:Serotonin Uptake Inhibitors; D020280:Sertraline; D017211:Treatment Failure",
"nlm_unique_id": "9105358",
"other_id": null,
"pages": "574-9",
"pmc": null,
"pmid": "26348088",
"pubdate": "2015-09",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "15180774;18329843;15572188;25463245;8083134;16239861;15959662;2684084;3264280;22176943;25130442;18725912;11928886;12880500;9204677;2404965;9183141;15507582;15939518;10986805;24354717;1461792;11918090;25239489;11589530",
"title": "Sertraline Treatment of Nonresponders to Extended Cognitive-Behavior Therapy in Pediatric Obsessive-Compulsive Disorder.",
"title_normalized": "sertraline treatment of nonresponders to extended cognitive behavior therapy in pediatric obsessive compulsive disorder"
} | [
{
"companynumb": "NO-LUPIN PHARMACEUTICALS INC.-2016-00217",
"fulfillexpeditecriteria": "2",
"occurcountry": "NO",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SERTRALINE HYDROCHLORIDE"
},
... |
{
"abstract": "To describe a case series of 7 patients presenting cluster headache (CH) criteria and a substance use disorder, reported to a French Addictovigilance center. Then, to assess clinical, pharmacological, and neurobiological linkages between substance use and CH onset.\n\n\n\nCH patients are presenting a higher prevalence of comorbidities, among which the use of psychoactive substances, licit or illicit, have been explored by a few authors. Recently, 3 cases of CH in patients seen in the hospital-based addiction care center have been reported to the Toulouse addictovigilance center.\n\n\n\nOther cases have been identified in the same tertiary hospital after a collaborative investigation done with the departments of neurology and psychiatry and included in the case series. A narrative review was performed to assess the potential of psychoactive substance consumption to induce or facilitate CH.\n\n\n\nFrom 2016 to 2018, 6 males and 1 female aged between 26 and 54 years old, presenting CH criteria and a substance use disorder, were included in our case series. Among substances used, there are: (1) daily use of tobacco and alcohol in 5/7 subjects; (2) daily or almost daily use of cocaine in 5/7 subjects; (3) regular use of cannabis before attacks beginning in 4/7 subjects; and (4) opioids, as a substitutive medication or abused, in 5/7 subjects. The intranasal route administration is reported by all the subjects and precedes the beginning of attacks for 5/7 subjects.\n\n\n\nWe have found a CH prevalence of 0.9% in our studied population, while it is estimated at 0.1% in the general population. The coexistence of cluster headache and addiction behaviors reflects possible common neurobiological pathways, which would include the hypothalamus. Research could be conducted on the potential of hypothalamic therapeutic targets.",
"affiliations": "Service de Pharmacologie Médicale et Clinique, Centre d'Evaluation et Information sur la Pharmacodépendance-Addictovigilance, Faculté de Médecine, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.;Service de Psychiatrie et Psychologie, Université de Toulouse III, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.;Service Universitaire de Psychiatrie et Psychologie Médicale, Centre de Soins d'Accompagnement et de Prévention en Addictologie, Hopital La Grave, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.;Service de Pharmacologie Médicale et Clinique, Centre d'Evaluation et Information sur la Pharmacodépendance-Addictovigilance, INSERM UMR 1027, CIC INSERM 1436, Faculté de Médecine, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.;Departement de Neurologie, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.;Service de Psychiatrie et Psychologie, INSERM UMR 1043, Université de Toulouse III, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.",
"authors": "Ponté|Camille|C|0000-0001-8616-5313;Giron|Aurélie|A|;Crequy|Marie|M|;Lapeyre-Mestre|Maryse|M|;Fabre|Nelly|N|;Salles|Juliette|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/head.13516",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0017-8748",
"issue": "59(4)",
"journal": "Headache",
"keywords": "addictovigilance; cluster headache; comorbidity; drugs",
"medline_ta": "Headache",
"mesh_terms": "D000328:Adult; D003027:Cluster Headache; D015897:Comorbidity; D005260:Female; D005602:France; D006801:Humans; D008297:Male; D008875:Middle Aged; D019966:Substance-Related Disorders",
"nlm_unique_id": "2985091R",
"other_id": null,
"pages": "576-589",
"pmc": null,
"pmid": "30957220",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Cluster Headache in Subjects With Substance Use Disorder: A Case Series and a Review of the Literature.",
"title_normalized": "cluster headache in subjects with substance use disorder a case series and a review of the literature"
} | [
{
"companynumb": "FR-PURDUE PHARMA-GBR-2019-0066564",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MORPHINE SULFATE"
},
"drugadditional"... |
{
"abstract": "To explore the role of chidamide, decitabine plus priming regimen in the salvage treatment of relapsed/refractory acute myeloid leukemia.\nA clinical trial was conducted in relapsed/refractory acute myeloid leukemia patients using chidamide, decitabine, cytarabine, idarubicin, and granulocyte-colony stimulating factor, termed CDIAG, a double epigenetic priming regimen.\nThirty-five patients were recruited. Three patients received 2 treatment cycles. In 32 evaluable patients and 35 treatment courses, the completed remission rate (CRR) was 42.9%. The median OS time was 11.7 months. The median OS times of responders were 18.4 months, while those of nonresponders were 7.4 months (P = 0.015). The presence of RUNX1 mutations was associated with a high CRR but a short 2-year OS (P = 0.023) and PFS (P = 0.018) due to relapse after treatment. The presence of IDH mutations had no effect on the remission rate (80.0% vs. 73.3%), but showed a better OS (2-year OS rate: 100.0% vs. 28.9%). Grade 3/4 nonhematological adverse events included pneumonia, hematosepsis, febrile neutropenia, skin and soft tissue infection and others.\nThe double epigenetic priming regimen (CDIAG regimen) showed considerably good antileukemia activity in these patients. Adverse events were acceptable according to previous experience. The study was registered as a clinical trial.\nhttps://clinicaltrials.gov/, identifier:NCT03985007.",
"affiliations": "National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.;National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.;National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.;Department of Hematology, The Affiliated Hospital of Jining Medical College, Jining, China.;Department of Hematology, Canglang Hospital of Suzhou, Suzhou, China.;National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.;National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.;National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.;National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.;National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.;National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.;National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.;National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.;Department of Hematology, The Affiliated Huai'an Hospital of Xuzhou Medical University and The Second People's Hospital of Huai'an, Huai'an, China.;National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.;National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.",
"authors": "Yin|Jia|J|;Wan|Chao-Ling|CL|;Zhang|Ling|L|;Zhang|Hao|H|;Bai|Lian|L|;Zhou|Hai-Xia|HX|;Xu|Ming-Zhu|MZ|;Chen|Li-Yun|LY|;Qian|Chong-Sheng|CS|;Qiu|Hui-Ying|HY|;Chen|Su-Ning|SN|;Tang|Xiao-Wen|XW|;Wu|De-Pei|DP|;Zhang|Yan-Ming|YM|;Sun|Ai-Ning|AN|;Xue|Sheng-Li|SL|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2021.726926",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X\nFrontiers Media S.A.\n\n10.3389/fonc.2021.726926\nOncology\nClinical Trial\nA Phase II Trial of the Double Epigenetic Priming Regimen Including Chidamide and Decitabine for Relapsed/Refractory Acute Myeloid Leukemia\nYin Jia 1 2 †\n\nWan Chao-Ling 1 2 †\nZhang Ling 1 2 †\nZhang Hao 3 †\n\nBai Lian 4\nZhou Hai-Xia 1 2\nXu Ming-Zhu 1 2\nChen Li-Yun 1 2\nQian Chong-Sheng 1 2\nQiu Hui-Ying 1 2\nChen Su-Ning 1 2\nTang Xiao-Wen 1 2\nWu De-Pei 1 2\nZhang Yan-Ming 5 *\nSun Ai-Ning 1 2 *\nXue Sheng-Li 1 2 *\n\n1National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China\n2Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China\n3Department of Hematology, The Affiliated Hospital of Jining Medical College, Jining, China\n4Department of Hematology, Canglang Hospital of Suzhou, Suzhou, China\n5Department of Hematology, The Affiliated Huai’an Hospital of Xuzhou Medical University and The Second People’s Hospital of Huai’an, Huai’an, China\nEdited by: Fei GAO, Beijing Genomics Institute (BGI), China\n\nReviewed by: Sergiu Pasca, Iuliu Hațieganu University of Medicine and Pharmacy, Romania; Garima Pandey, Moffitt Cancer Center, United States\n\n*Correspondence: Sheng-Li Xue, slxue@suda.edu.cn; Ai-Ning Sun, sunaining@suda.edu.cn; Yan-Ming Zhang, zhangyanming2005@126.com\nThis article was submitted to Hematologic Malignancies, a section of the journal Frontiers in Oncology\n\n†These authors have contributed equally to this work and share first authorship\n\n03 9 2021\n2021\n11 72692617 6 2021\n20 8 2021\nCopyright © 2021 Yin, Wan, Zhang, Zhang, Bai, Zhou, Xu, Chen, Qian, Qiu, Chen, Tang, Wu, Zhang, Sun and Xue\n2021\nYin, Wan, Zhang, Zhang, Bai, Zhou, Xu, Chen, Qian, Qiu, Chen, Tang, Wu, Zhang, Sun and Xue\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.\nObjective\n\nTo explore the role of chidamide, decitabine plus priming regimen in the salvage treatment of relapsed/refractory acute myeloid leukemia.\n\nMethods\n\nA clinical trial was conducted in relapsed/refractory acute myeloid leukemia patients using chidamide, decitabine, cytarabine, idarubicin, and granulocyte-colony stimulating factor, termed CDIAG, a double epigenetic priming regimen.\n\nResults\n\nThirty-five patients were recruited. Three patients received 2 treatment cycles. In 32 evaluable patients and 35 treatment courses, the completed remission rate (CRR) was 42.9%. The median OS time was 11.7 months. The median OS times of responders were 18.4 months, while those of nonresponders were 7.4 months (P = 0.015). The presence of RUNX1 mutations was associated with a high CRR but a short 2-year OS (P = 0.023) and PFS (P = 0.018) due to relapse after treatment. The presence of IDH mutations had no effect on the remission rate (80.0% vs. 73.3%), but showed a better OS (2-year OS rate: 100.0% vs. 28.9%). Grade 3/4 nonhematological adverse events included pneumonia, hematosepsis, febrile neutropenia, skin and soft tissue infection and others.\n\nConclusion\n\nThe double epigenetic priming regimen (CDIAG regimen) showed considerably good antileukemia activity in these patients. Adverse events were acceptable according to previous experience. The study was registered as a clinical trial.\n\nClinical Trial Registration\n\nhttps://clinicaltrials.gov/, identifier:NCT03985007\n\nepigenomics\nhistone deacetylase inhibitor (HDACi)\nCDIAG regimen\nrelapsed/refractory acute myeloid leukemia\nsalvage therapy\n==== Body\npmcIntroduction\n\nAlthough treatment of Acute myeloid leukemia (AML) is rapidly progressing, approximately 10% to 40% of newly diagnosed AML patients cannot achieve complete remission (CR) through induction chemotherapy, and more than 50% of AML patients will ultimately relapse (1). For patients with relapsed/refractory (R/R) AML, the goal of chemotherapy varies from achieving long-term remission to providing a “bridge” to stem cell transplantation (SCT). Most conventional chemotherapeutic drugs have a low reinduction remission rate of nearly 1/3, poor tolerability and a prolonged bone marrow (BM) suppression stage, often leading to serious infection, high mortality, and a short survival (2). Therefore, it is crucial to explore and formulate reasonable and effective combined therapeutic strategies to undergo curative treatment with allogeneic stem cell transplantation (allo-SCT) in CR status (3).\n\nAlthough several new small-molecule inhibitors have been developed (e.g., ABT-199, midostaurin, and IDH1/2 inhibitor) and have shown promising results in R/R AML treatment, they are not currently commercially available in mainland China. In recent decades, epigenetic treatment for hypermethylation or histone deacetylation has been a major breakthrough in AML treatment (4). The application of DNA demethylation drugs involved in epigenetic regulation to elderly (age ≥ 60 years) AML and R/R AML patients was the IA category recommendation for first-line induction therapy in the NCCN guidelines (5). Chidamide is the first subtype-selective oral histone deacetylation inhibitor (HDACi) commercially available in mainland China and has been certified internationally by the FDA because it is effective in treating R/R peripheral T-cell lymphoma (PTCL) (6). Chidamide possesses potent HDAC inhibitory properties by terminating the deacetylation of histones H3 and H4 via inhibiting HDAC types 1, 2, 3, and 10. Selective targeting of individual HDACs causes differentiation, apoptosis, cell cycle inhibition, migration inhibition, susceptibility to chemotherapy and anti-angiogenesis (7, 8).\n\nIn the treatment of R/R AML with low-dose cytarabine and anthracycline combined with granulocyte-colony stimulating factor (G-CSF) (priming regimen) (9), the sensitizing effect of hematopoietic growth factors on leukemic cells enhances the cytotoxicity of chemotherapy in AML. Previous studies have suggested that the combination of decitabine with G-CSF, low-dose cytarabine and aclarubicin (DCAG) improved the CR rate and was well-tolerated in newly diagnosed elderly AML patients (10). Moreover, patients with R/R or high-risk AML were treated with the DCAG regimen, which was proven to overcome drug resistance and improve therapeutic efficacy (11). HDACis in monotherapy are modestly active in high-risk myelodysplastic syndrome (MDS) and AML, and in vitro evidence supports the synergy between hypomethylating agents (HMAs) and HDACis (12). Decitabine used concurrently or sequentially with vorinostat (an HDACi) was safe and well tolerated in patients with R/R AML (n=29), with responses observed in 15% of patients (13). Several of the above rationales led us to design a regimen that included chidamide, decitabine, idarubicin, cytarabine, and G-CSF (the CDIAG double epigenetic priming regimen) to treat patients with R/R AML.\n\nMaterials and Methods\n\nPatients\n\nThe trial was conducted at four medical centers (the First Affiliated Hospitals of Soochow University, Affiliated Hospital of Jining Medical University, Second People’s Hospital of Huai’an, and Canglang Hospital of Suzhou), and the investigational agent chidamide was provided by Shenzhen Chipscreen Biosciences Ltd. (Shenzhen, China) under an agreement. All study subjects provided their voluntary, written informed consent. The current study was conducted in accordance with the Declaration of Helsinki. The protocol and all its amendments were approved by the Ethics Committee of the First Affiliated Hospital of Soochow University (ClinicalTrials.gov identifier NCT03985007).\n\nEligible patients met the R/R AML [non-acute promyelocytic leukemia (non-APL)] criteria (Figure 1 and Supplemental Table 1). At enrollment, the patients were required to be 18 to 70 years of age and have an Eastern Cooperative Oncology Group (ECOG) performance status score less than 3, adequate organic function, and no severe complications, such as active infections and bleeding. Women of childbearing potential were required to practice adequate birth control while participating in the protocol. The exclusion criteria were as follows: unable to tolerate induction chemotherapy and a life expectancy of less than 1 month. The principal investigators performed BM morphology, immunophenotyping, cytogenetics, and molecular genetic analyses by reviewing central laboratory reports.\n\nFigure 1 Flow diagram for patient categorization and treatment. AML, acute myeloid leukemia; ER, early relapse; LR, late relapse; IT, induction therapy; IF, induction failure; CR, complete remission; Cri, CR with incomplete hematologic recovery; MLFS, morphologic leukemia-free state; PR, partial response; SD, stable disease, PD, progressive disease; Allo-HSCT, allogeneic hematopoietic stem cell transplantation.\n\nStudy Design and Objectives\n\nThe therapeutic regimen comprised chidamide (30 mg orally twice every week for 2 weeks on days 1, 4, 8, and 11), decitabine [20 mg/m2 intravenously daily for 5 days (d1-d5)], and the IAG regimen [cytarabine (10 mg/m2 subcutaneously every 12 hrs. on days 4-17), idarubicin (5 mg intravenously every other day on days 4, 6, 8, 10, 12, and 14), and concurrent G-CSF (200 μg/m2/day subcutaneously daily on days 3-17)] (Supplemental Table 2). The patients were removed from the study therapy for disease progression, symptomatic deterioration, or per patient request. Subsequent therapy after CDIAG for patients who did not receive SCT is described in detail in Supplemental Table 3. Supportive treatments, including G-CSF, the transfusion of RBCs or PLTs, and antibiotics, could be routinely administered during CDIAG treatment.\n\nThe primary objective of this phase II trial was to evaluate the ORR (confirmed CR, CRi, MLFS and PR) and CR (confirmed CR and CRi) rate by a BM examination based on central site review (Supplemental Table 4). The secondary objectives were to estimate the OS, PFS, and RFS and to assess toxicity. The OS duration was measured from the onset of CDIAG treatment until death due to any cause or censored for patients who remained alive at the time of assessment. PFS was defined as the time from the date of entry into the trial until the date of disease progression at any site, including distant metastasis or second primary tumors, or death. RFS was defined only for patients who achieved CR or CRi and was measured from the date of achieving remission until the date of relapse or death from any cause. Patients not known to have relapsed or died at the last follow-up were censored on the date they were last examined.\n\nAssessments\n\nClinical data, biologic data (BM smears and MRD with 10-color MFC afforded 1:10-4 to 1:10-5 level sensitivity]), and response assessment were centrally reviewed. Twenty-four days after the start of treatment (7 days after the end of therapy), the efficacy was evaluated in the BM. Patients who did not achieve CR/CRi received a BM examination again 31 days after the commencement of treatment (14 days after the end of therapy), and the best BM response was documented. Patients who did not achieve CR/CRi after both assessments using our salvage chemotherapy regimen were allowed to receive a second course, but the evaluation was conducted for each course. Routine blood counts were monitored every day, and electrolyte levels, liver function, and creatinine levels were monitored twice weekly following CDIAG chemotherapy.\n\nThe response conditions were defined according to the 2017 ELN recommendations (3). Investigator-assessed AEs were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI CTCAE version 5.0). Treatment-related mortality (TRM), adverse reactions in hematology (agranulocytosis days, PLT/RBC transfusion units) and nonhematological adverse reactions (Supplemental Table 5) (infection and organ injury) were recorded to evaluate toxicities. TRM was defined as death within 28 days after the initiation of IT.\n\nStatistical Analysis\n\nThirty-five eligible patients were enrolled in this study. Standard statistical methods were used for all analyses in the trial: T-test for means between two groups, single-factor and multi-level variance analyses for multiple groups, Fisher’s exact test for categorical endpoints, Kaplan-Meier curves and the log-rank test for the time-to-event endpoints. Descriptive statistics (counts and percentages for categorical variables; mean and standard deviation, and medians and range for continuous variables) were used throughout the study. P values of 0.05 were considered significant for analysis. All statistical analyses were performed with Graphpad Prism (version 8.0.2). Patient age, sex, WHO classification, WBC count, BM blasts, SCT, previous HMA exposure (before CDIAG regimen), prognosis risk, response and R/R status, as well as treatments before CDIAG, were examined to assess their impact on the survival and remission rates. The follow-up cutoff date was defined as the end of June 2020.\n\nResults\n\nPatient Characteristics\n\nThirty-five patients from four institutions who met the eligibility criteria were registered between 12/15/2016 and 03/29/2020 (Table 1). There were 19 male and 16 female patients, with a median age of 39.5 years (range, 18 to 68 years). The 35 patients included 28 (28/35, 80.0%) patients with AML, not otherwise specified (AML, NOS), 5 (5/35, 14.3%) patients with AML with myelodysplasia-related changes (AML-MRC), 1 (1/35, 2.9%) patient with AML with t(8;21)(q22;q22.1)/RUNX1-RUNX1T1 and 1 (1/35, 2.9%) patient with AML with inv (16)(p13.1q22)/CBFβ-MYH11(concurrent with a KIT mutation). The most frequently mutated genes were FLT3-ITD (25.7%), DNMT3A (25.7%), NPM1 (20.0%), CEBPα (20.0%), WT1 (20.0%), TET2 (17.1%), IDH1/2 (14.3%), NRAS (11.4%) and RUNX1 (11.4%).\n\nTable 1 Characteristics of the 35 enrolled patients.\n\nCharacteristic\tValue\t\nRelapsed/refractory\t9/26\t\nMale/female, No.\t19/16\t\nAge, median (range), y\t39.5 (18-68)\t\nWBC count, median (range), ×10exp9/L\t26.0 (1.0-299.0)\t\nHemoglobin level, median (range), g/L\t76 (48-127)\t\nPlatelet count, median (range), ×10exp9/L\t54 (10-376)\t\nBM blasts, median (range), %\t63.0 (10-97.5)\t\nWHO classification, No. (%)\t\n AML, NOS\t28 (80.0)\t\n AML with MRC\t5 (14.3)\t\n AML with t(8; 21)\t1 (2.9)\t\n AML with inv(16)\t1 (2.9)\t\nPrognosis risk for R/R AML, No. (%)\t\n Favorable\t2 (5.7)\t\n Intermediate\t4 (11.4)\t\n Poor\t29 (82.9)\t\nPrior HMA exposure (before the CDIAG regimen), No. (%)\t\n 0\t27 (77.1)\t\n ≥ 1\t8 (22.9)\t\nSubgroup classification of R/R AML, No. (%)\t\n Early relapse\t4 (11.4)\t\n Late relapse\t5 (14.3)\t\n IF after 1 course of IT\t9 (25.7)\t\n IF after 2 consecutive courses of IT\t12 (34.3)\t\n IF after ≥ 3 consecutive courses of IT\t3 (8.6)\t\n Relapse ≥ twice\t2 (5.7)\t\nTherapy after regimen, No. (%)\t\n SCT\t19 (54.3)\t\n Others\t16 (45.7)\t\nGenes Mutated, No. (%)\t\n FLT3-ITD mutated\t9 (25.7)\t\n DNMT3A mutated\t9 (25.7)\t\n NPM1 type A mutated\t7 (20.0)\t\n CEBPα biallelic mutated\t7 (20.0)\t\n WT1 mutated\t7 (20.0)\t\n TET2 mutated\t6 (17.1)\t\n IDH1/IDH2 mutated\t5 (14.3)\t\n RUNX1 mutated\t4 (11.4)\t\n NRAS mutated\t4 (11.4)\t\n FLT3-TKD mutated\t3 (8.6)\t\n U2AF1 mutated\t2 (5.7)\t\n TP53 mutated\t2 (5.7)\t\nR/R AML, relapsed/refractory AML; AML, NOS, AML, not otherwise specified; AML with MRC, AML with myelodysplasia-related changes; HMA, hypomethylating agent; SCT, stem cell transplantation; WBC, white blood cell; FLT3, FMS-like tyrosine kinase 3, FLT3-ITD, FLT3-internal tandem duplication; DNMT3A, DNA-methyltransferase 3A; NPM1, nucleophosmin 1; CEBPα, CCAAT/enhancer binding protein alpha; WT1, Wilms’ tumor 1; IDH1, isocitrate dehydrogenase 1; IDH2, isocitrate dehydrogenase 2; TET2, Tet methylcytosine dioxygenase 2; RUNX1, runt-related transcription factor 1; NRAS, neuroblastoma RAS viral oncogene homolog; TP53, tumor protein 53; FLT3-TKD, FLT3-tyrosine kinase domain; U2AF1, U2 small nuclear RNA auxiliary factor 1.\n\nAmong the 35 patients, three were not evaluable for response and were refractory. Three of the remaining 32 eligible patients had completed 2 cycles; therefore, 32 patients and 35 courses were examined to assess efficacy (Supplemental Table 6). Regarding the disease status before CDIAG, 23 patients (25 courses) were refractory, and 9 patients (10 courses) relapsed. Four patients relapsed within 6 months (early relapse), 5 relapsed beyond 6 months (late relapse), 8 experienced induction failure (IF) after 1 course of IT (induction therapy), 10 had IF after 2 consecutive courses of IT, 3 had IF after ≥ 3 consecutive courses of IT, and 2 relapsed more than twice. On registering for this study, 2 patients were categorized as favorable risk, 4 as intermediate risk, and 26 as adverse risk with a poor prognosis according to the prognostic scoring system of R/R AML (Supplemental Table 7) (14). Nineteen of 32 (59.4%) eligible patients received allo-SCT after undergoing the prior CDIAG regimen (3 sibling donor type, 1 unrelated donor type, and 15 haploidentical donor type). Seven of 32 (21.9%) evaluable patients had received more than one cycle of HMA therapy before CDIAG.\n\nOutcomes\n\nAmong the 35 patients, three withdrew before the evaluation. The overall response rate (ORR) for 35 assessable courses in 32 patients was 74.3% (95% confidence interval (CI): 59%-86%), the CR/CR with incomplete hematologic recovery (CRi) rate was 42.9% (95% CI: 25.6%-60.1%), the morphologic leukemia-free state (MLFS) rate was 14.3% (n=5), and the partial remission (PR) rate was 17.1% (n= 6). The stable disease (SD) rate was 22.9% (n= 8), and the progressive disease (PD) rate was 2.9% (n= 1). The median follow-up time was 22.1 months (range, 8.2-48.6 months) for this patient cohort. The median overall survival (OS) time was 11.7 months, and the median progression-free survival (PFS) time was 11.7 months. The survival outcomes of the entire cohort of 32 patients are shown in Figure 2. The 2-year OS, PFS and relapse-free survival (RFS) rates were 38.2% (Figure 2A), 37.8% (Figure 2B), and 65.5% (Figure 2C), respectively (RFS was evaluated in 15 patients who achieved CR/CRi). The primary and secondary endpoints are summarized in Table 2.\n\nFigure 2 Main study results. Kaplan–Meier graphs illustrating the overall survival (A) and progression-free survival (B) of all 32 refractory/relapsed (R/R) acute myeloid leukemia (AML) patients after the CDIAG regimen and the distinction of overall survival between patients with or without transplantation. The 2-year relapse-free survival (RFS) rate was 40.7% in 15 patients who achieved CR/CRi (C).\n\nTable 2 Primary and secondary patient endpoints.\n\nEndpoint (evaluable patients=32, courses= 35)\tValue\t\nOverall response, No. (%)\t26 (74.3%)\t\n Complete remission, No. (%)\t15 (42.9%)\t\n CR, No. (%)\t9 (25.7%)\t\n CRi, No. (%)\t6 (17.1%)\t\n Morphologic leukemia-free state, No. (%)\t5 (14.3%)\t\n Partial remission, No. (%)\t6 (17.1%)\t\nStable disease, No. (%)\t8 (22.9%)\t\nProgressive disease, No. (%)\t1 (2.9%)\t\nMedian OS time\t11.7 months\t\nMedian PFS time\t11.7 months\t\n2-year OS rate\t38.2%\t\n2-year PFS rate\t37.8%\t\n2-year RFS rate\t65.5%\t\nOS, overall survival; PFS, progression-free survival; RFS, relapse-free survival.\n\nThe ORR and CRR were evaluated for 35 courses in 32 patients. OS and PFS were evaluated in 32 patients. RFS was evaluated in 15 patients who achieved CR.\n\nThe ORR for the 10 CDIAG induction courses in 9 relapsed patients was 70.0% (7/10) (3 of 4 courses in 4 patients who had an early relapse and 4 of 6 courses in 5 patients who had a late relapse before CDIAG). The CR/CRi rate for the 10 courses in 9 relapsed patients was 30.0% (3/10) (only 1 of 4 courses in 4 patients who had an early relapse and 2 of 6 courses in 5 patients who had a late relapse). No difference was found in the ORR/CRR or survival rates between patients who had early and late relapses (Table 3).\n\nTable 3 Clinical responses of R/R AML patients with subgroup univariate analysis.\n\nVariable\tResponse\tP-Value\tOR* (95% CI)\tCR/CRi\tP-Value\tOR* (95% CI)\t\nOverall\t26/35 (74.3%)\t\t\t15/35 (42.9%)\t\t\t\nAge\t\n <51 years\t22/28 (75.6%)\t0.340\t0.364 (0.063-2.089)\t13/28 (46.4%)\t0.669\t0.462 (0.076-2.793)\t\n ≥51 years\t4/7 (57.1%)\t2/7 (28.6%)\t\nSex\t\n Male\t16/21 (76.2%)\t1.000\t1.280 (0.276-5.934)\t11/21 (52.4%)\t0.163\t2.750 (0.651-11.624)\t\n Female\t10/14 (71.4%)\t4/14 (28.6%)\t\nBlast\t\n <0.3\t3/8 (37.5%)\t0.015\t9.583 (1.613-56.952)\t2/8 (25.0%)\t0.450\t2.786 (0.475-16.345)\t\n ≥0.3\t23/27 (85.2%)\t13/27 (48.1%)\t\nWBC\t\n <14 × 10E9/L\t7/12 (58.3%)\t0.220\t3.393 (0.703-16.385)\t3/12 (25.0%)\t0.123\t3.273 (0.700-15.291)\t\n ≥14 × 10E9/L\t19/23 (82.6%)\t12/23 (52.2%)\t\nHB\t\n <65 g/L\t7/11 (63.6%)\t0.416\t2.171 (0.450-10.486)\t2/11 (18.2%)\t0.069\t5.318 (0.943-29.993)\t\n ≥65 g/L\t19/24 (79.2%)\t13/24 (54.2%)\t\nPLT\t\n <40 × 10E9/L\t12/14 (85.7%)\t0.262\t0.333 (0.058-1.919)\t7/14 (50.0%)\t0.486\t0.615 (0.157-2.419)\t\n ≥40 × 10E9/L\t14/21 (66.7%)\t8/21 (38.1%)\t\nPrevious HMA or not\t\n Yes\t5/7 (71.4%)\t0.632\t0.625 (0.093-4.222)\t3/7 (42.9%)\t0.576\t0.813 (0.150-0.404)\t\n No\t20/25 (80.0%)\t12/25 (48.0%)\t\nPrognostic score of R/R AML*\t\n Favorable/intermediate risk\t5/7 (71.4%)\t1.000\t1.200 (0.189-7.628)\t2/7 (28.6%)\t0.672\t2.167 (0.358-13.110)\t\n Adverse risk\t21/28 (75.0%)\t13/28 (46.4%)\t\nRelapsed/Refractory\t\n Relapsed\t7/10 (70.0%)\t0.694\t1.357 (0.265-6.958)\t3/10 (30.0%)\t0.458\t2.154 (0.451-10.287)\t\n Refractory\t19/25 (76.0%)\t12/25 (48.0%)\t\nRelapsed/Refractory subgroup\t\n Early relapse\t3/4 (75.0%)\t0.765\t0.909 (0.484-1.705)\t1/4 (25.0%)\t0.661\t1.132 (0.651-1.969)\t\n Late relapse\t4/6 (66.7%)\t2/6 (30.0%)\t\n IF after 1 course of IT\t7/8 (87.5%)\t4/8 (50.0%)\t\n IF after 2 consecutive courses of IT\t9/12 (75.0%)\t7/12 (58.3%)\t\n IF after ≥ 3 consecutive courses of IT or relapse ≥ twice\t3/5 (60.0%)\t1/5 (20.0%)\t\nGenes Mutated\t\n FLT3-ITDmut\t7/10 (70.0%)\t0.694\t0.737 (0.144-3.778)\t3/10 (30.0%)\t0.458\t0.464 (0.097-2.217)\t\n FLT3-ITDwt\t19/25 (76.0%)\t12/25 (48.0%)\t\n DNMT3A mut\t6/9 (66.7%)\t0.665\t0.600 (0.114-3.153)\t3/9 (33.3%)\t0.700\t0.583 (0.119-2.849)\t\n DNMT3A wt\t20/26 (76.9%)\t12/26 (46.2%)\t\n NPM1 type Amut\t3/7 (42.9%)\t0.055\t0.163 (0.027-0.969)\t2/7 (28.6%)\t0.669\t0.462 (0.076-2.793)\t\n NPM1 type Awt\t23/28 (82.1%)\t13/28 (46.4%)\t\n CEBPα biallelicmut\t5/7 (71.4%)\t1.000\t0.833 (0.131-5.297)\t4/7 (57.1%)\t0.669\t2.061 (0.385-11.035)\t\n CEBPα biallelicwt\t21/28 (75.0%)\t11/28 (39.3%)\t\n WT1 mut\t6/7 (85.7%)\t0.648\t2.400 (0.248-23.236)\t4/7 (57.1%)\t0.669\t2.061 (0.385-11.035)\t\n WT1 wt\t20/28 (71.4%)\t11/28 (39.3%)\t\n TET2 mut\t3/6 (50.0%)\t0.156\t0.261 (0.042-1.635)\t3/6 (50.0%)\t1.000\t1.417 (0.243-8.256)\t\n TET2 wt\t23/29 (79.3%)\t12/29 (41.4%)\t\n IDH1/IDH2 mut\t4/5 (80.0%)\t0.747\t1.455 (0.141-15.039)\t2/5 (40.0%)\t1.000\t0.872 (0.127-6.003)\t\n IDH1/IDH2 wt\t22/30 (73.3%)\t13/30 (43.3%)\t\n RUNX1 mut\t4/4 (100.0%)\t0.303\tNot reached\t4/4 (100.0%)\t0.026\tNot reached\t\n RUNX1 wt\t21/31 (67.7%)\t11/31 (35.9%)\t\n NRAS mut\t2/3 (66.7%)\t0.758\t0.667 (0.053-8.372)\t2/3 (66.7%)\t0.794\t2.923 (0.239-35.681)\t\n NRAS wt\t24/32 (75.0%)\t13/32 (40.6%)\t\n FLT3-TKDmut\t2/3 (66.7%)\t0.758\t0.667 (0.053-8.372)\t2/3 (66.7%)\t0.794\t2.923 (0.239-35.681)\t\n FLT3-TKDwt\t24/32 (75.0%)\t13/32 (40.6%)\t\nOR, odds ratio.\n\nThe bolded text means that there are significant differences between groups.\n\nThe ORR for the 25 CDIAG induction courses in 23 refractory patients was 76.0% (19/25) (7 of 8 courses in 8 patients who had IF after 1 course of IT, 9 of 12 courses in 10 patients who had IF after 2 consecutive courses of IT, and only 3 of 5 courses in 5 patients who had IF after ≥ 3 consecutive courses of IT or relapsed ≥ twice). The CR/CRi rate for the 25 courses in 23 refractory patients was 48.0% (12/25) (4 of 8 courses in 8 patients who had IF after 1 course of IT, 7 of 12 courses in 10 patients who had IF after 2 consecutive courses of IT, and only 1 of 5 patients who had IF after ≥ 3 consecutive courses of IT or relapsed ≥ twice achieved CR/CRi by CDIAG reinduction). Among all the refractory subgroups, the best CRR of 58.3% was achieved in 12 courses of 10 patients who had IF after 2 consecutive courses of IT (Table 3). The 2-year OS and PFS rates for the three refractory groups were 28.6%, 60.0%, 0% and 28.6%, 54.0%, 0.0%, respectively (Table 4).\n\nTable 4 Overall survival and progress-free survival univariate analysis.\n\nVariable\tAlive (%)\tHR (95%CI)\tMedian OS(months)\t2-year OS (%)\tP-Value\tHR (95%CI)\tMedian PFS(months)\t2-year PFS (%)\tP-Value\t\nOverall\t17/35(48.6)\t-\t11.7\t38.2\t-\t-\t11.7\t37.8\t-\t\nAge\t\n < 51 years\t13/25(52.0)\t1.470(0.470-4.605)\t10.1\t32.1\t0.545\t1.586(0.525-4.796)\t10.8\t31.3\t0.462\t\n ≥ 51 years\t4/7(57.1)\t0.680(0.217-2.130)\tNot reached\t53.6\t0.630(0.209-1.906)\tNot reached\t53.3\t\nSex\t\n Male\t10/19(52.6)\t0.642(0.213-1.98)\t18.4\t43.5\t0.391\t0.711(0.244-2.073)\t11.7\t41.5\t0.501\t\n Female\t7/13(53.8)\t1.558(0.516-4.701)\t10.1\t29.0\t1.407(0.483-4.104)\t10.8\t31.1\t\nBM-Blast\t\n < 0.3\t3/6(42.9)\t1.550(0.359-6.698)\t8.9\tNot reached\t0.487\t1.458(0.350-6.070)\t7.4\tNot reached\t0.549\t\n ≥ 0.3\t14/26(53.8)\t0.645(0.149-2.787)\t13.8\t39.5\t0.686(0.165-2.857)\t13.8\t38.9\t\nWBC\t\n < 14 × 10E9/L\t5/10(50.0)\t1.151(0.383-3.464)\t10.1\t30.9\t0.795\t1.052(0.362-3.058)\t10.8\t30.9\t0.925\t\n ≥ 14 × 10E9/L\t12/22(54.5)\t0.869(0.289-2.613)\t13.8\t40.5\t0.951(0.327-2.765)\t13.8\t40.1\t\nHB\t\n < 65 g/L\t3/9(33.3)\t2.240(0.672-7.463)\t7.9\t15.2\t0.112\t2.067(0.639-6.684)\t7.4\t15.2\t0.147\t\n ≥ 65 g/L\t14/23(60.9)\t0.447(0.134-1.488)\t13.8\t49.2\t0.484(0.150-1.564)\t13.8\t47.7\t\nPLT\t\n < 40 × 10E9/L\t7/13(53.8)\t0.790(0.286-2.183)\t18.4\t34.0\t0.652\t0.966(0.360-2.587)\t11.7\t31.1\t0.944\t\n ≥ 40 × 10E9/L\t10/19(52.6)\t1.265(0.458-3.494)\t10.1\t39.0\t1.036(0.387-2.776)\t10.1\t40.9\t\nPrevious HMA or not\t\n Yes\t3/7(42.6)\t1.885(0.477-7.449)\t8.9\tNot reached\t0.267\t1.830(0.471-7.110)\t5.4\tNot reached\t0.285\t\n No\t14/25(51.9)\t0.531(0.134-2.097)\t13.8\t38.9\t0.546(0.141-2.123)\t11.7\t37.9\t\nPrognostic score of R/R AML†\t\n Favorable/intermediate risk\t2/6(33.3)\t1.750(0.458-6.687)\t8.9\t20.0\t0.324\t1.485(0.419-5.271)\t7.9\t20.0\t0.484\t\n Adverse risk\t15/26(57.7)\t0.572(0.150-2.185)\t18.4\t43.4\t0.673(0.190-2.390)\t13.8\t42.4\t\nRelapsed/Refractory\t\n Relapsed\t6/9(66.7)\t0.601(0.198-1.825)\tNot reached\t51.4\t0.422\t0.489(0.171-1.397)\tNot reached\t51.4\t0.250\t\n Refractory\t12/23(52.2)\t1.664(0.548-5.055)\t11.7\t32.7\t2.045(0.716-5.844)\t11.7\t31.5\t\nRelapsed/Refractory subgroup\t\n Early relapse\t2/4(50.0)\t-\t10.1\t33.3\t0.011\t-\t10.1\t33.3\t0.044\t\n Late relapse\t4/5(80.0)\tNot reached\t66.7\tNot reached\t66.7\t\n IF after 1 course of IT\t3/8(37.5)\t13.8\t28.6\t13.8\t28.6\t\n IF after 2 consecutive courses of IT\t7/10(70.0)\tNot reached\t60.0\tNot reached\t54.0\t\n IF after ≥ 3 consecutive courses of IT or relapse ≥ twice\t1/5(20.0)\t7.4\t0.0\t5.4\t0.0\t\nGenes Mutated\t\n FLT3-ITDmut\t5/9(55.6)\t1.014(0.322-3.195)\t13.8\t45.7\t0.981\t0.936(0.307-2.850)\t13.8\t48.6\t0.908\t\n FLT3-ITDwt\t12/23(52.2)\t0.987(0.313-3.110)\t10.8\t35.6\t1.068(0.351-3.253)\t10.8\t34.4\t\n DNMT3A mut\t6/9(66.7)\t0.516(0.175-1.519)\tNot reached\t62.2\t0.292\t0.701(0.246-1.999)\tNot reached\t53.3\t0.531\t\n DNMT3A wt\t11/23(47.8)\t1.937(0.658-5.701)\t10.1\t28.7\t1.427(0.500-4.071)\t10.1\t29.8\t\n NPM1 type Amut\t3/7(42.9)\t1.765(0.460-6.773)\t13.8\t26.8\t0.320\t1.407(0.405-4.886)\t13.8\t26.8\t0.549\t\n NPM1 type Awt\t14/25(56.0)\t0.567(0.148-2.174)\t11.7\t41.4\t0.711(0.205-2.469)\t11.7\t40.0\t\n CEBPα biallelicmut\t4/7(57.1)\t1.081(0.296-3.948)\t8.9\t42.9\t0.904\t1.430(0.409-4.999)\t7.4\t35.7\t0.531\t\n CEBPα biallelicwt\t13/25(52.0)\t0.925(0.253-3.380)\t11.7\t36.5\t0.699(0.200-2.444)\t13.8\t37.4\t\n WT1 mut\t4/7(57.1)\t1.160(0.308-4.365)\t10.8\t25.0\t0.816\t1.015(0.288-3.585)\t11.7\t26.7\t0.981\t\n WT1 wt\t13/25(52.0)\t0.862(0.229-3.243)\t13.8\t40.6\t0.985(0.279-3.477)\t13.8\t39.1\t\n TET2 mut\t3/6(50.0)\t1.866(0.389-8.947)\t7.4\t27.8\t0.319\t1.989(0.492-8.045)\t7.4\t22.2\t0.218\t\n TET2 wt\t14/26(53.8)\t0.536(0.112-2.571)\t13.77\t39.8\t0.503(0.124-2.034)\t13.8\t40.7\t\n IDH1/IDH2 mut\t5/5(100.00)\t0.280(0.079-0.997)\tNot reached\t100.0\t0.050\t0.278(0.082-0.939)\tNot reached\t100.0\t0.039\t\n IDH1/IDH2 wt\t12/27(44.4)\t3.566(1.003-12.680)\t10.1\t28.8\t3.595(1.065-12.140)\t10.1\t28.2\t\n RUNX1 mut\t0/4(0.00)\t0.294(0.053-1.630)\t7.8\t0.0\t0.023\t0.283(0.495-1.622)\t4.5\t0.0\t0.018\t\n RUNX1 wt\t18/31(58.1)\t3.405(0.613-18.900)\t18.4\t46.1\t3.531(0.616-20.220)\t17.4\t44.6\t\n NRAS mut\t1/3(33.3)\t1.413(0.258-7.736)\t10.8\t0.0\t0.642\t1.485(0.263-8.394)\t11.7\t0.0\t0.593\t\n NRAS wt\t16/29(55.2)\t0.708(0.129-3.877)\t13.8\t41.4\t0.673(0.119-3.805)\t13.8\t40.5\t\n FLT3-TKDmut\t1/3(33.3)\t1.084(0.234-5.027)\t13.8\t33.3\t0.915\t1.022(0.230-4.555)\t13.8\t33.3\t0.976\t\n FLT3-TKDwt\t16/29(55.2)\t0.922(0.199-4.277)\t11.7\t38.7\t0.978(0.220-4.357)\t11.7\t38.1\t\nResponse\t\n Yes\t15/25(60.0)\t0.296(0.066-1.341)\t18.4\t46.8\t0.015\t0.358(0.087-1.469)\t17.4\t46.0\t0.041\t\n No\t2/7(28.6)\t3.374(0.746-15.260)\t7.4\t0.0\t2.797(0.681-11.490)\t7.4\t0.0\t\nCR/CRi\t\n Yes\t10/15(66.7)\t0.384(0.1384-1.067)\tNot reached\t58.7\t0.067\t0.511(0.191-1.365)\tNot reached\t57.3\t0.179\t\n No\t7/17(41.2)\t2.603(0.938-7.224)\t10.1\t18.6\t1.959(0.733-5.236)\t10.1\t18.7\t\nMRD\t\n ≥ 10-1\t2/6(33.3)\t-\t7.40\t0.0\t< 0.0001\t-\t7.4\t0.0\t0.005\t\n <10-1 and ≥10-3\t8/15(53.3)\t18.4\t43.1\t17.4\t40.2\t\n <10-3\t7/8(87.5)\tNot reached\t75.0\tNot reached\t75.0\t\nSCT or not\t\n Yes\t11/19(57.9)\t0.485(0.160-1.467)\t18.4\t45.6\t0.150\t0.639(0.226-1.810)\t17.4\t44.3\t0.366\t\n No\t6/13(46.2)\t2.062(0.682-6.235)\t7.9\t24.2\t1.564(0.553-4.427)\t10.8\t25.4\t\nSCT with a response or not\t\n Yes\t9/15(60.0)\t0.194(0.011-3.528)\tNot reached\t51.3\t0.017\t0.387(0.044-3.430)\t17.4\t48.9\t0.204\t\n No\t2/4(50.0)\t5.146(0.283-93.420)\t7.4\t0.0\t2.584(0.292-22.910)\t7.4\t0.0\t\nSCT with CR/CRi or not\t\n Yes\t8/12(66.7)\t0.438(0.097-1.975)\tNot reached\t60.0\t0.227\t0.605(0.150-2.440)\tNot reached\t57.1\t0.447\t\n No\t3/7(42.9)\t2.282(0.506-10.290)\t10.1\t22.9\t1.651(0.410-6.650)\t10.1\t22.9\t\nResponders underwent SCT or not\t\n Yes\t9/15(60.0)\t0.493(0.117-2.075)\tNot reached\t51.3\t0.260\t0.710(0.193-2.617)\t17.4\t48.9\t0.579\t\n No\t6/10(60.0)\t2.027(0.482-8.521)\t10.8\t36.0\t1.408(0.382-5.186)\t10.8\t39.4\t\nCR/CRi underwent SCT or not\t\n Yes\t8/12(66.7)\t0.523(0.341-8.106)\tNot reached\t60.0\t0.558\t0.956(0.108-8.450)\tNot reached\t57.1\t0.965\t\n No\t2/3(66.7)\t1.902(0.123-29.320)\t13.2\tNot reached\t1.049(0.118-9.294)\tNot reached\t66.7\t\n†Prognostic score was graded by the European Prognostic Index score in ELN. HR, hazards ratio.\n\nThe bolded text means that there are significant differences between groups.\n\nFive subgroups among the entire cohort of R/R AML patients had different OS and PFS rates (P = 0.011 and 0.044, respectively), in which patients who had IF after ≥ 3 consecutive courses of IT or relapsed ≥ twice had the worst survival rate, and patients who had late relapse achieved the best survival rate (Table 4, Figure 3A, and Supplemental Figure 1A). The 2-year OS and PFS rates of relapsed and refractory patients were 51.4% vs. 32.7% and 51.4% vs. 31.5% (P = 0.422 and 0.250), respectively.\n\nFigure 3 Overall survival according to prognostic characteristics and treatment allocation. Kaplan–Meier graphs illustrating the overall survival of 32 R/R AML patients with 5 different subgroups (A), responders versus nonresponders (B), patients who achieved CR versus those who did not (C), patients according to the MRD status (D), patients with RUNX1 mut versus RUNX1 wt (E), patients with IDH mut versus IDH wt (F), patients who received SCT versus those who did not (G), and responders who underwent SCT versus nonresponders who underwent SCT (H).\n\nThe median OS and PFS times for patients who achieved a response were 18.4 and 17.4 months, respectively, while those for nonresponders were 7.4 and 7.4 months, respectively. Additionally, OS and PFS were significantly longer in responders than in nonresponders (P = 0.015 and 0.041, respectively) (Table 4, Figure 3B, and Supplemental Figure 1B). The 2-year OS and PFS rates for the 25 patients who achieved a response were 46.8% and 46.0%, respectively, while those for nonresponders (7 patients without a response after CDIAG) were 0.0% and 0.0%, respectively. The median OS and PFS rates for 15 patients who achieved CR were not available, while those for patients who did not were 10.1 and 10.1 months, respectively. The 2-year OS and PFS rates for patients who achieved CR were 58.7% and 57.3%, respectively, while those for 17 patients who could not achieve CR after CDIAG were 18.6% and 18.7%, respectively (P = 0.067 and 0.179, respectively) (Table 4, Figure 3C, and Supplemental Figure 1C).\n\nThe minimal residual disease (MRD) of flow cytometry (FCM) was analyzed in 29 patients and divided into the following three groups: 6 patients had MRD ≥ 10-1, 15 patients had MRD <10-1 and >10-3, 8 patients had MRD ≤10-3. The OS of the three groups were consistent with the clinical estimate. The lowest MRD group achieved the best survival (2-year OS rate: 75.0%), the MRD ≥ 10-1 group showed the worst OS and PFS (2-year OS rate: 0.0%), and the survival of the MRD <10-1 and >10-3 group was intermediate (2-year OS rate, 43.1 months). The survival difference among the three groups was statistically significant (OS: P < 0.0001; PFS: P = 0.005) (Table 4, Figure 3D, and Supplemental Figure 1D).\n\nAmong the 32 evaluable patients, all 4 with a RUNX1 gene mutation achieved CR after one course of the CDIAG regimen. However, in 28 patients with wild-type RUNX1, the response rate for 31 CDIAG induction courses was 67.7% (21/31), and the CR rate was 35.9% (11/31). The CRR in the RUNX1mut group was significantly higher than that in the RUNX1wt group (P = 0.026) (Table 3). The presence of the RUNX1 mutations was associated with a short median OS (7.8 vs. 18.4 months; P = 0.023) and PFS (4.5 vs. 17.4 months; P = 0.018) times, with a 2-year OS rate of 0.0% vs. 46.1% and a 2-year PFS rate of 0.0% vs. 44.6% (Table 4, Figure 3E, and Supplemental Figure 1E).\n\nNo significant difference was found in the response rate between five IDHmut (including IDH1 and IDH2) patients and 22 IDHwt patients (80.0% vs. 73.3%; P = 0.747). All five IDHmut patients were still alive. The survivals of these two groups were obviously different (2-year OS rate: 100.0% vs. 28.9%, P = 0.050; 2-year PFS rate, 100.0% vs. 28.2%, P = 0.039) (Table 4, Figure 3F, and Supplemental Figure 1F).\n\nThe ORR for 10 courses in 9 FLT3-ITDmut patients after the CDIAG regimen reached 70.0% (7/10) and that for 25 courses in 23 FLT3-ITDwt patients reached 76.0% (19/25). The CRR for 10 courses in 9 FLT3-ITDmut patients reached 30.0% (3/10) and that for 25 courses in 23 FLT3-ITDwt patients reached 48.0% (12/25). No difference was found in the ORR or CRR between FLT3-ITDmut and FLT3-ITDwt patients (P = 0.694 and 0.458, respectively), but FLT3-ITDwt patients showed a shorter median OS time (10.8 vs. 13.8 months, P = 0.981) and PFS time (10.77 vs. 13.77 months, P = 0.908) (Table 4). Additionally, no significant correlation was found between mutations in other genes (CEBPα, DNMT3A, NPM1, TET2, WT1, NRAS, FLT3-TKD) and the remission or survival rate.\n\nAmong the entire cohort, nineteen of the 32 eligible patients (59.4%) successfully bridged to SCT after CDIAG treatment. The 2-year OS and PFS rates of the 19 patients who had undergone SCT were 45.6% and 44.3%, respectively, and the rates of the 13 patients who did not undergo SCT were 24.2% and 25.4%, respectively. No significant difference was found in the OS or PFS between these groups (P = 0.150 and 0.366, respectively) (Table 4, Figure 3G, and Supplemental Figure 1G).\n\nAmong the 19 patients who had undergone SCT, the 2-year OS rate of 15 responders was significantly higher than that of 4 nonresponders (51.3% vs. 0.0%; P = 0.017), but no difference was found in the 2-year PFS rate (48.9% vs. 0.0%; P = 0.204) (Table 4, Figure 3H, and Supplemental Figure 1H). For the 25 responders, the 2-year OS and PFS rates of the 15 responders who had undergone SCT were not significantly different from those of the 10 responders who had not undergo SCT (51.3% vs. 36.0%, P = 0.260; 48.9% vs. 39.4%, P = 0.579).\n\nOf the 10 patients who achieved a response after CDIAG but did not receive SCT, four (including one who achieved CR) died from PD, two were lost to follow-up with a PD status, two (including one who achieved CR) were alive with a PD status, and only two (including one who achieved CR) were alive with a remission status under chemotherapy at the time of analysis.\n\nAt the time of analysis, five of 10 patients who received SCT from haploidentical donors survived and achieved CR; 1 died because of TRM, 3 died from relapse, and one was alive after relapse. One patient who received SCT from a sibling donor was lost to follow-up, and 1 patient who received a transplant from an unrelated donor remained alive and achieved CR. No early TRM (within 60 days of SCT) occurred in the 19 patients who had undergone SCT after the CDIAG regimen.\n\nNo difference was found in the ORR (71.4%, 5/7 vs. 80.0%, 20/25; P = 0.632), CRR (42.9%, 3/7 vs. 48.0%, 12/25; P = 0.576), median OS time (8.9 vs. 13.8 months, P = 0.267) or median PFS time (5.4 vs. 11.7 months, P = 0.285) between patients who had been treated with or without HMA (primary decitabine). Additionally, the 2-year OS and PFS rates were not significantly different between the groups (not reached vs. 38.9% and not reached vs. 37.9% (Table 4).\n\nNo significant difference was found in the ORR and CRR between groups with different prognosis risks: the ORR and CRR for 7 courses in 6 patients with a favorable or intermediate risk were 71.4% (5/7) and 28.6% (2/7), respectively, while those for 28 courses in 26 patients with an adverse risk were 75.0% (21/28) and 46.4% (13/28), respectively (P = 1.000 and 0.672, respectively); the 2-year OS rates were 20.0% vs. 43.4%, and the 2-year PFS rates were 20.0% vs. 42.4%, respectively, comparing the two groups (P = 0.324 and 0.484, respectively) (Table 4 and Supplemental Table 2).\n\nAge, sex, BM blasts, the white blood cell (WBC) count, the hemoglobin count and the platelet (PLT) count did not affect the response rates.\n\nSafety\n\nThirty-five patients received 38 courses of IT. Thus, all the toxicological evaluations were performed during these 38 courses.\n\nFor hematological adverse events (AEs), the median time for neutropenia was 18.4 (0-77) days, and G-CSF injections were administered in 34 of 38 courses because the neutrophil count was less than 1.0×10exp9/L. All the patients received red blood cell (RBC) transfusions at an average of 6 Units (1200 mL) because the hemoglobin levels were below 60 g/L. Additionally, all the patients required platelet transfusions at an average of 7.3 units per course because the platelet counts were below 10×10exp9/L.\n\nThe nonhematological AEs are summarized in Supplemental Table 3. Two (5.3%) patients died of AEs that were deemed treatment-related (both because of severe deterioration of liver and kidney function after the infective shock). Overall, the treatment was well tolerated, although most side effects were grade 3. The reason for this high rate of grade 3 AEs was that, in most cases, inflammation required intravenous treatment and blood transfusion in the hypoimmune state.\n\nDiscussion\n\nThe outcome of R/R AML remains poor, and treatment options are very limited. Exploring an effective and well-tolerated combination therapy is urgent. In the preclinical studies, chidamide and decitabine, two epigenetic modifiers, revealed a significant synergistic effect in both AML cell lines and primary R/R AML cells. In this phase II prospective multicenter trial, of the 32 evaluable patients treated with the CDIAG regimen, the ORR was 74.3% and CR/CRi rate was 42.9%, with a median OS of 11.7 months and a 2-year OS rate of 38.2%. Patients who achieved a response or MRD levels below 10-3 have a significantly better OS and PFS than those without. The clinical results were encouraging because many poor-risk individuals were enrolled and 81% of the patients had adverse cytogenetics.\n\nSCT was plausibly the best salvage treatment option for R/R AML until the development of effective and available novel drugs (15). SCT for AML yields good results when administered to patients in a CR status (16). In a previously published prospective study, sixty-seven percent of remitters received allo-transplantation in CR2, providing a superior survival rate than no stem cell transplantation (5-year OS rate: 42% vs. 16%) (17). In our study, 19 patients bridged to SCT after the CDIAG regimen. Their 2-year overall survival rate was higher than that of the non-SCT group (45.6% vs. 24.2%; P=0.150). The results were consistent with our expectations, suggesting that the CDIAG protocol could reduce the leukemia burden before transplantation and provide a bridge for subsequent transplantation. Responders after CDIAG should receive transplantation as soon as possible.\n\nAmong our entire cohort of refractory and relapsed patients, those with PIF after ≥ 3 consecutive courses of IT or who relapsed ≥ twice had the worst OS and PFS. The 2-year survival rate of these patients was 0.0%. The patients with a late relapse had the best survival rate of 66.7%. Importantly, the survival rate of the refractory patients receiving one course of IT was worse than that of patients who received two consecutive courses of IT because of the high proportion (4/8) of FLT3-ITD mutations in the former group. Most studies thus far have suggested no difference in the response rate with or without previous HMA exposure (18). Although no significantly difference, patients who had received HMA therapy had a shorter OS time than those who had not. The median OS time was 8.90 months for previous HMA exposure vs. 13.8 months for no previous HMA exposure (P = 0.267). (Table 4). The possible mechanism underlying the shorter tendency in the survival times of such patients could be due to the drug resistance property after screening by HMA drugs.\n\nImportantly, the response rate was improved in patients with RUNX1 mutations (100%; 4 of 4 patients), but the increased sensitivity could not compensate for the poor prognosis associated with RUNX1 mutation (19). The 2-year OS and PFS rates for 28 RUNX1 wt patients (courses=31) and 4 RUNX1 mut patients were 46.1% vs. 0% and 44.6% vs. 0.0%, respectively (P = 0.023 and 0.018, respectively). RUNX1 is an important regulator of myeloid differentiation and effective hematopoiesis (20). HDAC1 and 3 bind to RUNX1 and regulate the transcription activity of RUNX1 ( 21). Whether chidamide binds competitively to HDAC1 and 3 against RUNX1 and plays a role in CDIAG IT deserves further exploration. Interestingly, even the presence of IDH mutation did not affect the CR rate but achieved better OS and PFS. Although several studies have investigated the incidence and prognosis of IDH mutations in patients with AML, the significance of IDH mutations on AML outcome has been unclear (22). Better survival might benefit from the impact of IDH on histone modifications and DNA methylation (23, 24). As mentioned above, no difference was found in the response or survival rate between FLT3-ITDmut and FLT3-ITDwt patients, but FLT3-ITDmut patients had worse outcomes. Recently, Hu et al. revealed a novel resistance pathway involving FLT3-ITDmut: in AML cells, FLT3-ITDmut upregulates HDAC8, thereby promoting the persistence of FLT3-ITDmut AML cells even in the presence of an FLT3 inhibitor (25). This view confirms our findings. FLT3-ITDmut patients achieved a poor response, and 4 of 7 responders with FLT3-ITDmut ultimately achieved PD with poor outcomes, likely because of the ineffectiveness of chidamide for selectively inhibiting HDAC1, 2, 3 and 10 instead of HDAC8.\n\nDespite the clinical activity of chidamide combination therapy in R/R AML patients, toxicity is still commonly observed in this cohort. The degree of cytopenia and resulting complications reported in our study are not higher than those reported in treatment-naïve patients or other R/R populations, although the rates and degrees of baseline cytopenia were higher (26). We found that infections of grade 3 or higher were observed in nearly half of the cohort (18 courses), and 2 of the 18 courses developed infectious shock. Three patients died within 4 weeks after treatment, 2 of the 3 patients developed severe infection and shock, and one patient persistently maintained no response and died after receiving chemotherapy. Even with these toxicities, in our study, the median OS and PFS times were 11.7 and 11.7 months, respectively, and the 2-year OS and PFS rates were 38.2% and 37.8%, respectively, which are equivalent or superior to those of conventional salvage therapy (27).\n\nConclusion\n\nThe CDIAG regimen was well tolerated and associated with a higher clinical response rate than expected in the context of salvage therapy for R/R AML. The regimen delays disease progression and reduces the leukemia burden before transplantation, providing eligible patients with the chance of proceeding to allo-SCT. Our results show that epigenetic agents combining cytotoxic agents may represent a promising direction for patients with R/R AML. Further evaluations in larger population are needed to seek biological indicators benefiting from this regimen.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Soochow University. The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\n\nJY contributed to data curation, formal analysis, visualization, and writing-original draft. C-LW contributed to writing-original draft and visualization. LZ contributed to data curation. HZ contributed to methodology and investigation. LB contributed to methodology and investigation. H-XZ contributed to investigation and resources. M-ZX contributed to investigation and resources. L-YC contributed to investigation and resources. C-SQ contributed to investigation and resources. H-YQ contributed to methodology and validation. S-NC contributed to methodology and validation. X-WT contributed to investigation and resources. D-PW contributed to conceptualization, supervision, and writing-review and editing. Z-YM contributed to methodology and investigation. A-NS contributed to conceptualization, funding acquisition, supervision, and writing-review. S-LX contributed to conceptualization, funding acquisition, supervision, resources, and writing-review. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThis work was supported by grants from the National Natural Science Foundation of China (Grant No. 81970138), Translational Research Grant of NCRCH (Grant No. 2020ZKMB05), Jiangsu Province “333” project, Jiangsu Province Medical Youth Talent Program (Grant No. QNRC2016719), a C class sponsored project from Jiangsu Provincial Six Talent Peaks (Grant No. 2016-WSN-123) and Gusu Key Medical Talent Program (Grant No. GSWS2019007).\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublisher’s Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nAcknowledgments\n\nThe authors would like to thank the investigators and patients who participated in the CDIAG trial and Shenzhen Chipscreen Biosciences Ltd.(Shenzhen, China) for providing chidamide for this clinical trial.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.726926/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1 Cheson BD Bennett JM Kopecky KJ Büchner T Willman CL Estey EH . Revised Recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol (2003) 21 :4642–9. 10.1200/jco.2003.04.036\n2 Döhner H Estey EH Amadori S Appelbaum FR Büchner T Burnett AK . Diagnosis and Management of Acute Myeloid Leukemia in Adults: Recommendations From an International Expert Panel, on Behalf of the European LeukemiaNet. Blood (2010) 115 :453–74. 10.1182/blood-2009-07-235358\n3 Döhner H Estey E Grimwade D Amadori S Appelbaum FR Büchner T . Diagnosis and Management of AML in Adults: 2017 ELN Recommendations From an International Expert Panel. Blood (2017) 129 :424–47. 10.1182/blood-2016-08-733196\n4 Cashen AF Schiller GJ O’Donnell MR DiPersio JF . Multicenter, Phase II Study of Decitabine for the First-Line Treatment of Older Patients With Acute Myeloid Leukemia. J Clin Oncol (2010) 28 :556–61. 10.1200/jco.2009.23.9178\n5 Al-Ali HK Jaekel N Junghanss C Maschmeyer G Krahl R Cross M . Azacitidine in Patients With Acute Myeloid Leukemia Medically Unfit for or Resistant to Chemotherapy: A Multicenter Phase I/II Study. Leuk Lymphoma (2012) 53 :110–7. 10.3109/10428194.2011.606382\n6 Pan DS Yang Q-J Fu X Shan S Zhu JZ Zhang K . Discovery of an Orally Active Subtype-Selective HDAC Inhibitor, Chidamide, as an Epigenetic Modulator for Cancer Treatment. Med Chem Commun (2014) 5 :1789–96. 10.1039/C4MD00350K\n7 Witt O Deubzer HE Milde T Oehme I . HDAC Family: What are the Cancer Relevant Targets? Cancer Lett (2009) 277 :8–21. 10.1016/j.canlet.2008.08.016 18824292\n8 Khan AN Tomasi TB . Histone Deacetylase Regulation of Immune Gene Expression in Tumor Cells. Immunol Res (2008) 40 :164–78. 10.1007/s12026-007-0085-0\n9 Yamada K Furusawa S Saito K Waga K Koike T Arimura H . Concurrent Use of Granulocyte Colony-Stimulating Factor With Low-Dose Cytosine Arabinoside and Aclarubicin for Previously Treated Acute Myelogenous Leukemia: A Pilot Study. Leukemia (1995) 9 :10–4.\n10 Li J Chen Y Zhu Y Zhou J Xu Y Li Y . Efficacy and Safety of Decitabine in Combination With G-CSF, Low-Dose Cytarabine and Aclarubicin in Newly Diagnosed Elderly Patients With Acute Myeloid Leukemia. Oncotarget (2015) 6 :6448–58. 10.18632/oncotarget.3361\n11 Jiang X Wang Z Ding B Yin C Zhong Q Carter BZ . The Hypomethylating Agent Decitabine Prior to Chemotherapy Improves the Therapy Efficacy in Refractory/Relapsed Acute Myeloid Leukemia Patients. Oncotarget (2015) 6 :33612–22. 10.18632/oncotarget.5600\n12 Cameron EE Bachman KE Myöhänen S Herman JG Baylin SB . Synergy of Demethylation and Histone Deacetylase Inhibition in the Re-Expression of Genes Silenced in Cancer. Nat Genet (1999) 21 :103–7. 10.1038/5047\n13 Kirschbaum M Gojo I Goldberg SL Bredeson C Kujawski LA Yang A . A Phase 1 Clinical Trial of Vorinostat in Combination With Decitabine in Patients With Acute Myeloid Leukaemia or Myelodysplastic Syndrome. Br J Haematol (2014) 167 :185–93. 10.1111/bjh.13016\n14 Kurosawa S Yamaguchi T Miyawaki S Uchida N Sakura T Kanamori H . Prognostic Factors and Outcomes of Adult Patients With Acute Myeloid Leukemia After First Relapse. Haematologica (2010) 95 :1857–64. 10.3324/haematol.2010.027516\n15 Middeke JM Herbst R Parmentier S Bug G Hänel M Stuhler G . Long-Term Follow-Up and Impact of Comorbidity Before Allogeneic Hematopoietic Stem Cell Transplantation in Patients With Relapsed or Refractory Acute Myeloid Leukemia-Lessons Learned From the Prospective BRIDGE Trial. Biol Blood Marrow Transpl (2017) 23 :1491–7. 10.1016/j.bbmt.2017.05.014\n16 Freeman SD Hills RK Virgo P Khan N Couzens S Dillon R . Measurable Residual Disease at Induction Redefines Partial Response in Acute Myeloid Leukemia and Stratifies Outcomes in Patients at Standard Risk Without NPM1 Mutations. J Clin Oncol (2018) 36 :1486–97. 10.1200/jco.2017.76.3425\n17 Burnett AK Goldstone A Hills RK Milligan D Prentice A Yin J . Curability of Patients With Acute Myeloid Leukemia Who did Not Undergo Transplantation in First Remission. J Clin Oncol (2013) 31 :1293–301. 10.1200/jco.2011.40.5977\n18 Aldoss I Yang D Aribi A Ali H Sandhu K Al Malki MM . Efficacy of the Combination of Venetoclax and Hypomethylating Agents in Relapsed/Refractory Acute Myeloid Leukemia. Haematologica (2018) 103 :e404–7. 10.3324/haematol.2018.188094\n19 Della Porta MG Gallì A Bacigalupo A Zibellini S Bernardi M Rizzo E . Clinical Effects of Driver Somatic Mutations on the Outcomes of Patients With Myelodysplastic Syndromes Treated With Allogeneic Hematopoietic Stem-Cell Transplantation. J Clin Oncol (2016) 34 :3627–37. 10.1200/jco.2016.67.3616\n20 Grimwade D Ivey A Huntly BJ . Molecular Landscape of Acute Myeloid Leukemia in Younger Adults and Its Clinical Relevance. Blood (2016) 127 :29–41. 10.1182/blood-2015-07-604496 26660431\n21 Giannini G Cabri W Fattorusso C Rodriquez M . Histone Deacetylase Inhibitors in the Treatment of Cancer: Overview and Perspectives. Future Med Chem (2012) 4 :1439–60. 10.4155/fmc.12.80\n22 DiNardo CD Propert KJ Loren AW Paietta E Sun Z Levine RL . Serum 2-Hydroxyglutarate Levels Predict Isocitrate Dehydrogenase Mutations and Clinical Outcome in Acute Myeloid Leukemia. Blood (2013) 121 :4917–24. 10.1182/blood-2013-03-493197\n23 Lev Maor G Yearim A Ast G . The Alternative Role of DNA Methylation in Splicing Regulation. Trends Genet (2015) 31 :274–80. 10.1016/j.tig.2015.03.002\n24 Garrett-Bakelman FE Melnick AM . Mutant IDH: A Targetable Driver of Leukemic Phenotypes Linking Metabolism, Epigenetics and Transcriptional Regulation. Epigenomics (2016) 8 :945–57. 10.2217/epi-2016-0008\n25 Long J Jia MY Fang WY Chen XJ Mu LL Wang ZY . FLT3 Inhibition Upregulates HDAC8 via FOXO to Inactivate P53 and Promote Maintenance of FLT3-ITD+ Acute Myeloid Leukemia. Blood (2020) 135 :1472–83. 10.1182/blood.2019003538\n26 Hatsumi N Miyawaki S Yamauchi T Takeshita A Komatsu N Usui N . Phase II Study of FLAGM (Fludarabine + High-Dose Cytarabine + Granulocyte Colony-Stimulating Factor + Mitoxantrone) for Relapsed or Refractory Acute Myeloid Leukemia. Int J Hematol (2019) 109 :418–25. 10.1007/s12185-019-02606-0\n27 Giles F O’Brien S Cortes J Verstovsek S Bueso-Ramos C Shan J . Outcome of Patients With Acute Myelogenous Leukemia After Second Salvage Therapy. Cancer (2005) 104 :547–54. 10.1002/cncr.21187\n\n",
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"keywords": "CDIAG regimen; epigenomics; histone deacetylase inhibitor (HDACi); relapsed/refractory acute myeloid leukemia; salvage therapy",
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"title": "A Phase II Trial of the Double Epigenetic Priming Regimen Including Chidamide and Decitabine for Relapsed/Refractory Acute Myeloid Leukemia.",
"title_normalized": "a phase ii trial of the double epigenetic priming regimen including chidamide and decitabine for relapsed refractory acute myeloid leukemia"
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"abstract": "In addition to morbidity and mortality rate per se, COVID-19 outbreak leads to potential 'side effects', which are difficult to evaluate and predict. Lung transplantation is a consolidated treatment for end-stage chronic lung disease requiring significantly demanding management. Deciding whether to keep transplant programmes open during an epidemic of this size is not easy, as immunosuppressed subjects face the risk of infection and related mortality. Additionally, there is a chance for the patient's standard care process to be compromised.\nWe report the case of a patient undergoing bilateral lung transplantation during the explosion of COVID-19 epidemic in Lombardy; he died from definite early acute antibody-mediated rejection, clinically (persistent high fever, unresponsive to treatment) and radiologically mimicking viral pneumonia but persistently negative for SARS-CoV-2.\nThe diagnosis was difficult given this atypical presentation, confounded by global scenario. Grafts were procured from a donation after circulatory death donor in an uncontrolled setting and a donor-recipient transmission was possible. Our institute became a COVID-Hospital right during the first post-transplantation days. Radiological imaging had the same features of SARS-CoV-2 pneumonia.\nThis is the first report of lung transplantation of the COVID-19 era in Europe. Our extremely fragile patient was COVID-19 free up to the end. Donor-recipient transmission is conceivable, but the risk should be assessed with respect to waiting list mortality. Ultimately, treating COVID-19 patients can be a resource-consuming activity but we decided to keep our centre open.",
"affiliations": "Thoracic Surgery and Lung Transplantation Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico of Milan, Italy; University of Milan, Italy. Electronic address: alessandro.palleschi@unimi.it.;Thoracic Surgery and Lung Transplantation Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico of Milan, Italy; University of Milan, Italy.;Internal Medicine Department, Respiratory Unit and Adult Cystic Fibrosis Center, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico of Milan, Italy.;Pathology Unit, Center - Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico of Milan, Italy.;North Italy Transplant Program (NITp), Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico of Milan, Italy.;University of Milan, Italy; Infectious Diseases Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico of Milan, Italy.;University of Milan, Italy; Internal Medicine Department, Respiratory Unit and Adult Cystic Fibrosis Center, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico of Milan, Italy.;Thoracic Surgery and Lung Transplantation Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico of Milan, Italy; University of Milan, Italy.",
"authors": "Palleschi|Alessandro|A|;Rosso|Lorenzo|L|;Morlacchi|Letizia Corinna|LC|;Del Gobbo|Alessandro|A|;Ramondetta|Miriam|M|;Gori|Andrea|A|;Blasi|Francesco|F|;Nosotti|Mario|M|",
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"fulltext": "\n==== Front\nInt J Surg Case Rep\nInt J Surg Case Rep\nInternational Journal of Surgery Case Reports\n2210-2612\nElsevier\n\nS2210-2612(20)30983-4\n10.1016/j.ijscr.2020.10.105\nCase Report\nEarly acute rejection after lung transplantation mimicking viral pneumonia in the middle of COVID-19 pandemic: A case report\nPalleschi Alessandro alessandro.palleschi@unimi.it\nab⁎\nRosso Lorenzo ab\nMorlacchi Letizia Corinna c\nDel Gobbo Alessandro d\nRamondetta Miriam e\nGori Andrea bf\nBlasi Francesco bc\nNosotti Mario ab\na Thoracic Surgery and Lung Transplantation Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico of Milan, Italy\nb University of Milan, Italy\nc Internal Medicine Department, Respiratory Unit and Adult Cystic Fibrosis Center, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico of Milan, Italy\nd Pathology Unit, Center - Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico of Milan, Italy\ne North Italy Transplant Program (NITp), Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico of Milan, Italy\nf Infectious Diseases Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico of Milan, Italy\n⁎ Corresponding author at: Thoracic Surgery and Lung Transplantation Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122, Milan, Italy. alessandro.palleschi@unimi.it\n28 10 2020\n2020\n28 10 2020\n77 8085\n26 9 2020\n22 10 2020\n22 10 2020\n© 2020 The Authors\n2020\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nHighlights\n\n• An atypical clinical presentation of early antibody-mediated rejection in COVID era.\n\n• The radiological features mimicked SARS-CoV2 pneumonia, but tests were negative.\n\n• This is the first report of lung transplantation in the COVID era in Europe.\n\n• Decide whether to keep lung transplantation programmes open in a COVID Hospital.\n\nIntroduction\n\nIn addition to morbidity and mortality rate per se, COVID-19 outbreak leads to potential ‘side effects’, which are difficult to evaluate and predict. Lung transplantation is a consolidated treatment for end-stage chronic lung disease requiring significantly demanding management. Deciding whether to keep transplant programmes open during an epidemic of this size is not easy, as immunosuppressed subjects face the risk of infection and related mortality. Additionally, there is a chance for the patient’s standard care process to be compromised.\n\nPresentation of case\n\nWe report the case of a patient undergoing bilateral lung transplantation during the explosion of COVID-19 epidemic in Lombardy; he died from definite early acute antibody-mediated rejection, clinically (persistent high fever, unresponsive to treatment) and radiologically mimicking viral pneumonia but persistently negative for SARS-CoV-2.\n\nDiscussion\n\nThe diagnosis was difficult given this atypical presentation, confounded by global scenario. Grafts were procured from a donation after circulatory death donor in an uncontrolled setting and a donor-recipient transmission was possible. Our institute became a COVID-Hospital right during the first post-transplantation days. Radiological imaging had the same features of SARS-CoV-2 pneumonia.\n\nConclusions\n\nThis is the first report of lung transplantation of the COVID-19 era in Europe. Our extremely fragile patient was COVID-19 free up to the end. Donor-recipient transmission is conceivable, but the risk should be assessed with respect to waiting list mortality. Ultimately, treating COVID-19 patients can be a resource-consuming activity but we decided to keep our centre open.\n\nAbbreviations\n\nDSA, donor-specific antibodies\nNIV, non-invasive ventilation\nDCD, donation after circulatory death\nPaO2, partial arterial oxygen pressure\nFiO2, fraction of inspired oxygen\nICU, intensive care unit\nPOD, post-operative day\nBAL, bronchoalveolar lavage\nPCR, polymerase chain reaction\nCT, computed tomography\nAMR, antibody-mediated rejection\nKeywords\n\nSARS-CoV-2\nCOVID-19\nLung transplantation\nDonation after circulatory death donor\nAcute antibody-mediated rejection\nCase report\n==== Body\n1 Introduction\n\nThe first certified Coronavirus COVID-19 case in Italy was diagnosed on February 18th, 2020 [1]. The initial epicentre was Lombardy, from where the virus has spread rapidly throughout the country. On March 19th, Italy became the country with the highest number of confirmed deaths from SARS-CoV-2 in the world. In addition to the morbidity and mortality rate per se, an epidemic of this magnitude leads to potential ‘side effects’, which are more difficult to evaluate and predict. Lung transplantation is a consolidated treatment for end-stage chronic lung disease and requires significantly demanding management. Deciding whether to close or keep transplant programmes open during an outbreak of this size is not easy, as immunosuppressed subjects face the risk of infection and related mortality. Additionally, there is a chance for the standard care process of the patient to be significantly compromised. We hereby report the challenging case of a patient who underwent bilateral lung transplantation during the explosion of COVID-19 epidemic in Lombardy and died from early acute rejection mimicking viral pneumonia. Our article is drawn up in line with the SCARE 2018 criteria [2].\n\n2 Presentation of case\n\nWe present the case of a 31-year-old man with end-stage respiratory disease secondary to cystic fibrosis (CF), who underwent bilateral lung transplantation. The patient had been listed one year earlier: blood group was 0 and latest lung allocation score was 40.32. No pretransplant donor-specific antibodies (DSA) were identified. The patient suffered from Pseudomonas aeruginosa and Mycobacterium kansasii chronic colonization that caused frequent acute exacerbations (Fig. 1). He also required oxygen therapy during exercise and non-invasive ventilation (NIV). The lungs were procured on February 21st, 2020 from an uncontrolled donation after circulatory death (DCD) donor, following the technical protocol previously reported [3]. The donor was a 64-year-old non-smoker man with hypertension. The chest x-rays and bronchoscopy were negative for opacity and secretions. The ABO group was identical to the recipient’s and pre-transplant crossmatch test was negative. Lungs were flushed 225 min after the witnessed cardiac arrest. After the usual ex-vivo lung perfusion assessment (final PaO2/FiO2 ratio: 489), the grafts were deemed suitable for transplantation. No extracorporeal support was needed during surgery, but bilateral bronchorrhea occurred shortly after the closure of the clamshell incision. Invasive mechanical ventilation lasted 24 h postoperatively. The patient was then supported with NIV. Primary graft dysfunction was graded at level 2, 1 and 1 after 24, 48 and 72 h, respectively. In addition to usual immunosuppressive (tacrolimus, steroids, azathioprine) and prophylactic (voriconazole, ganciclovir) protocols, ceftazidime and colistin were administered according to the patient’s latest sputum culture, and antibiotics sensitivity. Specific therapy for Mycobacterium (ethambutol, rifampin, azithromycin) was continued. The recipient was transferred from the intensive care unit (ICU) to the ward on post-operative day (POD) 3. On the same night, he developed high fever without chills. Since the microbiological analyses of the donor were negative, a bronchoalveolar lavage (BAL) on POD 4 and a naso-pharyngeal swab on the following day were performed to rule out COVID-19. As the SARS-CoV-2 PCR test was negative, vancomycin was added to target potential Gram-positive pathogens. In addition, due to the confirmation of bronchial recolonization from the previous Pseudomonas strain, we switched from ceftazidime to ceftolozane/tazobactam. Despite the adjustment of antibiotic therapy, no clinical improvement was observed, with persistent hyperpyrexia (38–39 °C) and mild respiratory failure (PaO2/FiO2 ratio: 200–250). The daily chest radiographs showed unchanged findings: ill-defined bilateral confluent diffuse airspace opacities were initially interpreted as ischemia-reperfusion damage, but the progressive increase proved otherwise (Fig. 2). These assessments together with the general uncontrolled spread of SARS-CoV-2 cases in Lombardy and, specifically, in our institute, fuelled the suspicion about COVID-19, despite the negative SARS-CoV-2 PCR test on BAL. This hypothesis was reinforced by the results of the total-body computed tomography (CT) performed on POD 10 (Fig. 3). BAL and swab were immediately repeated but results were still negative for SARS-CoV-2. Therefore, on POD 11 a trans-thoracic pulmonary fine-needle aspiration for microbiological tests and a core-biopsy under ultrasound guidance were performed to the bedside for histological characterization. The pathology revealed a moderate/severe acute rejection as well as the presence of C4d staining (Fig. 4). The diagnosis was confirmed by blood tests that showed elevated anti HLA-DQ7 donor specific antibodies. Pulsed-dose methylprednisolone was administered for 3 days, followed by steroid tapering. After a moderate clinical improvement, which lasted for less than 48 h, the patient's conditions worsened again, with high fever and dyspnoea. Bronchoscopy with BAL was repeated and resulted negative for bacteria and viruses except for the previously known Pseudomonas aeruginosa strain. A new total-body CT showed an unchanged picture. We repeated a cycle of high-dose steroids while preparing the patient for plasmapheresis. On POD 22, the clinical condition of the patient deteriorated, requiring intubation. Therefore, the patient was tested again for COVID-19 on BAL. The result read negative once again. On POD 23, the patient underwent plasmapheresis in the ICU, but he died the following night due to multiorgan failure. Fig. 5 summarizes the clinical course of the patient.Fig. 1 Recipient’s chest CT scan pre-transplantation.\n\nFig. 1\n\nFig. 2 Post-transplantation chest x-rays.\n\nPOD: postoperative day.\n\nFig. 2\n\nFig. 3 Chest CT scan on POD10.\n\nFig. 3\n\nFig. 4 Lung core-biopsy stained glass slides.\n\nAcute alveolar damage with hyaline membrane deposition in the alveolar lumina, associated with patchy interstitial acute e chronic infiltrate, showing plurifocal infiltration of the bronchiolar wall and epithelium and plurifocal venulitis. C4d immunohistochemical staining showed a diffuse, weak staining of the capillary walls.\n\nFig. 4\n\nFig. 5 Clinical course of the patient.\n\nBAL: bronchoalveolar lavage; CT: computed tomography; FNAB: fine needle aspiration biopsy.\n\nFig. 5\n\n3 Discussion\n\nThe patient suffered from clinical definite acute antibody-mediated rejection (AMR) no responsive to treatment [4]. The clinical presentation consisted in persistent, drug-resistant high fever. To the best of the authors’ knowledge, such severe hyperthermia associated to AMR has not being reported so far [5]. The diagnosis of lung AMR was especially difficult given both the atypical picture and the complexity of the global scenario. The phenomenon of graft re-colonization after transplantation is well known. In patients suffering from CF, airway-colonizing bacteria and their antibiotic sensitivity are perfectly known prior to transplantation, resulting usually in an effective and comfortable therapeutic management. On the other hand, the re-colonization can be particularly alarming, considering that the very isolation of Pseudomonas aeruginosa is considered an independent factor associated with an increased risk of developing DSA [6]. More importantly, we had to deal with the COVID-19 outbreak, which escalated in this time frame, considering how it presents high unresponsive fever and lung involvement as the most frequent symptoms. Grafts were procured from a DCD donor in an uncontrolled setting. Up to his decease, the donor had displayed no fever nor dyspnoea. In this scenario, one must take into account that COVID-19 might be asymptomatic, especially in its early stages and the possibility of a donor-recipient transmission could not be excluded. Our institute was converted into a COVID-Hospital during the early post-transplant period. Despite the implementation of additional protective measures for transplant patients, the risk of contagion was substantial. Ultimately, radiological imaging requires special awareness. Initial chest x-rays showed diffuse opacities, the typical pattern of pulmonary oedema. The subsequent daily chest radiographs revealed diffuse bilateral pulmonary infiltrates with progressive consolidation, with the exception of upper areas. The CT at POD 10 confirmed an extensive bilateral pulmonary involvement, consisting of limited ground glass opacities (with or without intralobular septal thickening combined) with extended parenchymal consolidation with air bronchogram. The apical regions, the lingula and the middle lobe were relatively spared. There was no mediastinal lymphadenopathy, no cavitation and no pleural effusion. Those findings were consistent with advanced cases of SARS-CoV-2 pneumonia, as reported in literature [7]. Clearly, a complete CT-sequence history could have helped, in relation to the presence of multiple peripheral ground-glass images, typical of the earliest stages of the infection. To this date, there are limited reports regarding the radiological findings of AMR; data regarding management are also insufficient. Diagnostic criteria for definite AMR include histopathologic features, presence of DSA and positive C4d staining, exclusion of other causes [4]. Notably, we successfully performed the biopsy by trans-thoracic approach instead of the customary trans-bronchial one, given the patient’s condition.\n\n4 Conclusions\n\nTo the best of the authors’ knowledge, this is the first report of lung transplantation in the COVID-19 era in Europe. Caution is required when assessing whether to perform transplants in the context of the current COVID-19 pandemic. Transplant recipients are not necessarily at higher risk of SARS-CoV-2 infection. D’Antiga suggests that immunosuppression could even have protective effects, as the majority of Coronavirus-related injuries are caused by the host’s own immune response [8]. One must bear in mind that our patient, while being extremely fragile, tested COVID-19 free up to his death. Donor-recipient transmission has not been reported yet; nevertheless, such a risk should be assessed in consideration of the waiting list mortality rate. Treating COVID-19 patients can be a resource-consuming activity for centres and their staff, as an outbreak reduces hospital capacity and the healthcare manpower available for transplantation. Closing transplant centres may seem the only viable option [9]. We strongly believe that it is not the right way and we decided to preserve our activity. One must take into account that COVID-19 targets lungs, resulting in a restrictive alteration both in early and middle phases; the first transplants for this disease have already been carried out in China [10]. Health authorities should seek proper balance between the massive commitment to the pandemic and the identification of pathways reserved for the treatment of the most critical patients in need of a transplant.\n\nConflicts of interest\n\nNone.\n\nFunding\n\nNone.\n\nEthical approval\n\nThe study was approved by Ethics committee of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano. Mortality risk factors in patients waiting and submitted to lung transplant. Ref. n° 181 (24/01/2017).\n\nConsent\n\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nRegistration of research studies\n\nN/A.\n\nGuarantor\n\nAlessandro Palleschi, Mario Nosotti.\n\nProvenance and peer review\n\nNot commissioned, externally peer-reviewed.\n\nCRediT authorship contribution statement\n\nAlessandro Palleschi: Conceptualization, Formal analysis, Investigation, Data curation, Writing - original draft, Writing - review & editing, Visualization. Lorenzo Rosso: Resources, Data curation, Writing - original draft, Writing - review & editing, Visualization, Supervision. Letizia Corinna Morlacchi: Resources, Data curation, Writing - review & editing. Alessandro Del Gobbo: Resources, Data curation, Writing - review & editing. Miriam Ramondetta: Resources, Writing - review & editing. Andrea Gori: Writing - original draft, Writing - review & editing. Francesco Blasi: Writing - original draft, Writing - review & editing. Mario Nosotti: Writing - original draft, Writing - review & editing, Visualization, Supervision, Project administration.\n\nAcknowledgment\n\nNot applicable.\n==== Refs\nReferences\n\n1 Ministero della Salute d’Italia Covid 19. La situazione in Italia 2000 http://www.salute.gov.it/portale/nuovocoronavirus/dettaglioContenutiNuovoCoronavirus.jsp?lingua=italiano&id=5351&area=nuovoCoronavirus&menu=vuoto. Accessed 8 May 2020\n2 Agha R.A. Borrelli M.R. Farwana R. Koshy K. Fowler A.J. Orgill D.P. The SCARE 2018 statement: updating consensus surgical CAse REport (SCARE) guidelines Int. J. Surg. 60 2018 132 136 30342279\n3 Valenza F. Citerio G. Palleschi A. Successful transplantation of lungs from an uncontrolled donor after circulatory death preserved in situ by alveolar recruitment maneuvers and assessed by ex vivo lung perfusion Am. J. Transplant. 16 4 2016 1312 1318 10.1111/ajt.13612 26603283\n4 Levine D.J. Glanville A.R. Aboyoun C. Antibody-mediated rejection of the lung: a consensus report of the International Society for Heart and Lung Transplantation J. Heart Lung Transplant. 35 4 2016 397 406 10.1016/j.healun.2016.01.1223 27044531\n5 Parulekar A.D. Kao C.C. Detection, classification, and management of rejection after lung transplantation J. Thorac. Dis. 11 Suppl 14 2019 1732 1739 10.21037/jtd.2019.03.83\n6 Kulkarni H.S. Tsui K. Sunder S. Pseudomonas aeruginosa and acute rejection independently increase the risk of donor-specific antibodies after lung transplantation Am. J. Transplant. 20 4 2020 1028 1038 10.1111/ajt.15687 31677358\n7 Salehi S. Abedi A. Balakrishnan S. Coronavirus Disease 2019 (COVID-19): a systematic review of imaging findings in 919 patients Am. J. Roentgenol. 14 2020 1 7 10.2214/AJR.20.23034 [Epub ahead of print]\n8 D’Antiga L. Coronaviruses and immunosuppressed patients. The facts during the third epidemic Liver Transplant. 2020 10.1002/lt.25756 [Epub ahead of print]\n9 Chui A.K. Rao A.R. Chan H.L. Impact of severe acute respiratory syndrome on liver transplantation service Transplant. Proc. 36 October (8) 2004 2302 2303 10.1016/j.transproceed.2004.08.018 15561228\n10 Chen J.Y. Qiao K. Liu F. Lung transplantation as therapeutic option in acute respiratory distress syndrome for COVID-19-related pulmonary fibrosis Chin. Med. J. (Engl.) 2020 10.1097/CM9.0000000000000839 1 Apr. [Epub ahead of print]\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2210-2612",
"issue": "77()",
"journal": "International journal of surgery case reports",
"keywords": "AMR, antibody-mediated rejection; Acute antibody-mediated rejection; BAL, bronchoalveolar lavage; COVID-19; CT, computed tomography; Case report; DCD, donation after circulatory death; DSA, donor-specific antibodies; Donation after circulatory death donor; FiO2, fraction of inspired oxygen; ICU, intensive care unit; Lung transplantation; NIV, non-invasive ventilation; PCR, polymerase chain reaction; POD, post-operative day; PaO2, partial arterial oxygen pressure; SARS-CoV-2",
"medline_ta": "Int J Surg Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101529872",
"other_id": null,
"pages": "80-85",
"pmc": null,
"pmid": "33157338",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "30342279;32196933;15561228;27044531;26603283;32251003;31677358;31632750;32174129",
"title": "Early acute rejection after lung transplantation mimicking viral pneumonia in the middle of COVID-19 pandemic: A case report.",
"title_normalized": "early acute rejection after lung transplantation mimicking viral pneumonia in the middle of covid 19 pandemic a case report"
} | [
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"companynumb": "IT-ASTELLAS-2020US046332",
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"activesubstance": {
"activesubstancename": "VORICONAZOLE"
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"abstract": "We studied 72 consecutive simultaneous pancreas kidney transplant (SPKT) recipients. There were 14 patients with positive pretransplant cross-matches (positive CDC- B cell and/or positive flow T or B cross-match). The control group included all 58 SPKT recipients with a negative crossmatch. The study group received induction with low dose intravenous immunoglobulin (IVIg), rabbit antithymocyte globulin (rATG; total dose 6 mg/kg), or alemtuzumab (30 mg single dose) and maintenance with tacrolimus, mycophenolate mofetil (MMF), and corticosteroids. The control group was treated similarly, but with steroid avoidance and no IVIg. Biopsy-proven acute rejection (BPAR) of the kidney allograft occurred in 7 study patients (50%) compared with 10% in the control group (P = .022). One patient experienced acute cellular rejection (ACR); the other 6 (43%), antibody-mediated rejection (AMR). None of the cross-match negative patients had AMR (P = .001). The mean follow-up period was 18.7 months in the study group, and 18.3 months in the control group. The 1-year actuarial patient survival was 91.7% in the study group and 97% in the control group. Kidney allograft survival was 91.7% in the study group and 95.2% in the control group. Pancreas allograft survival was 76.9% in study group and 89.6% in the control group (P = .088). We concluded that patients with a positive pretransplant CDC-B cross-match and/or positive flow cross-match have an increased risk of AMR; more intensive desensitization is needed with low-dose IVIg and induction with either rATG or alemtuzumab.",
"affiliations": "Division of Nephrology and Hypertension and Transplant Medecine, The Mayo Clinic, Rochester, Minnesota 55905, USA.",
"authors": "Heilman|R L|RL|;Chakkera|H|H|;Mazur|M|M|;Petrides|S|S|;Moss|A|A|;Mekeel|K|K|;Mulligan|D|D|;Reddy|K S|KS|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D000961:Antilymphocyte Serum; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D000074323:Alemtuzumab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2008.08.154",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "41(1)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D000961:Antilymphocyte Serum; D004359:Drug Therapy, Combination; D005500:Follow-Up Studies; D006085:Graft Survival; D006650:Histocompatibility Testing; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D016035:Pancreas Transplantation; D012189:Retrospective Studies; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "303-6",
"pmc": null,
"pmid": "19249540",
"pubdate": "2009",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Outcomes of simultaneous kidney-pancreas transplantation with positive cross-match.",
"title_normalized": "outcomes of simultaneous kidney pancreas transplantation with positive cross match"
} | [
{
"companynumb": "NVSC2020US017553",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
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"abstract": "Dear Editors,Hypocalcemia is not unusual in patients hospitalized for critical illness and has also been described after general surgery in addition to head and neck surgical procedures 1 2 3. Hypocalcemic events commonly occur in the setting of massive blood transfusion, albumin deficiency, vitamin D deficiency, and/or hypomagnesemia. In the absence of these factors, only slight decreases in calcium levels within the normal range have been reported during surgical procedures 1. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) causing asymptomatic hypocalcemia has only been reported in two previous studies 4 5. The etiology is unclear. We here report a patient who developed severe symptomatic hypocalcemia likely as a result of a profound inflammatory reaction with transient hypoparathyroidism after HIPEC.",
"affiliations": "Fox Chase Cancer Center, Philadelphia, USA.;Fox Chase Cancer Center, Philadelphia, USA.;Fox Chase Cancer Center, Philadelphia, USA.;Fox Chase Cancer Center, Philadelphia, USA.",
"authors": "Tharmalingam|Senthuran|S|;Reddy|Sanjay|S|;Sharda|Pankaj|P|;Koch|Christian A|CA|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1055/a-1220-6971",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0018-5043",
"issue": "52(9)",
"journal": "Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme",
"keywords": null,
"medline_ta": "Horm Metab Res",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003110:Colonic Neoplasms; D003131:Combined Modality Therapy; D065426:Cytoreduction Surgical Procedures; D005260:Female; D006801:Humans; D000084262:Hyperthermic Intraperitoneal Chemotherapy; D006996:Hypocalcemia; D007011:Hypoparathyroidism; D011379:Prognosis",
"nlm_unique_id": "0177722",
"other_id": null,
"pages": "689-690",
"pmc": null,
"pmid": "32770533",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe Hypocalcemia and Transient Hypoparathyroidism After Hyperthermic Intraperitoneal Chemotherapy.",
"title_normalized": "severe hypocalcemia and transient hypoparathyroidism after hyperthermic intraperitoneal chemotherapy"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-20-05375",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "LEUCOVORIN"
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"abstract": "BACKGROUND Autoimmune heparin-induced thrombocytopenia (aHIT) refers to a condition, in which antiplatelet factor-4 (PF4) antibodies activate platelets even in the absence of heparin (heparin independent platelet activation). This is a severe hypercoagulable state triggering massive thrombin storm needing additional therapies and aggressive anticoagulation apart from stopping heparin. Thrombocytopenia in these cases seems to be very severe and prolonged compared to classic HIT and poses additional clinical challenges in terms of anticoagulation management. Recently, direct oral anticoagulants (DOACs) seem to be an attractive option in the management of HIT as an alternative to vitamin K antagonists (VKA). CASE REPORT We describe a case of a 55-year African American male who presented with pleuritic chest pain and was found to have worsening kidney disease. Clinical and electrocardiogram findings suggested uremic pericarditis, and dialysis was warranted. After 5 days of exposure to heparin flushes during dialysis, the patient developed thrombocytopenia, and subsequently HIT was diagnosed. Argatroban was started initially, however, his platelets count continued to drop, and he developed acute deep venous thrombosis of the right lower leg. IVIG (intravenous immunoglobulin) was started and his platelet count started to improve after several days. The patient was discharged on Eliquis and his platelet count returned to normal levels after 3 months. CONCLUSIONS This case emphasizes the challenge managing HIT, a condition that has a high rate of complications. Several studies have reported platelet recovery with IV immunoglobulin when standard therapies fail. Recent evidence also supports the safety and efficacy of DOACs in offering a simplified way of managing these patients, especially in outpatient settings.",
"affiliations": "Division of Hematology and Medical Oncology, Brookdale University Hospital, Brooklyn, NY, USA.;Division of Hematology and Medical Oncology, Brookdale University Hospital, Brooklyn, NY, USA.;Division of Hematology and Medical Oncology, Brookdale University Hospital, Brooklyn, NY, USA.;Division of Hematology and Medical Oncology, Brookdale University Hospital, Brooklyn, NY, USA.",
"authors": "Ramachandran|Preethi|P|;Farag|Fady|F|;Morcus|Rewais|R|;Gotlieb|Vladimir|V|",
"chemical_list": "D000925:Anticoagulants; D006493:Heparin",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.914575",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3085057610.12659/AJCR.914575914575ArticlesAutoimmune Heparin-Induced Thrombocytopenia: Treatment Obstacles and Challenging Length of Stay Ramachandran Preethi ABCDEFGFarag Fady BCEFMorcus Rewais FGotleib Vladimir ACDDivision of Hematology and Medical Oncology, Brookdale University Hospital, Brooklyn, NY, U.S.A.Authors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Preethi Ramachandran, e-mail: drpreethiram@hotmail.com2019 09 3 2019 20 310 313 11 12 2018 02 1 2019 © Am J Case Rep, 20192019This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 55\n\nFinal Diagnosis: Auto-immune heparin thrombocytopenia -Treatment obstacles and challenging length of stay\n\nSymptoms: Thrombocytopenia • thrombosis\n\nMedication: —\n\nClinical Procedure: IVIG\n\nSpecialty: Hematology\n\nObjective:\nUnusual clinical course\n\nBackground:\nAutoimmune heparin-induced thrombocytopenia (aHIT) refers to a condition, in which antiplatelet factor-4 (PF4) antibodies activate platelets even in the absence of heparin (heparin independent platelet activation). This is a severe hypercoagulable state triggering massive thrombin storm needing additional therapies and aggressive anticoagulation apart from stopping heparin. Thrombocytopenia in these cases seems to be very severe and prolonged compared to classic HIT and poses additional clinical challenges in terms of anticoagulation management. Recently, direct oral anticoagulants (DOACs) seem to be an attractive option in the management of HIT as an alternative to vitamin K antagonists (VKA).\n\nCase Report:\nWe describe a case of a 55-year African American male who presented with pleuritic chest pain and was found to have worsening kidney disease. Clinical and electrocardiogram findings suggested uremic pericarditis, and dialysis was warranted. After 5 days of exposure to heparin flushes during dialysis, the patient developed thrombocytopenia, and subsequently HIT was diagnosed. Argatroban was started initially, however, his platelets count continued to drop, and he developed acute deep venous thrombosis of the right lower leg. IVIG (intravenous immunoglobulin) was started and his platelet count started to improve after several days. The patient was discharged on Eliquis and his platelet count returned to normal levels after 3 months.\n\nConclusions:\nThis case emphasizes the challenge managing HIT, a condition that has a high rate of complications. Several studies have reported platelet recovery with IV immunoglobulin when standard therapies fail. Recent evidence also supports the safety and efficacy of DOACs in offering a simplified way of managing these patients, especially in outpatient settings.\n\nMeSH Keywords:\nAnticoagulantsHeparinImmunoglobulins, IntravenousThrombocytopenia\n==== Body\nBackground\nHeparin induced thrombocytopenia (HIT) is a prothrombotic condition caused by antibodies capable of recognizing cationic platelet factor 4 complexes bound to anionic heparin and forms PF4/heparin/IgG immune complexes on the platelet surfaces and cross-link with platelet FcgIIa receptors and activates platelets in a heparin-dependent fashion. Autoimmune HIT (aHIT) refers to certain variants of HIT that behave differently from the classic form. The antibodies in these patients activate platelets even in heparin absence. These patients also tend to present with severe thrombocytopenia (platelet count of <20×10 L−1) which may persist for weeks to months despite discontinuing heparin. Disseminated intravascular coagulation (DIC) and microvascular thrombosis may also be associated features of this variant. Baseline partial thromboplastin time (PTT) may be elevated when associated with DIC which may pose difficulty in using standard anticoagulation requiring PTT monitoring. Hence anticoagulants independent of activated PTT (aPTT) monitoring like fondaparinux, danaparoid and direct oral anticoagulants are used for long term management. Since aHIT is a severe hypercoagulable state, triggering massive thrombin generation, alternative therapy like intravenous immunoglobulin (IVIG) and aggressive anticoagulation remains the cornerstone of treatment and heparin cessation alone does not interrupt the pathogenesis. Thrombocytopenia may be severe and more prolonged when compared to classical HIT and hence should not preclude starting and continuing anticoagulation long-term as risk of thrombosis is high when compared to risk of bleeding.\n\nCase Report\nA 55-year-old African American male with a past medical history significant for alcohol abuse, cocaine abuse, and a 30-pack-year smoking history was admitted to the emergency department due to a 3-day history of dyspnea, hemoptysis, and left-sided pleuritic chest pain. In addition, his electrocardiogram was remarkable for ST elevations noted on anterior and inferior leads along with elevated blood urea nitrogen (BUN) of 104 mg/dL and creatinine of 10.70 mg/dL, that continued to rise during the hospital course. With suspicion of chronic kidney disease and uremic pericarditis, hemodialysis was newly initiated in the patient with exposure to unfractionated heparin intravascular flush. Heparin doses of 5000 U/mL were used during hemodialysis sessions over a period of 8 days. Five days after exposure to heparin, clotting of the venous line was noted 1.5 hours into the dialysis session and the patient’s platelet count showed a precipitous drop. Prior to hemodialysis with heparin flush, his platelet count was 253 000/μL, which steadily decreased to 169 000/μL and then to 50 000/μL by the tenth day.\n\nDue to the high suspicion for HIT, heparin flushes were withheld from further dialysis sessions and peripheral smear, platelet factor-4 (PF-4) antibody, and serotonin release assay were evaluated. A peripheral smear was unremarkable for schistocytes or platelet clumps. However, PF-4 antibodies were reported to be strongly positive with a value of 2.493 OD. Serotonin release assay was also positive thereby confirming the diagnosis of HIT.\n\nThe patient was started on argatroban, initially at 0.5 mcg/kg/min when his platelet count was 16 000/μL which then was increased subsequently to 2.5 mcg/kg/min over time when no evidence of bleeding was observed. However, his platelet counts did not show any improvement and the patient developed an acute deep venous thrombosis in the right lower extremity despite 6 days of argatroban therapy. Suspicion of autoimmune-mediated HIT was high and intravenous immunoglobulin (IVIG) was administered to offset the decline. The patient’s platelet counts showed a very slow improvement after several days, but since the patient remained stable and PTT was in therapeutic range, he was discharged on apixaban for outpatient management. Finally, platelet counts returned to baseline after 3 months of starting IVIG (Figure 1).\n\nOur case was unique in that it showed the failure of standard therapy and a response with IVIG. Our case is the first one to show a very slow response to IVIG, which has not been previously reported in literature studies. Our case also emphasizes the importance of starting anticoagulation therapy even in the setting of severe thrombocytopenia and this case is also the first of its kind where Eloquis was used for anticoagulation rather than warfarin.\n\nDiscussion\nAutoimmune HIT (aHIT) refers to a range of syndromes that share a common feature; the presence of antiPF4 antibodies which causes platelet activation even in the absence of heparin (heparin-independent platelet activation). The syndromes which involve this phenomenon include spontaneous HIT, delayed onset HIT, persisting HIT, HIT induced by exposure to heparin “flushes”, fondaparinux-associated HIT, and HIT associated DIC [1,2]. Sometimes severe thrombocytopenia (platelet count of <20×109/L−) may be one of the presenting feature which may persists for weeks and is often accompanied by DIC and microvascular thrombosis [1,2]. Although heparin cessation is the cornerstone of management of HIT, in the case of aHIT, it does not interrupt the pathogenesis. Treatment options in acute HIT have always focused on either on-label therapies such as argatroban or danaparoid, or off-label use of fondaparinux or bivalirudin. When long-term anticoagulation is needed due to associated thrombosis, then transition to vitamin K antagonist (VKA) such as warfarin is made when platelet count recovers. Due to an increased risk of warfarin associated microthrombosis, earlier transition to VKA antagonist should be avoided. In recent times, there has been an increasing trend in the use of direct oral anticoagulants (DOACs) such as direct factor Xa inhibitors which includes apixaban, rivaroxaban, and edoxaban, or direct thrombin inhibitors such as dabigatran. A few attractive reasons to consider using these agents are the absence of any immunological interactions between them and HIT antibodies, the absence of reduction in protein C during acute phase of HIT thereby reducing the risk of microthrombosis, and lastly the quick transition from parenteral therapy to oral DOACs without waiting for platelet count recovery thereby reducing the longer hospitalization otherwise required when transitioning to VKA antagonists.\n\nPatients with aHIT require full dose anticoagulation, and especially for a longer duration due to associated thrombosis. Severe thrombocytopenia usually associated with aHIT is not a contraindication for anticoagulation therapy and indeed patients require aggressive anticoagulation therapy to control the hypercoagulable state. An interesting finding in aHIT patients seems to be prolonged thrombocytopenia despite using alternative anticoagulation therapy. This represents the platelet activating effects of aHIT antibodies rather than ineffective anticoagulation. Hence measuring fibrinogen and D-dimers and sometimes measuring levels of anticoagulants, if possible, may be helpful in assessing the adequacy of anticoagulation. Dose increase is made based on the DIC parameters and the platelet counts.\n\nNot much data is available on the use of DOACs in aHIT, although a few case reports show effectiveness of rivaroxaban in these cases. Poudel et al. reported a case wherein spontaneous HIT syndrome was observed after knee replacement surgery which showed failure of direct thrombin inhibitor (DTI) therapy [3], as was found in the case with our patient. Alternatively, some case reports have described the efficacy of rivaroxaban in controlling hypercoagulability in aHIT patients who previously failed argatroban or fondaparinux. One of the possible disadvantages may be the fluctuating levels of DOACs during the first 24 hours, which may be overcome by increasing the dose and frequency.\n\nWarkentin et al. described the identification and classification of HIT patients treated with a DOAC [4]. The study involved 64 patients in total, of which 46 patients who had a probable HIT were treated with rivaroxaban [5–12]. Of these 46 patients, 25 patients were started on rivaroxaban as primary therapy and 21 patients as secondary therapy. In all, 2.2% of these patients had possible progression of thrombosis (central venous catheter-associated deep venous thrombosis resolved after catheter removal and during continued therapy with rivaroxaban). None of the 46 patients had any complications of major bleed whilst on rivaroxaban. Twenty-three patients were randomized to receive either apixaban (n=12) [7,13–15] or dabigatran (n=11) [8,16–20]. Possible thrombotic event was reported in 1 patient whilst on DOAC (multiple strokes, which might have been present before starting dabigatran).\n\nThe use of IVIG has been introduced for the management of aHIT, with the concept of interrupting the pathogenesis in aHIT. Tvito et al. reported abrupt platelet count recovery in 12 patients after administration of IVIG. One of these patients had a complication of recurrence of thrombocytopenia and was treated with a second dose of IVIG leading to complete recovery [21]. Plasma exchange theoretically would reduce aHIT antibodies thereby improving outcomes in aHIT; however, there is not enough evidence to support this technique. Our case was complex in that the platelet counts was very low when anticoagulation was initiated and there was also a delayed response to IVIG therapy for up to 3 months, which has not been reported so far.\n\nConclusions\nIn summary, aHIT is a devastating hypercoagulable state which continues to remain an important cause of mortality and morbidity in hospitalized patients. It needs special laboratory diagnostics and special treatment options. Differentiating HIT from aHIT is important when standard therapy fails, as immediate commencement of alternative therapy like IVIG is needed to reduce the mortality due to the high risk of complications associated with it when compared with classic HIT. Aggressive anticoagulation is often required to control the massive thrombin generation, and severe thrombocytopenia is not a contraindication for starting therapy. Adequate anticoagulation is achieved with non-PTT dependent rather than PTT dependent anticoagulants due to the associated DIC confounding the baseline PTT. DOAC offer a reasonable and practical option for these patients, although not much data is available to support their usage. Plasma exchange would theoretically reduce the burden of aHIT antibodies, but further studies are required to clarify its role.\n\nFigure 1. Trend in platelet counts depicted from the time of heparin exposure until platelet recovery.\n==== Refs\nReferences:\n1. Greinacher A Selleng K Warkentin TE Autoimmune heparin-induced thrombocytopenia J Thromb Haemost 2017 15 2099 114 28846826 \n2. Warkentin TE Pai M Linkins LA Direct oral anticoagulants for treatment of HIT: Update of Hamilton experience and literature review Blood 2017 130 1104 13 28646118 \n3. Poudel DR Ghimire S Dhital R Spontaneous HIT syndrome post-knee replacement surgery with delayed recovery of thrombocytopenia: A case report and literature review Platelets 2017 28 614 20 28856946 \n4. Kopolovic I Warkentin TE Progressive thrombocytopenia after cardiac surgery in a 67-year-old man CMAJ 2014 186 929 33 24756626 \n5. Kopolovic I Warkentin TE Progressive thrombocytopenia after cardiac surgery in a 67-year-old man CMAJ 2014 186 12 929 33 24756626 \n6. Ng HJ Than H Teo EC First experiences with the use of rivaroxaban in the treatment of heparin-induced thrombocytopenia Thromb Res 2015 135 1 205 7 24974053 \n7. Sharifi M Bay C Vajo Z New oral anticoagulants in the treatment of heparin-induced thrombocytopenia Thromb Res 2015 135 4 607 9 25613925 \n8. Hantson P Lambert C Hermans C Rivaroxaban for arterial thrombosis related to heparin-induced thrombocytopenia Blood Coagul Fibrinolysis 2015 26 2 205 6 25255239 \n9. Abouchakra L Khabbaz Z Abouassi S Badaoui G Rivaroxaban for treatment of heparin-induced thrombocytopenia after cardiac surgery: A case report J Thorac Cardiovasc Surg 2015 150 2 e19 20 26055438 \n10. Sartori M Favaretto E Cini M Rivaroxaban in the treatment of heparin induced thrombocytopenia J Thromb Thrombolysis 2015 40 3 392 94 25804370 \n11. Casan JM Grigoriadis G Chan N Chunilal S Rivaroxaban in treatment refractory heparin induced thrombocytopenia BMJ Case Rep 2016 2016 pii: bcr2016216110 \n12. Samoš M Bolek T Ivanková J Heparin induced thrombocytopenia presenting with deep venous thrombosis and pulmonary embolism successfully treated with rivaroxaban: Clinical case report and review of current experiences J Cardiovasc Pharmacol 2016 68 5 391 94 27464495 \n13. Larsen PB Jørgensen M Friis-Hansen L Ingeberg S Apixaban used for the management of heparin-induced thrombocytopenia in a 72-year-old woman with lung cancer Clin Case Rep 2015 3 12 987 89 26732728 \n14. Delgado-García G Monreal-Robles R Gallegos-Arguijo D Marfil-Rivera J [Apixaban as therapeutic option in nephropathy patients with heparin-induced thrombocytopenia (HIT)] Gac Med Mex 2015 151 6 798 801 [in Spanish] 26581538 \n15. Kunk PR Brown J McShane M Direct oral anticoagulants in hypercoagulable states J Thromb Thrombolysis 2017 43 1 79 85 27632140 \n16. Anniccherico FJ Alonso JL Dabigatran for heparin-induced thrombocytopenia Mayo Clin Proc 2013 88 9 1036 \n17. Mirdamadi A Dabigatran, a direct thrombin inhibitor, can be a life-saving treatment in heparin induced thrombocytopenia ARYA Atheroscler 2013 9 1 112 14 23690810 \n18. Tardy-Poncet B Piot M Montmartin A Delayed-onset heparin induced thrombocytopenia without thrombosis in a patient receiving postoperative thromboprophylaxis with rivaroxaban Thromb Haemost 2015 114 3 652 54 26062524 \n19. Noel E Abbas N Skaradinskiy Y Schreiber Z Heparin-induced thrombocytopenia in a patient with essential thrombocythemia: A case-based update Case Rep Hematol 2015 2015 985253 26579318 \n20. Bircan HA Alanoglu EG Massive pulmonary embolism in a patient with heparin induced thrombocytopenia: successful treatment with dabigatran Eurasian J Med 2016 48 1 65 68 27026768 \n21. Tvito A Bakchoul T Rowe JM Severe and persistent heparin-induced thrombocytopenia despite fondaparinux treatment Am J Hematol 2015 90 675 78 25683147\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "20()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000925:Anticoagulants; D006493:Heparin; D006801:Humans; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D016553:Purpura, Thrombocytopenic, Idiopathic",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "310-313",
"pmc": null,
"pmid": "30850576",
"pubdate": "2019-03-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23690810;24001499;24756626;24974053;25255239;25613925;25683147;25804370;26055438;26062524;26579318;26581538;26732728;27026768;27464495;27520997;27632140;28646118;28846826;28856946",
"title": "Autoimmune Heparin-Induced Thrombocytopenia: Treatment Obstacles and Challenging Length of Stay.",
"title_normalized": "autoimmune heparin induced thrombocytopenia treatment obstacles and challenging length of stay"
} | [
{
"companynumb": "US-MYLANLABS-2019M1081712",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "1",
... |
{
"abstract": "While per-oral pyloromyotomy (POP) has shown promise as a novel endoscopic procedure to treat medically refractory gastroparesis, standardized care pathways are not well-defined. We aimed to compare the safety and cost of same-day discharge (SDD) after POP with inpatient stay overnight or longer.\n\n\n\nAll patients with SDD after POP between January 2016 and May 2018 were retrospectively identified from a prospectively maintained registry. Propensity scores considering gender, age, gastroparesis etiology, and American Society of Anesthesiologists (ASA) class were used to match a comparison group which stayed overnight or longer. Statistical tests included two-sample t tests for continuous variables, Fisher's exact test for categorical variables, and paired sample t tests for within-group comparisons with repeated measures.\n\n\n\nFifty-four patients who underwent POP with SDD during the study period were propensity-matched with 54 patients with inpatient recovery. The SDD cohort was 85.2% female with a mean age of 44.8 years and median ASA class 3. The etiology of gastroparesis was idiopathic in 53.7% (n = 29), diabetic in 29.6% (n = 16), and post-surgical in 11.1% (n = 6). Operative time was shorter in the SDD cohort (25.4 vs. 31.3 min, p = 0.02). The mean post-procedure recovery time was 4 h in patients with SDD and 29.3 h in the inpatient cohort (p < 0.001). There was a trend towards less readmissions with SDD (7.4% vs. 18.5%, p = 0.08). There was no increased risk of complications with SDD (1.9% vs. 3.7%, p = 0.57). Compared to inpatient recovery, the average total cost for the procedure, recovery, and all subsequent care within 30 days was 26.0% less with SDD (p < 0.001).\n\n\n\nFollowing POP, patients can be safely discharged the same day with low risk of both complications and readmission. Total costs in the complete perioperative period are significantly less with SDD compared to inpatient recovery.",
"affiliations": "Department of General Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA. landrej@ccf.org.;Department of General Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA.;Department of General Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA.;Cleveland Clinic Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.;Department of General Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA.;Department of General Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA.;Department of General Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA.",
"authors": "Landreneau|Joshua P|JP|0000-0003-4689-0793;Strong|Andrew T|AT|;Ponsky|Jeffrey L|JL|;Tu|Chao|C|;Kroh|Matthew D|MD|;Rodriguez|John H|JH|;El-Hayek|Kevin|K|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00464-019-07085-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0930-2794",
"issue": "34(7)",
"journal": "Surgical endoscopy",
"keywords": "Gastric per-oral myotomy (G-POEM); Gastroparesis; Per-oral pyloromyotomy (POP)",
"medline_ta": "Surg Endosc",
"mesh_terms": "D000328:Adult; D015331:Cohort Studies; D005260:Female; D018589:Gastroparesis; D017048:Health Care Costs; D006801:Humans; D007297:Inpatients; D008297:Male; D008875:Middle Aged; D061646:Operative Time; D010351:Patient Discharge; D010359:Patient Readmission; D011183:Postoperative Complications; D000074882:Pyloromyotomy; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "8806653",
"other_id": null,
"pages": "3153-3162",
"pmc": null,
"pmid": "31482346",
"pubdate": "2020-07",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Enhanced recovery outcomes following per-oral pyloromyotomy (POP): a comparison of safety and cost with same-day discharge versus inpatient recovery.",
"title_normalized": "enhanced recovery outcomes following per oral pyloromyotomy pop a comparison of safety and cost with same day discharge versus inpatient recovery"
} | [
{
"companynumb": "US-ALLERGAN-2024783US",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SUCRALFATE"
},
"drugadditional": "3",
"... |
{
"abstract": "To analyze the clinical features of AIDS-related Kaposi's sarcoma (AIDS-KS) patients in Xinjiang Autonomous Region and the impact of CD4 (+)T lymphocyte count, highly active antiretroviral therapy (HAART) and systemic chemotherapy on the prognosis. The clinical information of 80 AIDS-KS patients admitted in Sixth People's Hospital of Xinjiang Autonomous Region from January 2008 to August 2014 was retrospectively reviewed. Population characteristics, extent of lesions, KS progress, CD4 (+)T lymphocyte count, combined opportunistic infections, treatment and prognosis of these patients were analyzed. The 80 patients were divided into five groups according to treatment methods, including HAART, HAART + chemotherapy, chemotherapy + HAART, chemotherapy, and untreated groups. The efficacy and prognosis of the five groups were compared. Among the 80 patients, 74 (92.50%) patients were Uygur. The average age was 39.5±9.9 years and male-to-female ratio was 3:1. The median of baseline CD4 (+)T lymphocyte count was 152.5 cells/μL and the interquartile was 233.25 cells/μL. CD4 (+)T lymphocyte counts were significantly increased after treatment in HAART, HAART + chemotherapy, and chemotherapy + HAART groups (P < 0.05). CD4 (+)T lymphocyte count in chemotherapy groups was significantly reduced after treatment (P < 0.05). The untreated group had the highest mortality rate (33.3%). In HAART group, KS-associated immune reconstitution inflammatory response syndrome (KS-IRIS) appeared in 45.5% cases and 2 death cases were caused by KS-IRIS. In Xinjiang Autonomous Region, the incidence of AIDS-KS is high in young Uygur male people. HAART followed by chemotherapy has ideal efficacy, reduces the incidence of KS-IRIS and improves the prognosis.",
"affiliations": "Department of Infectious Diseases, Sixth People's Hospital of Xinjiang Urumqi, P. R. China.;Department of Infectious Diseases, The First Teaching Hospital of Xinjiang Medical University Urumqi, P. R. China.;Department of Dermatology, The First Teaching Hospital of Xinjiang Medical University Urumqi, P. R. China.;Department of Infectious Diseases, The First Teaching Hospital of Xinjiang Medical University Urumqi, P. R. China.;Department of Infectious Diseases, Sixth People's Hospital of Xinjiang Urumqi, P. R. China.;Department of Infectious Diseases, The First Teaching Hospital of Xinjiang Medical University Urumqi, P. R. China.;Department of Infectious Diseases, The First Teaching Hospital of Xinjiang Medical University Urumqi, P. R. China.",
"authors": "Yang|Tongtong|T|;He|Li|L|;Wan|Xuefeng|X|;Maimaitiaili|Wubuli|W|;Song|Yuxia|Y|;Zhang|Yuexin|Y|;Lu|Xiaobo|X|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1940-5901",
"issue": "8(10)",
"journal": "International journal of clinical and experimental medicine",
"keywords": "Kaposi’s sarcoma; acquired immunodeficiency syndrome; prognosis",
"medline_ta": "Int J Clin Exp Med",
"mesh_terms": null,
"nlm_unique_id": "101471010",
"other_id": null,
"pages": "18697-704",
"pmc": null,
"pmid": "26770484",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "24631417;10767252;22503798;22395672;21575416;12692543;9488122;23578530;20229795;16232048;16077928;22672182;22227511",
"title": "The clinical characteristics of 80 cases of acquired immunodeficiency syndrome-associated Kaposi's sarcoma in Xinjiang Autonomous Region and the effect of different treatments on the prognosis.",
"title_normalized": "the clinical characteristics of 80 cases of acquired immunodeficiency syndrome associated kaposi s sarcoma in xinjiang autonomous region and the effect of different treatments on the prognosis"
} | [
{
"companynumb": "CN-GILEAD-2016-0193342",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TENOFOVIR DISOPROXIL FUMARATE"
},
"drugadditiona... |
{
"abstract": "Paroxetine is a selective serotonin reuptake inhibitor (SSRI) used in the treatment of depression and anxiety disorders. In some epidemiological studies, slightly increased risks of major malformations and cardiac malformations have been reported following paroxetine exposure in the first trimester of pregnancy. However, such findings have been inconsistent. There is only one report of any overdose of an SSRI during pregnancy, and that involved escitalopram. The aim of this case report was to describe the impact of a paroxetine overdose in the first trimester of pregnancy on the health of the foetus. A 21-year-old mother of one child who was pregnant with a second child was prescribed 20 mg/day paroxetine hydrochloride for the treatment of anxiety/depression. The patient ingested 15 or 16 20-mg tablets of paroxetine hydrochloride (300-320 mg) during the 5th week of pregnancy as a suicide attempt. Within 15 min of ingestion, she was admitted to hospital and treated for intoxication. No evidence of maternal SSRI intoxication was observed after treatment. The patient consulted our teratology information service for further risk assessment regarding possible major congenital malformations following the paroxetine overdose. We were unable to find previous reports of paroxetine overdose during pregnancy in the literature. The timely administration of the overdose treatment and the lack of maternal intoxication symptoms were considered positive for the foetal well-being, and the patient was referred for perinatology and psychiatry follow-ups. A healthy, 3 500-g male infant was born at 38 weeks' gestation, and his development at the age of 2 years was normal. This is the first reported case of paroxetine overdose during pregnancy. Comprehensive studies are needed to evaluate pregnancy outcomes after SSRI overdose.Key PointsThere are no reported data on paroxetine overdose during pregnancy.The aim of this case report was to describe the impact of a maternal paroxetine overdose in the first trimester of pregnancy on the health of the foetus. No evidence of maternal SSRI intoxication was observed.No congenital malformations or developmental disorders were observed in the child at 2 years of age.Comprehensive studies are needed to evaluate pregnancy outcomes following SSRI overdose.",
"affiliations": "Faculty of Medicine, Department of Pharmacology, Izmir Katip Celebi University, Izmir, Turkey.;Terafar (Izmir Katip Celebi University Teratology Information, Training and Research Center), Izmir, Turkey.;Terafar (Izmir Katip Celebi University Teratology Information, Training and Research Center), Izmir, Turkey.;Faculty of Medicine, Department of Pharmacology, Izmir Katip Celebi University, Izmir, Turkey.;Faculty of Medicine, Department of Pharmacology, Izmir Katip Celebi University, Izmir, Turkey.;Faculty of Medicine, Department of Pharmacology, Izmir Katip Celebi University, Izmir, Turkey.;Terafar (Izmir Katip Celebi University Teratology Information, Training and Research Center), Izmir, Turkey.",
"authors": "Acar|Selin|S|https://orcid.org/0000-0003-4083-8660;Erol|Hilal|H|https://orcid.org/0000-0001-7145-3400;Arslan|Elif Keskin|EK|https://orcid.org/0000-0001-9538-4817;Uysal|Nusret|N|https://orcid.org/0000-0002-0009-3951;Karadaş|Barış|B|https://orcid.org/0000-0001-9347-2565;Temiz|Tijen Kaya|TK|https://orcid.org/0000-0002-0069-6576;Cem Kaplan|Yusuf|Y|https://orcid.org/0000-0003-0369-7934",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/20961790.2021.1938802",
"fulltext": "\n==== Front\nForensic Sci Res\nForensic Sci Res\nForensic Sciences Research\n2096-1790\n2471-1411\nTaylor & Francis\n\n10.1080/20961790.2021.1938802\n1938802\nVersion of Record\nCase Report\nCase Report\nParoxetine overdose during pregnancy\nS. Acar et al.\nForensic Sciences Research\nhttps://orcid.org/0000-0003-4083-8660\nAcar Selin ab\nhttps://orcid.org/0000-0001-7145-3400\nErol Hilal b\nhttps://orcid.org/0000-0001-9538-4817\nArslan Elif Keskin b\nhttps://orcid.org/0000-0002-0009-3951\nUysal Nusret ab\nhttps://orcid.org/0000-0001-9347-2565\nKaradaş Barış ab\nhttps://orcid.org/0000-0002-0069-6576\nTemiz Tijen Kaya ab\nhttps://orcid.org/0000-0003-0369-7934\nCem Kaplan Yusuf b\na Faculty of Medicine, Department of Pharmacology, Izmir Katip Celebi University, Izmir, Turkey\nb Terafar (Izmir Katip Celebi University Teratology Information, Training and Research Center), Izmir, Turkey\nCONTACT Selin Acar ecz.selinacar@gmail.com\n28 9 2021\n2021\n28 9 2021\n6 3 Special Issue on Sharing clinical and forensic toxicology knowledge in the era of a pandemic and beyond; Guest editor: Nikolas P. Lemos 237239\n17 5 2021\n1 6 2021\n1 6 2021\nKnowledgeWorks Global Ltd.3 6 2021\npublished online as a final version in an issue17 11 2021\n© 2021 The Author(s). Published by Taylor & Francis Group on behalf of the Academy of Forensic Science.\n2021\nThe Author(s)\nhttps://creativecommons.org/licenses/by/4.0/ 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 cited.\n\nAbstract\n\nParoxetine is a selective serotonin reuptake inhibitor (SSRI) used in the treatment of depression and anxiety disorders. In some epidemiological studies, slightly increased risks of major malformations and cardiac malformations have been reported following paroxetine exposure in the first trimester of pregnancy. However, such findings have been inconsistent. There is only one report of any overdose of an SSRI during pregnancy, and that involved escitalopram. The aim of this case report was to describe the impact of a paroxetine overdose in the first trimester of pregnancy on the health of the foetus. A 21-year-old mother of one child who was pregnant with a second child was prescribed 20 mg/day paroxetine hydrochloride for the treatment of anxiety/depression. The patient ingested 15 or 16 20-mg tablets of paroxetine hydrochloride (300–320 mg) during the 5th week of pregnancy as a suicide attempt. Within 15 min of ingestion, she was admitted to hospital and treated for intoxication. No evidence of maternal SSRI intoxication was observed after treatment. The patient consulted our teratology information service for further risk assessment regarding possible major congenital malformations following the paroxetine overdose. We were unable to find previous reports of paroxetine overdose during pregnancy in the literature. The timely administration of the overdose treatment and the lack of maternal intoxication symptoms were considered positive for the foetal well-being, and the patient was referred for perinatology and psychiatry follow-ups. A healthy, 3 500-g male infant was born at 38 weeks’ gestation, and his development at the age of 2 years was normal. This is the first reported case of paroxetine overdose during pregnancy. Comprehensive studies are needed to evaluate pregnancy outcomes after SSRI overdose.Key Points\n\nThere are no reported data on paroxetine overdose during pregnancy.\n\nThe aim of this case report was to describe the impact of a maternal paroxetine overdose in the first trimester of pregnancy on the health of the foetus. No evidence of maternal SSRI intoxication was observed.\n\nNo congenital malformations or developmental disorders were observed in the child at 2 years of age.\n\nComprehensive studies are needed to evaluate pregnancy outcomes following SSRI overdose.\n\nKeywords\n\nForensic sciences\nforensic toxicology\nparoxetine\noverdose\nteratogenicity\ncase report\n==== Body\npmcIntroduction\n\nParoxetine is a selective serotonin reuptake inhibitor (SSRI) used in the treatment of depression and anxiety disorders. In a 2016 meta-analysis, it was reported that there were increased risks of any major congenital malformation (pooled odds ratio (OR): 1.23; 95% confidence interval (CI): 1.10–1.38; n = 15 studies) and major cardiac malformations (pooled OR: 1.28; 95%CI: 1.11–1.47; n = 18 studies) following paroxetine exposure in the first trimester of pregnancy [1]. However, the risk estimates differed depending on the characteristics of the comparison group. For example, the risk of cardiac malformations was not significantly higher than a disease-matched control group including women who were diagnosed with depression and/or anxiety but not exposed to any antidepressant. Further analysis revealed that there were no significant increases in the rates of major congenital or cardiac malformations when the exposed group was compared with disease-matched controls with or without antidepressant exposure (other than paroxetine), which suggested a possible bias by indication (confounded by underlying disease). Several studies have examined the impact of SSRI dose. Increased risks of major congenital malformations (adjusted OR: 2.23; 95%CI: 1.19–4.17) and major cardiac malformations (adjusted OR: 3.07; 95%CI: 1.00–9.42) were found following exposure to >25 mg/day paroxetine during the first trimester of pregnancy [2]. Exposure to a high dose of SSRIs was also associated with lower gestational age (P = 0.009) and a higher rate of prematurity (OR: 5.07; 95%CI: 1.34–19.23) [3]. To our knowledge, there is only one case report of an SSRI overdose during pregnancy [4, 5]. In that case, a 36-year-old pregnant woman ingested an overdose of escitalopram (280 mg) during the 31st week of amenorrhoea. The patient was given activated charcoal-carbomix 5 h after the intoxication. Because the patient presented a risk of premature delivery, tocolytic treatment was also given. The child was born spontaneously at 37 weeks and 4 days’ gestation, with no indication of respiratory distress, renal failure, vomiting or convulsions. The infant exhibited extreme agitation, constant irritability and significant nervousness that dissipated during a 17-day stay in hospital; consequently, the mother and the infant were discharged [4]. To date, there are no published data on paroxetine overdose during pregnancy. The aim of this case report was to describe the impact of a paroxetine overdose in the first trimester of pregnancy on the health of the foetus.\n\nCase\n\nA 21-year-old mother of one child who was pregnant with her second child was prescribed 20 mg/day paroxetine hydrochloride for the treatment of anxiety/depression. The patient ingested 15 or 16 20-mg tablets of paroxetine hydrochloride (300–320 mg) during the 5th week of pregnancy as a suicide attempt but was admitted to hospital within 15 min. A nasogastric tube was inserted, gastric lavage was applied and activated charcoal was given. The patient was monitored closely for 30 min and then discharged. No symptoms indicative of perfusion disorder or somnolence resulting from central nervous system depression, such as hypotension or syncope, occurred within the following 24 h. The patient was referred to Terafar-Izmir Katip Celebi University Teratology Information, Training and Research Center for further risk assessment of possible major congenital malformations. At her initial consultation she was at 10 weeks and 3 days’ gestation. Data and literature searches performed on the Reprotox® and PubMed databases, as well as the third edition of Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment [5], failed to retrieve any data on paroxetine overdose during pregnancy. The appropriateness of the patient’s intoxication treatment and lack of symptoms were considered to be positive signs for the continued healthy development of the foetus. Psychiatric follow-up and perinatological assessment (detailed ultrasonography and foetal ecocardiography) were recommended. In the postnatal follow-up via telephone call, the mother reported that a healthy 3 500-g male infant was born at 38 weeks’ gestation via caesarean section, and that the child’s development at the age of 2 years was normal.\n\nDiscussion\n\nTo the best of our knowledge, this is the first report of a case of paroxetine overdose during pregnancy. There is one case report describing an SSRI overdose in pregnancy, and that involved escitalopram in the third trimester [4, 5], for which treatment for intoxication was administered 5 h later [4]. Bérard et al. [2] reported increased risks of major congenital and major cardiac malformations following maternal ingestion of >25 mg/day of paroxetine. However, it is not known whether any of the patients in that study used short-term. In another study, Roca et al. [3] reported that the exposure to relatively higher dose of an SSRI was associated with lower gestational age and higher rates of prematurity. In our case, there was no evidence of SSRI intoxication in a woman exposed to a paroxetine overdose in the first trimester of pregnancy, nor were there any congenital malformations or developmental disorders in the infant up to 2 years later. Given the widespread use of the SSRIs, it is noteworthy that this is the first reported case of paroxetine overdose during pregnancy. Comprehensive studies are needed to evaluate pregnancy outcomes after SSRI overdose.\n\nAcknowledgements\n\nThe authors wish to acknowledge the assistance of Professor Thomas Gluodenis with English language polishing and Professor Nikolas P. Lemos with manuscript submission. This case report was presented as a poster at the 25th National Pharmacology Congress in 2019 in Aydın/Turkey, and as an oral presentation at the Autumn 2020 Virtual Meeting of the International Alliance of Clinical and Forensic Toxicologists in London/United Kingdom (www.iacft.online).\n\nAuthors’ contributions\n\nSelin Acar carried out the postnatal follow-up via telephone call and wrote the manuscript. Elif Keskin Arslan carried out the first patient interview during consultation. Barış Karadaş, Tijen Kaya Temiz and Yusuf Cem Kaplan participated in the manuscript design and coordination and edited the first manuscript drafting and supervised the revisions. Elif Keskin Arslan, Hilal Erol and Nusret Uysal helped with the first manuscript drafting. All authors contributed to the final text and approved it.\n\nCompliance with ethical standards\n\nAuthors are declared no conflicts of interest. This study is a case report. Verbal informed consent was obtained from the patient.\n\nDisclosure statement\n\nNo conflicts of interest are declared by any of the authors.\n==== Refs\nReferences\n\n1 Bérard A, Iessa N, Chaabane S, et al. The risk of major cardiac malformations associated with paroxetine use during the first trimester of pregnancy: a systematic review and meta-analysis. Br J Clin Pharmacol. 2016;81 :589–604.26613360\n2 Bérard A, Ramos E, Rey E, et al. First trimester exposure to paroxetine and risk of cardiac malformations in infants: the importance of dosage. Birth Defects Res B Dev Reprod Toxicol. 2007;80 :18–27.17187388\n3 Roca A, Garcia-Esteve L, Imaz ML, et al. Obstetrical and neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitors: the relevance of dose. J Affect Disord. 2011;135 :208–215.21890210\n4 Tixier H, Feyeux C, Girod S, et al. Acute voluntary intoxication with selective serotonin reuptake inhibitors during the third trimester of pregnancy: therapeutic management of mother and fetus. Am J Obstet Gynecol. 2008;199 :e9–e12.\n5 Yates LM, Stephens S. Poisonings and toxins. In: Schaefer C, Peters P, Miller RK, editors. Drugs during pregnancy and lactation: treatment options and risk assessment. 3rd ed. Amsterdam (The Netherlands): Academic Press; 2015. p. 575–597.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2471-1411",
"issue": "6(3)",
"journal": "Forensic sciences research",
"keywords": "Forensic sciences; case report; forensic toxicology; overdose; paroxetine; teratogenicity",
"medline_ta": "Forensic Sci Res",
"mesh_terms": null,
"nlm_unique_id": "101724928",
"other_id": null,
"pages": "237-239",
"pmc": null,
"pmid": "34868717",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "17187388;18984074;21890210;26613360",
"title": "Paroxetine overdose during pregnancy.",
"title_normalized": "paroxetine overdose during pregnancy"
} | [
{
"companynumb": "TR-GLAXOSMITHKLINE-TR2021GSK254495",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PAROXETINE HYDROCHLORIDE"
},
"drugad... |
{
"abstract": "Mechanisms of sudden unexpected death in epilepsy (SUDEP) are incompletely understood in part because the overwhelming majority of patients are not undergoing video telemetry when they die. Described here is a patient with Tourette syndrome and epilepsy who displayed a dangerous compulsive tic resulting in carotid occlusions and seizures as captured on video telemetry monitoring. He was later found dead, raising the possibility of SUDEP. Possible mechanisms of SUDEP are discussed in light of video, EEG, ECG, epilepsy and tic behaviors.",
"affiliations": "Swedish Epilepsy Center, Swedish Neuroscience Institute, Seattle, WA 98122, USA. Michael.doherty@swedish.org",
"authors": "Doherty|Michael J|MJ|;Sloan|Dane|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.yebeh.2009.11.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-5050",
"issue": "17(2)",
"journal": "Epilepsy & behavior : E&B",
"keywords": null,
"medline_ta": "Epilepsy Behav",
"mesh_terms": "D002341:Carotid Artery Thrombosis; D003645:Death, Sudden; D004562:Electrocardiography; D004569:Electroencephalography; D004827:Epilepsy; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D012720:Severity of Illness Index; D013686:Telemetry; D005879:Tourette Syndrome; D055815:Young Adult",
"nlm_unique_id": "100892858",
"other_id": null,
"pages": "285-6",
"pmc": null,
"pmid": "20056492",
"pubdate": "2010-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Tourette syndrome and epilepsy: a strange case of possible sudden unexpected death.",
"title_normalized": "tourette syndrome and epilepsy a strange case of possible sudden unexpected death"
} | [
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"companynumb": "US-GLAXOSMITHKLINE-US2021GSK014567",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PHENYTOIN"
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{
"abstract": "The aim of this study was to evaluate the effectiveness of lapatinib in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer.\n\n\n\nWe retrospectively reviewed the medical records of patients who received lapatinib for salvage treatment at any line setting from January 1, 2007 to August 31, 2019 at Shandong Cancer Hospital and Institute.\n\n\n\nA total of 115 (89.1%) patients were included in the study. In the overall cohort, the median disease-free survival (DFS) was 19.0 months; the median progression-free survival (PFS), 6.3 months; and median overall survival (OS), 88.0 months, with 32.2% of patients alive at 5 years. In the second line setting, the median PFS among trastuzumab, lapatinib, and trastuzumab plus lapatinib were 4.2 months, 5.2 months, and 7.3 months, respectively (P = 0.004). No significant differences between the median PFSs and OSs of the different line salvage treatments with lapatinib was observed (all P > 0.05). For brain metastasis patients, the median PFSs in first line, second line, and more than 3 lines were 7.2 months, 4.5 months, and 6.3 months, respectively.\n\n\n\nOur findings suggest that patients would benefit more from trastuzumab plus lapatinib than from lapatinib or trastuzumab alone for second line treatment in the advanced stages of the disease. Lapatinib could be used as an alternative selection for HER2-positive metastasic breast cancer patients when there is disease progression after trastuzumab or pyrotinib treatment, which is used as part of China's national health insurance.",
"affiliations": "Department of Breast Cancer Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People's Republic of China.;Qingdao Huangdao District Central hospital, Qingdao, Shandong, People's Republic of China.;Department of Surgery, Cleveland Clinic Florida, Weston, FL, USA.;Department of Breast Cancer Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People's Republic of China.;Department of Breast Cancer Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People's Republic of China.;Department of Breast Cancer Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People's Republic of China.;Department of Breast Cancer Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People's Republic of China.",
"authors": "Wang|Xinzhao|X|0000-0002-1027-6129;Wang|Lin|L|;Yu|Qian|Q|;Liu|Zhaoyun|Z|;Li|Chao|C|;Wang|Fukai|F|;Yu|Zhiyong|Z|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/15330338211037812",
"fulltext": "\n==== Front\nTechnol Cancer Res Treat\nTechnol Cancer Res Treat\nTCT\nsptct\nTechnology in Cancer Research & Treatment\n1533-0346\n1533-0338\nSAGE Publications Sage CA: Los Angeles, CA\n\n34342244\n10.1177/15330338211037812\n10.1177_15330338211037812\nOriginal Article\nThe Effectiveness of Lapatinib in HER2-Positive Metastatic Breast Cancer Patients Pretreated With Multiline Anti-HER2 Treatment: A Retrospective Study in China\nhttps://orcid.org/0000-0002-1027-6129\nWang Xinzhao MD 1\nWang Lin MD 2\nYu Qian PhD 3\nLiu Zhaoyun MD 1\nLi Chao MD 1\nWang Fukai MD 1\nYu Zhiyong MD, PhD 1\n1 Department of Breast Cancer Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China\n2 Qingdao Huangdao District Central hospital, Qingdao, Shandong, People’s Republic of China\n3 Department of Surgery, Cleveland Clinic Florida, Weston, FL, USA\nZhiyong Yu, MD, PhD, Department of Breast Cancer Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jiyan Road 440, Jinan, Shandong 250117, China. Email: drzhiyongyu@aliyun.com\n3 8 2021\n2021\n20 1533033821103781218 12 2020\n16 6 2021\n08 7 2021\n© The Author(s) 2021\n2021\nSAGE Publications\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nBackground:\n\nThe aim of this study was to evaluate the effectiveness of lapatinib in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer.\n\nMethods:\n\nWe retrospectively reviewed the medical records of patients who received lapatinib for salvage treatment at any line setting from January 1, 2007 to August 31, 2019 at Shandong Cancer Hospital and Institute.\n\nResults:\n\nA total of 115 (89.1%) patients were included in the study. In the overall cohort, the median disease-free survival (DFS) was 19.0 months; the median progression-free survival (PFS), 6.3 months; and median overall survival (OS), 88.0 months, with 32.2% of patients alive at 5 years. In the second line setting, the median PFS among trastuzumab, lapatinib, and trastuzumab plus lapatinib were 4.2 months, 5.2 months, and 7.3 months, respectively (P = 0.004). No significant differences between the median PFSs and OSs of the different line salvage treatments with lapatinib was observed (all P > 0.05). For brain metastasis patients, the median PFSs in first line, second line, and more than 3 lines were 7.2 months, 4.5 months, and 6.3 months, respectively.\n\nConclusions:\n\nOur findings suggest that patients would benefit more from trastuzumab plus lapatinib than from lapatinib or trastuzumab alone for second line treatment in the advanced stages of the disease. Lapatinib could be used as an alternative selection for HER2-positive metastasic breast cancer patients when there is disease progression after trastuzumab or pyrotinib treatment, which is used as part of China’s national health insurance.\n\nlapatinib\nHER2-positive\nmetastatic breast cancer\nretrospective study\ntarget therapy\nNatural Science Foundation of Shandong Province https://doi.org/10.13039/501100007129 ZR2017PH055 cover-dateJanuary-December 2021\ntypesetterts3\n==== Body\nIntroduction\n\nOverexpression of the human epidermal growth factor receptor 2 (HER2) occurs in approximately 15% of newly diagnosed early-stage breast cancer patients and approximately 20% of advanced breast cancer patients. 1 As a potent cancer-driving gene, it was first recognized in the 1980s. 2 Pharmacological targeting of HER2 has dramatically improved the outcomes of HER2-positive breast cancer regardless of staging. A growing number of novel anti-HER2 drugs have been developed, including monoclonal antibodies, such as trastuzumab and pertuzumab, the antibody-drug conjugated T-DM1, and tyrosine kinase inhibitors, such as lapatinib and neratinib. 3 First-line anti-HER2 therapy offers an overall response rate of 80% after dual target treatment and 69% after trastuzumab monotherapy. 4,5 Despite the addition of trastuzumab and/or pertuzumab to chemotherapy to improve the disease-free survival (DFS) and overall survival (OS) of early-stage breast cancer patients, 15% to 24% of HER2-positive patients will eventually develop recurrence or metastasic breast cancer (MBC) during the long-term follow-up period. 6,7\n\nLapatinib, first approved in 2007, is an oral reversible HER2 tyrosine kinase inhibitor that blocks the phosphorylation of HER1 and HER2. The combination therapy of capecitabine and lapatinib offers an enormous increase in the survival rate of HER2-positive MBC patients who are resistant to previous trastuzumab-containing therapy. 8,9 According to the National Comprehensive Cancer Network guidelines, lapatinib is a valid third-line treatment option, though it is inferior to T-DM1 in trastuzumab-resistant MBC patients.\n\nA clinical trial proved that pyrotinib plus capecitabine yielded a better overall response rate and progression-free survival (PFS) than lapatinib plus capecitabine in HER2-positive breast cancer patients previously treated with anthracyclines, taxanes, and/or trastuzumab. 10 Pertuzumab, which was approved on December 17, 2018 by the National Medical Products of Administration in China, was recommended as the first choice for first line salvage treatment in HER2-positive advanced breast cancer patients. Meanwhile, T-DM1 is not yet listed in China at the time of writing. Although the patients received the aforementioned medication, they eventually progressed.\n\nThe Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (known as “NeoALTTO”) trial showed that combined lapatinib and trastuzumab in neoadjuvant therapy settings could achieve higher pathological complete remission (pCR) and survival benefits. 11 The EGF100151 trial, 12 EGF104900 trial, 13 and ALTERNATIVE trial 14 indicated that lapatinib could be used as a valuable selection in salvage settings. However, lapatinib has been excluded from the national medical insurance in China since January 1, 2020. At the time of writing, the cost-effectiveness of lapatinib is not known; this is an important aspect since lapatinib is expensive in China. In this study, we performed a retrospective study to evaluate the effectiveness of lapatinib in HER2-positive MBC patients from a single center under the specific conditions of China.\n\nMaterials and Methods\n\nWe retrospectively reviewed the medical records of all HER2-positive MBC patients who received lapatinib for anti-HER2 treatment from January 1, 2007 to August 31, 2019 at Shandong Cancer Hospital and Institute. This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee at Shandong Cancer Hospital and Institute (SDTHEC201703010). All of the patients gave written informed consent before their participation in the study.\n\nThe characteristics of patients at the time of initial diagnosis (including age, performance status, and menstrual status), tumor characteristics (including tumor size, lymph nodes involved, grade, histology, and receptor status), and treatment regimen in the adjuvant and salvage settings (including chemotherapy, anti-HER2, endocrine regimen, dose reductions or delays, treatment for central nervous system metastasis, anti-bone destruction, and outcome of treatments in the adjuvant setting) were extracted from electronic medical records. Clinical response data were according to Response Evaluation Criteria in Solid Tumors, version 1.1. Adverse events (AEs) were graded based on the National Cancer Institute—Common Terminology Criteria for AEs, version 4.0.\n\nThe estrogen receptor (ER) and progesterone receptor (PR) were determined by at least 10% of nuclei being positively stained. HER2 positivity was defined as either an immunohistochemistry score of 3+ or 2+ together with HER2 gene amplification by fluorescence in situ hybridization. DFS was defined as the interval from surgery to the first occurrence resulting in inoperability, distant metastases, or death of any cause. 15 PFS after metastasis was defined as the time from treatment commencement until disease progression or death. Overall survival (OS) was defined as the time from the beginning of treatment until death from any cause or until the last follow-up date. Clinical benefit rate (CBR) was defined as the proportion of patients who achieved complete response (CR), partial response (PR) or stable disease (SD). Overall response rate (ORR) was defined as the proportion of patients who achieved CR or PR on anti-HER2 therapy.\n\nThe enrollment criteria were as follow: 1) female patients aged ≥ 18 years; 2) HER2-positive MBC; and 3) receiving lapatinib regardless of how many lines of treatment they have received. The exclusion criteria were as follow: 1) patients without complete medical records; 2) MBC at first diagnosis; and 3) non-measurable or non-evaluable lesions. All of the patients should have accepted lapatinib 1,250 mg once daily as an initial dose, administered orally in combination with chemotherapeutic drugs or other anti-HER2 target drugs of the appropriate dose and method of administration.\n\nTumor assessments were evaluated by 2 independent imaging physicians with computed tomography or magnetic resonance imaging. Throughout the study, each patient accepted the same method to evaluate therapeutic effects. Assessments were carried out at baseline every 2 or 3 months, and at the final visit.\n\nDescriptive analysis was performed to summarize the medical records by using counts and percentages for categorical variables. The chi-squared test was used to compare the differences between the various patient groups. The Kaplan-Meier method was used to assess the DFS, PFS and OS. Until the last follow-up date, patients who became progression-free and/or were lost to follow-up were considered censored data. The median time of the event was registered with a 95% confidence interval (CI), and different subgroups were compared using the log-rank test.\n\nResults\n\nPatients and Treatment Regimens\n\nA total of 129 patients with HER2-positive MBC who treated with lapatinib were recruited. A final total of 115 (89.1%) patients were included in the research after excluding the patients with incomplete medical records (Figure 1). The median age for first treatment was 45 years (ranging between 27 and 77 years). Baseline characteristics of the patients included are reported in Table 1. Of these, 55 patients (47.8%) had biopsy results indicative of metastatic disease, and 25 patients (45.5%) had ER-positive cancer, which was confirmed by the metastatic specimens. The Eastern Cooperative Oncology Group performance status was 0-1 in 108 patients (93.9%). Before commencing anti-HER2 therapy for MBC, the metastatic sites involved were found to be the liver in 45 (39.1%), the brain in 42 (36.5%), the lung in 47 (40.9%), the bone in 49 (42.6%), the lymph nodes in 46 (40.0%), and the other organs, such as the spleen, adrenal gland, pancreas, and pleura, in 36 patients (31.3%). For the patients with brain metastasis, 25 (59.5%) accepted brain radiotherapy. The bone metastasis patients were given bisphosphonates every month for the first 2 years and every 3 months for follow-up treatment. The involved organs for advanced diseases were only one organ in 52 (45.2%), 2 organs in 41 (35.7%), 3 organs in 13 (11.3%), and more than 3 organs in 9 patients (7.8%). Lapatinib was used as the first line treatment in 20 (17.4%), second line in 62 (53.9%), third line in 24 (20.9%), and more than 3 lines in 9 patients (7.8%). Meanwhile, as dual target therapy, lapatinib and trastuzumab in combination were used as the first line treatment in 6 (30.0%), second line in 17 (27.4%), and 3 or more lines in 7 patients (21.2%) (Table 2). The baseline characteristics of patients with or without anti-HER2 treatment in the adjuvant setting are summarized in Table 3. Lapatinib was used earlier in the salvage setting for patients who accepted trastuzumab than for trastuzumab-free patients in the curative setting (P = 0.001).\n\nFigure 1. Patient’s follow-up profile.\n\nTable 1. Baseline Characteristics (N = 115).\n\nVariables\tN\t%\t\nMenstrual status at first diagnosis\t\t\t\n Premenopausal\t80\t69.6\t\n Postmenopausal\t35\t30.4\t\nECOG performance status\t\t\t\n 0\t73\t63.5\t\n 1\t35\t30.4\t\n 2\t5\t4.4\t\n 3\t2\t1.7\t\nHistology\t\t\t\n Invasive ductal cancer\t104\t90.4\t\n Invasive lobular cancer\t4\t3.5\t\n Mixed\t2\t1.7\t\n Unknown\t5\t4.4\t\nGrade\t\t\t\n 1\t2\t1.7\t\n 2\t44\t38.3\t\n 3\t57\t49.6\t\n Unknown\t12\t10.4\t\nStage disease of first diagnosis\t\t\t\n IA\t11\t9.6\t\n IB\t1\t0.9\t\n IIA\t23\t20.0\t\n IIB\t10\t8.7\t\n IIIA\t20\t17.4\t\n IIIB\t5\t4.3\t\n IIIC\t33\t28.7\t\n Unknown\t12\t10.4\t\nER status\t\t\t\n Positive\t49\t42.6\t\n Negative\t58\t50.4\t\n Unknown\t8\t7.0\t\nPR status\t\t\t\n Positive\t31\t30.0\t\n Negative\t75\t65.2\t\n Unknown\t9\t7.8\t\nChemotherapy\t\t\t\n Adjuvant\t89\t77.4\t\n Neoadjuvant\t17\t14.8\t\n None\t9\t7.8\t\n pCR on neoadjuvant chemotherapy (N = 17)\t3\t17.6\t\nChemotherapy schedule (N = 106)\t\t\t\n Anthracyclines only\t8\t7.5\t\n Taxanes only\t13\t12.3\t\n Anthracyclines and taxanes\t85\t80.2\t\nEndocrine therapy (51 patients were HR positive)\t\t\t\n Yes\t42\t82.3\t\n No\t9\t17.7\t\nAnti-HER2 treatmenta\t\t\t\n Yes\t47\t40.9\t\n No\t68\t59.1\t\nMetastatic breast cancer re-biopsy (N = 55)\t\t\t\n ER positive\t25\t45.5\t\n ER negative\t30\t54.5\t\nMetastasis site\t\t\t\n Liver\t45\t39.1\t\n Brain\t42\t36.5\t\n Lung\t47\t40.9\t\n Bone\t49\t42.6\t\n Nodes\t46\t40.0\t\n other\t36\t31.3\t\nNumber of organs involved\t\t\t\n 1\t52\t45.2\t\n 2\t41\t35.7\t\n 3\t13\t11.3\t\n More than 3\t9\t7.8\t\nSalvage anti-HER2 treatment containing lapatinib\t\t\t\n First line\t20\t17.4\t\n Second line\t62\t53.9\t\n Third line\t24\t20.9\t\n More than 3 lines\t9\t7.8\t\na Anti-HER2 treatment only included trastuzumab rather than pertuzumab or combination.\n\nTable 2. Characteristics of the Patients Receiving Target Therapy in Curative Setting.\n\nTreatment combination\tN\t%\t\nFirst line (N = 20)\t\t\t\n Single target therapy\t14\t70.0\t\n Dual target therapya\t6\t30.0\t\nSecond line (N = 62)\t\t\t\n Single target therapy\t45\t72.6\t\n Dual target therapya\t17\t27.4\t\nEqual or more than 3 lines (N = 33)\t\t\t\n Single target therapy\t26\t78.8\t\n Dual target therapya\t7\t21.2\t\na Dual target therapy only referred to trastuzumab and lapatinib.\n\nTable 3. Characteristics of the Patients at Baseline.\n\nBaseline characteristics\tNo trastuzumab at curative setting (N = 68)\tApplication of trastuzumab at curative setting (N = 47)\tχ2\tP\t\nECOG (N, %)\t\t\t0.108\t0.742\t\n 0\t44(64.7)\t29(61.7)\t\t\t\n ≥1\t24(35.3)\t18(38.3)\t\t\t\nHR status at curative treatment (N, %)\t\t\t\t\t\n Positive\t27(39.7)\t22(46.8)\t0.574\t0.751\t\n Negative\t36(52.9)\t22(46.8)\t\t\t\n Unknown\t5(7.4)\t3(6.4)\t\t\t\nMetastasis site (N, %)\t\t\t\t\t\n Liver\t25(36.8)\t20(42.6)\t0.391\t0.532\t\n Brain\t21(30.9)\t21(44.7)\t2.282\t0.131\t\n Lung\t25(36.8)\t22(46.8)\t0.002\t0.962\t\n Bone\t31(45.6)\t18(38.3)\t0.604\t0.437\t\n Nodes\t29(42.6)\t17(36.2)\t0.486\t0.486\t\n Other\t22(32.4)\t14(29.8)\t0.085\t0.771\t\nNumber of organs involved (N, %)\t\t\t0.092\t0.337\t\n <3\t53(77.9)\t40(85.1)\t\t\t\n ≥3\t15(22.1)\t7(14.9)\t\t\t\nSalvage anti-HER2 treatment containing lapatinib\t\t\t27.454\t0.001\t\n First line\t2(2.9)\t18(38.3)\t\t\t\n Second line\t39(57.4)\t23(48.9)\t\t\t\n Third line\t20(29.4)\t4(8.5)\t\t\t\n More than 3 lines\t7(10.3)\t2(4.3)\t\t\t\n\nEfficacy\n\nAs shown in Figure 2A, in the overall cohort, the median DFS was 19.0 months (95% CI 15.2-22.8). A total of 79 patients (68.7%) achieved the clinical benefit criteria: with 5 CR (4.3%), 27 PR (23.5%), 47 SD (40.9%), and 36 PD (31.3%) (Table 4). In the overall cohort, ORR was 27.8% (32/115). In the subgroup analysis, the CBRs in first line, second line, third line, and more than 3 lines were 85.0%, 69.4%, 58.3%, and 55.6%, respectively. Similarly, the ORRs were 40.0%, 25.8%, 29.2% and 11.1%, respectively. We further investigated the median PFS and OS in the overall cohort, and we found that the median PFS was 6.3 months (95% CI 5.1-7.5) (Figure 2B) and the median OS was 88.0 months (95% CI 64.6-111.5) (Figure 2C), with 32.2% of patients alive at 5 years. For the subgroup analysis, in the salvage treatment setting, patients who received anti-HER2 treatment for early-stage tumors achieved a higher median PFS than patients without anti-HER2 treatment (8.3 months versus 5.1 months, respectively; P = 0.002) (Figure 2D). Between the median OSs between both groups were not significantly different (65.6 months versus 104.1 months, respectively; P = 0.317) (Figure 2E).\n\nFigure 2. Kaplan-Meier estimates of disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS), with 95% confidence interval (CI). In the overall cohort, the DFS (A), PFS (B) and OS (C) were illustrated. The PFS (D) and OS (E) were illustrated between trastuzumab in curative setting and no trastuzumab in curative setting.\n\nTable 4. Responses for Different Treatment Lines.\n\nResponses\tN (%)\t\nOverall sample (N = 115)\tFirst line (N = 20)\tSecond line (N = 62)\tThird line (N = 24)\t>3 lines (N = 9)\t\nCBR\t79 (68.7)\t17 (85.0)\t43 (69.4)\t14 (58.3)\t5 (55.6)\t\n CR\t5 (4.3)\t2 (10.0)\t3 (4.8)\t0\t0\t\n PR\t27 (23.5)\t6 (30.0)\t13 (21.0)\t7 (29.2)\t1 (11.1)\t\n SD\t47 (40.9)\t9 (45.0)\t27 (43.5)\t7 (29.2)\t4 (44.4)\t\nPD\t36 (31.3)\t3 (15.0)\t19 (30.6)\t10 (41.6)\t4 (44.4)\t\nORR\t32 (27.8)\t8 (40.0)\t16 (25.8)\t7 (29.2)\t1 (11.1)\t\nAbbreviations: CR, Complete response; PR, partial response; SD, stable disease; PD, disease progression; ORR, Overall response rate; CBR, Clinical benefit rate.\n\nTo determine the best combination for lapatinib, we investigated the second line anti-HER2 treatment in MBC. There were 95 patients who were eligible to be analyzed, and the median PFSs among trastuzumab, lapatinib, and trastuzumab plus lapatinib were 4.2 months, 5.2 months, and 7.3 months, respectively. There were obvious statistical differences among these 3 groups (P = 0.004) (Figure 3A), but no significant differences were observed between the median OSs of trastuzumab, lapatinib, and trastuzumab plus lapatinib (P = 0.773) (Figure 3B).\n\nFigure 3. Kaplan-Meier estimates of progress-free survival (PFS), and overall survival (OS), with 95% confidence interval (CI) for those patients with different drug combinations. For second line anti-HER2 treatment in MBC, the PFS (A) and OS (B) were compared among trastuzumab group, lapatinib group and trastuzumab plus lapatinib group.\n\nPrevious findings indicated that trastuzumab and lapatinib could be a better combination in second line anti-HER2 therapy. In order to research the best line for lapatinib in salvage treatment, we performed this study to compare the efficacy for various line treatments. No significant differences were found between the median PFSs and OSs of the different line salvage treatments (all P > 0.05, as shown in Figures 4A and 4B). The median PFS in first line was 8.5 months; second line, 5.3 months; third line, 7.0 months; and more than 3 lines, 5.8 months. The median OS in first line was 65.6 months; second line, 56.2 months; third line, 88.5 months; and more than 3 lines, 88.4 months.\n\nFigure 4. Kaplan-Meier estimates of PFS (A), and OS (B), with 95% CI for those patients with different lines of anti-HER2 treatment.\n\nFor brain metastasis patients, as shown in Table 5, the ORRs for first line, second line, and 3 or more lines were 36.4%, 28.6%, and 40%, respectively. The CBRs for first line, second line, and more than 3 lines were 81.8%, 61.9%, and 60%, respectively. The median PFSs in first line, second line, and more than 3 lines were 7.2 months, 4.5 months, and 6.3 months, respectively.\n\nTable 5. Responses and Survival for Different Treatment Lines in HER2 Positive Breast Cancer.\n\n\tORR\tCBR\tPFS (Months)\t\nFirst line\t36.4% (4/11)\t81.8% (9/11)\t7.2 (4.7∼9.7)\t\nSecond line\t28.6% (6/21)\t61.9% (13/21)\t4.5 (3.7∼5.3)\t\nEqual or more than third line\t40.0% (3/10)\t60.0% (6/10)\t6.3 (4.3∼8.3)\t\n\nSafety\n\nTreatment was well-tolerated and no patients died of toxicity. Gastrointestinal (all grades 55.9%) and skin (all grades 23.5%) events were the common toxicities. One toxicity-related treatment interruption was attributed to gastrointestinal disorder. Grade 3/4 AEs occurred in 18 patients (15.7%) and were mostly connected with gastrointestinal disorders (7.8%), hand-foot syndrome (1.7%), nervous system disorders (2.6%), and neutropenia (3.5%). All of the AEs resolved with the appropriate measures. No cardiac events grade 3 or higher in severity were observed. In our cohort, no incidence of severe cardiac toxicity was observed in our MBC patients who received anti-HER2 therapy; thus, no treatment discontinuity occurred that was due to cardiac AEs. Only one patient receiving lapatinib and capecitabine was discontinued to anti-HER2 treatment for gastrointestinal side effects. Most cases were reversible following adequate medical therapy.\n\nDiscussion\n\nClinical guidelines provide us an essential strategy for persistently inhibiting the HER2 pathway using several lines of therapy for HER2-positive MBC. For HER2-positive MBC, standard strategy upon progression to trastuzumab regimens include T-DM1, reusing trastuzumab combined with other chemotherapy, or a combination of lapatinib and capecitabine. 16 -18 Trastuzumab and pertuzumab combined with a taxane are currently recommended as the optimal first-line treatment for HER2-positive breast cancer, at the time of writing. 19 For metastatic patients that have progressed to using trastuzumab, T-DM1 is a superior option, based on its advantages when compared to the standard regimen, which includes a combination of lapatinib and capecitabine. Despite a number of target choices in the treatment of HER2-positive breast cancer that have been proposed by randomized trials, the best anti-HER2 strategy is still under debate. In a real-world scenario, due to the limitations of various realistic conditions in China, such as a patient’s habits or drug accessibility, most MBC patients were compelled to receive lapatinib as their anti-HER2 treatment in any line condition in China before 2020. Herceptin and lapatinib as dual target drugs are the first combination to clinical application and were also the longest dual target drugs in medical use in China before 2020. Lapatinib has been excluded from the national medical insurance from January 1, 2020, and trastuzumab plus pertuzumab or pyrotinib has since become the main treatment selection for HER2-positive advanced breast cancer in China. Therefore, a retrospective analysis of its clinical value, especially in the salvage treatment of breast cancer, has a certain practical significance in proving it as a treatment option.\n\nPhase III of Trial EGF100151 showed that lapatinib plus capecitabine for first line anti-HER2 treatment is superior to capecitabine monotherapy in HER2-positive MBC pretreated with anthracycline, taxanes, and trastuzumab, with a median PFS of 8.4 months versus 4.4 months, respectively. 12 Phase III of the EGF104900 study concluded that a regimen of trastuzumab plus lapatinib was superior to lapatinib alone, with a median PFS of 12 weeks versus 8.1 weeks and a median OS of 14 weeks versus 9.5 weeks, respectively. 13 the EGF100151 and EGF104900 trials indicated that a regimen of trastuzumab plus lapatinib>lapatinib>non-lapatinib for MBC anti-HER2 treatment, in terms of effectiveness. Interestingly, in our study, for second line anti-HER2 treatment, a similar phenomenon of PFS was observed, in that a regimen of trastuzumab plus lapatinib was superior to lapatinib or trastuzumab alone. However, although most patients enrolled in our study received post-progression treatment after lapatinib progression to achieve persistent suppression of the HER2 signaling pathway, no significant difference was observed in terms of the OSs. For those patients progressed from lapatinib, they may accept other anti-HER2 drugs such as pyrotinib or T-DM1, which could prolong the OS.\n\nWhen the MBC patients were divided into 4 subgroups according to different lines of salvage treatment, CBRs in first line, second line, third line, and more were 85.0%, 69.4%, 58.3%, and 55.6%, respectively. ORRs were 40.0%, 25.8%, 29.2% and 11.1%, respectively. It may achieve a better CBR or ORR for first line treatment. However, we found that no matter how many lines of anti-HER2 therapy were utilized, the PFSs and OSs between these subgroups were not significantly different. The results suggested that lapatinib as salvage treatment could be used in any line setting and that lapatinib combined with trastuzumab may be an effective combination. However, according to survival results of the EGF104900 and EGF100151 studies, subgroup analyses indicated that patients accepting fewer lines of prior anti-HER2 agents obtained a more PFS benefit. The reason may attribute to that most of our enrolled patients receiving anti-HER2 treatment for second line or more and many patients receiving lapatinib as single target for salvage treatment. Our results suggest that treatment regimen containing lapatinib may be a therapeutic alternative for heavily treated HER2 positive breast cancer.\n\nLapatinib, as a small molecule tyrosine kinase inhibitor, can enter the central nervous system by passing through the blood-brain barrier. In our study, for the first line, the ORR of brain metastasis was 36.4% and the median PFS in first line treatment was 7.2 months. The LANDSCAPE trial. 20 has proved that the objective central nervous system response of lapatinib in first line treatment was 65.9%, and that the time to progression was 5.5 months. When compared with the results of the LANDSCAPE trial, our results showed a low ORR but long PFS. As such, we concluded that lapatinib is an alternative regimen for HER2-positive breast cancer with brain metastases.\n\nOur results also indicated that continuation of targeted HER2 treatment remained safe and well-tolerated. Anti-HER2 treatment can increase the cardiotoxicity risk; therefore, regular monitoring of cardiac function is mandatory. 21 The incidence of cardiotoxicity varies depending on different patients’ conditions, such as previous chemotherapy regimens, comorbidities, and age. The event of gastrointestinal disorders was similar to that previously reported with lapatinib combined with trastuzumab, chemotherapy, or endocrine therapy. 13,22 In our study, most cases were reversible following adequate medical therapy.\n\nAdmittedly, there were several important limitations in our study. A retrospective design inevitably has problems, such as data selection bias and lack of useful information. Meanwhile, due to economic reasons, many patients received lapatinib more than 3 lines; as such, it is hard to draw firm conclusions because of only a few patients enrolled in some of the subgroups. In our study, the median follow-up period was 64.3 months, and 32.2% of the patients were still alive at 5 years. We will continue to follow up and to obtain more accurate data.\n\nConclusion\n\nNew agents are emerging rapidly in the management of HER2-positive breast cancer for any clinical stage. 23 In the setting of limited drug availability, methods to maximize the therapeutic effect is an important clinical issue. Lapatinib could be used as an alternative selection for HER2-positive MBC when progression occurs after trastuzumab or pyrotinib treatment, which is provided be the national health insurance in China.\n\nAbbreviations\n\nHER2 human epidermal growth factor receptor 2\n\nPFS progression-free survival\n\nDFS disease-free survival\n\nOS overall survival\n\nMBC metastasic breast cancer\n\npCR pathological complete remission\n\nAE adverse event\n\nER estrogen receptor\n\nPR progesterone receptor\n\nCBR clinical benefit rate\n\nCR complete response\n\nPR partial response\n\nSD stable disease\n\nORR overall response rate\n\nCI confidence interval.\n\nAuthors’ Note: Xinzhao Wang, MD, and Lin Wang, MD, contributed equally to this work. This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee at Shandong Cancer Hospital and Institute (SDTHEC201703010). All patients gave written informed consent before their participation in the study.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by Natural Science Foundation of Shandong Province (ZR2017PH055, ZR2019MH109), Key Research and Development Program of Shandong Province (2018GSF118089) and Medical and Health Development Plan of Shandong Province (2016WS0556).\n\nORCID iD: Xinzhao Wang, MD https://orcid.org/0000-0002-1027-6129\n==== Refs\nReferences\n\n1 Wolff AC Hammond MEH Allison KH Harvey BE McShane LM Dowsett M. HER2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline focused update summary. J Oncol Pract. 2018;14 (7 ):437–441.29920138\n2 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 (4785 ):177–182.3798106\n3 Ponde N Brandao M El-Hachem G Werbrouck E Piccart M . Treatment of advanced HER2-positive breast cancer: 2018 and beyond. Cancer Treat Rev. 2018;67 :10–20.29751334\n4 Baselga J Cortes J Kim SB , et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366 (2 ):109–119.22149875\n5 Swain SM Baselga J Kim SB , et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372 (8 ):724–734.25693012\n6 Cameron D Piccart-Gebhart MJ Gelber RD , et al. 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet. 2017;389 (10075 ):1195–1205.28215665\n7 Perez EA Romond EH Suman VJ , et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014;32 (33 ):3744–3752.25332249\n8 Cameron D Casey M Oliva C Newstat B Imwalle B Geyer CE . Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomized trial. Oncologist. 2010;15 (9 ):924–934.20736298\n9 Castellino S O’Mara M Koch K Borts DJ Bowers GD MacLauchlin C . Human metabolism of lapatinib, a dual kinase inhibitor: implications for hepatotoxicity. Drug Metab Dispos. 2012;40 (1 ):139–150.21965624\n10 Ma F Ouyang Q Li W , et al. Pyrotinib or lapatinib combined with capecitabine in HER2-positive metastatic breast cancer with prior taxanes, anthracyclines, and/or trastuzumab: a randomized, phase II study. J Clin Oncol. 2019;37 (29 ):2610–2619.31430226\n11 Baselga J Bradbury I Eidtmann H , et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379 (9816 ):633–640.22257673\n12 Geyer CE Forster J Lindquist D , et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355 (26 ):2733–2743.17192538\n13 Blackwell KL Burstein HJ Storniolo AM , et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 study. J Clin Oncol. 2012;30 (21 ):2585–2592.22689807\n14 Johnston SRD Hegg R Im SA , et al. Phase III, randomized study of dual human epidermal growth factor receptor 2 (HER2) blockade with lapatinib plus trastuzumab in combination with an aromatase inhibitor in postmenopausal women with HER2-positive, hormone receptor-positive metastatic breast cancer: ALTERNATIVE. J Clin Oncol. 2018;36 (8 ):741–748.29244528\n15 Cortazar P Zhang L Untch M , et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384 (9938 ):164–172.24529560\n16 Krop IE Kim SB Gonzalez-Martin A , et al. Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15 (7 ):689–699.24793816\n17 Pivot X Manikhas A Zurawski B , et al. CEREBEL (EGF111438): a phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2015;33 (14 ):1564–1573.25605838\n18 von Minckwitz G du Bois A Schmidt M , et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a German Breast Group 26/Breast International Group 03-05 Study. J Clin Oncol. 2009;27 (12 ):1999–2006.19289619\n19 Giordano SH Temin S Chandarlapaty S , et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: ASCO clinical practice guideline update. J Clin Oncol. 2018;36 (26 ):2736–2740.29939838\n20 Bachelot T Romieu G Campone M , et al. 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 (1 ):64–71.23122784\n21 Keefe DL . Trastuzumab-associated cardiotoxicity. Cancer. 2002;95 (7 ):1592–1600.12237930\n22 Rimawi MF Mayer IA Forero A , et al. Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006. J Clin Oncol. 2013;31 (14 ):1726–1731.23569315\n23 Pernas S Tolaney SM . HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance. Ther Adv Med Oncol. 2019;11 :1758835919833519.30911337\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1533-0338",
"issue": "20()",
"journal": "Technology in cancer research & treatment",
"keywords": "HER2-positive; lapatinib; metastatic breast cancer; retrospective study; target therapy",
"medline_ta": "Technol Cancer Res Treat",
"mesh_terms": null,
"nlm_unique_id": "101140941",
"other_id": null,
"pages": "15330338211037812",
"pmc": null,
"pmid": "34342244",
"pubdate": "2021",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "19289619;29244528;23569315;24793816;25605838;23122784;22149875;17192538;25693012;31430226;24529560;29751334;22689807;3798106;21965624;30911337;12237930;28215665;25332249;29939838;29920138;20736298;22257673",
"title": "The Effectiveness of Lapatinib in HER2-Positive Metastatic Breast Cancer Patients Pretreated With Multiline Anti-HER2 Treatment: A Retrospective Study in China.",
"title_normalized": "the effectiveness of lapatinib in her2 positive metastatic breast cancer patients pretreated with multiline anti her2 treatment a retrospective study in china"
} | [
{
"companynumb": "CN-ROCHE-2897073",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRASTUZUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "We present the case of a man in his 70s who had suffered two separate frontal lobe haemorrhages in the context of using dimethylsulfoxide (DMSO) to manage his low mood. The known pathophysiology of DMSO renders it a likely causative agent of the recurrent intracerebral haemorrhages. This case highlights the need for clinicians to robustly enquire about a patient's use of over-the-counter medications, of non-prescribed supplements and other substances, as part of the history. In addition, the case highlights the potential for highly debilitating adverse effects from using DMSO.",
"affiliations": "Later Life Liaison Psychiatry, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK jonathan.olds@nhs.net.;Department of Medicine, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK.;Department of Stroke Medicine, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK.;Department of Geriatric Medicine, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK.",
"authors": "Olds|Jonathan|J|;Yousif|Mohamed|M|;Abidakun|Oladotun|O|;Cannon|Abigail|A|",
"chemical_list": "D004121:Dimethyl Sulfoxide",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-240371",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(2)",
"journal": "BMJ case reports",
"keywords": "drugs misuse (including addiction); neurology (drugs and medicines); psychiatry (drugs and medicines); safety; stroke",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D002543:Cerebral Hemorrhage; D003863:Depression; D004121:Dimethyl Sulfoxide; D000076064:Drug Misuse; D006801:Humans; D008297:Male; D010146:Pain; D012008:Recurrence; D000073278:Self-Management; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33541956",
"pubdate": "2021-02-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case of recurrent cerebral haemorrhage in an older adult man who uses dimethylsulfoxide (DMSO) for self-management of low mood and pain.",
"title_normalized": "case of recurrent cerebral haemorrhage in an older adult man who uses dimethylsulfoxide dmso for self management of low mood and pain"
} | [
{
"companynumb": "GB-MYLANLABS-2021M1017860",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMISULPRIDE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo identify risk factors that may predispose patients to rifampin- and cefazolin-induced coagulopathy.\n\n\nCONCLUSIONS\nAn 86-year-old man with a history of rheumatoid arthritis on chronic prednisone and stage 3 chronic kidney disease, notably not on warfarin, presented to the hospital with a 10-day history of right hip pain, swelling, and drainage after a recent right total-hip arthroplasty. The patient underwent a combination of surgical intervention and medication therapy with rifampin and ceftriaxone. After discharge and at postoperative day 9, ceftriaxone was changed to cefazolin due to increasing alkaline phosphatase levels. Four weeks after the initial debridement, antibiotics, and implant retention, the patient underwent a second irrigation and debridement due to persistent infection. Cefazolin and rifampin therapy was extended. Three days later, the patient presented to the emergency room with significant bleeding at the surgical site and a profoundly elevated prothrombin time and international normalized ratio (INR). No potential contributors were identified. The Naranjo adverse drug reaction probability scale identified cefazolin and rifampin as the probable cause of elevated INR. The Liverpool adverse drug reaction avoidability assessment tool classified this adverse event as \"definitely avoidable.\"\n\n\nCONCLUSIONS\nRifampin-containing regimens are often recommended to treat staphylococcal prosthetic joint infections when the implant is retained. In methicillin-susceptible staphylococcal infections, cefazolin is routinely employed as the β-lactam backbone of definitive antimicrobial regimens. Although rifampin- and cefazolin-induced hypoprothrombinemia seems to be rare, adverse consequences of its occurrence may be prevented with appropriate monitoring.",
"affiliations": "Division of Infectious Diseases, Mayo Clinic, Rochester, MN, USA.;Department of Pharmacy, Mayo Clinic, Rochester, MN, USA.;Division of Infectious Diseases, Mayo Clinic, Rochester, MN, USA.;Department of Pharmacy, Mayo Clinic, Rochester, MN, USA.;Division of Infectious Diseases, Mayo Clinic, Rochester, MN, USA.",
"authors": "Castillo Almeida|Natalia E|NE|;Stevens|Ryan W|RW|;Gurram|Pooja|P|;Rivera|Christina G|CG|;Suh|Gina A|GA|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ajhp/zxab210",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "78(24)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": "\n N-methylthiodiazole; \n N-methylthiogetrazole; cefazolin; hypoprothrombinemia; international normalized ratio; rifampin",
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": null,
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "2204-2208",
"pmc": null,
"pmid": "34000006",
"pubdate": "2021-12-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cefazolin and rifampin: A coagulopathy-inducing combination.",
"title_normalized": "cefazolin and rifampin a coagulopathy inducing combination"
} | [
{
"companynumb": "US-DRREDDYS-SPO/USA/21/0136683",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
... |
{
"abstract": "Lactobacillus species may translocate from the gastrointestinal tract into systemic circulation from ingested probiotics or commensal flora. Their pathogenic potential is still debated. Lactobacillus endocarditis is a rare entity with only around 120 cases reported in the literature. Here, we report the first case of fatal Lactobacillus endocarditis with involvement of a transcatheter aortic valve replacement with the following goals: to reaffirm the pathological significance of Lactobacillus spp, to demonstrate the potential limitations of the modified Duke criteria in diagnosing infective endocarditis of transcatheter aortic valve replacement, and to urge clinicians to aggressively search for and consider empiric treatment for endocarditis in patients with prosthetic valves who develop Lactobacillus bacteraemia.",
"affiliations": "Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.;Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.;Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.;Department of Medicine, Division of Hospital Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA maria.theodorou@nm.org.",
"authors": "Agrawal|Saaket|S|http://orcid.org/0000-0002-2535-4759;Tuchman|Emily S|ES|;Bruce|Matthew J|MJ|;Theodorou|Maria E|ME|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-236835",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(11)",
"journal": "BMJ case reports",
"keywords": "cirrhosis; diet; infectious diseases; interventional cardiology; valvar diseases",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D001921:Brain; D002543:Cerebral Hemorrhage; D004697:Endocarditis, Bacterial; D017809:Fatal Outcome; D016908:Gram-Positive Bacterial Infections; D006350:Heart Valve Prosthesis; D006801:Humans; D007778:Lactobacillus; D008297:Male; D016459:Prosthesis-Related Infections; D065467:Transcatheter Aortic Valve Replacement",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33257370",
"pubdate": "2020-11-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal Lactobacillus endocarditis in a patient with transcatheter aortic valve replacement.",
"title_normalized": "fatal lactobacillus endocarditis in a patient with transcatheter aortic valve replacement"
} | [
{
"companynumb": "US-BAUSCH-BL-2021-009306",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GENTAMICIN"
},
"drugadditional": null,
... |
{
"abstract": "Atrial fibrillation (AF) is a common disease and can lead to cardioembolic stroke. Stroke prevention according to the CHA2DS2VASc score is achieved via oral anticoagulation. In recent years, interventional occlusion of the left atrial appendage (LAA) has become a common alternative. Besides showing non-inferiority in large trials compared with warfarin interventional LAA occlusion can lead to serious adverse events with most of them occurring peri-interventionally.\nA 75-year-old man with AF and recurrent gastrointestinal bleedings was referred for an interventional closure of the LAA. The intervention was successful with an ABBOTT® Amulet device. Four months later, the patient had to be resuscitated. Return of spontaneous circulation occurred after 10 min. On hospital arrival, echocardiography revealed a pericardial tamponade and 2 L of blood were drained. A coronary angiogram revealed a lesion with active leakage of contrast agent in the proximal circumflex artery. The patient was transferred to the cardiac surgery department immediately. Intra-operatively a perforation of the tissue at the basis of the LAA close to the left main coronary artery was discovered. The occluder was excised and the LAA was closed by endocardial sutures.\nIn this report, we review the literature concerning interventional LAA occlusion and the reported cases of LAA perforation. Retrospectively, it remains unclear whether the perforation caused the resuscitation or was induced by it. To our knowledge, this is the first reported case of a laceration of a coronary artery by an occlusion device.",
"affiliations": "Medical Clinic/Cardiology, Asklepios Klinik Barmbek, Ruebenkamp 220, 22291 Hamburg, Germany.;Department of Cardiac Surgery, Asklepios Klinik St. Georg, Lohmuehlenstraße 5, 20099 Hamburg, Germany.;Medical Clinic/Cardiology, Asklepios Klinik Altona, Paul-Ehrlich-Straße 1, 22763 Hamburg, Germany.;Medical Clinic/Cardiology, Asklepios Klinik Barmbek, Ruebenkamp 220, 22291 Hamburg, Germany.",
"authors": "Schenke|Karsten|K|0000-0002-0030-0623;Geidel|Stephan|S|;Keller|Christian|C|0000-0003-3350-0055;Grönefeld|Gerian|G|0000-0003-0079-1829",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ehjcr/ytz170",
"fulltext": "\n==== Front\nEur Heart J Case RepEur Heart J Case RepehjcrEuropean Heart Journal: Case Reports2514-2119Oxford University Press 10.1093/ehjcr/ytz170ytz170Case ReportsA case report of a late left atrial appendage perforation 4 months after occluder implant: reason for or caused by a resuscitation? http://orcid.org/0000-0002-0030-0623Schenke Karsten 1Geidel Stephan 2http://orcid.org/0000-0003-3350-0055Keller Christian 3http://orcid.org/0000-0003-0079-1829Grönefeld Gerian 11 \nMedical Clinic/Cardiology, Asklepios Klinik Barmbek, Ruebenkamp 220, 22291 Hamburg, Germany2 \nDepartment of Cardiac Surgery, Asklepios Klinik St. Georg, Lohmuehlenstraße 5, 20099 Hamburg, Germany3 \nMedical Clinic/Cardiology, Asklepios Klinik Altona, Paul-Ehrlich-Straße 1, 22763 Hamburg, Germanyde Potter Tom Handling EditorXaplanteris Panagiotis EditorDinov Borislav EditorVamvakidou Anastasia EditorPatel Peysh A Editor Corresponding author. Tel: +49 40 1818 82 4811, Email: k.schenke@asklepios.com12 2019 04 10 2019 04 10 2019 3 4 1 4 14 1 2019 29 3 2019 12 9 2019 © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.2019 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits 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\nAtrial fibrillation (AF) is a common disease and can lead to cardioembolic stroke. Stroke prevention according to the CHA2DS2VASc score is achieved via oral anticoagulation. In recent years, interventional occlusion of the left atrial appendage (LAA) has become a common alternative. Besides showing non-inferiority in large trials compared with warfarin interventional LAA occlusion can lead to serious adverse events with most of them occurring peri-interventionally.\n\nCase summary\nA 75-year-old man with AF and recurrent gastrointestinal bleedings was referred for an interventional closure of the LAA. The intervention was successful with an ABBOTT® Amulet device. Four months later, the patient had to be resuscitated. Return of spontaneous circulation occurred after 10 min. On hospital arrival, echocardiography revealed a pericardial tamponade and 2 L of blood were drained. A coronary angiogram revealed a lesion with active leakage of contrast agent in the proximal circumflex artery. The patient was transferred to the cardiac surgery department immediately. Intra-operatively a perforation of the tissue at the basis of the LAA close to the left main coronary artery was discovered. The occluder was excised and the LAA was closed by endocardial sutures.\n\nDiscussion\nIn this report, we review the literature concerning interventional LAA occlusion and the reported cases of LAA perforation. Retrospectively, it remains unclear whether the perforation caused the resuscitation or was induced by it. To our knowledge, this is the first reported case of a laceration of a coronary artery by an occlusion device.\n\nCase reportAtrial fibrillationStroke preventionCardiac tamponadeLAA occluder device Resuscitation\n==== Body\nLearning point\n\nCheck early for cardiac tamponade after left atrial appendage occlusion even when the procedure has been performed more than 3 months earlier, i.e. after an unexplained resuscitation.\n\n\n\n\n\n\n\nIntroduction\nAtrial fibrillation (AF) is a common disease and can lead to cardioembolic stroke.1 In patients with known AF and an elevated CHA2DS2 VASc score stroke prevention is advised using an oral anticoagulant (OAC).2 Owing to the observation that the majority of cardiogenic thrombi originate in the left atrial appendage (LAA), percutaneous interventional occlusion of the LAA has been introduced as an alternative for patients that have a high bleeding risk or are intolerant to OAC. For such patients, the current European Society of Cardiology (ESC) guidelines recommend the interventional LAA closure (LAAC) with a class of recommendation of IIb and a level of evidence B. Several studies demonstrated non-inferiority compared with warfarin.3,4 However, interventional LAAC can lead to serious adverse events most commonly occurring peri-interventionally. In a European registry, a procedure-related complication rate of 4% at 30 days has been reported.5 In this registry of 1021 patients undergoing LAAC, there were seven cases of pericardial effusion with three of them requiring pericardiocentesis within 30 days of the procedure.\n\nTimeline\nNovember 2016\t\nSuccessful percutaneous interventional closure of the left atrial appendage (LAA) with an ABBOTT® Amulet device (18 mm)\n\n\n\t\nApril 2017 8:30 a.m.\t\nPatient complained of acute progressive dyspnoea and called the emergency medical system (EMS)\n\n\n\t\n9 a.m.\t\nOn EMS arrival, the patient is conscious, vital signs show:\n\n blood pressure of 80/50 mmHg\n\n heart rate of 90/min\n\n oxygen saturation of 85%\n\nTreatment with bronchodilator medication is initiated for presumed exacerbated chronic obstructive pulmonary disease\n\nAfterwards, a pulseless electrical activity is registered on the electrocardiogram\n\nCardiac compressions and application of catecholamines led to a return of spontaneous circulation\n\n\n\t\n10 a.m.\t\nIn the ED Ultrasound revealed a cardiac tamponade, a drainage tube was installed and the patient transferred to the intensive care unit\n\n\n\t\n3 p.m.\t\nMore than 2 L of blood have been drained\n\nIn preparation of heart surgery, a coronary angiogram was performed\n\nA lesion with active leakage of contrast agent in the proximal circumflex artery was discovered\n\nThe patient was transferred to the cardiac surgery department\n\n\n\t\n6 p.m.\t\nIntra-operatively a perforation of the tissue at the basis of the LAA close to the left main coronary artery was discovered\n\nThe occluder was excised and the LAA was closed by endocardial sutures, two pledget sutures were used to seal the epicardial lesion at the LAA basis which stopped the bleeding\n\n\n\t\nJune 2017\t\nAfter prolonged weaning, the patient is discharged into rehabilitation facilities\n\n\n\t\nCase presentation\nA 75-year-old man with persistent AF, a CHA2DS2 VASc score of 4 and a HAS-BLED score of 4 with recurrent gastrointestinal bleedings was referred to a tertiary clinic for a LAAC. His medical history consisted of a chronic obstructive pulmonary disease (COPD), coronary artery disease, and a two-thirds gastric resection performed in the 1980s. The intervention was successfully performed with an ABBOTT® Amulet 18 mm device being implanted (Figure 1A). After the implantation, he received acetylsalicylic acid (ASA) and Clopidogrel for 6 months. Approximately 5 months post-intervention, the patient expressed acute dyspnoea and called the emergency medical services (EMS).\n\n\nFigure 1 (A) Transoesophageal echocardiography (TOE) of the implantation. (B) Coronary angiogram.\n\nOn arrival of the EMS, the patient was conscious, severely distressed and hypotensive with a blood pressure of 80/50 mmHg and a heart rate of 90/min. Peripheral oxygen saturation of 85% measured percutaneously was noted. After the administration of bronchodilator medication for a presumed COPD exacerbation, the patient’s clinical condition deteriorated with a resultant cardiac arrest with pulseless electrical activity. The patient received cardiopulmonary resuscitation including chest compressions, endotracheal intubation, and the administration of 3 mg Adrenaline. Return of spontaneous circulation occurred approximately 10 min later at which point he was transferred to a local hospital. During the transport, the cardiocirculatory parameters were relatively stable with a systolic pressure around 100 mmHg. The capnometry after return of spontaneous circulation measured a pCO2 of 60 mmHg. Upon arrival at the hospital, the physical examination showed jugular vein distension but no peripheral oedema.\n\nEchocardiography performed in the emergency department revealed a pericardial tamponade requiring pericardiocentesis via the subxiphoidal route, 800 mL of blood were initially evacuated. The differential diagnosis included primary respiratory failure or a sudden cardiac death with secondary pericardial effusion induced by cardiac compressions under double antiplatelet therapy, a ruptured aortic aneurysm, a myocardial rupture, or a primary laceration of a cardiac structure by the LAA occluder. A ruptured aneurysm of the ascending aorta was excluded by ultrasound. Electrocardiogram examination did not demonstrate any ST-segment elevation or low voltage. Blood gas analysis documented a stable respiratory situation with a pO2 of 230 mmHg and a pCO2 of 55 mmHg, the pH was 7, 3 and Lactate elevated with 10 mmol/L (<2 mmol/L). The haemoglobin was measured at 9 g/dL (12–16 g/dL). The chest X-ray demonstrated the proper placement of the endotracheal and pericardial tube and ruled out a pneumothorax or pulmonary oedema.\n\nIn the hours following pericardiocentesis, approximately 2 L of blood were evacuated. Conventional methods of coagulopathy management including application of tranexamic acid, fresh frozen plasma, and fibrinogen did not stop the bleeding. To stabilize the patient a total of eight packs of red blood cells were transfused.\n\nIn preparation of cardiac surgery, a coronary angiogram was performed (Figure 1B). It revealed active leakage of contrast agent in the proximal circumflex artery and the patient was transferred to the cardiac surgery department immediately. Intra-operatively a perforation of the tissue at the basis of the LAA close to the left main coronary artery was discovered. Under protection of cold blood cardioplegia on cardiopulmonary bypass the occluder was excised through the opened left atrium. The LAA was closed by endocardial sutures and two pledget sutures were used to seal the epicardial lesion at the LAA basis which stopped the bleeding. Fortunately, after prolonged treatment in the intensive care unit and weaning ward the patient was discharged and alive 4 months after the event without neurological deficit and on ASA monotherapy. Transthoracic echocardiogram in the weaning ward ruled out a persistent pericardial effusion.\n\nDiscussion\nIn any resuscitation point of care ultrasound is needed to exclude treatable courses of cardiac arrest.6 In this case, it revealed a pericardial tamponade and after insertion of a drainage tube the patient stabilized. As for the differential diagnosis, several reasons for a pericardial effusion need to be considered. Probably, the most common cause is an iatrogenic rupture of cardiac structures which is a possible complication of most cardiac interventions, i.e. coronary stenting, pacemaker implantation, or electrophysiology study. Ruptured aortic aneurysm can be diagnosed via ultrasound or computed tomography scan. A rare complication of a myocardial infarction is a rupture of a left ventricular aneurysm and is often fatal.\n\nIn the literature, there are reported cases of an acute perforation of the LAA during occluder implantation leading to cardiac tamponade.7,8 Sarcon et al.7 report a case of an unintended sheath motion during release of the device leading to a LAA perforation. Another case report of an implantation of an Amulet device describes a perforation of the pulmonary artery by the hooks of the device leading to a cardiac arrest 8 h after the implantation.9\n\nCases of delayed pericardial perforations have been reported following interventional septal occlusion. One case report describes a delayed pericardial tamponade by an atrial septal defect (ASD) occluder 79 days after implantation leading to cardiac arrest.10 Taggart et al.11 report a case of a pericardial perforation occurring 6 years after interventional patent foramen ovale (PFO) closure. In the setting of interventional septal occlusion, it has been postulated that these late pericardial perforations have been induced by the rigid material of the occluder that can potentially erode the left atrial roof or the aortic root.12 This complication is very rare but life-threatening after interventional placement of PFO and ASD closure devices, the incidence ranging from 0.1% to 0.3%.12 Patients that received an oversized septal occluder or have a short anterosuperior rim are at higher risk of device induced erosion.10\n\nIn review of the clinical information in the reported case, it remains unclear whether a primary perforation of the LAA led to the ambulatory cardiac arrest. Since there were more than one laceration of the LAA, it seems also possible that the thoracic compressions led to the perforation and consecutive pericardial tamponade while the initial collapse was caused by an exacerbated COPD.\n\nTo our knowledge, this is the first reported case of a potential late laceration of the circumflex artery by an LAA occluder. This possible complication has to be kept in mind when treating a patient with cardiac arrest and a history of LAA occluder placement.\n\nLead author biography\nDr Karsten Schenke was born in 1976 in Hannover. He is an Interventional Cardiologist working in Hamburg at academic hospital AK Barmbek. His fields of interests are radial access for coronary interventions, implantation of PFO/LAA occluder and intensive care.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\n\nConsent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient in line with COPE guidance.\n\n\nConflict of interest: none declared.\n\nSupplementary Material\nytz170_Supplementary_Slide_Set Click here for additional data file.\n==== Refs\nReferences\n1 \nHart RG , Pearce LA , Aguilar MI. \nMeta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation antithrombotic therapy in atrial fibrillation . Ann Intern Med 2007 ;146 :857 –867 .17577005 \n2 \nAhlsson A , Manolis AS , Casadei B , Putte B , Van Popescu BA , Atar D , Kotecha D , Hindricks G , Diener H-C , Heidbuchel H , Hendriks J , Oldgren J , Castella M , Vardas P , Schotten U , Kirchhof P , Benussi S ; ESC Scientific Document Group. \n2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS . Eur Heart J 2016 ;37 :2893 –2962 .27567408 \n3 \nHolmes DR , Reddy VY , Turi ZG , Doshi SK , Sievert H , Buchbinder M , Mullin CM , Sick P. \nPercutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial . Lancet 2009 ;374 :534 –542 .19683639 \n4 \nHolmes DR , Doshi SK , Kar S , Price MJ , Sanchez JM , Sievert H , Valderrabano M , Reddy VY. \nLeft atrial appendage closure as an alternative to warfarin for stroke prevention in atrial fibrillation: a patient-level meta-analysis . J Am Coll Cardiol 2015 ;65 :2614 –2623 .26088300 \n5 \nBoersma LVA , Schmidt B , Betts TR , Sievert H , Tamburino C , Teiger E , Pokushalov E , Kische S , Schmitz T , Stein KM , Bergmann MW , EWOLUTION investigators. \nImplant success and safety of left atrial appendage closure with the WATCHMAN device: peri-procedural outcomes from the EWOLUTION registry . Eur Heart J 2016 ;37 :2465 –2474 .26822918 \n6 \nBreitkreutz R , Walcher F , Seeger FH. \nFocused echocardiographic evaluation in resuscitation management: Concept of an advanced life support-conformed algorithm . Crit Care Med 2007 ;35 :S150 –S161 .17446774 \n7 \nSarcon A , Roy D , Laughrun D , Huntsinger M , Schwartz J , Sohn J , Doshi RN. \nLeft atrial appendage occlusion complicated by appendage perforation rescued by device deployment . J Investig Med High Impact Case Rep 2018 ;6 :2324709618800108 .\n8 \nHagl C , Shrestha M , Peterss S , Khaladj N. \nLeft atrial appendage perforation during interventional occluder implantation . Eur J Cardiothorac Surg 2011 ;41 :961 .22423069 \n9 \nBollmann A , Bayer R , Zwirner J , Dreßler J , Hädrich C , Ondruschka B , Klein N. \nPulmonary artery perforation and coronary air embolism—two fatal outcomes in percutaneous left atrial appendage occlusion . Int J Legal Med 2017 ;131 :191 –197 .27815629 \n10 \nArnaz A , Turkekul Y , Yalcinbas Y , Saygili A , Sarioglu T. \nLate cardiac rupture after Amplatzer septal occluder implantation . Tex Heart Inst J 2016 ;43 :541 –542 .28100979 \n11 \nTaggart NW , Dearani JA , Hagler DJ. \nLate erosion of an Amplatzer septal occluder device 6 years after placement . J Thorac Cardiovasc Surg 2011 ;142 :221 –222 .21463878 \n12 \nAmin Z , Hijazi ZM , Bass JL , Cheatham JP , Hellenbrand WE , Kleinman CS. \nErosion of Amplatzer septal occluder device after closure of secundum atrial septal defects: review of registry of complications and recommendations to minimize future risk . Catheter Cardiovasc Interv 2004 ;63 :496 –502 .15558755\n\n",
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"keywords": " Resuscitation; Atrial fibrillation; Cardiac tamponade; Case report; LAA occluder device; Stroke prevention",
"medline_ta": "Eur Heart J Case Rep",
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"title": "A case report of a late left atrial appendage perforation 4 months after occluder implant: reason for or caused by a resuscitation?",
"title_normalized": "a case report of a late left atrial appendage perforation 4 months after occluder implant reason for or caused by a resuscitation"
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"abstract": "Neurologic adverse effects of triazole antifungal compounds used for the treatment of systemic and deep mycoses are relatively rare. The most common presentation is the involvement of peripheral nervous system, usually presenting with subjective symptoms such as paresthesia, dysesthesia, or numbness. Among these compounds, fluconazole has relatively more frequent neurological adverse reactions.A 54-year-old man was admitted with numbness and weakness in his both feet, which gradually worsened and resulted in difficulty in ambulation over time. He had no morbidity other than hypertension. He developed polyneuropathy (PNP), lower gastrointestinal system bleeding, acute renal insufficiency, thrombotic thrombocytopenic purpura, and confusional state. Severely disabling axonal and demyelinating sensorimotor PNP which led to immobilization of the patient for a few weeks but was recovered. When a more detailed past medical history was taken, he admitted to ingestion of 200 mg/day fluconazole for 1 month for onychomycosis without any prescription. This unusual combination of these rare adverse reactions of fluconazole may be explained by activation of an immune mechanism triggered by the drugs and genetic factors, or some other unknown individual factors.This case is reported due to the presence of rare systemic and neurologic adverse events of fluconazole, leading to this unusual clinical picture. We would like to emphasize fluconazole-related systemic and neurologic adverse reactions with life-threatening potential should be kept in mind.",
"affiliations": "Department of Neurology, University of Health Science, Izmir Bozyaka Training and Education Hospital, Izmir, Turkey.;Department of Neurology, University of Health Science, Izmir Bozyaka Training and Education Hospital, Izmir, Turkey.;Department of Neurology, Batman State Hospital, Batman, Turkey.;Department of Hematology, Kütahya University of Health Sciences, Kütahya, Turkey.;Department of Hematology, University of Health Science, Izmir Bozyaka Training and Education Hospital, Izmir, Turkey.",
"authors": "Eşkut|Neslihan|N|;Gedizlioğlu|Muhteşem|M|;Ünal|Osman|O|;Özlü|Can|C|;Ergene|Ulku|U|",
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"keywords": "Fluconazole; acute renal insufficiency; adverse reactions; polyneuropathy; thrombotic thrombocytopenic purpura",
"medline_ta": "Postgrad Med",
"mesh_terms": "D058186:Acute Kidney Injury; D000935:Antifungal Agents; D003221:Confusion; D064420:Drug-Related Side Effects and Adverse Reactions; D015725:Fluconazole; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D014009:Onychomycosis; D005791:Patient Care; D011115:Polyneuropathies; D011697:Purpura, Thrombotic Thrombocytopenic; D016896:Treatment Outcome",
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"title": "Acute fluconazole toxicity: a case presenting with protean manifestations including systemic and neurologic symptoms.",
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"abstract": "Combigan (Allergan, Irvine, CA) is an ophthalmic solution that combines 0.2% brimonidine, a selective α-2 adrenergic agonist, with 0.5% timolol, a nonselective β-adrenergic antagonist. It is approved for the reduction of intraocular pressure in patients with glaucoma or ocular hypertension. There have been recent reports of successful treatment of superficial infantile hemangiomas (IHs) using Combigan topically. We report the case of a 2-month-old girl who developed life-threatening brimonidine toxicity requiring intubation and mechanical ventilation secondary to central nervous system depression and apnea after topical application to an ulcerated IH.",
"affiliations": "Department of Pediatrics, Cleveland Clinic, Cleveland, Ohio.;Department of Dermatology, Cleveland Clinic, Cleveland, Ohio.;Department of Pharmacy, Cleveland Clinic, Cleveland, Ohio.;Department of Pediatric Cardiology, Cleveland Clinic, Cleveland, Ohio.;Department of Pediatric Intensive Care, Cleveland Clinic, Cleveland, Ohio.;Department of Pediatrics, Cleveland Clinic, Cleveland, Ohio.",
"authors": "Gill|Kamalvir|K|;Bayart|Cheryl|C|;Desai|Ritu|R|;Golden|Alex|A|;Raimer|Patricia|P|;Tamburro|Joan|J|",
"chemical_list": "D000316:Adrenergic alpha-Agonists; D000319:Adrenergic beta-Antagonists; D009883:Ophthalmic Solutions; D000068438:Brimonidine Tartrate; D013999:Timolol",
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"issue": "33(4)",
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"mesh_terms": "D000287:Administration, Topical; D000316:Adrenergic alpha-Agonists; D000319:Adrenergic beta-Antagonists; D001049:Apnea; D000068438:Brimonidine Tartrate; D005260:Female; D018324:Hemangioma, Capillary; D006801:Humans; D007035:Hypothermia; D007223:Infant; D009883:Ophthalmic Solutions; D012121:Respiration, Artificial; D012127:Respiratory Distress Syndrome, Newborn; D012878:Skin Neoplasms; D012883:Skin Ulcer; D013999:Timolol",
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"title": "Brimonidine Toxicity Secondary to Topical Use for an Ulcerated Hemangioma.",
"title_normalized": "brimonidine toxicity secondary to topical use for an ulcerated hemangioma"
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"abstract": "We describe a case of an anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer with development of uterine metastasis after crizotinib and alectinib treatment. Gene analysis from the tissue of uterine metastasis revealed the presence of 1151Tins, which was considered to be a crizotinib and alectinib resistance mutation. Subsequent therapy with the third-generation ALK inhibitor lorlatinib, but not ceritinib, showed antitumor activity for 1 year. The uterus is an uncommon site for metastasis from lung cancer, and our case indicated that serial gene analysis could provide new information about ALK inhibitor resistance.",
"affiliations": "Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Japan.",
"authors": "Kobayashi|Takashi|T|;Kanda|Shintaro|S|0000-0001-7864-3928;Fukushima|Toshirou|T|;Noguchi|Takuro|T|;Sekiguchi|Nodoka|N|;Koizumi|Tomonobu|T|0000-0002-5182-0960",
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"doi": "10.1111/1759-7714.14056",
"fulltext": "\n==== Front\nThorac Cancer\nThorac Cancer\n10.1111/(ISSN)1759-7714\nTCA\nThoracic Cancer\n1759-7706\n1759-7714\nJohn Wiley & Sons Australia, Ltd Melbourne\n\n34184417\n10.1111/1759-7714.14056\nTCA14056\nCase Report\nCase Reports\nResponse to lorlatinib on a patient with ALK‐rearranged non‐small cell lung cancer harboring 1151Tins mutation with uterine metastasis\nKobayashi et al.\nKobayashi Takashi 1\nKanda Shintaro https://orcid.org/0000-0001-7864-3928\n1 skanda@shinshu-u.ac.jp\n\nFukushima Toshirou 1\nNoguchi Takuro 1\nSekiguchi Nodoka 1\nKoizumi Tomonobu https://orcid.org/0000-0002-5182-0960\n1\n1 Department of Comprehensive Cancer Therapy Shinshu University School of Medicine Matsumoto Japan\n* Correspondence\nShintaro Kanda, Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, 3‐1‐1, Asahi Matsumoto, 390‐8621, Japan.\nEmail: skanda@shinshu-u.ac.jp\n\n28 6 2021\n8 2021\n12 16 10.1111/tca.v12.16 22752278\n31 5 2021\n17 4 2021\n02 6 2021\n© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nWe describe a case of an anaplastic lymphoma kinase (ALK)‐rearranged non‐small cell lung cancer with development of uterine metastasis after crizotinib and alectinib treatment. Gene analysis from the tissue of uterine metastasis revealed the presence of 1151Tins, which was considered to be a crizotinib and alectinib resistance mutation. Subsequent therapy with the third‐generation ALK inhibitor lorlatinib, but not ceritinib, showed antitumor activity for 1 year. The uterus is an uncommon site for metastasis from lung cancer, and our case indicated that serial gene analysis could provide new information about ALK inhibitor resistance.\n\nA patient with ALK‐rearranged advanced non‐small cell lung cancer presented acquired resistance to alectinib and uterine metastasis. Gene analysis using the tissue from the uterine metastasis revealed the presence of 1151Tins. Lorlatinib showed antitumor activity on this disease for one year.\n\n1151Tins\nALK\ngynecological metastasis\nlorlatinib\nnon‐small cell lung cancer\nsource-schema-version-number2.0\ncover-dateAugust 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.5 mode:remove_FC converted:16.08.2021\nKobayashiT, KandaS, FukushimaT, NoguchiT, SekiguchiN, KoizumiT. Response to lorlatinib on a patient with ALK‐rearranged non‐small cell lung cancer harboring 1151Tins mutation with uterine metastasis. Thorac Cancer. 2021;12 :2275–2278. 10.1111/1759-7714.14056\n==== Body\nINTRODUCTION\n\nThe discovery of rearrangement in the anaplastic lymphoma kinase (ALK) gene has led to a marked improvement in treatment strategy in patients with non‐small cell lung cancer (NSCLC). Several ALK inhibitors showed high response rates (60%–90%) and prolonged overall survival in patients with ALK‐rearranged NSCLC.1, 2, 3 On the other hand, resistant mechanisms to ALK‐inhibitors, such as secondary mutations in ALK, were analyzed in several studies4, 5, 6, 7, 8 and the clinical manifestations of unique metastatic organs in ALK‐rearranged lung cancer were also reported.9, 10, 11 We describe a case of ALK‐rearranged NSCLC who developed uterus metastasis during the treatment with two ALK inhibitors (crizotinib and alectinib). The diagnosis of uterus metastasis was confirmed by immunohistological analysis and determination of ALK fusion gene status with secondary mutations, 1151Tins, conferring resistance to crizotinib and alectinib. The new ALK inhibitor lorlatinib was useful to control the metastatic diseases. We report the clinical course and review of uterine metastases in NSCLC and secondary ALK mutation.\n\nCASE PRESENTATION\n\nA 54‐year‐old woman was referred to our hospital about 10 years ago and diagnosed with stage IVA NSCLC [adenocarcinoma, T2bN3M1a (right pleura, left pulmonary), epidermal growth factor receptor (EGFR)‐wild type]. Seven years ago, re‐biopsy by bronchoscopy was performed due to progression after cytotoxic chemotherapies including cisplatin plus pemetrexed, docetaxel, vinorelbine, etc. Immunohistochemical analysis for ALK was positive and ALK fusion was detected by fluorescence in situ hybridization. The patient was therefore treated with crizotinib followed by alectinib. Partial response had been maintained for approximately 3 years, but she complained of lower abdominal pain. Abdominal computed tomography (CT) revealed a mass in the uterus (Figure 1a, left) and bilateral hydronephrosis. The uterus tumor caused postrenal acute renal failure due to bilateral ureter obstruction. Simultaneously, a palpable left cervical lymph node was observed, and chest CT also showed progression of primary and metastatic tumors (Figure 1a, right). A ureteral stent was implanted, which released the obstruction and resolved the renal failure. Cervical lymph node biopsy and endometrial curettage were performed. Histological findings confirmed both specimens to be metastases from the ALK‐rearranged NSCLC (Figure 2). In addition, gene analysis revealed the presence of 1151Tins in both specimens, which was considered to be a crizotinib and alectinib resistance mutation.4 She was treated with ceritinib. However, 3 months of ceritinib therapy failed to control the disease in both the uterus and pulmonary tumors (Figure 1b), and lower abdominal pain deteriorated. Subsequently, treatment was switched to lorlatinib because it became available for clinical use in Japan. She developed hyperlipidemia as an adverse event, but tumor reductions in both the uterus and pulmonary metastatic lesions were observed (Figure 3) and she has been treated for at least 1 year without recurrence. Analysis of ALK resistance mutations was performed by digital PCR using LBx Probe ALK (Riken Genesis, Tokyo, Japan) covering the ALK mutations 1151Tins, L1152R, C1156Y, I1171T, F1174L, V1180 L, L1196M, G1202R, S1206Y, G1269A, and L1198F.\n\nFIGURE 1 Lower abdominal and chest computed tomography findings at recurrence during alectinib therapy in the present case. (a) Uterus mass (arrows) and pulmonary mass (primary lesion in right lung and metastatic lesion in left lung). (b) Uterus and pulmonary mass after treatment with ceritinib in the present case\n\nFIGURE 2 Pathological findings in cervical lymph node (a) and uterus (b). Left, hematoxylin and eosin staining; middle, immunohistochemical staining of thyroid transcription factor −1; right, immunohistochemical staining for anaplastic lymphoma kinase (ALK)\n\nFIGURE 3 Lower abdominal and chest computed tomography findings before (a) and after (b) treatment with ceritinib in the present case\n\nDISCUSSION\n\nWe present a case with ALK‐rearranged advanced NSCLC harboring uterine metastasis. Uterine metastasis occurs with low frequency during the clinical course of advanced NSCLC, so we searched such case reports in the PubMed database and summarize the case reports of NSCLC with uterine metastases and this case (Table 1).12, 13, 14, 15, 16, 17 Interestingly, several cases of ALK‐rearranged NSCLC presenting initially and/or developing ovarian and adnexa metastasis have also been reported.10, 11, 12, 13, 14, 15, 16, 17, 18, 19 These case reports and our case suggest that metastases to gynecological organs are not always rare in patients with ALK‐rearranged NSCLC. A retrospective study that investigated the metastatic patterns according to the molecular oncogene status reported that ALK‐rearranged NSCLC was associated with significantly increased numbers of metastatic sites in comparison to EGFR‐mutated and ALK wild‐type NSCLC.8 Thus, we should consider the possibility of gynecological metastasis in female patients with ALK‐rearranged NSCLC.\n\nTABLE 1 Case reports of NSCLC with uterine metastases\n\nCase\tAge at uterus metastasis\tHistology\tStage at initial diagnosis\tDuration from initial diagnosis to uterus metastasis\tSymptoms of uterus metastasis\tDriver gene alteration\tRef.\t\n1\t73\tAd\tIV\t3 years\tVaginal bleeding\tN/A\t12\t\n2\t49\tAd\tIV\tSame time\tNo symptoms\tN/A\t13\t\n3\t69\tAd\tIIIA\t4 years\tVaginal bleeding\tN/A\t14\t\n4\t58\tAd\tIV\t10 months\tVaginal bleeding\tN/A\t15\t\n5\t55\tAd\tIIIB\t5 months\tNo symptoms\tN/A\t16\t\n6\t51\tAd\tIV\tSame time\tNo symptoms\tEGFR\t16\t\n7\t47\tAd\tN/A\t1 year 6 months\tVaginal bleedingAnemia\t(−)\t17\t\n8\t63\tAd\tIIIB\t2 years\tVaginal bleeding\tEGFR\t18\t\nCurrent case\t57\tAd\tIV\t3 years\tLower abdominal pain\tALK\t‐\t\nAbbreviations: Ad, adenocarcinoma; N/A, not evaluated.\n\n1151Tins was reported as a secondary ALK mutation associated to crizotinib resistance at first,4 though it is rare among the resistance mutations reported to date.5 A preclinical study revealed that cells harboring 1151Tins with ALK fusion were resistant to crizotinib, ceritinib, and alectinib.4 Although we could not confirm the presence or absence of 1151Tins before crizotinib and alectinib treatment, it seemed that 1151Tins became dominant secondary during alectinib treatment as the acquired resistance mechanism because the tumor initially responded to crizotinib and alectinib. The other preclinical study reported lorlatinib activity for cells harboring 1151Tins with ALK rearrangement.7 In the present report, lorlatinib was effective for salvage therapy, while ceritinib was not. To our knowledge, this is the first case clinically proving the sensitivity of lorlatinib to ALK‐rearranged NSCLC harboring 1151Tins. Brigatinib is also a novel second‐generation ALK inhibitor, but its antitumor activity for cells harboring 1151Tins might be inferior to that of lorlatinib.8 Further information is needed regarding the optimal treatment sequence of these agents and mechanisms of resistance to each agent. To achieve longer survival in patients with ALK rearrangement, serial tissue samples should be taken by re‐biopsy and secondary ALK mutations conferring resistance to each ALK‐TKI should be evaluated.\n\nIn conclusion, we described an ALK‐rearranged NSCLC harboring 1151Tins mutation presenting a rare metastatic site of the gynecological tract successfully treated with loratinib. We emphasize that serial gene analysis could provide a better understanding of acquired resistance in ALK‐rearranged NSCLC and allow the selection of optimal treatment regimens.\n\nCONFLICT OF INTEREST\n\nAll the authors have no conflict of interest to declare.\n==== Refs\nREFERENCES\n\n1 KwakEL, BangYJ, CamidgeDR, et al. Anaplastic lymphoma kinase inhibition in non‐small‐cell lung cancer. N Engl J Med. 2010;363 :1693–703.20979469\n2 ShawAT, KimDW, NakagawaK, et al. Crizotinib versus chemotherapy in advanced ALK‐rearranged lung cancer. N Engl J Med. 2013;368 :2385–94.23724913\n3 HidaT, NokiharaH, KondoM, et al. Alectinib versus crizotinib in patients with ALK‐rearranged non‐small‐cell lung cancer (J‐ALEX): an open‐label, randomised phase 3 trial. Lancet. 2017;390 :29–39.28501140\n4 KatayamaR, ShawAT, KhanTM, et al. Mechanisms of acquired crizotinib resistance in ALK‐rearranged lung cancers. Sci Transl Med. 2012;4 :120ra17.\n5 GainorJF, DardaeiL, YodaS, et al. Molecular mechanisms of resistance to first‐ and second‐generation ALK inhibitors in ALK‐rearranged lung cancer. Cancer Discov. 2016;6 :1118–33.27432227\n6 FribouletL, LiN, KatayamaR, et al. The ALK inhibitor ceritinib overcomes crizotinib resistance in non‐small cell lung cancer. Cancer Discov. 2014;4 :662–73.24675041\n7 ZouHY, FribouletL, KodackDP, et al. PF‐06463922, an ALK/ROS1 inhibitor, overcomes resistance to first and second generation ALK inhibitors in preclinical models. Cancer Cell. 2015;28 :70–81.26144315\n8 ZhangS, AnjumR, SquillaceR, et al. The potent ALK inhibitor Brigatinib (AP26113) overcomes mechanisms of resistance to first‐ and second‐generation ALK inhibitors in preclinical models. Clin Cancer Res. 2016;22 :5527–38.27780853\n9 DoebeleRC, LuX, SumeyC, et al. Oncogene status predicts patterns of metastatic spread in treatment‐naive non‐small cell lung cancer. Cancer. 2012;118 :4502–11.22282022\n10 FujiwaraA, HigashiyamaM, KanouT, et al. Bilateral ovarian metastasis of non‐small cell lung cancer with ALK rearrangement. Lung Cancer. 2014;83 :302–4.24360322\n11 MushiRT, YangY, CaiQ, et al. Ovarian metastasis from non‐small cell lung cancer with ALK and EGFR mutations: a report of two cases. Oncol Lett. 2016;12 :4361–6.28105150\n12 PariniCL, MathisD, LeathCA3rd. Occult metastatic lung carcinoma presenting as positron emission tomography / computed tomography imaging. Int J Gynecol Cancer. 2007;17 :731–4.17504386\n13 KhanAM, JainVR, SchlesingerK, et al. A rare case of primary lung adenocarcinoma detected by routine liquid‐based cervical cytology. Lung Cancer. 2007;58 :282–5.17566599\n14 KaiK, TakaiN, NasuK, et al. Metastatic uterine cervical cancer originating in the lung: a case report. Gynecol Obstet Invest. 2009;68 :269–71.19776615\n15 TiseoM, BersanelliM, CorradiD, et al. Endometrial metastasis of lung adenocarcinoma: a case report. Tumori. 2011;97 :411–4.21789025\n16 AhmadZ, RazaA, PatelMR. Endometrial metastasis of lung adenocarcinoma: a report of two cases. Am J Case Rep. 2015;16 :296–9.25981989\n17 RushSK, ToukatlyMN, KilgoreMR, et al. Metastases from lung adenocarcinoma within a leiomyoma: a case report. Gynecol Oncol Rep. 2017;20 :27–9.28243626\n18 ShibataM, ShizuM, WatanabeK, et al. Uterine metastasis of lung adenocarcinoma under molecular target therapy with epidermal growth factor receptor tyrosine kinase inhibitors: a case report and review of the literature. J Obstet Gynaecol Res. 2018;44 :352–8.29094453\n19 WestAH, YamadaSD, MacMahonH, et al. Unique metastases of ALK mutated lung cancer activated to the adnexa of the uterus. Case Rep Clin Pathol. 2014;1 :151–4.25541622\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1759-7706",
"issue": "12(16)",
"journal": "Thoracic cancer",
"keywords": "1151Tins; ALK; gynecological metastasis; lorlatinib; non-small cell lung cancer",
"medline_ta": "Thorac Cancer",
"mesh_terms": null,
"nlm_unique_id": "101531441",
"other_id": null,
"pages": "2275-2278",
"pmc": null,
"pmid": "34184417",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports",
"references": "25541622;24675041;29094453;19776615;28501140;23724913;27432227;17566599;17504386;27780853;34184417;28105150;28243626;25981989;24360322;22282022;21789025;26144315;22277784;20979469",
"title": "Response to lorlatinib on a patient with ALK-rearranged non-small cell lung cancer harboring 1151Tins mutation with uterine metastasis.",
"title_normalized": "response to lorlatinib on a patient with alk rearranged non small cell lung cancer harboring 1151tins mutation with uterine metastasis"
} | [
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"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-313654",
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"abstract": "OBJECTIVE\nTo describe a 71-year-old woman who developed clinical and neuroradiological features of posterior reversible leukoencephalopathy syndrome with a compromised blood-brain barrier after 5 days of intravenous linezolid therapy for an infected hip prosthesis.\n\n\nMETHODS\nCase report.\n\n\nMETHODS\nAcademic research.\n\n\nMETHODS\nPosterior reversible leukoencephalopathy syndrome was documented using serial cranial magnetic resonance imaging, and the blood-brain barrier disturbance was demonstrated by contrast enhancement of a lesion and by cerebrospinal fluid analysis.\n\n\nRESULTS\nOther causes of posterior reversible leukoencephalopathy syndrome, such as renal failure, severe hypertension, inflammatory syndromes, and infectious diseases of the central nervous system, were excluded during hospitalization. After discontinuation of linezolid therapy, the patient's condition improved rapidly.\n\n\nCONCLUSIONS\nTo our knowledge, this is the first report of likely linezolid-induced posterior reversible leukoencephalopathy syndrome with an altered blood-brain barrier after short-term intravenous therapy.",
"affiliations": "Department of Neurology, University of Heidelberg, Heidelberg, Germany. simon.nagel@med.uni-heidleberg.de",
"authors": "Nagel|Simon|S|;Köhrmann|Martin|M|;Huttner|Hagen B|HB|;Storch-Hagenlocher|Brigitte|B|;Schwab|Stefan|S|",
"chemical_list": "D000081:Acetamides; D000890:Anti-Infective Agents; D023303:Oxazolidinones; D000069349:Linezolid",
"country": "United States",
"delete": false,
"doi": "10.1001/archneur.64.5.746",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-9942",
"issue": "64(5)",
"journal": "Archives of neurology",
"keywords": null,
"medline_ta": "Arch Neurol",
"mesh_terms": "D000081:Acetamides; D000368:Aged; D000890:Anti-Infective Agents; D001812:Blood-Brain Barrier; D001927:Brain Diseases; D005260:Female; D006801:Humans; D020343:Hypertensive Encephalopathy; D007239:Infections; D000069349:Linezolid; D008279:Magnetic Resonance Imaging; D023303:Oxazolidinones",
"nlm_unique_id": "0372436",
"other_id": null,
"pages": "746-8",
"pmc": null,
"pmid": "17502475",
"pubdate": "2007-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Linezolid-induced posterior reversible leukoencephalopathy syndrome.",
"title_normalized": "linezolid induced posterior reversible leukoencephalopathy syndrome"
} | [
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"companynumb": "DE-ALKEM LABORATORIES LIMITED-DE-ALKEM-2021-08533",
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"abstract": "We present a patient of who ingested large dose of of atenolol and amlodipine and was treated successfully with continuous venovenous hemodiafiltration. Early recognition of indications for renal support and early initiation of the same is the key to successful management.",
"affiliations": "Department of Nephrology, SVIMS, Tirupati, Andhra Pradesh, India.;Department of Nephrology, SVIMS, Tirupati, Andhra Pradesh, India.;Department of General Medicine, SVIMS, Tirupati, Andhra Pradesh, India.;Department of General Medicine, SVIMS, Tirupati, Andhra Pradesh, India.;Department of General Medicine, SVIMS, Tirupati, Andhra Pradesh, India.;Department of General Medicine, SVIMS, Tirupati, Andhra Pradesh, India.;Department of Nephrology, SVIMS, Tirupati, Andhra Pradesh, India.",
"authors": "Sandeep|P|P|;Ram|R|R|;Sowgandhi|N|N|;Reddy|S A|SA|;Katyarmal|D T|DT|;Kumar|B S|BS|;Kumar|V S|VS|",
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"delete": false,
"doi": "10.4103/0971-4065.133033",
"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India IJN-24-32710.4103/0971-4065.133033Case ReportAtenolol and amlodipine combination overdose managed with continuous venovenous hemodiafiltration: A case report Sandeep P. Ram R. Sowgandhi N. 1Reddy S. A. 1Katyarmal D. T. 1Kumar B. S. 1Kumar V. S. Department of Nephrology, SVIMS, Tirupati, Andhra Pradesh, India1 Department of General Medicine, SVIMS, Tirupati, Andhra Pradesh, IndiaAddress for correspondence: Dr. Ram Rapur, Department of Nephrology, SVIMS, Tirupati, Andhra Pradesh, India. E-mail: ram_5_1999@yahoo.comSep-Oct 2014 24 5 327 329 Copyright: © Indian Journal of Nephrology2014This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.We present a patient of who ingested large dose of of atenolol and amlodipine and was treated successfully with continuous venovenous hemodiafiltration. Early recognition of indications for renal support and early initiation of the same is the key to successful management.\n\nAtenololamlodipinecontinuous veno-venous hemodiafiltrationMobitz type II block\n==== Body\nIntroduction\nOf all the deaths due to overdosage of cardiovascular medications more than 65% are due to ingestion of β-blockers (BBs) and calcium channel blockers (CCBs).[1] Co-ingestion of BBs and CCBs is dangerous owing to the similar changes they produce in the physiology. We present a patient who consumed large doses of BB and CCB with suicidal intent. She was successfully managed by continuous veno-venous hemodiafiltration (CVVHDF).\n\nCase Report\nA 35-year-old female patient was brought to our institute with history of consumption of 100 tablets each of amlodipine besylate of 10 mg and atenolol of 50 mg with a suicidal intention. She was brought 8 h after the ingestion. She was in altered sensorium with E2, V2, M4 on Glasgow coma scale. Her blood pressure was 70/50 mm Hg, pulse rate 62 bpm, respiratory rate 32/min and axillary body temperature 96.5°F. There was tachycardia and tachypnea with prolonged expiration. She was immediately placed on a mechanical ventilator and started on adrenaline, dopamine and vasopressin. The investigations showed serum creatinine 2.5 mg/dl, blood urea 68 mg/dl, random blood glucose 109 mg/dl, serum bicarbonate 10.8 mEq/L and pH 7.14, electrocardiogram showed Mobitz type II AV block [Figure 1]. Later investigations showed serum sodium 134 mEq/L, potassium 4.3 mEq/L, calcium 7.5 mg/dl, phosphorus 5.0 mg/dl, hemoglobin 11.7 g/dl. Echocardiography showed no regional wall motion abnormality, normal left ventricular systolic function and ejection fraction of 60%.\n\nFigure 1 Electrocardiogram: 2nd degree AV block, Mobitz type II\n\nShe was started on 10% solution of calcium carbonate, glucagon infusion at 5 mg/h for 20 h following the first 5 mg loading dose and regular insulin, 1 unit/kg loading dose followed by 0.5 unit/kg/h along with continuous infusion of glucose and potassium. Blood glucose was monitored once in 30 min and serum potassium was monitored for 6 h. Patient had no urine output for the first 6 h after admission. She had worsening metabolic acidosis and declining blood pressure despite these measures. She was initiated on CVVHDF. with a filter made of AN 69 membrane. The surface area of the membrane was 0.9 m2. The dose of continuous renal replacement therapy was 20 ml/kg/h and blood flow was 50 ml/min. Heparin was used as anticoagulation. All measures including CVVHDF were continued for 90 h after admission. The patient's sensorium and urine output improved gradually in these 90 h. The blood pressure normalized after intensive treatment for 120 h. Once the blood pressure returned to normal the pressors was discontinued and she was extubated. The serial values of serum creatinine after initiation of CVVHDF were 3.0, 2.8, 1.6 and 1.4 mg/dl.\n\nDiscussion\nCyclic AMP is the intracellular messenger of beta-stimulation; among its action is the “opening” of calcium channels to promote a positive inotropic effect.[2] The CCBs act by L-channel of calcium. The function of L-channel is to admit the substantial amount of calcium ions required for initiation of contraction via calcium induced calcium release from the sarcoplasmic reticulum.[3] The final effect of these two classes-BBs and CCBs of drugs is inhibition of calcium influx into cells. The consensus guidelines for toxic doses of BB and CCB have been published.[45] BBs with low lipid solubility that lack membrane stabilizing effects are safer so also the newer CCBs than the diltiazem and verapamil.[1678] The lowest reported toxic doses of common BBs and CCBs were reported recently. The lowest reported toxic dose of atenolol in for an adult was 500 mg and amlodipine was 30 mg.[9]\n\nThe presentation of combined BB and CCB overdose may have common manifestations such as hypotension and bradycardia.[9] The features such as bronchospasm, due to loss of β selectivity in overdose and central nervous system depression due to BB with lipophilicity are indicators of BB toxicity.[9] Carvedilol and propranolol are typically high lipid soluble whereas labetalol, metoprolol and pindolol are moderately lipid soluble and atenolol in low lipid soluble.[9] Prolonged QRS interval because of sodium channel block may also suggest BB toxicity. CCB overdose may result in sinus bradycardia and atrioventricular block.[8] Hyperglycemia is due to blocking of calcium influx into pancreatic cells which is required for the release of insulin.[10] The altered sensorium of our patient could be attributed to poor perfusion of the brain due to hypotension and not due to atenolol as the latter is not lipid soluble.\n\nThere were two reports[1112] of CVVHDF in combined BB and CCB overdose. The indications for performing CVVHDF in our patient were acute renal failure with anuria and metabolic acidosis with hypotension. The metabolic acidosis was due to lactic acidosis due to shock and acidosis due to acute renal failure. Ketoacidosis due to hyperglycemia could also be a cause but was not identified in this patient. The effluent dose was kept low owing to profound hypotension. The high protein binding (93%) nature of amlodipine makes it non-dialyzable.[13] Atenolol being only 10% protein bound can be removed by extracorporeal blood purification techniques.[714] High dose glucagon is recommended in cardiotoxicity due to BB because it activates adenylate cyclase in cardiac tissue by directly stimulating a G protein on the β receptor complex.[915] Insulin-dextrose-potassium infusion is effective in CCB overdose through enhanced cardiac carbohydrate metabolism and direct inotropic effects.[16]\n\nWe present a patient of co-ingestion of atenolol and amlodipine treated successfully with CVVHDF along with the other measures. Early recognition of indications for renal support and early initiation of the same is the key to successful management. Even if the drugs are not dialyzable the correction of electrolyte abnormalities, metabolic acidosis and thus hypotension improves the outcome.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\n1 Love JN Howell JM Litovitz TL Klein-Schwartz W Acute beta blocker overdose: Factors associated with the development of cardiovascular morbidity J Toxicol Clin Toxicol 2000 38 275 81 10866327 \n2 Opie LH Opie LH Gersh BJ β.blocking agents Drugs for Heart 2013 8th ed Philadelphia, PA Saunders 1 37 \n3 Opie LH Opie LH Gersh BJ Calcium channel blockers Drugs for Heart 2013 8th ed Philadelphia, PA Saunders 64 92 \n4 Wax PM Erdman AR Chyka PA Keyes DC Caravati EM Booze L beta-blocker ingestion: An evidence-based consensus guideline for out-of-hospital management Clin Toxicol (Phila) 2005 43 131 46 15906457 \n5 Olson KR Erdman AR Woolf AD Scharman EJ Christianson G Caravati EM Calcium channel blocker ingestion: An evidence-based consensus guideline for out-of-hospital management Clin Toxicol (Phila) 2005 43 797 822 16440509 \n6 Critchley JA Ungar A The management of acute poisoning due to beta-adrenoceptor antagonists Med Toxicol Adverse Drug Exp 1989 4 32 45 2565523 \n7 Reith DM Dawson AH Epid D Whyte IM Buckley NA Sayer GP Relative toxicity of beta blockers in overdose J Toxicol Clin Toxicol 1996 34 273 8 8667464 \n8 Salhanick SD Shannon MW Management of calcium channel antagonist overdose Drug Saf 2003 26 65 79 12534324 \n9 Shepherd G Treatment of poisoning caused by beta-adrenergic and calcium-channel blockers Am J Health Syst Pharm 2006 63 1828 35 16990629 \n10 Shepherd G Klein-Schwartz W High-dose insulin therapy for calcium-channel blocker overdose Ann Pharmacother 2005 39 923 30 15811898 \n11 Rona R Cortinovis B Marcolin R Patroniti N Isgrò S Marelli C Extra-corporeal life support for near-fatal multi-drug intoxication: A case report J Med Case Rep 2011 5 231 21699679 \n12 Pfaender M Casetti PG Azzolini M Baldi ML Valli A Successful treatment of a massive atenolol and nifedipine overdose with CVVHDF Minerva Anestesiol 2008 74 97 100 18288073 \n13 Last accessed on 2013 Aug 05 Available from: \nhttp://www.dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=5549 \n14 Frierson J Bailly D Shultz T Sund S Dimas A Refractory cardiogenic shock and complete heart block after unsuspected verapamil-SR and atenolol overdose Clin Cardiol 1991 14 933 5 1764831 \n15 Bailey B Glucagon in beta-blocker and calcium channel blocker overdoses: A systematic review J Toxicol Clin Toxicol 2003 41 595 602 14514004 \n16 Kline JA Leonova E Raymond RM Beneficial myocardial metabolic effects of insulin during verapamil toxicity in the anesthetized canine Crit Care Med 1995 23 1251 63 7600835\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-4065",
"issue": "24(5)",
"journal": "Indian journal of nephrology",
"keywords": "Atenolol; Mobitz type II block; amlodipine; continuous veno-venous hemodiafiltration",
"medline_ta": "Indian J Nephrol",
"mesh_terms": null,
"nlm_unique_id": "8914356",
"other_id": null,
"pages": "327-9",
"pmc": null,
"pmid": "25249727",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports",
"references": "10866327;15906457;8667464;2565523;12534324;14514004;16440509;21699679;16990629;15811898;18288073;1764831;7600835",
"title": "Atenolol and amlodipine combination overdose managed with continuous venovenous hemodiafiltration: A case report.",
"title_normalized": "atenolol and amlodipine combination overdose managed with continuous venovenous hemodiafiltration a case report"
} | [
{
"companynumb": "IN-LUPIN PHARMACEUTICALS INC.-2014-01904",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
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"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
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"abstract": "OBJECTIVE\nTo describe a second case of treatment refractory chronic cluster headache responsive to clomiphene citrate and with long-term follow-up.\n\n\nMETHODS\nCase report with 7-year evaluation.\n\n\nMETHODS\nA 63-year-old man with a 17-year history of chronic cluster headache preceded to have significant adverse events or was nonresponsive to multiple cluster headache preventive medications including verapamil, lithium, valproic acid, topiramate, baclofen as well as greater occipital nerve blocks and inpatient hospitalization. The patient experienced 3-5 headaches per day. On clomiphene citrate 100 mg/day he became 100% pain-free and remained so for 3.5 years with only mild fatigue as a side effect. He then had cluster headache recurrence and did well on gabapentin for another 3 years with repeat headache recurrence. Clomiphene was restarted, and he became pain-free once again.\n\n\nCONCLUSIONS\nThis is the second reported case of the effective use of clomiphene citrate for the preventive treatment of medicinal refractory chronic cluster headache. This is the first case to report long-term follow-up of this neurohormonal treatment. Clomiphene citrate appears to be safe for extended use in chronic cluster headache even in an elderly sufferer and has a minimal side effect profile. The mechanism of action of how clomiphene prevents cluster headache may involve both its ability to enhance testosterone production and its ability to bind to hypothalamic estrogen receptors. Clomiphene citrate should join the list of alternative cluster headache prophylactic treatments to be considered by headache specialists when conventional cluster headache preventives are ineffective.",
"affiliations": "Geisinger Health System, Department of Neurology, Geisinger Headache Clinic, Wilkes-Barre, PA, USA.",
"authors": "Rozen|Todd D|TD|",
"chemical_list": "D002996:Clomiphene",
"country": "United States",
"delete": false,
"doi": "10.1111/head.12491",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0017-8748",
"issue": "55(4)",
"journal": "Headache",
"keywords": "clomiphene citrate; cluster headache; estrogen; hypothalamus; orexin; testosterone",
"medline_ta": "Headache",
"mesh_terms": "D002908:Chronic Disease; D002996:Clomiphene; D003027:Cluster Headache; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "2985091R",
"other_id": null,
"pages": "571-4",
"pmc": null,
"pmid": "25828543",
"pubdate": "2015-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Clomiphene citrate as a preventive treatment for intractable chronic cluster headache: a second reported case with long-term follow-up.",
"title_normalized": "clomiphene citrate as a preventive treatment for intractable chronic cluster headache a second reported case with long term follow up"
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... |
{
"abstract": "OBJECTIVE\nTo investigate the benefits of denosumab in combination with nerve-sparing surgery for treatment of sacral giant cell tumours (GCTs).\n\n\nMETHODS\nThis is a retrospective cohort study of patients with GCT who presented between January 2011 and July 2017. Intralesional curettage was performed and patients treated from 2015 to 2017 also received denosumab therapy. The patients were divided into three groups: Cohort 1: control group (n = 36); cohort 2: adjuvant denosumab group (n = 9); and cohort 3: neo- and adjuvant-denosumab group (n = 17).\n\n\nRESULTS\nThere were 68 patients within the study period. Six patients were lost to follow-up. The mean follow-up was 47.7 months (SD 23.2). Preoperative denosumab was found to reduce intraoperative haemorrhage and was associated with shorter operating time for tumour volume > 200 cm3. A total of 17 patients (27.4%) developed local recurrence. The locoregional control rate was 77.8% (7/9) and 87.5% (14/16) respectively for cohorts 2 and 3, in comparison to 66.7% (24/36) of the control group. The recurrence-free survival (RFS) rate was significantly higher for adjuvant denosumab group versus those without adjuvant denosumab during the first two years: 100% vs 83.8% at one year and 95.0% vs 70.3% at two years. No significant difference was found for the three-year RFS rate.\n\n\nCONCLUSIONS\nPreoperative denosumab therapy was found to reduce intraoperative haemorrhage and was associated with shorter operating times. Adjuvant denosumab was useful to prevent early recurrence during the first two years after surgery. Cite this article: Bone Joint J 2020;102-B(2):177-185.",
"affiliations": "Department of Orthopaedic Surgery, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia.;Musculoskeletal Tumor Center, People's Hospital, Peking University, Beijing, China.;Musculoskeletal Tumor Center, People's Hospital, Peking University, Beijing, China.;Musculoskeletal Tumor Center, People's Hospital, Peking University, Beijing, China.;Musculoskeletal Tumor Center, People's Hospital, Peking University, Beijing, China.;Musculoskeletal Tumor Center, People's Hospital, Peking University, Beijing, China.;Musculoskeletal Tumor Center, People's Hospital, Peking University, Beijing, China.;Musculoskeletal Tumor Center, People's Hospital, Peking University, Beijing, China.",
"authors": "Lim|Chiao Yee|CY|;Liu|Xingyu|X|;He|Fangzhou|F|;Liang|Haijie|H|;Yang|Yi|Y|;Ji|Tao|T|;Yang|Rongli|R|;Guo|Wei|W|",
"chemical_list": "D000970:Antineoplastic Agents; D000069448:Denosumab",
"country": "England",
"delete": false,
"doi": "10.1302/0301-620X.102B2.BJJ-2019-0813.R1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2049-4394",
"issue": "102-B(2)",
"journal": "The bone & joint journal",
"keywords": "Denosumab; Giant cell tumour; Intralesional curettage; Nerve-sparing surgery; Sacrum",
"medline_ta": "Bone Joint J",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents; D001859:Bone Neoplasms; D002648:Child; D003131:Combined Modality Therapy; D003475:Curettage; D000069448:Denosumab; D005260:Female; D018212:Giant Cell Tumor of Bone; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012447:Sacrum; D055815:Young Adult",
"nlm_unique_id": "101599229",
"other_id": null,
"pages": "177-185",
"pmc": null,
"pmid": "32009426",
"pubdate": "2020-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Retrospective cohort study of 68 sacral giant cell tumours treated with nerve-sparing surgery and evaluation on therapeutic benefits of denosumab therapy.",
"title_normalized": "retrospective cohort study of 68 sacral giant cell tumours treated with nerve sparing surgery and evaluation on therapeutic benefits of denosumab therapy"
} | [
{
"companynumb": "CN-AMGEN-CHNSP2020025877",
"fulfillexpeditecriteria": "2",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
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"drugadditional": "3",
... |
{
"abstract": "We have reviewed 47 drug rash with eosinophilia and systemic symptoms (DRESS) cases associated to strontium ranelate reported up to March 2011 to the Marketing Holder. The main signs were skin rash, fever, face oedema hypereosinophilia and liver involvement. For ten patients, persistence of DRESS symptoms was reported at the latest news obtained, and DRESS was identified as the direct cause of death in one case. The maximum incidence of DRESS associated with strontium ranelate was 1/24,112 [95 % CI (1/14,859; 1/42,194)] newly treated patients in France. Because DRESS is a severe drug reaction, the occurrence of a rash in a patient treated with strontium ranelate should lead to prompt and permanent treatment discontinuation.\n\n\nBACKGROUND\nThis study aims to describe cases of DRESS reported to the Marketing Authorisation Holder worldwide for patients receiving strontium ranelate by practitioner or by regulatory authorities.\n\n\nMETHODS\nSpontaneously reported hypersensitivity events from the strontium ranelate pharmacovigilance database since marketing authorisation (2004) to March 2011 were reviewed by an expert committee. Cases of DRESS were classified as established, probable, possible or no DRESS according to expert judgement. National incidences of DRESS were estimated in relation to the number of newly treated patients.\n\n\nRESULTS\nUp to March 2011, 325 cases of strontium ranelate-induced hypersensitivity events were assessed from which 47 DRESS cases were confirmed. Mean age was 68.7 years and besides skin rash, the main signs and symptoms were hypereosinophilia, liver involvement, fever and face oedema. Median time to skin reaction was 33.5 days after treatment start. Most patients (62 %) recovered at the time of reporting or were recovering. For ten patients, persistence of DRESS symptoms was reported at the latest news obtained. Relapses were observed in a single case. The mortality rate was 8.5 %. The maximum incidence of DRESS associated with strontium ranelate was 1/24,112 [95 % CI (1/14,859; 1/42,194)] newly treated patients in France.\n\n\nCONCLUSIONS\nDRESS is a well-identified and characterised adverse reaction to strontium ranelate. This risk should be integrated in the risk-benefit balance evaluation of patient treatment, and the occurrence of a rash should lead to prompt and permanent treatment discontinuation with careful follow-up.",
"affiliations": "AP-HP, Department of Internal Medicine, Pitié-Salpêtrière Hospital, 83 Boulevard de l'hopital, 75013 Paris, France. patrice.cacoub@psl.aphp.fr",
"authors": "Cacoub|P|P|;Descamps|V|V|;Meyer|O|O|;Speirs|C|C|;Belissa-Mathiot|P|P|;Musette|P|P|",
"chemical_list": "D050071:Bone Density Conservation Agents; D013876:Thiophenes; C081587:strontium ranelate",
"country": "England",
"delete": false,
"doi": "10.1007/s00198-013-2265-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0937-941X",
"issue": "24(5)",
"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": null,
"medline_ta": "Osteoporos Int",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D050071:Bone Density Conservation Agents; D003875:Drug Eruptions; D004342:Drug Hypersensitivity; D004802:Eosinophilia; D005060:Europe; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D060735:Pharmacovigilance; D013876:Thiophenes",
"nlm_unique_id": "9100105",
"other_id": null,
"pages": "1751-7",
"pmc": null,
"pmid": "23361875",
"pubdate": "2013-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "9069593;17973540;16259349;12862499;15802211;21243321;15767024;21592453;22870464;21333824;20812008;19456761;17300272;19153346;3198757;11255328;19210353;20739682;19712264",
"title": "Drug rash with eosinophilia and systemic symptoms (DRESS) in patients receiving strontium ranelate.",
"title_normalized": "drug rash with eosinophilia and systemic symptoms dress in patients receiving strontium ranelate"
} | [
{
"companynumb": "FR-MYLANLABS-2015M1009677",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "STRONTIUM RANELATE"
},
"drugadditional": nul... |
{
"abstract": "BACKGROUND\nHepatitis C virus (HCV) infection is a recognised cause of secondary immune thrombocytopenia (ITP). While its incidence has been largely described during chronic HCV infection, only one case of ITP secondary to acute HCV infection has been reported at this time.\n\n\nMETHODS\nWe report herein the case of severe ITP secondary to an acute HCV genotype 1a reinfection in a human immunodeficiency virus (HIV)-negative man having sex with men who had been cured several years before of a previous acute genotype 4d HCV infection. After an unsuccessful standard therapy with two courses of intravenous immunoglobulin (at 1 g/kg daily for 2 days) associated with methylprednisolone 1 mg/kg daily, antiviral treatment with sofosbuvir-ledipasvir rapidly achieved virological response and normalised the platelet count.\n\n\nCONCLUSIONS\nAs a direct effect of HCV on megakaryocytes could be the predominant cause of ITP during acute infection, early antiviral treatment may be beneficial in this case.",
"affiliations": "Département d'hématologie clinique, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, 69495, Pierre-Bénite, France. vincent.alcazer@chu-lyon.fr.;Service des maladies infectieuses et tropicales, Hospices Civils de Lyon, Hôpital de la Croix Rousse, 69004, Lyon, France.;Inserm U1052, Centre de Recherche en Cancérologie de Lyon, 69008, Lyon, France.;Inserm U1052, Centre de Recherche en Cancérologie de Lyon, 69008, Lyon, France.;Service des maladies infectieuses et tropicales, Hospices Civils de Lyon, Hôpital de la Croix Rousse, 69004, Lyon, France.",
"authors": "Alcazer|Vincent|V|http://orcid.org/0000-0003-1843-6286;Miailhes|Patrick|P|;Ramière|Christophe|C|;Charre|Caroline|C|;Cotte|Laurent|L|",
"chemical_list": "D000998:Antiviral Agents; D001562:Benzimidazoles; D005449:Fluorenes; C000595958:ledipasvir, sofosbuvir drug combination; D014542:Uridine Monophosphate; D000069474:Sofosbuvir",
"country": "England",
"delete": false,
"doi": "10.1186/s12879-018-3597-4",
"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 359710.1186/s12879-018-3597-4Case ReportEarly sofosbuvir-ledipasvir treatment for acute HCV infection induced severe immune thrombocytopenia – a case report http://orcid.org/0000-0003-1843-6286Alcazer Vincent +33 (0)478 864 340vincent.alcazer@chu-lyon.fr 12Miailhes Patrick 3Ramière Christophe 245Charre Caroline 245Cotte Laurent 31 0000 0001 2163 3825grid.413852.9Département d’hématologie clinique, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, 69495 Pierre-Bénite, France 2 0000 0004 0384 0005grid.462282.8Inserm U1052, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France 3 0000 0004 4685 6736grid.413306.3Service des maladies infectieuses et tropicales, Hospices Civils de Lyon, Hôpital de la Croix Rousse, 69004 Lyon, France 4 0000 0004 4685 6736grid.413306.3Laboratoire de virologie, Hospices civils de Lyon, Hôpital de la Croix Rousse, 69004 Lyon, France 5 0000 0004 0450 6033grid.462394.eINSERM U1111, Centre International de Recherche en Infectiologie, Lyon, France 19 12 2018 19 12 2018 2018 18 68216 7 2018 7 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\nHepatitis C virus (HCV) infection is a recognised cause of secondary immune thrombocytopenia (ITP). While its incidence has been largely described during chronic HCV infection, only one case of ITP secondary to acute HCV infection has been reported at this time.\n\nCase presentation\nWe report herein the case of severe ITP secondary to an acute HCV genotype 1a reinfection in a human immunodeficiency virus (HIV)-negative man having sex with men who had been cured several years before of a previous acute genotype 4d HCV infection. After an unsuccessful standard therapy with two courses of intravenous immunoglobulin (at 1 g/kg daily for 2 days) associated with methylprednisolone 1 mg/kg daily, antiviral treatment with sofosbuvir-ledipasvir rapidly achieved virological response and normalised the platelet count.\n\nConclusions\nAs a direct effect of HCV on megakaryocytes could be the predominant cause of ITP during acute infection, early antiviral treatment may be beneficial in this case.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s12879-018-3597-4) contains supplementary material, which is available to authorized users.\n\nKeywords\nHepatitis C virusSofosbuvir-ledipasvirAcute immune thrombocytopeniaissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nImmune thrombocytopenia (ITP) is an acquired thrombocytopenia caused by immune platelet destruction. Most adults (80%) present a primary ITP in which different mechanisms contribute to a reduced platelet lifespan, involving mostly antibody- or T cell-mediated platelet destruction and impaired megakaryocytopoiesis [1]. Secondary ITP pathogenesis is slightly different and relates to underlying disorders among which infections, auto-immune diseases, and lymphoproliferative disorders are the leading causes [2].\n\nHepatitis C virus (HCV) infection is a recognised cause of secondary ITP [3]. Its occurrence has been well described in the case of chronic infection where the diagnosis can be difficult as different factors can contribute to thrombocytopenia including cross-reactive antibodies directed against platelet antigens, bone-marrow viral infection of progenitor cells, decreased production of thrombopoietin and splenic sequestration secondary to portal hypertension [2]. However, few cases of ITP secondary to acute hepatitis C virus (HCV) infection have been reported to date.\n\nHerein we report the case of a patient with severe secondary ITP during an acute HCV genotype 1a reinfection. Early treatment with sofosbuvir-ledipasvir allowed the prompt recovery of thrombocytopenia.\n\nCase presentation\nIn July 2017, a 54-year-old male was hospitalised for the recent appearance of multiple purpuric spots on the legs associated with gum bleeding. The patient was an HIV-negative man having sex with men, receiving HIV pre-exposure prophylaxis with tenofovir/emtricitabine for over a year. His medical history was significant for a primary syphilis in 2014 and multiple episodes of urethritis in the recent years. He reported frequent unprotected anal sex, with occasional bleeding, insertive and receiving fisting without gloves, and the use of nasal mephedrone during sexual encounters. He was previously diagnosed with an acute genotype 4 HCV infection in 2011 (Versant HCV genotype 2.0 assay (LiPA), Siemens Healthineers, Erlangen, Germany), cured following a 6-month course of pegylated interferon (IFN) and ribavirin. Acute genotype 1a HCV reinfection was diagnosed on 2017, June 26th (NS5A Sanger sequencing), while HCV-RNA was still negative on 2017, April 4th (Abbott RealTime HCV, Abbott, Molecular, Des Plaines, USA). The patient was asymptomatic at that time, platelet count was normal and HCV-RNA surveillance was scheduled, following the recommendations from the European AIDS clinical society [4].\n\nInitial physical examination found no other symptoms apart from a petechial purpura of the lower extremities and oral haemorrhagic blister. Blood pressure was 130/97 mmHg, heart rate 60 bpm with no fever, lymphadenopathy, or splenomegaly. There was no evidence of severe haemorrhage. Laboratory data at the admission are resumed in Table 1. Complete blood count found a severe thrombocytopenia (5 G/L) without any other cytopenia. Thrombocytopenia was confirmed on the peripheral blood smear which exhibited no morphological abnormalities and the absence of schistocytes. No other associated haemostasis abnormality was present (normal fibrinogen and factor V). Serum protein electrophoresis found no clonal gammopathy. Thyroid-stimulating hormone was normal. HIV serology was repeatedly negative and Hepatits B surface antibodies were detectable following a previous vaccination. At that time, mild elevation in aspartate transaminase (AST, 6 times the upper limit of normal (ULN)) and alanine transaminase (ALT, 7 x ULN) was found associated with a detectable HCV viral load of 4.9 log IU/mL (Fig. 1). There was no evidence of other replicating viruses including cytomegalovirus, parvovirus B19, human herpes virus type 6 and type 8 (except a slight Epstein-Barr virus replication which was considered insignificant (348 UI/mL). Cryoglobulin investigation was negative. No circulating anti-platelet IgG antibodies were detected. A bone marrow aspiration was performed; normal cellularity with an increased number of megakaryocytes and normal erythropoiesis and myelopoiesis was found, thus confirming the diagnosis of ITP secondary to acute HCV infection.Table 1 Laboratory data at the admission\n\nParameter\tBaseline value\tNormal value (range)\t\nComplete blood count\t\n Leucocytes\t5.69 G/L\t4.00–10.00\t\n Haemoglobin\t149 g/L\t130–170\t\n MCV\t95.0 fL\t80–100\t\n Platelet\t< 10 G/L\t150–400\t\n Schistocytes\t< 1%\t< 1%\t\n Neutrophils\t3.27 G/L\t1.8–7.5\t\n Eosinophils\t0.19 G/L\t0.02–0.8\t\n Lymphocytes\t1.65 G/L\t1–4\t\n Monocytes\t0.52 G/L\t0.2–0.9\t\nHaemostasis\tNormal PT and aPTT\t\t\n Fibrinogen\t2.23 g/L\t2.13–4.22\t\n Factor V\t> 150%\t61–142\t\nBlood chemistry\t\n Creatinine\t86 μmol/L\t59–104\t\n eGFR\t87.8 mL/min/1.73 m2\t90.0–120.0\t\n AST\t202 IU/L\t15–37\t\n ALT\t483 IU/L\t16–61\t\n Alkaline phosphatase\t101 IU/L\t50–136\t\n GGT\t292 IU/L\t15–85\t\n Total bilirubin\t13 μmol/L\t3–17\t\n Conjugated bilirubin\t4 μmol/L\t0–3\t\n Lacticodehydrogenase\t254 IU/L\t87–241\t\nSerum protein electrophoresis\tNormal\t\t\nCryoglobulin\tNegative\t\t\nMyelogram\tNormal cellularity\t\t\nSerology\t\n Syphilis\tNegative\t\t\n HIV\tNegative\t\t\n HBV\tPositive for Hbs Ab\t\t\n CMV\tPositive for IgG\t\t\n EBV\tPositive for IgG\t\t\nBlood / plasma viral load\t\n HCV RNA\t82,004 IU/mL\t< 12\t\n CMV DNA\t0 IU/mL\t150–500\t\n EBV DNA\t348 IU/mL\t182–500\t\n HIV RNA\t< 40 copies/mL\t< 40\t\n Parvovirus B19 DNA\t0 copies/mL\t70–87\t\n HHV6 DNA\t0 copies/mL\t\t\n HHV8 DNA\t0 copies/mL\t500–2000\t\nGGT Gamma Glutamine Transferase, PT Prothrombine time, aPTT Activated Partial Thromboplastin Time\n\nFig. 1 Platelet and HCV viral load. Acute genotype 1a HCV reinfection was diagnosed on August 2017 on a systematic survey, with 11 xULN ALT and 5.91 log IU/mL HCV RNA. Platelets were found at 5 G/L for the unit admission on August 30, 2017. First course of IVIG was administrated on August 31, at the dose of 1 g/kg on day 1 and day 3, with clinical benefit but no effect on the platelet count. Second IVIG course was administrated on September 05 in association with methylprednisolone 1 mg/kg daily. Sofosbuvir-ledipasvir was started on September 11, allowing a sustained recovery of the platelet count with a quick viral load control (basal blue line represents an undetectable HCV viral load, inferior to 12 IU/mL). IVIG: intravenous immunoglobulin, MP: methylprednisolone, SOF-LDV: sofusbuvir-ledispavir, ALT: Alanine transaminase, HCV: Hepatitis C virus\n\n\n\nAn initial administration of intravenous immunoglobulin (IVIG; at the dose of 1 g/kg on day 1 and day 3) had clinical benefit (regression of gum bleeding and purpura), but did not have any effect on the platelet count which remained below 10G/L. A second administration of IVIG (1 g/kg daily for 2 days) combined with methylprednisolone (1 mg/kg daily) improved platelet count which reached 40G/L but a normal value was not attained (Fig. 1). At which point it was decided after collegial discussion to start treating the infectious trigger. Pegylated IFN and ribavirin combination was contra-indicated because of severe thrombocytopenia, therefore a 12 weeks course of sofosbuvir-ledipasvir was indicated. At initiation of the treatment, the platelet count was 43 G/L and HCV viral load was 6.3 log IU/mL. At day 15 of antiviral treatment, HCV viral load was undetectable (< 12 IU/ml) and the platelet count had increased to 108 G/L allowing rapid tapering and discontinuation of corticosteroids before the end of antiviral therapy. HCV viral load remained undetectable until week 12 post-treatment, confirming HCV cure (Fig. 1). Platelet count fully normalised 5 weeks following treatment initiation and remained within normal range thereafter. The patient went through his 12 weeks course of sofosbuvir-ledipasvir with a good tolerance, without any specific adverse event reported.\n\nDiscussion and conclusions\nChronic HCV infection has been associated with immune thrombocytopenia; the incidence is estimated to be 30.2–53 cases / 100,000 person-years [5, 6]. Conversely, HCV antibodies have been found in 10 to 36% of patients with chronic ITP in cross-sectional studies [5, 6]. However, our case is a rare report of ITP in the context of acute hepatitis C. Only one similar case has already been reported by Narita et al. in 2003 [7]. According to this report, ITP also occurred at the second HCV infection after a first HCV infection cured by 6 months of IFN-α2b. HCV genotype was found to be 2a in this reinfection case, versus 2b for the first one. In contrary to our findings, platelet associated immunoglobulins (PAIgG) were found positive in this report, with no other circulating antibodies (antinuclear antibody and rheumatoid factor were negative). Additionally, platelet count increased up to 39,000 /μL spontaneously and the PAIgG returned to the normal ratio without any specific therapy while in our case, platelet count only recovered after specific antiviral therapy. Considering these differences, a distinct physiopathological mechanism may have been the source of ITP in these two cases.\n\nThrombocytopenia is frequent in viral infection. In such situations, a complex crosstalk between platelet and the virus is engaged and different mechanisms may contribute to two major events [8]: first, a decreased platelet production which can be induced by direct infection of megakaryocytes, infection of haematopoietic stem cells, induction of a type-1 IFN response leading to suppression of platelet formation, or modulation of liver thrombopoietin production; second, an increased platelet destruction, either by a direct contact during viraemia, interaction with immune complexes, cross-reactive antibodies directed against the virus, or proinflammatory events induced by the infection [8].\n\nThe exact mechanism of HCV-induced ITP is still not clear. Extra-hepatic manifestations are common in HCV-infected patients, most of which are immune-related manifestations including mixed cryoglobulinaemia, arthralgia/myalgia, and auto-antibody production [9]. Importantly, the presence of only anti-platelet antibodies is not associated with thrombocytopenia [10]. This leads to consider the potential role of immune complexes promoted by the presence of cross-reactive antibodies or a compensating mechanism following a decrease in thrombopoietin production [10]. A direct effect of the virus on megacaryocytes may also be suspected as HCV can bind to CD81 on the platelet membrane, and HCV-RNA has also been detected in washed platelets of infected patients [11]. Platelets could thus either favour the spread of the virus or contribute to its immune recognition by providing targetable antigens [10]. Moreover, detection of HCV-RNA with a higher frequency in platelets of thrombocytopenic patients suggest that HCV is directly involved in this process [12]. At this time, there is no evidence for a particular association between specific HCV genotypes and incidence of ITP [12].\n\nThe treatment of HCV-related ITP, particularly in the case of acute infection, is not standardized. Dufour et al. reported the outcome of 8 patients with HCV-related ITP [13]. Patients had a poor response to initial corticosteroids therapy, with only one complete response and three partial response. IVIG led to transient efficacy in three other patients. Of eight patients treated by antiviral therapy associating IFN-α with ribavirin, five responded. Normalisation of platelet count occurred in three responders, and normalisation of viral load was usually slow. Other authors have reported the increase of platelet count associated with complete HCV eradication after IFN therapy [14, 15]. However, kinetic of platelet recovery was usually low in these cases.\n\nHerein, we describe the case of a severe ITP associated with acute HCV reinfection. IVIG was chosen as the first-line therapy, owing to their efficacy in primary ITP and secondary ITP related to chronic HCV infection [6]. The absence of effect on the platelet count led to a second course of IVIG and administration of methylprednisolone, which improved only slightly the thombocytopenia. Sofosbuvir-ledipasvir treatment was then initiated which rapidly decreased viral load to under the limit of detection and normalised the platelet count. Interestingly, no drop back of platelet following corticosteroid discontinuation was observed. The acute installation of the thrombocytopenia, its refractoriness to the first-line immunomodulatory and immunosuppressive therapy, the rapid improvement following antiviral treatment and the absence of circulating anti-platelet antibodies suggest a predominant effect of direct viral-mediated platelet destruction in this context where the other adaptive mechanisms might not had the time to develop. Notably, the first HCV infection in the patient presented herein did not trigger any thrombocytopenia. There is currently no data on the risk on ITP following HCV reinfection and we can only speculate on the relation between the first infection and the ITP case.\n\nIn summary, we report herein the case of a secondary ITP associated with an acute genotype 1a HCV reinfection in a 54-year-old patient. Early treatment with sofosbuvir-ledispavir was followed by a rapid virological response and a sustained platelet count recovery, suggesting a viral-mediated platelet destruction corrected by the antiviral therapy.\n\nAdditional file\n\nAdditional file 1: Table S1. Laboratory data evolution. (XLSX 11 kb)\n\n \n\n\nAbbreviations\nHCVHepatitis C Virus\n\nITPImmune thrombocytopenia\n\nIVIGIntravenous Immunoglobulin\n\nAcknowledgements\nNot applicable\n\nFunding\nThis manuscript did not benefit from any funding.\n\nAvailability of data and materials\nAll data generated or analysed during this study are included in this published article and its Additional file 1.\n\nAuthors’ contributions\nVA, PM, CR, CC, and LC analysed and interpreted the patient data. VA wrote the final manuscript. PM and LC reviewed and gave correction on the final version. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable\n\nConsent for publication\nWritten consent for publication was obtained from the patient.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Lambert MP Gernsheimer TB Clinical updates in adult immune thrombocytopenia Blood 2017 129 21 2829 2835 10.1182/blood-2017-03-754119 28416506 \n2. Cines DB Liebman H Stasi R Pathobiology of secondary immune thrombocytopenia Semin Hematol 2009 46 1 Suppl 2 S2 14 10.1053/j.seminhematol.2008.12.005 19245930 \n3. Chiao EY Engels EA Kramer JR Pietz K Henderson L Giordano TP Risk of immune thrombocytopenic purpura and autoimmune hemolytic anemia among 120 908 US veterans with hepatitis C virus infection Arch Intern Med 2009 169 4 357 363 10.1001/archinternmed.2008.576 19237719 \n4. Ryom L Boesecke C Gisler V Manzardo C Rockstroh JK Puoti M Essentials from the 2015 European AIDS clinical society (EACS) guidelines for the treatment of adult HIV-positive persons HIV Med 2016 17 2 83 88 10.1111/hiv.12322 26548563 \n5. Pawlotsky JM Bouvier M Fromont P Deforges L Duval J Dhumeaux D Hepatitis C virus infection and autoimmune thrombocytopenic purpura J Hepatol 1995 23 6 635 639 10.1016/0168-8278(95)80027-1 8750160 \n6. Dimitroulis D, Valsami S, Stamopoulos P, Kouraklis G. Immunological HCV-Associated Thrombocytopenia: Short Review. Clin Dev Immunol. 2012;2012 Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3400398/. [cited 2018 Apr 24].\n7. Narita R Asaumi H Abe S Nakamura H Tabaru A Yoshikawa I Idiopathic thrombocytopenic purpura with acute hepatitis c viral infection J Gastroenterol Hepatol 2003 18 4 462 463 10.1046/j.1440-1746.2003.02967.x 12653900 \n8. Assinger A. Platelets and Infection – An Emerging Role of Platelets in Viral Infection. Front Immunol. 2014;5 Available from: https://www.frontiersin.org/articles/10.3389/fimmu.2014.00649/full. [cited 2018 Jan 24].\n9. Cacoub P Comarmond C Domont F Savey L Desbois AC Saadoun D Extrahepatic manifestations of chronic hepatitis C virus infection Ther Adv Infect Dis 2016 3 1 3 14 26862398 \n10. Panzer S Seel E Brunner M Körmöczi GF Schmid M Ferenci P Platelet autoantibodies are common in hepatitis C infection, irrespective of the presence of thrombocytopenia Eur J Haematol 2006 77 6 513 517 10.1111/j.0902-4441.2006.t01-1-EJH2888.x 17042765 \n11. Hamaia S Li C Allain JP The dynamics of hepatitis C virus binding to platelets and 2 mononuclear cell lines Blood 2001 98 8 2293 2300 10.1182/blood.V98.8.2293 11588022 \n12. de Almeida AJ Campos-de-Magalhães M de Melo Marçal OP Brandão-Mello CE Okawa MY de Oliveira RV Hepatitis C virus-associated thrombocytopenia: a controlled prospective, virological study Ann Hematol 2004 83 7 434 440 10.1007/s00277-004-0844-0 14963696 \n13. Dufour J-F Pradat P Ruivard M Hot A Dumontet C Broussolle C Severe autoimmune cytopenias in treatment-naive hepatitis C virus infection: clinical description of 16 cases Eur J Gastroenterol Hepatol 2009 21 3 245 10.1097/MEG.0b013e3283249908 19279468 \n14. Karasawa T Togashi H Tajima K Suzuki A Onodera S Haga H Case of chronic type C hepatitis complicated with idiopathic thrombocytopenic purpura that was successfully treated by interferon therapy Nihon Shokakibyo Gakkai Zasshi Jpn J Gastro-Enterol 2009 106 3 405 410 \n15. d’Alteroche L Assor P Lefrou L Senecal D Gaudy C Bacq Y Severe autoimmune neutropenia and thrombopenia associated with chronic C hepatitis: effect of antiviral therapy Gastroenterol Clin Biol 2005 29 3 297 299 10.1016/S0399-8320(05)80766-3 15864183\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "18(1)",
"journal": "BMC infectious diseases",
"keywords": "Acute immune thrombocytopenia; Hepatitis C virus; Sofosbuvir-ledipasvir",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000208:Acute Disease; D000998:Antiviral Agents; D001562:Benzimidazoles; D061345:Early Medical Intervention; D005449:Fluorenes; D016174:Hepacivirus; D006526:Hepatitis C; D006801:Humans; D008297:Male; D008875:Middle Aged; D016553:Purpura, Thrombocytopenic, Idiopathic; D012720:Severity of Illness Index; D000069474:Sofosbuvir; D013997:Time Factors; D014542:Uridine Monophosphate",
"nlm_unique_id": "100968551",
"other_id": null,
"pages": "682",
"pmc": null,
"pmid": "30567495",
"pubdate": "2018-12-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11588022;12653900;14963696;15864183;17042765;19237719;19245930;19262055;19279468;25566260;26548563;26862398;28416506;8750160",
"title": "Early sofosbuvir-ledipasvir treatment for acute HCV infection induced severe immune thrombocytopenia - a case report.",
"title_normalized": "early sofosbuvir ledipasvir treatment for acute hcv infection induced severe immune thrombocytopenia a case report"
} | [
{
"companynumb": "FR-SHIRE-FR201902507",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
"drugadditional": null,... |
{
"abstract": "A 49-year-old man presented to the emergency department with acute-onset dyspnoea and hypoxaemia 1 day following nasal surgery for obstructive sleep apnoea. A chest X-ray showed diffuse bilateral pulmonary infiltrates. Supplemental 100% fractional inspired oxygen (FiO2) via non-rebreather mask was delivered with resulting arterial oxygen tension:FiO2 ratio of 67. Transthoracic echocardiogram demonstrated normal heart function. A clinical diagnosis of severe acute respiratory distress syndrome (ARDS) was promptly made. Based on patient preference to avoid intubation and following a multidisciplinary approach, we decided to initiate venovenous extracorporeal membrane oxygenation (VV-ECMO) as an alternative strategy to mechanical ventilation. Though he ultimately required brief mechanical ventilation during ECMO cannulation, the patient spent a total of 5 days on VV-ECMO and a total of 8 days in the intensive care unit. Six days after discharge, his pulmonary function test demonstrated no significant abnormalities. We present a rare case of early initiation of VV-ECMO in a patient with severe ARDS that served as a bridge to recovery.",
"affiliations": "Internal Medicine, McGaw Medical Center of Northwestern University, Chicago, Illinois, USA.;Pulmonary and Critical Care, Mayo Clinic, Rochester, Minnesota, USA.",
"authors": "Raiker|Nisha Krishnakant|NK|;Cajigas|Hector|H|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-226223",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "adult intensive care; intensive care; mechanical ventilation; respiratory medicine",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D003937:Diagnosis, Differential; D004417:Dyspnea; D015199:Extracorporeal Membrane Oxygenation; D006801:Humans; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D012121:Respiration, Artificial; D012128:Respiratory Distress Syndrome; D012225:Rhinoplasty; D020181:Sleep Apnea, Obstructive",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30317205",
"pubdate": "2018-10-12",
"publication_types": "D016428:Journal Article",
"references": "22941546;24467647;22941324;22797452;22893749;23952860;22878882;21263315;15383787",
"title": "Early initiation of venovenous extracorporeal membrane oxygenation in a mechanically ventilated patient with severe acute respiratory distress syndrome.",
"title_normalized": "early initiation of venovenous extracorporeal membrane oxygenation in a mechanically ventilated patient with severe acute respiratory distress syndrome"
} | [
{
"companynumb": "US-009507513-1811USA003232",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": null,
... |
{
"abstract": "Thromboembolism is one of the most serious complications of nephrotic syndrome (NS). Although the occurrence of renal vein thrombosis or deep vein thrombosis is well recognized in NS patients, they rarely develop cerebral venous thrombosis (CVT). The mortality rate of CVT patients is still approximately 10%, and 6-10% of patients who survive have a severe and permanent disability. Herein, we report the case of a 26-year-old woman with multiple thrombotic risk factors, including the presence of NS, use of oral contraceptives, smoking, and alcohol consumption who developed wide-range CVT. Undetermined fraction heparin, albumin and AT-III transfusion, and direct mechanical catheter thrombectomy were insufficient for the improvement of CVT. However, CVT eventually improved along with the remission of NS by prednisolone administration. This process indicates that in the management of CVT associated with NS, it is crucial to control the activity of NS. Currently, knowledge on the treatment for NS associated with CVT is limited, and this is a subject of urgent investigation.",
"affiliations": "Division of Endocrinology, Metabolism and Nephrology Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.;Division of Endocrinology, Metabolism and Nephrology Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.;Division of Endocrinology, Metabolism and Nephrology Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.;Division of Endocrinology, Metabolism and Nephrology Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.;Division of Endocrinology, Metabolism and Nephrology Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.;Division of Endocrinology, Metabolism and Nephrology Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.;Division of Endocrinology, Metabolism and Nephrology Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. shuwakino@z8.keio.jp.;Division of Endocrinology, Metabolism and Nephrology Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.",
"authors": "Nakayama|Takashin|T|;Mitsuno|Ryunosuke|R|;Torimitsu|Takuto|T|;Yoshimoto|Norifumi|N|;Kanda|Takeshi|T|;Tokuyama|Hirobumi|H|;Wakino|Shu|S|;Itoh|Hiroshi|H|",
"chemical_list": "D005938:Glucocorticoids; D011239:Prednisolone",
"country": "Japan",
"delete": false,
"doi": "10.1007/s13730-020-00520-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-4449",
"issue": "10(1)",
"journal": "CEN case reports",
"keywords": "Cerebral venous thrombosis; Corticosteroid; Nephrotic syndrome; Thromboembolism",
"medline_ta": "CEN Case Rep",
"mesh_terms": "D000328:Adult; D002550:Cerebral Veins; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D008279:Magnetic Resonance Imaging; D009404:Nephrotic Syndrome; D011239:Prednisolone; D012307:Risk Factors; D016896:Treatment Outcome; D020246:Venous Thrombosis",
"nlm_unique_id": "101636244",
"other_id": null,
"pages": "132-138",
"pmc": null,
"pmid": "32949376",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "29625968;21293023;25072187;27099136;2437353;6477000;22895519;14976332;20402748;24699058;18705916;22344511;18696250;30005273;15495007;23546607;24990834;16609071;4161419;15858188;18158362;10698409;27308257;26220221;28820187",
"title": "Difficulty in managing nephrotic syndrome-associated cerebral venous thrombosis.",
"title_normalized": "difficulty in managing nephrotic syndrome associated cerebral venous thrombosis"
} | [
{
"companynumb": "JP-B.BRAUN MEDICAL INC.-2108270",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": n... |
{
"abstract": "The aim of treating epilepsy is to control or at least decrease seizures without producing unacceptable adverse effects that impair quality of life. Antiepileptic drugs (AEDs) have been considered amongst the drugs most frequently associated with fatal suspected adverse drug reactions. Physicians must therefore be as familiar with safety and tolerability data of AEDs as they are with the expected therapeutic effects. AEDs may cause dose-related adverse effects (i.e. drowsiness, fatigue, dizziness, blurry vision and incoordination) that, in most cases, may be obviated by lowering the dosage, reducing the number of drugs or switching to a better tolerated AED. AEDs also have the potential of precipitating idiosyncratic adverse effects (i.e. serious cutaneous, haematological and hepatic events), which are more common in children and usually require withdrawal of the AED. Although occurrence of idiosyncratic adverse effects can only rarely be predicted or prevented, there are known risk factors that can help in identifying patients at high risk. Occurrence of an idiosyncratic event in a close relative, a concomitant autoimmune disease, co-treatment with specific drugs, history of a previous allergic drug reaction, starting treatment with high doses and rapid titration have all been associated with a higher risk of idiosyncratic adverse effects. New AEDs have been developed in the last two decades with the aim of improving the benefit-risk balance of AED therapy. Available evidence suggests that the newer AEDs are no more effective but may be somewhat better tolerated than older molecules. We performed a literature review with the aim of evaluating safety and tolerability of second- and third-generation AEDs in children. A PubMed search was conducted with the purpose of identifying English-language studies published between 1 January 1989 and 1 January 2011 that reported any adverse event having occurred in children with epilepsy in whom second- and third-generation AEDs were administered.",
"affiliations": "Paediatric Neurology Unit and Laboratories, Childrens Hospital A. Meyer, University of Florence, Italy. r.guerrini@meyer.it",
"authors": "Guerrini|Renzo|R|;Zaccara|Gaetano|G|;la Marca|Giancarlo|G|;Rosati|Anna|A|",
"chemical_list": "D000927:Anticonvulsants",
"country": "New Zealand",
"delete": false,
"doi": "10.2165/11630700-000000000-00000",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0114-5916",
"issue": "35(7)",
"journal": "Drug safety",
"keywords": null,
"medline_ta": "Drug Saf",
"mesh_terms": "D000367:Age Factors; D000927:Anticonvulsants; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy; D006801:Humans; D007223:Infant; D012307:Risk Factors",
"nlm_unique_id": "9002928",
"other_id": null,
"pages": "519-33",
"pmc": null,
"pmid": "22702637",
"pubdate": "2012-07-01",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "17339510;19054414;18343174;20926323;8232984;15277643;12456539;21406334;10858057;11368548;11380578;10030434;9579889;18184224;8951223;20486734;11564122;16584116;19955344;14986274;15519117;10534214;2067658;16962380;18660469;8825264;2435290;16473127;20640233;18783433;17044823;21183127;7555986;11723291;8559384;21038416;9578009;2036029;12093356;10756416;9114984;12399159;16243221;19009550;19563348;16608550;2492646;21056937;14745074;10621883;18698874;12940653;17048972;9353388;1761843;17561952;11951032;10416094;9577998;11952035;7794310;8420497;14557585;11879376;19702752;10565591;14711721;15504714;18855540;9760271;16584283;17386054;3247145;18637038;16453247;11074188;17574461;17574448;18397299;8800634;15526967;17105455;14706468;20466520;9578520;3632000;19552653;15606131;15461683;3198757;16545206;9593229;11952769;10897158;19193587;21555051;6436733;20021326;16889941;20691934;8643784;21351809;8419804;16882184;11305405;15094729;15989140;16146489;8952010;10392983;15785938;10328748;3121292;19549063;11089822;14511902;10371378;12849151;17190918;16356781;16900938;10487478;7824115;19380070;9855327;12060006;10604603;16176888;10845739;14630501;15057820;18981374",
"title": "Safety and tolerability of antiepileptic drug treatment in children with epilepsy.",
"title_normalized": "safety and tolerability of antiepileptic drug treatment in children with epilepsy"
} | [
{
"companynumb": "GB-ALKEM LABORATORIES LIMITED-GB-ALKEM-2018-07831",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RIFAMPIN"
},
"drugadd... |
{
"abstract": "We report three cases of delusional parasitosis (DP) in patients with well-established Parkinson's disease, all of whom were taking dopamine agonists. In all three cases, the DP resolved rapidly when the drug was withdrawn.",
"affiliations": "Department of Dermatology, Orpington Hospital, Orpington, Kent, UK. sandy.flann@nhs.net",
"authors": "Flann|S|S|;Shotbolt|J|J|;Kessel|B|B|;Vekaria|D|D|;Taylor|R|R|;Bewley|A|A|;Pembroke|A|A|",
"chemical_list": "D018491:Dopamine Agonists",
"country": "England",
"delete": false,
"doi": "10.1111/j.1365-2230.2010.03810.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0307-6938",
"issue": "35(7)",
"journal": "Clinical and experimental dermatology",
"keywords": null,
"medline_ta": "Clin Exp Dermatol",
"mesh_terms": "D000368:Aged; D003702:Delusions; D018491:Dopamine Agonists; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010272:Parasitic Diseases; D010300:Parkinson Disease; D011602:Psychophysiologic Disorders",
"nlm_unique_id": "7606847",
"other_id": null,
"pages": "740-2",
"pmc": null,
"pmid": "20345988",
"pubdate": "2010-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Three cases of delusional parasitosis caused by dopamine agonists.",
"title_normalized": "three cases of delusional parasitosis caused by dopamine agonists"
} | [
{
"companynumb": "GB-PFIZER INC-2010141111",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CARBIDOPA\\LEVODOPA"
},
"drugadditional": nul... |
{
"abstract": "BACKGROUND\nSelf-poisoning and self-injury are associated with a high risk of suicide or death from any cause but the effect of routine aspects of hospital management on mortality risk is unknown.\n\n\nMETHODS\nWe did a prospective cohort study using data for adults who had self-harmed presenting to five emergency departments in the UK between 2000 and 2010. We assessed the relation between four aspects of management (psychosocial assessment, medical admission, psychiatric admission, referral for mental health follow-up) and death by suicide or any cause within 12 months of presentation.\n\n\nRESULTS\nOf 38 415 individuals presenting with self-harm, 261 (0·7%) died by suicide and 832 (2·2%) died from any cause within 12 months. Most aspects of management were associated with a higher mortality risk in unadjusted analyses. Psychiatric admission was associated with the highest risks for both suicide (hazard ratio 2·35, 95% CI 1·59-3·45) and all-cause mortality (2·35, 2·04-2·72). After adjustment for baseline variables, the hazard ratios were generally smaller, particularly for psychiatric admission. There were significant interactions by sex, age, and history of self-harm.\n\n\nCONCLUSIONS\nThis was an observational study and so we cannot infer causation. However, our finding that clinical services seem to reserve the most intensive levels of treatment for patients at highest risk is reassuring. Aspects of routine management might be associated with a lower mortality risk but these effects vary by clinical subgroup.\n\n\nBACKGROUND\nUK Department of Health.",
"affiliations": "Centre for Mental Health and Safety, Centre for Suicide Prevention, University of Manchester, Manchester, UK; Manchester Mental Health and Social Care Trust, Manchester, UK. Electronic address: nav.kapur@manchester.ac.uk.;Centre for Mental Health and Safety, Centre for Suicide Prevention, University of Manchester, Manchester, UK.;Centre for Mental Health and Safety, Centre for Suicide Prevention, University of Manchester, Manchester, UK.;Centre for Mental Health and Safety, Centre for Suicide Prevention, University of Manchester, Manchester, UK.;Centre for Suicide Research, University of Oxford, Department of Psychiatry, Warneford Hospital, Oxford, UK.;Centre for Suicide Research, University of Oxford, Department of Psychiatry, Warneford Hospital, Oxford, UK.;Centre for Suicide Research, University of Oxford, Department of Psychiatry, Warneford Hospital, Oxford, UK.;School of Psychology, University of Nottingham, Nottingham, UK.;Derbyshire Healthcare NHS Foundation Trust, Royal Derby Hospital, Derby, UK.;Derbyshire Healthcare NHS Foundation Trust, Royal Derby Hospital, Derby, UK.;Centre for Mental Health and Safety, Centre for Suicide Prevention, University of Manchester, Manchester, UK.",
"authors": "Kapur|Nav|N|;Steeg|Sarah|S|;Turnbull|Pauline|P|;Webb|Roger|R|;Bergen|Helen|H|;Hawton|Keith|K|;Geulayov|Galit|G|;Townsend|Ellen|E|;Ness|Jennifer|J|;Waters|Keith|K|;Cooper|Jayne|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2215-0366",
"issue": "2(9)",
"journal": "The lancet. Psychiatry",
"keywords": null,
"medline_ta": "Lancet Psychiatry",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004637:Emergency Services, Psychiatric; D005260:Female; D006760:Hospitalization; D006778:Hospitals, Psychiatric; D006801:Humans; D008297:Male; D008875:Middle Aged; D011216:Practice Management, Medical; D011379:Prognosis; D011446:Prospective Studies; D016728:Self-Injurious Behavior; D059020:Suicidal Ideation; D013406:Suicide, Attempted; D055815:Young Adult",
"nlm_unique_id": "101638123",
"other_id": null,
"pages": "809-16",
"pmc": null,
"pmid": "26254717",
"pubdate": "2015-09",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Hospital management of suicidal behaviour and subsequent mortality: a prospective cohort study.",
"title_normalized": "hospital management of suicidal behaviour and subsequent mortality a prospective cohort study"
} | [
{
"companynumb": "GB-JNJFOC-20150915762",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BENZODIAZEPINE"
},
"drugadditional": null,
... |
{
"abstract": "Irinotecan-based chemotherapy with bevacizumab is one of the first-line standard therapies for metastatic colorectal cancer (mCRC). TEGAFIRI (UFT/LV + irinotecan) is an irinotecan-based chemotherapy regimen. Currently, few clinical data regarding TEGAFIRI are available. This study evaluated the efficacy and safety of TEGAFIRI in Japanese patients with mCRC. This is a multicenter, randomized, phase II study. The major inclusion criteria were previously untreated patients with mCRC (age: 20-75 years, Eastern Cooperative Oncology Group performance status: 0-1). Eligible patients were randomly assigned (1:1) to receive either FOLFIRI ± bevacizumab or TEGAFIRI ± bevacizumab. The primary endpoint was progression-free survival (PFS). The secondary endpoints were response rate, overall survival, dose intensity and toxicity. From November 2007 to October 2011, 36 and 35 patients assigned to the FOLFIRI and TEGAFIRI groups were included in the primary analysis. No significant difference in PFS was observed between the groups {median PFS: TEGAFIRI 9.9 months [95% confidence interval (CI), 6.5-14.7], FOLFIRI 10.6 months [95% CI, 7.7-16.5]; Hazard ratio, 0.98, 95% CI, 0.57-1.66, p = 0.930}. The response rates in the FOLFIRI and TEGAFIRI groups were 56% and 66%, respectively. Relative dose intensity was similar between the groups. The most common Grade 3/4 adverse event was diarrhea (26%) in TEGAFIRI group and neutropenia (39%) in the FOLFIRI group. The results of the present study indicate that TEGAFIRI ± bevacizumab is an effective and tolerable first-line treatment regimen for mCRC.",
"affiliations": "Department of Surgery, Keio University School of Medicine, 35 Shinano-Machi, Shinjuku-Ku, Tokyo, 160-8582, Japan.;Department of Surgery, Keio University School of Medicine, 35 Shinano-Machi, Shinjuku-Ku, Tokyo, 160-8582, Japan.;Department of Surgery, Keio University School of Medicine, 35 Shinano-Machi, Shinjuku-Ku, Tokyo, 160-8582, Japan.;Department of Surgery, Keio University School of Medicine, 35 Shinano-Machi, Shinjuku-Ku, Tokyo, 160-8582, Japan.;Department of Surgery, Keio University School of Medicine, 35 Shinano-Machi, Shinjuku-Ku, Tokyo, 160-8582, Japan.;Department of Surgery, Keio University School of Medicine, 35 Shinano-Machi, Shinjuku-Ku, Tokyo, 160-8582, Japan.;Department of Surgery, Keio University School of Medicine, 35 Shinano-Machi, Shinjuku-Ku, Tokyo, 160-8582, Japan.;Department of Surgery, Keio University School of Medicine, 35 Shinano-Machi, Shinjuku-Ku, Tokyo, 160-8582, Japan.;Department of Surgery, Keio University School of Medicine, 35 Shinano-Machi, Shinjuku-Ku, Tokyo, 160-8582, Japan.",
"authors": "Shigeta|Kohei|K|;Hasegawa|Hirotoshi|H|;Okabayashi|Koji|K|;Tsuruta|Masashi|M|;Ishii|Yoshiyuki|Y|;Endo|Takashi|T|;Ochiai|Hiroki|H|;Kondo|Takayuki|T|;Kitagawa|Yuko|Y|",
"chemical_list": "D005641:Tegafur; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "United States",
"delete": false,
"doi": "10.1002/ijc.30127",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0020-7136",
"issue": "139(4)",
"journal": "International journal of cancer",
"keywords": "Irinotecan; Oral 5-FU; colorectal cancer; randomized phase II trial",
"medline_ta": "Int J Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D015179:Colorectal Neoplasms; D018450:Disease Progression; D005260:Female; D005472:Fluorouracil; D006801:Humans; D053208:Kaplan-Meier Estimate; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D016017:Odds Ratio; D016016:Proportional Hazards Models; D012008:Recurrence; D005641:Tegafur; D017211:Treatment Failure; D016896:Treatment Outcome",
"nlm_unique_id": "0042124",
"other_id": null,
"pages": "946-54",
"pmc": null,
"pmid": "27061810",
"pubdate": "2016-08-15",
"publication_types": "D017427:Clinical Trial, Phase II; D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Randomized phase II trial of TEGAFIRI (tegafur/uracil, oral leucovorin, irinotecan) compared with FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) in patients with unresectable/recurrent colorectal cancer.",
"title_normalized": "randomized phase ii trial of tegafiri tegafur uracil oral leucovorin irinotecan compared with folfiri folinic acid 5 fluorouracil irinotecan in patients with unresectable recurrent colorectal cancer"
} | [
{
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"activesubstancename": "TEGAFUR\\URACIL"
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{
"abstract": "Minocycline is a commonly prescribed tetracycline antibiotic used for the treatment of a number of dermatological conditions including acne and rosacea. Long-term adverse effects of minocycline include cutaneous hyperpigmentation. Various treatment options have been suggested for the treatment of minocycline pigmentation. We report a case of a patient on long-term low-dose minocycline for the treatment of rosacea with type III minocycline hyperpigmentation. A comparison was made between Q-Switch Nd:YAG and picosecond laser over a nine 9-period with treatments spaced 1 month apart, with a clearance in the patient pigmentation after four treatments with picosecond laser.",
"affiliations": "a New South Wales Health , Orange , Australia.;b Hunter New England Local Health District , Department of Dermatology , Royal Newcastle Center , New Lambton , Australia.",
"authors": "Barrett|Tom|T|;de Zwaan|Sally|S|",
"chemical_list": "D000900:Anti-Bacterial Agents; D008911:Minocycline",
"country": "England",
"delete": false,
"doi": "10.1080/14764172.2017.1418514",
"fulltext": null,
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"issn_linking": "1476-4172",
"issue": "20(7-8)",
"journal": "Journal of cosmetic and laser therapy : official publication of the European Society for Laser Dermatology",
"keywords": "Lasers and light sources; minocycline; picosecond; pigmentation",
"medline_ta": "J Cosmet Laser Ther",
"mesh_terms": "D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D005260:Female; D006801:Humans; D017495:Hyperpigmentation; D053844:Lasers, Solid-State; D028022:Low-Level Light Therapy; D008911:Minocycline",
"nlm_unique_id": "101136419",
"other_id": null,
"pages": "387-390",
"pmc": null,
"pmid": "29400580",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Picosecond alexandrite laser is superior to Q-switched Nd:YAG laser in treatment of minocycline-induced hyperpigmentation: A case study and review of the literature.",
"title_normalized": "picosecond alexandrite laser is superior to q switched nd yag laser in treatment of minocycline induced hyperpigmentation a case study and review of the literature"
} | [
{
"companynumb": "AU-BAUSCH-BL-2018-005169",
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"activesubstancename": "CALCIUM"
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{
"abstract": "Modafinil is generally known as a drug with low addiction potential. There are few case reports in the literature demonstrating that Modafinil, stated being capable of diminishing symptoms of attention deficit/hyperactivity disorder (ADHD), causes addiction. In the present article a Modafinil addicted ADHD case, consuming usurious doses (5,000 mg/per day) of Modafinil is presented. The case presented to our psychiatry outpatient clinic due to: requirement of in taking high dose Modafinil in order to achieve the initial effects, difficulty in obtaining the drug, irritability, anxiousness, sleep irregularities, fatigue and unpleasant vivid dreams when he did not use the drug. It was realized that the patient, himself increased doses of Modafinil incrementally, in order to keep its effects on attention symptoms at the same level. It has to be kept in mind that ADHD patients can develop Modafinil addiction. It is necessary to carry out systemic studies on this subject.",
"affiliations": "Department of Psychiatry, Faculty of Medicine, Pamukkale University, Denizli, Turkey.;Department of Child and Adolescent Psychiatry, Faculty of Medicine, Pamukkale University, Denizli, Turkey.;Department of Psychiatry, Faculty of Medicine, Pamukkale University, Denizli, Turkey.;Department of Psychiatry, Faculty of Medicine, Pamukkale University, Denizli, Turkey.;Department of Psychiatry, Faculty of Medicine, Pamukkale University, Denizli, Turkey.",
"authors": "Alacam|Huseyin|H|;Basay|Omer|O|;Tumkaya|Selim|S|;Mart|Mehmet|M|;Kar|Gokce|G|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.30773/pi.2016.10.25",
"fulltext": "\n==== Front\nPsychiatry InvestigPsychiatry InvestigPIPsychiatry Investigation1738-36841976-3026Korean Neuropsychiatric Association 10.30773/pi.2016.10.25pi-2016-10-25Case ReportModafinil Dependence: A Case with Attention-Deficit/Hyperactivity Disorder Alacam Huseyin 1Basay Omer 2Tumkaya Selim 1Mart Mehmet 1Kar Gokce 1\n1 Department of Psychiatry, Faculty of Medicine, Pamukkale University, Denizli, Turkey\n2 Department of Child and Adolescent Psychiatry, Faculty of Medicine, Pamukkale University, Denizli, TurkeyCorrespondence: Huseyin Alacam, MD Department of Pschiatry, Faculty of Medicine, Pamukkale University, Camlaraltı Street, No: 7, 20070, Pamukkale, Denizli, Turkey Tel: +90 258 296 60 00-4509, Fax: +90 258 296 60 01 E-mail: dr.huseyinalacam@hotmail.com4 2018 30 3 2018 15 4 424 427 7 4 2016 20 6 2016 25 10 2016 Copyright © 2018 Korean Neuropsychiatric Association2018This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Modafinil is generally known as a drug with low addiction potential. There are few case reports in the literature demonstrating that Modafinil, stated being capable of diminishing symptoms of attention deficit/hyperactivity disorder (ADHD), causes addiction. In the present article a Modafinil addicted ADHD case, consuming usurious doses (5,000 mg/per day) of Modafinil is presented. The case presented to our psychiatry outpatient clinic due to: requirement of in taking high dose Modafinil in order to achieve the initial effects, difficulty in obtaining the drug, irritability, anxiousness, sleep irregularities, fatigue and unpleasant vivid dreams when he did not use the drug. It was realized that the patient, himself increased doses of Modafinil incrementally, in order to keep its effects on attention symptoms at the same level. It has to be kept in mind that ADHD patients can develop Modafinil addiction. It is necessary to carry out systemic studies on this subject.\n\nModafinilDependenceAttention-deficit/hyperactivity disorder\n==== Body\nINTRODUCTION\nModafinil is a non-amphetamine type stimulant used in narcolepsy, obstructive sleep apnea syndrome and circadian rhythm disorder [1]. Modafinil has also been tried for diseaserelated fatigue, attention-deficit disorder, Alzheimer’s disease, age-related memory decline, depression, cognitive impairment in schizophrenia, idiopathic hypersomnia, myotonic dystrophy, post-anaesthesia grogginess and everyday cat-napping [2]. Even though the action mechanism is not clear, it is thought to be distinct from other stimulant drugs [3]. Modafinil is known to act via its effects on noradrenergic (activation of alpha-1 receptors) [4] and dopaminergic [5] neurotransmission. Its wakefulness and activity-promoting properties are mostly related to its effects on these neuromediators [6].\n\nDue to its dopaminergic activity and low abuse potential, Modafinil has been used in treatment of cocaine [7] and methamphetamine [8] abuse and correction of disturbed cognitive functions in alcohol dependent subjects [9]. Even though Modafinil abuse is not frequent, it’s still possible to encounter patients abusing the substance [1]. There are rare reports of Modafinil abuse in literature. In two of the three case reports that we encountered, subjects with Modafinil abuse concurrently had history of alcohol and benzodiazepine dependence, whereas a case who had schizoaffective disorder did not have history of alcohol or drug abuse. Maximum amount of Modafinil intake of the cases in these reports was 3,000 mg/day [10-12].\n\nIn this report, we present a case with high-dose (5,000 mg/day) Modafinil dependence who had no history of alcohol or substance abuse and was diagnosed with attention deficit hyperactivity disorder (ADHD).\n\nCASE\nTwenty-four years old male, single student, living in county town with his parents stated, in his own words that; he had been facing difficulty in listening to classes since primary school, had issue in concentrating, difficulty in making friends, had low academic success, had coerced particularly during transition to higher education and due to performance anxiety had clinical psychologist visits. Developmental and past psychiatric history, corroborated by his parents confirmed these complaints. During childhood he was obviously more active than peers, and he was easily distracted by external stimulus. The parents reported that, when he was 10 years old, they admitted to a child psychiatry policlinic complaining of inattention, difficulty in completing school work, organizing activities, following instructions, committing frequent mistakes, losing belongings and forgetting daily routines. He was diagnosed with ADHD by the child psychiatrist and stimulant medication was indicated. However, parents refused medical treatment due to concerns related to side effects. No further treatment was searched.\n\nPatient reported that approximately 5 years ago, he begun consuming omega 3-6-9 preparations and vitamin supplements in order to increase his social and academic performance. Subsequently approximately 3 years ago, without any doctor suggestion, he commenced taking Modafinil in 50 mg/day dose, and gained improvements in attention, self-reliance, academic success and social activity. After a while, in order to be able to maintain initial effects, he necessitated increasing the dose and went on using Modafinil at 300–400 mg/day dose during 2 years. It was ascertained that since his ailments were not totally resolved and his exam load increased, 1 year ago he presented to a different psychiatry clinic than ours, where 20 mg/day short-acting Methylphenidate was initiated for attention deficiency and hyperactivity disorder diagnose. It’s realized that, as an addition to Modafinil he used short-acting Methylphenidate 60 mg/day. The patient stated that, even though he benefited from the Methylphenidate treatment, he did not use regularly and discontinued the drug. During the last year, he increased the Modafinil dose, in order to achieve the initial effects Modafinil and resulted in consuming 100 mg tablets, 5 times a day and 10 tablets most of the time. Whenever he quit using Modafinil or diminished the amount, he experienced irritability, anxiousness, sweating, tremor and an urge to take excessive Modafinil. The case presented to a different psychiatry clinic with a desire to quit Modafinil, where Modafinil was stopped and Venlafaxine at 75 mg/day, Risperidone 2 mg/day, Propranolol 80 mg/day and Olanzapine 5 mg/day were initiated. After discontinuation of Modafinil, he experienced fatigue, vivid and unpleasant dreams, sleeping irregularities, anxiousness, and functionality impairment, as previously. Since, despite the given treatment his complaints did not subside, he abandoned treatment and revert using Modafinil.\n\nModafinil that could be purchased over the counter before, became a prescription medicine with recent regulations in Turkey. Therefore the patient encountered difficulty in accessing the drug and presented to our polyclinic. During his anamnesis he presented his complaints as necessity to consume usurious doses of Modafinil, to be able to achieve the initial effects, difficulty in obtaining the medicine, irritability, tremor, anxiety, sleep disorder, fatigue, and unpleasant vivid dreams when he did not use the drug. It was realized that he was consuming 5,000 mg/day Modafinil since 1 month. After evaluation, he was admitted to our psychiatry ward with the initial diagnosis of “stimulant use disorder” according to DSM-5 classification.\n\nDuring mental state examination performed in our clinic, he appeared at his age, was self-sufficient, his associations were normal, his speaking rate and amount was partially increased, and was anxious. He did not have active psychotic thought content, evaluation of actuality was normal. He had irregular sleeping pattern, decreased appetite and normal libido.\n\nFamily history revealed that his elder brother previously had alcohol addiction.\n\nIn our psychiatry ward, the patient was introduced Lorazepam 2.5 mg/day, Risperidon 1 mg/day and Ketiapin 25 mg/day. Following abandoning of Modafinil, cravings, pschomotor agitation, sweating, tremor, fatigue were observed. Therefore his treatment was modified to Diazepam 15 mg/day, Ketiapin 100 mg/day, Risperidon 2 mg/day. On the third day of his admission, the patient was discharged from the ward upon his own will. During his first control in outpatient clinic, it was realized that, although he had some benefits from treatment, his compliance to medication was poor. He requested prescription of Modafinil, and he did not attend to further control visits.\n\nDISCUSSION\nDue to weak inhibition of dopamine reuptake pumps, Modafinil increases dopamine in some areas of the brain, mainly the cortex, striatum and nucleus accumbens [13]. Studies investigating this mechanism revealed that, cortex and striatum are diffusely activated following amphetamine administration to rats. With Modafinil use, activated areas are restricted with paraventricular and suprachiasmatic nuclei, anterior hypothalamus, amygdala and tuberomamillary nucleus [14]. Modafinil increases the effects of dopamine and norepinephrine by binding to carrier proteins of these catecholamines [15]. Unlike amphetamine, Modafinil does not have an influence on dopamine release and cycle in mouse striatum, has very little influence on blood flow to the brain cortex, and results in a metabolic activation that is different from amphetamine [6]. This may be the explanation for its low abuse potential. Despite all these diversities, Modafinil’s effect related with stimulation and behavioral activity are supposed to be at least partially involving dopamine [16]. D1 and D2 receptors also take role in effects of Modafinil on cognitive functions and behavior [6].\n\nAffinity of Modafinil to dopamine receptors resembles methylphenidate. This can be reason of possible risk for abuse [13,17]. Modafinil dependence may be related to its dopamine increasing effect in dopaminergic areas of the brain via reuptake inhibition [5]. Postsynaptic D1 receptors are one of the mediators of sensitization; increased dopamine transmission results in increased stimulation of D1 receptors, compulsive use of Modafinil may be related to this [18-20].\n\nModafinil is thought to enhance cognitive functions such as attention, learning and memory via acting differently from the typical psychostimulants [5]. Promotion of cognitive functions by Modafinil has been investigated in many mental disorders that result in decreased cognitive functions [6]. As an example, a study with schizophrenic patients using Modafinil, in addition to antipsychotic treatment, aiming to decrease cognitive functions had promising results [21]. Our case had symptoms of ADHD that impaired cognitive functions, such as lack of attention, difficulty in concentrating and difficulty in educational life. Modafinil was helping him to overcome these symptoms. There are also studies that presented Modafinil to be effective in treatment of ADHD [22,23]. Illegal use of Modafinil has been reported in substance abusers and patients with organic mental disease in order to enhance cognitive functions. This is also supported with the fact that two of the previously reported cases had history of alcohol and benzodiazepine addiction, and the third reported case had schizoaffective disorder [24].\n\nOne report from India mentioned 1,200 mg/day Modafinil dose, whereas one report from Turkey mentioned 3,000 mg/day Modafinil dose [10-12]. In the present case, utilization of Modafinil at extremely high doses up to 5,000 mg/day may be due to a self-medication in order to reinforce its cognitive enhancing property and to treat symptoms of ADHD. High doses of Modafinil can cause several side effects like agitation, insomnia, tachycardia and elevated blood pressure [25]. Our case described palpitations, agitation and insomnia after using high doses of Modafinil. This was one of the reasons whys for seeking treatment. These symptoms were taken into account during his treatment planning. There is no controlled study on Modafinil dependence; treatment with antidepressants like Bupropion and Duloxetine and treatment with benzodiazepines like Clonazepam had been attempted in previously reported cases [10-12].\n\nThere are 2 case reports in the literature stating that Modafinil dependence can occur in patients with previous history of addiction [10,11]. ADHD patients are known to be more prone to addiction, however as far as we know, this is the first study demonstrating Modafinil dependence of a case with ADHD. Recent suggestion on Modafinil use for ADHD increases the significance of the present case report [23].\n\nAnother important point in this case report is that, to our knowledge, there is no report in the literature demonstrating Modafinil use as high as 5,000 mg/day. Despite symptoms presenting at high dose, the drug did not cause any life threatening condition.\n\nIt has to be kept in mind that Modafinil can cause dependence in patients with ADHD. Systematic studies are necessary on this field.\n==== Refs\nREFERENCES\n1 Kumar R Approved and investigational uses of modafinil: an evidencebased review Drugs 2008 68 1803 1839 18729534 \n2 Kim D Practical use and risk of modafinil, a novel waking drug Environ Health Toxicol 2012 27 e2012007 22375280 \n3 Wisor J Modafinil as a catecholaminergic agent: empirical evidence and unanswered questions Front Neurol 2013 4 139 24109471 \n4 Stone EA Cotecchia S Lin Y Quartermain D Role of brain alpha 1B-adrenoceptors in modafinil-induced behavioral activity Synapse 2002 46 269 270 12373742 \n5 Mereu M Bonci A Newman AH Tanda G The neurobiology of modafinil as an enhancer of cognitive performance and a potential treatment for substance use disorders Psychopharmacology (Berl) 2013 229 415 434 23934211 \n6 Minzenberg MJ Carter CS Modafinil: a review of neurochemical actions and effects on cognition Neuropsychopharmacology 2008 33 1477 1502 17712350 \n7 Anderson AL Reid MS Li SH Holmes T Shemanski L Slee A Modafinil for the treatment of cocaine dependence Drug Alcohol Depend 2009 104 133 139 19560290 \n8 Shearer J Darke S Rodgers C Slade T van Beek I Lewis J A double-blind, placebo-controlled trial of modafinil (200 mg/day) for methamphetamine dependence Addiction 2009 104 224 233 19149817 \n9 Schmaal L Goudriaan AE Joos L Krüse AM Dom G van den Brink W Modafinil modulates resting-state functional network connectivity and cognitive control in alcohol-dependent patients Biol Psychiatry 2013 73 789 795 23399373 \n10 Cengiz Mete M Şenormancı Ö Saraçlı Ö Atasoy N Atik L Compulsive modafinil use in a patient with a history of alcohol use disorder Gen Hosp Psychiatry 2015 37 e7 e8 25655923 \n11 Kate N Grover S Ghormode D Dependence on supratherapeutic doses of modafinil: a case report Prim Care Companion CNS Disord 2012 14 \n12 Krishnan R Chary KV A rare case modafinil dependence J Pharmacol Pharmacother 2015 6 49 50 25709356 \n13 Schmitt KC Reith ME The atypical stimulant and nootropic modafinil interacts with the dopamine transporter in a different manner than classical cocaine-like inhibitors PLoS One 2011 6 e25790 22043293 \n14 Lin JS Hou Y Jouvet M Potential brain neuronal targets for amphetamine-, methylphenidate-, and modafinil-induced wakefulness, evidenced by c-fos immunocytochemistry in the cat Proc Natl Acad Sci U S A 1996 93 14128 14133 8943072 \n15 Madras BK Xie Z Lin Z Jassen A Panas H Lynch L Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro J Pharmacol Exp Ther 2006 319 561 569 16885432 \n16 de Saint Hilaire Z Orosco M Rouch C Blanc G Nicolaidis S Variations in extracellular monoamines in the prefrontal cortex and medial hypothalamus after modafinil administration: a microdialysis study in rats Neuroreport 2001 12 3533 3537 11733706 \n17 Kim W Tateno A Arakawa R Sakayori T Ikeda Y Suzuki H In vivo activity of modafinil on dopamine transporter measured with positron emission tomography and [18F]FE-PE2I Int J Neuropsychopharmacol 2014 17 697 703 24451483 \n18 Fava M Rush AJ Thase ME Clayton A Stahl SM Pradko JF 15 years of clinical experience with bupropion HCl: from bupropion to bupropion SR to bupropion XL Prim Care Companion J Clin Psychiatry 2005 7 106 113 16027765 \n19 Hummel M Unterwald EM D1 dopamine receptor: a putative neurochemical and behavioral link to cocaine action J Cell Physiol 2002 191 17 27 11920678 \n20 Möller HJ Amisulpride: limbic specificity and the mechanism of antipsychotic atypicality Prog Neuropsychopharmacol Biol Psychiatry 2003 27 1101 1111 14642970 \n21 Farrow TFD Hunter MD Haque R Spence SA Modafinil and unconstrained motor activity in schizophrenia: double-blind crossover placebo-controlled trial Br J Psychiatry 2006 189 461 462 17077439 \n22 Biederman J Swanson JM Wigal SB Boellner SW Earl CQ Lopez FA A comparison of once-daily and divided doses of modafinil in children with attention-deficit/hyperactivity disorder: a randomized, double-blind, and placebo-controlled study J Clin Psychiatry 2006 67 727 735 16841622 \n23 Gomez Z Noble P Meta-analysis of the effect of modafinil in children and adolescents with attention deficit and hyperactive disorder Eur Psychiatry 2015 30 577 \n24 Spiller HA Borys D Griffith JR Klein-Schwartz W Aleguas A Sollee D Toxicity from modafinil ingestion Clin Toxicol (Phila) 2009 47 153 156 18787992 \n25 Lackey G Alsop J Albertson T A 24 month retrospective study of adult modafinil ingestions Clin Toxicol 2007 45 641\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1738-3684",
"issue": "15(4)",
"journal": "Psychiatry investigation",
"keywords": "Attention-deficit/hyperactivity disorder; Dependence; Modafinil",
"medline_ta": "Psychiatry Investig",
"mesh_terms": null,
"nlm_unique_id": "101242994",
"other_id": null,
"pages": "424-427",
"pmc": null,
"pmid": "29593204",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article",
"references": "16027765;18787992;11920678;12373742;23934211;24451483;25709356;16885432;22043293;25655923;11733706;17712350;23469316;14642970;8943072;23399373;22375280;16841622;24109471;19560290;17077439;18729534;19149817",
"title": "Modafinil Dependence: A Case with Attention-Deficit/Hyperactivity Disorder.",
"title_normalized": "modafinil dependence a case with attention deficit hyperactivity disorder"
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{
"abstract": "Pulmonary abnormalities are not frequently encountered in patients with inflammatory bowel diseases. However, lung toxicity can be induced by conventional medications used to maintain remission, and similar evidence is also emerging for biologics. We present the case of a young woman affected by colonic Crohn's disease who was treated with oral mesalamine and became steroid-dependent and refractory to azathioprine and adalimumab. She was referred to our clinic with a severe relapse and was treated with infliximab, an anti-tumor necrosis factor α (TNF-α) antibody, to induce remission. After an initial benefit, with decreases in bowel movements, rectal bleeding and C-reactive protein levels, she experienced shortness of breath after the 5(th) infusion. Noninfectious interstitial lung disease was diagnosed. Both mesalamine and infliximab were discontinued, and steroids were introduced with slow but progressive improvement of symptoms, radiology and functional tests. This represents a rare case of interstitial lung disease associated with infliximab therapy and the effect of drug withdrawal on these lung alterations. Given the increasing use of anti-TNF-α therapies and the increasing reports of pulmonary abnormalities in patients with inflammatory bowel diseases, this case underlines the importance of a careful evaluation of respiratory symptoms in patients undergoing infliximab therapy.",
"affiliations": "Department of Surgical, Oncological and Gastroenterological Sciences, Gastroenterology Section, University of Padova, 35128 Padova, Italy. roberta.caccaro@gmail.com",
"authors": "Caccaro|Roberta|R|;Savarino|Edoardo|E|;D'Incà|Renata|R|;Sturniolo|Giacomo Carlo|GC|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D005765:Gastrointestinal Agents; D013256:Steroids; D000069285:Infliximab",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v19.i32.5377",
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"issn_linking": "1007-9327",
"issue": "19(32)",
"journal": "World journal of gastroenterology",
"keywords": "Crohn’s disease; Drug-induced toxicity; Infliximab; Interstitial lung disease; Mesalamine",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000328:Adult; D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D003424:Crohn Disease; D057915:Drug Substitution; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D000069285:Infliximab; D008168:Lung; D017563:Lung Diseases, Interstitial; D020127:Recovery of Function; D012129:Respiratory Function Tests; D013256:Steroids; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "5377-80",
"pmc": null,
"pmid": "23983443",
"pubdate": "2013-08-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "9219789;19373466;1267553;14555914;7146309;20954282;15564013;22688498;21467710;16670533;12225784;15062599;20082474;22090006;17632266;20467775;20166813;11866276;12496444;16906378;14506385;15340375;16622902;12769444;21277618;16511933;17098602;16937463;18946068;21172186;8633548;15718004",
"title": "Noninfectious interstitial lung disease during infliximab therapy: case report and literature review.",
"title_normalized": "noninfectious interstitial lung disease during infliximab therapy case report and literature review"
} | [
{
"companynumb": "IT-BAUSCH-BL-2020-016179",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ADALIMUMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe use of radioactive iodine, or iodine 131 (131I), for remnant thyroid ablation and the treatment of cervical and distant metastatic disease in patients with thyroid cancer is well accepted. 131I concentrates in the bladder, and irradiation to the ovaries has been theorized to increase the risk of infertility and birth defects in subsequent offspring.\n\n\nMETHODS\nWe conducted a retrospective review of the charts of 154 children and adolescents treated at our institution for thyroid cancer between 1951 and 1991. Review of these charts identified 68 females diagnosed with thyroid cancer, < or = 20 years of age, who received 131I as part of their therapy at our institution. Charts were reviewed and patients recontacted, and initial tumor, date of diagnosis, and 131I administration, including doses, were recorded. Complete pregnancy histories including current health status of the children were also recorded.\n\n\nRESULTS\nTwenty-two patients who never attempted pregnancy were excluded from analysis. Eleven patients could not be contacted and were considered lost to follow-up and thus excluded from the study. In the remaining 35 patients, mean age at 131I administration was 18.3 years (range 14.1-20.8), mean follow-up, 16.8 years (range 5.6-39.8), and mean 131I dose, 148.53 mCi (range 77.2-250). Three patients were diagnosed infertile after extensive workup (8.6%). The remaining 32 patients had 69 pregnancies resulting in 60 term and four premature deliveries. There were two elective abortions for nonmedical reasons and three spontaneous abortions. Only two children were conceived within 1 year of 131I therapy. Both were born with birth defects that proved fatal within 8 months. No other children were born with birth defects. One other child born with an estimated gestational age of 27 weeks died due to complications related to his prematurity. No anomalies were noted at autopsy. Of the 61 children alive for follow-up, no major health problems were identified other than asthma in two children.\n\n\nCONCLUSIONS\n131I, used in doses up to 250 mCi, is not associated with any long-term risk of infertility. The risks of infertility or birth defects are not different from those of the general population. Because the two children with birth defects were born to mothers treated either during pregnancy or 6 months before conception, it might be wise to suggest avoiding pregnancy for up to 1 year after 131I treatment.",
"affiliations": "Department of Surgical Oncology, University of Texas M. D. Anderson Cancer Center, Houston.",
"authors": "Smith|M B|MB|;Xue|H|H|;Takahashi|H|H|;Cangir|A|A|;Andrassy|R J|RJ|",
"chemical_list": "D007457:Iodine Radioisotopes",
"country": "United States",
"delete": false,
"doi": "10.1007/BF02303556",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1068-9265",
"issue": "1(2)",
"journal": "Annals of surgical oncology",
"keywords": null,
"medline_ta": "Ann Surg Oncol",
"mesh_terms": "D000016:Abnormalities, Radiation-Induced; D000293:Adolescent; D000328:Adult; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007247:Infertility, Female; D007457:Iodine Radioisotopes; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012189:Retrospective Studies; D013964:Thyroid Neoplasms",
"nlm_unique_id": "9420840",
"other_id": null,
"pages": "128-31",
"pmc": null,
"pmid": "7834437",
"pubdate": "1994-03",
"publication_types": "D016428:Journal Article",
"references": "6268681;2261912;583466;3194842;6409459;4815916;45842;4022871;766956;944243",
"title": "Iodine 131 thyroid ablation in female children and adolescents: long-term risk of infertility and birth defects.",
"title_normalized": "iodine 131 thyroid ablation in female children and adolescents long term risk of infertility and birth defects"
} | [
{
"companynumb": "US-CURIUM-2022000358",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SODIUM IODIDE I-131"
},
"drugadditional": "4",
... |
{
"abstract": "Idiopathic hypothalamitis is a rare condition that can cause anterior pituitary dysfunction and central diabetes insipidus (CDI), occasionally accompanied by a disturbance of autonomic regulation known as hypothalamic syndrome. This condition has been described as a subtype of autoimmune (lymphocytic) hypophysitis; however, some cases of isolated hypothalamic involvement with no inflammatory lesions in either the pituitary gland or infundibulum have been reported. The detailed epidemiology and pathophysiology of isolated hypothalamitis have not been clarified. We herein report a case of a solitary hypothalamic lesion in a young woman who showed spontaneous development of CDI and panhypopituitarism accompanied by hyperphagia. The hypothalamic lesion increased from 11 × 7 to 17 × 7 mm over 16 months based on the sagittal slices of magnetic resonance imaging examinations. The negative results for anti-pituitary antibodies and anti-Rabphilin-3A antibodies suggested that upward extension of lymphocytic adenohypophysitis or infundibulo-neurohypophysitis was unlikely. Infectious disease, granulomatosis, Langerhans cell histiocytosis, vasculitis, and systemic neoplastic diseases were excluded by the findings of a laboratory investigation, cerebrospinal fluid examination, and imaging studies. To make a definitive diagnosis, we performed a ventriculoscopic biopsy of the hypothalamic lesion. Histology revealed an infiltration of nonspecific lymphoplasmacytes with no evidence of neoplasm, which was consistent with a diagnosis of idiopathic hypothalamitis. Subsequently, the patient was treated with methylprednisolone pulse therapy followed by oral prednisolone. The hypothalamic lesion improved and remained undetectable after withdrawal of the prednisolone, suggesting that the glucocorticoid treatment was effective for isolated hypothalamitis while the patient remains dependent on the replacement of multiple hormones.",
"affiliations": "Department of Endocrinology and Metabolism, Nagasaki University Hospital, Nagasaki, Japan.;Department of Endocrinology and Metabolism, Nagasaki University Hospital, Nagasaki, Japan.;Department of Endocrinology and Metabolism, Nagasaki University Hospital, Nagasaki, Japan.;Department of Endocrinology and Metabolism, Nagasaki University Hospital, Nagasaki, Japan.;Department of Hypothalamic and Pituitary Surgery, Toranomon Hospital, Tokyo, Japan.;Department of Hypothalamic and Pituitary Surgery, Toranomon Hospital, Tokyo, Japan.;Department of Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan.;Department of Endocrinology and Metabolism, Fujita Health University, Toyoake, Japan.;Department of Endocrinology and Metabolism, Fujita Health University, Toyoake, Japan.;Department of Endocrinology and Metabolism, Fujita Health University, Toyoake, Japan.;Department of Endocrinology and Metabolism, Nagasaki University Hospital, Nagasaki, Japan.;Department of Endocrinology and Metabolism, Nagasaki University Hospital, Nagasaki, Japan.",
"authors": "Niri|Tetsuro|T|;Horie|Ichiro|I|;Kawahara|Hiromi|H|;Ando|Takao|T|;Fukuhara|Noriaki|N|;Nishioka|Hiroshi|H|;Inoshita|Naoko|N|;Fujisawa|Haruki|H|;Suzuki|Atsushi|A|;Sugimura|Yoshihisa|Y|;Abiru|Norio|N|;Kawakami|Atsushi|A|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1507/endocrj.EJ20-0300",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-8959",
"issue": "68(1)",
"journal": "Endocrine journal",
"keywords": "Diabetes insipidus; Hypophysitis; Hypothalamitis; Hypothalamus; Rabphilin-3A",
"medline_ta": "Endocr J",
"mesh_terms": "D000328:Adult; D000568:Amenorrhea; D000069281:Autoimmune Hypophysitis; D020790:Diabetes Insipidus, Neurogenic; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D006963:Hyperphagia; D007018:Hypopituitarism; D007027:Hypothalamic Diseases; D007564:Japan; D008279:Magnetic Resonance Imaging",
"nlm_unique_id": "9313485",
"other_id": null,
"pages": "119-127",
"pmc": null,
"pmid": "32963149",
"pubdate": "2021-01-28",
"publication_types": "D002363:Case Reports; D003160:Comparative Study; D016428:Journal Article; D016454:Review",
"references": null,
"title": "A case of isolated hypothalamitis with a literature review and a comparison with autoimmune hypophysitis.",
"title_normalized": "a case of isolated hypothalamitis with a literature review and a comparison with autoimmune hypophysitis"
} | [
{
"companynumb": "JP-PFIZER INC-2020393407",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "1",
... |
{
"abstract": "GHB intoxication must be considered in children with coma and a suspicion of drug intoxication. Furthermore, mixed intoxication with several substances and the possibility of unpredictable symptom profiles should be anticipated to ensure optimal symptomatic treatment of patients.",
"affiliations": "Department of Pediatrics Hvidovre University Hospital Hvidovre Denmark.;Department of Clinical Biochemistry Vendsyssel Hospital Aalborg University Aalborg Denmark.;Department of Clinical Pharmacology and Danish Poison Information Center Bispebjerg Hospital University of Copenhagen Copenhagen Denmark.;Department of Pediatrics Hvidovre University Hospital Hvidovre Denmark.;Department of Pediatrics Hvidovre University Hospital Hvidovre Denmark.",
"authors": "de Knegt|Victoria Elizabeth|VE|;Breindahl|Torben|T|;Harboe|Kirstine Moll|KM|;Møller|Gitte Leth|GL|;Børresen|Malene Landbo|ML|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.492",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.492CCR3492Case ReportCase ReportsGamma‐hydroxybutyrate and cocaine intoxication in a Danish child V. E. de Knegt et al.de Knegt Victoria Elizabeth \n1\nBreindahl Torben \n2\nHarboe Kirstine Moll \n3\nMøller Gitte Leth \n1\nBørresen Malene Landbo \n1\n1 Department of PediatricsHvidovre University HospitalHvidovreDenmark2 Department of Clinical BiochemistryVendsyssel HospitalAalborg UniversityAalborgDenmark3 Department of Clinical Pharmacology and Danish Poison Information CenterBispebjerg HospitalUniversity of CopenhagenCopenhagenDenmark* Correspondence\n\nVictoria Elizabeth de Knegt, Department of Pediatrics, 460, Hvidovre Hospital, Kettegård Alle 30, 2650 Hvidovre, Denmark. Tel/Fax: +45 50469429; E‐mail: victoriadeknegt@gmail.com\n11 1 2016 3 2016 4 3 10.1111/ccr3.2016.4.issue-3228 231 11 10 2015 25 11 2015 12 12 2015 © 2016 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Key Clinical Message\n\nGHB intoxication must be considered in children with coma and a suspicion of drug intoxication. Furthermore, mixed intoxication with several substances and the possibility of unpredictable symptom profiles should be anticipated to ensure optimal symptomatic treatment of patients.\n\ngamma‐hydroxybutyrategamma‐hydroxybutyric acidGHBcocainepediatricchildintoxication source-schema-version-number2.0component-idccr3492cover-dateMarch 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.7.6 mode:remove_FC converted:01.03.2016\n\nClinical Case Reports \n2016 ; 4 (3 ): 228 –231\n==== Body\nIntroduction\nGamma‐Hydroxybutyrate (GHB) is an endogenic gamma‐aminobutyric acid analog originally used in the 1960s as an anesthetic drug. It was revoked due to side effects but later reintroduced as a drug for treatment of narcolepsy. In the 1980s GHB was promoted as a bodybuilding and weight loss aid due to its purported growth hormone stimulatory effects 1, 2. After it was banned in the US in 1990, its use in body building 3 and as a recreational drug 4 expanded. GHB reached the UK in the mid 1990s 5 and shortly thereafter Denmark as a substance of abuse 6. The prevalence of GHB use in Scandinavia is considered to be low, but the proportion of intoxications with GHB relative to other drugs‐of‐abuse is high and numerous fatalities have been described 7.\n\nGamma‐butyrolactone (GBL) and 1,4‐butanediol (BD) are prodrugs of GHB. Both substances are accessible as pure industrial solvents (>98%) and purchasing opportunities as well as recipes for converting these prodrugs into GHB are easily available 8. The legal status of GBL and BD vary and only a few countries have classified the compounds as controlled substances.\n\nGHB, GBL, and BD intoxication in children has been described. Accidental ingestion of GBL solvents 9, 10, 11, ingestion of BD coated toy beads 12, 13, 14, 15, and cases of children and adolescents unintentionally drinking GHB laced soft drinks have been reported 16, 17. We report a case of a 3‐year‐old boy ingesting GHB from a fluid container found in a fitness center. To our knowledge, GHB intoxication in children as a result of the substance's supposed growth hormone stimulatory effects and misuse among bodybuilders has not been reported before.\n\nCase\nA 3‐year‐old Danish boy was admitted to hospital with sudden onset lethargy, vomiting, and unconsciousness. The child was with his father in a fitness center, where he was left unsupervised in a children's play area. Shortly after, the child came up to his father and said that he had drunk something from a fluid container left on a nearby table. Approximately 40 min later, when the family was eating at a nearby restaurant, the child suddenly became lethargic and distant and was rushed to hospital.\n\nUpon arrival the patient was cyanotic and unconscious with a Glasgow Coma Score (GCS) of 8 and a saturation of 84%. All other vital parameters were normal. Initial blood sugar was 5.2 mmol/L. The patient exhibited equally dilated pupils that had slow response to light bilaterally. The patient woke up after 10 min and after another 15 min was fully awake with a GCS of 15. Active charcoal was given. Initial blood tests including hemoglobin, capillary blood gas, kidney, electrolyte, liver enzyme, and infection parameters were normal. Plasma ethanol was below 3.0 mmol/L. Since the hospital did not have a pediatric department, the patient was transferred to an appropriate hospital for observation.\n\nApproximately 90 min after time of ingestion, the patient again suddenly became bradycardic and desaturated to 60%. The patient exhibited dilated pupils and increased tonus in his hands and arms, but showed otherwise no signs of cramping. The patient improved spontaneously within 3 min with normal pulse and saturation but fell into deep sleep. Cerebral CT was normal. Continuous ECG monitoring showed sinus rhythm. A urine sample was acquired by bladder puncture. A urine toxicology screening (immunoassay panel test) was negative for amphetamines, benzodiazepines, cocaine metabolites, cannabis, cannabis metabolites, methadone, and opiates. A urine sample was saved for further testing. The patient was stabilized without ABC problems, but with continued lowered GCS. He was transferred to the intensive care unit where repeated blood tests were normal. Approximately 6 h after ingestion, the patient woke up and presented no further symptoms.\n\nThe patient's father was aware of GHB use in the fitness center. On the basis of the symptoms as well as the history, we suspected GHB intoxication. Isocratic high‐performance liquid chromatography with tandem mass spectrometry (LC‐MS/MS) was used to determine GHB and prodrugs with a method adopted from Wood et al. 18 using a Symmetry C18 column, 2 × 100 mm (3.5 μm) from Waters. The GHB concentration in the patient's urine sample retrieved 1.5–2 h after ingestion was 186 μg/mL. GBL was 15 μg/mL and BD was not detected. The urinal cut‐off concentration used to distinguish exogenous GHB ingestion from endogenous levels is 10 μg/mL.\n\nDiscussion\nThe urine GHB concentration found in this case report (186 μg/mL) was 18 times higher than the maximum endogenous level. In comparison, a study of 8 healthy adult volunteers who were administered a single 25 mg/kg dose of GHB showed peak urine concentrations of 230 ± 86.3 μg/mL 60 min after ingestion 19. Another study of 12 adult volunteers ingesting the same dose of GHB reported peak concentrations in the range 32.6–161.3 μg/mL (average 67.6 μg/mL) 20. In a study of 16 adult volunteers, doses of 50 mg/kg resulted in peak urine concentrations averaging 150–200 μg/mL in samples collected 0–3 h after drug administration 21. Due to insufficient urine sample volume, it was not possible to determine the creatinine level of our patient's urine sample. We are, therefore, unable to comment on the degree of urinal dilution. We can, however, conclude that the urine GHB concentration in this case report corresponds to levels found in adults who are administered GHB doses of 25–50 mg/kg.\n\nOur case demonstrates previously described symptoms of GHB toxicity. These are vomiting, lethargy, somnolence, respiratory distress, bradycardia, and CNS depression. The patient showed sudden onset of symptoms and spontaneous remission – two very characteristic traits of GHB intoxication 22. One symptom that did not fit the profile of GHB intoxication, however, was the dilation of the patient's pupils.\n\nThe patient's symptom pattern exhibited a biphasic profile. Sedative symptoms with affected GCS appeared twice, initially 40 min after ingestion and then again 1.5–2 h after ingestion. GHB is known to show a mixed stimulant‐sedative pattern where psychostimulant effects appear first and sedative effects appear later 23. A double‐peaked sedative effect, however, has not been described previously. It is known that elimination of GHB from the body is biphasic. The first phase follows linear, zero‐order kinetics where the rate of elimination is independent of the drug concentration. Remaining elimination follows a inversely proportional, concentration‐dependent first‐order kinetic rate of elimination 19, 24, 25. A biphasic symptom profile should, therefore, not be possible.\n\nThe biphasic clinical presentation of symptoms raises the suspicion of the possible involvement of other toxic agents. The observed dilated pupils support this suspicion but at the same time could have been the result of parasympathetic effects caused by vomiting and a fall in blood pressure, pulse, and respiration frequency. Subsequent comprehensive urine drug screening was, therefore, carried out to determine the possible presence of other drugs not detected in the immunoassay panel test. A low concentration of benzoylecgonine – a metabolite of cocaine – estimated to 20 ng/mL was found by LC‐MS/MS. The combination of GHB and cocaine is well‐known in the world of fitness and bodybuilding, where the stimulatory effects of cocaine are used to counteract the sedative effects of GHB. The presence of cocaine in conjunction with GHB in our patient was, therefore, not surprising.\n\nInitial urine analysis by immunoassay was false negative for cocaine. Screening tests for benzoylecgonine have cut‐off concentrations between 150 and 300 ng/mL and concentrations less than this remain undetectable. Since the amount of cocaine in the urine sample was below the limit of quantification and because the patient received active charcoal within the appropriate time interval, we believe that this treatment may have terminated further absorption of cocaine.\n\nAnother factor that needs to be considered is the effect of food on the symptom profile of GHB and cocaine. The patient had eaten a meal shortly after ingesting the unknown fluid. Food could have played a role in the absorption rate of both GHB and cocaine and may have contributed to the biphasic symptom profile seen.\n\nAnother plausible cause of the biphasic profile seen in our patient may be ingestion of a mixture of GHB, GBL and/or BD. It is known that both prodrugs of GHB have the same toxic effects as GHB but GBL has more rapid absorption, greater lipid solubility, higher serum concentration, and more prolonged hypnotic effects than GHB 26, 27, 28. The concentration of GBL and GHB in urine is, however, inconclusive with regard to GBL ingestion due to the dynamic equilibrium that exists between GHB and GBL in vitro\n29.\n\nHence, it remains speculative whether a mixture of GBH, GBL and/or BD could produce the symptom profile observed in our patient or if it may have been caused by food ingestion or by the presence of other drugs that were not detected. On the basis of our patient's clinical presentation and resolution of symptoms and a confirmatory high urine level of GHB, we conclude that GHB was the most likely cause of our patient's symptoms.\n\nConclusion\nGHB intoxication must be considered in children with coma and a suspicion of drug intoxication. Furthermore, mixed intoxication with several substances and the possibility of unpredictable symptom profiles should be anticipated to ensure optimal symptomatic treatment of patients. The use of GHB and cocaine in the world of bodybuilding and our account of a new child victim demonstrates a new area of concern.\n\nConsent\nWritten informed consent was obtained from the parents of the patient for publication of this case report. A copy of the written consent is available for review by the Editor of this journal.\n\nConflict of Interests\nThe authors declare that they have no competing interests. There are no relevant financial relationships that should be disclosed. There are no conflicts of interest.\n\nAcknowledgments\nWe wish to thank Jørgen Bo Hasselstrøm and Mette Findal Andreasen, Section of Forensic Chemistry, Department of Forensic Medicine, Aarhus University, Denmark for their kind help in confirming our analytical results for GHB and benzoylecgonine. No funding was received.\n==== Refs\nReferences\n1 \n\nTakahara , J. \n, \nS. \nYunoki \n, \nW. \nYakushiji \n, \nJ. \nYamauchi \n, and \nY. \nYamane \n. 1977 \nStimulatory effects of gamma‐hydroxybutyric acid on growth hormone and prolactin release in humans . J. Clin. Endocrinol. Metab. \n44 :1014 –1017 .858775 \n2 \n\nGalloway , G. P. \n, \nS. L. \nFrederick \n, \nF. E. \nStaggers \n, \nM. \nGonzales \n, \nS. A. \nStalcup \n, and \nD. E. \nSmith \n. 1997 \nGamma‐hydroxybutyrate: an emerging drug of abuse that causes physical dependence . Addict. Abingdon. Engl. \n92 :89 –96 .\n3 \n\nMyrenfors , P. \n. 1996 \n[Ten cases of poisoning with gamma hydroxybutyrate. An endogenous substance used by body builders] . Läkartidningen \n93 :1973 –1974 .8667837 \n4 \nFrom the Centers for Disease Control \n. 1991 \nMultistate outbreak of poisonings associated with illicit use of gamma hydroxy butyrate . JAMA \n265 :447 –448 .1985226 \n5 \n\nStell , J. M. \n, and \nJ. M. \nRyan \n. 1996 \nEcstasy and neurodegeneration. Gamma‐Hydroxybutyrate is a new recreational drug that may lead to loss of consciousness . BMJ \n313 :424 .8761242 \n6 \n\nEngelsen , J. \n, and \nH. R. \nChristensen \n. 1999 \n[Gamma‐hydroxybutyrate–an endogenous substance and a new central nervous system stimulant. Clinical aspects of acute poisoning] . Ugeskr. Laeger \n161 :6903 –6907 .10643375 \n7 \n\nKnudsen , K. \n, \nJ. \nGreter \n, and \nM. \nVerdicchio \n. 2008 \nHigh mortality rates among GHB abusers in Western Sweden . Clin. Toxicol. Phila. Pa. \n46 :187 –192 .\n8 \n\nSanguineti , V. R. \n, \nA. \nAngelo \n, and \nM. R. \nFrank \n. 1997 \nGHB: a home brew . Am. J. Drug Alcohol. Abuse \n23 :637 –642 .9366979 \n9 \n\nRambourg‐Schepens , M. O. \n, \nM. \nBuffet \n, \nC. \nDurak \n, and \nM. \nMathieu‐Nolf \n. 1997 \nGamma butyrolactone poisoning and its similarities to gamma hydroxybutyric acid: two case reports . Vet. Hum. Toxicol. \n39 :234 –235 .9251175 \n10 \n\nPiastra , M. \n, \nR. \nBarbaro \n, \nA. \nChiaretti \n, \nA. \nTempera \n, \nS. \nPulitanò \n, and \nG. \nPolidori \n. 2002 \nPulmonary oedema caused by «liquid ecstasy» ingestion . Arch. Dis. Child. \n86 :302 –303 .11919114 \n11 \n\nSavage , T. \n, \nA. \nKhan \n, and \nB. G. \nLoftus \n. 2007 \nAcetone‐free nail polish remover pads: toxicity in a 9‐month old . Arch. Dis. Child. \n92 :371 .17376952 \n12 \n\nOrtmann , L. A. \n, \nM. W. \nJaeger \n, \nL. P. \nJames \n, and \nS. M. \nSchexnayder \n. 2009 \nComa in a 20‐month‐old child from an ingestion of a toy containing 1,4‐butanediol, a precursor of gamma‐hydroxybutyrate . Pediatr. Emerg. Care \n25 :758 –760 .19915428 \n13 \n\nRunnacles , J. L. M. \n, and \nJ. \nStroobant \n. 2008 \n[gamma]‐Hydroxybutyrate poisoning: poisoning from toy beads . BMJ \n336 :110 .18202042 \n14 \n\nGunja , N. \n, \nE. \nDoyle \n, \nK. \nCarpenter \n, \nO. T. \nChan \n, \nS. \nGilmore \n, \nG. \nBrowne \n, et al. 2008 \nGamma‐hydroxybutyrate poisoning from toy beads . Med. J. Aust. \n188 :54 –55 .18021061 \n15 \n\nSuchard , J. \n, \nS. \nNizkorodov \n, and \nS. \nWilkinson \n. 2009 \n1,4‐Butanediol content of aqua dots children's craft toy beads . J. Med. Toxicol. Off J. Am. Coll. Med. Toxicol. \n5 :120 –124 .\n16 \n\nSuner , S. \n, \nC. S. \nSzlatenyi \n, and \nR. Y. \nWang \n. 1997 \nPediatric gamma hydroxybutyrate intoxication . Acad. Emerg. Med. Off J. Soc. Acad. Emerg. Med. \n4 :1041 –1045 .\n17 \n\nShannon , M. \n, and \nL. S. \nQuang \n. 2000 \nGamma‐hydroxybutyrate, gamma‐butyrolactone, and 1,4‐butanediol: a case report and review of the literature . Pediatr. Emerg. Care \n16 :435 –440 .11138892 \n18 \n\nWood , M. \n, \nM. \nLaloup \n, \nN. \nSamyn \n, \nM. R. \nMorris \n, \nE. A. \nde Bruijn \n, \nR. A. \nMaes \n, et al. 2004 \nSimultaneous analysis of gamma‐hydroxybutyric acid and its precursors in urine using liquid chromatography‐tandem mass spectrometry . J. Chromatogr. A \n1056 :83 –90 .15595536 \n19 \n\nBrenneisen , R. \n, \nM. A. \nElsohly \n, \nT. P. \nMurphy \n, \nJ. \nPassarelli \n, \nS. \nRussmann \n, \nS. J. \nSalamone \n, et al. 2004 \nPharmacokinetics and excretion of gamma‐hydroxybutyrate (GHB) in healthy subjects . J. Anal. Toxicol. \n28 :625 –630 .15538955 \n20 \n\nBrailsford , A. D. \n, \nD. A. \nCowan \n, and \nA. T. \nKicman \n. 2012 \nPharmacokinetic properties of γ‐hydroxybutyrate (GHB) in whole blood, serum, and urine . J. Anal. Toxicol. \n36 :88 –95 .22337777 \n21 \n\nHaller , C. \n, \nD. \nThai \n, \nP. \nJacob \n, and \nJ. E. \nDyer \n. 2006 \nGHB urine concentrations after single‐dose administration in humans . J. Anal. Toxicol. \n30 :360 –364 .16872565 \n22 \n\nChin , R. L. \n, \nK. A. \nSporer \n, \nB. \nCullison \n, \nJ. E. \nDyer \n, and \nT. D. \nWu \n. 1998 \nClinical course of gamma‐hydroxybutyrate overdose . Annu. Emerg. Med. \n31 :716 –722 .\n23 \n\nAbanades , S. \n, \nM. \nFarré \n, \nM. \nSegura \n, \nS. \nPichini \n, \nD. \nBarral \n, \nR. \nPacifici \n, et al. 2006 \nGamma‐hydroxybutyrate (GHB) in humans: pharmacodynamics and pharmacokinetics . Annu. N. Y. Acad. Sci. \n1074 :559 –576 .\n24 \n\nAbanades , S. \n, \nM. \nFarré \n, \nM. \nSegura \n, \nS. \nPichini \n, \nA. \nPastor \n, \nR. \nPacifici \n, et al. 2007 \nDisposition of gamma‐hydroxybutyric acid in conventional and nonconventional biologic fluids after single drug administration: issues in methodology and drug monitoring . Ther. Drug Monit. \n29 :64 –70 .17304152 \n25 \n\nPalatini , P. \n, \nL. \nTedeschi \n, \nG. \nFrison \n, \nR. \nPadrini \n, \nR. \nZordan \n, \nR. \nOrlando \n, et al. 1993 \nDose‐dependent absorption and elimination of gamma‐hydroxybutyric acid in healthy volunteers . Eur. J. Clin. Pharmacol. \n45 :353 –356 .8299669 \n26 \n\nKohrs , F. P. \n, and \nW. H. \nPorter \n. 1999 \nGamma‐Hydroxybutyrate intoxication and overdose . Annu. Emerg. Med. \n33 :475 –476 .\n27 \n\nLettieri , J. \n, and \nH. L. \nFung \n. 1978 \nImproved pharmacological activity via pro‐drug modification: comparative pharmacokinetics of sodium gamma‐hydroxybutyrate and gamma‐butyrolactone . Res. Commun. Chem. Pathol. Pharmacol. \n22 :107 –118 .725311 \n28 \n\nRoth , R. H. \n, \nJ. M. \nDelgado \n, and \nN. J. \nGiarman \n. 1966 \nGamma‐butyrolactone and gamma‐hydroxybutyric acid. II. The pharmacologically active form . Int. J. Neuropharmacol. \n5 :421 –428 .4293055 \n29 \n\nCiolino , L. A. \n, \nM. Z. \nMesmer \n, \nR. D. \nSatzger \n, \nA. C. \nMachal \n, \nH. A. \nMcCauley \n, and \nA. S. \nMohrhaus \n. 2001 \nThe chemical interconversion of GHB and GBL: forensic issues and implications . J. Forensic Sci. \n46 :1315 –1323 .11714141\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2050-0904",
"issue": "4(3)",
"journal": "Clinical case reports",
"keywords": "GHB; child; cocaine; gamma‐hydroxybutyrate; gamma‐hydroxybutyric acid; intoxication; pediatric",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "228-31",
"pmc": null,
"pmid": "27014439",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports",
"references": "22337777;9624311;10643375;8761242;18344100;11919114;27014439;19655283;17105953;16872565;8667837;18021061;1985226;18202042;858775;9251175;17304152;10092734;9060200;9366979;4293055;15538955;11714141;11138892;19915428;8299669;9383489;725311;17376952;15595536",
"title": "Gamma-hydroxybutyrate and cocaine intoxication in a Danish child.",
"title_normalized": "gamma hydroxybutyrate and cocaine intoxication in a danish child"
} | [
{
"companynumb": "DK-JAZZ-2016-DK-004813",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SODIUM OXYBATE"
},
"drugadditional": null,
... |
{
"abstract": "Lidocaine is absorbed from mucous membranes of the oropharynx, gastrointestinal tract, and tracheobronchial tree. First-pass hepatic metabolism of the drug greatly reduces the amount reaching the general systemic circulation in the normal individual. In patients whose hepatic metabolism is reduced by disease or drugs, or in whom liver blood flow is reduced, this first-pass effect is decreased and lidocaine concentrations may be higher than those produced by the same dose in normal patients. We report an elderly man taking cimetidine with congestive heart failure in whom the accidental ingestion of lidocaine solution for esophageal anesthesia was followed by seizures and elevated serum lidocaine concentrations.",
"affiliations": null,
"authors": "Parish|R C|RC|;Moore|R T|RT|;Gotz|V P|VP|",
"chemical_list": "D008012:Lidocaine",
"country": "United States",
"delete": false,
"doi": "10.1177/106002808501900305",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-6578",
"issue": "19(3)",
"journal": "Drug intelligence & clinical pharmacy",
"keywords": null,
"medline_ta": "Drug Intell Clin Pharm",
"mesh_terms": "D000368:Aged; D000772:Anesthesia, Local; D004947:Esophagus; D006801:Humans; D008012:Lidocaine; D008297:Male; D008875:Middle Aged; D012640:Seizures",
"nlm_unique_id": "0212457",
"other_id": null,
"pages": "199-201",
"pmc": null,
"pmid": "3979259",
"pubdate": "1985-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Seizures following oral lidocaine for esophageal anesthesia.",
"title_normalized": "seizures following oral lidocaine for esophageal anesthesia"
} | [
{
"companynumb": "US-PFIZER INC-3078162",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LIDOCAINE HYDROCHLORIDE"
},
"drugadditional": "3"... |
{
"abstract": "BACKGROUND\nAfrican Americans have a greater incidence of lung cancer than whites and have been underrepresented in clinical trials. In the PointBreak trial (pemetrexed-carboplatin-bevacizumab and maintenance pemetrexed-bevacizumab [PemCBev] vs. paclitaxel-carboplatin-bevacizumab and maintenance bevacizumab [PacCBev]), 10% of the patients were African American. PointBreak had negative findings; PemCBev did not demonstrate superior overall survival (OS).\n\n\nMETHODS\nPointBreak subgroup efficacy and safety data were retrospectively analyzed: African Americans versus whites for PemCBev; PemCBev versus PacCBev in African Americans; and academic versus community settings for African Americans. Hazard ratios (HRs) and P values were derived from a multivariate Cox proportional hazards model after adjusting for covariates.\n\n\nRESULTS\nOf 939 intent-to-treat (ITT) patients, 94 were African American and 805 were white. African-American enrollment was uniform across the study sites (median, 1 African American per site). In the PemCBev arm, OS (HR, 1.125; P = .525), progression-free survival (PFS) (HR, 1.229; P = .251), response (P = .607), and toxicity profiles were similar in African Americans versus whites. For African Americans, OS (HR, 1.375; P = .209), PFS (HR, 0.902; P = .670), response (P = 1.000), and toxicity profiles were similar in the PemCBev versus PacCBev arm. For African Americans, no significant differences were seen in OS (HR, 0.661; P = .191) or PFS (HR, 0.969; P = .915) in academic versus community practice settings.\n\n\nCONCLUSIONS\nIn the PemCBev arm, this exploratory analysis showed no significant differences between African Americans and whites for the efficacy outcomes or toxicity profiles. Consistent with the ITT population negative trial result, for African Americans, the median OS was not superior for either arm. For African Americans, PFS and OS were similar in the academic and community settings. Additional outcomes data for African Americans should be collected in lung cancer studies.",
"affiliations": "US Oncology Research, Ocala, FL. Electronic address: craig.reynolds@usoncology.com.;Northwestern University Feinberg School of Medicine, Chicago, IL.;University of California, Los Angeles, David Geffen School of Medicine, Translational Research in Oncology-United States, Los Angeles, CA.;Tulsa Cancer Institute, Tulsa, OK.;Rush University Medical Center, Chicago, IL.;Washington University School of Medicine, St Louis, MO.;Eli Lilly and Company, Indianapolis, IN.;Eli Lilly and Company, Indianapolis, IN.;Eli Lilly and Company, Indianapolis, IN.;Eli Lilly and Company, Indianapolis, IN.;Sarah Cannon Research Institute, Nashville, TN and Tennessee Oncology, PLLC, Nashville, TN.;Northwest Georgia Oncology Centers, PC, Marietta, GA.;Division of Hematology/Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA.;Eli Lilly and Company, Indianapolis, IN.",
"authors": "Reynolds|Craig H|CH|;Patel|Jyoti D|JD|;Garon|Edward B|EB|;Olsen|Mark R|MR|;Bonomi|Philip|P|;Govindan|Ramaswamy|R|;Pennella|Eduardo J|EJ|;Liu|Jingyi|J|;Guba|Susan C|SC|;Li|Shi|S|;Spigel|David R|DR|;Hermann|Robert C|RC|;Socinski|Mark A|MA|;Obasaju|Coleman K|CK|",
"chemical_list": "D000068437:Pemetrexed; D000068258:Bevacizumab; D016190:Carboplatin; D017239:Paclitaxel",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-7304",
"issue": "16(3)",
"journal": "Clinical lung cancer",
"keywords": "Alimta; Avastin; Minority groups",
"medline_ta": "Clin Lung Cancer",
"mesh_terms": "D000328:Adult; D001741:African Americans; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D016190:Carboplatin; D002289:Carcinoma, Non-Small-Cell Lung; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel; D000068437:Pemetrexed; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome",
"nlm_unique_id": "100893225",
"other_id": null,
"pages": "200-8",
"pmc": null,
"pmid": "25516338",
"pubdate": "2015-05",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Exploratory Subset Analysis of African Americans From the PointBreak Study: Pemetrexed-Carboplatin-Bevacizumab Followed by Maintenance Pemetrexed-Bevacizumab Versus Paclitaxel-Carboplatin-Bevacizumab Followed by Maintenance Bevacizumab in Patients With Stage IIIB/IV Nonsquamous Non-Small-Cell Lung Cancer.",
"title_normalized": "exploratory subset analysis of african americans from the pointbreak study pemetrexed carboplatin bevacizumab followed by maintenance pemetrexed bevacizumab versus paclitaxel carboplatin bevacizumab followed by maintenance bevacizumab in patients with stage iiib iv nonsquamous non small cell lung cancer"
} | [
{
"companynumb": "US-CIPLA LTD.-2015US03527",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nTacrolimus (FK506, Prograf) is a potent immunosuppressant, which inhibits cytokine synthesis and blocks T-cell development. Optic neuropathy from tacrolimus toxicity is very uncommon but, when present, can result in severe vision loss.\n\n\nMETHODS\nCase series and review of the literature.\n\n\nRESULTS\nWe present 3 patients with tacrolimus optic neuropathy after bone marrow transplantation complicated by graft-vs-host disease and demonstrate the differing clinical and radiologic presentation of this presumed toxic optic neuropathy.\n\n\nCONCLUSIONS\nTacrolimus optic neuropathy can manifest in a multitude of clinical presentations and can have devastating visual consequences.",
"affiliations": "Department of Ophthalmology (NR), Harkness Eye Institute, Columbia University, New York, New York; Deartment of Ophthalmology (KB), University of Montreal, Montreal, Quebec, Canada; Department of Ophthalmology (SL, DMC), Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts; and Department of Ophthalmology (SP), Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.",
"authors": "Rasool|Nailyn|N|;Boudreault|Katherine|K|;Lessell|Simmons|S|;Prasad|Sashank|S|;Cestari|Dean M|DM|",
"chemical_list": "D007166:Immunosuppressive Agents; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1097/WNO.0000000000000635",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1070-8022",
"issue": "38(2)",
"journal": "Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society",
"keywords": null,
"medline_ta": "J Neuroophthalmol",
"mesh_terms": "D000368:Aged; D016026:Bone Marrow Transplantation; D002555:Cerebrospinal Fluid; D006086:Graft vs Host Disease; D006801:Humans; D007166:Immunosuppressive Agents; D007964:Leukocytosis; D008214:Lymphocytes; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009898:Optic Disk; D009901:Optic Nerve Diseases; D016559:Tacrolimus; D014792:Visual Acuity; D058609:Visual Field Tests; D014794:Visual Fields",
"nlm_unique_id": "9431308",
"other_id": null,
"pages": "160-166",
"pmc": null,
"pmid": "29420328",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Tacrolimus Optic Neuropathy.",
"title_normalized": "tacrolimus optic neuropathy"
} | [
{
"companynumb": "PHHY2019US188027",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SIROLIMUS"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Headache disorders are burdensome, both in terms of the number of people they affect, and in terms of associated healthcare spending. This report presents a 36-year-old female admitted to a tertiary university hospital with a primary complaint of intractable headache, caused by a combination of medication overuse headache, and headache secondary to aseptic meningitis. During her hospital stay, opioid analgesic doses were initially increased without success in an attempt to control her headache. Despite multiple medication trials the patient's headache failed to improve. On day ten of her hospitalization, she underwent a thirty-minute acupuncture session which resulted in immediate relief of her headache. She received one more acupuncture treatment the following day and was discharged to an acute inpatient rehabilitation facility on a vastly reduced dose of opioids. Instructions on how to taper the remaining opioids were provided, and the patient was scheduled for outpatient acupuncture therapy sessions for further headache management. This report demonstrates the importance of recognizing acupuncture as a viable treatment option for medication overuse headache and for headache secondary to systemic diseases such as aseptic meningitis. Furthermore, acupuncture should also be considered as a nonpharmacological modality to be used when tapering a patient off of high doses of opioids.",
"affiliations": "Department of Physical Medicine and Rehabilitation, Penn State Milton S. Hershey Medical Center and Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA. Electronic address: rrudra@pennstatehealth.psu.edu.;Department of Anesthesiology, Penn State Milton S. Hershey Medical Center and Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA. Electronic address: vgordin@pennstatehealth.psu.edu.;Department of Gastroenterology, Penn State Milton S. Hershey Medical Center and Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA. Electronic address: lihuaxu@pennstatehealth.psu.edu.",
"authors": "Rudra|Renuka T|RT|;Gordin|Vitaly|V|;Xu|Lihua|L|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.1016/j.jams.2020.01.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2005-2901",
"issue": "13(2)",
"journal": "Journal of acupuncture and meridian studies",
"keywords": "acupuncture; aseptic meningitis; headache; medication overuse headache; opioids",
"medline_ta": "J Acupunct Meridian Stud",
"mesh_terms": "D015670:Acupuncture Therapy; D000328:Adult; D005260:Female; D006261:Headache; D051271:Headache Disorders, Secondary; D006801:Humans; D008582:Meningitis, Aseptic; D000067490:Prescription Drug Overuse; D016896:Treatment Outcome",
"nlm_unique_id": "101490763",
"other_id": null,
"pages": "58-60",
"pmc": null,
"pmid": "31953043",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Acupuncture in the Management of Medication Overuse and Drug-induced Aseptic Meningitis Headache: A Case Report.",
"title_normalized": "acupuncture in the management of medication overuse and drug induced aseptic meningitis headache a case report"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-251091",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXYCODONE"
},
"druga... |
{
"abstract": "Background: Hyperprolactinemia is a common consequence of treatment with antipsychotics. It is usually defined by a sustained prolactin level above the laboratory upper level of normal in conditions other than that where physiologic hyperprolactinemia is expected. Normal prolactin levels vary significantly among different laboratories and studies. Several studies indicate that olanzapine does not significantly affect serum prolactin levels in the long term, although this statement has been challenged. Aims: Our aim is to report two olanzapine-induced hyperprolactinemia cases observed in psychiatric consultations. Methods: Medical records of the patients who developed this clinical situation observed in psychiatric consultations in the Psychiatry Department of the Prof. Dr. Fernando Fonseca Hospital during the year of 2017 were analyzed, complemented with a non-systematic review of the literature. Results: The case reports consider two women who developed prolactin-related symptoms after the initiation of olanzapine. No baseline prolactinemia was obtained, and prolactin serum levels were only evaluated after prolactin-related symptoms developed: at the time of its measurement, both patients had been taking olanzapine for more than 24 weeks. Hyperprolactinemia was found to be present in Case 2, whereas Case 1 (a 49-year-old woman) had \"normal\" serum prolactin levels for premenopausal and prolactin levels slightly above the maximum levels for postmenopausal women. Both patients underwent similar pharmacological adjustments, which comprised switches from olanzapine to aripiprazole. After all pharmacological changes, prolactin serum levels decreased to normal range values and prolactin-related symptoms disappeared. Discussion/Conclusions: Laboratorial and literature prolactinemia values variability and discrepancies may make the management of borderline hyperprolactinemia clinical situations difficult. Baseline prolactin levels should have been obtained, as they help in the management of patients who develop neuroleptic-induced hyperprolactinemia. Prolactin-related symptoms can occur with borderline or normal standardized prolactinemia values. Olanzapine-induced hyperprolactinemia is a rare but possible event. Aripiprazole was used as a suitable alternative for olanzapine-induced hyperprolactinemia.",
"affiliations": "Departamento de Psiquiatria, Hospital Prof. Dr. Fernando da Fonseca, EPE, Amadora, Portugal.;Departamento de Psiquiatria, Hospital Prof. Dr. Fernando da Fonseca, EPE, Amadora, Portugal.;Departamento de Psiquiatria, Hospital Prof. Dr. Fernando da Fonseca, EPE, Amadora, Portugal.;Departamento de Psiquiatria, Hospital Prof. Dr. Fernando da Fonseca, EPE, Amadora, Portugal.",
"authors": "Barata|Pedro Cabral|PC|;Santos|Mário João|MJ|;Melo|João Carlos|JC|;Maia|Teresa|T|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fphar.2019.00846",
"fulltext": "\n==== Front\nFront PharmacolFront PharmacolFront. Pharmacol.Frontiers in Pharmacology1663-9812Frontiers Media S.A. 10.3389/fphar.2019.00846PharmacologyCase ReportOlanzapine-Induced Hyperprolactinemia: Two Case Reports Barata Pedro Cabral \n*\nSantos Mário João Melo João Carlos Maia Teresa Departamento de Psiquiatria, Hospital Prof. Dr. Fernando da Fonseca, EPE, Amadora, PortugalEdited by: Angel L. Montejo, University of Salamanca, Spain\n\nReviewed by: Carlos Spuch, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Spain; Lucio Tremolizzo, University of Milano-Bicocca, Italy\n\n*Correspondence: Pedro Cabral Barata, p.barata9@gmail.com\nThis article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology\n\n29 7 2019 2019 10 84614 5 2019 02 7 2019 Copyright © 2019 Barata, Santos, Melo and Maia2019Barata, Santos, Melo and MaiaThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nBackground: Hyperprolactinemia is a common consequence of treatment with antipsychotics. It is usually defined by a sustained prolactin level above the laboratory upper level of normal in conditions other than that where physiologic hyperprolactinemia is expected. Normal prolactin levels vary significantly among different laboratories and studies. Several studies indicate that olanzapine does not significantly affect serum prolactin levels in the long term, although this statement has been challenged.\n\n\nAims: Our aim is to report two olanzapine-induced hyperprolactinemia cases observed in psychiatric consultations.\n\n\nMethods: Medical records of the patients who developed this clinical situation observed in psychiatric consultations in the Psychiatry Department of the Prof. Dr. Fernando Fonseca Hospital during the year of 2017 were analyzed, complemented with a non-systematic review of the literature.\n\n\nResults: The case reports consider two women who developed prolactin-related symptoms after the initiation of olanzapine. No baseline prolactinemia was obtained, and prolactin serum levels were only evaluated after prolactin-related symptoms developed: at the time of its measurement, both patients had been taking olanzapine for more than 24 weeks. Hyperprolactinemia was found to be present in Case 2, whereas Case 1 (a 49-year-old woman) had “normal” serum prolactin levels for premenopausal and prolactin levels slightly above the maximum levels for postmenopausal women. Both patients underwent similar pharmacological adjustments, which comprised switches from olanzapine to aripiprazole. After all pharmacological changes, prolactin serum levels decreased to normal range values and prolactin-related symptoms disappeared.\n\n\nDiscussion/Conclusions: Laboratorial and literature prolactinemia values variability and discrepancies may make the management of borderline hyperprolactinemia clinical situations difficult. Baseline prolactin levels should have been obtained, as they help in the management of patients who develop neuroleptic-induced hyperprolactinemia. Prolactin-related symptoms can occur with borderline or normal standardized prolactinemia values. Olanzapine-induced hyperprolactinemia is a rare but possible event. Aripiprazole was used as a suitable alternative for olanzapine-induced hyperprolactinemia.\n\nhyperprolactinemiaolanzapineolanzapine interactionsaripiprazolefluoxetine\n==== Body\nIntroduction\nHyperprolactinemia is a common (Yasui-Furukori et al., 2010; Montejo et al., 2016; Montejo et al., 2017) and underappreciated consequence of the treatment with antipsychotic drugs (Montejo et al., 2016; Montejo et al., 2017). It is usually defined by a sustained prolactin level above the laboratory upper level of normal in conditions other than those where physiologic hyperprolactinemia is expected (e.g., pregnancy and lactation) (Peuskens et al., 2014; Montejo et al., 2017). Prolactin is a polypeptide hormone that is mainly synthesized and secreted from lactotroph cells of the anterior lobe of the pituitary gland. Normal prolactin levels range at 10–20 ng/ml for men and 10–25 ng/ml for women, although there is significant variability among different laboratories and studies (Peuskens et al., 2014). Furthermore, there are important interindividual differences (e.g., gender, age, stress, nutrition, and exercise) (Peuskens et al., 2014; Yang et al., 2018) and pronounced circadian variations (Peuskens et al., 2014). Hyperprolactinemia can be divided according to its severity: mild (50 ng/ml), moderate (51–75 ng/ml), and severe (>100 ng/ml) (Montejo et al., 2016).\n\nIn women, hyperprolactinemia can cause amenorrhea, galactorrhea, cessation of normal cyclic ovarian function, and hirsutism. In men, it can cause gynecomastia, impotence, loss of libido, and hypospermatogenesis. Long-term hypogonadism due to hyperprolactinemia has also been associated with low bone density, osteoporosis, hip fracture (Yasui-Furukori et al., 2010; Pérez-Iglesias et al., 2012; Montejo et al., 2016), prolactinoma (Montejo et al., 2017), and increased cardiovascular risk (Montejo et al., 2016; Montejo et al., 2017). Women are considered to be more susceptible to be affected by antipsychotic-induced hyperprolactinemia; in spite of that, there is little literature reporting the trajectory of olanzapine-induced hyperprolactinemia in females (Yang et al., 2018). Preclinical animal models indicate that prolonged high levels of prolactin may predispose to breast cancer (Pérez-Iglesias et al., 2012); what is more, recent clinical studies have strengthened such association. The symptoms that accompany prolactin elevation not only are unpleasant but also contribute to increased stigma (e.g., gynecomastia in males), jeopardizing their health and their treatment adherence (Montejo et al., 2016).\n\nAntipsychotic drugs have differences in their propensity to cause hyperprolactinemia. Several mechanisms have been proposed to explain these variances (Pérez-Iglesias et al., 2012; Montejo et al., 2016; Montejo et al., 2017): D2 receptor-binding affinity (the stronger the dopamine blockade, the higher the prolactin elevation) (Pérez-Iglesias et al., 2012; Peuskens et al., 2014; Montejo et al., 2016; Montejo et al., 2017), differential penetrability across the blood–brain barrier (Pérez-Iglesias et al., 2012; Montejo et al., 2016; Montejo et al., 2017), and central mechanisms modulated by monoamines other than dopamine (Pérez-Iglesias et al., 2012).\n\nAlthough first-generation antipsychotics are associated with pronounced elevations of prolactin levels (Pérez-Iglesias et al., 2012; Montejo et al., 2016; Montejo et al., 2017), the highest rates of hyperprolactinemia have been reported with sulpiride (Peuskens et al., 2014), amisulpride, risperidone (Peuskens et al., 2014; Montejo et al., 2016; Montejo et al., 2017), and paliperidone (Montejo et al., 2016; Montejo et al., 2017). These rates can be as high as 80–90% and are consistently greater than those found with other neuroleptics (Peuskens et al., 2014). Other second-generation agents are less likely to generate sustained hyperprolactinemia (Yasui-Furukori et al., 2010; Montejo et al., 2016; Montejo et al., 2017). While some authors argue that prolactin response to antipsychotic treatments weakens over time (Yasui-Furukori et al., 2010), others report that serum prolactin levels tend to remain elevated during the length of neuroleptic treatment (Montejo et al., 2017). A Multidisciplinary Consensus Group of Experts has proposed a routine prolactin level measurement to all antipsychotic-treated patients, at baseline and at 3-month time (Montejo et al., 2016). Olanzapine, an antipsychotic with an intermediary D2 receptor binding affinity, induces a moderate elevation of prolactin levels (Peuskens et al., 2014). This elevation is regarded as transient and mild compared with that induced by other antipsychotics, such as risperidone (Yasui-Furukori et al., 2010; Montejo et al., 2016), with studies pointing that olanzapine does not significantly affect serum prolactin levels in the long term (Pérez-Iglesias et al., 2012; Montejo et al., 2016). There have been inconsistent results regarding the relationship between serum prolactin levels and doses/plasma concentrations of olanzapine (Peuskens et al., 2014; Takeuchi et al., 2014), although most studies have demonstrated a dose-dependent effect of oral olanzapine on the plasma prolactin level of patients with schizophrenia, with higher doses linked to higher prolactin levels (Peuskens et al., 2014; Takeuchi et al., 2014; Yang et al., 2018). All things considered, prolactin elevation induced by olanzapine remains an unclear matter (Yang et al., 2018). Some D2 receptor and 5-HT2A receptor gene polymorphisms have been involved in prolactin levels after administration of olanzapine (Peuskens et al., 2014); DRD2 and ANKK1 polymorphisms have been associated with prolactin increase in olanzapine-treated women (Houston et al., 2011).\n\nMethods\nWe present two case reports of patients observed in psychiatric consultations in the Psychiatry Department of the Prof. Dr. Fernando Fonseca Hospital during the year of 2017. The case description is done through clinical record analysis. Informed consent was obtained from the participants for the publication of this case report.\n\nA review of the literature considering psychopharmacy-induced hyperprolactinemia and its relationship with olanzapine was also performed: PubMed/MEDLINE database search of scientific articles [MeSH (Medical Subject Headings) terms “hyperprolactinemia,” “olanzapine,” “prolactin,” “olanzapine interactions,” and “fluoxetine”; written in English and Spanish; from the year 1999 to 2018] and the use of psychopharmacology textbooks.\n\nCase Presentation\nTwo cases of olanzapine-induced hyperprolactinemia are presented, whose sociodemographic and clinical characteristics can be found in \nTables 1\n and \n2\n.\n\nTable 1 Patients’ sociodemographic and basic clinical data.\n\n\tCase 1\tCase 2\t\n\nAge (in years)\n\t49\t29\t\n\nGender\n\tFemale\tFemale\t\n\nPsychiatric diagnosis (ICD-10)\n\tBipolar affective disorder (F31)\tDelusional disorder (F22.0)\t\n\nSomatic comorbidities\n\tNone\tNone\t\n\nTobacco smoking\n\tNo\tNo\t\nTable 2 Prolactin-related clinical data [laboratorial prolactinemia dose ranges (ng/ml): (6.0–29.9) for pre-menopause and (1.8–20.3) for post-menopause].\n\n\tCase 1\tCase 2\t\n\nBaseline prolactin-related symptoms\n\tGalactorrhea and breast pain\tGalactorrhea, breast tension, and amenorrhea\t\n\nBaseline medication\n\tFluoxetine 20 mg/day\nOlanzapine 5 mg/day\tOlanzapine 20 mg/day\nAripiprazole 2.5 mg/day\t\n\nPharmacological changes\n\tSwitch olanzapine–aripiprazole through partial overlap (switch duration: 1 month)\tSwitch olanzapine 20 mg/day to aripiprazole 20 mg/day through partial overlap (switch duration: 2 months)\t\n\nPsychiatric disorder relapse\n\tNo\tYes\t\n\nSecond pharmacological modification due to relapse\n\tN/A\tInitiation of aripiprazole injectable formulation 400 mg every 4 weeks. Gradual stoppage of aripiprazole oral 20 mg/day\t\n\nMedication after all pharmacological adjustments\n\tFluoxetine 20 mg/day\nAripiprazole 20 mg/day\tAripiprazole injectable formulation 400 mg every 4 weeks\t\n\nProlactinemia before pharmacological adjustments (ng/ml)\n\t20.73\t50\t\n\nProlactinemia after pharmacological all adjustments (ng/ml)\n\t7.27\t8.51\t\n\nProlactin-related symptoms after all pharmacological adjustments\n\tAsymptomatic\tAsymptomatic\t\n\nPsychiatric disorder after all pharmacological adjustments\n\tStable\tStable\t\nBoth patients developed prolactin-related symptoms after the initiation of olanzapine. These patients complained about the symptoms at their psychiatric consultations, referring that they were significantly disturbing their quality of life. Prolactinemia levels were only obtained after these complaints, as there were no asymptomatic prolactin serum levels. At the time when prolactinemia levels were obtained, both patients had been taking olanzapine for more than 24 weeks.\n\nPatient 1 required one pharmacological adjustment (from oral olanzapine 5 mg/day to oral aripiprazole 20 mg/day), allowing prolactin-related symptoms to disappear and prolactin serum levels to diminish while maintaining psychiatric stability.\n\nPatient 2, on the other hand, showed a symptomatic recrudescence from her psychiatric condition after the psychopharmacological modification (oral olanzapine 20 mg/day to oral aripiprazole 20 mg/day), with the resurgence of autoreferential delusion and olfactory hallucinations. Such clinical decompensation demanded further pharmacological changes, with the initiation of an injectable formulation of aripiprazole (400 mg, every 4 weeks) and gradual stoppage of oral aripiprazole (20 mg per day). This second adjustment allowed for the remission of psychiatric symptoms and simultaneous achievement of psychiatric stability. After all pharmacological changes, prolactin serum levels decreased to normal range values and prolactin-related symptoms vanished.\n\nDiscussion\nThe reference prolactinemia levels available in scientific literature did not match with the laboratory values from the hospital where these patients were followed up—a discrepancy that may prove problematic when managing borderline hyperprolactinemia clinical situations. Nevertheless, it is important to bear in mind that these “normal” range levels have been found to be significantly variable among different laboratories and studies (Peuskens et al., 2014).\n\nIn Case 1, there was a prolactin increase with only 5 mg of olanzapine per day. Being aware that the increases in prolactin serum levels induced by olanzapine are uncommon and dose related, one might think that the reason behind it would be related with its interaction with fluoxetine. However, it is known that the changes in olanzapine pharmacokinetics from its coadministration with fluoxetine are clinically insignificant (Callaghan et al., 1999). What is more, even though there were prolactin-related symptoms (which disappeared after prolactin serum levels fell), the prolactinemia levels in this patient were considered “normal” for premenopausal and slightly above the maximum levels for postmenopausal women. Taking into account her age (49 years), her prolactin levels, and her prolactin-related symptom evolution, a possible explanation is that this patient was perimenopausal. Otherwise, we may just be sitting in front of a patient with lower normal-range values for prolactinemia when compared with those of general population; or it may just be the reflection of the laboratorial value variability.\n\nThe clinical aggravation in Case 2 was possibly related with the switch from 20 mg of olanzapine to 20 mg of aripiprazole. According to the literature, 20 mg of olanzapine is equivalent to 30 mg of aripiprazole (Taylor et al., 2018). Therefore, this psychopharmacological change leads to a lower antipsychotic dosage, a probable cause of symptom worsening. After a further dosage adjustment (oral aripiprazole 20 mg/day to injectable aripiprazole 400 mg every 4 weeks), the patient became psychiatrically asymptomatic.\n\nAnother possible cause for Case 2 relapse may have been due to a switch being done between a dopamine receptor antagonist (olanzapine) and a dopamine receptor partial agonist (aripiprazole), together with the fact that aripiprazole strongly binds to dopamine receptors, displacing almost every other antipsychotic and stimulating receptors from minimal dopamine activity to about 30%, which can be acutely distressing and aversive (Bazire, 2014).\n\nOlanzapine-induced prolactin serum level elevation has been described as transient, equaling placebo at week 6 (Callaghan et al., 1999; Montejo et al., 2016). However, both patients were medicated with olanzapine for more than 24 weeks, a fact that reinforces their clinical atypicality and, consequently, their scientific importance.\n\nContrary to what is suggested in the literature, there were no baseline plasma prolactin levels, as they were only obtained after patients complained of prolactin-related symptoms. If these levels had been collected, an earlier pharmacological intervention might have been possible, perhaps lessening the appearance, duration, or disturbance caused by prolactin-related symptoms.\n\nThe switch to aripiprazole, as advised in the literature (Montejo et al., 2016; Montejo et al., 2017), was a successful approach in both patients, not only diminishing serum prolactin values but also solving prolactin-related symptoms and maintaining clinical stabilization.\n\nConclusion\nLiterature prolactinemia values do not always correspond with laboratory values from clinical practice, a discrepancy that may make the management of borderline hyperprolactinemia clinical situations difficult. Baseline prolactin level collection may help in the management of patients who develop neuroleptic-induced hyperprolactinemia. Prolactin-related symptoms can occur with borderline or normal standardized prolactinemia values. Olanzapine-induced hyperprolactinemia is a rare event, but it is not nonexistent. Aripiprazole was used as a suitable alternative for olanzapine-induced hyperprolactinemia.\n\nData Availability\nAll datasets generated for this study are included in the manuscript and/or supplementary files.\n\nEthics Statement\nThis study was approved by the ethical committee of the investigators Hospital. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nPB contributed to the conception and design of the study. PB and MS wrote the first draft of the manuscript. All authors contributed to manuscript revision and edition and read and approved the submitted version.\n\nFunding\nThe authors declare that this study received funding from Lundbeck Pharmaceutical Company, as it subsidized the author publication fee. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\nConflict of Interest Statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n\nBazire S. (2014 ). “Switching or discontinuing psychotropics ,” in Psychotropic drug directory . Ed. Bazire S (Dorsington : Lloyd-Reinhold Communications LLP ).\n\nCallaghan J. T. Bergstrom R. F. Ptak L. R. Beasley C. M. (1999 ). Olanzapine: pharmacokinetic and pharmacodynamic profile . Clin. Pharmacokinet. \n37 (3 ), 177 –193 . 10.2165/00003088-199937030-00001 \n10511917 \n\nHouston J. Dharia S. Bishop J. R. Ellingrod V. L. Fijal B. Jacobson J. G. (2011 ). Association of DRD2 and ANKK1 polymorphisms with prolactin increase in olanzapine-treated women . Psychiatry Res. \n187 (1–2 ), 74 –79 . 10.1016/j.psychres.2010.10.020 \n21095016 \n\nMontejo ÁL Arango C. Bernardo M. Carrasco J. L. Crespo-Facorro B. Cruz J. J. (2016 ). Spanish consensus on the risks and detection of antipsychotic drug-related hyperprolactinaemia . Rev. Psiquiatr. Salud Ment. \n9 (3 ), 158 –173 . 10.1016/j.rpsm.2015.11.003 \n26927534 \n\nMontejo ÁL Arango C. Bernardo M. Carrasco J. L. Crespo-Facorro B. Cruz J. J. (2017 ). Multidisciplinary consensus on the therapeutic recommendations for iatrogenic hyperprolactinemia secondary to antipsychotics . Front. Neuroendocrinol. \n45 , 25 –34 . 10.1016/j.yfrne.2017.02.003 \n28235557 \n\nPérez-Iglesias R. Mata I. Martínez-García O. Garcia-Unzueta M. T. Amado J. A. Valdizán E. M. (2012 ). Long-term effect of haloperidol, olanzapine, and risperidone on plasma prolactin levels in patients with first-episode psychosis . J. Clin. Psychopharmacol. \n32 (6 ), 804 –808 . 10.1097/JCP.0b013e318272688b \n23131886 \n\nPeuskens J. Pani L. Detraux J. De Hert M. (2014 ). The effects of novel and newly approved antipsychotics on serum prolactin levels: a comprehensive review . CNS Drugs \n28 (5 ), 421 –453 . 10.1007/s40263-014-0157-3 \n24677189 \n\nTakeuchi H. Suzuki T. Remington G. Watanabe K. Mimura M. Uchida H (2014 ). Lack of effect of risperidone or olanzapine dose reduction on metabolic parameters, prolactin, and corrected QT interval in stable patients with schizophrenia . J. Clin. Psychopharmacol. \n34 (4 ), 517 –520 . 10.1097/JCP.0000000000000142 \n24911439 \n\nTaylor DM Barnes TRE Young AH , editors. (2018 ). “Akathisia ,” in The Maudsley Prescribing guidelines in psychiatry , 13th ed (Chichester : John Wiley & Sons Ltd ), 94 –97 .\n\nYang F. Chen L. Fang X. Zheng K. Zhu C. Xu C. (2018 ). Influence of olanzapine on serum prolactin levels and BMI in female patients with schizophrenia . Neuropsychiatr. Dis. Treat. \n14 , 3373 –3379 . 10.2147/NDT.S180303 \n30587989 \n\nYasui-Furukori N. Saito M. Nakagami T. Sugawara N. Sato Y. Tsuchimine S. (2010 ). Gender-specific prolactin response to antipsychotic treatments with risperidone and olanzapine and its relationship to drug concentrations in patients with acutely exacerbated schizophrenia . Prog. Neuropsychopharmacol. Biol. Psychiatry \n34 (3 ), 537 –540 . 10.1016/j.pnpbp.2010.02.014 \n20170699\n\n",
"fulltext_license": "CC BY",
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"issue": "10()",
"journal": "Frontiers in pharmacology",
"keywords": "aripiprazole; fluoxetine; hyperprolactinemia; olanzapine; olanzapine interactions",
"medline_ta": "Front Pharmacol",
"mesh_terms": null,
"nlm_unique_id": "101548923",
"other_id": null,
"pages": "846",
"pmc": null,
"pmid": "31417404",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "10511917;20170699;21095016;23131886;24677189;24911439;26927534;28235557;30587989",
"title": "Olanzapine-Induced Hyperprolactinemia: Two Case Reports.",
"title_normalized": "olanzapine induced hyperprolactinemia two case reports"
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{
"abstract": "Diamond-Blackfan anemia (DBA) is a congenital red cell aplasia arising from ribosomal protein (RP) defects. Affected patients present with neonatal anemia, occasional dysmorphism, and cancer predisposition. An anemic newborn was diagnosed with DBA due to RPL5 mutation (c.473_474del, p.K158SfsX26). Refractory anemia required regular transfusions and iron chelation therapy. Pancytopenia occurred at age 16 years. Bone-marrow studies showed myelodysplasia, erythroblastosis, and clonal evolution of del(20)(q11.2q13.3). Severe anemia required transfusions. Del(20q), including the L3MBTL1 gene, is reported to be relevant to the hematological phenotype of Shwachman-Diamond syndrome. A combined defect of RPL5 and L3MBTL1 may contribute to the aberrant erythropoiesis in the present case.",
"affiliations": "Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. sonoda-m@pediatr.med.kyushu-u.ac.jp.;Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Transfusion Medicine and Cell Processing, Tokyo Women's Medical University, Tokyo, Japan.;Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.;Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.;Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.",
"authors": "Sonoda|Motoshi|M|http://orcid.org/0000-0003-0167-3322;Ishimura|Masataka|M|;Ichimiya|Yuko|Y|;Terashi|Eiko|E|;Eguchi|Katsuhide|K|;Sakai|Yasunari|Y|;Takada|Hidetoshi|H|;Hama|Asahito|A|;Kanno|Hitoshi|H|;Toki|Tsutomu|T|;Ito|Etsuro|E|;Ohga|Shouichi|S|",
"chemical_list": "D002868:Chromosomal Proteins, Non-Histone; C120887:L3MBTL1 protein, human; D012097:Repressor Proteins; D012269:Ribosomal Proteins; D025521:Tumor Suppressor Proteins; C549166:ribosomal protein L5, human",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-018-2424-4",
"fulltext": null,
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"issn_linking": "0925-5710",
"issue": "108(2)",
"journal": "International journal of hematology",
"keywords": "Deletion 20q; L3MBTL1; Myelodysplastic syndrome; Pure red cell aplasia; Ribosomopathy",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000293:Adolescent; D029503:Anemia, Diamond-Blackfan; D001803:Blood Transfusion; D002868:Chromosomal Proteins, Non-Histone; D002872:Chromosome Deletion; D002890:Chromosomes, Human, Pair 20; D060965:Clonal Evolution; D018450:Disease Progression; D004899:Erythroblastosis, Fetal; D004920:Erythropoiesis; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D009190:Myelodysplastic Syndromes; D010198:Pancytopenia; D012097:Repressor Proteins; D012269:Ribosomal Proteins; D012720:Severity of Illness Index; D025521:Tumor Suppressor Proteins",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "228-231",
"pmc": null,
"pmid": "29476317",
"pubdate": "2018-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19810012;16317735;28147343;24942156;26892688;19061985;27909223;22362038;21396711;22706301;17663681;10952764;20585043;25659730;28211564;17994571;24611452;26872907;16041310;14979474;18671700;27553422;25237201",
"title": "Atypical erythroblastosis in a patient with Diamond-Blackfan anemia who developed del(20q) myelodysplasia.",
"title_normalized": "atypical erythroblastosis in a patient with diamond blackfan anemia who developed del 20q myelodysplasia"
} | [
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"companynumb": "JP-EDENBRIDGE PHARMACEUTICALS, LLC-JP-2018EDE000255",
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{
"abstract": "Background: fMRI of mental phenomena is quite difficult to perform because lack of patient's cooperation or because the symptoms are stable. In some exceptional cases, however, fMRI and DTI are capable to provide insights on the anatomy of organic hallucinations. Methods: In this report we describe a 14-year-old boy with a left fronto-dorsal tumor who experienced chronic complex brief, frequent and repetitive complex visual and auditory hallucinations. His clinical picture included multiple and severe social and mood problems. During a presurgical fMRI mapping the patient complained of having the visual and auditory hallucinations. A block-design FMRI paradigm was obtained from the event timecourse. Deterministic DTI of the brain was obtained seeding the lesion as ROI. The patient underwent surgery and electrocorticography of the lesional area. Results: The fMRI of the hallucinations showed activation in the left inferior frontal gyrus (IFG) and the peri-lesional area. The tractography of the tumor revealed structural aberrant connectivity to occipital and temporal areas in addition to the expected connectivity with the IFG via the aslant fasciculus and homotopic contralateral areas. Intraoperative EEG demonstrated epileptic discharges in the tumor and neighboring areas. After resection, the patient's hallucinations stopped completely. He regained his normal social life and recover his normal mood. He remained asymptomatic for 90 days. Afterwards, hallucinations reappeared but with less intensity. Conclusions: To our knowledge, this is the first reported case of combined functional and structural connectivity imaging demonstrating brain regions participating in a network involved in the generation of complex auditory and visual hallucinations.",
"affiliations": "a Department of Radiology , Miami Children's Hospital , Miami, FL , USA.;a Department of Radiology , Miami Children's Hospital , Miami, FL , USA.;c Department of Neurosurgery , Miami Children's Hospital , Miami, FL , USA.;a Department of Radiology , Miami Children's Hospital , Miami, FL , USA.;c Department of Neurosurgery , Miami Children's Hospital , Miami, FL , USA.;d Department of Psychiatry , Miami Children's Hospital , Miami, FL , USA.;d Department of Psychiatry , Miami Children's Hospital , Miami, FL , USA.;e Department of Neurology , Miami Children's Hospital , Miami, FL , USA.",
"authors": "Bernal|Byron|B|;Guillen|Magno|M|;Ragheb|John|J|;Altman|Nolan|N|;Ibrahim|George M|GM|;LaPlante|Philip|P|;Padilla|Americo|A|;Duchowny|Michael|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/13554794.2019.1611866",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1355-4794",
"issue": "25(3-4)",
"journal": "Neurocase",
"keywords": "DTI; Fmri; connectivity; frontal lobe; hallucinations; psychosis",
"medline_ta": "Neurocase",
"mesh_terms": "D000293:Adolescent; D001921:Brain; D001932:Brain Neoplasms; D004569:Electroencephalography; D059907:Functional Neuroimaging; D006212:Hallucinations; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D016896:Treatment Outcome",
"nlm_unique_id": "9511374",
"other_id": null,
"pages": "91-97",
"pmc": null,
"pmid": "31094654",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Functional imaging localization of complex organic hallucinations.",
"title_normalized": "functional imaging localization of complex organic hallucinations"
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{
"abstract": "A 76-year-old man presented with right critical limb ischemia. An angiography revealed right SFA occlusion. Therefore, two paclitaxel-eluting stents (Zilver PTXs 6.0 mm × 120 mm stents; Cook Medical, Bloomington, Indiana) were placed, which promoted good blood flow. Follow-up angiography at 6 months also showed no restenosis. However, 10 months later, the patient suddenly visited with acute-onset pain in the right leg. Computed tomography showed the acute occlusion at the stented SFA. Eventually, above-knee amputation was performed due to the poor general condition and progressive limb ischemia. As the pathological finding, heterogeneous neointima formation at the stented site was mainly found. Although neointimal layer consisting of smooth muscle cell (SMC) was partly observed, necrotic tissue was evident in the remaining portion. At the necrotic tissue site, the majority of the components of the material covered by the stent strut were fibrin deposits. The findings of regenerative endothelial cells were not observed at the luminal surface. Nuclei of medial SMCs were also lost between the arterial media and the stent strut. Late stent thrombosis after paclitaxel-eluting stenting for SFA lesion has not been sufficiently evaluated. Here, we report a case of late stent thrombosis with a review including pathological findings. <Learning objective: We reported that a 76-year-old man received paclitaxel-eluting stent for femoropopliteal disease. Ten months later, stent thrombosis was occurred and above-knee amputation was performed. As the pathological finding, heterogeneous neointima formation was mainly found and the regenerative endothelial cells were not observed. Our report suggested that delayed healing and uncovered strut caused by paclitaxel-exposure resulted in late stent thrombosis.>.",
"affiliations": "Department of Cardiology, Kokura Memorial Hospital, Japan.;Laboratory Medicine, Kokura Memorial Hospital, Japan.;Department of Vascular Surgeon, Kokura Memorial Hospital, Japan.",
"authors": "Soga|Yoshimitsu|Y|;Inoue|Katsumi|K|;Kuma|Sosei|S|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1016/j.jccase.2014.10.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-5409",
"issue": "11(2)",
"journal": "Journal of cardiology cases",
"keywords": "Drug-eluting stent; Stent thrombosis; Superficial femoral artery",
"medline_ta": "J Cardiol Cases",
"mesh_terms": null,
"nlm_unique_id": "101549579",
"other_id": null,
"pages": "39-41",
"pmc": null,
"pmid": "30534254",
"pubdate": "2015-02",
"publication_types": "D002363:Case Reports",
"references": "23583245;23839329;21419649;17438147;23771810;19463470",
"title": "Pathological findings of late stent thrombosis after paclitaxel-eluting stent implantation for superficial femoral artery disease.",
"title_normalized": "pathological findings of late stent thrombosis after paclitaxel eluting stent implantation for superficial femoral artery disease"
} | [
{
"companynumb": "JP-PFIZER INC-2018119567",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
... |
{
"abstract": "We describe a case of apparent mineralocorticoid excess (hypertension, hypokalemia, metabolic alkalosis and low plasma renin activity) secondary to itraconazole therapy. Inhibition of 11β-hydroxysteroid dehydrogenase 2 was demonstrated, and withholding itraconazole led to resolution of adverse effects that did not recur with voriconazole. This report adds to a growing body of evidence linking apparent mineralocorticoid excess with certain triazoles.",
"affiliations": "Department of Pharmacy, University of California Davis Medical Center, Sacramento, CA, USA.;Department of Medical Microbiology and Immunology, University of California-Davis, Davis, CA, USA.;Department of Medical Microbiology and Immunology, University of California-Davis, Davis, CA, USA.",
"authors": "Hoffmann|Wesley J|WJ|http://orcid.org/0000-0001-7722-6321;McHardy|Ian|I|;Thompson|George R|GR|http://orcid.org/0000-0001-8518-5750",
"chemical_list": "D000935:Antifungal Agents; D008901:Mineralocorticoids; D017964:Itraconazole; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468387:HSD11B2 protein, human",
"country": "Germany",
"delete": false,
"doi": "10.1111/myc.12749",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0933-7407",
"issue": "61(5)",
"journal": "Mycoses",
"keywords": "hypertension; itraconazole; mineralocorticoid excess; side-effects",
"medline_ta": "Mycoses",
"mesh_terms": "D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D000935:Antifungal Agents; D006801:Humans; D006973:Hypertension; D007008:Hypokalemia; D017964:Itraconazole; D008297:Male; D008875:Middle Aged; D008901:Mineralocorticoids",
"nlm_unique_id": "8805008",
"other_id": null,
"pages": "337-339",
"pmc": null,
"pmid": "29385285",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Itraconazole induced hypertension and hypokalemia: Mechanistic evaluation.",
"title_normalized": "itraconazole induced hypertension and hypokalemia mechanistic evaluation"
} | [
{
"companynumb": "CN-ALKEM LABORATORIES LIMITED-CN-ALKEM-2018-03269",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ITRACONAZOLE"
},
"dru... |
{
"abstract": "BACKGROUND\nIdiosyncratic Drug Induced Liver Injury (DILI) is a rare adverse event to drugs that occasionally leads to severe liver damage, being one of the leading causes of Acute Liver Failure (ALF) in developed countries. DILI is largely a diagnosis of exclusion.\n\n\nCONCLUSIONS\nCareful history of drug taking and ruling out other competing etiologies is mandatory given that DILI can present with an extremely variable phenotype. Several prognostic scores have been developed to promptly identify patients with potential risk of developing ALF. New biomarkers to diagnose and predict DILI evolution are under study and hopefully we will benefit from these novel tools in the near future.",
"affiliations": "Hepatology and Liver Transplant Unit, Hospital Universitario Austral, Pilar, Buenos Aires, Argentina.;Hepatology and Liver Transplant Unit, Hospital Universitario Austral, Pilar, Buenos Aires, Argentina.;Hospital Provincial del Centenario, University of Rosario School of Medicine, Rosario, Santa Fe, Argentina.",
"authors": "Colaci|Carla Stefania|CS|;Mendizabal|Manuel|M|;Bessone|Fernando|F|",
"chemical_list": "D015415:Biomarkers",
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1574886314666190215115434",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1574-8863",
"issue": "14(2)",
"journal": "Current drug safety",
"keywords": "Drug-induced liver injury; Hepatotoxicity; acute liver failure; drug hepatotoxicity; hepatitis; liver transplant.",
"medline_ta": "Curr Drug Saf",
"mesh_terms": "D015415:Biomarkers; D056486:Chemical and Drug Induced Liver Injury; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D017114:Liver Failure, Acute; D012307:Risk Factors",
"nlm_unique_id": "101270895",
"other_id": null,
"pages": "94-101",
"pmc": null,
"pmid": "30767751",
"pubdate": "2019",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Idiosyncratic Drug-Induced Acute Liver Failure: A Challenging and Distressing Scenario.",
"title_normalized": "idiosyncratic drug induced acute liver failure a challenging and distressing scenario"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2019-10461",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CEPHALEXIN"
},
"druga... |
{
"abstract": "BACKGROUND\nTumor lysis syndrome can occur after treatment of fast-growing cancers. Early detection of tumor lysis is crucial to minimize the toxic effects on organs and potentially life-threatening complications.\n\n\nMETHODS\nA patient with acute monocytic leukemia presented with spurious thrombocytosis. A peripheral blood smear was stained with alpha-naphthyl butyrate esterase to discriminate tumor cell fragments from platelets.\n\n\nRESULTS\nPeripheral blood smears showed widespread leukemic cell fragmentation. Tumor lysis syndrome (TLS) after treatment for acute monocytic leukemia was diagnosed. The patient underwent chemo- and radiotherapy followed by umbilical cord blood transplantation and remains symptom-free two years after transplantation.\n\n\nCONCLUSIONS\nFor patients with thrombocytosis accompanied by bizarre scatter-grams on automatic hematologic analyzers, further diagnostic procedures should be performed to determine the exact cause of thrombocytosis.",
"affiliations": null,
"authors": "Ogasawara|Shu|S|;Saito|Norihoro|N|;Itoga|Masamichi|M|;Kushibiki|Mihoko|M|;Nakata|Ryoko|R|;Ohta|Emi|E|;Fujita|Eriko|E|;Kojima|Keiya|K|;Terui|Kiminori|K|;Ito|Etsuro|E|;Kayaba|Hiroyuki|H|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.7754/Clin.Lab.2016.151218",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1433-6510",
"issue": "62(8)",
"journal": "Clinical laboratory",
"keywords": null,
"medline_ta": "Clin Lab",
"mesh_terms": "D002675:Child, Preschool; D006801:Humans; D007948:Leukemia, Monocytic, Acute; D008297:Male; D013922:Thrombocytosis; D015275:Tumor Lysis Syndrome",
"nlm_unique_id": "9705611",
"other_id": null,
"pages": "1575-1577",
"pmc": null,
"pmid": "28164618",
"pubdate": "2016-08-01",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Spurious Thrombocytosis Caused by Tumor Cell Lysis in a Patient with Acute Monocytic Leukemia.",
"title_normalized": "spurious thrombocytosis caused by tumor cell lysis in a patient with acute monocytic leukemia"
} | [
{
"companynumb": "JP-MYLANLABS-2016M1051443",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Methotrexate (MTX) is a highly renal and liver toxicity drug used in hematological malignancy treatment in children and adults. High-dose methotrexate (HD-MTX) therapy may cause impairment of kidney and decrease the elimination of MTX, at the same time, the serum concentration of MTX increased. Today the treatment for preventing MTX toxicity after renal shutdown is Carboxypeptidase. We report a patient who experienced nephrotoxicity after the HD-MTX infusions during the treatment for non-Hodgkin lymphoma (NHL) and received hemodiafiltration (HDF) with large dose of leucovorin (LV) to treat MTX intoxication. LV is very potent in the prevention of neurotoxicity and administration of LV could protect the normal cells, but the dosage and duration of LV should be according to the MTX concentration. Although a large dose of LV was applied, the patient's condition did not improve. It was found that the HDF with large dose of LV to save the patient and steadily improved the patient's clinical condition.",
"affiliations": "Department of Pharmacy, Changhai Hospital, Second Military Medical University, Shanghai, China.;Department of Hematology, Changhai Hospital, Second Military Medical University, Shanghai, China.;Department of Pharmacy, Changhai Hospital, Second Military Medical University, Shanghai, China.;Department of Pharmacy, Changhai Hospital, Second Military Medical University, Shanghai, China.;Department of Pharmacy, Changhai Hospital, Second Military Medical University, Shanghai, China.;Department of Pharmacy, Changhai Hospital, Second Military Medical University, Shanghai, China.;Department of Pharmacy, Changhai Hospital, Second Military Medical University, Shanghai, China.",
"authors": "Yang|Yun-Yun|YY|;Gao|Lei|L|;Ding|Nan|N|;Wang|Xue-Bin|XB|;Zhang|Li-Peng|LP|;Gao|Li-Hong|LH|;Wang|Zhuo|Z|",
"chemical_list": "D000931:Antidotes; D000964:Antimetabolites, Antineoplastic; D002955:Leucovorin; D008727:Methotrexate",
"country": "Pakistan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1011-601X",
"issue": "33(3)",
"journal": "Pakistan journal of pharmaceutical sciences",
"keywords": null,
"medline_ta": "Pak J Pharm Sci",
"mesh_terms": "D000931:Antidotes; D000964:Antimetabolites, Antineoplastic; D017583:Hemodiafiltration; D006801:Humans; D007674:Kidney Diseases; D002955:Leucovorin; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008727:Methotrexate; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9426356",
"other_id": null,
"pages": "1163-1167",
"pmc": null,
"pmid": "33191243",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "How to rescue high-dose methotrexate induced nephrotoxicity and literature review about hemodiafiltration?",
"title_normalized": "how to rescue high dose methotrexate induced nephrotoxicity and literature review about hemodiafiltration"
} | [
{
"companynumb": "CN-ACCORD-202151",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "1",
"dru... |
{
"abstract": "Stiff-Person Syndrome (SPS) is a rare neurologic disorder characterized by severe and progressively worsening muscle stiffness and rigidity. SPS can be very painful due to unpredictable muscle spasms which can be triggered by various stimuli, such as noise, touch, or emotional experiences. There is thought to be an autoimmune component to the disorder. We present the case of a 59-year-old woman diagnosed with SPS who appears to have experienced a dramatic reduction in her symptoms after being treated with Low-Dose Naltrexone (LDN). Prior to this treatment regimen, she had tried many treatments with only limited derived benefit. She was started on LDN and after 6 weeks, reported reductions in pain, anxiety, depression, agoraphobia, and muscle tightness. Upon multiple follow-ups, leading up to 12 months, she continually displayed reduced symptoms and improved quality of life. We conclude that LDN may have some utility in treating and managing the symptoms of SPS. We hypothesize that this may be possible due to LDN operating via anti-inflammatory pathways as well as acting as an opioid antagonist. We assert that further research as it relates to LDN and SPS in addition to other chronic pain conditions is warranted.",
"affiliations": "Synovation Medical Group, Pasadena, CA 91105, USA; Department of Physical Medicine and Rehabilitation, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA. Electronic address: mzappaterra@synovationmedicalgroup.com.;Harmonae Psychological Services, Inc., 130 S. Euclid Ave, Suite 8, Pasadena, CA 91101, USA. Electronic address: drelizabethshouse@gmail.com.;Synovation Medical Group, Pasadena Rehabilitation Institute, 1017 S. Fair Oaks Ave, Pasadena, CA 91105, USA. Electronic address: rlevine@synovationmedicalgroup.com.",
"authors": "Zappaterra|Mauro|M|;Shouse|Elizabeth|E|;Levine|Reed Loring|RL|",
"chemical_list": "D009271:Naltrexone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.mehy.2019.109546",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0306-9877",
"issue": "137()",
"journal": "Medical hypotheses",
"keywords": "Chronic pain; Low Dose Naltrexone; Stiff-Person Syndrome",
"medline_ta": "Med Hypotheses",
"mesh_terms": "D005260:Female; D006801:Humans; D008875:Middle Aged; D009271:Naltrexone; D011788:Quality of Life; D013035:Spasm; D016750:Stiff-Person Syndrome",
"nlm_unique_id": "7505668",
"other_id": null,
"pages": "109546",
"pmc": null,
"pmid": "31954293",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Low-Dose Naltrexone reduces symptoms in Stiff-Person Syndrome.",
"title_normalized": "low dose naltrexone reduces symptoms in stiff person syndrome"
} | [
{
"companynumb": "NVSC2020US030094",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUPROPION"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Autoimmune lymphoproliferative syndrome is a disorder of lymphoid system regulation characterized by chronic splenomegaly, lymphadenopathy and autoimmune phenomena especially immune-mediated cytopenias. The hallmark of the disease is the presence in peripheral blood and lymphoid tissue of increased numbers of a normally rare T lymphocyte subset, usually referred to as \"double-negative\" T cells. Here the authors report a 16-year-old boy when he was first hospitalized for diffuse petechiae, purpura and epistaxis at 9 years of age. One year later,he was readmitted for high fever and recurring cytopenia. On examination several enlarged, nontender lymph nodes involving cervical and submandibular areas and a huge spleen were detected. Lymph node biopsy was performed two times. According to flowcytometry of peripheral blood and immunophenotyping of lymph node tissues which revealed increased numbers of CD3+CD4-CD8- T-lymphocytes autoimmune lymphoproliferative syndrome was suggested for him. Autoimmune lymphoproliferative syndrome should be considered in differential diagnosis of any patient with unexplained Coomb's positive cytopenias, hypergammaglobulinemia, generalized lymphadenopathy and splenomegaly. The confirmation of the diagnosis should be based upon genetic analysis and detection of the affected genes involved in fas pathway.",
"affiliations": "Department of Pediatric Hematology/Oncology, Shaheed Beheshti Medical University, Tehran, Iran. saminalavi@hotmail.com.",
"authors": "Alavi|Samin|S|;Taghi Arzanian|Mohammad|M|;Chavoshzadeh|Zahra|Z|;Esteghamati|Maryam|M|",
"chemical_list": null,
"country": "Iran",
"delete": false,
"doi": "04.03/ijaai.149152",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1735-1502",
"issue": "4(3)",
"journal": "Iranian journal of allergy, asthma, and immunology",
"keywords": null,
"medline_ta": "Iran J Allergy Asthma Immunol",
"mesh_terms": null,
"nlm_unique_id": "101146178",
"other_id": null,
"pages": "149-52",
"pmc": null,
"pmid": "17301439",
"pubdate": "2005-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Autoimmune lymphoproliferative syndrome; a case report.",
"title_normalized": "autoimmune lymphoproliferative syndrome a case report"
} | [
{
"companynumb": "PHHY2016IR076489",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
"d... |
{
"abstract": "OBJECTIVE\nIt is common practice to switch antipsychotic medications in the treatment of patients with schizophrenia to enhance clinical efficacy and/or reduce drug-related side effects. The conventional Clinical Global Impression (CGI) of severity scale is a well-understood measure to track switching effects but does not differentiate between the severity of clinical symptoms and the impact of side effects..\n\n\nMETHODS\nWe developed a CGI-switch instrument that contains distinct global severity scales for clinical efficacy, safety and/or tolerability, and a third unified (integrated) CGI severity score to assess these interrelated assessments. An integrated Clinical Global Impression of Change was also created to assess global clinical change relative to the initiation of treatment.\n\n\nRESULTS\nInterrater reliability conducted as part of a rater-training program for a clinical study (Novartis protocol CIL0522D; clinitrials.gov identifier: CT01207414) revealed high interrater agreement (Cronbach's alpha = 0.945). Data were collected from 1066 CGI assessments during the course of the trial. CGI raters easily grasped the utility of the instrument. The distinction made between efficacy and safety/tolerability facilitated serial tracking of each condition during the course of treatment.\n\n\nCONCLUSIONS\nThe modified CGI-switch instrument is a simple, reliable, and practical metric to assess the benefits, if any of switching antipsychotic medications in patients with schizophrenia.",
"affiliations": "Clintara LLC, Boston, Massachusetts, USA. sdtargum@yahoo.com",
"authors": "Targum|Steven D|SD|;Pestreich|Linda|L|;Reksoprodjo|Petra|P|;Pereira|Heidi|H|;Guindon|Carrie|C|;Hochfeld|Marla|M|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "England",
"delete": false,
"doi": "10.1002/hup.2247",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0885-6222",
"issue": "27(5)",
"journal": "Human psychopharmacology",
"keywords": null,
"medline_ta": "Hum Psychopharmacol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015588:Observer Variation; D011569:Psychiatric Status Rating Scales; D015203:Reproducibility of Results; D012559:Schizophrenia; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8702539",
"other_id": null,
"pages": "455-63",
"pmc": null,
"pmid": "22826027",
"pubdate": "2012-09",
"publication_types": "D017429:Clinical Trial, Phase IV; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "A global measure to assess switching antipsychotic medications in the treatment of schizophrenia.",
"title_normalized": "a global measure to assess switching antipsychotic medications in the treatment of schizophrenia"
} | [
{
"companynumb": "US-JNJFOC-20121009797",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "Since the emergence of a novel coronavirus (severe acute respiratory syndrome coronavirus 2) in Wuhan, China, at the end of December 2019, coronavirus disease 2019 has been associated with severe morbidity and mortality and has left world governments, healthcare systems, and providers caring for vulnerable populations, such as pregnant women, wrestling with the optimal management strategy. Unique physiologic and ethical considerations negate a one-size-fits-all approach when caring for critically ill pregnant women with coronavirus disease 2019, and few resources exist to guide the multidisciplinary team through decisions regarding optimal maternal-fetal surveillance, intensive care procedures, and delivery timing. We present a case of rapid clinical decompensation and development of severe acute respiratory distress syndrome in a woman at 31 weeks' gestation to highlight these unique considerations and present an algorithmic approach to the diagnosis and management of the disease.",
"affiliations": "Divisions of Maternal-Fetal Medicine, TriHealth-Good Samaritan Hospital, Cincinnati, OH.;Pulmonology and Critical Care Medicine, TriHealth-Good Samaritan Hospital, Cincinnati, OH.;Divisions of Maternal-Fetal Medicine, TriHealth-Good Samaritan Hospital, Cincinnati, OH.",
"authors": "Schnettler|William T|WT|;Al Ahwel|Yousef|Y|;Suhag|Anju|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajogmf.2020.100120",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2589-9333",
"issue": "2(3)",
"journal": "American journal of obstetrics & gynecology MFM",
"keywords": "ARDS; COVID-19; acute SARS-CoV-2; coronavirus; pneumonia; pregnancy; respiratory distress syndrome",
"medline_ta": "Am J Obstet Gynecol MFM",
"mesh_terms": "D000328:Adult; D000086382:COVID-19; D000086742:COVID-19 Testing; D017604:Cesarean Section, Repeat; D000075902:Clinical Deterioration; D003422:Critical Care; D005260:Female; D006801:Humans; D017053:Infection Control; D008168:Lung; D056888:Patient Positioning; D011024:Pneumonia, Viral; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011256:Pregnancy Outcome; D011263:Pregnancy Trimester, Third; D012121:Respiration, Artificial; D012128:Respiratory Distress Syndrome; D000086402:SARS-CoV-2; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014463:Ultrasonography",
"nlm_unique_id": "101746609",
"other_id": null,
"pages": "100120",
"pmc": null,
"pmid": "32363337",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "32091533;23688302;32020029;32292903;32104729;32164080;32065221;32180426;32292902;32226295;32040667;30445912;32835205;11463593",
"title": "Severe acute respiratory distress syndrome in coronavirus disease 2019-infected pregnancy: obstetric and intensive care considerations.",
"title_normalized": "severe acute respiratory distress syndrome in coronavirus disease 2019 infected pregnancy obstetric and intensive care considerations"
} | [
{
"companynumb": "US-SLATE RUN PHARMACEUTICALS-20US000295",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OSELTAMIVIR"
},
"drugadditional... |
{
"abstract": "The most common complication in cancer patients is catheter-related bloodstream infection (CRBSI), of which Staphylococcus aureus is a common pathogen. Although S. aureus CRBSI patients are recommended for prolonged intravenous therapy, this is often not feasible. We assessed the effectiveness of switching from intravenous to oral antimicrobial therapy in cancer patients with CRBSI due to methicillin-sensitive S. aureus (MSSA). We conducted a retrospective observational study of 60 patients at one tertiary-care cancer center between April 2005 and March 2016. Patients who received effective intravenous (IV) antibiotics for at least 10 days (IV group) were compared to the IV group of patients who had switched to effective oral (PO) antibiotics after IV treatment for at least 10 days (IV + PO group). The primary endpoint was all-cause mortality within 90 days. Univariate and propensity score-adjusted multivariate logistic regression analyses using variables likely to influence the outcomes were performed. Of the 60 patients, 32 (53.3%) and 28 (46.7%) were in the IV and IV + PO groups, respectively. The median antibiotic treatment durations in the IV and IV + PO groups were 17 (13-31) and 33 (26-52) days, respectively (p<0.001). The 90-day mortality in the IV and IV + PO groups were 53.1% (17/32) and 10.7% (3/28), respectively (p = 0.001). Univariate logistic regression model showed that the odds ratios of oral switch therapy for 90-day mortality was 0.106 (95% confidence interval [CI]: 0.027-0.423; p = 0.001). The propensity score-adjusted multivariate logistic regression model estimated the odds ratios of oral switched therapy for 90-day mortality as 0.377 (95% CI: 0.037-3.884; p = 0.413). Our results suggest that oral switch therapy was not associated with mortality in cancer patients with CRBSI due to MSSA compared with no oral switch therapy. Oral switch therapy may be a reasonable option for patients with CRBSI due to MSSA.",
"affiliations": "Division of Infectious Diseases, Shizuoka Cancer Center Hospital, Sunto-gun, Shizuoka, Japan.;Department of Infection Control and Prevention, Tokyo Medical and Dental University Hospital, Bunkyo-ku, Tokyo, Japan.;AMR Clinical Reference Center, Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan.;Division of Infectious Diseases, Shizuoka Cancer Center Hospital, Sunto-gun, Shizuoka, Japan.;Department of Medical Statistics, Satista Co., Ltd, Uji-city, Kyoto, Japan.;Division of Infectious Diseases, Shizuoka Cancer Center Hospital, Sunto-gun, Shizuoka, Japan.",
"authors": "Itoh|Naoya|N|0000-0001-6269-7884;Hadano|Yoshiro|Y|0000-0002-6873-3791;Saito|Sho|S|;Myokai|Michiko|M|;Nakamura|Yasunobu|Y|;Kurai|Hanako|H|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0207413",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0207413PONE-D-18-25787Research ArticleMedicine and Health SciencesPharmacologyDrugsAntimicrobialsAntibioticsBiology and Life SciencesMicrobiologyMicrobial ControlAntimicrobialsAntibioticsMedicine and Health SciencesHematologyBloodstream InfectionsMedicine and Health SciencesPharmacologyRoutes of AdministrationIntravenous InjectionsMedicine and Health SciencesInfectious DiseasesBacterial DiseasesBacteremiaMedicine and Health SciencesInfectious DiseasesNosocomial InfectionsMedicine and Health SciencesOncologyCancer TreatmentBiology and Life SciencesAnatomyBody FluidsBloodMedicine and Health SciencesAnatomyBody FluidsBloodBiology and Life SciencesPhysiologyBody FluidsBloodMedicine and Health SciencesPhysiologyBody FluidsBloodBiology and Life SciencesOrganismsBacteriaStaphylococcusStaphylococcus AureusBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensBacterial PathogensStaphylococcusStaphylococcus AureusMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensBacterial PathogensStaphylococcusStaphylococcus AureusIntravenous to oral switch therapy in cancer patients with catheter-related bloodstream infection due to methicillin-sensitive Staphylococcus aureus: A single-center retrospective observational study Intravenous to oral switch therapy in cancer patients with S. aureus bloodstream infectionhttp://orcid.org/0000-0001-6269-7884Itoh Naoya ConceptualizationData curationInvestigationMethodologyProject administrationResourcesWriting – original draftWriting – review & editing1*http://orcid.org/0000-0002-6873-3791Hadano Yoshiro Supervision2Saito Sho Data curation3Myokai Michiko Data curation1Nakamura Yasunobu Formal analysis4Kurai Hanako Data curationSupervisionWriting – review & editing11 \nDivision of Infectious Diseases, Shizuoka Cancer Center Hospital, Sunto-gun, Shizuoka, Japan2 \nDepartment of Infection Control and Prevention, Tokyo Medical and Dental University Hospital, Bunkyo-ku, Tokyo, Japan3 \nAMR Clinical Reference Center, Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan4 \nDepartment of Medical Statistics, Satista Co., Ltd, Uji-city, Kyoto, JapanOmri Abdelwahab EditorLaurentian, CANADACompeting Interests: An author of this manuscript has the following competing interests: YN received support in the form of salary from Satista Co., Ltd and has performed data analysis that was supported by fees from NI. NI, YH, SS, MM, and HK declare no conflict of interest and have no affiliation with or financial involvement in any organization or entity with a direct financial interest in the subject matter or materials discussed in this manuscript. The authors have no other conflicts of interest that are directly relevant to the content of this manuscript and does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.\n\n* E-mail: itohnaoya0925@ybb.ne.jp29 11 2018 2018 13 11 e02074133 9 2018 30 10 2018 © 2018 Itoh et al2018Itoh et alThis 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.The most common complication in cancer patients is catheter-related bloodstream infection (CRBSI), of which Staphylococcus aureus is a common pathogen. Although S. aureus CRBSI patients are recommended for prolonged intravenous therapy, this is often not feasible. We assessed the effectiveness of switching from intravenous to oral antimicrobial therapy in cancer patients with CRBSI due to methicillin-sensitive S. aureus (MSSA). We conducted a retrospective observational study of 60 patients at one tertiary-care cancer center between April 2005 and March 2016. Patients who received effective intravenous (IV) antibiotics for at least 10 days (IV group) were compared to the IV group of patients who had switched to effective oral (PO) antibiotics after IV treatment for at least 10 days (IV + PO group). The primary endpoint was all-cause mortality within 90 days. Univariate and propensity score-adjusted multivariate logistic regression analyses using variables likely to influence the outcomes were performed. Of the 60 patients, 32 (53.3%) and 28 (46.7%) were in the IV and IV + PO groups, respectively. The median antibiotic treatment durations in the IV and IV + PO groups were 17 (13–31) and 33 (26–52) days, respectively (p<0.001). The 90-day mortality in the IV and IV + PO groups were 53.1% (17/32) and 10.7% (3/28), respectively (p = 0.001). Univariate logistic regression model showed that the odds ratios of oral switch therapy for 90-day mortality was 0.106 (95% confidence interval [CI]: 0.027–0.423; p = 0.001). The propensity score-adjusted multivariate logistic regression model estimated the odds ratios of oral switched therapy for 90-day mortality as 0.377 (95% CI: 0.037–3.884; p = 0.413). Our results suggest that oral switch therapy was not associated with mortality in cancer patients with CRBSI due to MSSA compared with no oral switch therapy. Oral switch therapy may be a reasonable option for patients with CRBSI due to MSSA.\n\nSatista Co., LtdThis work was supported by Satista Co., Ltd. The funder provided support in the form of salaries for author YN. The funder did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. Data AvailabilityAll relevant data are within the paper and its Supporting Information files.Data Availability\nAll relevant data are within the paper and its Supporting Information files.\n==== Body\nIntroduction\nStaphylococcal infections are common and represent an important therapeutic problem, as bacterial complications frequently arise [1]. Staphylococcus aureus bacteremia (SAB) is a leading bloodstream infection in hospitals, with mortality rates of 10%–30% [2]. Therefore, such infections require adequate management and highly effective anti-infective treatment. Current guidelines recommend that patients with S. aureus catheter-related bloodstream infection (CRBSI) should have the infected catheter removed, and that SAB should be treated with prolonged intravenous therapy for a minimum of 14 days in those with uncomplicated disease, and 4–6 weeks in those with deep focus of infection [3, 4]. Furthermore, 4–6 weeks of antibiotic therapy should be administered to patients with active malignancy or immunosuppression [3]. However, long-term therapy mandates additional hospital stay for the patients, which is often difficult to comply with in actual clinical practice.\n\nPatients with low risk of complications may thus benefit from an early switch to oral medication with earlier discharge and fewer intravenous therapy complications. The effectiveness of oral antimicrobial therapy in SAB was previously assessed in a multicenter randomized controlled trial; 104 patients with SAB either received oral combination of fluoroquinolone plus rifampicin or standard parenteral treatment, and the cure rates in both groups were similar (82% versus 80%, respectively), with patients on oral antibiotics being discharged earlier [5]. This study suggests that administering oral antimicrobials may be as effective as intravenous therapy. Thwaites et al. also reported the management practices of patients with SAB in the UK and Vietnam [6]. Although they found that 25% of patients received oral antimicrobials alone for more than 50% of the treatment duration, the efficacy and safety of oral therapy were not evaluated. The Staphylococcus aureus Bacteremia Antibiotic Treatment Options (SABATO) trial is currently ongoing to assess whether an early switch to oral medication is as safe and effective as intravenous standard therapy in SAB [7]; however, few studies have focused on the oral switch therapy in patients with CRBSI due to methicillin-sensitive Staphylococcus aureus (MSSA). Central venous access is necessary for cancer patients who require chemotherapy and parenteral nutrition. Additionally, cancer patients, who are often immunocompromised, are more susceptible to CRBSI [8]. Therefore, CRBSI remains the most common complication in cancer patients.\n\nTo assess the effectiveness of switching from intravenous to oral antimicrobial therapy in cancer patients with CRBSI due to MSSA, we compared between patients who received effective intravenous (IV) antibiotics for more than 10 days and patients who were switched to an effective oral (PO) antibiotics after IV treatment for at least 10 days.\n\nMethods and materials\nStudy design and patient population\nWe conducted a retrospective observational study at the Shizuoka Cancer Center Hospital, a 611-bed tertiary care hospital, from April 1, 2005 to March 31, 2016. The inclusion criteria were at least one of the following: patients with MSSA-positive blood culture, patients with CRBSI caused by MSSA, and patients who received effective intravenous antibiotics for more than 10 days or switched to an effective oral antibiotic after IV treatment for at least 10 days. Duration of intravenous antibiotics was at least 10 days for comparison with oral antibiotics after IV treatment for at least 10 days. Exclusion criteria were: (1) being less than 18 years of age, (2) polymicrobial bacteremia, (3) duplicated cases, (4) duration of IV therapy was less than 10 days, (5) patient death within 2 days after the positive blood culture, and (6) patients deemed to be palliative cases (specifically, patients who did not receive any antibiotics).\n\nThe primary outcome was all-cause mortality at 90 days. The secondary outcomes were all-cause mortality within 30 days and recurrence within 30 days after treatment.\n\nEthics approval and consent to participate\nEthical approval was obtained from the Shizuoka Cancer Center Hospital’s Ethics Review Board, which also deemed it unnecessary to obtain consent directly from patients, as this was a retrospective study with no intervention.\n\nData collection\nData were retrieved from patients’ electronic medical records and entered into case report forms by four infectious disease (ID) doctors. Information retrieved included age, gender, microbiological data, focus of infection, place of acquisition (nosocomial, health care-associated, and community-acquired), types of neoplasm, organ transplantation, immunosuppressant therapy, glucocorticoid therapy, antineoplastic chemotherapy, total parenteral nutrition, comorbidity, type of central venous catheters (CVCs), foreign body, severity of bacteremia, secondary foci, persistent bacteremia, removal of infectious catheter, source control, reinsertion of central intravascular catheter during treatment, complications after treatment, ID consultation, received echocardiogram (transthoracic echocardiography or transesophageal echocardiography), antibiotic treatment, duration of antibiotics, recurrence, the number of days till death following positive blood culture, and infection-related death.\n\nStudy definitions\nStaphylococcal bacteremia was defined as at least one blood culture positive for S. aureus with clinical symptoms and clinically apparent signs and symptoms of sepsis [9].\n\nCRBSI was defined as a primary bloodstream infection in patients with CVC that was present for at least 48 hours before the onset of bacteremia and had no identifiable source of infection other than the catheter. Persistent bacteremia was defined when bacteremia occurred for ≥3 days and <5 days while patients were receiving appropriate antibiotic therapy. An immunosuppressant was defined as a drug used to prevent the rejection of transplanted organs or to treat autoimmune diseases within 3 months of the onset of SAB. Glucocorticoid therapy was also defined as a dose of 25 mg prednisone/day for >1 month, or a cumulative dose of >700 mg prednisone within 3 months of the onset of SAB [10]. Antineoplastic chemotherapy was defined as any antineoplastic chemotherapy received in the 3 months prior to culture collection [11]. Nosocomial bloodstream infection was defined as a positive blood culture obtained from patients who had been hospitalized for 48 hours or longer. If a patient was transferred from another hospital, that patient’s data was included as nosocomial bloodstream infection [12]. Health care-associated bloodstream infection was defined as a positive blood culture obtained from a patient at the time of hospital admission or within 48 hours of admission if the patient fulfilled any of the following four criteria. (1) Received intravenous therapy at home; received wound care or specialized nursing care through a health care agency, family, or friends; or had self-administered intravenous medical therapy in the 30 days before the bloodstream infection. Patients who received only oxygen therapy at home were excluded. (2) Attended a hospital or hemodialysis clinic, or received intravenous chemotherapy in the 30 days before the bloodstream infection. (3) Was hospitalized in an acute care hospital for ≥2 days in the 90 days before the bloodstream infection. (4) Resided in a nursing home or long-term care facility. Community-acquired bloodstream infection was defined as a positive blood culture obtained at the time of hospital admission or within 48 hours after hospital admission in patients not fitting the health care-associated infection criteria. The severity of bacteremia was based on the Pitt Bacteremia Score [13]. Recurrence was defined as the return of S. aureus bacteremia after the documentation of negative blood cultures or clinical improvement within 30 days of completing a course of anti-staphylococcal therapy. Duration of antibiotic therapy was defined as the number of days that the patient received effective antibiotic therapy. Effective antibiotic therapy was defined as therapy wherein the patient’s isolate was susceptible to all antibiotics and appropriate dosing. Infection-related death was defined as death attributable to bacteremia if at least one of the following was present: (1) positive blood culture at the time of death; (2) persistent signs and symptoms of infection due to that microorganism at death; (3) no other apparent cause of death other than bacteremia.\n\nStatistical analyses\nContinuous variables with non-parametric distribution were expressed as median and interquartile range (IQR) [25%, 75%] or number and rate, and were compared using Mann-Whitney U test. Categorical variables were expressed as number and rate and compared using Fisher’s exact test. Univariate and propensity score-adjusted multivariate logistic regression analyses were performed. The propensity scores were adjusted using variables likely to influence the outcomes, and the primary outcome (i.e. all-cause mortality within 90 days) was estimated using logistic regression analysis. In the analysis, missing data were excluded, and imputation was not performed. All tests were 2-tailed, and statistical significance was defined by a P value <0.05. Statistical analyses were performed with R version 3.2.4.\n\nResults\nA total of 109 patients were screened for inclusion; of these, 49 were excluded (Fig 1) [one patient with polymicrobial bacteremia also being less than 18 years of age]. One case had missing data for the Pitt Bacteremia Score. Our study included a final total of 60 patients (IV group, n = 32 [53.3%]; IV + PO group, n = 28 [46.7%]). Table 1 shows the characteristics of patients in each group. The median (IQR) age of the patients was 60 (range, 50–71.0) years. The distribution of place of acquisition was significantly different between the two groups: while hospital onset was higher in the IV group, community-acquired and health care-associated were higher in the IV + PO group (p = 0.039). Significant differences occurred in the rate of thromboembolism (IV group, n = 0 [0.0%]; IV + PO group, n = 6 [21.4%]; p = 0.008), ID consultation (IV group, n = 21 [65.6%]; IV + PO group, n = 26 [92.9%]; p = 0.013), received echocardiogram (IV group, n = 14 [43.8%]; IV + PO group, n = 24 [85.7%]; p = 0.001), and intravenous vancomycin (IV group, n = 23 [71.9%]; IV + PO group, n = 27 [96.4%]; p = 0.014). Furthermore, the median durations of therapy (IV group, 17 days [13–31 days]; IV + PO group, 33 days [26–52 days]; p<0.001) were significantly different between the two groups. Recurrence within 30 days of treatment did not show any statistical differences between the two groups (IV group, n = 1 [3.13%]; IV + PO group, n = 0; p>0.999). Both groups had no infection-related death.\n\n10.1371/journal.pone.0207413.g001Fig 1 Flow diagram of patients included in the study.\nAbbreviation: MSSA, methicillin-sensitive Staphylococcus aureus; CRBSI, catheter-related bloodstream infection; IV, intravenous; PO, oral.\n\n10.1371/journal.pone.0207413.t001Table 1 Comparison of demographic and clinical characteristics between IV and IV + PO groups.\n\t\tAll (n = 60)\tIV group (n = 32)\tIV+PO group (n = 28)\tP-value\t\t\nAge (median, IQR)\t60.0(50.0, 71.0)\t62.5(58.0, 71.0)\t57.5(44.3, 70.0)\t0.060\ta\t\nMale gender\t35(58.33%)\t20(62.50%)\t15(53.57%)\t0.601\tb\t\nPlace of acquisition\t\t\t\t0.039\tb\t\n\tCommunity-acquired\t1(1.67%)\t0(0.00%)\t1(3.57%)\t\t\t\n\tHospital onset\t39(65.00%)\t25(78.13%)\t14(50.00%)\t\t\t\n\tHealthcare-associated\t20(33.33%)\t7(21.88%)\t13(46.43%)\t\t\t\nHematologic malignancy\t4(6.67%)\t2(6.25%)\t2(7.14%)\t>0.999\tb\t\nSolid tumor\t56(93.33%)\t30(93.75%)\t26(92.86%)\t>0.999\tb\t\nTypes of neoplasm\t\t\t\t0.543\tb\t\n\tLip, oral cavity, and pharynx\t7(11.67%)\t6(18.75%)\t1(3.57%)\t\t\t\n\tDigestive organs\t30(50.00%)\t16(50.00%)\t14(50.00%)\t\t\t\n\tRespiratory and intrathoracic organs\t5(8.33%)\t3(9.38%)\t2(7.14%)\t\t\t\n\tBone and articular cartilage\t2(3.33%)\t0(0.00%)\t2(7.14%)\t\t\t\n\tMesothelial and soft tissue\t3(5.00%)\t1(3.13%)\t2(7.14%)\t\t\t\n\tFemale genital organs\t2(3.33%)\t1(3.13%)\t1(3.57%)\t\t\t\n\tUrinary tract\t3(5.00%)\t2(6.25%)\t1(3.57%)\t\t\t\n\tIll-defined, other secondary, and unspecified sites\t4(6.67%)\t2(6.25%)\t2(7.14%)\t\t\t\n\tOthers\t4(6.67%)\t1(3.13%)\t3(10.71%)\t\t\t\nOrgan transplantation\t0(0.00%)\t0(0.00%)\t0(0.00%)\t\t\t\nImmunosuppressant\t0(0.00%)\t0(0.00%)\t0(0.00%)\t\t\t\nGlucocorticoid therapy\t7(11.67%)\t2(6.25%)\t5(17.86%)\t0.235\tb\t\nTotal parenteral nutrition\t27(45.00%)\t16(50.00%)\t11(39.29%)\t0.446\tb\t\nAntineoplastic chemotherapy\t45(75.00%)\t24(75.00%)\t21(75.00%)\t>0.999\tb\t\nDiabetes mellitus\t14(23.33%)\t8(25.00%)\t6(21.43%)\t0.770\tb\t\nChronic kidney disease\t3(5.00%)\t3(9.38%)\t0(0.00%)\t0.241\tb\t\nNeutropenia\t1(1.85%)\t1(3.33%)\t0(0.00%)\t>0.999\tb\t\nHemodialysis\t2(3.33%)\t2(6.25%)\t0(0.00%)\t0.494\tb\t\nValve disease\t4(6.67%)\t3(9.38%)\t1(3.57%)\t0.616\tb\t\nType of CVCs\t\t\t\t0.064\tb\t\n\tShort-term central venous catheter\t23(38.33%)\t16(50.00%)\t7(25.00%)\t\t\t\n\tPICC\t1(1.67%)\t0(0.00%)\t1(3.57%)\t\t\t\n\tImplanted port\t36(60.00%)\t16(50.00%)\t20(71.43%)\t\t\t\nPresence of a non-removable foreign body\t\t\t\t0.402\tb\t\n\tIV filter\t1(1.67%)\t0(0.00%)\t1(3.57%)\t\t\t\n\tNone\t56(93.33%)\t31(96.88%)\t25(89.29%)\t\t\t\n\tOthers\t3(5.00%)\t1(3.13%)\t2(7.14%)\t\t\t\nPitt Bacteremia Score\t\t\t\t0.841\ta\t\n0\t31(52.54%)\t16(51.61%)\t15(53.57%)\t\t\t\n1\t19(32.20%)\t10(32.26%)\t9(32.14%)\t\t\t\n2\t1(1.69%)\t1(3.23%)\t0(0.00%))\t\t\t\n3\t2(3.39%)\t1(3.23%)\t1(3.57%)\t\t\t\n4\t4(6.78%)\t1(3.23%)\t3(10.71%)\t\t\t\n8\t2(3.39%)\t2(6.45%)\t0(0.00%)\t\t\t\nSecondary foci\t\t\t\t\t\t\n\tPostoperative wound\t1(1.67%)\t1(3.13%)\t0(0.00%)\t>0.999\tb\t\n\tPneumonia\t1(1.67%)\t0(0.00%)\t1(3.57%)\t0.467\tb\t\n\tSkin soft tissue\t1(1.67%)\t1(3.13%)\t0(0.00%)\t>0.999\tb\t\n\tEndocarditis\t1(1.67%)\t1(3.13%)\t0(0.00%)\t>0.999\tb\t\n\tThromboembolism\t6(10.00%)\t0(0.00%)\t6(21.43%)\t0.008\tb\t\n\tLiver abscess\t1(1.67%)\t0(0.00%)\t1(3.57%)\t0.467\tb\t\nPersistent bacteremia\t6(20.00%)\t1(7.69%)\t5(29.41%)\t0.196\tb\t\nRemoved CVCs\t55(91.67%)\t27(84.38%)\t28(100.00%)\t0.055\tb\t\nDrainage except for removing CVCs\t5(8.33%)\t2(6.25%)\t3(10.71%)\t0.657\tb\t\nCVCs reinsertion during antibiotic treatment\t24(40.00%)\t15(46.88%)\t9(32.14%)\t0.297\tb\t\nComplication after treatment\t\t\t\t\t\t\n\tThromboembolism\t5(8.33%)\t1(3.13%)\t4(14.29%)\t0.175\tb\t\n\tOsteomyelitis\t1(1.67%)\t0(0.00%)\t1(3.57%)\t0.467\tb\t\n\tSkin soft tissue\t1(1.67%)\t0(0.00%)\t1(3.57%)\t0.467\tb\t\n\tNone\t55(91.67%)\t31(96.88%)\t24(85.71%)\t0.175\tb\t\nID consultation\t47(78.33%)\t21(65.63%)\t26(92.86%)\t0.013\tb\t\nReceived echocardiogram\t38(63.33%)\t14(43.75%)\t24(85.71%)\t0.001\tb\t\nIV antibiotics\t\t\t\t\t\t\n\tCEZ\t56(93.33%)\t29(90.63%)\t27(96.43%)\t0.616\tb\t\n\tCMZ\t3(5.00%)\t2(6.25%)\t1(3.57%)\t>0.999\tb\t\n\tCTRX\t4(6.67%)\t3(9.38%)\t1(3.57%)\t0.616\tb\t\n\tCFPM\t24(40.00%)\t9(28.13%)\t15(53.57%)\t0.065\tb\t\n\tSBT/CPZ\t5(8.33%)\t4(12.50%)\t1(3.57%)\t0.359\tb\t\n\tSBT/ABPC\t6(10.00%)\t3(9.38%)\t3(10.71%)\t>0.999\tb\t\n\tTAZ/PIPC\t12(20.00%)\t5(15.63%)\t7(25.00%)\t0.520\tb\t\n\tIPM/CS\t3(5.00%)\t1(3.13%)\t2(7.14%)\t0.594\tb\t\n\tMEPM\t3(5.00%)\t2(6.25%)\t1(3.57%)\t>0.999\tb\t\n\tVCM\t50(83.33%)\t23(71.88%)\t27(96.43%)\t0.014\tb\t\n\tCLDM\t6(10.00%)\t2(6.25%)\t4(14.29%)\t0.404\tb\t\n\tothers\t2(3.34%)\t2(6.25%)\t0(0.00%)\t\t\t\nPO antibiotics\t\t\t\t\t\t\n\tCEX\t19(31.67%)\t\t19(67.86%)\t\t\t\n\tCVA/AMPC\t4(6.67%)\t\t4(14.29%)\t\t\t\n\tLVFX\t4(6.67%)\t\t4(14.29%)\t\t\t\n\tST\t2(3.33%)\t\t2(7.14%)\t\t\t\n\tCLDM\t6(10.00%)\t\t6(21.43%)\t\t\t\n\tothers\t2(3.33%)\t\t2(7.14%)\t\t\t\nDuration of antibiotics days (median, range)\t26.0(15,0, 34.0)\t16.5(13.0,30.5)\t32.5(26.0,52.3)\t<0.001\tb\t\nDuration of IV antibiotics (median, range)\t17.0(13.0,24.75)\t16.5(13.0,30.5)\t17.5(13.0,24.0)\t0.935\tb\t\nRecurrence\t1(1.67%)\t1(3.13%)\t0(0.00%)\t>0.999\tb\t\nInfection-related death\t0(0.00%)\t0(0.00%)\t0(0.00%)\t\t\t\nDeath within 90 days\t20(33.33%)\t17(53.13%)\t3(10.71%)\t0.001\tb\t\nDeath within 30 days\t7(11.67%)\t7(21.88%)\t0(0.00%)\t0.012\tb\t\ndata: n, %; median [interquartile range (IQR): 25%, 75%].\n\na, Mann-Whitney U test\n\nb, Fisher's Exact Test.\n\nAbbreviations; IV, intravenous; PO, oral; IQR, interquartile range; CVCs, central venous catheters; PICC, peripherally inserted central catheter; ID, infectious disease; CEZ, Cefazolin; CMZ, Cefmetazole; IPM/CS, Imipenem/Cilastatin; MEPM, Meropenem; VCM, vancomycin; CLDM, Clindamycin; CEX, Cefalexin; CVA/AMPC, Amoxicillin/Clavulanate; LVFX, Levofloxacin; ST, Sulfamethoxazole/Trimethoprim.\n\nThe 90-day mortality in the IV and IV + PO groups were 53.1% (17/32) and 10.7% (3/28), respectively (p = 0.001). The 30-day mortality in the IV and IV + PO groups were 21.9% (7/32) and 0% (0/28), respectively (p = 0.012). The propensity score was estimated using multivariable logistic regression analysis with the following variables: age, gender, place of acquisition, Pitt Bacteremia Score, glucocorticoid therapy, antineoplastic chemotherapy, diabetes mellitus, hematologic malignancy, solid tumor, types of neoplasm, chronic kidney disease, hemodialysis, valve disease, presence of non-removable foreign body, ID consultation, and duration of therapy of more than 1 month. Compared to the IV group, the odds ratios of 90-day mortality in the IV + PO group was 0.106 (95% CI: 0.027–0.423; p = 0.001) (Table 2). In the propensity score-adjusted multivariate logistic regression model, compared to the IV group, the odds ratios of 90-day mortality in the IV + PO group was 0.377 (95% CI: 0.037–3.884; p = 0.413).\n\n10.1371/journal.pone.0207413.t002Table 2 Univariate and propensity score-adjusted analysis of risk factors associated with mortality within 90 days.\n\tAlive (n = 40)\tDeath (n = 20)\tUnadjusted OR (95% CI)\tP-value\tPS-adjusted OR (95% CI)\tP-value\t\nIV group\t15(37.50%)\t17(85.00%)\tref.\t\t\t\t\nIV + PO group\t25(62.50%)\t3(15.00%)\t0.106(0.027–0.423)\t0.001\t0.377(0.037–3.884)\t0.413\t\nOR: odds ratio, 95% CI: 95% confidence interval.\n\nAbbreviations: PS, Propensity score; IV, intravenous; ref, reference; PO, oral.\n\nDiscussion\nThis study compared the 90-day mortality of IV therapy with IV + PO therapy in cancer patients with CRBSI due to MSSA, and provides the first known evidence of the efficacy of oral switch therapy in cancer patients with CRBSI due to MSSA. The findings of the present study suggest that oral switch therapy might be a reasonable option for this patient population, in whom prolonged intravenous therapy can often be difficult to implement. In the propensity score-adjusted multivariate logistic regression model using variables likely to influence the outcomes, no significant association was found with mortality.\n\nThe univariate logistic regression model showed that mortality in patients who switched to oral therapy (IV + PO group) was significantly lower than that in the IV treatment group. The switch might have confounded our findings since current guidelines do not recommend oral switch therapy [3,4]. We considered that the presence of confounding factors might have influenced mortality in our study, and thus performed multivariate analysis; however, the adjusted mortality was not significantly different between groups. Although many experts have considered that IV treatment is necessary for this patient population, our findings showed that switching to oral therapy was not associated with poorer outcomes in cancer patients with CRBSI due to MSSA. Therefore, the results of the present study are quite novel.\n\nPrevious studies have shown that adherence to evidence-based quality-of-care indicators (QCIs), as well as ID consultation, which is associated with adherence to QCIs in the management of SAB, could result in reduced mortality [2,14,15]. The main QCIs consist of the following five aspects: (1) follow-up blood cultures; (2) early source control when applicable; (3) echocardiography; (4) the early use of appropriate antibiotics, and (5) the appropriate duration of therapy [15]. In our study, there was a low adherence rate to follow-up blood cultures, echocardiography, and removal of CVCs in the IV group compared to the proposed QCIs. However, some reports do not recommend routine echocardiography [16–18], and performing routine echocardiography for SAB is controversial. Only 84% of patients in the IV group had the CVCs removed, which was primarily due to consideration of their cancer prognosis.\n\nHowever, ID consultation, which adheres to QCIs, has also been shown to be associated with reduced mortality [2]. In this study, it is not known why oral switch therapy was adopted in certain patients, and this may have led to an unknown bias. However, it is possible that oral switch therapy could be an option for patients with CRBSI due to MSSA if they adhere to QCIs and ID consultation.\n\nPharmacist-facilitated antimicrobial stewardship initiatives can aid in switching from IV to PO [19]. While IV medications may be more bioavailable and have greater effects, some oral drugs produce serum levels comparable to the parenteral form [5]. In our study, cefalexin was the most common oral antibiotic option. The antimicrobial activity of cephalexin has been shown to be active against common Gram-positive organisms, including MSSA [20]. Furthermore, orally-administered cephalexin has been shown to be almost completely absorbed from the gastrointestinal tract [20].\n\nThe mortality in our study was significantly higher than that in previous studies, particularly in patients on IV treatment [2]. This finding might have resulted from the fact that all participants in the present study were cancer patients. In some studies, cancer is reported to be a predictor of mortality in S. aureus bacteremia [21–23]. Although the design of our study did not provide an opportunity to determine the weight of this association, we did evaluate variables related to neoplastic disease that could explain this outcome.\n\nThe recurrence of MSSA infections complicated by bacteremia was similar between the two treatment groups in our study. Our findings were similar to those of a meta-analysis that included 11 studies, which showed that the relapse rate after conventional 4- to 6-week antibiotic regimens for catheter-related S. aureus bacteremia is expected to be less than 1% [1].\n\nThe present study has several limitations. First, a relatively small number of patients were enrolled in the study. Second, because the study used data from retrospective medical records review, the patients were not treated according to defined protocol. Thus, type of antibiotics, dose, and duration of treatment differed in our participants. In addition, echocardiography and follow-up blood culture were not performed in all patients; therefore, the true incidence of complications and recurrences may have been underestimated. Additionally, there were some missing data in our study; however, rigorous and consistent data collection and verification were ensured by four ID doctors. Likewise, both groups had no infection-related death in our study. The reason for this finding is unclear, and we considered this as a limitation of retrospective data collection. Therefore, we evaluated 30-day mortality in addition to 90-day mortality.\n\nThird, data were collected at a single institution treating cancer patients with CRBSI, and the predominant places of acquisition of infection were hospital onset and health care-associated infections; hence, our results may not be generalizable. Our results should therefore be validated in other cohorts, especially in non-cancer patients. Finally, there was a potential for confounding by indication. The majority of patients, at the time of admission to the hospital for severe infections, often tend to opt for IV medications and continue to receive them until discharge. Patients receiving IV antibiotics might differ from patients receiving oral antibiotics after IV treatment in ways that could have been associated with mortality. Furthermore, cancer staging and performance status, which might have influenced mortality, were not obtained in our study. However, patient characteristics were not significantly different between groups. We attempted to limit the potential for unadjusted confounding by including both measures of illness severity based on vital signs at baseline (i.e., Pitt Bacteremia Score) and comorbidities.\n\nIn conclusion, our study suggests that CRBSI due to MSSA in cancer patients can be treated by switching to oral therapy, rather than relying on conventionally recommended IV therapy. Future prospective randomized trials are needed to better clarify our findings and confirm whether switching to oral therapy for CRBSI due to MSSA is indicated in cancer patients.\n\nSupporting information\nS1 File Raw data of our patients.\n(XLSX)\n\nClick here for additional data file.\n==== Refs\nReferences\n1 Jernigan JA , Farr BM . Short-course therapy of catheter-related Staphylococcus aureus bacteremia: a meta-analysis . Ann Intern Med . 1993 ;119 : 304 –311 . 8328740 \n2 Bai AD , Showler A , Burry L , Steinberg M , Ricciuto DR , Fernandes T , et al\nImpact of Infectious Disease Consultation on Quality of Care, Mortality, and Length of Stay in Staphylococcus aureus Bacteremia: Results From a Large Multicenter Cohort Study . Clin Infect Dis . 2015 ;60 : 1451 –1461 . 10.1093/cid/civ120\n25701854 \n3 Mermel LA , Allon M , Bouza E , Craven DE , Flynn P , O'Grady NP , et al\nClinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America . Clin Infect Dis . 2009 ;49 : 1 –45 . 10.1086/599376\n19489710 \n4 Liu C , Bayer A , Cosgrove SE , Daum RS , Fridkin SK , Gorwitz RJ , et al\nClinical practice guidelines by the infectious diseases society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children . Clin Infect Dis . 2011 ;52 : e18 –55 . 10.1093/cid/ciq146\n21208910 \n5 Schrenzel J , Harbarth S , Schockmel G , Genné D , Bregenzer T , Flueckiger U , et al\nA randomized clinical trial to compare fleroxacin-rifampicin with flucloxacillin or vancomycin for the treatment of staphylococcal infection . Clin Infect Dis . 2004 ;39 : 1285 –1292 . 10.1086/424506\n15494904 \n6 Thwaites GE , United Kingdom Clinical Infection Research Group (UKCIRG) . The management of Staphylococcus aureus bacteremia in the United Kingdom and Vietnam: a multi-centre evaluation . PLoS One . 2010 ;5 : e14170 \n10.1371/journal.pone.0014170\n21179193 \n7 Kaasch AJ , Fätkenheuer G , Prinz-Langenohl R , Paulus U , Hellmich M , Weiß V , Jung N , et al\nEarly oral switch therapy in low-risk Staphylococcus aureus bloodstream infection (SABATO): study protocol for a randomized controlled trial . Trials . 2015 ;16 : 450 \n10.1186/s13063-015-0973-x\n26452342 \n8 Vashi PG , Virginkar N , Popiel B , Edwin P , Gupta D . Incidence of and factors associated with catheter-related bloodstream infection in patients with advanced solid tumors on home parenteral nutrition managed using a standardized catheter care protocol . BMC Infect Dis . 2017 ;17 : 372 \n10.1186/s12879-017-2469-7\n28558699 \n9 Soriano A , Martínez JA , Mensa J , Marco F , Almela M , Moreno-Martínez A , Sánchez F , et al\nPathogenic significance of methicillin resistance for patients with Staphylococcus aureus bacteremia . Clin Infect Dis . 2000 ;30 : 368 –373 . 10.1086/313650\n10671343 \n10 Asgeirsson H , Kristjansson M , Kristinsson KG , Gudlaugsson O . Staphylococcus aureus bacteraemia—Nationwide assessment of treatment adequacy and outcome . J Infect . 2011 ;62 : 339 –346 . 10.1016/j.jinf.2011.03.003\n21402101 \n11 Lodise TP , Graves J , Evans A , Graffunder E , Helmecke M , Lomaestro BM , et al\nRelationship between vancomycin MIC and failure among patients with methicillin-resistant Staphylococcus aureus bacteremia treated with vancomycin . Antimicrob Agents Chemother . 2008 ;52 : 3315 –3320 . 10.1128/AAC.00113-08\n18591266 \n12 Friedman ND , Kaye KS , Stout JE , McGarry SA , Trivette SL , Briggs JP , et al\nHealth care—associated bloodstream infections in adults: a reason to change the accepted definition of community-acquired infections . Ann Intern Med . 2002 ;137 : 791 –797 . 12435215 \n13 Paterson DL , Ko WC , Von Gottberg A , Mohapatra S , Casellas JM , Goossens H , et al\nInternational prospective study of Klebsiella pneumoniae bacteremia: implications of extended-spectrum beta-lactamase production in nosocomial Infections . Ann Intern Med . 2004 ;140 : 26 –32 . 14706969 \n14 Nagao M , Yamamoto M , Matsumura Y , Yokota I , Takakura S , Teramukai S , et al\nComplete adherence to evidence-based quality-of-care indicators for Staphylococcus aureus bacteremia resulted in better prognosis . Infection . 2017 ;45 : 83 –91 . 10.1007/s15010-016-0946-3\n27709434 \n15 López-Cortés LE , Del Toro MD , Gálvez-Acebal J , Bereciartua-Bastarrica E , Fariñas MC , Sanz-Franco M , et al\nImpact of an evidence-based bundle intervention in the quality-of-care management and outcome of Staphylococcus aureus bacteremia . Clin Infect Dis . 2013 ;57 : 1225 –1233 . 10.1093/cid/cit499\n23929889 \n16 Palraj BR , Baddour LM , Hess EP , Steckelberg JM , Wilson WR , Lahr BD , et al\nPredicting Risk of Endocarditis Using a Clinical Tool (PREDICT): Scoring System to Guide Use of Echocardiography in the Management of Staphylococcus aureus Bacteremia . Clin Infect Dis . 2015 ;61 : 18 –28 . 10.1093/cid/civ235\n25810284 \n17 Heriot G , Yeoh J , Street A , Ratnam I . Echocardiography has minimal yield and may not be warranted in Staphylococcus aureus bacteremia without clinical risk factors for endocarditis . Eur J Clin Microbiol Infect Dis . 2015 ;34 : 1231 –1236 . 10.1007/s10096-015-2352-7\n25717023 \n18 Naucler P , Berge A . Screening algorithm to perform transesophageal echocardiography in patients with staphylococcus aureus bacteremia . Clin Infect Dis . 2015 ;61 : 1630 .\n19 Dunn K , O'Reilly A , Silke B , Rogers T , Bergin C . Implementing a pharmacist-led sequential antimicrobial therapy strategy: a controlled before-and-after study . Int J Clin Pharm . 2011 ;33 : 208 –214 . 10.1007/s11096-010-9475-9\n21744190 \n20 Meyers BR , Kaplan K , Weinstein L . Cephalexin: microbiological effects and pharmacologic parameters in man . Clin Pharmacol Ther . 1969 ;10 : 810 –816 . 4900202 \n21 Cuervo SI , Cortés JA , Sánchez R , Rodríguez JY , Silva E , Tibavizco D , et al\nRisk factors for mortality caused by Staphylococcus aureus bacteremia in cancer patients . Enferm Infecc Microbiol Clin . 2010 ;28 : 349 –354 . 10.1016/j.eimc.2009.06.015\n20430483 \n22 Hill PC , Birch M , Chambers S , Drinkovic D , Ellis-Pegler RB , Everts R , et al\nProspective study of 424 cases of Staphylococcus aureus bacteraemia: determination of factors affecting incidence and mortality . Intern Med J . 2001 ;31 : 97 –103 . 11480485 \n23 Kim SH , Park WB , Lee KD , Kang CI , Kim HB , Oh MD , et al\nOutcome of Staphylococcus aureus bacteremia in patients with eradicable foci versus noneradicable foci . Clin Infect Dis . 2003 ;37 : 794 –799 . 10.1086/377540\n12955640\n\n",
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"mesh_terms": "D061605:Administration, Intravenous; D000284:Administration, Oral; D000368:Aged; D000900:Anti-Bacterial Agents; D055499:Catheter-Related Infections; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D008875:Middle Aged; D009369:Neoplasms; D012189:Retrospective Studies; D013203:Staphylococcal Infections; D015996:Survival Rate; D013997:Time Factors",
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"title": "Intravenous to oral switch therapy in cancer patients with catheter-related bloodstream infection due to methicillin-sensitive Staphylococcus aureus: A single-center retrospective observational study.",
"title_normalized": "intravenous to oral switch therapy in cancer patients with catheter related bloodstream infection due to methicillin sensitive staphylococcus aureus a single center retrospective observational study"
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"abstract": "A 27-year-old human immunodeficiency virus--positive man presented with abdominal pain. Computed tomography of the abdomen revealed large right pleural effusion, pericardial effusion and marked ascites with diffuse intra- and extraperitoneal lymphadenopathy. Echocardiography showed severely reduced left ventricular systolic function. After drainage of pleural and pericardial fluid, the patient developed severe hypotension and hypoxic respiratory failure. Extra- and intracranial neurovascular sonography demonstrated low carotid artery flow volume and dicrotic pulse waveforms in all vessels insonated bilaterally. This case report demonstrates an atypical dicrotic waveform pattern of transcranial Doppler in advanced ventricular dysfunction with shock.",
"affiliations": "Department of Neurology, Wake Forest University Baptist Medical Center, Winston-Salem.;Department of Neurology, Wake Forest University Baptist Medical Center, Winston-Salem.;Department of Neurology, Wake Forest University Baptist Medical Center, Winston-Salem.;Department of Neurology, Wake Forest University Baptist Medical Center, Winston-Salem.",
"authors": "Suwatcharangkoon|Sureerat|S|;Meads|Dana B|DB|;Tegeler|Charles H|CH|;Reynolds|Patrick S|PS|",
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"issue": "25(4)",
"journal": "Journal of neuroimaging : official journal of the American Society of Neuroimaging",
"keywords": "Cardiomyopathy; HIV; dicrotic pulse; transcranial Doppler",
"medline_ta": "J Neuroimaging",
"mesh_terms": "D000328:Adult; D009202:Cardiomyopathies; D002561:Cerebrovascular Disorders; D003937:Diagnosis, Differential; D015658:HIV Infections; D006801:Humans; D008297:Male; D017585:Ultrasonography, Doppler, Transcranial",
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"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Transcranial Doppler Sonography: Atypical Dicrotic Pulse Waveforms in a Man with HIV Infection and Severe Cardiomyopathy.",
"title_normalized": "transcranial doppler sonography atypical dicrotic pulse waveforms in a man with hiv infection and severe cardiomyopathy"
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"abstract": "Management for continuous flow left ventricular assist device (LVAD) thrombosis often relies on speculation of individual clinical risk factors and integration of indirect evidence for device dysfunction. There are no comprehensive guidelines for treatment of this serious complication, and most of our current knowledge comes from anecdotal experience or observational study. More data on effective treatment, both with aggressive pharmacologic and device-based interventions, are needed for improving our understanding of mechanisms driving device thrombosis and for preventing future events. We present a case of LVAD thrombosis with emphasis on recognition and treatment of acute pump thrombosis, and discuss a potentially novel strategy using percutaneous mechanical circulatory support for pump salvage.",
"affiliations": "From the *Division of Cardiology, Department of Medicine, †Department of Cardiothoracic Surgery, Cardiovascular Institute, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, Pennsylvania.",
"authors": "Agarwal|Richa|R|;Raina|Amresh|A|;Lasorda|David M|DM|;Moraca|Robert J|RJ|;Bailey|Stephen H|SH|;Kanwar|Manreet|M|;Sokos|George|G|;Murali|Srinivas|S|;Benza|Raymond L|RL|",
"chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator",
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"issue": "61(1)",
"journal": "ASAIO journal (American Society for Artificial Internal Organs : 1992)",
"keywords": null,
"medline_ta": "ASAIO J",
"mesh_terms": "D000328:Adult; D005260:Female; D005343:Fibrinolytic Agents; D006353:Heart-Assist Devices; D006801:Humans; D011475:Prosthesis Failure; D012770:Shock, Cardiogenic; D015912:Thrombolytic Therapy; D013927:Thrombosis; D010959:Tissue Plasminogen Activator",
"nlm_unique_id": "9204109",
"other_id": null,
"pages": "98-101",
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"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of acute left ventricular assist device thrombosis and cardiogenic shock with intraventricular thrombolysis and a tandem heart.",
"title_normalized": "successful treatment of acute left ventricular assist device thrombosis and cardiogenic shock with intraventricular thrombolysis and a tandem heart"
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"abstract": "BACKGROUND\nNeuromyelitis optica spectrum disorder (NMOSD) associated with active replication of hepatitis B virus (HBV) is rare. High-dose corticosteroids are the mainstay treatment of NMOSD; however, these may cause reactivation of viral replication in patients with stable HBV which may lead to liver damage. Therefore, care should be placed in corticosteroid use in patients with NMOSD and HBV infection.\nHerein, we report the case of a 31-year-old woman with NMOSD and HBV infection who was seropositive for anti-aquaporin-4 antibody. The stable and HBV carrier status of the patient led to the deferment of antiviral and hepatoprotective agents in early treatment. However, liver function impairment was detected during follow-up, with an improvement in the best-corrected visual acuity.\nThe patient was diagnosed with NMOSD with active replication of HBV and seropositive anti-aquaporin-4 antibody considering the medical history and ancillary examinations.\n\n\nMETHODS\nTo manage NMOSD, intravenous high-dose methylprednisolone (20 mg/kg d) was administered for 5 days which was gradually tapered to oral steroids. However, liver function impairment was observed during follow-up; therefore, anti-HBV drugs (entecavir) and hepatoprotective drugs (bicyclol or polyunsaturated phosphatidylcholine) were administered.\n\n\nRESULTS\nA marked improvement was observed in the patient's best-corrected visual acuity after 4 weeks of treatment. However, follow-up examinations revealed liver function damage which necessitated administration of antiviral and hepatoprotective drugs. Liver function normalized after 1 month.\nThis case underscores the importance of preventive treatment of liver protection in patients with HBV infection prior to or simultaneous with glucocorticoid therapy and furthermore, there is an urgent need to develop authoritative guidelines regulating corticosteroid use in the treatment of patients with HBV infection.",
"affiliations": "Qilu Hospital of ShanDong University, Jinan, China.",
"authors": "Lei|Jiaying|J|0000-0001-9972-0988;Wang|Hong|H|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D051401:Aquaporin 4; D001323:Autoantibodies; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000027207",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974\n1536-5964\nLippincott Williams & Wilkins Hagerstown, MD\n\nMD-D-21-03728\n10.1097/MD.0000000000027207\n27207\n5800\nResearch Article\nClinical Case Report\nNeuromyelitis optica spectrum disorder with active replication of hepatitis B virus and seropositive anti-aquaporin-4 antibody\nA case report\nLei Jiaying MM\nWang Hong PhD ∗\nSaranathan. Maya\nQilu Hospital of ShanDong University, Jinan, China.\n∗ Correspondence: Hong Wang, Qilu Hospital of ShanDong University, Wenhua West Road, Jinan 250012, China (e-mail: dr.wanghong@163.com).\n24 9 2021\n24 9 2021\n100 38 e2720725 5 2021\n4 8 2021\n27 8 2021\nCopyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0\n\nAbstract\n\nRationale:\n\nNeuromyelitis optica spectrum disorder (NMOSD) associated with active replication of hepatitis B virus (HBV) is rare. High-dose corticosteroids are the mainstay treatment of NMOSD; however, these may cause reactivation of viral replication in patients with stable HBV which may lead to liver damage. Therefore, care should be placed in corticosteroid use in patients with NMOSD and HBV infection.\n\nPatient concerns:\n\nHerein, we report the case of a 31-year-old woman with NMOSD and HBV infection who was seropositive for anti-aquaporin-4 antibody. The stable and HBV carrier status of the patient led to the deferment of antiviral and hepatoprotective agents in early treatment. However, liver function impairment was detected during follow-up, with an improvement in the best-corrected visual acuity.\n\nDiagnoses:\n\nThe patient was diagnosed with NMOSD with active replication of HBV and seropositive anti-aquaporin-4 antibody considering the medical history and ancillary examinations.\n\nInterventions:\n\nTo manage NMOSD, intravenous high-dose methylprednisolone (20 mg/kg d) was administered for 5 days which was gradually tapered to oral steroids. However, liver function impairment was observed during follow-up; therefore, anti-HBV drugs (entecavir) and hepatoprotective drugs (bicyclol or polyunsaturated phosphatidylcholine) were administered.\n\nOutcomes:\n\nA marked improvement was observed in the patient's best-corrected visual acuity after 4 weeks of treatment. However, follow-up examinations revealed liver function damage which necessitated administration of antiviral and hepatoprotective drugs. Liver function normalized after 1 month.\n\nLesson:\n\nThis case underscores the importance of preventive treatment of liver protection in patients with HBV infection prior to or simultaneous with glucocorticoid therapy and furthermore, there is an urgent need to develop authoritative guidelines regulating corticosteroid use in the treatment of patients with HBV infection.\n\nKeywords\n\naquaporin-4\ncorticosteroid\nHBV\nliver function\nneuromyelitis optica spectrum disorder\nOPEN-ACCESSTRUE\n==== Body\npmc1 Introduction\n\nNeuromyelitis optica (NMO) is an acute or subacute demyelinating inflammatory disease of the central nervous system (CNS), traditionally understood to be confined to the optic nerve and spinal cord. However, there is a group of demyelinating diseases with a limited form that do not meet the clinical diagnostic criteria for NMO. Similar pathogenesis and clinical characteristics are observed between this group and NMO, including single or recurrent optic neuritis (ON) and longitudendelitis extensive transverse myelitis, ON or longitudendelitis extensive transverse myelitis with rheumatoid immune disease, and positive rheumatoid immune-related autoimmune antibodies. In 2007, Wingerchuk et al[1] named this group of diseases as neuromyelitis optica spectrum disorder (NMOSD). However, previous research has found no significant difference regarding the biological characteristics and treatment strategies between NMO and NMOSD; furthermore, patients with NMOSD eventually develop NMO. In June 2015, the International Panel for NMO Diagnosis revised the nomenclature and diagnostic criteria for NMO; particularly, they removed the separate definition of NMO and included NMO in the broader category of NMOSD.[2]\n\nChronic hepatitis B (CHB) infection is a global health problem. In 2009, more than 2 billion people have been infected with hepatitis B virus (HBV) worldwide.[3] In China, the infection rate of HBV is higher, and approximately 20% of patients with HBV infection exhibit extrahepatic manifestations.[4] HBV infection and vaccination are associated with CNS demyelinating diseases, such as ON, transverse myelitis, acute disseminated encephalomyelitis, and multiple sclerosis.[5–8] Furthermore, previous studies in the US have investigated the incidence of NMOSD postHBV vaccination.[9] Zhao et al[7] found that patients with NMOSD and concomitant CHB infection exhibited severe manifestations. Liu et al[5] analyzed the clinical features of 10 Chinese patients with NMOSD combined with CHB infection who were seropositive for aquaporin-4; they explained the possible pathologic mechanism between the association of NMOSD and HBV infection. However, the role of HBV infection in the emergence of NMOSD was not specified, and no recommendations regarding the use of corticosteroids in patients with NMOSD and HBV infection were outlined.\n\nHere, we report a case of NMOSD with CHB infection who was seropositive for aquaporin-4-antibodies.\n\n2 Case presentation\n\n2.1 Patient information\n\nIn November 14, 2020, a 31-year-old woman consulted our hospital due to acute vision loss of the right eye for 1 week. This was associated with lightening of the visual object and painful eye rotation for 1 week. One week prior to admission, the visual color above the nose of the right eye turned white; however, no triggering factors were identified. Upon admission, visual field examination was performed which revealed “partial visual defect of the right eye” (Fig. 1). She experienced rapid decrease in her right eye visual acuity, which progressed to “hand motion” 1 day before admission. One year prior to consultation, she was diagnosed as an asymptomatic HBV carrier and received no treatment. However, further probing of past medical history was unremarkable for other comorbid diseases. She denies history of trauma and surgery. Furthermore, she is allergic to mango and ultraviolet light. She had a regular routine, and denies history of tobacco and alcohol use. Her family history was unremarkable.\n\nFigure 1 Visual field examination of right eye upon admission showed a defect of upper visual field in the right eye.\n\n2.2 Clinical findings\n\nAfter admission, the visual acuity of the right eye was hand motion (–11.00/–2.50∗150 = no improvement), and the left eye was 0.08 (–14.00/–3.50∗175 = 0.8). The intra-ocular pressure of both eyes were 19 mm Hg. The pupil diameter of the right and left eye were approximately 5 and 3 mm, respectively. Additionally, the penlight examination of the right eye revealed absence of the direct light pupillary reflex, presence of the indirect light pupillary reflex, and positive RAPD; on the other hand, the indirect and direct light pupillary reflex of the right eye were both present. Upon fundoscopic examination, the optic disc boundary of both eyes was clear with a light red color; furthermore, no reflection was observed in the fovea of the macula.\n\n2.3 Diagnostic assessment\n\nThe flash visual evoked potential showed a delay in the P2 peak time and decrease in the P2 wave amplitude of the right eye compared with the left eye. Results from the optical disc optical coherence tomography, electrocardiogram, chest radiography, spinal cord magnetic resonance imaging (MRI), routine complete blood count, urinalysis, coagulation studies, erythrocyte sedimentation rate, C-reactive protein, anti-nuclear antibody spectrum 17 items, treponema pallidum specific antibody, and liver and kidney function tests were unremarkable. Furthermore, HBV profile revealed (+) HBsAg, (+) HBeAg (+), (–) HBeAb, (+) HBcAb-IgG, (–) HCV-Ab, (–) HCV-Ag, and (+) PreS1-Ag. Antibodies against demyelinating diseases of the CNS revealed seropositive anti-aquaporin-4 antibody (AQP4-Ab). Computer visual field: defect of the upper visual field of the right eye (Fig. 1). MRI scans of the brain showed a long T2 signal in the intra-orbital segment of the right optic nerve, consistent with ON. The patient was diagnosed with the following conditions considering the medical history, and physical and ancillary examinations:\n\n1. NMOSD,\n\n2. binocular ametropia,\n\n3. stage of active HBV replication.\n\n2.4 Therapeutic intervention\n\nDuring the first week, intravenous high-dose methylprednisolone (20 mg/kg d) was administered for 5 days with drugs that nourish the nerve and reduce adverse hormone effects; the methylprednisolone were tapered to oral prednisone tablets therapy (1 mg/kg d) after 5days. She remained in the hospital for 10 days. Prior to discharge, improvements were observed in the patient's visual acuity, color vision, and right eye shapes and details. Particularly, the visual acuity of the right eye was “finger count”/30 cm (–11.00/–2.50∗150 = no improvement), and the left was 0.08 (–14.00/3.50∗175 = 4.9).\n\n2.5 Follow-up and outcomes\n\nFollowing discharge, the patient was maintained on oral prednisone tablets therapy whose dosage was gradually reduced by 5 mg every 2 weeks. This was administered with adjuvant drugs to nourish the nerve and reduce adverse hormone reactions. On December 14, 2020, patient was followed up. During this consult, visual examination revealed best-corrected visual acuity of the right and left eyes as 0.1 and 0.8, respectively. A visual field examination is shown in Figure 2. Her second follow-up was on January 4, 2021 which revealed best-corrected visual acuity of the right and left eye as 0.12 and 0.8, respectively.\n\nFigure 2 Visual field examination of right eye at first review showed that the area of visual field defect in the right eye was slightly improved compared with that at admission.\n\nOn February 21, 2021, the patient felt limited visual field and unsatisfactory improvement of the right eye; therefore, she was admitted in the General Hospital of the People's Liberation Army for 7 days. On admission, the visual acuity of right eye was 0.04 (–14.5/–2.50∗180 = 0.6), while that of the left eye was 0.08 (–14.50/2.50∗175 = 0.8). Additionally, upon analysis, cerebrospinal fluid and blood were reactive for HBsAg, HBeAg, and core antibodies; furthermore, quantitative determination of HBV DNA was 8.44 × 107 copies/mL. T-cell analysis was performed for tuberculosis infection, which revealed antigen A (–), antigen B (–), anti-cardiolipin antibodies (–), and HLA-B27(–). Furthermore, liver function tests revealed that alanine aminotransferase and aspartate aminotransferase were 287.5 U/L and 272.1 U/L, respectively. The patient received a reduced dose of oral prednisone tablets therapy (20 mg/d) combined with adjuvant drugs to improve microcirculation, nourish nerve, anti-HBV drugs (entecavir 0.5 mg/d), and hepatoprotective drugs (bicyclol 25 mg tid, or polyunsaturated phosphatidylcholine 228 mg tid). Once the patient's condition was stable, she was discharged. On March 22, 2021, 1 month after discharge, her liver function tests and HBV DNA quantification were re-evaluated. The results revealed alanine aminotransferase and aspartate aminotransferase of 20.4 U/L and 80.3 U/L respectively, indicating a return to normal for the patient's liver function. Quantitative determination of HBV DNA revealed 1.46 × 103 copies/mL, indicating a significant decrease in the HBV replication activity.\n\n3 Discussion\n\nNMOSD is a group of inflammatory demyelinating diseases mediated by antigens and antibodies of the humoral immunity which affects the CNS. AQP4 is a protein located in the cell membrane of neurons, such as astrocytes. The international consensus for NMOSD diagnosis revised in 2015 proposed to divide NMOSD into NMOSD with or without AQP4-IgG.[2] For patients with AQP4-IgG, only 1 of the following core clinical features is required to be diagnosed with NMOSD. These core clinical features include clinical syndromes or MRI findings related to spinal cord, optic nerve, area postrema, other brainstem, cerebral, or diencephalic presentations. The detection of AQP4-Ab is 99% specific to NMO disease; a seropositive AQP4-Ab is needed to establish a diagnosis of NMO or NMOSD, which was observed in our patient. ON is an inflammatory lesion of the optic nerve caused by various causes,[10] According to etiology, it can be classified as idiopathic, autoimmune, infectious, or unclassified ON. Notably, precursors of viral infections may induce factors causing idiopathic ON. Furthermore, infection-related ON can lead to autoimmune disorders when the infection triggers whole-body or local inflammatory response of the optic nerve; therefore, overlaps may be observed between idiopathic and infectious ON in some classifications. In 2014, Toosy et al[10] proposed the concept of typical and atypical ON according to the relationship of ON to either multiple sclerosis or demyelinating disease of the CNS. Zhao et al[7] showed that 92.3% of patients with ON and HBV infection were atypical. Our patient reported no history of autoimmune diseases and infection or close contact, except for being diagnosed as an HBV carrier. Additionally, anti-nuclear antibody spectrum test results were unremarkable. Therefore, differential diagnosis between infectious ON and connective tissue disease-induced optic neuropathy. The patient lived their life routinely and reported no history of smoking, alcohol drinking, or gastrointestinal disease; these factors exclude the diagnosis of toxic and malnourished metabolic optic neuropathy. The brain MRI findings results suggest that only the right optic nerve signal was abnormal; therefore, visual acuity loss caused by compression of intra-cranial tumor or sinus inflammation involving the optic nerve could be ruled out. In addition, the young age of the patient, and the presentation of decreased vision with ocular rotation pain and unremarkable fundoscopic examination rule out Leber hereditary optic neuropathy. Therefore, it was considered that the disease was caused by HBV infection, resulting in autoimmune dysfunction which caused ON symptoms.\n\nIt has been reported that HBV infection may aggravate ON.[7] Furthermore, a confirmation of a patient's HBV infection or vaccination status and the presence of clinical manifestations that meet the NMOSD diagnostic criteria are required to establish a diagnosis of HBV-associated NMOSD. In our patient, HBeAg was positive, and quantitative determination of HBV DNA was 8.44 × 107 copies/mL, indicating active HBV replication. Furthermore, her AQP4-Ab IgG level was serologically positive. Therefore, the diagnosis of HBV-associated NMOSD was confirmed after exclusion of other infectious factors. Liu et al[5] speculated that the molecular simulation and immune cross-reaction between HBsAg and myelin antigen of the CNS may potentially explain the primary pathophysiologic mechanisms underlying NMOSD with HBV infection. Molecular simulation of T cell infective factors has been suggested as a potential mechanism of demyelination of the CNS after HBV vaccination.\n\nAt treatment initiation, the patient was only an HBV carrier with normal liver functions; therefore, antiviral and hepatoprotective medications were not administered; however, continuous glucocorticoid administration for 2 months led to liver damage. To address this, the steroid dose was gradually tapered while administering antiviral and hepatoprotective medications. After 1 month, liver function gradually returned to normal and HBV replication was controlled. An increased risk of hepatitis flare is observed in patients with CHB undergoing glucocorticoid therapy even if administered as short-term and high dose; therefore, researchers suggest the effectiveness of prophylactic antiviral therapy in patients receiving high-dose glucocorticoids regardless of duration.[11] Curras-Martin et al[12] reported a 46-year-old African-American man with a history of untreated HBV infection, who presented with blurred vision; he was diagnosed with ON with chronic or acute HB infection, twice. The first treatment was a combination of hormonal and antiviral therapy. The second treatment was considered to be viral hepatitis flare; therefore, steroids were avoided and only antiviral medication was administered. In both treatments, the patient's visual acuity improved after a few days; furthermore, in the second treatment, after 5 days of treatment with antiviral drugs, a rapid recovery of the liver function and gradual reduction of symptoms of systemic discomfort were observed. Liu et al.[5] retrospectively analyzed 10 patients with NMOSD with CHB infection who were seropositive for AQP4-Ab; they found an increased risk of liver damage in these patients after high-dose glucocorticoid therapy. Therefore, they suggested that patients with NMOSD should be aware of the possibility of HBV infection once liver damage occurs, which would necessitate adjustments to treatment. Teng et al[13] reported a case of hepatitis B-related optic neuritis that was treated with therapeutic plasma exchange. This finding demonstrated the correlation between hepatitis B-related optic neuritis and immunopathogenesis, which presents an alternative treatment for hormone-invalid and disabled ON.\n\nHowever, a standardized guideline of treatment of patients with HBV and NMOSD remains uncreated. Furthermore, conflicts regarding the medication remain for patients with hepatitis B complicated with NMOSD. These conflicts are attributed to the liver damage caused by high-dose glucocorticoids in patients with HBV despite it being the routine treatment of patients with NMOSD. This case report suggests the importance of glucocorticoid therapy with antiviral drugs in the management of asymptomatic HBV carriers.\n\nAuthor contributions\n\nJiaying Lei presented the idea, learned about optic neuritis, hepatitis B virus, and immune complex disease, she also wrote the manuscript. Hong Wang reviewed and corrected the manuscript.\n\nConceptualization: Hong Wang.\n\nFormal analysis: Jiaying Lei.\n\nInvestigation: Jiaying Lei.\n\nSupervision: Jiaying Lei.\n\nWriting – original draft: Jiaying Lei.\n\nWriting – review & editing: Hong Wang.\n\nAbbreviations: AQP4-Ab = seropositive anti-aquaporin-4 antibody, CHB = chronic hepatitis B, CNS = central nervous system, HBV = hepatitis B virus, NMO = neuromyelitis optica, NMOSD = neuromyelitis optica spectrum disorder, ON = optic neuritis.\n\nHow to cite this article: Lei J, Wang H. Neuromyelitis optica spectrum disorder with active replication of hepatitis B virus and seropositive anti-aquaporin-4 antibody: a case report. Medicine. 2021;100:38(e27207).\n\nEthics approval and consent to participate were not applicable to this study.\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nThe authors have no funding and conflicts of interest to disclose.\n\nData sharing not applicable to this article as no datasets were generated or analyzed during the current study.\n==== Refs\nReferences\n\n[1] Wingerchuk DM Lennon VA Lucchinetti CF Pittock SJ Weinshenker BG . The spectrum of neuromyelitis optica. Lancet Neurol 2007;6 :805–15.17706564\n[2] Wingerchuk DM Banwell B Bennett JL . International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 2015;85 :177–89.26092914\n[3] Hepatitis B vaccines. WHO position paper. Wkly Epidemiol Rec 2009;84 :405–19.19817017\n[4] Cacoub P Terrier B . Hepatitis B-related autoimmune manifestations. Rheum Dis Clin North Am 2009;35 :125–37.19481001\n[5] Liu J Xu L Chen ZL Li M Yi H Peng FH . Comprehensive analysis of patients with neuromyelitis optica spectrum disorder (NMOSD) combined with chronic hepatitis B (CHB) infection and seropositive for anti-aquaporin-4 antibody. Bosn J Basic Med Sci 2018;18 :35–42.29144890\n[6] Lazibat I Brinar V . Acute disseminated encephalomyelitis associated with hepatitis B virus reinfection—consequence or coincidence? Clin Neurol Neurosurg 2013;115 : Suppl 1 : S35–7.24321152\n[7] Zhao S Chen T Peng C . The putative acceleration of optic neuritis when combined with chronic hepatitis B. J Neurol Sci 2015;358 :207–12.26363926\n[8] Jiang ZC Liu ZH Li HY Wei SH . Optic neuritis combined with hepatitis B and neurosyphilis. Chin Med J (Engl) 2013;126 :3580–1.24034115\n[9] Geier DA Geier MR Geier MR . A case-control study of serious autoimmune adverse events following hepatitis B immunization. Autoimmunity 2005;38 :295–301.16206512\n[10] Toosy AT Mason DF Miller DH . Optic neuritis. Lancet Neurol 2014;13 :83–99.24331795\n[11] Wong GL Yuen BW Chan HL . Impact of dose and duration of corticosteroid on the risk of hepatitis flare in patients with chronic hepatitis B. Liver Int 2019;39 :271–9.30179316\n[12] Curras-Martin D Campbell N Haroon A Hossain MA Asif A . Recurrent optic neuritis as the only manifestation of chronic hepatitis B virus flare: a case report. BioMed Central 2018;1 :12.\n[13] Teng D Tan S Yang M . A case report of hepatitis B related optic neuritis treated with plasma exchange. Medicine 2019;98 :e15432.31045806\n\n",
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"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D051401:Aquaporin 4; D001323:Autoantibodies; D003937:Diagnosis, Differential; D005260:Female; D019694:Hepatitis B, Chronic; D006801:Humans; D007262:Infusions, Intravenous; D008775:Methylprednisolone; D009471:Neuromyelitis Optica",
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"title": "Neuromyelitis optica spectrum disorder with active replication of hepatitis B virus and seropositive anti-aquaporin-4 antibody: A case report.",
"title_normalized": "neuromyelitis optica spectrum disorder with active replication of hepatitis b virus and seropositive anti aquaporin 4 antibody a case report"
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"abstract": "Scedosporium species are fungal opportunistic pathogens frequently seen in chronic lung diseases such as in cystic fibrosis (CF). They can cause a wide spectrum of diseases mainly in immunodeficient patients. Invasive, disseminated infections with poor prognosis have been described after lung transplantation. We present a CF-patient with disseminated Scedosporium apiospermum infection after lung transplantation. The patient had skin, surgical wound, spinal cord, and brain involvements. She recovered fully after prolonged course of voriconazole treatment.",
"affiliations": "Department of Pulmonary Medicine, Heart and Lung Center, University of Helsinki and Helsinki University Hospital, Finland.;Department of Pulmonary Medicine, Heart and Lung Center, University of Helsinki and Helsinki University Hospital, Finland.;Department of Radiology, University of Helsinki and Helsinki University Hospital, Finland.;Department of Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, Finland.",
"authors": "Paajanen|Juuso|J|;Halme|Maija|M|;Palomäki|Maarit|M|;Anttila|Veli-Jukka|VJ|",
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"doi": "10.1016/j.mmcr.2019.03.003",
"fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(19)30022-310.1016/j.mmcr.2019.03.003Case ReportDisseminated Scedosporium apiospermum central nervous system infection after lung transplantation: A case report with successful recovery Paajanen Juuso juuso.paajanen@hus.fia∗Halme Maija aPalomäki Maarit bAnttila Veli-Jukka ᶜa Department of Pulmonary Medicine, Heart and Lung Center, University of Helsinki and Helsinki University Hospital, Finlandb Department of Radiology, University of Helsinki and Helsinki University Hospital, Finlandc Department of Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, Finland∗ Corresponding author. Department of Pulmonary Medicine, Heart and Lung Center, Helsinki University Hospital, Haartmaninkatu 4, 00029, Helsinki, Finland. juuso.paajanen@hus.fi16 3 2019 6 2019 16 3 2019 24 37 40 19 2 2019 5 3 2019 12 3 2019 © 2019 The Authors2019This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Scedosporium species are fungal opportunistic pathogens frequently seen in chronic lung diseases such as in cystic fibrosis (CF). They can cause a wide spectrum of diseases mainly in immunodeficient patients. Invasive, disseminated infections with poor prognosis have been described after lung transplantation. We present a CF-patient with disseminated Scedosporium apiospermum infection after lung transplantation. The patient had skin, surgical wound, spinal cord, and brain involvements. She recovered fully after prolonged course of voriconazole treatment.\n\nKeywords\nCystic fibrosisLung transplantationScedosporium apiospermumDisseminated CNS infectionVoriconazole\n==== Body\n1 Introduction\nCystic fibrosis (CF) is an inherited disease due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene [1]. Defective CFTR protein causes abnormal ion transport across the apical surfaces of epithelia in multiple organ systems. One consequence of abnormal ion transport in the lung is dehydration and thickening of airway secretions. The disease is characterized by recurrent bacterial and fungal infections and progressive respiratory failure. Lung transplantation (LT) is a therapeutic option for patients with end-stage lung disease.\n\nScedosporium is a saprophytic fungus isolated from soil, polluted water and plant residues worldwide. The genus Scedosporium consists of three medically important species: Scedosporium apiospermum (S.apiospermum), Scedosperium boydii (formerly Pseudoallescheria boydii) and Scedosporium aurantiacum [2]. Scedosporium spp. is the second most prevalent opportunistic fungus after Aspergillus spp. found to colonize chronic lung diseases such as CF [3]. The role and pathogenicity of S. apiospermum in lung diseases is controversial, but either local or disseminated infections are described in immunodeficient patients [4]. Especially after organ transplant, the colonization may develop into invasive, disseminated infection with central nervous system (CNS) involvement leading to dismal outcome [5]. Thus, Scedosporium colonization prior to LT is considered as a contra-indication in some transplantation centers [3]. Unlike Aspergillus, Scedosporium spp. is inherently resistant to many antifungals such as amphotericin B and echinocandins. Voriconazole used alone or in combination is reported to be the most active agent against Scedosporium [6]. Also, a reduction in immunosuppression or surgical drainage should be considered when suitable.\n\nHere, we present the first successfully treated disseminated S. apiospermum CNS infection after a lung transplantation.\n\n2 Case\nAn 18-year-old woman with CF was considered as a candidate for bilateral LT. Her respiratory failure had advanced, so that a supplemental oxygen therapy and night-time non-invasive ventilation were initiated. Bilateral pneumothoraxes with subcutaneous emphysema were detected on an elective control in March 2015. At that time, her FEV1 had decreased to 1.35 L (34% of predicted). She was referred to the respiratory department where her ventilatory failure acutely progressed. After a short resuscitation she was connected to ventilator and subsequently to extracorporeal membrane oxygenation (ECMO). She was listed for a Scandinavian emergency LT. S. apiospermum was detected in fungal culture of the tracheal aspirate with susceptibility testing showing minimal inhibitory concentrations of: voriconazole 0.125mg/L, itraconazole 6mg/L, posaconazole 6mg/L and amphotericin B 12mg/L. After five days on ECMO, she underwent a bilateral LT (defined as day 0). Pseudomonas aeruginosa and S. apiospermum colonizations were detected in the extracted native lungs. The peri-operative course was complicated by pseudomonas septicemia which was treated with intravenous (IV) tazobactam/piperacillin, tobramycin, and oral ciprofloxacin with a good clinical outcome. IV caspofungin was started postoperatively for antifungal prophylaxis with a single loading dose of 70mg, followed by 50mg daily for 17 days.\n\nHer baseline immunosuppression regimen consisted of tacrolimus, mycophenolate mofetil, and prednisolone. Prophylactic valganciclovir, azithromycin, trimethoprim/sulfamethoxazole and nebulized colistin and amphotericin B were initiated.\n\nThe first postoperative bronchoscopy at day 30 postoperatively revealed normal anastomotic healing process and otherwise unremarkable endobronchial findings. Bacterial and fungal cultures of bronchoalveolar lavage (BAL) were negative. Histological acute minimal rejection (A1B1) was detected in transbronchial lung biopsy (TBB). The patient was not treated with additional corticosteroids considering her good clinical condition and previous infections and colonizations.\n\nAt the second control visit 60 days postoperatively, she presented with upper back pain that radiated to the left leg. Symmetric, painful, palpable, and slightly pigmented nodules with small ulcerations had appeared on both legs (Fig. 1). The surgical wound had started to secrete. She had no fever. Her C-reactive protein was 31 mg/l, erythrocyte sedimentation rate 58 mm/h and leukocyte level 9.8 E9/l. Systemic fungal infection was suspected, and IV voriconazole was initiated at 300mg twice a day for 24 hours and at 200mg twice a day thereafter. At that time, her immunosuppression consisted of prednisolone, tacrolimus and mycophenolate mofetil. The latter was discontinued due to suspicion of systemic infection. Control bronchoscopy with TBB revealed no histological signs of rejection. In the following days, she developed neurological symptoms: headache, nausea, vertigo and her right side of the mouth was slightly dropped. Also, her left leg was numb, and the muscular strength was decreased. Computerized tomography showed no infiltrates in the lung parenchyma but there were small subcutaneous collections under the sternotomy. Brain magnetic resonance imaging (MRI) revealed multiple ring-enhancing lesions with perifocal oedema compatible with abscesses (Fig. 2a and b). Spine MRI showed oedema and multiple abscesses as well in cervical and thoracic spinal cord (Fig. 2c). Subsequently, the histopathological findings from initial skin nodule revealed septal panniculitis with fungal culture and nucleic acid test positive for S. apiospermum. S. apiospermum was also cultured from BAL fluid and the surgical wound secretion. Multiple blood cultures were taken with no signs of fungemia. We refrained from CNS biopsy due to consisted cultural findings matching with radiological appearance.Fig. 1 A photograph of the patient's lower extremity: slightly pigmented nodules sized one to two cm in diameter with small ulcerations is shown. The histological finding was septal panniculitis with fungal culture and nucleic acid test positive for S. apiospermum.\n\nFig. 1Fig. 2 a–d: MRI T2 weighted imaging revealed multiple lesions with perifocal oedema (arrows) (a). Most of the lesions had ring-enhancement with gadolinium compatible with abscess (arrows). There were also nodular enhancing lesions (arrowheads) (b). Spinal cord MRI shows multiple ring-enhancing lesions (arrows) (c). The latest control image shows only small residual T2-lesions (arrows) that had remained stable over 8 months after completion of 35 months of voriconazole treatment (d).\n\nFig. 2\n\nNeurological symptoms vanished gradually, and the patient was discharged from the hospital after three weeks of treatment. Intravenous voriconazole was continued at home for ten months. Miltefosine was combined to the therapy one month after initiation of voriconazole but it was discontinued after two days due to nausea, interactions with tacrolimus and on the other hand good clinical response to voriconazole. MRIs and clinical status were controlled every one to four months. After ten months of intravenous administration voriconazole was switched to oral tablets with a dose of 300mg twice daily. Therapeutic serum levels were confirmed by repeated measurements (target therapeutic limits 2–5.5mg/l). At a control visit in June 2018 three years after LT and 35 months of treatment, the voriconazole treatment was terminated. After the discontinuation of antifungal treatment, the patient has visited our clinic for two controls with no signs of fungal re-infection. The last visit was in January 2019, nearly four years after the LT and eight months after the termination of voriconazole. She was symptomless with preserved lung allograft function: Her FEV1 was 2.7 L (77% predicted). Brain MRI revealed only few residual lesions (Fig. 2d), which had been stable and inactive for months.\n\n3 Discussion\nTo the best of our knowledge, the presented case is the first published S. apiospermum disseminated infection with brain and spinal cord abscesses after LT leading to a full recovery Previous reports have shown a good response to antifungals with or without surgical drainage in patients with S. apiospermum local spondylodiscitis, osteomyelitis, septic arthritis, or lung infections in LT recipients [7,8]. However, the case reports after LT on both disseminated and CNS involvement have been disappointing [5,[9], [10], [11], [12], [13], [14]]. Previously reported disseminated S. apiospermum infections after LT are reviewed in Table 1.Table 1 Clinical characteristics of previously reported patients of disseminated Scedosporium apiospermum infections after lung transplantation.\n\nTable 1Age, years\tSex\tAntifungal prophylaxis\tTime to diagnosis after LT\tInfection sites\tAntifungal therapy\tOutcome (Survival time after diagnosis)\tReference\t\n43\tM\tITC\t18 months\tPulmonary, mediastinum, joint, vertebra\tITC, CAS, AMB\tDeath (13 months)\t[13]\t\n57\tF\tITC\t14 months\tPulmonary, brain, breast implant, skin\tVRC, TRB, POS\tDeath (shortly after diagnosis)\t[13]\t\n19\tF\tVRC\t1 month\tEye, skin, mediastinum, chest wall, pulmonary, sinus, joint, vertebra\tVRC, CAS, TRB, POS, AMB, PEN\tDeath (14 months)\t[13]\t\n20\tF\tNone\t11 months\tKidneys, eye, pulmonary, vertebra\tNA\tDeath (5 months)\t[3]\t\n37\tF\tNone\t2 months\tPulmonary, brain, heart, eye\tITC, AMB\tDeath (1 month)\t[3]\t\n64\tF\tNone\t3 years\tPulmonary, septicemia, heart\tAMB, ITC\tDeath (18 days)\t[11]\t\n37\tF\tVRC\t2 months\tSkin, brain, septicemia, heart\tVRC, CAS, TRB\tDeath (6 months)\t[14]\t\n24\tF\tNone\t7.5 months\tHeart, spleen, kidneys, brain\tITC, MIC\tDeath (1 month)\t[14]\t\n30\tM\tNone\t2 weeks\tPulmonary, heart\tAMB, MIC\tDeath (7 days)\t[10]\t\n26\tF\tITC, AMB\t3 weeks\tSkin, eye, brain\tVRC, MIC\tDeath (6 months)\t[9]\t\n33\tF\tAMB, ITC, CAS\t3 months\tJoint, pulmonary\tVRC\tAlive\t[8]\t\n27\tM\tNone\t6 weeks\tBrain, pulmonary\tAMB\tDeath (shortly after diagnosis)\t[8]\t\n27\tM\tVRC, AMB\t1 month\tPulmonary, heart, septic thrombus\tVRC, TRB, CAS, POS, ANF, MTF\tDeath (7 months)\t[12]\t\nLT, lung transplantation; M, male; ITC, itraconazole; CAS, caspofungin; AMB, amphotericin B; F, female; VRC, voriconazole; TRB, terbinafine; POS, posaconazole; PEN, pentamidine; NA, Not available; MIC, miconazole; ANF, anidulafungin; MTF, miltefosine.\n\n\n\nCareful balance in immunosuppression is needed to successfully manage patients after LT to prevent and treat both the rejection of the lung allograft and bacterial, viral, and fungal infections. Although less frequent than bacterial and viral infections, invasive fungal infection is associated with higher morbidity and mortality after LT [15]. The depth of immunosuppression is associated with both increased incidence and worse outcome of invasive fungal infections [5,15].\n\nThere is no widely accepted optimal recommendation for antifungal prophylaxis after LT [15]. The standard regimen used in our institute is trimethoprim/sulfamethoxazole for Pneumocystis jirovecii. In selected high-risk patients for Aspergillus infection, we have used nebulized amphotericin B and short-term systemic caspofungin prophylaxis with low invasive Aspergillus infection incidence [16]. However, this regimen has no effect in S. apiospermum. Several positive reports with either itraconazole, posaconazole or voriconazole prophylaxis have been reported in S. apiospermum colonization, even if the optimal dose or length of treatment are not well known [3,13]. In contrast, there are also reports with fatal invasive Scedosporium infections in spite of long-term voriconazole prophylaxis [13,14]. In our case, we didn't use any prophylactic antifungal targeted to Scedosporium before LT. After LT, the patient received inhaled amphotericin B among other prophylactic agents without measurable prophylactic effects. The use of prophylactic triazole should be considered for the first months after LT or in the event of temporary additional immunosuppression in high-risk patients for Scedosporium infections.\n\nThe exact dosage, duration or combination of antimycotic therapies in Scedosporium infections are not well known due to the lack of prospective studies. A successful therapeutic response in 57% of patients and a median survival time of 133 days were reported in a retrospective study of 107 patients with Scedosporium infections treated with voriconazole [17]. The median duration of the treatment was 103 days (range 1–802 days), while 21% of patients received treatment for a year or more. The initial treatment was similar to our case: intravenous 6mg/kg twice a day for one day, followed by 4mg/kg twice a day after switching to oral therapy. In another report of an LT patient, an initial response was seen in a disseminated S. apiospermum infection with ocular, skin and cerebrospinal fluid involvement [9]. However, a fatal relapse was seen only two days after the discontinuation of a six-month treatment period. In our case, we think that the immediate initiation of voriconazole was important for the good outcome. We used prolonged intravenous voriconazole regimen for ten months. The main reasons for that were slow recovery seen in MRI images, lack of side effects, and fear of inadequate therapeutic levels due to CF-related malabsorption. Mild photosensitivity reaction was the only adverse event reported by the patient. In hindsight, an earlier switch to oral treatment with voriconazole and repeated concentration controls could have been possible. We added miltefosine as combination therapy based on previously published in vitro susceptibility testing, but the treatment was terminated due to unwanted side effects and good clinical response to voriconazole [18].\n\nIn conclusion, we reported a lung transplant patient with disseminated S. apiospermum infection with CNS manifestation leading to a good and rapid response to voriconazole. Considering the preceding evidence in the literature, we think that prior colonization of Scedosporium should not be an absolute contraindication for a lung transplant. However, in the absence of prospective clinical trials, a careful case-by-case evaluation is needed to prevent and treat disseminated diseases. Especially the role of prophylactic antifungal therapy, preoperative clearance of potential reservoirs (e.g. sinuses), use of surgical drainage, and reduced immunotherapy will be needed to consider when treating LT patients with Scedosporium spp. colonization and infection.\n\nConflict of interest\nThere are none.\n\nAcknowledgements\nWe thank our patient for her agreement on this case report. This research did not receive any specific grand from funding agencies in the public, commercial, or not-for-profit sectors.\n==== Refs\nReferences\n1 Elborn J.S. Cystic fibrosis Lancet 388 2016 2519 2531 27140670 \n2 Lackner M. Hagen F. Meis J.F. Vu D. Robert V. Fritz J. Moussa T.A.A. De Hoog G.S. Susceptibility and diversity in the therapy-refractory genus Antimicrob. Agents Chemother. 58 2014 5877 5885 25070092 \n3 Parize P. Boussaud V. Poinsignon V. Sitterlé E. Botterel F. Lefeuvre S. Guillemain R. Dannaoui E. Billaud E.M. Clinical outcome of cystic fibrosis patients colonized by Scedosporium species following lung transplantation : a single-center 15-year experience Transpl. Infect. Dis. 19 2017 e12738 \n4 Cortez K.J. Roilides E. Quiroz-telles F. Meletiadis J. Antachopoulos C. Knudsen T. Buchanan W. Milanovich J. Sutton D.A. Fothergill A. Rinaldi M.G. Shea Y.R. Zaoutis T. Kottilil S. Walsh T.J. Infections caused by Scedosporium spp Clin. Microbiol. Rev. 21 2008 157 197 18202441 \n5 Husain S. Mun P. Forrest G. Alexander B.D. Somani J. Brennan K. Wagener M.M. Singh N. Maran G. Infections due to Scedosporium apiospermum and Scedosporium prolificans in transplant Recipients : clinical characteristics and impact of antifungal agent therapy on outcome Clin. Infect. Dis. 40 2005 89 99 15614697 \n6 Johnson E.M. Szekely A. Warnock D.W. In-vitro activity of voriconazole, itraconazole and amphotericin B against filamentous fungi J. Antimicrob. Chemother. 42 1998 741 745 10052897 \n7 Malouf M. Glanville A. Pulmonary scedosporium infection following lung transplantation Transpl. Infect. Dis. 3 2001 189 194 11844150 \n8 Abela I.A. Murer C. Schuurmans M.M. Schmitt J.W. Muller F. Imkamp F. Mueller N.J. Benden C. A cluster of scedosporiosis in lung transplant candidates and recipients : the Zurich experience and review of the literature Transpl. Infect. Dis. 2018 1 7 \n9 Symoens F. Knoop C. Schrooyen M. Denis O. Disseminated Scedosporium apiospermum infection in a cystic fibrosis patient After double-lung transplantation J. Heart Lung Transplant. 25 2006 603 607 16678041 \n10 Castiglioni B K.S. Sutton D.A. Rinaldi G.M. Fung J. Pseudallescheria boydii ( anamorph Scedosporium apiospermum ) infection in solid organ transplant recipients in a tertiary medical center and review of the literature Medicine (Baltim.) 81 2002 333 348 \n11 Raj R. Frost A.E. Scedosporium apiospermum fungemia in a lung transplant recipient* Chest 121 2002 1714 1716 12006471 \n12 Balandin B. Aguilar M. Sánchez I. Monzón A. Rivera I. Salas C. Valdivia M. Alcántara S. Pérez A. Ussetti P. Scedosporium apiospermum and S . prolificans mixed disseminated infection in a lung transplant recipient : an unusual case of long-term survival with combined systemic and local antifungal therapy in intensive care unit Med. Mycol. Case Rep. 11 2016 53 56 27222774 \n13 Sahi H. Avery R.K. Minai O.A. Hall G. Mehta A.C. Raina P. Budev M. Scedosporium apiospermum ( Pseudoallescheria boydii ) infection in lung transplant recipients Transplant. Infect. 26 2007 350 356 \n14 Morio F. Horeau-langlard D. Talarmin J. Haloun A. Treilhaud M. Despins P. Nourry L. Danner-boucher I. Pattier S. Bouchara J. Le Pape P. Miegeville M. Disseminated Scedosporium/Pseudallescheria infection after double-lung transplantation in patients with cystic fibrosis J. Clin. Microbiol. 48 2010 1978 1982 20220160 \n15 Cassie R.R.R. Kennedy C. Fungal infections after lung transplantation Clin. Chest Med. 38 2017 511 520 28797492 \n16 Eriksson M. Lemström K. Martelius T. Harjula A. Sipponen J. Halme M. Piilonen A. Salmenkivi K. Anttila V.J. Hämmäinen P. Control of early Aspergillus mortality after lung Transplantation : outcome and risk factors Transplant. Proc. 42 2010 4459 4464 21168718 \n17 Troke P. Aguirrebengoa K. Arteaga C. Ellis D. Heath C.H. Lutsar I. Nguyen Q. Slavin M. Chen S.C.A. Treatment of Scedosporiosis with Voriconazole : clinical experience with 107 patients 52 2008 1743 1750 \n18 Compain F D.E. Botterel F. Sitterle E. Paugam A. Bougnoux M.E. In vitro activity of miltefosine in combination with voriconazole or amphotericin B against clinical isolates of Scedosporium spp J. Med. Microbiol. 64 2015 309 311 25596124\n\n",
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"issue": "24()",
"journal": "Medical mycology case reports",
"keywords": "Cystic fibrosis; Disseminated CNS infection; Lung transplantation; Scedosporium apiospermum; Voriconazole",
"medline_ta": "Med Mycol Case Rep",
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"pages": "37-40",
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"pmid": "30956943",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports",
"references": "10052897;11844150;12006471;12352630;15614697;16678041;17403476;18202441;18212110;20220160;21168718;25070092;25596124;27140670;27222774;28618155;28797492;29044831",
"title": "Disseminated Scedosporium apiospermum central nervous system infection after lung transplantation: A case report with successful recovery.",
"title_normalized": "disseminated scedosporium apiospermum central nervous system infection after lung transplantation a case report with successful recovery"
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"abstract": "Background Pregnant women with Marfan syndrome (MFS) are known to be at increased risk of aortic dissection; however, cases of aortic rupture are extremely rare. There is lack of consensus on the exact site and size of aortic diameter measurement that increases this risk, and whether this applies to both Type A and Type B dissections. Case A 23-year-old G2P1001 with known Marfan syndrome who underwent an uncomplicated antepartum and intrapartum course. She experienced persistent backache 10 days postpartum that led to the diagnosis of Stanford Type B dissection. The patient was hospitalized for close observation. Dissection progressed to aortic rupture within 24 hours that required emergent thoracic endovascular aortic repair. She had an uncomplicated postoperative course. Conclusion Our report demonstrates rupture of a known aortic dissection within a very short time in the postpartum period. The case highlights the importance of patient education and close surveillance especially in the postpartum period. It also brings home the value of imaging of the whole aorta rather than focusing on the ascending alone. Multidisciplinary care and timely diagnosis and intervention likely led to the favorable outcome in our case.",
"affiliations": "Department of Obstetrics and Gynecology, Irvine Medical Center, University of California, Orange, California.;Department of Obstetrics and Gynecology, Irvine Medical Center, University of California, Orange, California.;Department of Obstetrics and Gynecology, Irvine Medical Center, University of California, Orange, California.",
"authors": "Patberg|Elizabeth|E|0000-0003-3843-6179;Duffy|Jennifer|J|;Hameed|Afshan B|AB|",
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"fulltext": "\n==== Front\nAJP RepAJP Rep10.1055/s-00000169AJP Reports2157-69982157-7005Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA. 10.1055/s-0039-1692712190031Case ReportRupture of a Type B Aortic Dissection in a Postpartum Patient with Marfan Syndrome http://orcid.org/0000-0003-3843-6179Patberg Elizabeth MD1Duffy Jennifer MD1Hameed Afshan B. MD11 Department of Obstetrics and Gynecology, Irvine Medical Center, University of California, Orange, CaliforniaAddress for correspondence Elizabeth Patberg, MD Department of Obstetrics and Gynecology, University of California, Irvine333 City Blvd. West, Ste 1400, Orange, CA 92868epatberg@uci.edu7 2019 20 8 2019 9 3 e256 e261 01 5 2019 14 5 2019 This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License, which permits unrestricted reproduction and distribution, for non-commercial purposes only; and use and reproduction, but not distribution, of adapted material for non-commercial purposes only, provided the original work is properly cited.\nBackground\n Pregnant women with Marfan syndrome (MFS) are known to be at increased risk of aortic dissection; however, cases of aortic rupture are extremely rare. There is lack of consensus on the exact site and size of aortic diameter measurement that increases this risk, and whether this applies to both Type A and Type B dissections.\n\n\n\nCase\n A 23-year-old G2P1001 with known Marfan syndrome who underwent an uncomplicated antepartum and intrapartum course. She experienced persistent backache 10 days postpartum that led to the diagnosis of Stanford Type B dissection. The patient was hospitalized for close observation. Dissection progressed to aortic rupture within 24 hours that required emergent thoracic endovascular aortic repair. She had an uncomplicated postoperative course.\n\n\n\nConclusion\n Our report demonstrates rupture of a known aortic dissection within a very short time in the postpartum period. The case highlights the importance of patient education and close surveillance especially in the postpartum period. It also brings home the value of imaging of the whole aorta rather than focusing on the ascending alone. Multidisciplinary care and timely diagnosis and intervention likely led to the favorable outcome in our case.\n\n\nKeywords\nMarfan syndromepregnancyaortic ruptureType B aortic dissection\n==== Body\nMarfan syndrome (MFS) is an autosomal dominant condition affecting 1:3000 to 1:5000 individuals due to a mutation in the gene encoding the connective tissue protein fibrillin-1 (FBN-1).\n1\nAffected individuals have a wide variety of phenotypic manifestations involving skeletal, renal, ocular, skin, and cardiovascular organ systems. Aortic root disease including aneurysm, regurgitation, and dissection accounts for the majority of the cardiovascular morbidity and mortality in MFS. This morbidity likely stems from the loss of elastic lamellae and smooth muscle cells in the medial layer of the aorta, leaving it more vulnerable to shearing forces and dynamic changes in circulatory pressures.\n2\n3\nThe physiologic changes of pregnancy that make pregnant women with MFS more vulnerable to complications of aortic disease are primarily related to intimal shear forces due to increase in cardiac output and hormonally mediated connective tissue alterations that may cause weakness of the arterial wall.\n4\n5\nHemodynamic changes are more pronounced in the third trimester and postpartum period which may explain the increased propensity of aortic complications during this time frame.\n\n\n\nThe majority of the literature regarding pregnancy-related aortic dissection in MFS patients is limited to case studies, case series, or retrospective reviews, and therefore, the precise risk of aortic dissection in pregnancy remains unclear. Much of the data originates from studies in which the diagnosis of MFS was unknown during the index pregnancy. A literature review that included 1,142 pregnant patients with MFS demonstrated that the rate of cardiovascular complications in was 2% to 6%,\n6\nwhich may be an overestimate due to selection bias. Investigators have attempted to stratify risk of dissection in pregnancy based on aortic root diameter. Risk of dissection has been reported to be <1% if aortic root is <40 mm\n7\n8\nand as high as 10% if >40 mm\n9\n; however, evidence to support the latter claim is lacking.\n10\n11\nNevertheless, the 2010 American College of Cardiology Foundation (ACCF/AHA) thoracic aortic disease guidelines recommend against pregnancy in women with MFS and an aortic root >40 mm, or for prophylactic repair in the event that they would like to become pregnant.\n12\n\n\n\nControversy exists regarding the aortic root diameter at which the risk of dissection and other cardiac complications becomes clinically significant. Based on prospective studies in which women were followed with serial aortic root measurements and were under the care of a cardiologist/multidisciplinary team during pregnancy, the risk of aortic complications appears to be low, including when the aortic root is >40 mm but less than 45 mm.\n7\n11\n13\n14\n15\n16\nConsistent with these findings, the 2014 European Society of Cardiology (ESC) guidelines on diagnosis and treatment of aortic disease\n17\nand the 2014 Canadian Cardiovascular Society position statement on the management of thoracic aortic disease,\n18\nas well as the ESC guidelines for the management of cardiovascular diseases during pregnancy,\n19\nrecommend against pregnancy when the aortic root is >45 mm, or 41 to 45 mm in cases a rapidly enlarging aortic root or family history of dissection/sudden death.\n\n\nWe describe a case of an adverse pregnancy-related outcome in a woman with MFS whose aortic root was <45 mm at the sinus of Valsalva and <40 mm at the sinotubular junction, despite preconception planning, early establishment of prenatal care, and close monitoring with a multidisciplinary specialty team in a quaternary care facility.\n\nCase\n\nThe patient is a 23-year-old G2P1001 who established prenatal care at our institution at 13 weeks of pregnancy. Her past medical history was significant for MFS diagnosed at age 12 years based on Revised Ghent Nosology.\n20\nThere was no family history of MFS, cardiac disease, or sudden death. She had a prior uncomplicated, term vacuum-assisted vaginal delivery approximately 2 years ago at our institution. The aortic root was stable throughout that pregnancy and postpartum period at 3.9 cm. Postnatally, an FBN1 mutation was confirmed in both the patient and her newborn.\n\n\nOne month prior to conception in the currently described pregnancy, an echocardiogram at an outside hospital demonstrated an aortic root diameter of 42 mm. Computed tomography (CT) angiogram of the chest confirmed this measurement and there were no ascending or descending aortic aneurysms or dissections noted. The abdominal aorta was not imaged. Repeat echocardiogram at our institution was performed at 17 weeks EGA that revealed aortic root of 42 mm at the sinus of Valsalva and 31 mm at the sinotubular junction. She was counseled on the risks of MFS in pregnancy and desired to continue the pregnancy. She was started on metoprolol 12.5 mg twice daily at 16 weeks EGA and continued at this dose throughout her pregnancy. Her blood pressure remained within normal limits throughout pregnancy with systolic pressures 90 to 120 mm Hg and diastolics of 50 to 80 mm Hg. A repeat echocardiogram was performed at 28 weeks EGA demonstrating an aortic root measurement of 41.8 mm at the sinus of Valsalva and 37.6 at the sinotubular junction. The remainder of her prenatal course was unremarkable. At 37 weeks 1 day EGA she underwent an uncomplicated vacuum-assisted vaginal delivery of a 3,140 g male infant with 1- and 5-minute APGAR scores of 8 and 9, respectively.\n\nThe patient was discharged to home 2 days after an uncomplicated postpartum hospital stay. On postpartum day 5 she presented to an outside hospital emergency department with back pain. A noncontrast CT was unremarkable and she was discharged to home with treatment for a urinary tract infection. On postpartum day 10, she represented to an outside emergency department with severe mid-to-upper back pain, worse with deep inspiration, and shortness of breath. Vital signs were all within normal limits. A CT angiogram revealed a Stanford Type B aortic dissection. She was transferred to our facility for higher level of care. On arrival she continued to be hemodynamically stable with systolic blood pressures ranging from 100 to 120 mm Hg. Vascular Surgery consultation was obtained and decision was made to continue with medical management at that time. Mean arterial pressure remained within goal without use of intravenous nicardipine. The patient was transferred to the surgical intensive care unit for continued observation and pain control with intravenous narcotics.\n\n\nApproximately 12 hours after admission she developed excruciating back and chest pain radiating to her left arm and left side of her neck, which was no longer responsive to pain medications. At this time, she was afebrile with blood pressure ranging from 100 to 139 mm Hg systolic, heart rate 59 to 88 beats per minute, respiratory rate of 12 breaths per minute and oxygen saturation of 90% to 97%. An emergent CT angiography of the chest, abdomen, and pelvis was performed which reconfirmed the type B dissection originating 1.5 cm from the left subclavian take off and extending to the proximal left common iliac artery (\nFigs. 1a\n,\nb\nand\n2\n). Importantly, a new hyperdense foci in the distal aortic arch suggestive of active contrast extravasation was detected (\nFigs. 3a\n,\nb\n). On concurrent echocardiogram the aortic root measured 41.6 mm at the sinus of Valsalva with flattening at the sinotubular junction (measuring 36.8 mm).\n\n\nFig. 1 \nCT angiography of chest—(a) sagittal and (b) coronal—demonstrating Stanford Type B aortic dissection originating in the distal aortic arch (arrows).\n\n\nFig. 2 \nCT angiography 3D reconstruction demonstrating dissection of distal aortic arch/proximal descending aorta (arrow) originating just distal to subclavian artery take-off.\n\n\nFig. 3 \nCT angiography—(a) axial and (b) coronal—images of region suspicious for contrast extravasation (arrows) along proximal descending aortic arch dissection.\n\n\nThe patient was taken emergently to the operating room. Intraoperatively, the type B dissection was noted to have expanded to the level of the subclavian orifice from a few hours prior on imaging and rupture of the dissection was confirmed. Two Bolton Relay thoracic stent grafts were used, the proximal one measuring 26 mm and 10 cm long, the distal one measuring 28 to 24 mm tapered measuring 20 cm long with 5 cm of overlap. The entire stented region started just distal to the takeoff of the left common carotid and extended to 2 cm above the takeoff of the celiac axis. The procedure was uncomplicated. The estimate blood loss was 100 mL and one unit of packed red blood cells was given.\n\nRepeat CT angiography of the whole aorta on postoperative day 2 showed patent stent extending to the true lumen of supraceliac proximal abdominal aorta with exclusion of distal aortic arch—proximal descending aorta aneurysm without evidence of perigraft contrast extravasation. Postoperative course was uncomplicated and she was discharged home on postoperative day 10 with follow-up with vascular surgery. She was continued on metoprolol. At her 6-week postpartum visit she was asymptomatic and was strongly counseled to avoid future pregnancy. She elected to undergo laparoscopic bilateral tubal ligation which was performed several months later without complications.\n\nDiscussion\n\nThis case highlights the ongoing controversy over how pregnant patients with MFS and an aortic root between 40 mm and 45 mm should be managed. Our patient was managed in accordance with the most recent consensus guidelines, including those published by the European Society of Cardiology and the Canadian Cardiology Society, which agree that pregnancy is not recommended if the aortic root is >45 mm (or >40 mm in the presence of rapidly enlarged dilation or family history, neither of which our patient had).\n17\n18\nOn the other hand, the 2010 American College of Cardiology guidelines recommend against pregnancy for MFS patients if the aortic root is >40 mm, or for prophylactic repair prior to conceiving.\n12\nLack of consensus on aortic root diameter and risk of dissection is confounded by the fact that standardization of aortic root measurements is lacking. Some experts advocate for aortic root measurement at the sinus of Valsalva, claiming that this is the segment that dilates first and is most prone to dissection in MFS.\n12\n21\nHowever, dilation of the root at the level of the sinotubular junction, or extending to the ascending aorta, is known to portend a poor prognosis and so these measurements should also be considered.\n22\nIn our case, the patient was felt to be lower risk because of stable measurements <45 mm at the sinus of Valsalva and <40 mm at the sinotubular junction.\n\n\n\nIn the primary literature on MFS in pregnancy, some authors describe measurements of the aortic root being taken at the sinus of Valsalva\n11\n13\nwhile others do not specify.\n8\nConsensus guidelines on management of thoracic aortic disease in MFS do not specify how or where the aortic root should be measured.\n12\n17\nFurthermore, studies that have reported echocardiographic measurements of aortic root at the Sinus of Valsalva for MFS in pregnancy also differ in convention of timing of measurement, with some taken during end-diastole\n16\nand others during mid-systole.\n11\nWhether to measure leading-edge to leading-edge, outer-edge to outer-edge, versus inner-edge to inner-edge differs between the pediatric and adult literature and varies depending on mode of imaging (CT vs. echo) and has changed over time.\n16\n17\n21\nThese discrepancies are important as they may cause variations of up to 4 mm, which could significantly change counseling. In our case, echocardiographic measurements were obtained during diastole measuring the widest portion of the right coronary to left coronary sinus from leading-edge to leading-edge in the parasternal long-axis view in accordance with 2015 American Society of Echocardiography guidelines.\n23\nWe advocate for multiple, standardized measurements along various segments of the aorta including at the sinus of Valsalva, the sinotubular junction, and the ascending aorta with consistency over time for better comparison and prognostication.\n\n\n\nThe lack of standardization and consensus regarding aortic root diameter and risk of dissection and other aortic complications underscores the importance of identifying all potential risk factors when counseling and managing pregnant women with MFS. For example, the rate of aortic root growth is an important consideration and has been shown to be a poor prognostic indicator.\n22\nWhile our patient did not exhibit growth at the sinus of Valsalva, she did exhibit some extension along the length of the root, consistent with effacement at the sinotubular junction (3.12 mm in the first trimester to 3.76 mm in the second trimester and postpartum). While these measurements remained <4 cm, it is known that extension of the aneurysmal dilation beyond the sinus is associated with worse outcomes.\n22\nThus, providers should be careful to measure multiple portions of the root and to pay attention to changes other than just at the sinus of Valsalva.\n\n\n\nIn an attempt to standardize aortic measurements, some experts factor in body surface area, such as the Aortic Size Index (ASI). Davies et al first described this measurement of relative aortic size (aortic root diameter [mm]/body surface area [m\n2\n]) in predicting rupture of thoracic aortic aneurysms in nonpregnant adults.\n24\nThe utility of ASI measurements was particularly evident in a retrospective review in a Japanese cohort which found a high rate of complications in pregnant women with aortic root <40 mm and it was hypothesized that this is secondary to small stature.\n25\nThe authors concluded that an ASI score rather than an absolute diameter size is important in determining risk and that an ASI of >25 mm/m\n2\nwas predictive of aortic complications in their population. Our patient's ASI in the first trimester was 21.5 mm/m\n2\n. Further research is needed to validate this novel measurement tool in pregnant patients with MFS.\n\n\n\nOur case highlights the fact that the postpartum period remains a high-risk period for women with MFS. In a literature review that identified 88 cases of aortic dissection complicating pregnancy in MFS patient, 26% of cases occurred postpartum.\n10\nMany of these cases occurred in women whose aortic root was <40 mm. Consistently, the literature suggests that the postpartum period is the second most frequent time for aortic complications to occur, after the third trimester.\n10\n26\n27\nED physicians should be alerted to the fact that the postpartum period remains a significantly elevated risk time period for MFS patients. In a large database study of MFS patients followed longitudinally, 7 aortic dissections occurred out of 227 pregnancies, 6 of which happened postpartum.\n28\nConsideration for close follow-up postpartum with repeat imaging should be given, even in cases where the aortic root is not dilated.\n\n\n\nAneurysms and dissections can occur anywhere along the aorta in pregnant MFS patients, as evidence by our case. Predicting Type B (distal) aortic dissections poses a particular dilemma. According to one large international registry database study, 36% of dissections in nonpregnant MFS patients are Type B.\n29\nBased on less robust data, this number is cited to be ∼33% in the MFS in pregnancy literature.\n10\n26\nBecause MFS is classically associated with Type A dissection, the focus has been on measuring the aortic root in predicting risk of complications; however, there is insufficient evidence to conclude whether or not aortic root dilation is also predictive of Type B dissection. In a literature review of 1,112 pregnancies in MFS patient from 2005 to 2015, Kim et al found no clear association between aortic diameter and type of dissection.\n10\nMinsart et al prospectively followed 21 pregnancies in women with MFS and reported two complications, both of which were Type B dissections in women with an aortic root <40 mm.\n16\nProviders should be alerted to the fact that a substantial minority of MFS pregnancy related complications will occur more distally along the aorta and, therefore, the entire aorta should be imaged prior to pregnancy or as early on as possible. Serial measurements of the descending and abdominal aorta are costly and there is no established cutoff at which a patient is at increased risk; however, this may be considered in patients who have aneurysmal dilation of distal portions of the aorta at baseline. Our patient did not exhibit descending arch aneurysm in her prepregnancy CT angiogram; however, the abdominal aorta was not imaged. Whole aorta screening imaging was not repeated given the lack of early dilation but perhaps would be warranted, at least early postpartum once radiation exposure no longer poses a risk to the fetus.\n\n\n\nReports of aortic rupture complicating a pregnancy in MFS are rare. In a recent literature review of all reported cases of MFS in pregnancy from 2005 to 2015 including 1,112 pregnancies, there were only five cases of aortic rupture/tamponade identified, 3 of which led to maternal deaths.\n10\nTypically, uncomplicated Type B dissections are managed medically, but pregnant MFS patients have different pathophysiology and risk factors that may require a different approach. The poor outcomes in medically managed Type B dissections in MFS patients has led some to argue for early endovascular repair.\n30\nThe timely diagnosis and repair likely accounted for the good outcome in our patient's case.\n\n\nConclusion\nWe described a case of aortic rupture following a Type B aortic dissection in a postpartum patient with MFS with aortic root (at the sinus of Valsalva) <4.5 cm. The timely diagnosis and prompt intervention by a multidisciplinary team led to a favorable outcome. Patient and health care provider education, close surveillance and frequent monitoring, preferably of the whole aorta, may be warranted given that the Type B dissections may not be visualized by the routine transthoracic echocardiographic assessment of the aortic root. Early surgical repair of Type B aortic dissection in postpartum MFS patients should be considered. There is a need to standardize how and where the aorta is measured in patients with MFS to assess risk of complications during pregnancy.\n\nAcknowledgments\nWe would like to thank Deniz Urgun, MD, with the Department of Radiology at the University of California, Irvine, for her assistance in interpreting and selecting the radiographic images for this manuscript.\n\nConflict of Interest/Disclosure Statement There were no sources of funding or financial support for this study. The authors report no conflicts of interest.\n==== Refs\nReferences\n1 Judge D P Dietz H C Marfan's syndrome Lancet 2005 366 (9501):1965 1976 16325700 \n2 Collins M J Dev V Strauss B H Fedak P W Butany J Variation in the histopathological features of patients with ascending aortic aneurysms: a study of 111 surgically excised cases J Clin Pathol 2008 61 04 519 523 17938162 \n3 Trotter S E Olsen E G Marfan's disease and Erdheim's cystic medionecrosis. A study of their pathology Eur Heart J 1991 12 01 83 87 \n4 Manalo-Estrella P Barker A E Histopathologic findings in human aortic media associated with pregnancy Arch Pathol 1967 83 04 336 341 4225694 \n5 Goland S Elkayam U Cardiovascular problems in pregnant women with Marfan syndrome Circulation 2009 119 04 619 623 19188522 \n6 Goland S Elkayam U Pregnancy and Marfan syndrome Ann Cardiothorac Surg 2017 6 06 642 653 29270376 \n7 Rossiter J P Repke J T Morales A J Murphy E A Pyeritz R E A prospective longitudinal evaluation of pregnancy in the Marfan syndrome Am J Obstet Gynecol 1995 173 05 1599 1606 7503207 \n8 Pyeritz R E Maternal and fetal complications of pregnancy in the Marfan syndrome Am J Med 1981 71 05 784 790 7304650 \n9 Goland S Barakat M Khatri N Elkayam U Pregnancy in Marfan syndrome: maternal and fetal risk and recommendations for patient assessment and management Cardiol Rev 2009 17 06 253 262 19829173 \n10 Kim S Y Wolfe D S Taub C C Cardiovascular outcomes of pregnancy in Marfan's syndrome patients: a literature review Congenit Heart Dis 2018 13 02 203 209 29063738 \n11 Donnelly R T Pinto N M Kocolas I Yetman A T The immediate and long-term impact of pregnancy on aortic growth rate and mortality in women with Marfan syndrome J Am Coll Cardiol 2012 60 03 224 229 22789886 \n12 Hiratzka L F Bakris G L Beckman J A 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with thoracic aortic disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine Circulation 2010 121 13 e266 e369 20233780 \n13 Meijboom L J Vos F E Timmermans J Boers G H Zwinderman A H Mulder B J Pregnancy and aortic root growth in the Marfan syndrome: a prospective study Eur Heart J 2005 26 09 914 920 15681576 \n14 Omnes S Jondeau G Detaint D Pregnancy outcomes among women with Marfan syndrome Int J Gynaecol Obstet 2013 122 03 219 223 23810486 \n15 Kuperstein R Cahan T Yoeli-Ullman R Ben Zekry S Shinfeld A Simchen M J Risk of aortic dissection in pregnant patients with the Marfan syndrome Am J Cardiol 2017 119 01 132 137 27788933 \n16 Minsart A F Mongeon F P Laberge A M Morin F Dore A Leduc L Obstetric and cardiac outcomes in women with Marfan syndrome and an aortic root diameter ≤ 45 mm Eur J Obstet Gynecol Reprod Biol 2018 230 68 72 30243228 \n17 Erbel R Aboyans V Boileau C 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult Eur Heart J 2014 35 41 2873 2926 25173340 \n18 Boodhwani M Andelfinger G Leipsic J Canadian Cardiovascular Society position statement on the management of thoracic aortic disease Can J Cardiol 2014 30 06 577 589 24882528 \n19 Regitz-Zagrosek V Roos-Hesselink J W Bauersachs J 2018 ESC Guidelines for the management of cardiovascular diseases during pregnancy Eur Heart J 2018 39 34 3165 3241 30165544 \n20 Loeys B L Dietz H C Braverman A C The revised Ghent nosology for the Marfan syndrome J Med Genet 2010 47 07 476 485 20591885 \n21 Wright M Connolly H Post T Management of Marfan syndrome and related disorders In:, ed. UpToDate Website.https://www.uptodate.com/contents/management-of-marfan-syndrome-and-related-disorders. Accessed April 13, 2019\n22 Roman M J Rosen S E Kramer-Fox R Devereux R B Prognostic significance of the pattern of aortic root dilation in the Marfan syndrome J Am Coll Cardiol 1993 22 05 1470 1476 8227807 \n23 Goldstein S A Evangelista A Abbara S Multimodality imaging of diseases of the thoracic aorta in adults: from the American Society of Echocardiography and the European Association of Cardiovascular Imaging: endorsed by the Society of Cardiovascular Computed Tomography and Society for Cardiovascular Magnetic Resonance J Am Soc Echocardiogr 2015 28 02 119 182 25623219 \n24 Davies R R Gallo A Coady M A Novel measurement of relative aortic size predicts rupture of thoracic aortic aneurysms Ann Thorac Surg 2006 81 01 169 177 16368358 \n25 Katsuragi S Ueda K Yamanaka K Pregnancy-associated aortic dilatation or dissection in Japanese women with Marfan syndrome Circ J 2011 75 11 2545 2551 21817813 \n26 Smith K Gros B Pregnancy-related acute aortic dissection in Marfan syndrome: a review of the literature Congenit Heart Dis 2017 12 03 251 260 28371362 \n27 Elkayam U Ostrzega E Shotan A Mehra A Cardiovascular problems in pregnant women with the Marfan syndrome Ann Intern Med 1995 123 02 117 122 7778824 \n28 Roman M J Pugh N L Hendershot T P Aortic complications associated with pregnancy in Marfan syndrome: The NHLBI National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) J Am Heart Assoc 2016 5 08 e004052 27515814 \n29 de Beaufort H WL Trimarchi S Korach A Aortic dissection in patients with Marfan syndrome based on the IRAD data Ann Cardiothorac Surg 2017 6 06 633 641 29270375 \n30 Umaña J P Miller D C Mitchell R S What is the best treatment for patients with acute type B aortic dissections--medical, surgical, or endovascular stent-grafting? Ann Thorac Surg 2002 74 05 S1840 S1843 , discussion S1857–S186312440677\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2157-7005",
"issue": "9(3)",
"journal": "AJP reports",
"keywords": "Marfan syndrome; Type B aortic dissection; aortic rupture; pregnancy",
"medline_ta": "AJP Rep",
"mesh_terms": null,
"nlm_unique_id": "101569862",
"other_id": null,
"pages": "e256-e261",
"pmc": null,
"pmid": "31435486",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports",
"references": "12440677;15681576;16325700;16368358;17938162;19188522;19829173;2009899;20233780;20591885;21817813;22789886;23810486;24882528;25173340;25623219;27515814;27788933;28371362;29063738;29270375;29270376;30165544;30243228;4225694;7304650;7503207;7778824;8227807",
"title": "Rupture of a Type B Aortic Dissection in a Postpartum Patient with Marfan Syndrome.",
"title_normalized": "rupture of a type b aortic dissection in a postpartum patient with marfan syndrome"
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"abstract": "Coronavirus disease 2019 (COVID-19) is a novel infectious disease that continues to spread on a global scale. There has been growing concern about donor-derived transmissions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Herein, we present the case of a patient who underwent ABO-incompatible living donor liver transplantation without knowing that the liver donor was infected with COVID-19 during the donation procedure. In this case, the donor-derived transmission to the recipient was not identified, and the liver donor was found to be recovering from a COVID-19 infection. The donor-derived transmission was not identified.",
"affiliations": "Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, Republic of Korea.;Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.;Surgery and Abdominal Organ Transplantation, Department of Surgery, Daegu Catholic University School of Medicine, Daegu, Republic of Korea.;Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, Republic of Korea.",
"authors": "Hong|Hyo-Lim|HL|0000-0003-2147-1381;Kim|Sung-Han|SH|0000-0003-2002-1098;Choi|Dong Lak|DL|0000-0002-6071-9012;Kwon|Hyun Hee|HH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.15997",
"fulltext": null,
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"issn_linking": "1600-6135",
"issue": "20(10)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "COVID-19; liver transplantation",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000328:Adult; D000073640:Betacoronavirus; D001706:Biopsy; D000086382:COVID-19; D018352:Coronavirus Infections; D018562:Disease Transmission, Infectious; D005260:Female; D006801:Humans; D008099:Liver; D016031:Liver Transplantation; D019520:Living Donors; D008875:Middle Aged; D058873:Pandemics; D011024:Pneumonia, Viral; D000086402:SARS-CoV-2",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "2938-2941",
"pmc": null,
"pmid": "32400013",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A case of coronavirus disease 2019-infected liver transplant donor.",
"title_normalized": "a case of coronavirus disease 2019 infected liver transplant donor"
} | [
{
"companynumb": "KR-ASTELLAS-2020US036215",
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"activesubstancename": "LOPINAVIR\\RITONAVIR"
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{
"abstract": "Safety issues have been raised about dabigatran. We aimed to investigate the occurrence of safety outcomes in patients who had atrial fibrillation and a risk of stroke. We analyzed 439 patients prescribed dabigatran (n = 220) or warfarin (n = 219). Ischemic stroke occurred in 15 (6.8%) patients in the warfarin group versus 5 (5.2%) patients in the 110-mg group versus 1 (0.8%) patient in the 150-mg dabigatran group (P = .015). Intracranial hemorrhage occurred in 6 (2.7%) patients in the warfarin group versus 3 (2.4%) patients in the 150-mg dabigatran group (P = .104). Death from any cause occurred in 10 (4.6%) patients in the warfarin group versus 1 (1.0%) patient in the 110-mg dabigatran group (P = .005). Dabigatran was associated with less ischemic stroke and death from any cause than warfarin. Dabigatran may be a better option for stroke prophylaxis, where recommended monitoring with warfarin is suboptimal.",
"affiliations": "Division of Cardiology, Ağrı State Hospital, Ağrı, Turkey.;Department of Cardiology, Faculty of Medicine, Pamukkale University, Denizli, Turkey yaylalimd@gmail.com.;Division of Emergency Medicine, Ağrı State Hospital, Ağrı, Turkey.;Department of Cardiology, Van Region Training and Research Hospital, Van, Turkey.;Department of Biostatistics, Faculty of Medicine, Pamukkale University, Denizli, Turkey.;Department of Cardiology, Faculty of Medicine, Pamukkale University, Denizli, Turkey.;Department of Cardiology, Van Region Training and Research Hospital, Van, Turkey.",
"authors": "Aslan|Onur|O|;Yaylali|Y T|YT|;Yildirim|S|S|;Yurtdas|M|M|;Senol|H|H|;Ugur-Yildiz|M|M|;Ozdemir|M|M|",
"chemical_list": "D014859:Warfarin; D000069604:Dabigatran",
"country": "United States",
"delete": false,
"doi": "10.1177/1076029614546327",
"fulltext": null,
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"issn_linking": "1076-0296",
"issue": "22(2)",
"journal": "Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis",
"keywords": "drug monitoring; hemorrhage; myocardial infarction; stroke; thromboembolism",
"medline_ta": "Clin Appl Thromb Hemost",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001281:Atrial Fibrillation; D002545:Brain Ischemia; D000069604:Dabigatran; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020521:Stroke; D014421:Turkey; D014859:Warfarin",
"nlm_unique_id": "9508125",
"other_id": null,
"pages": "147-52",
"pmc": null,
"pmid": "25115764",
"pubdate": "2016-03",
"publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Dabigatran Versus Warfarin in Atrial Fibrillation: Multicenter Experience in Turkey.",
"title_normalized": "dabigatran versus warfarin in atrial fibrillation multicenter experience in turkey"
} | [
{
"companynumb": "TR-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2014-BI-38614GD",
"fulfillexpeditecriteria": "1",
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"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "Tunneled dialysis catheter-associated right atrial thrombus (RAT) is a rarely reported complication. We reviewed hospital records of 10 patients from a teaching hospital dialysis unit, in whom RAT was diagnosed by trans-esophageal echocardiography (TEE). Patients were treated with chronic anticoagulation (heparin followed by warfarin) and followed over time. The group included 7 women; 6 patients were African American, 3 were Caucasian, and 1 was Hispanic. The average age was 52.1 ± 15.3 years. The most common presenting symptom was poor catheter flow on hemodialysis followed by fever and chills. On average, the patients had had 3.4 ± 2.7 catheter insertions before diagnosis of RAT, and the tunneled dialysis catheter (TC) had been in place for a mean of 91 ± 89.4 days when the thrombi were diagnosed. Trans-thoracic echocardiography (2-D echo) was done in 4 patients, but it identified RAT in only 1 patient. The catheter tip was at the junction of the superior vena cava and right atrium (SVC/RA) in most patients. Thrombolysis (unsuccessful) was attempted with urokinase in 3 patients, complicated in 2 patients by hemorrhage. After anticoagulation, 90% of the RAT resolved on repeated TEE. One patient had persistent RAT for 23 weeks and underwent surgical thrombolysis, but died postoperatively. We conclude that RAT is a frequently missed complication of a TC. Positioning the tip of the TC at the SVC/RA junction may not prevent RAT. Trans-esophageal echocardiography is a more sensitive diagnostic tool than 2-D echo and should be obtained early. Most patients can be successfully treated with anticoagulation alone. Thrombolytic therapy and surgical thrombolysis have high morbidity and mortality.",
"affiliations": "Kraftsow Division of Nephrology, Albert Einstein Medical Center, Philadelphia, Pennsylvania, U.S.A.;Kraftsow Division of Nephrology, Albert Einstein Medical Center, Philadelphia, Pennsylvania, U.S.A.;Kraftsow Division of Nephrology, Albert Einstein Medical Center, Philadelphia, Pennsylvania, U.S.A.;Department of Cardiology, Albert Einstein Medical Center, Philadelphia, Pennsylvania, U.S.A.;Kraftsow Division of Nephrology, Albert Einstein Medical Center, Philadelphia, Pennsylvania, U.S.A.",
"authors": "Kung|Shiang-Cheng|SC|;Aravind|Bonapally|B|;Morse|Stephen|S|;Jacobs|Larry E|LE|;Raja|Rasib|R|",
"chemical_list": null,
"country": "Canada",
"delete": false,
"doi": "10.1111/hdi.2001.5.1.32",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1492-7535",
"issue": "5(1)",
"journal": "Hemodialysis international. International Symposium on Home Hemodialysis",
"keywords": "Tunneled catheter; anticoagulation; atrial thrombus; urokinase",
"medline_ta": "Hemodial Int",
"mesh_terms": null,
"nlm_unique_id": "101093910",
"other_id": null,
"pages": "32-36",
"pmc": null,
"pmid": "28452431",
"pubdate": "2001-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Tunneled Catheter-Associated Atrial Thrombi: Successful Treatment with Chronic Anticoagulation.",
"title_normalized": "tunneled catheter associated atrial thrombi successful treatment with chronic anticoagulation"
} | [
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"companynumb": "US-PFIZER INC-2017201325",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"activesubstance": {
"activesubstancename": "VANCOMYCIN"
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... |
{
"abstract": "The most common cause of spontaneous intracranial hypotension headache is a cerebrospinal fluid (CSF) leakage, but the underlying mechanisms remain unknown. Intracranial hypotension is characterised by diffuse pachymeningeal enhancement on cranial MRI features, low CSF pressure and orthostatic headaches mostly caused by the dural puncture. We report a 31-year-old woman who presented to our services with reports of continuous severe bifrontal headache, which increased on sitting up and resolved on lying down. MRI of the cervical and lumbosacral spine showed signs of CSF leak; hence, patient was diagnosed with spontaneous intracranial hypotension headache. A CT-guided epidural blood patch was done at L4-5 with fibrin glue injected at the site of leak. The patient's signs and symptoms improved after the procedure.",
"affiliations": "Neurology, Indraprastha Apollo Hospital, New Delhi, Delhi, India pnrenjen@hotmail.com.;Neurology, Indraprastha Apollo Hospital, New Delhi, Delhi, India.;Radio Diagnosis, Indraprastha Apollo Hospital, New Delhi, Delhi, India.;Neurology, Indraprastha Apollo Hospital, New Delhi, Delhi, India.",
"authors": "Renjen|Pushpendra Nath|PN|;Chaudhari|Dinesh Mohan|DM|;Goyal|Nidhi|N|;Ahmed|Kamal|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-243179",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(6)",
"journal": "BMJ case reports",
"keywords": "headache (including migraines); neuroimaging; neurology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D017217:Blood Patch, Epidural; D065634:Cerebrospinal Fluid Leak; D005260:Female; D006261:Headache; D006801:Humans; D019585:Intracranial Hypotension; D008279:Magnetic Resonance Imaging",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34172480",
"pubdate": "2021-06-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe acute orthostatic headache: spontaneous intracranial hypotension (SIH).",
"title_normalized": "severe acute orthostatic headache spontaneous intracranial hypotension sih"
} | [
{
"companynumb": "IN-MYLANLABS-2021M1052837",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAFFEINE"
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"drugadditional": "3",
... |
{
"abstract": "Sugammadex hypersensitivity is an uncommon event that typically occurs at higher doses. We report a case of suspected sugammadex hypersensitivity in a patient who developed hypoxia and bronchospasm following three administrations of the standard 2 mg/kg doses of sugammadex within 26 hours due to flap takebacks. Hypersensitivity to sugammadex was not initially suspected given that the patient had previous exposures. Diagnoses of pneumothorax, hemothorax, mucus plug, and tracheal tube malposition were immediately ruled out. Furthermore, the onset of hypoxia with sudden loss of tidal volume, development of high peak airway pressures, and temporal correlation with sugammadex administration all supported bronchospasm secondary to a hypersensitivity reaction. Sugammadex is a useful agent for neuromuscular blockade reversal; however, it is critical to carefully examine all adverse reactions. This case report highlights the importance of considering hypersensitivity reactions in the setting of repeat sugammadex administrations in a limited timeframe, such as in free flap reconstruction requiring multiple takebacks to the operating room in the setting of flap compromise.",
"affiliations": "Department of Plastic and Reconstructive Surgery, MedStar Georgetown University Hospital, 3800 Reservoir Road Northwest, Washington, DC 20007, USA.;Department of Anesthesiology, MedStar Georgetown University Hospital, 3800 Reservoir Road Northwest, Washington, DC 20007, USA.;Department of Plastic and Reconstructive Surgery, MedStar Georgetown University Hospital, 3800 Reservoir Road Northwest, Washington, DC 20007, USA.;Department of Plastic and Reconstructive Surgery, MedStar Georgetown University Hospital, 3800 Reservoir Road Northwest, Washington, DC 20007, USA.;Department of Plastic and Reconstructive Surgery, MedStar Georgetown University Hospital, 3800 Reservoir Road Northwest, Washington, DC 20007, USA.;Department of Plastic and Reconstructive Surgery, MedStar Georgetown University Hospital, 3800 Reservoir Road Northwest, Washington, DC 20007, USA.;Department of Plastic and Reconstructive Surgery, MedStar Georgetown University Hospital, 3800 Reservoir Road Northwest, Washington, DC 20007, USA.",
"authors": "Zolper|Elizabeth G|EG|;Kim|Alan H|AH|;Kim|Kevin G|KG|;Dekker|Paige K|PK|;Bekeny|Jenna C|JC|;Song|David H|DH|;Fan|Kenneth L|KL|https://orcid.org/0000-0001-5951-5576",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/5716159",
"fulltext": "\n==== Front\nCase Rep Anesthesiol\nCase Rep Anesthesiol\nCRIA\nCase Reports in Anesthesiology\n2090-6382\n2090-6390\nHindawi\n\n10.1155/2021/5716159\nCase Report\nSuspected Sugammadex Hypersensitivity following Repeated Administration in the Setting of Multiple Flap Takebacks in a Brief Timespan\nZolper Elizabeth G. 1\nKim Alan H. 2\nKim Kevin G. 1\nDekker Paige K. 1\nBekeny Jenna C. 1\nSong David H. 1\nhttps://orcid.org/0000-0001-5951-5576\nFan Kenneth L. kenneth.l.fan@medstar.net\n1\n1Department of Plastic and Reconstructive Surgery, MedStar Georgetown University Hospital, 3800 Reservoir Road Northwest, Washington, DC 20007, USA\n2Department of Anesthesiology, MedStar Georgetown University Hospital, 3800 Reservoir Road Northwest, Washington, DC 20007, USA\nAcademic Editor: Chun-Sung Sung\n\n2021\n23 8 2021\n2021 571615923 4 2021\n16 8 2021\nCopyright © 2021 Elizabeth G. Zolper et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nSugammadex hypersensitivity is an uncommon event that typically occurs at higher doses. We report a case of suspected sugammadex hypersensitivity in a patient who developed hypoxia and bronchospasm following three administrations of the standard 2 mg/kg doses of sugammadex within 26 hours due to flap takebacks. Hypersensitivity to sugammadex was not initially suspected given that the patient had previous exposures. Diagnoses of pneumothorax, hemothorax, mucus plug, and tracheal tube malposition were immediately ruled out. Furthermore, the onset of hypoxia with sudden loss of tidal volume, development of high peak airway pressures, and temporal correlation with sugammadex administration all supported bronchospasm secondary to a hypersensitivity reaction. Sugammadex is a useful agent for neuromuscular blockade reversal; however, it is critical to carefully examine all adverse reactions. This case report highlights the importance of considering hypersensitivity reactions in the setting of repeat sugammadex administrations in a limited timeframe, such as in free flap reconstruction requiring multiple takebacks to the operating room in the setting of flap compromise.\n==== Body\n1. Introduction\n\nSugammadex, a reversal agent for rocuronium bromide- or vecuronium bromide- induced neuromuscular blockade, was approved by the United States Food and Drug Administration (FDA) in 2015. [1] It antagonizes binding of neuromuscular blocking agents to nicotinic cholinergic receptors by forming a complex with the agent [1]. The recommended dose for routine reversal is 2–4 mg/kg but ultimately depends on the depth of the residual neuromuscular blockade [1]. The half-life of sugammadex is approximately two hours [1]. The incidence of sugammadex hypersensitivity is 0.3 to 7% at the recommended doses for routine reversal [2, 3]. We report a case of suspected sugammadex hypersensitivity in a patient undergoing autologous breast reconstruction requiring multiple flap takebacks and repetitive low-dose sugammadex exposures within a twenty-six hour period. The required Institutional Review Board approval and written Health Insurance Portability and Accountability Act (HIPAA) authorization have been obtained. This manuscript adheres to the applicable CARE guidelines (for CAse REports).\n\n2. Case Description\n\nA 48-year-old female (92.8 kg) with a history of hypertension, tachycardia, gastroesophageal reflux disease, anemia, and obesity underwent bilateral mastectomy and immediate deep inferior epigastric perforator (DIEP) flap reconstruction performed under general endotracheal tube anesthesia (GETA) with rocuronium. She had previously undergone general anesthesia without complications. The intraoperative course was uncomplicated. Intraoperative fluids targeted a urinary output of 0.5 mL/kg/hr. The estimated blood loss was 250 ml. She received a 250 mg dose of sugammadex for reversal and was extubated without complication.\n\nTwelve hours later, concerns for left flap compromise and hematoma necessitated emergent takeback. Her hematocrit had dropped from 34.7 to 25.6 over five hours, and lactate was elevated to 8.2. She was resuscitated appropriately preoperatively and received two units of packed red blood cells intraoperatively. She underwent GETA with rapid sequence induction (RSI) with succinylcholine and rocuronium for neuromuscular blockade maintenance. After hemostasis was achieved, 200 mg of sugammadex was administered for reversal. Extubation and postanesthesia monitoring proceeded without complication.\n\nSeven hours after initial takeback, the patient returned to the operating room (OR) due to recurrent flap compromise. She had been adequately resuscitated after the second operation. She remained hemodynamically stable and off vasopressors. GETA with RSI with rocuronium was utilized again. The intraoperative course was uncomplicated with minimal blood loss. The patient was on a heparin infusion throughout. Further fluid resuscitation was provided due to reduced urinary output. Initial arterial blood gas (ABG) was stable (T1, Table 1).\n\nDuring closure, 185.6 mg of sugammadex was administered. About five minutes later, end tidal CO2 acutely diminished in amplitude without change in patient positioning. There was a sudden loss in tidal volume (TV) from 350 ml to absent breath with high-pressure alarm. Ventilation was immediately switched from mechanical to manual. Increased inspiratory pressure was required to maintain TV over 200 mL. After dropping to 63%, SpO2 recovered to 93% with ventilation at 100% FiO2.\n\nBreath sounds were equal but diminished in intensity bilaterally with wheezing. Albuterol was administered via the endotracheal tube (ETT). A suction catheter passed along the length of the ETT did not reveal significant secretions or kinking. The head of the bed was elevated to minimize compressive effects. The patient maintained her saturations on mechanical ventilation with additional positive end-expiratory pressure.\n\nWhen attempting to wean mechanical ventilation, SpO2 dropped again requiring increased peak inspiratory pressures to recover. Blood pressure and heart rate were relatively unchanged. There were no cutaneous changes. ABG revealed low PaO2 (T2 Table 1). Ultrasound was unrevealing for pneumothorax. ETT position was unchanged at a depth of 22 cm consistent with prior cases. Portable chest radiograph (CXR) confirmed absence of pneumothorax and ETT positioning. Given the lack of a clear etiology for acute hypoxemia, she remained intubated and was transferred to the intensive care unit (ICU). She passed a spontaneous breathing trial the next morning and was successfully extubated. She was discharged home in stable condition five days later.\n\n3. Discussion\n\nIn this case, suspected hypersensitivity occurred immediately following administration of a 2–3 mg/kg sugammadex dose. Sugammadex hypersensitivity presenting with acute oxygen desaturation has been previously reported, however decreased SpO2 is typically associated with erythema, soft tissue edema, urticaria, or hypotension [4, 5]. Furthermore, hypersensitivity reactions have been reported more frequently at higher doses of sugammadex [2, 3]. Nonetheless, there is no clear dose-dependent relationship, and hypersensitivity has been reported at doses as low as 1.9 mg/kg [5]. Hypersensitivity associated with multiple sugammadex exposures over a short interval and presentation as isolated bronchospasm with hypoxia are both unique (Table 2).\n\nSugammadex has a half-life of approximately two hours. [1] The preceding dose of sugammadex should have therefore minimally impacted exposure to sugammadex, as the period between the doses exceeded that of four half-lives. Sugammadex is renally cleared; moderate renal impairment can increase exposure by a factor of 2.42 [1, 6]. Our patient's estimated creatinine clearance decreased to 45.12 mL/min after the third operation, corresponding with moderate renal impairment in the study by Min et al. [6]. Renal function may have declined prior to the second and third doses of sugammadex, increasing exposure and resulting in hypersensitivity despite a low administered dose.\n\nHypersensitivity to sugammadex was not initially suspected as the patient had previous exposures. Differential diagnoses of pneumothorax, hemothorax, mucus plug, and ETT kinking were ruled out first. Postoperative CXR showed the ETT just superior to the carina. This was attributed to patient positioning shifting the ETT towards the carina, as changes in peak airway pressure, TV, or end tidal CO2 indicative of an ETT positioned in the mainstem were not observed intraoperatively. The sudden loss of TV, development of high peak airway pressures, temporal correlation with sugammadex administration, and consistent depth of ETT placement all support bronchospasm.\n\nSeveral factors may have contributed to airway hyperreactivity during the third operation, including prolonged and repeated intubation which could have irritated the airways, increasing susceptibility to subsequent insult. There are reports of bronchospasm secondary to sugammadex in combination with desflurane in patients with undiagnosed underlying pulmonary disease or no history of pulmonary disease [7, 8].\n\nDue to multiple takebacks for flap compromise, sugammadex was administered three times within 25 hours and 25 minutes. Multiple returns to the OR also necessitated repeated intubation and inadvertently led to decreased renal clearance in association with hypovolemia. In this setting, the third, albeit low, dose of sugammadex tipped the proverbial scales into bronchospasm. This is of utmost importance in the setting of free tissue transfer in which takebacks occur in 5.9 to 8.8% of flaps dependent on the site of reconstruction [9, 10]. Although bronchospasm is multifactorial and the contribution of sugammadex is difficult to prove definitively, the impetus remains to reconsider repeated administration of sugammadex in a short timeframe, especially in the setting of recurrent flap takeback or other surgical procedures which may necessitate multiple takeback procedures.\n\nData Availability\n\nData are available from the corresponding author upon request, to protect patient privacy.\n\nConflicts of Interest\n\nDr. Song receives royalties from Elsevier for Plastic Surgery 3e/4e and Biomet Microfixation for Sternalock. All other authors declare no conflicts of interest.\n\nTable 1 Arterial blood gases from the third operation.\n\nLabs\tT1a\tT2b\tT3c\t\npH\t7.32\t7.20\t7.26\t\npCO2 (mmHg)\t47.0\t54.0\t54.0\t\npO2 (mmHg)\t157.0\t61.0\t173.0\t\nHgb (g/dL)\t7.5\t7.1\t7.1\t\nK+ (mmol/L)\t3.6\t4.1\t4.2\t\nNa+ (mmol/L)\t138\t142\t141\t\nBE (mmol/L)\t−1.9\t−6.5\t−5.3\t\nGlucose (mmol/L)\t129\t155\t182\t\nLactate (mmol/L)\t0.8\t1.3\t1.1\t\naT1 is intraoperative during the second takeback, mechanically ventilated with FiO2 of 75%. bT2 is obtained at 24 minutes following sugammadex administration and onset of acute hypoxia, manually ventilated with FiO2 of 100%. cT3 is postoperative when the patient had stabilized and was admitted to the ICU, mechanically ventilated with FiO2 of 100%. BE: base excess.\n\nTable 2 Sugammadex dosing.\n\nSugammadex dose (mg/kg)\tElapsed time from prior dose (hours:minutes)\t\n2.69\tN/A\t\n2.15\t15 : 56\t\n2.00\t9 : 29\t\nThe patient (92.8 kg) received a dose of sugammadex during each operation for a total of three doses given over 25 hours and 25 minutes.\n==== Refs\n1 Merck Sharp & Dohme Corp Bridion (Sugammadex) [Prescribing Information] 2015 Whitehouse Station, NJ, USA Merck Sharp & Dohme Corp\n2 Min K. C. Bondiskey P. Schulz V. Hypersensitivity incidence after sugammadex administration in healthy subjects: a randomised controlled trial British Journal of Anaesthesia 2018 121 4 749 757 10.1016/j.bja.2018.05.056 2-s2.0-85052097485 30236237\n3 de Kam P.-J. Nolte H. Good S. Sugammadex hypersensitivity and underlying mechanisms: a randomised study of healthy non-anaesthetised volunteers British Journal of Anaesthesia 2018 121 4 758 767 10.1016/j.bja.2018.05.057 2-s2.0-85049798367 30236238\n4 Asahi Y. Omichi S. Adachi S. Kagamiuchi H. Kotani J. Hypersensitivity reaction probably induced by sugammadex Acta Anaesthesiologica Taiwanica 2012 50 4 183 184 10.1016/j.aat.2012.08.010 2-s2.0-84873414070 23385042\n5 Godai K. Hasegawa-Moriyama M. Kuniyoshi T. Three cases of suspected sugammadex-induced hypersensitivity reactions British Journal of Anaesthesia 2012 109 2 216 218 10.1093/bja/aes137 2-s2.0-84863956591 22617091\n6 Min K. C. Lasseter K. C. Marbury T. C. Pharmacokinetics of sugammadex in subjects with moderate and severe renal impairment International Journal of Clinical Pharmacology and Therapeutics 2017 Sep 55 9 746 752 10.5414/CP203025.PMID:28679468 28679468\n7 Eskander J. P. Cornett E. M. Stuker W. Fox C. J. Breehl M. The combination of sugammadex and desflurane may increase the risk of bronchospasm during general anesthesia Journal of Clinical Anesthesia 2017 41 p. 73 10.1016/j.jclinane.2017.06.017 2-s2.0-85021988746\n8 Amao R. Zornow M. H. Cowan R. M. Cheng D. C. Morte J. B. Allard M. W. Use of sugammadex in patients with a history of pulmonary disease Journal of Clinical Anesthesia 2012 24 4 289 297 10.1016/j.jclinane.2011.09.006 2-s2.0-84861164573 22608583\n9 Stranix J. T. Lee Z.-H. Jacoby A. Forty years of lower extremity take-backs Plastic and Reconstructive Surgery 2018 141 5 1282 1287 10.1097/prs.0000000000004322 2-s2.0-85053929466 29697629\n10 Khansa I. Chao A. H. Taghizadeh M. Nagel T. Wang D. Tiwari P. A systematic approach to emergent breast free flap takeback: clinical outcomes, algorithm, and review of the literature Microsurgery 2013 33 7 505 513 10.1002/micr.22151 2-s2.0-84885958093 23946137\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6390",
"issue": "2021()",
"journal": "Case reports in anesthesiology",
"keywords": null,
"medline_ta": "Case Rep Anesthesiol",
"mesh_terms": null,
"nlm_unique_id": "101581025",
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"pubdate": "2021",
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"title": "Suspected Sugammadex Hypersensitivity following Repeated Administration in the Setting of Multiple Flap Takebacks in a Brief Timespan.",
"title_normalized": "suspected sugammadex hypersensitivity following repeated administration in the setting of multiple flap takebacks in a brief timespan"
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"activesubstancename": "SUGAMMADEX"
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"abstract": "The title \"great imitator\" refers to conditions which can cause varied manifestations and mimic many diseases. Lymphoma is worthy of this title. We describe three cases of lymphoma in which lymphoma mimicked other diseases causing neurological dysfunction, specifically sarcoidosis, vasculitis and infection respectively. Case 1 was a 66-year-old man with subacute progressive diplopia and gait disturbance and investigations revealing a supratentorial para-falcine soft tissue lesion, mid-thoracic cord enhancement and right axillary mass and an elevated serum ACE. Right axillary mass core biopsy was diagnostic of Burkitt lymphoma. Case 2 was a 50-year-old man with several weeks of constitutional symptoms and development of lower limb weakness and numbness, urinary retention and confusion while in hospital. MRI brain demonstrated multi-territory cerebral infarcts. Intravascular lymphoma was diagnosed on random skin biopsy. Case 3 was a 65-year-old man with several weeks of headache and diplopia on a background of previously treated Burkitt lymphoma. CSF analysis showed a lymphocytic pleocytosis and markedly low glucose with cytologic analysis negative for malignancy. Investigations for an infective cause were negative. FDG-PET demonstrated marked, disseminated spinal and cranial leptomeningeal disease and a multi-focal, intra-dural relapse of Burkitt lymphoma was diagnosed. The varied manifestations in our cases demonstrate the ability for lymphoma to mimic infective, inflammatory, granulomatous (including sarcoidosis) and neoplastic aetiologies. An elevated serum ACE appears insufficiently diagnostic to confirm sarcoidosis and tissue for histological examination should be sought whenever possible. When the diagnosis is uncertain, the possibility of this great imitator should be considered, especially for multi-focal disease.",
"affiliations": "Department of Neurology, St Vincent's Hospital Melbourne, 41 Victoria Parade, Fitzroy VIC 3065, Australia. Electronic address: wyehneuro@gmail.com.;Department of Neurology, St Vincent's Hospital Melbourne, 41 Victoria Parade, Fitzroy VIC 3065, Australia.;Department of Anatomical Pathology, St Vincent's Hospital Melbourne, 41 Victoria Parade, Fitzroy VIC 3065, Australia.;Department of Neurology, St Vincent's Hospital Melbourne, 41 Victoria Parade, Fitzroy VIC 3065, Australia.;Department of Neurology, St Vincent's Hospital Melbourne, 41 Victoria Parade, Fitzroy VIC 3065, Australia.;Department of Haematology, St Vincent's Hospital Melbourne, 41 Victoria Parade, Fitzroy VIC 3065, Australia.;Medical Imaging Department, St Vincent's Hospital Melbourne, 41 Victoria Parade, Fitzroy VIC 3065, Australia; Faculty of Medicine, University of Melbourne, Parkville, Australia.;Medical Imaging Department, St Vincent's Hospital Melbourne, 41 Victoria Parade, Fitzroy VIC 3065, Australia.;Department of Neurology, St Vincent's Hospital Melbourne, 41 Victoria Parade, Fitzroy VIC 3065, Australia.",
"authors": "Yeh|Wei Zhen|WZ|;Muthusamy|Subramanian|S|;McKelvie|Penny|P|;Collins|Steven|S|;French|Ann|A|;Filshie|Robin|R|;Sutherland|Tom|T|;Trost|Nicholas|N|;Reardon|Katrina|K|",
"chemical_list": null,
"country": "Scotland",
"delete": false,
"doi": "10.1016/j.jocn.2020.02.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0967-5868",
"issue": "73()",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Angiotensin Converting Enzyme; Burkitt lymphoma; Diagnosis; Lymphoma; Neurology; Sarcoidosis; Vasculitis",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D000368:Aged; D003937:Diagnosis, Differential; D006801:Humans; D008223:Lymphoma; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D049268:Positron-Emission Tomography; D012507:Sarcoidosis; D012867:Skin; D013116:Spinal Cord; D014657:Vasculitis",
"nlm_unique_id": "9433352",
"other_id": null,
"pages": "308-310",
"pmc": null,
"pmid": "32081598",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Lymphoma, a great imitator in neurology.",
"title_normalized": "lymphoma a great imitator in neurology"
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"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
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"abstract": "Respiratory infection with Burkholderia cenocepacia is associated with accelerated decline in lung function and increased mortality in cystic fibrosis (CF) patients (A. M. Jones, M. E. Dodd, J. R. W. Govan, V. Barcus, C. J. Doherty, J. Morris, and A. K. Webb, Thorax 59:948-951, 2004, http://dx.doi.org/10.1136/thx.2003.017210). B. cenocepacia often possesses innate resistance to multiple antimicrobial classes, making eradication uncommon in established infection (P. B. Davis, Am J Respir Crit Care Med 173:475-482, 2006, http://dx.doi.org/10.1164/rccm.200505-840OE). We report the use of clinafloxacin in a CF patient with advanced B. cenocepacia infection, present pharmacokinetic (PK) data, and discuss the potential therapeutic role of clinafloxacin in patients with this condition.",
"affiliations": "Division of Pulmonary & Critical Care, Maine Medical Center, Portland, Maine, USA.;Center for Anti-Infective Research & Development, Hartford Hospital, Hartford, Connecticut, USA.;Department of Pharmacy, Maine Medical Center, Portland, Maine, USA.;Division of Pulmonary & Critical Care, Maine Medical Center, Portland, Maine, USA jzuckerman@cmamaine.com Valerie.waters@sickkids.ca.;Division of Infectious Diseases, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada jzuckerman@cmamaine.com Valerie.waters@sickkids.ca.",
"authors": "Balwan|Akshu|A|;Nicolau|David P|DP|;Wungwattana|Minkey|M|;Zuckerman|Jonathan B|JB|;Waters|Valerie|V|",
"chemical_list": "D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; C057477:clinafloxacin",
"country": "United States",
"delete": false,
"doi": "10.1128/AAC.01428-15",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0066-4804",
"issue": "60(1)",
"journal": "Antimicrobial agents and chemotherapy",
"keywords": null,
"medline_ta": "Antimicrob Agents Chemother",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D019121:Burkholderia Infections; D057508:Burkholderia cenocepacia; D003550:Cystic Fibrosis; D048909:Diabetes Complications; D003920:Diabetes Mellitus; D010188:Exocrine Pancreatic Insufficiency; D017809:Fatal Outcome; D024841:Fluoroquinolones; D006801:Humans; D008168:Lung; D008297:Male; D011552:Pseudomonas Infections; D011550:Pseudomonas aeruginosa; D017211:Treatment Failure",
"nlm_unique_id": "0315061",
"other_id": null,
"pages": "1-5",
"pmc": null,
"pmid": "26722110",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11739142;11581236;15170040;6420530;4032134;3142350;7695254;8549411;8629607;9710677;15516469;16126935;18318775;18469108;20880411;23076960;23867250;24176390;25267676;25592656;11158750;11048725;26220706;11170945;11208624;11502525;12202570",
"title": "Clinafloxacin for Treatment of Burkholderia cenocepacia Infection in a Cystic Fibrosis Patient.",
"title_normalized": "clinafloxacin for treatment of burkholderia cenocepacia infection in a cystic fibrosis patient"
} | [
{
"companynumb": "US-BAYER-2017-122586",
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"abstract": "Nitrofurantoin is a common treatment for urinary tract infections. Acute lung injury resulting from nitrofurantoin is a rare, life-threatening complication with women being at greater risk. Symptoms include respiratory distress with fevers, rash, eosinophilia, and new-onset atrial fibrillation. Treatment includes discontinuing the drug and possibly glucocorticoids for persistent oxygen demand.",
"affiliations": "Touro College of Osteopathic Medicine Middletown New York USA.;Touro College of Osteopathic Medicine Middletown New York USA.;Touro College of Osteopathic Medicine Middletown New York USA.;Department of Family Medicine Garnet Health Medical Center Middletown New York USA.",
"authors": "Karmali|Rehan|R|https://orcid.org/0000-0002-1941-6546;Stawitzky|Kyle|K|;Srisethnil|Isrin|I|;Simpson|Kaitlyn|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.3314",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.3314\nCCR33314\nCase Report\nCase Reports\nA rare case of nitrofurantoin‐induced acute lung injury\nKARMALI et al.Karmali Rehan https://orcid.org/0000-0002-1941-6546\n1\nrkarmali@student.touro.edu Stawitzky Kyle \n1\n Srisethnil Isrin \n1\n Simpson Kaitlyn \n2\n \n1 \nTouro College of Osteopathic Medicine\nMiddletown\nNew York\nUSA\n\n\n2 \nDepartment of Family Medicine\nGarnet Health Medical Center\nMiddletown\nNew York\nUSA\n\n* Correspondence\n\nRehan Karmali, Touro College of Osteopathic Medicine, Middletown, New York.\n\nEmail: rkarmali@student.touro.edu\n\n16 9 2020 \n10 2020 \n8 10 10.1002/ccr3.v8.102029 2033\n13 5 2020 05 7 2020 28 7 2020 © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons LtdThis is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nNitrofurantoin is a common treatment for urinary tract infections. Acute lung injury resulting from nitrofurantoin is a rare, life‐threatening complication with women being at greater risk. Symptoms include respiratory distress with fevers, rash, eosinophilia, and new‐onset atrial fibrillation. Treatment includes discontinuing the drug and possibly glucocorticoids for persistent oxygen demand.\n\nNitrofurantoin is a common treatment for urinary tract infections. Acute lung injury resulting from nitrofurantoin is a rare, life‐threatening complication with women being at greater risk. Symptoms include respiratory distress with fevers, rash, eosinophilia, and new‐onset atrial fibrillation. Treatment includes discontinuing the drug and possibly glucocorticoids for persistent oxygen demand.\n\n\nacute lung injurydrug‐induced pulmonary toxicitynitrofurantoinGarnet Health Medical Center source-schema-version-number2.0cover-dateOctober 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.2 mode:remove_FC converted:16.10.2020\n\n\nKarmali \nR \n, \nStawitzky \nK \n, \nSrisethnil \nI \n, \nSimpson \nK \n. A rare case of nitrofurantoin‐induced acute lung injury\n. Clin Case Rep . 2020 ;8 :2029 –2033\n. 10.1002/ccr3.3314\n==== Body\n1 INTRODUCTION\nSince its approval by the FDA in 1953, nitrofurantoin has been commonly prescribed as a treatment for lower urinary tract infections.\n1\n Besides allergies, one known complication of nitrofurantoin use is pulmonary toxicity in both the acute and chronic settings.\n2\n Acute pulmonary toxicity is categorized as a hypersensitivity reaction with common symptoms being fever, dyspnea, and cough with eosinophilia seen in lab findings. The chronic form is better characterized by direct tissue damage causing dyspnea, a dry cough, and fatigue.\n3\n The most common pulmonary complication is the acute hypersensitivity reaction with an incidence rate of approximately 1 in 5000 patients after first‐time nitrofurantoin use.\n1\n Here we present the case of a 79‐year‐old female who was diagnosed with acute nitrofurantoin‐induced lung injury after an extensive workup ruling out cardiac, pulmonary, and cancerous etiologies.\n\n2 CASE PRESENTATION\nThe patient is a 79‐year‐old‐female with a past medical history of coronary artery disease (CAD) status/post 6 stents (last in 2006), hypertension (HTN), hyperlipidemia (HLD), and type 2 diabetes (T2DM) who presented to the emergency department (ED) with mid‐sternal nonradiating chest pain that became generalized across her chest wall. The pain started 6 hours before presentation when she was on a 3‐hour drive home after visiting her daughter. She initially went to Urgent Care where she took some aspirin, but her pain did not improve prompting her visit to the ED. She reported some associated nausea, but otherwise denied fevers, chills, shortness of breath, abdominal pain, vomiting, diarrhea, headache, tingling, or dizziness. Her chronic medications included amlodipine, aspirin, atorvastatin, losartan‐hydrochlorothiazide, metformin, and metoprolol. She was started on nitrofurantoin, twice daily, 2 days prior to presentation for a urinary tract infection (UTI), which was discontinued on admission. She did not use any supplemental oxygen at home and her most recent cardiac stress test 1 year prior to admission was normal. On physical exam, she had a regular heart rate and rhythm without any murmurs, rubs, or gallops. Her lungs were clear to auscultation bilaterally without any wheezing, rales, or rhonchi. She did not have any extremity edema, cyanosis, calf tenderness, and had 2+ pulses bilaterally. Her abdomen was soft and nondistended and she was alert and oriented without any focal neurological deficits. Her oxygen saturation was 89% on room air and remaining vital signs were within normal limits.\n\nWhile in the emergency room, serial troponins were negative, D‐dimer, and BNP were within normal limits, and EKG was unremarkable. She had mild leukocytosis with elevated eosinophils and transaminitis, but an initial liver ultrasound was unremarkable (Table 1). She was started on 2 L oxygen via nasal cannula which improved her saturation to 94%. An initial chest x‐ray showed bibasilar infiltrates with small left‐sided effusion. A computer tomography (CT) scan of her chest showed left lower lobe consolidation, interstitial disease with fibrosis, vascular congestion, pleural nodule in right lung base (8.2 mm), and a left upper lobe nodule (5.4 × 5.6 mm) suggestive of neoplasm (Figure 1). She was admitted for acute respiratory failure with hypoxia and further investigation of pleuritic chest pain in the setting of a newly diagnosed lung mass.\n\nTable 1 Initial ED labs on presentation\n\nCBC with differential\tGeneral chemistry and coagulation\t\nWBC\t12.9 × 103/µL\tSodium\t137 mEq/L\t\nRBC\t4.79 × 106/µL\tPotassium\t3.2 mEq/L\t\nHemoglobin\t14.6 g/dL\tChloride\t99 mEq/L\t\nHematocrit\t43.4%\tCO2\n\t24 mEq/L\t\nMCV\t90.6 fL\tBUN\t12 mg/dL\t\nMCH\t30.5 pg\tGlucose\t162 mg/dL\t\nMCHC\t33.6 g/dL\tCalcium\t9.9 mg/dL\t\nRDW\t11.9%\tCreatinine, serum\t0.68 mg/dL\t\nPlatelets\t217 × 103/µL\tTotal bilirubin\t1.2 mg/dL\t\nAbs neutrophil count\t9843 cells/mm3\n\tBilirubin, Direct\t0.31 mg/dL\t\nNeutrophils relative\t76.3%\tBilirubin indirect\t0.89 mg/dL\t\nLymphocytes relative\t6.7%\tAlbumin\t4.3 g/dL\t\nMonocytes relative\t9.0%\tTotal protein\t7.8 g/dL\t\nEosinophils relative\t7.0%\tAlkaline phosphatase\t42 U/L\t\nBasophils relative\t0.5%\tAST\t139 U/L\t\nIG relative\t0.5%\tALT\t57 U/L\t\nNeutrophils absolute\t9.9 × 103/µL\tAnion Gap\t14 mEq/L\t\nLymphocytes absolute\t0.9 × 103/µL\teGFR non‐African‐American\t>60 mL/min/1.732 m2\n\t\nMonocytes absolute\t1.2 × 103/µL\tProtime\t12.5 s\t\nEosinophils absolute\t0.91 × 103/µL\tINR\t1.09\t\nBasophils absolute\t0.1 × 103/µL\taPTT\t26.4 s\t\nCardiac biomarkers\tUrinalysis\t\nTotal CK\t46 U/L\tColor\tAmber\t\nTroponin I\t<0.03 ng/mL\tClarity\tHazy\t\nBNP\t71 pg/mL\tSpecific gravity\t1.017\t\n\t\tProtein, ketone, glucose, bilirubin\tAll negative\t\nSpecial chemistry\t\tBlood\tsmall\t\nD‐dimer\t419 ng/mL\tLeukocyte, nitrite\tBoth negative\t\n\t\tUrobilinogen\tNegative\t\nJohn Wiley & Sons, LtdFIGURE 1 Chest CT scan without contrast showing 8.2 mm pleural nodule in right lung base (top), a 5.4 × 5.6 mm left upper lobe nodule (middle) and left lower lobe pleural effusion (bottom) that all together are suggestive of neoplasm\n\n3 INPATIENT INVESTIGATIONS\nA follow‐up CT scan of her chest, abdomen, and pelvis with contrast showed enlarged mediastinal lymph nodes without any evidence of a hilar or lung parenchymal mass. (Figure 2) Pulmonology was consulted and a follow‐up endobronchial ultrasound (EBUS) guided biopsy was negative for lymphoma or other malignancy. Cardiology was also consulted and an echocardiogram showed a normal left ventricular ejection fraction and was otherwise unremarkable. Also, her pre‐existing UTI was being treated with ceftriaxone while inpatient.\n\nFIGURE 2 A follow‐up chest, abdomen, and pelvis CT scan with contrast showing multiple enlarged mediastinal lymph nodes without any evidence of a hilar or lung parenchymal mass\n\nOn the third day following admission, the patient developed a fever and new‐onset atrial fibrillation for which she was started on rivaroxaban and an increased metoprolol dose. She also received doxycycline for suspected hospital‐acquired pneumonia given her fever and imaging findings. Shortly after, she developed a maculopapular rash across her abdomen and back while becoming hypoxic with increased work of breathing and 6 L oxygen demand. A CT angiogram of her chest ruled out a pulmonary embolism and showed bilateral pleural effusions. Antibiotics were broadened to piperacillin/tazobactam and vancomycin, and she was admitted to the intensive care unit (ICU).\n\n4 NITROFURANTOIN‐INDUCED LUNG INJURY DIAGNOSIS AND TREATMENT\nShe had a 2‐day ICU stay where she was on BiLevel Positive Airway Pressure (BiPAP) support, supplemental oxygen, and IV furosemide diuresis. Infectious disease was consulted and given negative blood cultures, absence of clinical or radiological evidence of pneumonia, or a cardiac cause of fluid overload, a diagnosis of nitrofurantoin‐induced lung injury was suspected. This was supported by the patient's fever, worsening dyspnea, pleural effusion, new‐onset atrial fibrillation, erythema multiforme rash, and eosinophilia. All antibiotics, including ceftriaxone, piperacillin/tazobactam, vancomycin, and doxycycline were discontinued. The patient's symptoms improved, and she was gradually weaned off oxygen and downgraded. Despite improvement, she still had a 2 L O2 requirement with persistent eosinophilia and was started on high dose prednisone. Eosinophils dramatically improved and she was able to be weaned off O2 completely. She passed her home O2 evaluation and was discharged on 20 mg PO that was gradually tapered over 3 weeks, furosemide, and rivaroxaban in addition to her prior to admission medications. At her follow‐up 1 week after discharge, her eosinophil count and leukocyte count returned to within normal limits and her shortness of breath improved markedly. She continued showing improvement at subsequent monthly follow‐up visits and per her most recent follow‐up in July 2020 she remains symptom free.\n\n5 DISCUSSION\nLung injury following nitrofurantoin use is a rare complication in the acute setting. Previous studies indicate the incidence of pulmonary injury due to nitrofurantoin use to be between 0.0001% and 0.001%, with 90% of these cases being acute.\n4\n Patients with renal disease, older age (60‐70 years), and females are most at risk.\n5\n Women represent 85%‐95% of the cases of lung injury due to nitrofurantoin and are accountable for almost all adverse reactions besides blood dyscrasia.\n2\n, \n6\n Women are more susceptible to UTI's, thus, are more likely to receive treatment with nitrofurantoin.\n5\n Renal disease is significant because roughly 50%‐55% of the drug is removed unmetabolized via glomerular filtration and tubular secretion.\n7\n Although a recent study found no difference in adverse reactions in women over 65 years with mild to moderate reduction in eGFR.\n8\n Diagnosis is through exclusion. Given its rarity, patient workups predictably rule out more common or severe causes of lung injury such as pulmonary embolism, congestive heart failure, myocardial infarction, pneumonia, lung malignancy, COPD, ARDS, and others.\n9\n This also occurred in our case.\n\nFor first‐time users, acute pulmonary reactions presented on average 8.7 days after nitrofurantoin use, 24 hours with repeat exposure.\n10\n In our case, the patient presented with symptoms 2 days after beginning nitrofurantoin therapy with worsening of symptoms after 5 days. Patients typically present with the following symptoms in the acute setting: fever (82%), dyspnea (60%), irritating dry cough (43%), rash (20%), fatigue (12%), flu‐like symptoms (9%), cyanosis (4%), jaundice (3%), and weight loss (2%).\n2\n, \n11\n Pulmonary specific lung injury is associated with fever (80%), increased erythrocyte sedimentation rate (80%), eosinophilia (80%), and a dry cough (66%).\n12\n Our patient experienced chest pain, fever, rash, and eosinophilia, typical of other known reports. It is worth noting it is unknown whether the patient had any previous history of nitrofurantoin use. It is also possible the patient suffered an allergic reaction to ceftriaxone or doxycycline but highly unlikely. She was experiencing symptoms before these two drugs were administered, had previous use of ceftriaxone without issues, and her rash was not consistent with that of doxycycline use. Furthermore, our patient did not fully satisfy any known diagnostic criteria for DRESS syndrome such as the RegiSCAR, Bocquet's criteria, or Japanese‐induced hypersensitivity syndrome (DIHS) criteria.\n13\n Also, given the rarity of DRESS syndrome and limited evidence of association with nitrofurantoin, nitrofurantoin‐induced lung injury was the most likely diagnosis for this case.\n\nPhysical exam and imaging for nitrofurantoin‐induced lung injury are nonspecific. Patients may show respiratory distress, rales, crackles, or nothing on physical exam.\n14\n Chest x‐ray may be normal or reveal bilateral lower lobe interstitial infiltrates with or without pleural effusions.\n14\n Chest CT typically will show bilateral ground glass opacities.\n10\n Other comorbidities may convolute the findings of imaging. For example, on chest x‐ray both pulmonary edema due to heart failure and nitrofurantoin‐induced lung injury look very similar. Chest x‐ray and CT scan findings in our patient were consistent with expected imaging. Pathophysiology of nitrofurantoin‐induced lung injury is multifaceted. Studies have indicated the following mechanisms: interstitial inflammation, reactive type II pneumocytes, vasculitis, eosinophilia, focal hemorrhage, small organizing microthrombi, and alveolar exudates associated with macrophages.\n5\n, \n10\n, \n15\n, \n16\n, \n17\n These mechanisms are possibly initiated via oxidation reactions in the lung. Sasame et al demonstrated via an in vivo study that there was a reduction in injury to lung tissue when nitrofurantoin was administered with Vitamin C compared to nitrofurantoin alone.\n17\n This mechanism is not entirely understood, but it might be due to Vitamin C's antioxidant properties and its ability to negate the products of nitrofurantoin‐induced superoxide production, hydrogen peroxide production, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidation.\n10\n, \n15\n, \n17\n\n\n\nTreatment for nitrofurantoin‐induced lung injury in the acute setting is the discontinuation of the drug. Patients experience improvement of symptoms in a relatively short time period, days to weeks.\n10\n, \n12\n A common treatment for nitrofurantoin‐induced lung injury is the use of glucocorticoids. Glucocorticoids have not been proven to be effective in changing prognosis or decreasing recovery time.\n5\n One caveat to this may be that most studies about glucocorticoid use in the context of lung injury from nitrofurantoin use are in the chronic setting. More studies need to be conducted in the acute setting. In this case, the patient's persistent need for O2 and eosinophilia following nitrofurantoin use were indications to start the patient on high dose prednisone. After the addition of the prednisone the patient O2 requirements were weaned off and eosinophil levels decreased to normal levels. It is unclear whether this was due to more time following nitrofurantoin discontinuation or as a result of the glucocorticoid.\n\n6 CONCLUSION\nNitrofurantoin has been proven to be an effective first‐line antibiotic for the treatment of lower UTI in the general population. In this particular case, our patient most likely suffered from a rare but serious adverse effect of nitrofurantoin therapy leading to a presentation of acute lung injury. With the initiation of nitrofurantoin 2 days prior to presentation as well as the exclusion of other possible etiologies such as pulmonary embolism, malignancy, and myocardial infarction, this points to nitrofurantoin as the most likely causative agent. Although the mechanism behind the cause of acute lung injury is still unclear, the management of this rare presentation includes discontinuation of nitrofurantoin with possible initiation of oral glucocorticoids if there is suspicion of respiratory distress.\n\nCONFLICT OF INTEREST\nThe authors declare no conflict of interest.\n\nAUTHOR CONTRIBUTIONS\nRK: initiated this case report; performed literature review and wrote the final manuscript draft. KS: performed literature review and contributed substantially to this manuscript's contents. IS: reviewed the manuscript for intellectual content and contributed key content. KS: advised authors and reviewed this manuscript for intellectual content.\n\nETHICAL APPROVAL\nThis case report does not contain any clinical studies with human participants performed by any of the authors.\n\nCONSENT\nPatient provided written consent for the publication of this case report.\n\nACKNOWLEDGMENT\nThe authors would also like to acknowledge Dr Eleonora Feketeova, research director at Garnet Health Medical Center, who aided in submission to the journal.\n==== Refs\nREFERENCES\n1 \n\nHuttner \nA \n, \nVerhaegh \nEM \n, \nHarbarth \nS \n, \nMuller \nAE \n, \nTheuretzbacher \nU \n, \nMouton \nJW \n. Nitrofurantoin revisited: a systematic review and meta‐analysis of controlled trials\n. J Antimicrob Chemother . 2015 ;70 (9 ):2456 ‐2464\n.26066581 \n2 \n\nHolmberg \nL \n, \nBoman \nG \n, \nBottiger \nLE \n, \nEriksson \nB \n, \nSpross \nR \n, \nWessling \nA \n. Adverse reactions to nitrofurantoin. Analysis of 921 reports\n. Am J Med . 1980 ;69 (5 ):733 ‐738\n.7435512 \n3 \n\nOzkan \nM \n, \nDweik \nRA \n, \nAhmad \nM \n. Drug‐induced lung disease\n. Clevel Clin J Med . 2001 ;68 (9 ):782 ‐795\n.\n4 \n\nYalcin \nS \n, \nSahin \nA \n, \nYalcin \nB \n, \nAltinok \nG \n. Nitrofurantoin toxicity to both liver and lungs\n. Liver . 1997 ;17 (3 ):166 ‐167\n.9249732 \n5 \n\nde Zeeuw \nJ \n, \nGillison \nAG \n. Nitrofurantoin‐induced pulmonary injury. UpToDate\n. https://www.uptodate.com/contents/nitrofurantoin‐induced‐pulmonary‐injury. Updated February 24, 2020. Accessed April 22, 2020.\n6 \n\nSyed \nH \n, \nBachuwa \nG \n, \nUpadhaya \nS \n, \nAbed \nF \n. Nitrofurantoin‐induced interstitial pneumonitis: albeit rare, should not be missed\n. BMJ Case Rep . 2016 ;2016 :bcr2015213967.\n7 \n\nKoulaouzidis \nA \n, \nBhat \nS \n, \nMoschos \nJ \n, \nTan \nC \n, \nRamon \nAD \n. Nitrofurantoin‐induced lung‐ and hepatotoxicity\n. Ann Hepatol . 2007 ;6 (2 ):119 ‐121\n.17519837 \n8 \n\nSingh \nN \n, \nGandhi \nS \n, \nMcarthur \nE \n, et al. Kidney function and the use of nitrofurantoin to treat urinary tract infections in older women\n. Can Med Assoc J . 2015 ;187 (9 ):648 ‐656\n.25918178 \n9 \n\nKabbara \nWK \n, \nKordahi \nMC \n. Nitrofurantoin‐induced pulmonary toxicity: a case report and review of the literature\n. J Infect Public Health . 2015 ;8 (4 ):309 ‐313\n.25747822 \n10 \n\nSovijärvi \nAR \n, \nLemola \nM \n, \nStenius \nB \n, \nIdänpään‐Heikkilä \nJ \n. Nitrofurantoin‐induced acute, subacute and chronic pulmonary reactions\n. Scand J Respir Dis . 1977 ;58 (1 ):41 ‐50\n.841294 \n11 \n\nMullerpattan \nJB \n, \nDagaonkar \nRS \n, \nShah \nHD \n, \nUdwadia \nZF \n. Fatal nitrofurantoin lung\n. J Assoc Physicians India . 2013 ;61 (10 ):758 ‐760\n.24772739 \n12 \n\nHolmberg \nL \n, \nBoman \nG \n. Pulmonary reactions to nitrofurantoin. 447 cases reported to the Swedish adverse Drug Reaction Committee 1966–1976\n. Eur J Respir Dis . 1981 ;62 :180 ‐189\n.7308333 \n13 \n\nKim \nD \n, \nKoh \nY \n. Comparison of diagnostic criteria and determination of prognostic factors for drug reaction with eosinophilia and systemic symptoms syndrome\n. Allergy Asthma Immunol Res . 2014 ;6 (3 ):216 .24843796 \n14 \n\nChudnofsky \nCR \n, \nOtten \nEJ \n. Acute pulmonary toxicity to nitrofurantoin\n. J Emerg Med . 1989 ;7 (1 ):15 ‐19\n.2703684 \n15 \n\nMartin \nWJ \n. Nitrofurantoin: evidence for the oxidant injury of lung parenchymal cells 1,2\n. Am Rev Respir Dis . 1983 ;127 (4 ):482 ‐486\n.6838054 \n16 \n\nD'Arcy \nPF \n. Nitrofurantoin\n. Drug Intell Clin Pharm . 1985 ;19 :540 ‐547\n.3896715 \n17 \n\nSasame \nHA \n, \nBoyd \nMR \n. Superoxide and hydrogen peroxide production and NADPH oxidation stimulated by nitrofurantoin in lung microsomes: possible implications for toxicity\n. Life Sci . 1979 ;24 (12 ):1091 ‐1096\n.36538\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "8(10)",
"journal": "Clinical case reports",
"keywords": "acute lung injury; drug‐induced pulmonary toxicity; nitrofurantoin",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "2029-2033",
"pmc": null,
"pmid": "33088545",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports",
"references": "841294;25747822;25918178;26066581;24843796;24772739;6838054;36538;7308333;9249732;2703684;3896715;11563482;7435512;17519837;26912767",
"title": "A rare case of nitrofurantoin-induced acute lung injury.",
"title_normalized": "a rare case of nitrofurantoin induced acute lung injury"
} | [
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"companynumb": "US-ALVOGEN-2020-ALVOGEN-115136",
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"activesubstance": {
"activesubstancename": "VANCOMYCIN"
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"drugadditional": "1",
... |
{
"abstract": "Diphenhydramine toxicity manifests with signs of anticholinergic toxicity; therapy is generally supportive. In rare cases, patients can also present with a wide complex tachycardia due to sodium channel blockade. Treatment involves sodium bicarbonate. Lidocaine and hypertonic saline are used for arrhythmias refractory to sodium bicarbonate. Although intravenous fat emulsion (IFE) therapy is proposed as an adjunctive therapy due to the lipophilicity of diphenhydramine (octanol/water partition coefficient of 3.3), successful use of IFE after a confirmed sole ingestion of diphenhydramine is not previously reported. We present the case of a 30-year-old woman presenting with seizures, a wide complex tachycardia, and cardiovascular collapse after an ingestion of diphenhydramine refractory to other therapies with rapid improvement after IFE administration.",
"affiliations": "1Barnes-Jewish Hospital, Division of Emergency Medicine, St Louis, MO; 2Division of Emergency Medicine, Washington University School of Medicine, St Louis, MO; and Barnes-Jewish Hospital, Department of Pharmacy, St Louis, MO.",
"authors": "Abdelmalek|Dimyana|D|;Schwarz|Evan S|ES|;Sampson|Christopher|C|;Halcomb|Sarah E|SE|;McCammon|Craig|C|;Arroyo-Plasencia|Anna|A|;Stenger|Adam|A|;Krehbiel|Nick|N|;Mullins|Michael E|ME|",
"chemical_list": "D005217:Fat Emulsions, Intravenous; D004155:Diphenhydramine",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0b013e318281191b",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-2765",
"issue": "21(6)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000328:Adult; D004155:Diphenhydramine; D062787:Drug Overdose; D005217:Fat Emulsions, Intravenous; D005260:Female; D006801:Humans; D012640:Seizures; D013610:Tachycardia",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "542-4",
"pmc": null,
"pmid": "24096706",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Life-threatening diphenhydramine toxicity presenting with seizures and a wide complex tachycardia improved with intravenous fat emulsion.",
"title_normalized": "life threatening diphenhydramine toxicity presenting with seizures and a wide complex tachycardia improved with intravenous fat emulsion"
} | [
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"companynumb": "US-MYLANLABS-2015M1026095",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "DIPHENHYDRAMINE"
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... |
{
"abstract": "BACKGROUND\nCyclosporine A-associated neurotoxicity has been reported mainly after organ transplantation. Only a small number of children with steroid-resistant nephrotic syndrome and cyclosporine A-associated neurotoxicity have been reported.\n\n\nMETHODS\nWe report three children, aged 4, 11, and 15, with steroid-resistant nephrotic syndrome and cyclosporine A-associated neurotoxicity. In two of the patients, primary diagnosis was idiopathic nephrotic syndrome, and in one it was IgA nephropathy. Magnetic resonance with diffusion-weighted imaging, combined with quantification of apparent diffusion coefficient values, showed lesions caused by cytotoxic edema indicating irreversible brain damage. Nonetheless, the patients fully recovered clinically and radiologically after prompt discontinuation of cyclosporine A.\n\n\nCONCLUSIONS\nNeurotoxic effects should be suspected in any child with nephrotic syndrome treated with cyclosporine A in whom sudden neurological symptoms occur. Cytotoxic edema is a rare finding in pediatric patients. However, even in such cases with seemingly irreversible brain damage, full recovery without permanent neurological sequels is possible with prompt cyclosporine A discontinuation and supportive therapy.",
"affiliations": "University Zagreb School of Medicine, Department of Pediatrics, University Hospital Center Zagreb, Kišpatićeva 12, 10000, Zagreb, Croatia. danka.batinic@zg.t-com.hr.;University Zagreb School of Medicine, Department of Pediatrics, University Hospital Center Zagreb, Kišpatićeva 12, 10000, Zagreb, Croatia.;University Zagreb School of Medicine, Department of Pediatrics, University Hospital Center Zagreb, Kišpatićeva 12, 10000, Zagreb, Croatia.;University Zagreb School of Medicine, Department of Anesthesiology and Intensive Care, University Hospital Center Zagreb, Zagreb, Croatia.;University Zagreb School of Medicine, Department of Pediatrics, University Hospital Center Zagreb, Kišpatićeva 12, 10000, Zagreb, Croatia.;School of Medicine, University of Zagreb, Zagreb, Croatia.",
"authors": "Batinić|Danica|D|;Milošević|Danko|D|;Filipović-Grčić|Boris|B|;Topalović-Grković|Marija|M|;Barišić|Nina|N|;Turudić|Daniel|D|",
"chemical_list": "D016572:Cyclosporine",
"country": "Austria",
"delete": false,
"doi": "10.1007/s00508-017-1221-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0043-5325",
"issue": "129(15-16)",
"journal": "Wiener klinische Wochenschrift",
"keywords": "Children; Cyclosporine A neurotoxicity; Steroid-resistant nephrotic syndrome",
"medline_ta": "Wien Klin Wochenschr",
"mesh_terms": "D000293:Adolescent; D001921:Brain; D001925:Brain Damage, Chronic; D001929:Brain Edema; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine; D004351:Drug Resistance; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009404:Nephrotic Syndrome; D012307:Risk Factors",
"nlm_unique_id": "21620870R",
"other_id": null,
"pages": "579-582",
"pmc": null,
"pmid": "28600697",
"pubdate": "2017-08",
"publication_types": "D016428:Journal Article",
"references": "21152945;10399863;21556718;20497762;21785849;23052648;14758527;25120830;18445907",
"title": "Neurotoxicity of cyclosporine A in children with steroid-resistant nephrotic syndrome: is cytotoxic edema really an unfavorable predictor of permanent neurological damage?",
"title_normalized": "neurotoxicity of cyclosporine a in children with steroid resistant nephrotic syndrome is cytotoxic edema really an unfavorable predictor of permanent neurological damage"
} | [
{
"companynumb": "HR-TEVA-808970ROM",
"fulfillexpeditecriteria": "1",
"occurcountry": "HR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "1",
"dr... |
{
"abstract": "Selinexor is an oral Selective Inhibitor of Nuclear Export compound that specifically blocks Chromosomal Region Maintenance protein 1.\n\n\n\nTo evaluate the safety and tolerability of escalating doses of selinexor plus 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) in metastatic colorectal cancer (mCRC) patients.\n\n\n\nIn this multicenter phase I trial, mCRC patients, eligible for oxaliplatin-based treatment, were enrolled to receive oral selinexor on days 1, 3, and 8 plus mFOLFOX6 every two weeks. Primary endpoint was the maximum tolerated dose. Secondary endpoints were toxicity, overall response rate, progression free survival, and overall survival.\n\n\n\nOverall, 10 patients were enrolled, who had prior treatment with oxaliplatin (6/10), irinotecan (8/10), bevacizumab (6/10) or anti-EGFR therapy (5/10). Four consecutive patients received 40 mg selinexor plus mFOLFOX6. All four experienced dose-limiting toxicities and withdrew from the study after a median of two cycles. Thus, this dose level was regarded as toxic and no further patients were evaluated at this dose. Six patients were enrolled with 20 mg selinexor plus mFOLFOX6. Despite better tolerability, four patients withdrew (patient wish) after the first cycle and only two patients continued until disease progression. Most commonly reported treatment emergent adverse events were nausea (80%), diarrhea (70%), vomiting (60%), fatigue (60%), anorexia (40%), and impaired vision (40%). Due to the short treatment exposure, no relevant clinical activity was observed.\n\n\n\nIn patients with metastatic colorectal cancer, selinexor on this dose schedule plus mFOLFOX6 was not tolerable. Other dosing schedules or combinations may be evaluated. Clinical trial identifier NCT02384850.",
"affiliations": "II. Medical Clinic and Polyclinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;II. Medical Clinic and Polyclinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Phase I- Early Clinical Trials Unit, Antwerp University Hospital, Edegem, Belgium;GSO Global Clinical Research B.V., Amsterdam, the Netherlands;II. Medical Clinic and Polyclinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Phase I- Early Clinical Trials Unit, Antwerp University Hospital, Edegem, Belgium;GSO Gesellschaft für Studienmanagement und Onkologie mbH, Hamburg, Germany;GSO Gesellschaft für Studienmanagement und Onkologie mbH, Hamburg, Germany;II. Medical Clinic and Polyclinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany",
"authors": "Nilsson|Sven|S|;Stein|Alexander|A|;Rolfo|Christian|C|;Kranich|Anne L|AL|;Mann|Julia|J|;Papadimitriou|Konstantinos|K|;Theile|Susann|S|;Amberg|Stefanie|S|;Bokemeyer|Carsten|C|",
"chemical_list": "D006834:Hydrazines; D014230:Triazoles; D000077150:Oxaliplatin; C585161:selinexor; D002955:Leucovorin; D005472:Fluorouracil",
"country": "Netherlands",
"delete": false,
"doi": "10.2174/1568009620666200628105727",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1568-0096",
"issue": "20(10)",
"journal": "Current cancer drug targets",
"keywords": "FOLFOX; KPT-330; Metastatic colorectal cancer; SINE; colorectal cancer; mCRC; phase I clinical trial; selinexor",
"medline_ta": "Curr Cancer Drug Targets",
"mesh_terms": "D021581:Active Transport, Cell Nucleus; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D015179:Colorectal Neoplasms; D005260:Female; D005472:Fluorouracil; D005500:Follow-Up Studies; D006801:Humans; D006834:Hydrazines; D002955:Leucovorin; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D000077150:Oxaliplatin; D011379:Prognosis; D015996:Survival Rate; D014230:Triazoles",
"nlm_unique_id": "101094211",
"other_id": null,
"pages": "811-817",
"pmc": null,
"pmid": "32598257",
"pubdate": "2020",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Selinexor (KPT-330), an Oral Selective Inhibitor of Nuclear Export (SINE) Compound, in Combination with FOLFOX in Patients with Metastatic Colorectal Cancer (mCRC) - Final Results of the Phase I Trial SENTINEL.",
"title_normalized": "selinexor kpt 330 an oral selective inhibitor of nuclear export sine compound in combination with folfox in patients with metastatic colorectal cancer mcrc final results of the phase i trial sentinel"
} | [
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"abstract": "A 30-year-old man with advanced HIV and disseminated histoplasmosis deteriorated after stepping down from intravenous liposomal amphotericin B to itraconazole. Therapeutic levels of itraconazole and posaconazole were not achieved, therefore liposomal amphotericin B was reintroduced. Stepdown treatment was switched to oral isavuconazole; since then the patient has remained well.",
"affiliations": "Alexander Pringle Centre, North Middlesex University Hospital, Sterling Way, N18 1QX, London, UK.;Alexander Pringle Centre, North Middlesex University Hospital, Sterling Way, N18 1QX, London, UK.;Alexander Pringle Centre, North Middlesex University Hospital, Sterling Way, N18 1QX, London, UK.;Alexander Pringle Centre, North Middlesex University Hospital, Sterling Way, N18 1QX, London, UK.;Alexander Pringle Centre, North Middlesex University Hospital, Sterling Way, N18 1QX, London, UK.;Alexander Pringle Centre, North Middlesex University Hospital, Sterling Way, N18 1QX, London, UK.",
"authors": "Mazzella|Andrea|A|;Stone|Neil R H|NRH|;Pool|Erica R M|ERM|;García Mingo|Ana|A|;Bolache|Sorina|S|;Wood|Chris|C|",
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"fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(19)30130-710.1016/j.mmcr.2019.12.013Case ReportHIV-associated disseminated histoplasmosis successfully treated with isavuconazole consolidation therapy Mazzella Andrea andrea.mazzella@nhs.neta∗Stone Neil R.H. aPool Erica R.M. abGarcía Mingo Ana aBolache Sorina aWood Chris aa Alexander Pringle Centre, North Middlesex University Hospital, Sterling Way, N18 1QX, London, UKb University College London, Gower Street, WC1E 6BT, London, UK∗ Corresponding author. Present address: London School of Hygiene & Tropical Medicine, Keppel Street, WC1E 7HT, London, UK. andrea.mazzella@nhs.net20 12 2019 3 2020 20 12 2019 27 42 43 18 12 2019 19 12 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).A 30-year-old man with advanced HIV and disseminated histoplasmosis deteriorated after stepping down from intravenous liposomal amphotericin B to itraconazole.\n\nTherapeutic levels of itraconazole and posaconazole were not achieved, therefore liposomal amphotericin B was reintroduced. Stepdown treatment was switched to oral isavuconazole; since then the patient has remained well.\n\nHighlights\n• Isavuconazole was effective in disseminated histoplasmosis as consolidation therapy.\n\n• Lower plasma isavuconazole levels (1.6–2 μg/mL) were associated with a good outcome.\n\n• With low plasma itraconazole levels, isavuconazole was a viable alternative.\n\n\n\nKeywords\nHistoplasmosisIsavuconazoleItraconazoleHIVHistoplasma capsulatum\n==== Body\n1 Introduction\nDisseminated histoplasmosis, an infection caused by dimorphic fungus Histoplasma capsulatum, is well described in patients with advanced HIV, and it carries a high mortality [1]. Standard therapy is with intravenous liposomal amphotericin B (LAmB), followed by oral itraconazole [2,3], however itraconazole has variable patient-to-patient pharmacokinetics, and its inadequate plasma concentrations can lead to subtherapeutic drug levels and treatment failure [4]. Isavuconazole is a newer azole antifungal that has in vitro activity against H. capsulatum [5]; the evidence for its clinical use to treated disseminated histoplasmosis is however scarce. Here we present a case of disseminated histoplasmosis successfully treated with isavuconazole consolidation therapy.\n\n2 Case\nA 30-year-old man, born and raised in Ghana but recently moved to the UK, presented with a 2-week history of fever, cough, diarrhoea, and weight loss. He had been recently diagnosed with HIV infection but had not yet started treatment. HIV viral load was 1.5 million copies/mL, and CD4 count was 20/μL (2%). On admission (day 0), he was pyrexial with hepatosplenomegaly and oral candidiasis; blood tests showed a normocytic anaemia, neutrophilia, eGFR >90 mL/min, AST 120 U/L, ALT 88 U/L, bilirubin 10 μmol/L, CRP 112 μmol/L.\n\nCT scan of the thorax, abdomen and pelvis revealed clear lung fields, mild cardiomegaly, and hepatosplenomegaly. There was no significant lymphadenopathy. β-D-glucan level was elevated at 146 pg/mL (url: 80 pg/mL) and serum galactomannan antigen index was 11.187.\n\nA liver biopsy was performed; Grocott staining showed small spherical organism consistent with Histoplasma. Nuclear ribosomal repeat region sequencing was positive for H. capsulatum fungal 18s rRNA gene. A bone marrow biopsy revealed haemophagocytosis and yeasts. Additionally, H. capsulatum was isolated from a sputum culture.\n\nMRI brain and CSF analysis showed no evidence of CNS involvement. Histoplasma urinary antigen was positive, although testing is not routinely available in the UK, therefore the result was obtained after the diagnosis had been obtained by PCR of the liver biopsy.\n\nA diagnosis of disseminated histoplasmosis in the context of advanced HIV was made. Treatment with intravenous LAmB (3 mg/kg once daily) was commenced on day 22, followed a week later by antiretroviral therapy with emtricitabine, tenofovir disoproxil and dolutegravir. The patient had a marked clinical improvement, with resolution of pyrexia and decrease of inflammatory markers.\n\nOn day 39, LAmB was switched to oral itraconazole capsules, 200mg twice daily.\n\nThe patient was followed up as an outpatient on a weekly basis. He reported good compliance with both antiretrovirals and itraconazole. Repeated HIV viral load was undetectable, and CD4 count had increased to 50/μL.\n\nOn week 10, he was found to be pyrexial at 39.6 °C, therefore he was re-admitted to hospital. Plasma itraconazole concentration was 0.2 mg/L (reference range 1–2 mg/L). Due to presumed relapse of histoplasmosis (as no other cause of fever was found), intravenous LAmB was restarted at the same dose alongside oral itraconazole, this time in liquid suspension given the low drug levels with capsules. Despite directly observed treatment as an inpatient, trough itraconazole levels remained subtherapeutic.\n\nItraconazole was switched to posaconazole on week 18 (liquid suspension, 400 mg once daily), alongside LAmB. Plasma trough posaconazole levels, however, were also subtherapeutic, at 0.09 mg/L. Voriconazole was avoided due to concerns regarding drug interactions and toxicity.\n\nOral isavuconazole was therefore introduced in month 7 (loading dose 200 mg 8-hourly for 48 hours, followed by 200mg once daily) alongside LAmB. An isavuconazole plasma trough level after one week of treatment was 1.72 μg/mL, and later consistently >1.6 μg/mL.\n\nThe patient significantly improved with resolution of fever and was able to continue on isavuconazole monotherapy and has since made a complete clinical recovery. He remains well on isavuconazole therapy one year later.\n\n3 Discussion\nThis patient was from Ghana, where the burden of histoplasmosis is unknown, but likely to be grossly underestimated due to lack of diagnostics. However, there are 12 case reports of histoplasmosis from Ghana over 60 years, mostly associated with HIV [6].\n\nTreatment is usually with oral itraconazole after amphotericin-based therapy.\n\nIsavuconazole is a newer antifungal triazole, used for treatment of both invasive aspergillosis and mucormycosis [7]. It also has in vitro activity against H. capsulatum [5], reliable pharmacokinetics and relatively few drug interactions, making it an attractive agent for use in this context. Additionally, it is unique amongst azole antifungals in that it shortens rather than prolongs the QT interval, which can preclude use of azoles in some patients [8].\n\nTo date, there has been very limited experience with isavuconazole to treat disseminated histoplasmosis. In the VITAL study [9], seven patients with histoplasmosis were treated with primary or salvage isavuconazole therapy. Out of the four with disseminated disease, half had treatment success, one had a partial success, and another had progression. Isavuconazole was also used successfully in a case of Histoplasma endocarditis [10] and in a case of oesophageal histoplasmosis in the context of advanced HIV infection [11].\n\nWe are not aware of any previously reported cases treated with isavuconazole as a consolidation treatment after induction with LAmB.\n\nAs there is high interpersonal variability in itraconazole and posaconazole pharmacokinetics, it is strongly suggested to routinely perform therapeutic drug monitoring (TDM) after starting treatment [4]. Additionally, their absorptions are highly variable and are not consistent between drug formulations. As isavuconazole has reliable more pharmacokinetics, its TDM is not routinely indicated [4], but may be required in complex cases, or in renal impairment. The Public Health England Mycology Reference Laboratory refers to 2.0–4.0 μg/mL as the normal range for isavuconazole. However, a clinically relevant therapeutic range has yet to be established, as no drug level threshold has been linked to outcome [12]. In our case, measured isavuconazole levels were slightly below this range.\n\nThis case describes successful consolidation treatment of disseminated histoplasmosis with isavuconazole, in a person living with HIV and in whom therapeutic drug levels were not achievable with itraconazole or posaconazole. This suggests that isavuconazole is a viable therapeutic option as an alternative to itraconazole and requires further evaluation as consolidation therapy in the treatment of histoplasmosis and other invasive fungal infections.\n\nDeclaration of competing interest\nThere are none.\n\nErica Pool is funded by a National Institute for Health Research Academic Clinical Fellowship. The views expressed are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health.\n\nAcknowledgements\nWe are thankful to Dr Elizabeth Johnson (PHE Mycology Reference Laboratory), Joyce Mahungu and Dr Jonathan Ainsworth (NMUH Alexander Pringle Centre), Dr Mariyam Mirfenderesky and Dr Nehal Draz (NMUH Microbiology) for the extremely helpful advice.\n==== Refs\nReferences\n1 Baddley J.W. Sankara I.R. Rodriquez J.M. Pappas P.G. Many W.J. Histoplasmosis in HIV-infected patients in a southern regional medical center: poor prognosis in the era of highly active antiretroviral therapy Diagn. Microbiol. Infect. Dis. 62 2 2008 151 156 18597967 \n2 Wheat L.J. Freifeld A.G. Kleiman M.B. Baddley J.W. McKinsey D.S. Loyd J.E. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the infectious diseases society of America Clin. Infect. Dis. 45 7 2007 807 825 17806045 \n3 Nelson M. Dockrell D. Edwards S. British HIV Association and British Infection Association guidelines for the treatment of opportunistic infection in HIV-seropositive individuals 2011 HIV Med. 12 2011 1 5 September \n4 Stott K.E. Hope W.W. Therapeutic drug monitoring for invasive mould infections and disease: pharmacokinetic and pharmacodynamic considerations. J Antimicrob Chemother 2017 \n5 Spec A. Connolly P. Montejano R. Wheat L.J. In vitro activity of isavuconazole against fluconazole-resistant isolates of Histoplasma capsulatum Med. Mycol. 56 7 2018 834 837 29253204 \n6 Oladele R.O. Ayanlowo O.O. Richardson M.D. Denning D.W. Histoplasmosis in Africa: an emerging or a neglected disease? PLoS Neglected Trop. Dis. 12 1 2018 1 17 \n7 Maertens J.A. Raad I.I. Marr K.A. Patterson T.F. Kontoyiannis D.P. Cornely O.A. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial Lancet 387 10020 2016 760 769 26684607 \n8 Mellinghoff S.C. Bassetti M. Dörfel D. Hagel S. Lehners N. Plis A. Isavuconazole shortens the QTc interval Mycoses 61 4 2018 256 260 29178247 \n9 Thompson G.R. Rendon A. Ribeiro Dos Santos R. Queiroz-Telles F. Ostrosky-Zeichner L. Azie N. Isavuconazole treatment of cryptococcosis and dimorphic mycoses Clin. Infect. Dis. 63 3 2016 356 362 27169478 \n10 Wiley Z. Woodworth M.H. Jacob J.T. Lockhart S.R. Rouphael N.G. Gullett J.C. Diagnostic importance of hyphae on heart valve tissue in Histoplasma endocarditis and treatment with isavuconazole Open Forum Infect. Dis. 4 4 2017 1 2 \n11 Finniss M. Lewis P. Myers J. Ibrahim L. Patel P. A case of gastrointestinal histoplasmosis with esophageal involvement [Internet] Clin. J. Gastroenterol. 2019 0123456789 Available from: \n12 Desai A.V. Kovanda L.L. Hope W.W. Andes D. Mouton J.W. Kowalski D.L. Exposure-response relationships for isavuconazole in patients with invasive aspergillosis and other filamentous fungi Antimicrob. Agents Chemother. 61 12 2017 1 9\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2211-7539",
"issue": "27()",
"journal": "Medical mycology case reports",
"keywords": "HIV; Histoplasma capsulatum; Histoplasmosis; Isavuconazole; Itraconazole",
"medline_ta": "Med Mycol Case Rep",
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"pages": "42-43",
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"pubdate": "2020-03",
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"references": "29346384;21851517;29253204;18597967;27169478;17806045;29255737;28355463;26684607;28923872;29178247;31486020",
"title": "HIV-associated disseminated histoplasmosis successfully treated with isavuconazole consolidation therapy.",
"title_normalized": "hiv associated disseminated histoplasmosis successfully treated with isavuconazole consolidation therapy"
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"abstract": "BACKGROUND\nPheochromocytoma, especially for noncatecholamine-secreting pheochromocytoma, is an extremely rare cause of ectopic corticotrophin-releasing hormone (CRH) syndrome.\n\n\nMETHODS\nA 27-year-old Chinese woman was administered dexamethasone for a skin allergy, but her general condition rapidly deteriorated over a month. She was subsequently hospitalized for typical clinical features of Cushing's syndrome. Endocrinological investigation confirmed severe hypercortisolism along with elevated plasma adrenocorticotropin hormone (ACTH). However, magnetic resonance imaging (MRI) revealed no pituitary adenoma. Abdominal contrast-enhanced computed tomography (CT) revealed a 6.5 cm heterogeneous right adrenal mass with mildly contrast enhancement. The tumor was found during a routine physical check-up at a local hospital 16 months ago; however, the patient did not have any symptoms and did not seek further medical attention at that time. Laparoscopic resection of the right adrenal tumor led to a rapid remission of Cushing's syndrome. Based on pathological findings and the presence of normal catecholamine metabolites in her serum and urine, the patient was diagnosed with noncatecholamine-secreting pheochromocytoma. Immunohistochemical staining of the adrenal tumor revealed positive staining for CRH and negative staining for ACTH.\n\n\nCONCLUSIONS\nThis is an extremely rare case of ectopic CRH syndrome caused by an adrenal noncatecholamine-secreting pheochromocytoma. Both ectopic ACTH syndrome and ectopic CRH syndrome should be considered in patients presenting with ACTH-dependent Cushing's syndrome caused by extrapituitary diseases.",
"affiliations": "Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, No 154 Anshan Road, Heping District, Tianjin, 300052, China.;Department of Gerontology, Beijing ChuiYangLiu Hospital (Chui Yang Liu Hospital affiliated to TsingHua University), Beijing, 100022, China.;Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, No 154 Anshan Road, Heping District, Tianjin, 300052, China.;Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, No 154 Anshan Road, Heping District, Tianjin, 300052, China.;Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, No 154 Anshan Road, Heping District, Tianjin, 300052, China.;Department of Urology, Tianjin Medical University General Hospital, No 154 Anshan Road, Heping District, Tianjin, 300052, China.;Department of Pathology, Tianjin Medical University General Hospital, No 154 Anshan Road, Heping District, Tianjin, 300052, China.;Department of Medical Imaging, Tianjin Medical University General Hospital, No 154 Anshan Road, Heping District, Tianjin, 300052, China.;Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, No 154 Anshan Road, Heping District, Tianjin, 300052, China. mingliu@tmu.edu.cn.",
"authors": "Wang|Bao-Ping|BP|;Yang|Lei-Lei|LL|;Wang|Hao|H|;He|Qing|Q|;Ma|Zhong-Shu|ZS|;Lin|Yi|Y|;Jiang|Chang-Xin|CX|;Sun|Hao-Ran|HR|;Liu|Ming|M|",
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"fulltext": "\n==== Front\nBMC Endocr DisordBMC Endocr DisordBMC Endocrine Disorders1472-6823BioMed Central London 26910.1186/s12902-018-0269-8Case ReportAn unusual case of ectopic corticotrophin-releasing hormone syndrome caused by an adrenal noncatecholamine-secreting pheochromocytoma: a case report Wang Bao-Ping ghwbp@126.com 1Yang Lei-Lei lei_lei_yang@163.com 2Wang Hao tijmuwanghao@163.com 1He Qing hech69@hotmail.com 1Ma Zhong-Shu zhongshuma@sina.com 1Lin Yi linyi6312@hotmail.com 3Jiang Chang-Xin jiangchx2009@163.com 4Sun Hao-Ran sunhaoran2006@Hotmail.com 5Liu Ming mingliu@tmu.edu.cn 11 0000 0004 1757 9434grid.412645.0Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, No 154 Anshan Road, Heping District, Tianjin, 300052 China 2 grid.414343.5Department of Gerontology, Beijing ChuiYangLiu Hospital (Chui Yang Liu Hospital affiliated to TsingHua University), Beijing, 100022 China 3 0000 0004 1757 9434grid.412645.0Department of Urology, Tianjin Medical University General Hospital, No 154 Anshan Road, Heping District, Tianjin, 300052 China 4 0000 0004 1757 9434grid.412645.0Department of Pathology, Tianjin Medical University General Hospital, No 154 Anshan Road, Heping District, Tianjin, 300052 China 5 0000 0004 1757 9434grid.412645.0Department of Medical Imaging, Tianjin Medical University General Hospital, No 154 Anshan Road, Heping District, Tianjin, 300052 China 19 6 2018 19 6 2018 2018 18 4121 7 2017 8 6 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\nPheochromocytoma, especially for noncatecholamine-secreting pheochromocytoma, is an extremely rare cause of ectopic corticotrophin-releasing hormone (CRH) syndrome.\n\nCase presentation\nA 27-year-old Chinese woman was administered dexamethasone for a skin allergy, but her general condition rapidly deteriorated over a month. She was subsequently hospitalized for typical clinical features of Cushing’s syndrome. Endocrinological investigation confirmed severe hypercortisolism along with elevated plasma adrenocorticotropin hormone (ACTH). However, magnetic resonance imaging (MRI) revealed no pituitary adenoma. Abdominal contrast-enhanced computed tomography (CT) revealed a 6.5 cm heterogeneous right adrenal mass with mildly contrast enhancement. The tumor was found during a routine physical check-up at a local hospital 16 months ago; however, the patient did not have any symptoms and did not seek further medical attention at that time. Laparoscopic resection of the right adrenal tumor led to a rapid remission of Cushing’s syndrome. Based on pathological findings and the presence of normal catecholamine metabolites in her serum and urine, the patient was diagnosed with noncatecholamine-secreting pheochromocytoma. Immunohistochemical staining of the adrenal tumor revealed positive staining for CRH and negative staining for ACTH.\n\nConclusions\nThis is an extremely rare case of ectopic CRH syndrome caused by an adrenal noncatecholamine-secreting pheochromocytoma. Both ectopic ACTH syndrome and ectopic CRH syndrome should be considered in patients presenting with ACTH-dependent Cushing’s syndrome caused by extrapituitary diseases.\n\nKeywords\nAdrenocorticotropinDexamethasoneEctopic CRH syndromePheochromocytomaNoncatecholamine secretingissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nCushing’s syndrome is classified as either ACTH-independent or ACTH-dependent, which can be further classified as either Cushing’s disease or ectopic ACTH syndrome (EAS). EAS accounts for 10–20% of all cases of Cushing’s syndrome [1]. The most common origins of the tumors responsible for EAS are the lungs (45%), thymus (11%), pancreas (8%), and thyroid (6%) [2]. Pheochromocytoma accounts for approximately 5% of EAS cases [2]. Approximately 1.3% of all identified pheochromocytomas have ectopic ACTH secretion [3]; in rare cases, the ectopically secreted hormone is CRH, with ACTH being secreted by the pituitary gland [4]. To date, only one case has been reported where a patient with an ectopic CRH-secreting pheochromocytoma had normal catecholamine metabolites [5]. Dexamethasone has negative feedback on CRH gene expression and secretion in the hypothalamus. However, dexamethasone could stimulate CRH expression in the placenta and the bed nucleus of the stria terminalis, suggesting that dexamethasone regulation might be tissue-specific [6]. Here, we reported a patient with ectopic CRH syndrome caused by an adrenal noncatecholamine-secreting pheochromocytoma that was associated with a use of dexamethasone.\n\nCase presentation\nPrior to this admission, a 27-year-old woman sought medical attention at a local hospital because of facial redness and edema caused by eating a mango. She was treated with dexamethasone (5 mg intravenously daily) for five days. The patient gradually developed a round face, acne, hirsutism, hypokalemia, and 5 kg of weight loss over the course of one month since receiving dexamethasone. Upon hospitalization, the patient presented with a one-month history of facial edema, weight loss, and acne. She had no family history of Cushing’s syndrome, pheochromocytoma, or multiple endocrine neoplasia type 2. A 5.5-cm mass located in the right posterior lobe of the liver was detected by ultrasound in a routine physical examination 16 months ago at a local hospital; however, the patient had no symptom and did not seek further medical attention at that time.\n\nThe patient’s blood pressure was 120/75 mmHg in both arms in the supine position, with a regular pulse of 76 bpm. Her height was 164 cm and her weight was 48 kg (body mass index:17.8 kg/m2). The patient had “moon face” and severe facial edema, beard, central deposition of fat with slim extremities and atrophic muscles, and no pretibial edema. The skin was diffused with acne and both armpits had hyperpigmentaion.\n\nLaboratory tests revealed marked hypokalemia (2.1 mmol/L; normal range, 3.5–5.5 mmol/L), which could not be normalized with oral and intravenous potassium supplementation until spironolactone was added. A 75-g oral glucose tolerance test confirmed diabetes mellitus with a fasting blood glucose level of 9.19 mmol/l and a 2-h glucose level of 21.66 mmol/L, with a HbA1c level of 6.3%. She was started on insulin aspart30 (48 U daily).\n\nEndocrinological investigation identified severe hypercortisolism with loss of circadian rhythm. Plasma ACTH level was elevated to 1157 pg/mL, confirming ACTH-dependent Cushing’s syndrome. Except for testosterone, the catecholamine metabolites, growth hormone, calcitonin, and prolactin levels were all within the normal range (Table 1).Table 1 Laboratory findings of pertinent hormones\n\n\tBaseline value\tOvernight dexamethasone suppression test\tNormal range\t\nSerum cortisol\t\t\t5–25 μg/dL\t\n 08:00 h\t>50\t>50\t\t\n 16:00 h\t>50\t\t\t\n 00:00 h\t>50\t\t\t\nUrine free cortisol\t>2000\t\t30–110 μg/24 h\t\nACTH\t\t\t0–46 pg/mL\t\n 08:00 h\t1157\t625\t\t\n 16:00 h\t459\t\t\t\n 00:00 h\t350\t\t\t\nVMA\t20.5\t\t<72 μmol/24 h\t\nMetanephrine\t0.15\t\t≤0.5 nmol/L\t\nNormetanephrine\t0.13\t\t≤0.9 nmol/L\t\nFSH\t5.36\t\t2.5–10.2 IU/L\t\nLH\t0.4\t\t1.9–12.5 IU/L\t\nGH\t0.12\t\t0.06–5 ng/mL\t\nPRL\t0.3\t\t2.8–29.2 ng/mL\t\nT\t154.9\t\t14–76 ng/dL\t\nE2\t26.18\t\t19–144 pg/mL\t\nCT\t<2\t\t0–5 pg/mL\t\nTSH\t0.014\t\t0.3–5.0 IU/mL\t\nFT4\t11.94\t\t11.5–23.5 ng/dL\t\nFT3\t2.21\t\t3.5–5.5 ng/dL\t\nrT3\t0.34\t\t0.2–0.4 ng/mL\t\nVMA: 24-hurinary vanillylmandelicacid; FSH: follicle-stimulating hormone; LH: luteinizing hormone; E2: estradiol; CT: calcitonin; PRL: prolactin; T: testosterone; FT3: free thyroxin; FT4: free triiodothyronine; TSH: thyroid stimulating hormone; rT3: reverse thyroxin\n\n\n\nMRI and contrasted MRI revealed no pituitary adenoma and EAS was considered. Abdominal contrast-enhanced CT scanning revealed that the mass lesion was located in the right adrenal gland and not in the right hepatic posterior lobe. The mass was a heterogeneous solid tumor which was mildly enhanced with some patchy nonenhancing areas (Fig. 1a). PET/CT showed moderate fluorodeoxyglucose (FDG) uptake in the mass (Fig. 1b). Both contrasted CT and PET-CT revealed bilateral adrenal hyperplasia, but the neck, thorax, and pelvis were normal.Fig. 1 The CT and PET/CT image of the adrenal pheochromocytoma. a Abdominal contrast-enhanced CT revealing a mass with a diameter 6.5 cm in the right adrenal gland. The mass was a heterogeneous solid tumor which was mildly enhanced with some patchy nonenhancing areas (arrow). b PET/CT showed moderate FDG uptake in the right adrenal mass(arrow)\n\n\n\nWe prepared to do inferior petrosal sinus sampling (IPSS) for ACTH assays, adrenal vein sampling for ACTH assays to make out the origin of ACTH. But the patient’s general condition rapidly deteriorated after admission, Adrenal tumorectomy was performed. During surgery, when the right adrenal mass was mobilized, no hypertensive crisis occurred. A 6.5-cm black mass was found arising from the medial branch of the right adrenal gland (Fig. 2a). Hematoxylin-eosin staining of the tumor revealed that most of the cells were chromaffin-like cells. In addition, there were multifocal oval eosinophilic cells under the tumor capsule (Fig. 2b). Immunohistochemical staining showed positive staining for chromogranin A (CgA) (Fig. 2c) and CD56 (Fig. 2d), with a Ki67 labeling index of approximately 16% (Fig. 2e) for chromaffin-like cells. No positive ACTH immunostaining was noticed (Fig. 2f). Positive immunostaining for CRH and Melan-A (Fig. 2g and h) and negative immunostaining for CgA and CD56 were found in the eosinophilic cells, indicating that CRH production is indeed derived from the tumor’s peripheral cells.Fig. 2 External appearance and histopathology of the pheochromocytoma. a External appearance of the resected tumor, 6.5 cm in diameter and black in color, from the medial branch of right adrenal gland with enlargement of the lateral branch. b Histopathology revealed that the majority of cells were chromaffin-like cells with a very rich vascular sinus (thin blue arrow). Beneath the tumor capsule, there were multifocal oval eosinophilic cells with oval nucleus (thin black arrow). Adrenocortical hyperplasia was also revealed (bold black arrow; HE staining, 100×). Positive immunohistostaining is shown for CgA (c 200×), CD56 (d 200×), and Ki67 (e 100×) for chromaffin-like cells. No positive ACTH immunostaining was noticed (f 200×). Positive immunohistostaining is shown for CRH (g 400×) and Melan-A (h 200×) in the eosinophilic cells\n\n\n\nOne day after surgery, ACTH levels had decreased from 715 to 14.3 pg/ml and serum cortisol level had decreased from more than 50 to 10.4 μg/dl. One week postoperatively, blood potassium and glucose levels normalized without the need for medication. The signs and symptoms of Cushing’s syndrome gradually disappeared within two months, and the hydrocortisone supplementation (initial dosage was 60 mg daily and tapered gradually) was discontinued seven weeks postoperatively. CT revealed that the left adrenal gland was almost reduced to the normal size three months later. The patient is currently under regular follow-up and remains well nine months after surgery.\n\nDiscussion\nEAS is rare, with approximately 5% of all cases caused by pheochromocytoma [2]. In our patient, a diagnosis of EAS was suggested by the relatively short history, severe Cushing’s syndrome associated with refractory hypokalemia, the absence of a definitive lesion on the pituitary MRI scan, and the extremely elevated plasma ACTH levels. Histology confirmed that the right adrenal mass was a pheochromocytoma. The clinical features and the presence of normal catecholamine metabolites in the patient’s serum and urine confirmed the presence of a noncatecholamine-secreting pheochromocytoma. Chen et al. proposed criteria for the diagnosis of ACTH-secreting pheochromocytomas [7]. Except for the biochemical evidence of pheochromocytoma, this case satisfied all criteria for ACTH-secreting pheochromocytoma.\n\nSome CRH-secreting tumors (pheochromocytoma in this case) could be misdiagnosed as ACTH-secreting tumors because preoperative inferior petrosal sinus sampling (IPSS) for ACTH assays, adrenal vein sampling for ACTH and CRH assays, and postoperative immunostaining for ACTH and CRH are not routinely performed. Quinton et al. reported three patients with ACTH-dependent Cushing’s syndrome; in two cases, immunostaining showed reactivity for CRH instead of ACTH, supporting CRH (or related peptide) -secreting pheochromocytoma [8]. In the current case, the patient’s rapidly deteriorating condition did not allow us to perform IPSS and adrenal vein sampling. Yet, negative immunostaining for ACTH and positive immunostaining for CRH strongly suggested that the elevated ACTH resulted from an adrenal CRH-secreting pheochromocytoma.\n\nStudies have reported that EAS and ectopic CRH syndrome have different effects on the hypothalamic-pituitary-adrenal axis [8]. Post-operative recovery from the clinical symptoms and elevated cortisol levels is much faster in patients with ectopic CRH syndrome than in those with ectopic ACTH syndrome [5, 8]. In the present case, the rapid postoperative recovery of clinical features, elevated serum ACTH, potassium and glucose levels, and short-term application of prednisone supported the classification of the pheochromocytoma as a CRH-secreting tumor, with ACTH secreted from the pituitary gland. Pathological evidence, clinical presentations, and outcomes supported the ectopic CRH syndrome diagnosis.\n\nAn ectopic CRH-secreting pheochromocytoma is an extremely rare cause of ACTH-dependent Cushing’s syndrome. The first case of isolated ectopic CRH-secreting pheochromocytoma was reported in 1999 [4]. To date, six cases of isolated ectopic CRH-secreting pheochromocytoma and three cases of ectopic ACTH/CRH co-secreting pheochromocytoma have been reported [4, 5, 8–13]. Usually, a pheochromocytoma produces catecholamines and causes symptoms such as hypertension [14]. Among these six cases of isolated CRH-secreting pheochromocytoma, only one case had normal plasma and urinary epinephrine, normetanephrine, and metanephrine concentrations [5]. Although there is no record of hypertensive crisis during surgery, the event cannot be completely ruled out for functional pheochromocytoma because the patient was treated preoperatively with the somatostatin analog octreotide [5]. In the current case, the lack of catecholamine hypersecretion, the clinical manifestations, and the consistently normal blood and urinary levels of catecholamines and their metabolites provided no indication of a pheochromocytoma. To our knowledge, this is the second reported case of Cushing’s syndrome caused by ectopic CRH secreted from an adrenal noncatecholamine-secreting pheochromocytoma.\n\nIn this case, the patient had an adrenal tumor without any symptoms for 16 months before this hospitalization. The typical clinical features of Cushing’s syndrome appeared to be associated with administration of dexamethasone that was used to treat a skin allergy caused by eating mango. To our knowledge, mangoes or allergies have no effect on CRH synthesis and secretion, but this is not true for dexamethasone. Dexamethasone has negative feedback on hypothalamus CRH gene expression and secretion, but tissue-specific regulation of dexamethasone on CRH gene expression and secretion may exist. Indeed, glucocorticoids could stimulate CRH synthesis and secretion in the human placenta [6], and dexamethasone could up-regulate CRH gene expression in the pheochromocytoma [13]. In this case, a pre-existing tumor, chronological dexamethasone administration, and clinical symptoms and signs suggested that dexamethasone might induce CRH gene expression and/or secretion in the adrenal pheochromocytoma, thereby may provoke ectopic CRH syndrome. However, due to lack of blood tests before onset of symptom, we cannot rule out the possibility that the patient might have mild hypercortisolism before dexamethasone administration. Nevertheless, the current case suggests that performing dexamethasone suppression test may need to be evaluated if ectopic CRH syndrome is considered.\n\nThis study has several limitations. First, owing to the lack of a CRH assay, plasma CRH levels were not measured. Therefore, there was no direct evidence of elevated plasma CRH levels in this patient. Second, because the patient’s condition rapidly deteriorated, pre-surgery IPSS and adrenal vein sampling for measuring ACTH were not performed, which could have provided direct evidence of the source of elevated ACTH. Finally, dexamethasone’s effect on the onset and development of ectopic CRH syndromes was postulated based on the chronology of dexamethasone administration and presentation of clinical features and syndromes. Further experimental studies are warranted to confirm the tissue-specific regulation of dexamethasone on CRH expression and secretion.\n\nConclusions\nIn conclusion, we report an extremely rare case of ectopic CRH syndrome caused by an adrenal noncatecholamine-secreting pheochromocytoma. Both ectopic ACTH syndrome and ectopic CRH syndrome should be considered in patients presenting with ACTH-dependent Cushing’s syndrome caused by extrapituitary diseases.\n\nAbbreviations\nACTHAdrenocorticotropin hormone\n\nCRHCorticotrophin-releasing hormone\n\nCTComputed tomography\n\nEASEctopic ACTH syndrome\n\nFDGFluorodeoxyglucose\n\nIPSSInferior petrosal sinus sampling\n\nMRIMagnetic resonance imaging\n\nPETPositron emission tomography\n\nAcknowledgements\nWe are very thankful to Qian Wang for immunohistochemical staining of ACTH and CD56, Xin Zhang for immunohistochemical staining of CRH.\n\nFunding\nThis research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.\n\nAvailability of data and materials\nThe datasets analyzed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nB-PW, L-LY, HW and YL made the diagnosis, treatment, follow-up and wrote the manuscript. QH, Z-SM and ML reviewed literature, drafted the manuscript, and reviewed the manuscript for final publication. H-RS and C-XJ performed the histological examination of the tumor and reviewed the manuscript for final publication. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nEthical approval for this study was obtained from the Ethics Committee of Tianjin Medical University General Hospital, Tianjin China (No. IRB2016-YX-050). Informed consent was obtained from the patient.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\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. Isidori AM Kaltsas GA Pozza C Frajese V Newell-Price J Reznek RH The ectopic Adrenocorticotropin syndrome: clinical features, diagnosis, management, and long-term follow-up The Journal of Clinical Endocrinology & Metabolism 2006 91 371 377 10.1210/jc.2005-1542 16303835 \n2. Isidori AM Lenzi A Ectopic ACTH syndrome Arq Bras Endocrinol Metab 2007 51 1217 1225 10.1590/S0004-27302007000800007 \n3. Alhammar H Calissendorff J Höybye C Frequency of Cushing’s syndrome due to ACTH-secreting adrenal medullary lesions: a retrospective study over 10 years from a single center Endocrine 2017 55 296 302 10.1007/s12020-016-1127-y 27699708 \n4. Eng PHK Tan LHC Wong KS Cheng CWS Fok ACK Khoo DHC Cushing’s syndrome in a patient with a corticotropin-releasing hormone-producing pheochromocytoma Endocr Pr 1999 5 84 87 10.4158/EP.5.2.84 \n5. Ruggeri RM Ferraù F Campennì A Simone A Barresi V Giuffrè G Tuccari G Baldari STF Immunohistochemical localization and functional characterization of somatostatin receptor subtypes in a corticotropin releasing hormone- secreting adrenal phaeochromocytoma: review of the literature and report of a case Eur J Histochem 2009 53 1 6 10.4081/ejh.2009.e1 19351607 \n6. Kageyama K Hanada K Takayasu S Iwasaki Y Sakihara S Nigawara TST Involvement of regulatory elements on corticotropin-releasing factor gene promoter inhypothalamic 4B cells J Endocrinol Investig 2008 31 1078 1085 10.1007/BF03345656 \n7. Chen H Doppman JL Chrousos GP Norton JA Nieman LKUR Adrenocorticotropic hormone-secreting pheochromocytomas: the exception to the rule Surgery 1995 118 994 995 10.1016/S0039-6060(05)80104-7 \n8. Lois KB Santhakumar A Vaikkakara S Mathew S Long A Johnson SJ Phaeochromocytoma and ACTH-dependent cushing’s syndrome: tumour crf secretion can mimic pituitary cushing's disease Clin Endocrinol 2016 84 177 184 10.1111/cen.12960 \n9. Bayraktar F Kebapcilar L Kocdor MA Asa SL Yesil S Canda S Demir T Saklamaz A Seçil M Akinci B Yener SCA Cushing’s syndrome due to ectopic CRH secretion by adrenal pheochromocytoma accompanied by renal infarction Exp Clin Endocrinol Diabetes 2006 114 444 447 10.1055/s-2006-924154 17039427 \n10. Mondello S Fodale V Cannavo S Aloisi C Almoto B Buemi M Hypophosphatemia as unusual cause of ARDS in Cushing’s syndrome secondary to ectopic CRH production. A case report Sci World J 2008 8 138 144 10.1100/tsw.2008.20 \n11. Jessop DS Cunnah D Millar JG Neville E Coates P Doniach I Besser GMRL A phaeochromocytoma presenting with Cushing’s syndrome associated with increased concentrations of circulating corticotrophin-releasing factor J Endocrinol 1987 113 133 138 10.1677/joe.0.1130133 3035046 \n12. O’Brien T Young WF Jr Davila DG Scheithauer BW Kovacs K Horvath E Cushing’s syndrome associated with ectopic production of corticotrophin-releasing hormone, corticotrophin and vasopressin by a phaeochromocytoma Clin Endocrinol 1992 37 460 467 10.1111/j.1365-2265.1992.tb02359.x \n13. Liu J, Päivi H, Voutilainen R, Karonen S-L, Kahri AI. Pheochromocytoma expressing adrenocorticotropin and corticotropin-releasing hormone; regulation by glucocorticoids and nerve growth. Eur J Endocrinol. 1994;131:221–8.\n14. Pacak K Linehan WM Eisenhofer G Walther MM Goldstein DS Recent advances in genetics , diagnosis , localization , and treatment of Pheochromocytoma Ann Intern Med 2001 134 315 329 10.7326/0003-4819-134-4-200102200-00016 11182843\n\n",
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"journal": "BMC endocrine disorders",
"keywords": "Adrenocorticotropin; Dexamethasone; Ectopic CRH syndrome; Noncatecholamine secreting; Pheochromocytoma",
"medline_ta": "BMC Endocr Disord",
"mesh_terms": "D000310:Adrenal Gland Neoplasms; D000328:Adult; D003346:Corticotropin-Releasing Hormone; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D009384:Paraneoplastic Endocrine Syndromes; D010673:Pheochromocytoma",
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"title": "An unusual case of ectopic corticotrophin-releasing hormone syndrome caused by an adrenal noncatecholamine-secreting pheochromocytoma: a case report.",
"title_normalized": "an unusual case of ectopic corticotrophin releasing hormone syndrome caused by an adrenal noncatecholamine secreting pheochromocytoma a case report"
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"abstract": "We report three patients with superficial haemangiomas treated topically with Combigan ophthalmic solution (brimonidine 0.2%-timolol 0.5%), a combination selective α-2-adrenergic agonist and non-selective β-blocker Food and Drug Administration-approved for use in glaucoma. Topical brimonidine 0.2%-timolol 0.5% therapy improved the appearance of haemangiomas in all the cases. Two patients did not experience any adverse effects. One patient had hypothermic episodes which were initially thought to be because of brimonidine 0.2%-timolol 0.5% therapy. However, an episode occurred a few weeks after discontinuation and brimonidine 0.2%-timolol 0.5% therapy was ruled out as a cause. Despite the benefit, off-label use of brimonidine 0.2%-timolol 0.5% therapy served as a pitfall in the evaluation of an unusual constellation of worrisome symptoms. In conclusion, brimonidine 0.2%-timolol 0.5% therapy is a promising alternative in the topical treatment of haemangiomas. It may have synergistic effects and increased efficacy by targeting haemangiomas via two mechanisms (α-agonism and β-inhibition), but the risk of unforeseen adverse effects must always be considered when prescribing off-label treatment, especially in infants.",
"affiliations": "Department of Dermatology, St Louis University, St Louis, Missouri, USA. chumb@slu.edu",
"authors": "Chu|Melinda B|MB|;Searcy|Garrett|G|;Siegfried|Elaine|E|",
"chemical_list": "D000068599:Brimonidine Tartrate, Timolol Maleate Drug Combination; D004338:Drug Combinations; D011810:Quinoxalines; D013999:Timolol",
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"mesh_terms": "D000068599:Brimonidine Tartrate, Timolol Maleate Drug Combination; D004338:Drug Combinations; D005260:Female; D006391:Hemangioma; D006801:Humans; D007223:Infant; D008297:Male; D056687:Off-Label Use; D011810:Quinoxalines; D013999:Timolol",
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"references": "22971306;23121703;21403002;22804809;22713439;22150436;22670151;22190187;23045296;20479314;22253126;22299307;22224018;22734302;23227404;22944359;22731954;21915449;22471694;22874493;23278381;23266916;22303875;23305438;20479291;22870699;23252446;22967870;22844824;22503260;22777220;20142555;22486338;22279391;22179543;23141442;23014679;22410658;22050040",
"title": "Efficacy of topical brimonidine-timolol for haemangioma of infancy and perils of off-label prescribing.",
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"abstract": "Neonatal seizures are difficult to diagnose and, when they are, tradition dictates first line treatment is phenobarbital. There is little data on how consultants diagnose neonatal seizures, choose when to treat or how they choose aetiological investigations or drug treatments. The purpose of this study was to assess the variation across the UK in the management of neonatal seizures and explore paediatricians' views on their diagnosis and treatment.\n\n\n\nAn explanatory sequential mixed methods approach was used (QUAN→QUAL) with equal waiting between stages. We collected quantitative data from neonatology staff and paediatric neurologists using a questionnaire sent to neonatal units and via emails from the British Paediatric Neurology Association. We asked for copies of neonatal unit guidelines on the management of seizures. The data from questionnaires was used to identify16 consultants using semi-structured interviews. Thematic analysis was used to interpret qualitative data, which was triangulated with quantitative questionnaire data.\n\n\n\nOne hundred questionnaires were returned: 47.7% thought levetiracetam was as, or equally, effective as phenobarbital; 9.2% thought it was less effective. 79.6% of clinicians had seen no side effects in neonates with levetiracetam. 97.8% of unit guidelines recommended phenobarbital first line, with wide variation in subsequent drug choice, aetiological investigations, and advice on when to start treatment. Thematic analysis revealed three themes: 'Managing uncertainty with neonatal seizures', 'Moving practice forward' and 'Multidisciplinary team working'. Consultants noted collecting evidence on anti-convulsant drugs in neonates is problematic, and recommended a number of solutions, including collaboration to reach consensus guidelines, to reduce diagnostic and management uncertainty.\n\n\n\nThere is wide variation in the management of neonatal seizures and clinicians face many uncertainties. Our data has helped reveal some of the reasons for current practice and decision making. Suggestions to improve certainty include: educational initiatives to improve the ability of neonatal staff to describe suspicious events, greater use of video, closer working between neonatologists and neurologists, further research, and a national discussion to reach a consensus on a standardised approach to managing neonatal epileptic seizures.",
"affiliations": "University of Sheffield Medical School, Beech Hill Road, Sheffield, S10 2RX, UK.;Department of Neuroscience, University of Sheffield, Sheffield Institute for Translational Neuroscience, 385a Glossop Road, Sheffield, S10 2HQ, UK.;Department of Neuroscience, University of Sheffield, Sheffield Institute for Translational Neuroscience, 385a Glossop Road, Sheffield, S10 2HQ, UK.;Department of Paediatric and Neonatal Neurology, Sheffield Children's Hospital NHS Foundation Trust, Ryegate Children's Centre, Tapton Crescent Road, Sheffield, S10 5DD, UK. a.r.hart@sheffield.ac.uk.",
"authors": "Gossling|Lucy|L|;Alix|James J P|JJP|;Stavroulakis|Theocharis|T|;Hart|Anthony R|AR|0000-0003-4018-3238",
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"fulltext": "\n==== Front\nBMC PediatrBMC PediatrBMC Pediatrics1471-2431BioMed Central London 191810.1186/s12887-020-1918-4Research ArticleInvestigating and managing neonatal seizures in the UK: an explanatory sequential mixed methods approach Gossling Lucy lgossling1@sheffield.ac.uk 1Alix James J. P. j.alix@sheffield.ac.uk 2Stavroulakis Theocharis t.stavroulakis@sheffield.ac.uk 2http://orcid.org/0000-0003-4018-3238Hart Anthony R. a.r.hart@sheffield.ac.uk 31 0000 0004 1936 9262grid.11835.3eUniversity of Sheffield Medical School, Beech Hill Road, Sheffield, S10 2RX UK 2 0000 0004 1936 9262grid.11835.3eDepartment of Neuroscience, University of Sheffield, Sheffield Institute for Translational Neuroscience, 385a Glossop Road, Sheffield, S10 2HQ UK 3 0000 0004 0641 6082grid.413991.7Department of Paediatric and Neonatal Neurology, Sheffield Children’s Hospital NHS Foundation Trust, Ryegate Children’s Centre, Tapton Crescent Road, Sheffield, S10 5DD UK 28 1 2020 28 1 2020 2020 20 3615 3 2019 8 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\nNeonatal seizures are difficult to diagnose and, when they are, tradition dictates first line treatment is phenobarbital. There is little data on how consultants diagnose neonatal seizures, choose when to treat or how they choose aetiological investigations or drug treatments. The purpose of this study was to assess the variation across the UK in the management of neonatal seizures and explore paediatricians’ views on their diagnosis and treatment.\n\nMethods\nAn explanatory sequential mixed methods approach was used (QUAN→QUAL) with equal waiting between stages. We collected quantitative data from neonatology staff and paediatric neurologists using a questionnaire sent to neonatal units and via emails from the British Paediatric Neurology Association. We asked for copies of neonatal unit guidelines on the management of seizures. The data from questionnaires was used to identify16 consultants using semi-structured interviews. Thematic analysis was used to interpret qualitative data, which was triangulated with quantitative questionnaire data.\n\nResults\nOne hundred questionnaires were returned: 47.7% thought levetiracetam was as, or equally, effective as phenobarbital; 9.2% thought it was less effective. 79.6% of clinicians had seen no side effects in neonates with levetiracetam. 97.8% of unit guidelines recommended phenobarbital first line, with wide variation in subsequent drug choice, aetiological investigations, and advice on when to start treatment. Thematic analysis revealed three themes: ‘Managing uncertainty with neonatal seizures’, ‘Moving practice forward’ and ‘Multidisciplinary team working’. Consultants noted collecting evidence on anti-convulsant drugs in neonates is problematic, and recommended a number of solutions, including collaboration to reach consensus guidelines, to reduce diagnostic and management uncertainty.\n\nConclusions\nThere is wide variation in the management of neonatal seizures and clinicians face many uncertainties. Our data has helped reveal some of the reasons for current practice and decision making. Suggestions to improve certainty include: educational initiatives to improve the ability of neonatal staff to describe suspicious events, greater use of video, closer working between neonatologists and neurologists, further research, and a national discussion to reach a consensus on a standardised approach to managing neonatal epileptic seizures.\n\nKeywords\nInfant / newbornSeizuresAnticonvulsantsDifferential diagnosisNeurophysiologyHypoxia-ischemia, Brainhttp://dx.doi.org/10.13039/501100000858University of Sheffieldissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nSeizures are common in the neonatal period because of the relative excitability of the neonatal brain and high risk of pathologies leading to acute symptomatic seizures [1–7]. The true incidence of neonatal seizures is unknown, but proposed rates are 3/1000 term live births and between 132/1000 preterm neonates [8] One reason why incidence figures may be inaccurate is because neonatal seizures are difficult to diagnose: multiple studies using EEG have shown that most neonatal seizures have no clinical features at all (electrographic seizures) [9–14], and the accurate differentiation of epileptic seizures from non-epileptic events based on clinical skills alone is poor [9, 10, 15, 16]. For example, one study of term neonates showed only 34% of neonatal seizures having had clinical features and 73% of suspected seizures having had no epileptiform discharges associated with them on electroencephalography (EEG) [9]. As a result, neurophysiological techniques are used to support diagnosis, but the gold standard, continuous video EEG, is not available in all UK neonatal units, and the logistics of siting leads, checking recording quality, starting the monitor, and interpreting the EEG, 24 h a day, 7 days a week are enormous. Instead, amplitude integrated EEG (aEEG) is used routinely on neonatal units, particularly in term babies with hypoxic ischaemic encephalopathy (HIE) [17, 18], and can detect 1/3 of single seizures and 2/3 of repetitive seizures, missing those that are brief or distant from the EEG leads [17, 19]. Having two channels and the single lead EEG trace available for review on the aEEG monitor improves seizure detection rates [19–21].\n\nOnce a diagnosis of neonatal seizures has been made, health care professionals have to decide what the likely aetiologies are, which investigations to perform, whether to treat the seizures and, if so, with what drugs. One particular conundrum is whether to treat electrographic seizures. There is little published data on how health care professionals view this, but 36.7% of US health care professionals presented with a theoretical case treated isolated electrical seizures in neonates with mild HIE, and 74.6% treated recurrent electrographic seizures in moderate HIE. Variation was also noted in how long neonatal seizures had to last before treatment was initiated and whether the baby was given a single dose or started on regular maintenance doses [22].\n\nIn the UK, there is no universally accepted guideline on the management of neonatal seizures, although the World Health Organisation recommends electrographic seizures should be treated in the same way as clinical seizures [23]. Little data exists on the variation in UK management of neonatal seizures, nor the reasons for any observed variation. Once treatment is commenced, Phenobarbital is recommended as first line treatment in the UK [5], although little data exists on health care professionals’ views of its effectiveness, what their choice of second line treatment is, nor how they choose when to treat and with what drug.\n\nOur aims were the answer the following questions:\nWhat factors influence health care professionals when diagnosing neonatal seizures?\n\nHow many health care professionals utilise aEEG when diagnosing neonatal seizures and what were health care professionals’ views of its use?\n\nHow many health care professionals routinely treated clinical and electrographic seizures and what factors lead them to treat a neonate with anti-convulsant drugs?\n\nWhat anti-convulsant drugs are health care professionals using to treat neonatal epileptic seizures and in what order?\n\nWhy health care professionals choose the drugs they do, and what are their attitudes on their effectiveness and side effects?\n\nWhat steps or evidence are needed to improve confidence in diagnosis and treatment of neoantal seizures,and to reduce variation in care between health care professionals when treating neonatal epileptic seizures?\n\n\n\nMethods\nThe mixed nature of our research questions (containing interconnected quantitative and qualitative features) required the use of a study design integrating both quantitative and qualitative methodologies [24]. We adopted an explanatory sequential mixed methods approach in two distinct phases (QUAN→QUAL) [25]. We conducted a questionnaire survey (Phase I) to examine health care professionals’ practice when diagnosing and treating neonatal epileptic seizures, followed by qualitative interviews (Phase II) to explore the reasoning for any variation noted. Equal weighting was given to both aspects of this approach.\n\nPhase I\nWe designed a questionnaire in paper and electronic versions on health care professionals’ views of neonatal seizures (Additional file 1, available online) based on the published findings of variation in care in the US and Sweden [22, 26] and the authors’ observations of UK practice. We included specific questions about levetiracetam because our experience is levetiracetam is being increasingly used in clinical practice and recommendations in the UK have suggested it could be incorporated into guidelines [5]. 196 Neonatal units were identified from a national transport group website (ukntg.net/uk-neonatal-units), which lists all UK neonatal units. The clinical lead of each unit was asked if they and other members of their staff would complete the questionnaire. Members of the British Paediatric Neurology Association (BPNA) were asked to complete the electronic version of the questionnaire via a monthly e-newsletter. Frequencies and percentages of answers were calculated and copies of seizure guidelines were requested.\n\nIntermediate stage - connection of the two phases. The last question of the questionnaire asked if responders were willing to attend a qualitative interview to explore their views in more depth. From the list of volunteers, we used a purposeful sampling approach to ensure we obtained a range of views from different specialities, geographical areas, and years of experience. As such, the identities, specialisms and year of registration on the Specialist Register of the General Medical Council were available to us. Adhering to the explanatory sequential mixed methods design, the results of the questionnaire guided the choice of questions in the interview schedule, with a focus specifically on attitudes to the diagnosis of neonatal epileptic seizures and the timing and choice of anti-convulsant drug treatment.\n\nPhase II\nWritten informed consent was obtained from interview participants. Data was collected with semi-structured interviews conducted by a single member of the research team (LG) at a time and location of the participants’ choice. The topic guide for the interviews is available online (Additional file 2). Interviews were digitally recorded, transcribed verbatim and checked for accuracy. Thematic analysis was performed as per Braun and Clarke (2006) [27]. This included familiarisation of data, initial coding of all data using an inductive approach by two researchers (LG and ARH), review of initial codes, agreement on a coding structure for the whole dataset, and identification of a thematic structure to determine main and subthemes. Themes were developed using an iterative process to capture all range of views. We ceased recruiting for interviews when we reached thematic saturation, mindful of published recommendations on cohort size [28–30]. NVivo for Mac version 12 (QSR International PTY Ltd., 2018) was used to aid data analysis. Finally, the results of the quantitative and qualitative phases were integrated to find explanations for any observed variations in practice. This is presented in the discussion section of this manuscript.\n\nEthical approval was obtained from the University of Sheffield (Reference Number 017700).\n\nResults\nPhase I: quantitative data on neonatal seizures\nOne hundred questionnaires were returned: 81 consultants, 7 nursing staff, 1 trainee, and 11 unknown staff members. Thirty-three worked in neonatal intensive care (Level 3) units, 45 in local neonatal (level 2 or 1) units or paediatric departments, and 22 in paediatric neurology. The 78 responders who worked in neonatal units represented 68 different units, which is 34.7% of all UK units caring for neonates. The BPNA includes members from many specialities, including neurophysiologists, disability paediatricians and allied health care professionals, around the world, all of whom will have the option of receiving the e-newsletter. Reporting response rates for this distribution list is not appropriate as the project was not relevant to all subscribers. There are 120 consultant paediatric neurologists in the UK, so 22 responses represent 18.3% of this total population, although not all of these consultants are involved in the care of neonates with seizures. All answers were treated equally, irrespective of the degree of seniority or specialism of the respondent.\n\nThe results of our questionnaire are summarised in Table 1. 34.0% of responders routinely treated electrographic seizures, 49.0% treated them sometimes, and 17.0% reported they did not treat electrical seizures. 53.0% thought that electrical seizures were as important as clinical seizures, compared to 16.0% who thought they were less important. When asked whether seizures cause harm to the brain independent of the underlying aetiology, 62.0% thought they did and 15.0% did not. The frequency of replies for neonatologists and neurologists, as well as for only the responders identifying themselves as consultants, is shown separately in Table 1.\nTable 1 Frequency of responses to questions in our questionnaire separated by primary type of unit in which responders work\n\nQuestion\tResponders\t\nAll responders\tWorking predominately in a NICU - Level 3\tWorking in paediatrics, Level 2 unit, or interest in epilepsy\tWorking predominately in paediatric neurology / neurodisability unit\tAll Consultant Responders\t\nDo you treat clinical seizures (i.e. where there is no available aEEG / EEG data to confirm abnormal movements are seizures?\tYes\t65/100 (65.0%)\t18/33 (54.6%)\t38/45 (84.4%)\t9/22 (40.9%)\t54/81 (66.7%)\t\nNo\t9/100 (9.0%)\t4/33 (12.1%)\t3/45 (6.7%)\t2/22 (9.1%)\t5/81 (6.1%)\t\nSometimes\t26/100 (26.0%)\t11/33 (33.3%)\t4/45 (8.9%)\t11/22 (50.0%)\t22/81 (27.2%)\t\nDo you treat electrical seizures (i.e. diagnosed on aEEG/EEG) which do not have any clinical features to see?\tYes\t34/100 (34.0%)\t14/33 (42.4%)\t15/45 (33.3%)\t5/22 (22.7%)\t27/81 (33.3%)\t\nNo\t17/100 (17.0%)\t1/33 (3.0%)\t15/45 (33.3%)\t1/22 (4.5%)\t11/81 (13.6%)\t\nSometimes\t49/100 (49.0%)\t18/33 (54.6%)\t15/45 (33.3%)\t16/22 (72.7%)\t43/81 (53.1%)\t\nDo you think electrical seizures are:\tAs important as clinical seizures\t53/100 (53.0%)\t17/33 (51.5%)\t25/45 (55.6%)\t11/22 (50.0%)\t43/81 (53.1%)\t\nMore important than clinical seizures\t9/100 (9.0%)\t2/33 (6.1%)\t4/45 (8.9%)\t3/22 (13.6%)\t6/81 (7.4%)\t\nLess important than clinical seizures\t16/100 (16.0%)\t6/33 (18.2%)\t5/45 (11.1%)\t5/22 (22.8%)\t14/81 (17.3%)\t\nI don’t know\t22/100 (22.0%)\t8/33 (24.2%)\t11/45 (24.4%)\t3/22 (13.6%)\t18/81 (22.2%)\t\nDo you think seizures themselves cause harm to the brain/ development (i.e. not related to apnoea/hypoxia and independent of the underlying cause)?\tYes\t62/100 (62.0%)\t24/33 (72.7%)\t27/45 (60.0%)\t11/22 (50.0%)\t53/81 (65.4%)\t\nNo\t15/100 (15.0%)\t3/33 (9.1%)\t9/45 (20.0%)\t3/22 (13.6%)\t12/81 (14.8%)\t\nI don’t know\t23/100 (23.0%)\t6/33 (18.2%)\t9/45 (20.0%)\t8/22 (36.4%)\t16/81 (19.8%)\t\nDo you routinely use cerebral function monitoring (aEEG) for monitoring neonates at high risk of seizures or those having recurrent seizures?\tWe use it in all neonates at risk of seizures\t44/94 (46.8%)\t20/31 (64.5%)\t12/43 (28.0%)\t12/20 (60.0%)\t39/78 (50.0%)\t\nWe use it only in those with HIE\t10/94 (10.6%)\t5/31 (16.1%)\t5/43 (11.6%)\t0/20 (0.0%)\t9/78 (11.5%)\t\nWe use it in selected cases, HIE and non-HIE\t20/94 (21.3%)\t5/31 (16.1%)\t8/43 (18.6%)\t7/20 (35.0%)\t14/78 (18.0%)\t\nWe don’t use it at all\t19/94 (20.2%)\t1/31 (3.3%)\t17/43 (39.5%)\t1/20 (5.0%)\t16/78 (20.5%)\t\nI don’t know\t1/94 (1.1%)\t0/31 (0%)\t1/43 (2.3%)\t0/20 (0%)\t0/78 (0%)\t\nWith reference to Phenobarbital, do you think it is …\tVery effective\t29/94 (30.9%)\t6/31 (19.4%)\t16/43 (37.2%)\t7/20 (35.0%)\t25/78 (32.1%)\t\nStops some seizures but not all\t65/94 (69.1%)\t25/31 (80.6%)\t27/43 (62.8%)\t13/20 (65.0%)\t53/78 (67.9%)\t\nNot at all effective\t0/94 (0%)\t0/31 (0%)\t0/43 (0%)\t0/20 (0%)\t0/78 (0%)\t\nHave you tried Levetiracetam for treatment of neonatal seizures?\tYes\t65/94 (69.1%)\t26/31 (83.9%)\t19/43 (44.2%)\t20/20 (100%)\t59/78 (75.6%)\t\nNo\t29/94 (30.9%)\t5/31 (16.1%)\t24/43 (55.8%)\t0/20 (0%)\t19/78 (24.4%)\t\nDo you think Levetiracetam (Keppra) is …\tVery effective\t21/65 (32.3%)\t8/26 (30.8%)\t9/19 (47.4%)\t4/20 (20.0%)\t19/59 (32.2%)\t\nStops some seizures but not all\t44/65 (67.7%)\t18/26 (69.2%)\t10/19 (52.6%)\t16/20 (80.0%)\t40/59 (67.8%)\t\nNot at all effective\t0/65 (0%)\t0/26 (0%)\t0/19 (0%)\t0/20 (0%)\t0/59 (0%)\t\nCompared to Phenobarbital, do you think Levetiracetam is\tBetter than phenobarbital\t14/65 (21.5%)\t7/26 (26.9%)\t3/19 (15.8%)\t4/20 (20.0%)\t13/59 (22.0%)\t\nAs good as phenobarbital\t17/65 (26.2%)\t3/26 (11.5%)\t9/19 (47.4%)\t5/20 (25.0%)\t14/59 (23.7%)\t\nLess good than phenobarbital\t6/65 (9.2%)\t1/26 (3.9%)\t1/19 (5.2%)\t4/20 (20.0%)\t6/59 (10.2%)\t\nI don’t know\t28/65 (43.1%)\t15/26 (57.7%)\t6/19 (31.6%)\t7/20 (35.0%)\t26/59 (44.1%)\t\n\n\n73/94 (77.7%) responders’ units had a guideline for the management of neonatal seizures. 90 (95.7%) responders indicated their guideline’s first line anti-convulsant medication: 83/90 (92.2%) used phenobarbital, 1 (1.1%) phenytoin, 2 (2.2%) used either phenobarbital or phenytoin, 1 (1.1%) levetiracetam, and 3 (3.4%) either phenobarbital or levetiracetam. In addition to phenobarbital, a range of other drugs were used to treat neonatal seizures (Table 2).\nTable 2 Other anti-convulsant drugs responders reported they used\n\nDrug\tProportion of responders saying they had experience of using in neonates\n(n = 94)\t\nPhenytoin\t74 (78.2%)\t\nLevetiracetam\t65 (73.3%)\t\nMidazolam\t62 (66.0%)\t\nLorazepam\t18 (19.2%)\t\nParaldehyde\t13 (13.8%)\t\nLignocaine\t15 (16.0%)\t\nVitamins / pyridoxine\t12 (13.3%)\t\nDiazepam\t5 (5.3%)\t\nClonazepam\t4 (4.4%)\t\nTopiramate\t3 (3.3%)\t\nCarbamazepine\t3 (3.3%)\t\nSodium valproate\t1 (1.1%)\t\nVigabatrin\t1 (1.1%)\t\nPrednisolone\t1 (1.1%)\t\n\n\n29/94 (30.1%) responders reported that phenobarbital was very effective at treating neonatal seizures, 65 (69.2%) said that it stopped some seizures but not all. No responder thought that phenobarbital was ineffective.\n\n65 (73.3%) responders had experience of using levetiracetam, and their views on its effectiveness were similar to phenobarbital (Table 1). When asked to directly compare levetiracetam to phenobarbital, 14/65 (21.5%) thought levetiracetam was more effective, 17 (26.2%) equally effective, 6 (9.2%) less effective, and 28 (43.1%) did not know. Reported side effects seen with levetiracetam were:\nNone 39/49 (79.6%)\n\nIrritability, hyperkinetic movements / jitteriness 5 (10.2%)\n\nSleepiness 3 (6.1%)\n\nElectrolyte disturbance 2 (4.1%)\n\nRespiratory depression 1 (2.0%)\n\n\n\nWe received 18 different neonatal unit or network guidelines. Network guidelines included a number of centres of different levels, some of which will and will not have on-site access to aEEG and EEG. Variation was noted in recommended aetiological investigations for neonatal seizures (Fig. 1), guidance on when to treat seizures, and choice of anti-convulsant drugs if phenobarbital was ineffective (Fig. 2). Thirty-eight responders agreed to consider being involved in Phase 2.\nFig. 1 Investigations recommended on received guidelines to determine the aetiology of neonatal seizures: Red – 1st line; blue – 2nd line or only to be requested under certain circumstances; orange – 3rd line. Guideline from centre G did not attempt to recommend investigations. Abbreviations: FBC – full blood count; U&E – urea and electrolytes; LFT – liver function tests; CK – creatine kinase, TFT – thyroid function test; AA – amino acids; VLCFA – very long chain fatty acids; CRP – C-reactive protein; OA – organic acids; AASA – alpha amino adipic semialdehyde; MRI – magnetic resonance imaging; aEEG – amplitude integrated electroencephalography; EEG – electroencephalography\n\n\nFig. 2 Information from received guidelines on when to treat neonatal seizures, and recommended treatments and doses. Red – 1st line; blue - 2nd line; orange – 3rd line; pink – 4th line; green – 5th line; turquoise – 6th line; grey – 7th line; black – 8th line; purple – 9th line; yellow – to be tried at the discretion of the consultant at any time. Abbreviations: D – diazepam; L – lorazepam; mg – milligram; mcg – microgram; kg – kilogram; h – hour; d- day, BD – twice a day; TDS – three times a day\n\n\n\nPhase II: qualitative data on the diagnosis and treatment of neonatal seizures\nSixteen consultants were interviewed: 5 Level 3 Neonatologists, 7 Paediatric Neurologists, 4 Paediatricians at a local neonatal (level 2) unit / district general hospital: 3 with expertise in neonatology and 1 in epilepsy. Eleven were male and 5 female. We chose interviewees from different geographic regions to ensure we were not finding views linked only to local practice. The mean years of consultant experience was 11 years and 2 months (range 2 months to 28 years). The length of interviews ranged from 45 min to 1 h 40 min, with a median length of 1 h 10 min. Pseudonyms are used to maintain anonymity.\n\nThree themes emerged from the study (Fig. 3):\nManaging uncertainty with neonatal seizures\n\nMoving practice forward\n\nMultidisciplinary team working.\n\n\nFig. 3 Summary of results of thematic analysis from qualitative interview study\n\n\n\nManaging uncertainty associated with neonatal seizures\nThis theme explored the uncertainty clinicians face when deciding whether a neonate is having seizures and, if so, how to treat them. It contained the following subthemes:\nweighing up the evidence for a diagnosis of seizures\n\ndeciding when to treat\n\nchoosing anti-convulsant medication.\n\n\n\nWeighing up the evidence for a diagnosis of seizures\nConsultants found diagnosing neonatal seizures difficult, and consultants reported uncertainty increases with experience and seniority because of a greater awareness of differential diagnoses. Consultants were suspicious of diagnoses made by junior staff, particularly doctors in training, who were seen as over-diagnosing seizures and being too influenced by nursing staff. Lucy, a neonatologist, explained:\n\n\n\n“You’re much more persuaded by the nursing staff as a junior doctor cos you totally trust them … . So, if they said to you ‘that baby had a seizure’ you probably would have been much more likely to go along”.\n\n\n\n\n\nWhen a consultant was sceptical about a diagnosis, they wanted descriptions of the events to confirm the diagnosis of a seizure was correct. Tim noted a cultural difference in how junior doctors obtain descriptions of neonatal events to older children and adolescents:“If you are sitting in an outpatient clinic and the GP [General Practitioner] has made a referral that this patient has had episodes of funny movements and they are worried they might be seizures, the thing that you put great emphasis on is the history. You listen to what the parent has to say, they may have taken a video of it on their phone.... Flip to a post-natal ward, nobody believes a parent - ever. So, if a parent presents their baby having funny movements, a midwife will not believe anything until she has seen it for herself. Bizarrely, the doctors, who if they were in paediatrics would have no problem going on the maternal story, will not believe the maternal story until they have seen it for themselves. And you have to ask yourself ‘what is it that so changes their attitude to being in paediatrics and being in neonates?’”\n\n\n\nThe consultant paediatric neurologists particularly lamented the quality of the descriptions they received and noted nearly all seizures were described as “tonic clonic”. Bella, a Consultant Paediatric Neurologist, noted:“We will be told that they’re fitting and when you ask for a description it is often hard to get specific detail about that. So, it sometimes is hard to know whether what they are describing is a true seizure or whether it is an involuntary movement or some other, um, neurological phenomenon.”\n\n\n\nChristopher noted that junior colleagues gave him the seizure type rather than a description:“I think it’s difficult with medical colleagues, isn’t it? If they say ‘it’s clonic’, I probably wouldn’t quiz them in great detail about whether their limbs are stiff and consistent, you know what I mean? … I would probably be a bit more inclined to accept at face value their interpretation of the seizure type, but of course that might incorrect.”\n\n\n\nOne way to improve diagnosis suggested by both neonatologists and neurologists was to video events on smartphones, although one interviewee was worried doing this on the neonatal unit might imply care was suboptimal: “It’s obviously an attractive idea I just feel it makes you look a little bit sort of silly if you’re in intensive care unit and say ‘oh can you video as well’, but you know perhaps I shouldn’t be, perhaps it’s my own pride”.\n\nEEG or aEEG were also used to improve diagnostic certainty. Neurologists preferred to use a combination of history and EEG with video but were concerned about the quality of neonatal EEG recordings and reporting, and noted some neurophysiologists lacked confidence and competence to interpret neonatal EEG. On the other hand, neonatologists struggled with the accessibility of EEG, as Fiona explained:“The unit has got semi-direct access to an EEG machine and even that sometimes takes us a day. … And then in other units, I have only just learned this, because we were discussing the network seizure guideline, that they didn’t have access to EEG machines at all. I was a bit shocked actually.”\n\n\n\nInstead, neonatologists saw aEEG as a pragmatic solution for improving diagnostic certainty, but acknowledged it was “not the answer to your prayers” because it missed brief seizures and those distant from the leads. Consultants highlighted a number of training needs including: how to site the leads, set up the monitor, and interpret the trace. Neonatologists correctly perceived neurologists were wary of aEEG: neurologists thought its introduction had “jumped the gun” before the optimal way to manage neonatal seizures was understood. A proportion of the neurologists’ scepticism reflected their own lack of confidence in interpreting aEEG, as Suresh explained:“I’m not particularly competent or confident from my perspective. I don’t, we never used it in my training.”\n\n\n\nBoth neurologists and neonatologists suggested time-locked video alongside aEEG would improve diagnosis, but such monitors were not readily available.\n\nDeciding when to treat neonatal seizures\nOnce a seizure was diagnosed, consultants weighed-up the risks and benefits of medication. The aetiology of seizures was critical: seizures related to a severe neonatal epilepsy syndrome, structural brain abnormalities, or metabolic conditions were not treated as aggressively. Where the seizures were caused by HIE, the following factors were important when deciding whether to treat:\nThe natural history of the seizures, i.e. acute symptomatic seizures “burn out”\n\nWhether the seizures were accompanied by significant clinical features like profound apnoea / desaturation\n\nFrequency and duration\n\nWhether electrical seizures were as important as clinical seizures\n\nWhether seizures cause harm independent of the underlying aetiology\n\nThe side effects of the anti-convulsant drugs\n\nParental or nursing staff anxiety.\n\n\n\nThere were clear benefits of treating seizures with severe clinical features. For clinical seizures with milder manifestations or electrical seizures, most consultants made a judgement on a “case-by-case basis” about whether the frequency and duration were sufficient to warrant treatment, agreeing to treat “a high burden of seizure activity”. Interviewees explained there was no agreement about what a high burden of seizure activitiy meant and scientific evidence was not a part of clinician thinking, with variation seen even within single units, as Fiona explained:\n\n\n“I have not got any set rules. Within the unit we really have not got any set rules. Um, we’ve all got slightly different thresholds from when we would treat, really depending on the clinical scenario.”\n\n\n\n\nA number of neonatologists held onto algorithms they were taught as trainees, as Tim explained:“We used to have the Levene rule of 3. So, you needed to have 3 seizures or a seizure lasting more than 3 minutes, before we would treat, okay, I think that was in an hour”.\n\n\n\nA proportion of neonatologists aggressively treated both electrical seizures and clinical seizures with minor manifestations, driven by a belief that all seizures directly contributed the “burden of brain injury”. Neurologists were more comfortable not treating electrical seizures, as Bella explained:“The question is, ‘Is it better to have a more normal background EEG if you can, but a child that’s really flat and moribund because you’ve got them on 5, 6 drugs?’. … in certainly my training, it was very much ‘treat the child or the infant, not the EEG’”.\n\n\n\nSuresh summed up the consultant neurologists’ thoughts by saying:“the link between seizure frequency and severity and brain development is weak and difficult. We don’t really understand it, why do some children do very badly with their development and others do well.”\n\n\n\nConsultants of all specialities also considered the risk of anti-convulsants affecting neuro-developmental outcome themselves. Most thought adverse neuro-developmental outcome was more likely to occur after long-term administration of anti-convulsants, rather than isolated doses, and were sceptical about relying on animal study data. Some consultants were concerned the sedative properties of traditional drugs made a neonate’s “neurological examination probably seem more abnormal than it may be”, making “their progress or lack of it” impossible to determine and inpatient stays longer. Ben noted:“The problem with the phenobarbitone yes, so the half life time was 5-7 days. So, we treat HIE babies with phenobarb, maybe for electrical seizures, and then you have to tell the parents ‘Well, because we had to treat with this, it will take the baby at least 3 days to wake up and to come back to normal and that is not because the brain is damaged’.”\n\n\n\nIf initial drugs are ineffective, consultants appraised the balance between the benefits of treatments and side effects again, but many consultants avoided multiple drugs because of sedative side effects and the need for ventilatory support. If several drugs did not work, consultants reached a “plateau” where they accepted seizures rather than using further drugs.\n\nThe final driver that consultants perceived pushed them towards deciding to treat neonatal seizures was parental or staff anxiety. They wanted to “feel like we’re doing something”, although this could lead to them “treating the parents and the nurses rather than the baby”. As Lucy explained:“I think there’s sometimes pressure, I mean that in a nice way, not in you know not a bad way at all, from nursing staff to get to get rid of all funny movements.”\n\n\n\nChoosing anti-convulsant medication\nPhenobarbital was the first line drug for all of our interviewees because of tradition, familiarity, and local or network guidelines, as Ben explained:\n\n\n“Neonatology people are quite traditional in what they use … you will find that most people stick to what they know, what they use, and therefore they will always follow the guidelines.”\n\n\n\n\nNeonatologists thought it was “inappropriate” to deviate unilaterally from the guideline and thought they would face questions or criticisms from nursing staff or colleagues if they did. This reduced their experience of alternative treatments, because seizures that had not responded to initial anti-convulsant drugs were more likely to be refractory to other medications too.\n\nNeurologists reported they were not often involved in initiating treatments for neonatal seizures. When they were involved in treatment decisions, neurologists were less protocol-driven, would tailor drug choice to underlying aetiology, and were more comfortable with a wider repertoire of drugs than neonatologists. Neurologists liked levetiracetam, having had experience of its use in older children, and thought it was effective at treating neonatal seizures. John was an exception, noting “We use quite a lot and I, the more I have used it, I think it might not be working as good as I expected it to work. … Maybe the dose is not right”. Few side effects were noted with levetiracetam in neonates, and it was described by neurologists as “clean” and “forgiving”. Overall, neurologists couldn’t “see a reason why it can’t be first line.”\n\nMoving practice forward\nThis theme examined how practice could be improved in the future. There were three main suggestions: education; further research studies; and consensus agreement on national guidelines.\n\nTraining for medical trainees, consultants and nurses on the neurological assessment of the neonate, patterns of movements likely to be seizures, differential diagnoses, how to set up and interpret aEEG, the use of EEG, and aetiological investigations was reported to be “the most important thing” to be doing now. In comparison, research was seen as more important for long-term improvements. Consultants formed two groups: ‘purists’ insisted on evidence from randomised controlled trials on drug effectiveness, side effects, how aggressively to treat seizures, whether to treat electrical seizures, and the long-term developmental effects before they would change guidelines. The second group were ‘Pragmatists’, who accepted organising formal studies was problematic, expensive, and would take a long time. They suggested drawing on the cumulative experience of clinicians to form a national consensus guideline. Ben explained:“It’s not research, it’s just identifying ‘what is happening?’ and ‘What are people doing and why are they doing it?’ This is exactly what you want to understand, and you need to understand why people feel safe or what is needed to make them feel safe … it’s not about research knowing why levetiracetam might be better, but if you can just point out the new doctrine has same efficacy but they wake up earlier, so the parents are more pleased about whatever this is about it, and then you can set up a new strategy including all these aspects … I think that this is ending up may be in a national survey and a guideline and that might be influential … Neonatologists are not brave. It’s not like neurosurgeons: you give them a new toy and they will stick the toy in the head of a patient.”\n\n\n\nMultidisciplinary team working\nThis theme described working relationship between specialities. Neonatologists worked in networks with other centres, but only a small number worked regularly with neurologists. When they did, they gained “more insight maybe into seizures, and how, what we should treat”.\n\nNeurologists were not routinely called when seizures were first treated and were only consulted in a child who was not responding as the neonatologists expected. Neurologists thought they could be consulted more frequently and saw positives in collaboration: they felt deskilled when they were only consulted for complex cases, leading to “book based” advice, and wanted to see a wider spectrum of conditions. They thought their experience on a wide range of neurological conditions, drugs, and developmental outcome would be useful for neonatologists and reported cross fertilisation of “information from conferences” and experience would promote creativity. One neurologist suggested the neonatologists have wide experience of a limited number of conditions and, without formal neurology training, have a blinkered view: “I think sometimes people don’t know what they don’t know”.\n\nDiscussion\nConsultants face many challenges when considering the cause of abnormal neonatal movements and need to reach a “point of certainty” before making a diagnosis of a seizure. A number of factors increase this degree of certainty, the main one being the ability to witness the events themselves. This is a challenge because consultants are typically called to review a baby after the event has stopped and find that junior medical or nursing staff give bland “seizure types”, which are often wrong, instead of detailed descriptions of what happened. This may be a result of a cultural difference between neonatology and general paediatrics / neurology, where ictal phenomenology and the use of videos is an essential part of the diagnostic process. As a result, consultants find an abnormal neonatal event has often been attributed and treated as a seizure before they attend, without consideration of differential diagnoses. This, and the traditional classifications of seizures types in neonates, as described by Volpe [31], may explain to some extent why over-diagnosis of neonatal seizures is common and why consultants think diagnostic accuracy could be improved without neurophysiology support using a thorough approach to diagnosis. Even if it this is true, it would not improve the diagnosis rates of the large majority of neonatal seizures, which have either subtle, brief or no clinical features at all [9], supporting calls for neonatal seizures to be reliant on neurophysiological techniques [15, 32, 33].\n\nWhere neurophysiological techniques are used in neonates, consultants disagree on which method is the most suitable. Nearly all tertiary neonatology services routinely use aEEG, compared to 39.5% from secondary level neonatal and paediatric units. Although we did not plan our interview schedule to discuss the use of aEEG in secondary level units, one paediatrician in a district general hospital was actively seeking to purchase a monitor, whilst another thought it was inappropriate for their unit to have one because their staff lacked training and expertise in its use. Neonatal and neurology networks need to decide whether they support the introduction of aEEG into secondary level units and general paediatric wards. From a practical perspective, it is feasible with appropriate training and support [34], but others argue the National Institute of Clinical Excellence recommend young children with seizures should be reviewed by a paediatric neurologist [35], and aEEG may delay access to specialist opinion. Away from secondary level centres, neurologists prefer EEG and are wary of aEEG, thinking neonatologists place undue reliance on its ability to detect neonatal seizures. Some of this negativity may reflect neurologists’ own lack of training and confidence in using aEEG. We should also be aware that, whilst EEG is seen as the gold standard investigation for the diagnosis of neonatal seizures, it is only as good as the neurophysiologist interpreting it, and differences in opinions on what EEG findings are neonatal seizures will exist in practice [36, 37]. In contrast, neonatologists recognise the value of EEG but do not have the same ease of access as neurologists, taking a pragmatic view that aEEG is a flawed tool, but one that allows for monitoring over longer periods of time than EEG, is more likely to capture recurrent seizures, is accessible, relatively easy to interpret, and better than clinical diagnosis on its own.\n\nA further area of controversy relates to whether electrographic seizures are important or not. Tertiary neonatologists are twice as likely as neurology consultants to treat all electrographic seizures. This observation cannot occur because neurologists think electrographic seizures are unimportant; in fact, twice as many neurologists as neonatologists reported in our questionnaire that electrical seizures were more important than seizures with clinical features. Instead, it probably reflects whether consultants think seizures cause additional harm to the brain independent of the underlying aetiology: almost three quarters of neonatal staff answering our questionnaire thought seizures cause harm to the developing brain, compared to half of neurology staff, and neonatal interviewees indicated this was a major driver for them to treat electrical seizures aggressively.\n\nThe published evidence on whether clinical or electrical seizures causes harm in neonates is unclear: animal studies are contradictory about whether induced seizures are associated with brain injury without hypoxia-ischaemia [38, 39], and one study shows seizures and hypoxia-ischaemia in rats combine to produce worse brain injury [39]. In neonates with HIE, near infrared spectroscopy demonstrates increased cerebral oxygenation, blood flow and oxygen metabolism during seizures [40, 41], and MR spectroscopy results are affected by seizure severity [42]. Evidence on whether seizures are associated with poor outcome is similarly contradictory. Small studies show that treating clinical and electrical seizures using aEEG and / or EEG is associated with improved MRI scores at discharge compared to treating only clinically suspected seizures [43, 44]. Whilst there no statistically significant difference in developmental assessment is noted between groups at 18-24 months of age, one study shows a trend to better outcomes when neurophysiological techniques were used and electrographic seizures treated [44]. Another study found the presence of clinical seizures without neurophysiological confirmation is associated with worse outcomes at 4 years of age when the severity of MRI abnormalities is controlled for [45]. Larger studies, however, have shown the association between the presence of seizures and outcome is complex [46–48]. One group found there is no clear link between the presence of seizures and outcome in HIE, but there is an association between increasing seizure frequency and duration and outcome [46]. A large retrospective cohort study using a national insurance database found that neonatal seizures are associated with greater risk of epilepsy and intellectual disability later in life, independent of the aetiology of the neonatal seizures [48]. None of these studies show conclusively that aggressive treatment of neonatal electrical seizures improves outcome.\n\nAnother explanation why neonatologists are more likely than neurologists to treat electrical seizures aggressively relates to the aetiologies they see: neonatologists commonly see acute symptomatic seizures, so anti-convulsant drug use is short-lived and within the realm of neuroprotection. Neurologists see more refractory neonatal seizure, epilepsy, and a wider range of seizure types and aetiologies, so treatment is more likely to be unsuccessful, of longer duration, and with greater risk of side effects. The published literature on whether short term anti-convulsant drug use is harmful to neonates is controversial: anti-convulsant drugs are associated with neuronal apoptosis and inhibited neurogenesis in animal models [49, 50] but little is known about this relationship in humans. Levetiracetam and topiramate are less implicated [51, 52], and topiramate may be neuroprotective [53, 54]. A single retrospective study found increasing doses of phenobarbital for neonatal seizures is associated with worse cognitive outcome and cerebral palsy than levetiracetam [55], and long-term treatment with phenobarbital in children with febrile convulsions is associated with cognitive difficulties [56, 57].\n\nWhen neonatal seizures do have clinical features, there is variation in when consultants commence anti-convulsant treatments: neonatologists who think seizures cause harm treat them aggressively; others wait until the baby has had “enough” seizures to warrant treatment. The timeframe for this decision is entirely arbitrary and relates to dogmatic rules consultants were taught as trainees. When a decision is made to treat neonatal seizures, the choice of first line drug is almost always phenobarbital because of familiarity and tradition. Published evidence shows that phenobarbital stops between 28 and 63% of neonatal seizures [11, 58–61], so all neonatologists have seen it work and feel comfortable with its side effects. The downside of this approach is that it stops neonatologists gaining experience of other drugs and, on the rare occasions they do use alternatives, it is as second or third-line treatment in naturally more refractory seizures. Neonatologists feel they cannot unilaterally change their first-line drug choice because they worry about what their colleagues would think if they broke with ingrained, guideline-driven practice. Some neonatologists look towards neurologists for their experience of alternative drugs and want a national discussion to share experiences and reach a consensus on drug treatment.\n\nNeurologists have greater experience of a wide range of drugs, and choose their first line treatment based on seizure type and aetiology; for example, epileptic spasms are treated with steroids and / or vigabatrin and tonic seizures related to benign familial neonatal seizures with carbamazepine. For acute symptomatic seizures, neurologists also choose phenobarbital first because of tradition, but are more comfortable than neonatologists using newer drugs, like levetiracetam. We found genuine equipoise in both groups on whether Levetiracetam or Phenobarbital is more effective, although neurologists are more likely to report Levetiracetam as less effective, perhaps reflecting the aetiologies they see. Reassuringly, few reported side effects are seen with Levetiracetam, as nearly 80% of questionnaire responders reporting Levetiracetam had either no or mild side effects, reflecting similar data from small studies [55, 60–66]. Interviewees report they would like to change their first line treatment to Levetiracetam if it was found to be equally as effective as phenobarbital with less side effects, because phenobarbital’s sedative properties may prolong hospital stays.\n\nWe found extreme variation in the choice and dosage of second-line, third-line and subsequent drugs for neonatal seizures. Our interviews reveal that consultants do not know which drugs are the most effective and rely on the local traditions and network guidelines that often reflect the personal preference of their local expert. Both specialities report the need larger-scale studies into seizure treatments, but acknowledge their methodology and logistics are problematic.\n\nFinally, neurologists in our study reported they want closer collaboration with neonatologists to share knowledge and experience. Neonatologists are more focussed on working in neonatal networks, and only the interviewees who had close liaison with neurology colleagues saw the value of closer relationships. Currently, services appear disparate. Promoting training and collaboration between the two specialisms could improve care for neonates, drive forward developments in education, and help standardise care across the UK. An alternative model could be the formation of Neonatal Neurology Intensive Care Units [67], but it remains to be seen if this is the optimal method of delivering care in the UK given large numbers of neonates are at risk of neurological complications.\n\nThere are limitations to our data. Our response rate for the questionnaire is reasonable, but there is no way to determine whether the views and practices of individuals who responded are the same as those who did not. Some responders worked in the same units as others, and it is possible that the culture of specific units where multiple questionnaires were returned influenced the interpretation of our questionnaire results. We only interviewed consultants because the decision to investigate and treat ultimately resides with them, but the views of junior medical and nursing staff are important as they are “first-line” when recognising abnormal movements and seizures. We would have need a larger sample size to reach data saturation as the range of views would have been larger, and we did not have the resources to do this. It is a potential future area of research to determine if the views of consultants are substantially different from other members of staff. We also acknowledge that the responders to our questionnaire in Phase one were from a mixture of staff members, so the data from Phase One may not be directly transferable to the results of our interviews. However, 81.0% of questionnaire responders were consultants, so the effect of having other health care professionals answer the questionnaire is likely to be small. We purposefully chose consultants from different units, specialities, sex and experience levels to obtain as wide a range of their views as possible, but we cannot comment on the views of consultants who did not volunteer to be interviewed. Therefore, as with any qualitative interview study, we cannot guarantee our results are generalisable to all consultants managing neonatal seizures. Finally, we are aware that medicine, where possible, should be evidence-based. There are many limitations to relying on clinicians’ perceptions of what they think they do, which can be very different from their practice in real life, and the effectiveness of drug therapies. However, understanding perceptions is important because they explain why some people follow (or not) evidence and guidelines, and why clinicians make the choices they do when evidence is limited or of poor quality, as with the treatments of neonatal seizures. Where good quality exists, it is important it is followed because perceptions may be wrong.\n\nConclusion\nHealth care professionals face many uncertainties when diagnosing, investigating and treating neonatal seizures, resulting in wide variations in practice throughout the UK. Our data is the first to reveal the views of paediatricians and the challenges they face, along with the solutions they suggest. These include: development of nationwide educational packages to improve the descriptions taken of neonatal seizures and aEEG interpretation; increased use of video; improved access to neurophysiology investigations; a national discussion on whether aEEG should be available in level 2 units or if evaluation of all neonates with suspected seizures should be centralised to level 3 units; and closer collaboration between neurology and neonatal teams to drive forward a national consensus guideline, which would standardise the management of neonatal seizures across the UK.\n\nSupplementary information\n\nAdditional file 1. questionnaire sent to neonatal and paediatric neurology centres.\n\n \nAdditional file 2. topic guide used for qualitative interviews.\n\n \n\n\nAbbreviations\naEEGAmplitude integrated electroencephalography\n\nBPNABritish Paediatric Neurology Association\n\nEEGElectroencephalography\n\nGPGeneral Practitioner\n\nHIEHypoxic ischaemic encephalopathy\n\nQUALQualitative data or methods\n\nQUANQuantitative data or methods\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/s12887-020-1918-4.\n\nAcknowledgements\nWe thank Mrs. Vanda Cupit for transcribing the interviews recorded in this study.\n\nAuthors’ contributions\nLG: Collated and analysed data from the questionnaires used in phase one, performed the qualitative interviews, coded the data, performed initial thematic analysis, and reviewed the final draft of the paper. JA: Helped conceive the idea for the study, reviewed the data, assisted with interpretation, and reviewed and revised the final draft of the paper. TS: Provided support and advice on analysis of the qualitative aspects of the paper and advised on presentation and explanation of methods and results during write-up. TS reviewed and significantly revised the paper. AH: Conceived the study, wrote the questionnaire used in phase one, reviewed and interpreted data from phase one, wrote the interview schedule, trained LG in qualitative interview methods, performed coding and thematic analysis, interpreted the results and wrote the first draft of the paper. All authors reviewed the manuscript and approved it for print.\n\nFunding\nFunding was provided by the University of Sheffield as part of the first author’s MSc in Clinical Neurology. The funder had no role in study design, data collection, analaysis or interpretation, nor decision to publish the data.\n\nAvailability of data and materials\nThe data from the quantitative questionnaire and qualitative interview phases are not publicly available to maintain confidentiality of centres and individuals, as per ethical approval. However, all reasonable requests for information will be provided on request to the corresponding author.\n\nEthics approval and consent to participate\nEthical approval was obtained from the University of Sheffield (Reference Number 017700) for this project. All participants involved in the qualitative interview study provided signed consent for enrolment.\n\nConsent for publication\nAll authors have reviewed the final draft of the paper and consent to its publication.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. 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Khan O Chang E Cipriani C Wright C Crisp E Kirmani B Use of intravenous levetiracetam for managment of acute seizures in neonates Pediatr Neurol 2011 44 4 265 269 10.1016/j.pediatrneurol.2010.11.005 21397167 \n65. Rakshasbhuvankar A Rao S Kohan R Simmer K Nagarajan L Intravenous levetiracetam for treatment of neonatal seizures J Clin Neurosci 2013 20 8 1165 1167 10.1016/j.jocn.2012.08.014 23664133 \n66. Ramantani G Ikonomidou C Walter B Rating D Dinger J Levetiracetam: safety and efficacy in neonatal seizures Eur J Paediatr Neurol 2011 15 1 1 7 10.1016/j.ejpn.2010.10.003 21094062 \n67. Van Meurs KP Yan ES Randall KS Chock VY Davis AS Glennon CS Development of a NeuroNICU with a broader focus on all newborns at risk of brain injury: the first 2 years Am J Perinatol 2018 35 12 1197 1205 10.1055/s-0038-1646954 29702712\n\n",
"fulltext_license": "CC BY",
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"journal": "BMC pediatrics",
"keywords": "Anticonvulsants; Differential diagnosis; Hypoxia-ischemia, Brain; Infant / newborn; Neurophysiology; Seizures",
"medline_ta": "BMC Pediatr",
"mesh_terms": "D000927:Anticonvulsants; D001291:Attitude of Health Personnel; D019937:Diagnostic Techniques and Procedures; D004569:Electroencephalography; D006801:Humans; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases; D007407:Interviews as Topic; D000077287:Levetiracetam; D000072156:Neonatologists; D010348:Patient Care Team; D000072143:Pediatricians; D010634:Phenobarbital; D010818:Practice Patterns, Physicians'; D012640:Seizures; D011795:Surveys and Questionnaires; D006113:United Kingdom",
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"other_id": null,
"pages": "36",
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"pmid": "31992265",
"pubdate": "2020-01-28",
"publication_types": "D016428:Journal Article",
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"title": "Investigating and managing neonatal seizures in the UK: an explanatory sequential mixed methods approach.",
"title_normalized": "investigating and managing neonatal seizures in the uk an explanatory sequential mixed methods approach"
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"abstract": "OBJECTIVE\nDose-dense regimens have been shown to improve outcome when given as adjuvant therapy to patients with breast cancer compared with their three weekly counterparts. We investigated the feasibility of a dose-dense regimen with carboplatin/paclitaxel followed by pegfilgrastim in patients with advanced ovarian cancer. We also investigated the toxicities including the percentage of patients with grade 2 or greater peripheral neurotoxicity and the clinical response of this regimen.\n\n\nMETHODS\nWomen with untreated Stage III or IV epithelial ovarian, (fallopian) tubal, or primary peritoneal cancer were treated with carboplatin area under the curve (AUC) 5 and paclitaxel 175 mg/m(2) day one, and pegfilgrastim 6 mg day two every 2 weeks for six cycles.\n\n\nRESULTS\nBetween 9/06 and 9/08, 43 patients enrolled. Thirty-one patients completed six or more cycles of therapy. The dose limiting toxicities resulting in treatment discontinuation included: grade 3 and 4 neuropathy, grade 4 thrombocytopenia, grade 4 thrombocytopenia/grade 3 febrile neutropenia, and grade 4 supraventricular tachycardia. Twelve patients (30%) had >or=grade 2 neuropathy from this regimen. The overall response rate in patients with measurable disease was 58% (11 out of 19).\n\n\nCONCLUSIONS\nDose-dense carboplatin/paclitaxel appears to be effective. However, based on dose limiting toxicities occurring when administering 6 cycles of treatment, it is not feasible. Given the neuropathy and thrombocytopenia, we do not recommend 6 cycles of this regimen without modification.",
"affiliations": "New York University Cancer Institute, New York, NY 10016, USA. amy.tiersten@med.nyu.edu",
"authors": "Tiersten|Amy D|AD|;Sill|Michael W|MW|;Knight|Danielle|D|;Muggia|Franco|F|;Garcia|Agustin A|AA|;Swensen|Ron|R|;Warshal|David P|DP|;Mannel|Robert S|RS|;Fracasso|Paula M|PM|",
"chemical_list": "D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D016190:Carboplatin; D017239:Paclitaxel; D000069585:Filgrastim",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ygyno.2010.05.020",
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"issn_linking": "0090-8258",
"issue": "118(3)",
"journal": "Gynecologic oncology",
"keywords": null,
"medline_ta": "Gynecol Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005185:Fallopian Tube Neoplasms; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D006402:Hematologic Diseases; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms; D017239:Paclitaxel; D010523:Peripheral Nervous System Diseases; D010534:Peritoneal Neoplasms; D011092:Polyethylene Glycols; D011994:Recombinant Proteins",
"nlm_unique_id": "0365304",
"other_id": null,
"pages": "303-7",
"pmc": null,
"pmid": "20547415",
"pubdate": "2010-09",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "15661211;12953086;8411257;10550131;19767092;19223898;12504627;10655437;9719081;2681557;9164196;19446318;7602348;17499348;12668651;4748282;9275000",
"title": "A phase I trial of dose-dense (biweekly) carboplatin combined with paclitaxel and pegfilgrastim: a feasibility study in patients with untreated Stage III and IV ovarian, tubal or primary peritoneal cancer: a Gynecologic Oncology Group study.",
"title_normalized": "a phase i trial of dose dense biweekly carboplatin combined with paclitaxel and pegfilgrastim a feasibility study in patients with untreated stage iii and iv ovarian tubal or primary peritoneal cancer a gynecologic oncology group study"
} | [
{
"companynumb": "US-AMGEN-USASP2021169523",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PEGFILGRASTIM"
},
"drugadditional": "4",
... |
{
"abstract": "Caregiver-fabricated illness in a child (CFIC) can result in unnecessary, potentially harmful medical investigations and treatment. As pediatric pain has historically been undertreated, the movement for more compassionate treatment has led to an increase in analgesic prescribing in children and adolescents. Overall, this has been a positive change but this may also lead to unintentional harm, partic-ularly if CFIC is not considered as a possibility in the presentation. We present a case in which CFIC was associated with long-term prescribing of opioids, benzodiazepines, and other central nervous system depressants.",
"affiliations": "Assistant Professor, Department of Anesthesiology, McMaster University, Hamilton, Ontario, Canada; McMaster Children's Hospital, Hamilton Health Sciences, Hamilton, Ontario, Canada.;Professor, Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada; McMaster Children's Hospital, Hamilton Health Sciences, Hamilton, Ontario, Canada.",
"authors": "Kattail|Deepa|D|;Niec|Anne|A|",
"chemical_list": "D000701:Analgesics, Opioid; D002492:Central Nervous System Depressants; D001569:Benzodiazepines",
"country": "United States",
"delete": false,
"doi": "10.5055/jom.2020.0562",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1551-7489",
"issue": "16(2)",
"journal": "Journal of opioid management",
"keywords": null,
"medline_ta": "J Opioid Manag",
"mesh_terms": "D000293:Adolescent; D000701:Analgesics, Opioid; D001569:Benzodiazepines; D017028:Caregivers; D002492:Central Nervous System Depressants; D002648:Child; D006801:Humans; D016735:Munchausen Syndrome by Proxy",
"nlm_unique_id": "101234523",
"other_id": null,
"pages": "155-159",
"pmc": null,
"pmid": "32329891",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Caregiver-fabricated illness in a child prescribed long-term opioids and benzodiazepines.",
"title_normalized": "caregiver fabricated illness in a child prescribed long term opioids and benzodiazepines"
} | [
{
"companynumb": "CA-DRREDDYS-USA/CAN/20/0125409",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUOXETINE HYDROCHLORIDE"
},
"drugadditi... |
{
"abstract": "Three patterns of lithium poisoning are recognized: acute, acute-on-chronic, and chronic. Intravenous fluids with or without an extracorporeal treatment are the mainstay of treatment; their respective roles may differ depending on the mode of poisoning being treated. Recommendations for treatment selection are available but these are based on a small number of observational studies and their uptake by clinicians is not known. Clinician decision-making in the treatment of four cases of lithium poisoning was assessed at a recent clinical toxicology meeting using an audience response system. Variability in treatment decisions was evident in addition to discordance with published recommendations. Participants did not consistently indicate that hemodialysis was the first-line treatment, instead opting for a conservative approach, and continuous modalities were viewed favorably; this is in contrast to recommendations in some references. The development of multidisciplinary consensus guidelines may improve the management of patients with lithium poisoning but prospective randomized controlled trials are required to more clearly define the role of extracorporeal treatments.",
"affiliations": "Department of Renal Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom; Burns, Trauma and Critical Care Research Centre, School of Medicine, University of Queensland, Brisbane, Queensland, Australia.",
"authors": "Roberts|Darren M|DM|;Gosselin|Sophie|S|",
"chemical_list": "D008094:Lithium",
"country": "United States",
"delete": false,
"doi": "10.1111/sdi.12235",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0894-0959",
"issue": "27(4)",
"journal": "Seminars in dialysis",
"keywords": null,
"medline_ta": "Semin Dial",
"mesh_terms": "D019468:Disease Management; D006801:Humans; D008094:Lithium; D011041:Poisoning; D006435:Renal Dialysis",
"nlm_unique_id": "8911629",
"other_id": null,
"pages": "390-4",
"pmc": null,
"pmid": "24655138",
"pubdate": "2014",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Variability in the management of lithium poisoning.",
"title_normalized": "variability in the management of lithium poisoning"
} | [
{
"companynumb": "CA-GLAXOSMITHKLINE INC.-CA2015GSK060979",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional"... |
{
"abstract": "BACKGROUND\nMultiple sclerosis (MS) is a T-cell-mediated chronic inflammatory disorder of the central nervous system. Several agents have been approved for the treatment of MS; however, their efficacy is limited and short term. Autologous hematopoietic stem cell (HSC) transplantation may remain an encouraging option for some MS patients who failed prior conventional treatment. Objective To assess the safety and effectiveness of HSCs mobilization in patients with MS.\n\n\nMETHODS\nThirty-nine patients (20 females and 19 males) with relapsing-remitting MS at median age of 40 years (range: 25-63) were included in this study. As a stem cell mobilization, they received either granulocyte colony-stimulating factor (G-CSF) alone (10 µg/kg s.c. daily; n = 1) or cyclophosphamide (CY; 2.0 g/m(2) i.v. on days 1-2) followed by G-CSF (n = 38).\n\n\nRESULTS\nThe median number of mobilized HSCs per kg was 6.32 × 10(6) (range: 2.64-26.3 × 10(6)). One apheresis was sufficient for collection of HSCs in 30 out of 39 MS patients (77%). Two aphereses were required for seven patients, three for one and four for one (17, 3, and 3%; respectively). Side effects of HSCs mobilization have been reported for eight patients (30%) and they were following: Staphylococcus epidermidis bacteremia (n = 1), fever of unknown origin (n = 3), diarrhea (n = 3), and headache (n = 1).\n\n\nCONCLUSIONS\nMobilization using CY and/or G-CSF resulted in effective mobilization in all MS patients. This procedure was found to be safe. No fatal outcome has been reported.",
"affiliations": null,
"authors": "Kyrcz-Krzemień|Sławomira|S|;Helbig|Grzegorz|G|;Torba|Karolina|K|;Koclęga|Anna|A|;Krawczyk-Kuliś|Małgorzata|M|",
"chemical_list": "D016179:Granulocyte Colony-Stimulating Factor; D003520:Cyclophosphamide",
"country": "England",
"delete": false,
"doi": "10.1179/1607845415Y.0000000049",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1024-5332",
"issue": "21(1)",
"journal": "Hematology (Amsterdam, Netherlands)",
"keywords": "Autologous hematopoietic stem cell transplantation; Mobilization; Multiple sclerosis; Safety",
"medline_ta": "Hematology",
"mesh_terms": "D000328:Adult; D016470:Bacteremia; D001781:Blood Component Removal; D002452:Cell Count; D003520:Cyclophosphamide; D003967:Diarrhea; D004334:Drug Administration Schedule; D005260:Female; D005334:Fever; D016179:Granulocyte Colony-Stimulating Factor; D006261:Headache; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis; D061214:Patient Safety; D014182:Transplantation, Autologous",
"nlm_unique_id": "9708388",
"other_id": null,
"pages": "42-5",
"pmc": null,
"pmid": "26330136",
"pubdate": "2016-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Safety and efficacy of hematopoietic stem cells mobilization in patients with multiple sclerosis.",
"title_normalized": "safety and efficacy of hematopoietic stem cells mobilization in patients with multiple sclerosis"
} | [
{
"companynumb": "PHHY2018PL177825",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Klebsiella oxytoca (K. oxytoca) is a causative organism for hemorrhagic antibiotic-associated colitis. K. oxytoca infection is a typical example of microbial substitution diseases caused by exposure to antibiotics prior to the onset of diarrhea. Here, we repot a case with ileitis associated with K. oxytoca infection in the absence of preceding antibiotic treatment. Interestingly, abdominal computed tomography revealed wall thickening of the ileum and hepatic portal venous gas (HPVG). K. oxytoca was isolated from the stool. This very elderly patient had been treated with azathioprine for long-standing history of ulcerative colitis. Immuno-compromised state of this patient was considered to allow overgrowth of K. oxytoca in the small bowel to cause not only ileitis but also HPVG.",
"affiliations": "Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.;Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan. tomohiro@med.kindai.ac.jp.;Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.;Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.;Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.;Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.;Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.",
"authors": "Tanaka|Hidekazu|H|;Watanabe|Tomohiro|T|;Nagai|Tomoyuki|T|;Minaga|Kosuke|K|;Kamata|Ken|K|;Komeda|Yoriaki|Y|;Kudo|Masatoshi|M|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-019-00947-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "12(4)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Antibiotics; Hepatic portal venous gas; Klebsiella oxytoca",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D004618:Embolism, Air; D005260:Female; D006801:Humans; D007079:Ileitis; D007710:Klebsiella Infections; D041121:Klebsiella oxytoca; D011169:Portal Vein; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "316-319",
"pmc": null,
"pmid": "30739249",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15636750;15902735;17151365;17368233;18808355;19653334;20053860;20724146;21172241;25157164;26963452;28328258;29096338;30084095;30120320;637584",
"title": "Hepatic portal venous gas associated with Klebsiella oxytoca infection in the absence of preceding antibiotic treatment.",
"title_normalized": "hepatic portal venous gas associated with klebsiella oxytoca infection in the absence of preceding antibiotic treatment"
} | [
{
"companynumb": "JP-SEBELA IRELAND LIMITED-2019SEB00045",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional... |
{
"abstract": "Immunobiologic therapy is indicated for severe forms of psoriasis, resistant to conventional therapy. There is growing concern about their safety profile and possible association with cancer development. This article documents two cases of renal cell cancer during treatment with biologic therapy, reviewing what is described in the literature . The risk of solid tumors as a complication of using TNF-alpha inhibitors is controversial. No conclusion can be drawn from the data in the literature, however, we believe that special attention should be given to those with known risk factors for a specific neoplasm.",
"affiliations": "Instituto de Dermatologia Prof. Rubem David Azulay, Santa Casa da Misericórdia do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.;Instituto de Dermatologia Prof. Rubem David Azulay, Santa Casa da Misericórdia do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.;Instituto de Dermatologia Prof. Rubem David Azulay, Santa Casa da Misericórdia do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.;Instituto de Dermatologia Prof. Rubem David Azulay, Santa Casa da Misericórdia do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.;Instituto de Dermatologia Prof. Rubem David Azulay, Santa Casa da Misericórdia do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.",
"authors": "Zarur|Fabiana Palmieri|FP|;d'Almeida|Luiza Ferreira Vieira|LF|;Mafort|Monique Samy Pamplona|MS|;Gusmão|Paula Regazzi de|PR|;Avelleira|João Carlos Regazzi|JC|",
"chemical_list": "D000911:Antibodies, Monoclonal; D003879:Dermatologic Agents; D007074:Immunoglobulin G; D007155:Immunologic Factors; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068800:Etanercept",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nAn Bras DermatolAn Bras DermatolAnais Brasileiros de Dermatologia0365-05961806-4841Sociedade Brasileira de Dermatologia 2538751710.1590/abd1806-4841.20143257CommunicationTwo cases of renal cell cancer during immunobiologic therapy for\npsoriasis*\n Zarur Fabiana Palmieri 1d'Almeida Luiza Ferreira Vieira 1Mafort Monique Samy Pamplona 1de Gusmão Paula Regazzi 1Avelleira João Carlos Regazzi 11 Instituto de Dermatologia Prof. Rubem David Azulay - Santa Casa da\nMisericórdia do Rio de Janeiro (IDPRDA - SCMRJ) - Rio de Janeiro (RJ), Brazil.MAILING ADDRESS: Fabiana Palmieri Zarur, Rua Guimarães Rosa 203 apto\n705 - Barra da Tijuca, 22793-620 - Rio de Janeiro - RJ, Brazil. E-mail:\nfabianazarur@hotmail.comNov-Dec 2014 Nov-Dec 2014 89 6 1017 1018 08 11 2013 19 11 2013 This is an Open Access article distributed under the terms of the Creative\nCommons Attribution Non-Commercial License which permits unrestricted\nnon-commercial use, distribution, and reproduction in any medium, provided the\noriginal work is properly cited.Immunobiologic therapy is indicated for severe forms of psoriasis, resistant to\nconventional therapy. There is growing concern about their safety profile and\npossible association with cancer development. This article documents two cases of\nrenal cell cancer during treatment with biologic therapy, reviewing what is described\nin the literature . The risk of solid tumors as a complication of using TNF-alpha\ninhibitors is controversial. No conclusion can be drawn from the data in the\nliterature, however, we believe that special attention should be given to those with\nknown risk factors for a specific neoplasm.\n\nBiological therapyKidney neoplasmsPsoriasis\n==== Body\nPsoriasis is a chronic autoimmune disease that affects the skin and joints, with worldwide\nprevalence ranging from 0.8 to 4.6%.1 A\nlarge number of topical and systemic treatments are available, and immunobiologic therapy\nis indicated for moderate to severe resistant forms, or individuals for whom conventional\ntherapy is contraindicated. However, there is a growing concern about the safety profile,\nmainly due to the possible association of these drugs with an increased incidence of\nneoplasia. This article documents two cases of renal cell cancer during treatment with\nbiologic therapy, reviewing the literature so far.\n\nThe first case concerns a 41-year-old man with eleven years of severe psoriasis and\npsoriatic arthritis (polyarticular and axial involvement). His level on the Psoriasis Area\nand Severity Index (PASI) remained at 28.9 despite taking methotrexate (MTX). Infliximab\n4mg/kg was thus added to existing therapy and he responded excellently. After a year of\ntreatment, the calculated PASI was 1.8. At one hundred and eight weeks of infliximab,\nhepatitis was diagnosed due to the development of jaundice and elevated transaminase\nlevels. An abdominal ultrasound was requested, which revealed a mass in the right kidney.\nAfter a urology evaluation, a total nephrectomy was performed with a diagnosis of clear\ncell renal carcinoma by histopathological analysis. The surgery was curative and\nadministration of leflunomide 10mg/day stabilized joint symptoms and partially controlled\nthe cutaneous lesions.\n\nThe following report concerns a 66 year-old-man with a 40-year history of psoriasis. He had\nalready used MTX and was undergoing psoralen in addition to UVA light therapy (PUVA)\ntreatment twice a week, and taking acitretin 30mg once a day. Despite the instituted\ntherapy, new cutaneous lesions and joint symptoms appeared, leading consequently to the\ninitiation of etanercept at a dose of 50mg per week. He achieved disease control with\nresolution of the joint symptoms and a decline in PASI of more than 90%. After two hundred\nand eighteen weeks of therapy, prostatic symptoms led to an abdominal ultrasonography. In\nthis case, a renal mass was also found and the patient underwent a total nephrectomy, whose\nhistopathological examination revealed papillary renal carcinoma. Surgery was also\ncurative, and the patient kept the disease under control with 30mg/day of acitretin.\n\nRenal cell carcinoma accounts for 3% of all malignancies, is twice as common in men and the\nage group 50-70 years is the most affected.2 The most common histologic type is clear cell carcinoma (75-85%)\nfollowed by papillary (10-15%), chromophobe (5-10%), oncocytic (3-7%) and collecting duct\n(<1%).3 Since it is a silent\ncancer, the increased availability and improvement of imaging methods have led to a large\nincrease in the percentage of incidental renal tumors, with 50% classified as\nincidentalomas.4\n\nData on the risk of solid tumors as a complication of using TNFa (Tumor necrosis factor\nalpha) inhibitors are controversial. A study in Sweden with three cohorts found that the\nrisk of solid malignancies in patients with rheumatoid arthritis treated with TNFa\ninhibitors is not greater than what would be expected with the disease alone.5 A meta-analysis of 63 studies, including a\ntotal of 29,423 patients, found no significant risk among those undergoing biologic\ntherapy, compared with disease-modifying drugs or placebo, with a follow-up of at least 24\nweeks.6 However, a double-blind,\nrandomized study, showed increased risk of solid tumors in patients with Wegener's\ngranulomatosis treated with TNFa inhibitors and cyclophosphamide, compared with those\ntreated only with cyclophosphamide.7 Do\nTNFa inhibitors increase the chance of solid tumors, such as renal neoplasia? Or have they\nbeen overdiagnosed due to advances in imaging methods, leading to bias in studies?\n\nIn the specific case of renal cell carcinoma, few reports showed renal neoplasia in\npatients undergoing immunobiologic therapy. Some authors studied the benefit of TNFa\ninhibitors as an adjunctive therapy in treating these tumors, based on the fact that TNFa\nreceptors were found in neoplasic renal cells.8 We have found evidence in the literature that patients with psoriasis\nhave an increased incidence of lymphoproliferative disorders, particularly Hodgkin's\nlymphoma and cutaneous T-cell lymphoma.9\nThere is also a higher risk of solid tumors, and associated characteristics include the use\nof oral medication (gravity indicators) and long duration of disease (> 4\nyears).10\n\nTNFa inhibitors are associated with potentially serious adverse effects. However, these\nrisks must be interpreted in the context of the potential benefits associated with such\nproducts.\n\nThe adverse effects of conventional treatments, including the risk of inducing malignancy,\nare also significant in most cases. Thus, the decision to use a TNF inhibitor should be\nindividual, based on the specific clinical characteristics and specific risk profile of a\nparticular patient.\n\nWith respect to the patients described above, we cannot draw conclusions from the data\nfound in the literature regarding the development of renal cancer with the instituted\ntherapy. However, we believe that special attention should be given to those with known\nrisk factors for a specific neoplasm, who use these medications.\n\nConflict of interest: None\n\nFinancial funding: None\n\nHow to cite this article: Zarur FP, d'Almeida LFV, Mafort M, Gusmão PR, Avelleira\nJCR. Two cases of renal cell cancer during immunobiologic therapy for psoriasis. An\nBras Dermatol. 2014;89(6):1017-8.\n\n* Work performed at the Instituto de Dermatologia Prof. Rubem David Azulay- Santa Casa\nda Misericórdia do Rio de Janeiro (IDPRDA - SCMRJ) - Rio de Janeiro (RJ), Brazil.\n==== Refs\nReferences\n1 Naldi L Epidemiology of psoriasis Curr Drug Targets Inflamm Allergy 2004 3 121 128 15180464 \n2 Figlin RA Renal cell carcinoma: management of advanced disease J Urol 1999 161 381 386 9915408 \n3 Störkel S van den Berg E Morphological classification of renal cancer World J Urol 1995 13 153 158 7550386 \n4 Landis SH Murray T Bolden S Wingo PA Cancer statistics, 1999 CA Cancer J Clin 1999 49 8 31 8-31,1 10200775 \n5 Askling J Fored CM Brandt L Baecklund E Bertilsson L Feltelius N et al Risks of solid cancers in patients with rheumatoid arthritis and after\ntreatment with tumour necrosis factor antagonists Ann Rheum Dis 2005 64 1421 1426 15829572 \n6 Lopez-Olivo MA Tayar JH Martinez-Lopez JA Pollono EN Cueto JP Gonzales-Crespo MR et al Risk of Malignancies in Patients whith rheumathoid arthritis treated\nwith biologic therapy: a meta-analysis JAMA 2012 308 898 908 22948700 \n7 Stone JH Holbrook JT Marriott MA Tibbs AK Sejismundo LP Min YI et al Solid Malignancies Among Patients in the Wegner's Granulomatosis\nEtanercept Trial Arthritis Rheum 2006 54 1608 1618 16646004 \n8 Harrison ML Obermueller E Maisey NR Hoare S Edmonds K Li NF et al Tumor Necrosis Factor α as a new target for renal cell carcinoma: two\nsequential Phase IItrials of Infliximab at standart and high dose J Clin Oncol 2007 25 4542 4549 17925549 \n9 Gelfand JM Shin DB Neimann AL Wang X Margolis DJ Troxel AB The risk of lymphoma in patients with psoriasis J Invest Dermatol 2006 126 2194 2201 16741509 \n10 Brauchli YB Jick SS Miret M Meier CR Psoriasis and Risk of Incident Cancer: An Inception Cohort Study with\na Nested Case-Control Analysis J Invest Dermatol 2009 129 2604 2612 19440219\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0365-0596",
"issue": "89(6)",
"journal": "Anais brasileiros de dermatologia",
"keywords": null,
"medline_ta": "An Bras Dermatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D002292:Carcinoma, Renal Cell; D003879:Dermatologic Agents; D000068800:Etanercept; D006801:Humans; D007074:Immunoglobulin G; D007155:Immunologic Factors; D000069285:Infliximab; D007680:Kidney Neoplasms; D008297:Male; D008875:Middle Aged; D011565:Psoriasis; D018124:Receptors, Tumor Necrosis Factor; D012307:Risk Factors; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "0067662",
"other_id": null,
"pages": "1017-8",
"pmc": null,
"pmid": "25387517",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15180464;7550386;9915408;10200775;22948700;16646004;16741509;17925549;19440219;15829572",
"title": "Two cases of renal cell cancer during immunobiologic therapy for psoriasis.",
"title_normalized": "two cases of renal cell cancer during immunobiologic therapy for psoriasis"
} | [
{
"companynumb": "BR-AMGEN-BRASP2014095364",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETANERCEPT"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo evaluate the safety and effects of irinotecan, an inhibitor of topoisomerase I, on refractory lupus nephritis.\n\n\nMETHODS\nA patient with refractory lupus nephritis under medication with mycophenolic acid, prednisolone, and hydroxychloroquine was treated with add-on low-dose irinotecan. Irinotecan was applied every fourth week at a dose of 50 mg/m2 for four cycles followed by 100 mg/m2 for another eight cycles. Renal function and anti-double-stranded DNA antibodies as well as blood count for evaluation of side effects were assessed during the treatment with irinotecan.\n\n\nRESULTS\nBefore starting the treatment with irinotecan, a urine protein/creatinine ratio of 1298 mg/g was determined. This declined to 613 mg/g after four cycles with 50 mg/m2 irinotecan and was further reduced to 198 mg/g when using the higher dose of irinotecan. Kidney function remained stable, with creatinine levels of 1.66 mg/dL at the beginning and 1.76 mg/dL at the end of treatment with irinotecan. Importantly, no side effects, such as diarrhoea or neutropenia, were observed during the entire course of treatment.\n\n\nCONCLUSIONS\nAdministration of low-dose irinotecan as add-on medication for the treatment of refractory lupus nephritis was shown to be safe. Clinical trials are needed to determine whether irinotecan can improve kidney function and the outcome of patients with refractory lupus nephritis.",
"affiliations": "Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany.;Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), a Leibniz Institute, Berlin, Germany.;Department of Nephrology and Intensive Care Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany.;Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), a Leibniz Institute, Berlin, Germany.;Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany.;Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), a Leibniz Institute, Berlin, Germany.",
"authors": "Biesen|R|R|;Frese-Schaper|M|M|;Enghard|P|P|;Cheng|Q|Q|;Hiepe|F|F|;Frese|S|S|",
"chemical_list": null,
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"abstract": "BACKGROUND\nMycobacterium tuberculosis is responsible for high morbidity and mortality in immune-compromised hosts.\n\n\nMETHODS\nWe present a rare case of cutaneous tuberculosis after orthotopic liver transplantation without involvement of any other organs.\n\n\nCONCLUSIONS\nTB risk-factors assessment, careful LTBI screening and treatment according to national guidelines, as well as a reduction in missed opportunity for prevention are necessary to avoid MTB related disease in fragile patients.",
"affiliations": "Infectious Diseases and Tropical Medicine Department, Ospedale Policlinico San Martino IST, University of Genoa, Genoa, Italy.;Infectious Diseases Unit, Ente Ospedaliero Ospedali Galliera, Mura delle Cappuccine, 14, 16128, Genoa, Italy. giovanni.cenderello@galliera.it.;TB Supranational Reference Laboratory, IRCCS San Raffaele Scientific Institute, Milan, Italy.;Pathology Department, Ente Ospedaliero Ospedali Galliera, Genoa, Italy.;TB Supranational Reference Laboratory, IRCCS San Raffaele Scientific Institute, Milan, Italy.",
"authors": "Riccardi|Niccolò|N|;Cenderello|Giovanni|G|http://orcid.org/0000-0002-1600-0449;Borroni|Emanuele|E|;Rutigliani|Mariangela|M|;Cirillo|Daniela Maria|DM|",
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"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 334710.1186/s12879-018-3347-7Case ReportA case report of mucocutaneous tuberculosis after orthotopic liver transplantation: a challenging diagnosis Riccardi Niccolò niccolo.riccardi@yahoo.it 1http://orcid.org/0000-0002-1600-0449Cenderello Giovanni +390105634475giovanni.cenderello@galliera.it 2Borroni Emanuele borroni.emanuele@hsr.it 3Rutigliani Mariangela mariangela.rutigliani@galliera.it 4Cirillo Daniela Maria cirillo.daniela@hsr.it 31 0000 0001 2151 3065grid.5606.5Infectious Diseases and Tropical Medicine Department, Ospedale Policlinico San Martino IST, University of Genoa, Genoa, Italy 2 0000 0004 1757 8650grid.450697.9Infectious Diseases Unit, Ente Ospedaliero Ospedali Galliera, Mura delle Cappuccine, 14, 16128 Genoa, Italy 3 0000000417581884grid.18887.3eTB Supranational Reference Laboratory, IRCCS San Raffaele Scientific Institute, Milan, Italy 4 0000 0004 1757 8650grid.450697.9Pathology Department, Ente Ospedaliero Ospedali Galliera, Genoa, Italy 29 8 2018 29 8 2018 2018 18 43119 12 2017 20 8 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nMycobacterium tuberculosis is responsible for high morbidity and mortality in immune-compromised hosts.\n\nCase presentation\nWe present a rare case of cutaneous tuberculosis after orthotopic liver transplantation without involvement of any other organs.\n\nConclusion\nTB risk-factors assessment, careful LTBI screening and treatment according to national guidelines, as well as a reduction in missed opportunity for prevention are necessary to avoid MTB related disease in fragile patients.\n\nKeywords\nCutaneous tuberculosisOLTHCCLTBIissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nTuberculosis (TB) is principally a disease of the lungs (PTB) but, in the extra-pulmonary form (EPTB) it can affect almost any organ in the body [1].\n\nIn 2016 Mycobacterium tuberculosis (MTB) was responsible for 1.6 million deaths, an estimated 10.4 million people developed the disease worldwide and 15% of those had EPTB [2]. Italy is a low TB incidence country, defined by the World Health Organization (WHO) as a nation where TB frequency is lower than 10 cases per 100.000 of population [3].\n\nEPTB is marginally responsible to the transmission of MTB but it may be difficult to diagnose, and it may remarkably contribute to TB related morbidity and lifelong disabilities [4, 5];\n\nit is otherwise difficult to be recognised and diagnosed. In addition, cutaneous tuberculosis (CTB), due to either direct inoculation from an exogenous source, from an endogenous source or due to haematogenous dissemination of MTB, is a rare manifestation, accounting for 1 to 1.5% of all EPTB. Due to MTB heterogeneous manifestations, its diagnosis may be problematic in European countries where TB incidence is low [2–6].\n\nFor rifampicin susceptible TB, a 2 months, induction phase with oral isoniazid (H), rifampicin (R), ethambutol (E) and pyrazinamide (Z) is followed by 4 months of maintenance with oral rifampicin and isoniazid is needed to manage and eventually cure CTB; in few cases surgical removal of the lesion may be considered [6].\n\nIn this report, we are presenting a case of a patient who underwent orthotopic liver transplantation (OLT), due to hepatocellular carcinoma (HCC), 14 months before clinical presentation of CTB. The patient was under immunosuppressive treatment with both tacrolimus and everolimus when he developed CTB of the lower lip. We will also discuss optimum clinical management of CTB.\n\nCase report\nA 59-year-old Italian male, weighting 69 kg and 173 cm tall, came to our attention for an ulcerative lesion of the left lower lip (Fig. 1, Panel A). He had already received antibiotic treatment with amoxicillin/clavulanate plus antiviral acyclovir for 10 days in other outpatient facilities without any clinical improvement. His clinical history was remarkable for hepatitis B (HBV) and Genotype 3 hepatitis C (HCV) co-infection, which led to OLT due to HCC, and several years spent in foreign countries. In fact, when he was in his late 40 he had spent 6 years in Nigeria and one and a half year in the South of China where he worked at sea as a kitchen supervisor. The patient was HIV negative. Six months before the OLT he had received treatment with daclatasvir (60 mg/die), sofosbuvir (400 mg/die) and ribavirin (1000 mg/die) for HCV, successfully reaching sustained virological response (SVR) 12 weeks after the end of treatment. A QuantiFERON®-TB Gold In-Tube (QFT-G) was performed among the pre-transplant screening and resulted positive.Fig. 1 a Ulcerative lesion of the left lower lip as it appears at the first clinical visit at our outpatients department. b Ziehl-Neelsen staining showing Acid fast bacilli (AFB) in the patient’s sample. Smear scored 1+. c Subcutaneos granuloma: degenerate collagen is surrounded by a palisade of hystiocytes, lymphocites, fibroblasts and note of intensely eosinophilic necrobiosis (E&E × 20). d Complete resolution of the lesion after 6 month of treatment\n\n\n\nNeither before nor after OLT, latent TB infection (LTBI) therapy was administered.\n\nPatient received OLT and 14 months post-transplant presented with a lower lip lesion. At the time of presentation patient was on the following medications: entecavir1000 mg daily for chronic HBV with lamivudine resistance, tacrolimus 3 mg daily and everolimus 1 mg twice a day for immunosuppression.\n\nA punch biopsy of the lower lip lesion was performed and submitted for extended microbiology and histological examination.\n\nThe histological examination suggested chronic granulomatous inflammation (Fig. 1, Panel B).\n\nReal time PCR (Xpert MTB/Rif™– Cepheid Sunnyvale, CA United States) was positive for MTB by high grading, implying a high bacterial load in the analysed specimen. No rpo-B mutation, affecting rifampicin resistance, was detected. Conventional microbiological investigations were also carried out: smear microscopy and automated liquid cultures (Bactec MGIT960™– Becton and Dickinson Franklin Lakes, NJ) were positive and the subsequent susceptibility testing showed sensitivity to all first-line drugs tested. A total body CT scan was performed to rule out presence of granuloma or signs of pulmonary or other extra-pulmonary site involvement. Moreover, Xpert MTB/Rif™–, Ziehl Neelsen and MTB colture on sputum resulted negative.\n\nA treatment with rifabutin (450 mg/daily), isoniazid (300 mg/daily), ethambutol (1200 mg/daily), pyrazinamide (1500 mg/daily) and daily supplementation of B6 vitamin was started for the intensive phase of 2 months. The therapeutic regimen was then simplified to rifabutin (300 mg/daily) plus isoniazid (300 mg/daily) for the following 4 months.\n\nLiver function and level of immune-suppressive treatment were monitored weekly. No increase in transaminases was observed and only a slight decrease in both tacrolimus (from5 μg/L to 3; normal value 5–7 μg/L) and everolimus (from 3 μg/L to 1.9 μg/L; normal value 2.5–3 μg/L) was noticed after 1 month of treatment; therefore, to achieve satisfactory blood-level concentrations, tacrolimus dosage was increased to 6 mg/ daily and everolimus was progressively titrated to 2.75 mg/ daily in two doses. After 3 weeks of therapy, a dramatic clinical improvement was observed and after 6 months of treatment the lesion was cured (Fig. 1, Panel D).\n\nDiscussion and conclusion\nThis case highlights a rare localisation of TB, without pulmonary or other organs involvement, in a chronic immunosuppressed host. Prior to transplant, a detailed anamnesis is necessary to estimate the risk of LTBI and/or active TB. In fact, even if our patient was born and raised in a low TB prevalence country, he lived and worked for several years, in high TB prevalence nations [2].\n\nSubsequently screening for latent TB in patients undergoing OLT and other solid organ-transplant (SOT) is mandatory to assess the risk of developing active-TB and planning LTBI treatment or prophylaxis [7, 8]. As suggested by Zenner et al., either TST or IGRA-test may be used to annually monitor candidates to SOT [9]. In this case, the patient had a positive IGRA-test and, although drug related toxicity may be a concern, the benefit of LTBI treatment in a host undergoing chronic-immunosuppression should drive the choice. Furthermore, a 3 months isoniazid-rifampicin dual regimen has been proven to be safe and efficient [10]. Unfortunately, due to fear of liver toxicity and possible drug-drug interactions, treatment of LTBI before and after SOT was postponed.\n\nAlthough CTB diagnosis is often overlooked due to the variety of possible differential diagnosis, the molecular diagnostic tools for TB detection approved by WHO, remarkably reduce time to diagnosis and are both sensitive and specific [11, 12].\n\nCTB often represents the haematogenous or lymphatic spread of MTB from other foci therefore, treatment of sensible CTB follows the same rules of TB of other organs with an intensive phase of 2 months with isoniazid, rifampicin, ethambutol and pyrazinamide followed by a maintenance phase of 4 months with isoniazid and rifampicin. Thus, when CTB is suspected, a diagnostic approach aimed to exclude internal organ involvement, especially PTB, is mandatory.\n\nRarely CTB is confined as only cutaneous, probably for direct inoculation of MTB, like in the case of tuberculosis verrucosa cutis and lupus vulgaris: these forms of CTB are not associated with internal organ involvement but, the length and the regimen of sensible MTB treatment remain the same [12].\n\nTreatment with rifabutin was initiated to decrease the chance of drug to drug interactions due to the use of molecules which share the same cytochrome P 450 (CYP450) metabolic pathway. Rifampicin is a metabolic inducer of CYP450 and may decrease calcineurin inhibitors haematic level [13, 14]. Rifabutin, as a milder inducer of CYP450, may have a lower impact on both calcineurin inhibitors then rifampicin [14]. Therefore, according to previous studies that compared rifamycins in TB treatment, rifabutin was started along with careful monitoring of both tacrolimus and everolimus in order to decrease the likelihood of modifications in calcineurin inhibitors haematic level [15–18].\n\nA clinical relevant reduction in tacrolimus and everolimus blood levels was then expected, but the extent was not predictable [14]. In addition, all drugs used for the CTB are known to potentially cause liver toxicity, undermining the treatment tolerability, OLT and clinical outcome. However, different reports described efficacy and safety of rifabutin in treating TB patients who presented allergy to rifampicin or potential harmful drug-drug interactions [15].\n\nFinally, cost-effectiveness of TB screening is also an important issue. In Italy different protocols are in use to screen categories at risk. TST is often used as first screening because of the very low cost and in some referral medical centres positive cases are confirmed by IGRAs. IGRAs sensitivity has been reported higher then TST in several studies in HIV infected individuals [19]. In any case the intention to test should be linked to the intention to treat or, if treatment is not possible, to monitor the patient, particularly if the immunity is impaired.\n\nAs suggested by the TBNET consensus, treatment of LTBI in transplant candidates and after SOT should be offered according to national guidelines, thus reflecting regional drug availability and resistance patterns [20]. However, if LTBI treatment is not possible both during pre-transplant phase and in the post-transplant phase, close monitoring of signs and symptoms of active TB is recommended [20]. In patients undergoing SOT in low TB prevalence countries, careful anamnesis, TB risk factors assessment and LTBI screening are recommended. Although a rare presentation of active TB, due to the plethora of cutaneous presentation, CTB should be suspected in immune-compromised host.\n\nMolecular tests and classical microbiological investigations on bioptic specimen are helpful tools to facilitate correct diagnosis of CTB.\n\nAbbreviations\nCTBCutaneous Tuberculosis\n\nCYP 450Cytochromes P450\n\nEEthambutol\n\nEPTBExtra-pulmonary Tuberculosis\n\nHIsoniazid\n\nHBVHepatitis B virus\n\nHCCHepatocellular carcinoma\n\nHCVHepatitis C virus\n\nHIVHuman Immunodeficiency Virus\n\nIGRAInterferon Gamma Release Assay\n\nLTBILatent TB infection\n\nMTBMycobacterium tuberculosis\n\nOLTOrthotopic liver transplantation\n\nPPyrazinamide\n\nPTBPulmonary Tuberculosis\n\nQFT-GQuantiFERON®-TB Gold In-Tube\n\nRRifampicin\n\nSOTSolid organ-transplant\n\nSVRSustained virological response\n\nTBTuberculosis\n\nTSTTubercolin skin test\n\nWHOWorld Health Organization\n\nThe authors are deeply grateful to Monica Valento for her help in reviewing the manuscript.\n\nAll the authors declare no conflict of interest.\n\nAuthors’ contributions\nNR and GC made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data. NR, GC, EB and DMC been involved in drafting the manuscript or revising it critically for important intellectual content. NR, GC, EB, MR and DMC given final approval of the version to be published. NR and GC took care of the patient. EB and MR took care of patient’s specimens. GC and DMC supervised the creation of the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent for publication of their clinical details and clinical images was obtained from the patient (19 Dec 2017). A copy of the consent form is available for review by the Editor of this journal, it was submitted with the first version.\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. Golden MP Vikram HR Extrapulmonary tuberculosis: an overview Am Fam Physician. 2005 72 9 1761 1768 16300038 \n2. Global Tuberculosis Report 2017, WHO. Available at: http://apps.who.int/iris/bitstream/10665/259366/1/9789241565516-eng.pdf?ua=1 (accessed on: 8 Feb 2018).\n3. Blasi F, Matteelli A, Sotgiu G, Cirillo DM, Palmieri F, Fattorini L, Migliori GB. Moving towards tuberculosis elimination: a call for action from Italy and a possible model for other low tuberculosis incidence countries. Eur Respir J. 2017;49(2). 10.1183/13993003.02242-2016. Print 2017 Feb. PubMed PMID: 28153873.\n4. Gambhir S Ravina M Rangan K Dixit M Barai S Bomanji J International Atomic Energy Agency Extra-pulmonary TB Consortium.Imaging in extrapulmonary tuberculosis Int J Infect Dis 2017 56 237 247 10.1016/j.ijid.2016.11.003 27838445 \n5. Hopewell PC Pai M Maher D Uplekar M Raviglione MC International standards for tuberculosis care Lancet Infect Dis 2006 6 11 710 725 10.1016/S1473-3099(06)70628-4 17067920 \n6. vanZyl L du Plessis J Viljoen J Cutaneous tuberculosis overview and current treatment regimens Tuberculosis 2015 95 6 629 638 10.1016/j.tube.2014.12.006 26616847 \n7. Moon HH Park SY Kim JM Park JB Kwon CHD Peck KR Kim SJ Lee SK Joh JW Isoniazid Prophylaxis for Latent Tuberculosis Infections in Liver Transplant Recipients in a Tuberculosis-Endemic Area Ann Transplant 2017 22 338 345 10.12659/AOT.902989 28579606 \n8. Getahun H Matteelli A Abubakar I Aziz MA Baddeley A Barreira D Den Boon S Borroto Gutierrez SM Bruchfeld J Burhan E Cavalcante S Cedillos R Chaisson R Chee CB Chesire L Corbett E Dara M Denholm J de Vries G Falzon D Ford N Gale-Rowe M Gilpin C Girardi E Go UY Govindasamy D D Grant A Grzemska M Harris R Horsburgh CR Jr Ismayilov A Jaramillo E Kik S Kranzer K Lienhardt C LoBue P Lönnroth K Marks G Menzies D Migliori GB Mosca D Mukadi YD Mwinga A Nelson L Nishikiori N Oordt-Speets A Rangaka MX Reis A Rotz L Sandgren A Sañé Schepisi M Schünemann HJ Sharma SK Sotgiu G Stagg HR Sterling TR Tayeb T Uplekar M van der Werf MJ Vandevelde W van Kessel F van’t Hoog A Varma JK Vezhnina N Voniatis C Vonk Noordegraaf-Schouten M Weil D Weyer K Wilkinson RJ Yoshiyama T Zellweger JP Raviglione M Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries Eur Respir J 2015 46 6 1563 1576 10.1183/13993003.01245-2015 26405286 \n9. Roth PJ Grim SA Gallitano S Adams W Clark NM Layden JE Serial testing for latent tuberculosis infection in transplant candidates: a retrospectivereview Transpl Infect Dis 2016 18 1 14 21 10.1111/tid.12489 26671024 \n10. Zenner D Beer N Harris RJ Lipman MC Stagg HR van der Werf MJ Treatment of Latent Tuberculosis Infection: An Updated Network Meta-analysis Ann Intern Med 2017 167 4 248 255 10.7326/M17-0609 28761946 \n11. Handog EB Gabriel TG Pineda RT Management of cutaneous tuberculosis Dermatol Ther 2008 21 3 154 161 10.1111/j.1529-8019.2008.00186.x 18564245 \n12. Denkinger CM Schumacher SG Boehme CC Dendukuri N Pai M Steingart KR Xpert MTB/RIF assay for the diagnosis of extrapulmonary tuberculosis: a systematic review and meta-analysis Eur Respir J 2014 44 435 446 10.1183/09031936.00007814 24696113 \n13. Motta I Calcagno A Bonora S Pharmacokinetics and pharmacogenetics of anti-tubercular drugs: a tool for treatment optimization? Expert Opin Drug Metab Toxicol 2018 14 1 59 82 10.1080/17425255.2018.1416093 29226732 \n14. Lefeuvre S Rebaudet S Billaud EM Wyplosz B Management of rifamycins-everolimus drug-drug interactions in a liver-transplant patient with pulmonary tuberculosis Transpl Int 2012 25 11 e120 e123 10.1111/j.1432-2277.2012.01561.x 22994607 \n15. Horne DJ Spitters C Narita M Experience with RifabutinReplacingRifampin in the Treatment of Tuberculosis Int J Tuberc Lung Dis 2011 15 11 1485 1490 10.5588/ijtld.11.0068 22008761 \n16. Baciewicz AM Chrisman CR Finch CK Self TH Update on rifampin and rifabutin drug interactions Am J Med Sci. 2008 335 2 126 136 10.1097/MAJ.0b013e31814a586a 18277121 \n17. Sun HY Treating tuberculosis in solid organ transplant recipients Curr Opin Infect Dis 2014 27 6 501 505 10.1097/QCO.0000000000000102 25211360 \n18. Demir E Sever MS Posttransplant Tuberculosis Exp Clin Transplant 2017 15 Suppl 1 10 15 28260424 \n19. Ramos JM Robledano C Masiá M Belda S Padilla S Rodríguez JC Gutierrez F Contribution of interferon gamma release assays testing to the diagnosis of latent tuberculosis infection in HIV-infected patients: a comparison of QuantiFERON-TB Gold In Tube, T-SPOT.TB and tuberculin skin test BMC Infect Dis 2012 12 169 10.1186/1471-2334-12-169 22849726 \n20. Bumbacea D Arend SM Eyuboglu F Fishman JA Goletti D Ison MG Jones CE Kampmann B Kotton CN Lange C Ljungman P Milburn H Morris MI Muller E Muñoz P Nellore A Rieder HL Sester U Theodoropoulos N Wagner D Sester M The risk of tuberculosis in transplant candidates and recipients: a TBNET consensus statement Eur Respir J 2012 40 4 990 1013 10.1183/09031936.00000712 22496318\n\n",
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"keywords": "Cutaneous tuberculosis; HCC; LTBI; OLT",
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"mesh_terms": "D006801:Humans; D055985:Latent Tuberculosis; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009092:Mucous Membrane; D009169:Mycobacterium tuberculosis; D014382:Tuberculosis, Cutaneous",
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"abstract": "COVID-19 might potentially give rise to a more severe infection in solid organ transplant recipients due to their chronic immunosuppression. These patients are at a higher risk of developing concurrent or secondary bacterial and fungal infections. Co-infections can increase systemic inflammation influencing the prognosis and the severity of the disease, and can in turn lead to an increased need of mechanical ventilation, antibiotic therapy and to a higher mortality. Here we describe, for the first time in Europe, a fatal case of co-infection between SARS-CoV-2 and Pneumocystis jirevocii in a kidney transplant recipient.",
"affiliations": "Institute of Microbiology, Department of Molecular and Translational Medicine, University of Brescia-ASST Spedali Civili di Brescia, 25123 Brescia, Italy.;Department of Medical and Surgical Specialties, Radiologic Sciences and Public Health, University of Brescia, 25123 Brescia, Italy.;Nephrology Unit, Spedali Civili Hospital, ASST Spedali Civili di Brescia, 25123 Brescia, Italy.;Department of Medical and Surgical Specialties, Radiologic Sciences and Public Health, University of Brescia, 25123 Brescia, Italy.;First Division of Anesthesiology and Intensive Care Unit, ASST Spedali Civili di Brescia, 25123 Brescia, Italy.;First Division of Anesthesiology and Intensive Care Unit, ASST Spedali Civili di Brescia, 25123 Brescia, Italy.;Institute of Microbiology, Department of Molecular and Translational Medicine, University of Brescia-ASST Spedali Civili di Brescia, 25123 Brescia, Italy.",
"authors": "De Francesco|Maria A|MA|0000-0003-2221-6286;Alberici|Federico|F|0000-0002-1686-5709;Bossini|Nicola|N|;Scolari|Francesco|F|;Pascucci|Federico|F|;Tomasoni|Gabriele|G|;Caruso|Arnaldo|A|0000-0001-5178-566X",
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"fulltext": "\n==== Front\nVaccines (Basel)\nVaccines (Basel)\nvaccines\nVaccines\n2076-393X MDPI \n\n32962148\n10.3390/vaccines8030544\nvaccines-08-00544\nCase Report\nPneumocystis jirevocii and SARS-CoV-2 Co-Infection: A Common Feature in Transplant Recipients?\nhttps://orcid.org/0000-0003-2221-6286De Francesco Maria A. 1* https://orcid.org/0000-0002-1686-5709Alberici Federico 23 Bossini Nicola 3 Scolari Francesco 23 Pascucci Federico 4 Tomasoni Gabriele 4 https://orcid.org/0000-0001-5178-566XCaruso Arnaldo 1 1 Institute of Microbiology, Department of Molecular and Translational Medicine, University of Brescia-ASST Spedali Civili di Brescia, 25123 Brescia, Italy; arnaldo.caruso@unibs.it\n2 Department of Medical and Surgical Specialties, Radiologic Sciences and Public Health, University of Brescia, 25123 Brescia, Italy; federico.alberici@unibs.it (F.A.); francesco.scolari@unibs.it (F.S.)\n3 Nephrology Unit, Spedali Civili Hospital, ASST Spedali Civili di Brescia, 25123 Brescia, Italy; bossini-nicola@libero.it\n4 First Division of Anesthesiology and Intensive Care Unit, ASST Spedali Civili di Brescia, 25123 Brescia, Italy; pas.fede@gmail.com (F.P.); gabriele.tomasoni@asst-spedalicivili.it (G.T.)\n* Correspondence: maria.defrancesco@unibs.it; Tel.: (+39)-030-399-5860; Fax: (+39)-030-399-6071\n18 9 2020 \n9 2020 \n8 3 54419 8 2020 15 9 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).COVID-19 might potentially give rise to a more severe infection in solid organ transplant recipients due to their chronic immunosuppression. These patients are at a higher risk of developing concurrent or secondary bacterial and fungal infections. Co-infections can increase systemic inflammation influencing the prognosis and the severity of the disease, and can in turn lead to an increased need of mechanical ventilation, antibiotic therapy and to a higher mortality. Here we describe, for the first time in Europe, a fatal case of co-infection between SARS-CoV-2 and Pneumocystis jirevocii in a kidney transplant recipient.\n\nCOVID-19pneumoniaimmunosuppression\n==== Body\n1. Introduction\nIn December 2019, in Hubei Province, China, a new virus called SARS-CoV-2 was identified as similar in its genome to the severe acute respiratory syndrome coronavirus (SARS-CoV), responsible for the SARS global pandemic in 2003. Its fast and global diffusion led to the declaration by the World Health Organization (WHO) as a pandemic virus in March 2020. \n\nBy August 2020, 17,841,669 cases of COVID-19 have been reported worldwide, including 685,281 deaths [1].\n\nSARS-CoV-2 belongs to the subfamily of beta-coronavirus [2,3], which are responsible for respiratory, enteric, hepatic and neurologic diseases [4,5], due to their broad tissue tropism.\n\nPatients affected by SARS-CoV-2 have a spectrum of disease ranging from asymptomatic or mild involvement to severe disease with acute respiratory distress syndrome (ARDS) and a “white lung” image on chest computed tomography (CT) [6,7]. \n\nThe mortality rate in the general population has been reported at about 1–6% [8]. Age, sequential organ failure assessment (SOFA) and D-dimer are the main prognostic factors in patients affected by COVID-19 [9]. However, the presence of other secondary infections or co-infections may also have an important impact on mortality, especially in critically ill patients [10], which are more likely to be older or have co-morbidities. In these patients, the immune dysfunction may determine a greater viral replication that induces hyperinflammation and severe complications such as ARDS [11], characterized by difficulty in breathing and low blood oxygen level [12] that facilitates secondary infections [13]. The release of higher concentrations of cytokines (interleukin (IL)-6, tumor necrosis factor (TNF), macrophage, monocyte chemoattractant protein (MCP) 1 and interferon-gamma induced protein (IP)-10) by the immune system in response to the viral infection and/or to secondary infections which induces a cytokine storm that is associated with endothelial dysfunction [8] and hyperactive CCR6+Th17+T cells in the lung [14]. This altered inflammation blocks the development of protective immunity to the infection, therefore making the patient more susceptible to sepsis, thrombotic events and to multi-organ failure. Pneumocystis jirevocii pneumonia is an opportunistic infection affecting patients with cellular immunity defects due to human immunodeficiency virus (HIV) infections or iatrogenic immunosuppression [15,16]. \n\nIn HIV patients, Pneumocystis jirevocii pneumonia is characterized by a significant level of fungal proliferation, while the inflammatory reaction was weak. The incidence of this opportunistic infection has decreased after the introduction of highly active anti-retrovirus therapy (HAART) and routine use of anti-Pneumocystis prophylaxis [17]. \n\nThe other groups of patients are individuals with immunodeficiency induced by immunosuppressive therapy for tumors, hematological disorders or organ transplant recipients [18]. Immunosuppressive agents act by inducing a reduction of CD4+T cells, important in the host defense against the fungus.\n\nIt has been shown that non-HIV patients present a more severe clinical picture with a rapid progression to acute respiratory failure and a worse prognosis in comparison with the HIV-infected patients [19].\n\nThese symptoms include severe hypoxemia and the need for intensive care and mechanical ventilation [16,20]; both symptoms are associated with poor prognosis. \n\nHere, we report the fatal case of a SARS-CoV-2 and Pneumocystis jirevocii co-infection in a kidney transplant recipient.\n\n2. Case\nA 65-year-old male, who underwent kidney transplantation from a deceased donor in 2006, was admitted on 27 March 2020, at the emergency unit of the Spedali Civili Hospital in Brescia, Italy with a fever (38.5 °C), cough and dyspnea over the previous two days. His immunosuppressive treatment included tacrolimus, mycophenolate mofetil and methylprednisolone. Past medical history included the development of post-transplant insulin-dependent type 2 diabetes, hypertension, recurrent thromboembolic events requiring therapy with oral anticoagulants and recurrent urinary tract infections. Baseline creatinine was 5 mg/dL.\n\nPhysical examination was unremarkable; blood pressure was 145/70 mm Hg and cardiac rate was 65 beats per minute with an oxygen saturation of 98% on room air. Initial laboratory tests showed normal white blood counts, with lymphopenia and 81.5% neutrophils (Table 1), a markedly elevated C reactive protein (CRP) and an acute kidney injury (serum creatinine 7.87 mg/dL). Chest computed tomography (CT) showed bilateral pulmonary infiltrates with characteristic patchy areas of ground glass opacities. A nasopharyngeal swab specimen was collected and was reported positive for SARS-CoV-2 by a real-time reverse transcriptase polymerase chain reaction (rRT-PCR) assay (Seegene Allplex 2019 nCoV assay, Arrow Diagnostics, Genova, Italy); the patient was then admitted in isolation at the nephrology unit in a COVID cohort.\n\nAs per local protocol, baseline immunosuppression was withdrawn and methylprednisolone was increased to 16 mg/day; intravenous immunoglobulin (IVIG, 2g/kg) and antiviral therapy (darunavir/ritonavir) plus hydroxychloroquine were given as well. The patient also started empirical antibiotic therapy with azithromycin and piperacillin/tazobactam.\n\nOn the morning of the second day of admission, several infectious investigations for virus, bacteria and fungi were performed. The results showed that the patient had a negative diagnosis for all respiratory viruses tested on a nasopharyngeal swab (influenza A and B, adenovirus and respiratory syncytial virus) by real-time PCR assays (Respiratory Viral ELITe MGB Panel and Adenovirus ELITe MGB Kit, ELITechGroup, Torino, Italy). The patient also had a negative diagnosis for Streptococcus pneumoniae and for some interstitial pneumonia causing bacteria (Legionella pneumophyla and Mycoplasma pneumoniae). An increase of Immunoglobulin A (IgA) for Chlamydia pneumoniae was conversely detected. Mycobacterium DNA on sputum by a real-time PCR (Xpert MTB/RIF Ultra, Cepheid, Milano, Italy) and HIV RNA on plasma by a real-time PCR (COBAS® AmpliPrep/COBAS TaqMan HIV-1 Test, Roche Diagnostics, Monza, Italy) were not detected (Table 2).\n\nA sputum sample was positive for Pneumocystis jirevocii by a PCR real-time (Bosphore Pneumocystis jirevocii detection Kit, Anatolia geneworks, Istanbul, Turkey). Following this diagnosis, the patient received trimethoprim-sulfamethoxazole as therapy.\n\nOn 2 April, the patient, due to ARDS and progressive respiratory failure due to COVID-19, received dexamethasone 20 mg/day for five days and two tocilizumab infusions as per our protocol. After transient improvement of the respiratory exchanges on 17 April, the patient showed increasing oxygen demand requiring a reservoir mask with oxygen at 15 L/min and high-flow nasal ventilation.\n\nDuring the hospitalization, the results of laboratory examinations showed that the peripheral blood lymphocyte count continued to be significantly reduced (nadir 160/mm3) and neutrophils was elevated (maximum level 20640/mm3); CRP tended to remain increased and serum levels of IL-6 and D-dimer were elevated as well (Table 1). After about two months since the initial symptoms, the patient’s respiratory symptoms worsened further, with hypoxia and septic shock and he was moved to the intensive care unit. \n\nThe patient was intubated, with ventilator supportive care using high positive end-respiratory pressure (PEEP). He developed pulmonary embolism and an invasive pulmonary aspergillosis, treated with thrombolitics and voriconazole. The patient, despite the antifungal and antibacterial treatment, presented deterioration of his clinical condition and on 19 June died from respiratory failure and multiple organ dysfunction syndrome. \n\n3. Discussion\nThis is, to the best of our knowledge, the first case of co-infection between SARS-CoV-2 and Pneumocystis jirevocii reported in Europe in a kidney transplant recipient. Another case was reported in an immunocompetent patient in the United States [21]. In this reported case, the patient was an 83-year-old female non-smoker, who did not have an underlying immunodeficiency nor any classical risk for Pneumocystis infection. However, both cases show an impaired cell mediated immune response with low numbers of CD4+T cells, confirming their increased susceptibility to fungal infection. The first patient was successfully treated and showed an improvement of CD4+T cell values, while in our patient, we had a persistence of low lymphocyte counts, high CRP values, high IL-6 values, elevated D-dimer and high LDH levels throughout the disease course; all laboratory markers associated with disease worsening and mortality [22,23].\n\nPneumocystis is a ubiquitous fungus that localizes on type 1 pneumocytes and is responsible of severe pneumonia in immunocompromised patients. It is well known that CD4+T cells play a central role in contrasting Pneumocystis infection. In fact, an absolute lymphocyte count of ≤500 × 106 cells/μL was strongly associated with Pneumocystis pneumonia, with a 19-fold higher risk of the disease [24]. \n\nLymphopenia associated to SARS-CoV-2 may be a mechanism that leads to a higher predisposition for fungal infection. In this case, the count of CD4+ was 35 cells/mL. There was an inversion of ratio CD4+/CD8+ and prevalence in lymphocyte subpopulations of memory CD4+ cells (CD45 RA-CCR7-) than in naïve CD4+ cells (CD45RA+CCR7+). Furthermore, in non-HIV patients it was also shown that low numbers of the organism could induce a severe inflammatory response in the lungs, as reflected by the higher BAL neutrophil counts present in these patients [20]. Then, the existing immunosuppression favoring Pneumocystis infection may predispose the infection with other opportunistic microorganisms, in particular CMV or Aspergillus infection. Concurrent infections are considered as indicators of poor prognosis [25,26]. \n\nOther respiratory viruses, such as influenza virus, parainfluenza virus and respiratory syncytial virus, have been found to predispose patients to invasive pulmonary aspergillosis [27]. The probable mechanism may be the direct damage of the airway epithelium and of the normal ciliary clearance that give the opportunity to the Aspergillus to invade into tissues [28,29,30].\n\nA reactivation of CMV infection and an invasive pulmonary aspergillosis were both detected in our patient further complicating the already critical clinical picture.\n\nFurthermore, different studies have shown that about 20% of patients affected by COVID-19 have abnormal coagulation [26]. Monocytes and tissue cells are activated after lung damage, determining the release of cytokines and then the hypercoagulability of blood. This leads to an increased risk of thrombosis, ischemia and hypoxia due to the embolization of organs, which may progress to severe disease or death. In fact, the patient developed a pulmonary embolism.\n\n4. Conclusions\nIn conclusion, Pneumocystis jirevocii and COVID-19 share similar characteristics such as the presence of dry cough, dyspnea, ground glass opacities on chest CT scans and elevated levels of LDH. A more comprehensive microbiological evaluation is suggested to prevent a missing diagnosis of this fungal infection, especially in patients with impaired immunity, in order to better monitor the patient’s progress.\n\nAuthor Contributions\nM.A.D.F. designed the study and wrote the manuscript; F.A., N.B. and F.S. were directly involved in the patient care and participated in the drafting and critical revision of the manuscript; F.P. and G.T. were directly involved in the patient care and participated in the critical revision of the manuscript; A.C. designed the study and participated in the critical revision of the manuscript. M.A.D.F., F.A., N.B., F.C., F.P., G.T. and A.C. approved the final version. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nEthical Statement\nDue to the case report nature of the manuscript, no ethical approval was required.\n\nvaccines-08-00544-t001_Table 1Table 1 Clinical laboratory results.\n\nHematologic and Clinical Parameters\tReference Value\tBaseline\tD7\tD16\tD25\tD32\tD45\tD54\tD61\tD74\tD83\t\nWBC (×103 × mL)\t4–10\t7.1\t\n11.4\n\t8.3\t\n20.9\n\t10\t8.5\t10.3\t\n13.5\n\t10\t\n15\n\t\nLymphocyte (%)\t20–45\t\n10.4\n\t\n2.2\n\t\n2.6\n\t\n1.5\n\t\n4\n\t\n10.6\n\t\n10.7\n\t\n\t\n\t\n\t\nMonocyte (%)\t3.4–9\t8\t4.5\t\n1.9\n\t\n1.7\n\t\n4.1\n\t3.4\t\n2.5\n\t\n\t\n\t\n\t\nNeutrophil (%)\t40–74\t81.5\t\n93.2\n\t\n93.8\n\t\n96.7\n\t\n91.5\n\t\n85.8\n\t\n86.4\n\t\n\t\n\t\n\t\nHemoglobin (g/dL)\t14–18\t\n11.9\n\t\n10.9\n\t\n9.3\n\t\n8.6\n\t\n9.1\n\t\n9\n\t\n9.1\n\t\n9.1\n\t\n9.4\n\t\n8.9\n\t\nHematocrit (%)\t42–52\t\n36.7\n\t\n33.1\n\t\n29.2\n\t\n25.9\n\t\n27.2\n\t\n28.7\n\t\n28.8\n\t\n28.6\n\t\n28.2\n\t\n27.5\n\t\nPlateletes (×103 × mL)\t130–400\t134\t150\t\n128\n\t\n98\n\t\n94\n\t\n67\n\t147\t212\t\n117\n\t237\t\nCRP (mg/L)\t<5\t\n108\n\t\n43.2\n\t\n12.2\n\t1.9\t3\t\n91.2\n\t\n63.5\n\t\n53.6\n\t\n114\n\t\n186\n\t\nLDH (U/L)\t135–225\t\n\t\n380\n\t\n873\n\t\n548\n\t\n412\n\t\n\t\n301\n\t\n\t\n\t\n\t\nD-dimer (ng/mL)\t<232\t\n208\n\t\n263\n\t\n3109\n\t\n1866\n\t\n1021\n\t\n2542\n\t\n\t\n3502\n\t\n\t\n\t\nIL-6 (ng/mL)\t<7\t\n\t\n206\n\t\n>5000\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\nS-Creatinine (mg/dL)\t0.7–1.2\t\n7.87\n\t\n\t\n\t\n\t\n\t\n2.7\n\t\n3.26\n\t\n3.17\n\t\n1.35\n\t\n1.34\n\t\nAbbreviations: D, day; WBC, white blood cells; C whether ref. 16 is the same as ref. 20RP, C-reactive protein; LDH, lactate dehydrogenase; IL, interleukin. Values in bold were either above normal or below normal.\n\nvaccines-08-00544-t002_Table 2Table 2 Microbiological results.\n\nPathogens\tResult \t\nSARS-CoV-2 RNA\t\nPositive\n\t\nInfluenza A and B RNA\tNegative\t\nAdenovirus DNA\tNegative\t\nRespiratory syncytial virus RNA\tNegative\t\nEBV DNA\tNegative\t\nHIV RNA\tNegative\t\nMycobacterium DNA\tNegative\t\nLegionella urine antigen\tNegative\t\nS. pneumoniae urine antigen\tNegative\t\nM. pneumoniae IgM Ab+\tNegative\t\nC. pneumoniae IgM/IgA Ab+\t\nPositive\n\t\nPneumocystis jirevocii DNA\t\nPositive\n\t\nAspergillus fumigatus culture\t\nPositive\n==== Refs\nReferences\n1. ECDC Coronavirus Disease 2019 (COVID-19) in the EU/EEA and the UK—Eleventh Update ECDC Stockholm, Sweden 2020 \n2. Zhu N. Zhang D. Wang W. Li X. Yang B. Song J. Zhao X. Huang B. Shi W. Lu R. A novel coronavirus from patients with pneumonia in China, 2019 N. Engl. J. Med. 2020 382 727 733 10.1056/NEJMoa2001017 31978945 \n3. Zhou P. Yang X.L. Wang X.G. Hu B. Zhang L. Zhang W. Si H.R. Zhu Y. Li B. Huang C.L. A pneumonia outbreak associated with a new coronavirus of probable bat origin Nature 2020 579 270 273 10.1038/s41586-020-2012-7 32015507 \n4. Weiss S.R. Leibowitz J.L. Coronavirus pathogenesis Adv. Virus Res 2011 81 85 164 22094080 \n5. De Wilde A.H. Snijder E.J. Kikkert M. van Hemert M.J. Host Factors in Coronavirus Replication Roles of Host Gene and Non-Coding RNA Expression in Virus Infection Tripp R.A. Tompkins S.M. Springer International Publishing Berlin/Heidelberg, Germany 2018 1 42 \n6. Xu Z. Li S. Tian S. Li H. Kong L.Q. Full spectrum of COVID-19 severity still being depicted Lancet 2020 395 947 948 10.1016/S0140-6736(20)30308-1 \n7. Yuan M. Yin W. Tao Z. Tan W. Hu Y. Association of radiologic findings with mortality of patients infected with 2019 novel coronavirus in Wuhan, China PLoS ONE 2020 15 e0230548 10.1371/journal.pone.0230548 32191764 \n8. Sun P. Lu X. Xu C. Sun W. Pan B. Understanding of COVID-19 based on current evidence J. Med. Virol. 2020 92 548 551 10.1002/jmv.25722 32096567 \n9. Zhou F. Yu T. Du R. Fan G. Liu Y. Liu Z. Xiang J. Wang Y. Song B. Gu X. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study Lancet 2020 20 1054 1062 10.1016/S0140-6736(20)30566-3 \n10. Zhou P. Liu Z. Chen Y. Xiao Y. Huang X. Fan X.G. Bacterial and fungal infections in COVID-19 patients: A matter of concern Infect. Control Hosp. Epidemiol. 2020 41 1124 1125 10.1017/ice.2020.156 32317036 \n11. Netea M.G. Giamarello-Bourbolis E.J. Dominguez-Andres J. Curtis N. Crevel R. Veerdonk F.L. Bonten M. Trained immunity: A tool for reducing susceptibility to and severity of SARS-CoV-2 infection Cell 2020 181 969 977 10.1016/j.cell.2020.04.042 32437659 \n12. Zhang B. Zhou X. Qiu Y. Song Y. Feng F. Feng J. Song Q. Jia Q. Wang J. Clinical characteristics of 82 cases of death from COVID-19 PLoS ONE 2020 15 e023458 10.1371/journal.pone.0235458 \n13. Chen N. Zhou M. Dong X. Qu J. Gong F. Han Y. Qiu Y. Wang J. Liu Y. Wei Y. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study Lancet 2020 395 507 513 10.1016/S0140-6736(20)30211-7 32007143 \n14. Xu Z. Shi L. Wang Y. Zhang J. Huang L. Zhang C. Liu S. Zhao P. Liu H. Zhu L. Pathological findings of COVID-19 associated with acute respiratory distress syndrome Lancet Respir. Med. 2020 8 420 422 10.1016/S2213-2600(20)30076-X 32085846 \n15. Buchacz K. Baker R.K. Palella F.J. Jr. Chmiel J.S. Lichtenstein K.A. Novak R.M. Wood K.C. Brooks J.T. HOPS Investigators AIDS—Defining opportunistic illnesses in US patients, 1994–2007: A cohort study AIDS 2010 24 1549 1559 10.1097/QAD.0b013e32833a3967 20502317 \n16. Roblot F. Godet C. Le Moal G. Garo B. Faouzi Souala M. Dary M. De Gentile L. Gandji J.A. Guimard Y. Lacroix C. Analysis of underlying diseases and prognosis factors associated with Pneumocystis carinii pneumonia in immunocompromised HIV-negative patients Eur. J. Clin. Microbiol. Infect. Dis. 2002 21 523 531 12172743 \n17. Kaplan J.E. Hanson D. Dworkin M.S. Frederick T. Bertolli J. Lindegren M.L. Holmberg S. Jones J.L. Epidemiology of human immunodeficiency virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy Clin. Infect. Dis. 2000 30 5 14 10.1086/313843 \n18. Li M.C. Lee N.Y. Lee C.C. Chang C.M. Ko W.C. Pneumocystis jirevocii pneumonia in immunocompromised patients: Delayed diagnosis and poor outcomes in non-HIV infected individuals J. Microbiol. Immunol. Infect 2014 47 42 47 10.1016/j.jmii.2012.08.024 23063081 \n19. Festic E. Gajic O. Limper A.H. Aksamit T.R. Acute respiratory failure due to Pneumocystis pneumonia in patients without human immunodeficiency virus infection: Outcome and associated features Chest 2005 128 573 579 10.1378/chest.128.2.573 16100140 \n20. Monnet X. Vidal-Petiot E. Osman D. Hamzaoui O. Durrbach A. Gouiard C. Miceli C. Bourée P. Richard C. Critical care management and outcome of severe Pneumocystis pneumonia in patients with and without HIV infection Crit. Care 2008 12 R28 10.1186/cc6806 18304356 \n21. Menon A.A. Berg D.D. Brea E.J. Deutsch A.J. Kidia K.K. Thurber E.G. Polsky S.B. Yeh T. Duskin J.A. Holliday A.M. A case of COVID-19 and Pneumocystis jirovecii co-infection Am. J. Respir. Crit. Care Med. 2020 202 136 138 10.1164/rccm.202003-0766LE 32412848 \n22. Gong J. Dong H. Xia Q. Huang Z. Wang D. Zhao Y. Liu W. Tu S. Zhang M. Wang Q. Correlation analysis between diseases severity and inflammation related parameters in patients with COVID-19 pneumonia Cell Host Microbe 2020 27 992 1000 32320677 \n23. Ruan Q. Yang K. Wang W. Jiang L. Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China Intens. Care Med. 2020 46 846 848 10.1007/s00134-020-05991-x 32125452 \n24. Werbel W.A. Ison M.G. Angarone M.P. Yang A. Stosor V. Lymphopenia is associated with late onset Pneumocystis jirovecii pneumonia in solid organ transplantation Transpl. Infect. Dis. 2018 20 e12876 10.1111/tid.12876 29512868 \n25. Matsumara Y. Shindo Y. Iinuma Y. Yamamoto M. Shirano M. Matsushima A. Nagao M. Ito Y. Takakura S. Hasegawa Y. Clinical characteristics of Pneumocystis pneumonia in non –HIV patients and prognostic factors including microbiological genotypes BMC Infect. Dis. 2011 11 76 10.1186/1471-2334-11-76 21439061 \n26. Kim S.J. Lee J. Cho Y.J. Park Y.S. Lee C.H. Yoon H.I. Lee S.M. Yim J.J. Yoo C.G. Lee C.T. Prognostic factors of Pneumocystis jirovecii pneumonia in patients without HIV infection J. Infect. 2014 69 88 95 10.1016/j.jinf.2014.02.015 24607411 \n27. Magira E.E. Chemaly R.F. Jiang Y. Tarrand J. Kontoviannis D.P. Outcomes in invasive pulmonary aspergillosis infections complicated by respiratory viral infections in patients with hematologic malignancies: A case-control study Open Forum Infect. Dis. 2019 6 247 10.1093/ofid/ofz247 \n28. Gill J.R. Sheng Z.M. Ely S.F. Guinee D.G. Beasley M.B. Suh J. Deshpande C. Mollura D.J. Morens D.M. Bray M. Pulmonary pathologic findings of fatal 2009 pandemic influenzaA/H1N1 viral infections Arch. Pathol. Lab. Med. 2010 134 235 243 20121613 \n29. Pittet L.A. Hall-Stoodley L. Rutkowski M.R. Harmsen A.G. Influenza virus infection decreases tracheal mucociliary velocity and clearance of Streptococcus pneumoniae Am. J. Respir. Cell. Mol. Biol. 2010 42 450 460 10.1165/rcmb.2007-0417OC 19520922 \n30. Thompson G.R. Cornely O.A. Pappas P.G. Patterson T.F. Hoenigl M. Jenks J.D. Clancy C.J. Nguyen M.H. Invasive aspergillosis as an under-recognized superinfection in COVID-19 Open Forum Infect. Dis. 2020 6 1 3 10.1093/ofid/ofaa242\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2076-393X",
"issue": "8(3)",
"journal": "Vaccines",
"keywords": "COVID-19; immunosuppression; pneumonia",
"medline_ta": "Vaccines (Basel)",
"mesh_terms": null,
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"pages": null,
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"pmid": "32962148",
"pubdate": "2020-09-18",
"publication_types": "D002363:Case Reports",
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"title": "Pneumocystis jirevocii and SARS-CoV-2 Co-Infection: A Common Feature in Transplant Recipients?",
"title_normalized": "pneumocystis jirevocii and sars cov 2 co infection a common feature in transplant recipients"
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"abstract": "BACKGROUND\nThe transmission of fungi via transplant, although well-known, has not often been molecularly proven. We describe a case of donor-derived candidiasis verified by whole genome sequencing.\n\n\nMETHODS\nThe multiorgan donor was a 42-year-old woman with subdural hemorrhage. Procurement of the thoracic organs was performed followed by the abdominal organs. Tissue from the left bronchus grew Candida dubliniensis. The liver recipient was a 63-year-old woman with cryptogenic liver cirrhosis. She was noted to have worsening leukocytosis on postoperative day (POD) 9. Computed tomography of the abdomen and pelvis showed multiple rim-enhancing collections around the graft. Percutaneous drainage was performed. Fluid cultures grew C dubliniensis. C dubliniensis isolated from the donor's left bronchus and the liver recipient's abscesses were verified to be related by whole genome sequencing. We postulate that C dubliniensis colonizing the donor's transected trachea could have contaminated the inferior vena cava when the former was left open after explant of the donor's lungs. A portion of the donor's contaminated inferior vena cava was transplanted along with the liver graft, resulting in the infected collections in the recipient.\n\n\nCONCLUSIONS\nOur case report highlights the importance of maintaining a sterile field during organ procurement, especially in a multiorgan donor whose organs are explanted in succession.",
"affiliations": "Department of Infectious Diseases, Singapore General Hospital, Singapore. Electronic address: teh.yii.ean@singhealth.com.sg.;National Public Health Laboratory, Ministry of Health, Singapore.;Department of Laboratory Medicine, Changi General Hospital, Singapore.;Bioinformatics Institute, Agency for Science, Technology and Research, Singapore.;Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore.;Department of Microbiology, Singapore General Hospital, Singapore.;National Public Health Laboratory, Ministry of Health, Singapore; Department of Laboratory Medicine, National University Hospital, Singapore.;Department of Infectious Diseases, Singapore General Hospital, Singapore.;Department of Hepato-pancreato-biliary and Transplant Surgery, Singapore General Hospital, Singapore.;Heart and Lung Transplant Unit, Department of Cardiothoracic Surgery, National Heart Centre Singapore, Singapore.;Department of Infectious Diseases, Singapore General Hospital, Singapore.",
"authors": "Teh|Y E|YE|;Ang|M L T|MLT|;La|M V|MV|;Gunalan|V|V|;Tan|C K|CK|;Tan|A L|AL|;Lin|R T P|RTP|;Tan|T T|TT|;Jeyaraj|P R|PR|;Cumaraswamy|S|S|;Tan|B H|BH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2018.01.017",
"fulltext": null,
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"issn_linking": "0041-1345",
"issue": "50(3)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D002175:Candida; D002177:Candidiasis; D005260:Female; D006801:Humans; D008100:Liver Abscess; D016031:Liver Transplantation; D008875:Middle Aged; D014019:Tissue Donors; D009927:Tissue and Organ Procurement; D019737:Transplants; D014682:Vena Cava, Inferior; D000073336:Whole Genome Sequencing",
"nlm_unique_id": "0243532",
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"pages": "915-919",
"pmc": null,
"pmid": "29661462",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Donor-Derived Candida dubliniensis Resulting in Perigraft Abscesses in a Liver Transplant Recipient Proven by Whole Genome Sequencing: A Case Report.",
"title_normalized": "donor derived candida dubliniensis resulting in perigraft abscesses in a liver transplant recipient proven by whole genome sequencing a case report"
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"companynumb": "SG-ASTELLAS-2018US022534",
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"abstract": "We report the use of voriconazole troughs to achieve appropriate therapeutic levels in treatment of a cutaneous Scedosporium apiospermum infection. Following heart transplantation, a 63-year-old immunocompromised patient presented with post-traumatic nodular lesions on his right shin. Pathology showed fungal yeasts with culture revealing Scedosporium apiospermum. According to therapeutic drug monitoring, initial voriconazole treatment was subtherapeutic requiring increased dosing until appropriate therapeutic trough levels were attained, and resolution of the fungal infection was achieved.",
"affiliations": "Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, United States.;Department of Dermatology, Baylor College of Medicine, 1977 Butler Blvd, Houston, TX 77030, United States.;Department of Cardiology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, United States.;Department of Pathology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, United States.;Department of Infectious Disease, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467, United States.",
"authors": "Boyd|McKenna E|ME|;Dao|Harry|H|;Estep|Jerry D|JD|;Huttenbach|Yve T|YT|;Hemmige|Vagish|V|",
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"doi": "10.1016/j.mmcr.2018.09.002",
"fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(18)30089-710.1016/j.mmcr.2018.09.002Case ReportUtilization of voriconazole drug monitoring in the treatment of cutaneous Scedosporium apiospermum infection Boyd McKenna E. mckenna.boyd@bcm.eduaDao Harry bEstep Jerry D. cHuttenbach Yve T. dHemmige Vagish vahemmig@montefiore.orge⁎a Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, United Statesb Department of Dermatology, Baylor College of Medicine, 1977 Butler Blvd, Houston, TX 77030, United Statesc Department of Cardiology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, United Statesd Department of Pathology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, United Statese Department of Infectious Disease, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467, United States⁎ Corresponding author. vahemmig@montefiore.org13 9 2018 12 2018 13 9 2018 22 52 54 1 7 2018 16 8 2018 11 9 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We report the use of voriconazole troughs to achieve appropriate therapeutic levels in treatment of a cutaneous Scedosporium apiospermum infection. Following heart transplantation, a 63-year-old immunocompromised patient presented with post-traumatic nodular lesions on his right shin. Pathology showed fungal yeasts with culture revealing Scedosporium apiospermum. According to therapeutic drug monitoring, initial voriconazole treatment was subtherapeutic requiring increased dosing until appropriate therapeutic trough levels were attained, and resolution of the fungal infection was achieved.\n\nKeywords\nCutaneous Scedosporium apiospermumVoriconazoleTroughTransplantImmunocompromised\n==== Body\n1 Introduction\nIn recent years, Scedosporium apiospermum has gained recognition as a causative agent of infection in immunocompromised hosts, notably transplant recipients [1], [2], [3]. Even in immunocompetent hosts, traumatic inoculation can result in localized cutaneous infections [4]. Diagnosis can prove difficult owing to clinical and morphological similarity with other fungal species, namely Aspergillus and Fusarium\n[1], [4]. Accurate diagnosis is essential, as this opportunist is highly antifungal-resistant often requiring unconventional antifungal treatment [1], [2], [4], [5].\n\nIn this report, we present a case of cutaneous Scedosporium apiospermum infection treated with voriconazole. Therapeutic drug monitoring revealed subtherapeutic voriconazole levels requiring repeated dosage increases. Once therapeutic voriconazole levels were achieved, the patient's infection successfully resolved. A previous study reported successful use of voriconazole drug monitoring to treat lung scedosporiosis [6]. However, to our knowledge, this is the only reported case of cutaneous S. apiospermum infection utilizing voriconazole troughs to achieve therapeutic antifungal treatment.\n\n2 Case\nA 63-year-old African American male with past medical history significant for heart transplantation, on mycophenolic acid, prednisone, and tacrolimus immunosuppressant therapy, presented to dermatology on Day 0 for disseminated cutaneous zoster. The patient also reported sustaining an injury to his right shin two weeks prior, appearing on Day 0 as non-specific nodules and tumors (Fig. 1a).Fig. 1 Progression of cutaneous S. apiospermum infection. (a) Day 0 (b) Day 168 (c) Day 350 (d) Day 516.\n\nFig. 1\n\nThe patient returned for follow-up on Day 27 with healing cutaneous zoster lesions; however, the wound on his right shin was larger. A biopsy of the right shin revealed granulomatous inflammation and abscesses with numerous fungal yeasts and structures suggestive of pseudohyphae when stained with Grocott's methenamine silver (GMS) (Fig. 2). Subsequent fungal culture, processed by Clinical Pathology Laboratories in Austin, Texas using the lab's standard procedures*, revealed a Scedosporium apiospermum fungal infection for which the patient was referred to infectious disease. Treatment with this team began on Day 42 at which time the lesion was approximately 5 cm in length with two nodules at the superior and inferior borders. The lesion was freely movable above the underlying tibia, suggesting no bony involvement. At this time voriconazole 200 mg PO BID was prescribed. Therapeutic drug monitoring was also ordered due to the non-linear and idiosyncratic pharmacokinetics of voriconazole combined with its augmenting effects on tacrolimus levels, an immunosuppressant taken by the patient after his heart transplantation.Fig. 2 GMS stain showing numerous fungal yeasts and structures suggestive of pseudohyphae.\n\nFig. 2\n\nAt his follow-up on Day 77, the patient reported tolerating the medication well; however, the wound was healing slowly. A voriconazole trough collected on Day 82 revealed a level of 0.1 mcg/mL, far below the therapeutic range of 1.0–5.5 mcg/mL [7]. The voriconazole dose was subsequently raised to 250 mg BID on Day 105 and again to 300 mg BID on Day 133 after trough levels continued to be low at 0.3 mcg/mL.\n\nDelays in treatment were encountered due to multiple issues including patient being lost to follow-up and drug cost and consequently the skin lesion showed no improvement during this time (Fig. 1b). A voriconazole trough at the 300 mg dose was not collected until Day 250 which revealed a level of 0.6 mcg/mL. The dosage was increased to 400 mg BID on Day 259 and finally to a maximum dose of 500 mg BID on Day 308. By Day 350 marked improvement was noted in the size and elevation of the nodules (Fig. 1c). In the following months several voriconazole troughs were taken, many of which were in the therapeutic range reaching the maximal value of 2.0 mcg/mL. By Day 392 the cutaneous nodules were decreased in size and by Day 516 the skin lesions were essentially resolved (Fig. 1d). At this time, the patient was advised to continue treatment for an additional 3 months to achieve 6 months of therapy at therapeutic range.\n\n*Clinical Pathology Laboratories tissue sample fungal procedure: Ground tissue is plated on the following media: sabouraud dextrose, sabouraud dextrose with clindamycin and cycloheximide, and brain heart infusion agar with gentamicin and chloramphenicol. Fungal structures are observed using lactophenol cotton blue tape preparation. No genetic analysis was performed.\n\n3 Discussion\nScedosporium apiospermum is a highly antifungal resistant, opportunistic pathogen. This organism was previously considered the asexual form Pseudallescheria boydii; however, recent DNA sequence analysis show that these are two distinct species [8]. S. apiospermum infections present in various ways: 1) localized disease due to trauma 2) cavity colonization, and 3) systemic, invasive disease. In immunocompetent hosts, inoculation is typically trauma induced and results in a localized infection, specifically a subcutaneous mycetoma [1]. Most localized infections involve the feet or lower extremities. A mycetoma begins as a firm, small, painless nodule and progressively softens and ulcerates. In immunocompromised patients, such as the one reported in this case, the fungus produces scattered hyphae while in immunocompetent individuals the fungus will produce a grain formation [1], [9]. Localized cutaneous infections are rare, but most often occur in the immunosuppressed and solid organ transplant recipients [4], [5]. Invasive, systemic infections typically occur in immunocompromised hosts and victims of near drownings [1].\n\nDue to antifungal resistance, treatment options for S. apiospermum infections are limited. Compared to other antifungals, such as amphotericin B and itraconazole, voriconazole shows superior activity and lower MIC values in the treatment of S. apiospermum\n[10], [11]. Furthermore, a large retrospective study including over 100 patients supports the use of voriconazole for the treatment of this species [12]. Voriconazole has successfully treated cutaneous, subcutaneous, and disseminated S. apiospermum infections [13], [14], [15]. While voriconazole is widely accepted as an appropriate treatment option for S. apiospermum, the appropriate dosing is less clear. Currently, the recommended dose according to the manufacturer is 200 mg PO BID; however, this dose often results in low serum concentrations and in such cases an increased dose is required to reach therapeutic levels [7]. When an appropriate dose is determined, antifungal therapy should continue until no signs and symptoms of infection persist, often requiring several months or even years of treatment.\n\nIn addition to antifungal treatment, surgical debridement is highly recommended due to improved outcomes [2]. For this patient, debridement was seriously considered, and plastic surgery was consulted. However, this option was not initially pursued due to the infection's proximity to the tibia which would require skin grafting to an area with slow healing rates. Thankfully, an increased dose of voriconazole resolved the infection and surgical intervention was not necessary.\n\nFor invasive Scedosporium infections, current guidelines suggest monitoring serum voriconazole levels five to seven days into therapy. The therapeutic range of voriconazole is 1.0–5.5 mcg/mL and, for sub-therapeutic trough concentrations, it is recommended to increase the dose of voriconazole [16]. Serum voriconazole trough levels were taken to both evaluate therapeutic serum levels and interactions with other medications, namely the calcineurin inhibitor tacrolimus. Voriconazole is an inhibitor of the CYP450 system and will thus increase levels of substances metabolized through this system. Consequently, during treatment with voriconazole, the patient's dose of tacrolimus was monitored and lowered with each increase in antifungal dosage in close collaboration with a transplant pharmacist.\n\nTreatment of this patient was prolonged due to continuous sub-therapeutic concentrations of voriconazole; however, continued analysis via serum trough concentrations allowed the treatment team to find a dose that adequately controlled the infection. Thus, this case presents a strong argument for the use of voriconazole trough levels in all S. apiospermum infections treated with this antifungal.\n\nAcknowledgements\nNone.\n\nConflict of interest\nThere are none.\n\nEthical form\nPlease note that this journal requires full disclosure of all sources of funding and potential conflicts of interest. The journal also requires a declaration that the author(s) have obtained written and signed consent to publish the case report from the patient or legal guardian(s).\n\nThe statements on funding, conflict of interest and consent need to be submitted via our Ethical Form that can be downloaded from the submission site www.ees.elsevier.com/mmcr. Please note that your manuscript will not be considered for publication until the signed Ethical Form has been received.\n==== Refs\nReferences\n1 Guarro J. Kantarcioglu A.S. Horré R. Rodriguez-Tudelas J. Estrella M.C. Berenguer J. Sybren de Hoog S. Scedosporium apiospermum : changing clinical spectrum of a therapy-refractory opportunist Med. Mycol. 44 2006 295 327 16772225 \n2 Husain S. Muñoz P. Forrest G. Alexander B.D. Somani J. Brennan K. Wagener M.M. Singh N. Infections due to Scedosporium apiospermum and Scedosporium prolificans in transplant recipients: clinical characteristics and impact of antifungal agent therapy on outcome Clin. Infect. Dis. 40 1 2005 89 99 15614697 \n3 Nucci M. Emerging moulds: fusarium, Scedosporium and Zygomycetes in transplant recipients Curr. Opin. Infect. Dis. 16 2003 607 612 14624113 \n4 Miele P.S. Levy C.S. Smith M.A. Primary cutaneous fungal infections in solid organ transplantation: a case series Am. J. Transpl. 2 2002 678 683 \n5 Uenotsuchi T. Moroi Y. Urabe K. Cutaneous Scedosporium apiospermum infection in an immunocompromised patient and review of the literature Acta Derm. Venereol. 85 2005 156 159 15823912 \n6 Ogata R. Hagiwara E. Shiihara J. Ogura T. Takahashi H. Kamei K. A case of lung scedosporiosis successfully treated with monitoring of plasma voriconazole concentration level Nihon Kokyuki Gakkai Zasshi J. Jpn. Respir. Soc. 49 2011 388 392 (in Japanese) \n7 Pascual A. Calandra T. Bolay S. Buclin T. Bille J. Marchetti O. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes Clin. Infect. Dis. 46 2 2008 37 40 18171211 \n8 Gilgado F. Cano J. Gené J. Guarro J. Molecular phylogeny of the Pseudallescheria boydii species complex: proposal of two new species J. Clin. Microbiol. 43 10 2005 4930 4942 16207945 \n9 Ichikawa T. Saiki M. Tokunaga S. Saida T. Scedosporium apiospermum skin infection in a patient with nephrotic syndrome Acta Derm. Venereol. 77 1997 172 173 9111845 \n10 Cuenca-Estrella M. Ruiz-Diez B. Martinez-Suarez J.V. Monzon A. Rodriguez-Tudela J.L. Comparative in-vitro activity of voriconazole (UK-109,496) and six other antifungal agents against clinical isolates of Scedosporium prolificans and Scedosporium apiospermum J. Antimicrob. Chemother. 43 1 1999 149 151 10381115 \n11 Meletiadis J. JFGM Meis Mouton J.W. In vitro activities of new and conventional antifungal agents against clinical Scedosporium isolates Antimicrob. Agents Chemother. 46 1 2002 62 68 11751112 \n12 Troke P. Aguirrebengoa K. Arteaga C. Ellis D. Heath C.H. Lutsar I. Rovira M. Nguyen Q. Slavin M. Chen S.C. Global Scedosporium Study Group Treatment of scedosporiosis with voriconazole: clinical experience with 107 patients Antimicrob. Agents Chemother. 52 5 2008 1743 1750 18212110 \n13 Girmenia C. Giovanni L. Monaco M. Martino P. Use of Voriconazole in treatment of Scedosporium apiospermum infection: case report J. Clin. Microbiol. 36 5 1998 1436 1438 9574724 \n14 Stur-Hofmann K. Stos S. Saxa-Enenkel M. Rappersberger K. Primary cutaneous infection with Scedosporium apiospermum successfully treated with voriconazole Mycoses 54 4 2011 201 204 \n15 Azofra M.M. Somovilla J.L.P. Porras M.C. Carrillo L.H. Pérez R.D. Use of intralesional voriconazole for the treatment of cutaneous Scedosporium apiospermum infection Clin. Infect. Dis. 51 2 2010 255 257 \n16 Vfend® package insert. Roerig, a Division of Pfizer, Inc., New York, NY. 〈http://media.pfizer.com/files/products/uspi_vfend.pdf〉.\n\n",
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"keywords": "Cutaneous Scedosporium apiospermum; Immunocompromised; Transplant; Trough; Voriconazole",
"medline_ta": "Med Mycol Case Rep",
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"title": "Utilization of voriconazole drug monitoring in the treatment of cutaneous Scedosporium apiospermum infection.",
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"abstract": "The management of chronic myelogenous leukemia (CML) in children changed dramatically with the introduction of tyrosine kinase inhibitors (TKIs). Unfortunately, outcomes for patients presenting in an advanced stage-accelerated phase or blast crisis CML-continues to be poor, requiring chemotherapy and allogeneic hematopoietic stem cell transplant (HSCT) to attempt cure. Integration of TKIs in the therapy of advanced CML is still an area of active investigation. There are little published data on TKI use in children with advanced stage CML. We performed a retrospective review of all children treated at our institution between January 1, 2010 and June 30, 2013, and identified 5 children, age 12 to 18 years, with advanced stage CML. All patients were treated with a TKI before HSCT and TKIs were restarted post-HSCT in 4/5 with a goal of continuing until 2 years posttransplant. At time of HSCT all were in a morphologic and cytogenetic remission; 1 patient had also achieved molecular remission. All patients are alive and in molecular remission at an average of 38 months (range, 14 to 51 mo) following transplant. Our experience indicates that TKIs are safe and well tolerated in children both pretransplant and posttransplant and may improve outcomes in this aggressive disease.",
"affiliations": "*Boston Children's Hospital †Pediatric Stem Cell Transplantation Center, Dana-Farber Cancer Institute/Boston Children's Hospital, Boston, MA.",
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"mesh_terms": "D000293:Adolescent; D001752:Blast Crisis; D016026:Bone Marrow Transplantation; D002648:Child; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D015465:Leukemia, Myeloid, Accelerated Phase; D047428:Protein Kinase Inhibitors; D012074:Remission Induction; D012189:Retrospective Studies; D016896:Treatment Outcome",
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"title": "Outcomes Following Bone Marrow Transplantation in Children With Accelerated Phase or Blast Crisis Chronic Myelogenous Leukemia in the Era of Tyrosine Kinase Inhibitors.",
"title_normalized": "outcomes following bone marrow transplantation in children with accelerated phase or blast crisis chronic myelogenous leukemia in the era of tyrosine kinase inhibitors"
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"abstract": "Methimazole (MMI)-induced acute pancreatitis is very rare but severe adverse reaction. A 51-yr-old male developed a high fever, chills, and abdominal pain, two weeks after commencement on MMI for the treatment of Graves' disease. There was no evidence of agranulocytosis, and fever subsided soon after stopping MMI treatment. However, 5 hr after taking an additional dose of MMI, abdominal pain and fever developed again. His symptoms, biochemical, and imaging studies were compatible with acute pancreatitis. After withdrawal of MMI, he showed clinical improvement. This is the first case of MMI-induced acute pancreatitis in Korea. Clinicians should be aware of the rare but possible MMI-induced pancreatitis in patients complaining of fever and abdominal pain.",
"affiliations": "Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinju, Korea. ; Institute of Health Science, Gyeongsang National University School of Medicine, Jinju, Korea.;Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinju, Korea. ; Institute of Health Science, Gyeongsang National University School of Medicine, Jinju, Korea.;Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinju, Korea. ; Institute of Health Science, Gyeongsang National University School of Medicine, Jinju, Korea.;Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinju, Korea. ; Institute of Health Science, Gyeongsang National University School of Medicine, Jinju, Korea.;Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinju, Korea.;Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinju, Korea.;Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinju, Korea.;Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinju, Korea. ; Institute of Health Science, Gyeongsang National University School of Medicine, Jinju, Korea.;Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinju, Korea. ; Institute of Health Science, Gyeongsang National University School of Medicine, Jinju, Korea.;Institute of Health Science, Gyeongsang National University School of Medicine, Jinju, Korea. ; Department of Laboratory Medicine, Gyeongsang National University School of Medicine, Jinju, Korea.",
"authors": "Jung|Jung Hwa|JH|0000-0001-6285-8262;Hahm|Jong Ryeal|JR|0000-0003-4785-7119;Jung|Jaehoon|J|0000-0001-6550-139X;Kim|Soo Kyoung|SK|0000-0003-1810-7642;Kim|Sungsu|S|0000-0002-8858-1932;Kim|Kyong Young|KY|0000-0002-7709-1284;Kim|Bo Ra|BR|0000-0002-2820-7463;Kim|Hong Jun|HJ|0000-0002-0411-668X;Jeong|Yi Yeong|YY|0000-0003-1015-1411;Kim|Sun Joo|SJ|0000-0001-8099-8891",
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"doi": "10.3346/jkms.2014.29.8.1170",
"fulltext": "\n==== Front\nJ Korean Med SciJ. Korean Med. SciJKMSJournal of Korean Medical Science1011-89341598-6357The Korean Academy of Medical Sciences 10.3346/jkms.2014.29.8.1170Case ReportEndocrinology, Nutrition & MetabolismAcute Pancreatitis Induced by Methimazole Treatment in a 51-Year-Old Korean Man: A Case Report http://orcid.org/0000-0001-6285-8262Jung Jung Hwa 12http://orcid.org/0000-0003-4785-7119Hahm Jong Ryeal 12http://orcid.org/0000-0001-6550-139XJung Jaehoon 12http://orcid.org/0000-0003-1810-7642Kim Soo Kyoung 12http://orcid.org/0000-0002-8858-1932Kim Sungsu 1http://orcid.org/0000-0002-7709-1284Kim Kyong Young 1http://orcid.org/0000-0002-2820-7463Kim Bo Ra 1http://orcid.org/0000-0002-0411-668XKim Hong Jun 12http://orcid.org/0000-0003-1015-1411Jeong Yi Yeong 12http://orcid.org/0000-0001-8099-8891Kim Sun Joo 231 Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinju, Korea.2 Institute of Health Science, Gyeongsang National University School of Medicine, Jinju, Korea.3 Department of Laboratory Medicine, Gyeongsang National University School of Medicine, Jinju, Korea.\nAddress for Correspondence: Jong Ryeal Hahm, MD. Department of Internal Medicine, Gyeongsang National University School of Medicine, 15 Jinju-daero 816-Beongil, Jinju 660-290, Korea. Tel: +82.55-750-8736, Fax: +82.55-758-9122, jrhahm@hanmail.net8 2014 30 7 2014 29 8 1170 1173 15 1 2014 31 3 2014 © 2014 The Korean Academy of Medical Sciences.2014This 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.Methimazole (MMI)-induced acute pancreatitis is very rare but severe adverse reaction. A 51-yr-old male developed a high fever, chills, and abdominal pain, two weeks after commencement on MMI for the treatment of Graves' disease. There was no evidence of agranulocytosis, and fever subsided soon after stopping MMI treatment. However, 5 hr after taking an additional dose of MMI, abdominal pain and fever developed again. His symptoms, biochemical, and imaging studies were compatible with acute pancreatitis. After withdrawal of MMI, he showed clinical improvement. This is the first case of MMI-induced acute pancreatitis in Korea. Clinicians should be aware of the rare but possible MMI-induced pancreatitis in patients complaining of fever and abdominal pain.\n\nGraphical Abstract\n\n\nMethimazoleGraves DiseasePancreatitisDrug-Related Side Effects and Adverse Reactions\n==== Body\nINTRODUCTION\nMethimazole (1-methyl-2-mercaptoimidazole, MMI) is an effective and generally safe antithyroid drug for the treatment of Graves' disease. It has been associated with various adverse reactions, which are generally minor and include skin reactions (usually urticaria or macular rashes), arthralgia, and gastrointestinal upset. Major side effects such as agranulocytosis, hepatitis, and vasculitis occur rarely, but are sometimes fatal. MMI-induced acute pancreatitis is also a major side effect (1). Only four cases of acute pancreatitis after MMI treatment have been reported worldwide (2, 3, 4) since the first report in 1999 (3). In this report, we describe the clinical course, imaging and HLA typing of a case of acute pancreatitis induced by MMI in a 51-yr-old Korean male with Graves' disease and review relevant literature.\n\nCASE DESCRIPTION\nA 51-yr-old Korean male visited the emergency room with complaints of high fever, chills, and abdominal pain in August 2013. He described the pain as increasing progressively in intensity, worsening after meals, and accompanied by nausea. He also suffered from diarrhea twice. He was diagnosed with Graves' disease 2 weeks ago, and was being treated with MMI (20 mg per day). His other medications included bisoprolol and 100 mg aspirin for atrial fibrillation. He did not have any history of drug or food allergies. He denied the use of tobacco, alcohol, and any dietary supplements. His family history was unremarkable, and did not include thyroid disease or gastrointestinal disorders.\n\nUpon admission, his vital signs were as follows: blood pressure of 100/70 mmHg, heart rate of 121 beats per minute, a respiratory rate of 21 times per minute, and a body temperature of 39.0℃. He had a slightly enlarged thyroid gland, but there was no pharyngeal injection. Physical examination revealed tenderness in the epigastric and upper abdomen without rebound tenderness, guarding, or rigidity.\n\nThe results of blood tests were as follows: white blood cell count of 5,460/µL, hemoglobin of 16.3 g/dL, and platelet count of 103,000/µL. Biochemical parameters were glucose of 222 mg/dL, triglycerides of 113 mg/dL, blood urea nitrogen of 30.3 mg/dL, creatinine of 1.45 mg/dL, sodium of 133.8 mM/L, potassium of 3.9 mM/L, chloride of 97.3 mM/L, aspartate transaminase of 34 IU/L, alanine transaminase of 46 IU/L, alkaline phosphatase of 46 U/L, total bilirubin of 2.60 mg/dL, C-reactive protein (CRP) of 46.7 mg/L, amylase of 86 IU/L (normal range: 29-110), and lipase of 86 IU/L (normal range: 14-60).\n\nA thyroid function test at the first visit revealed TSH of 0.01 mIU/L (normal range: 0.27-4.20), free T4 of 3.89 ng/dL (normal range: 0.93-1.70), total T3 of 199.8 ng/dL (normal range: 80-200), anti-TPO antibody of 17.84 (normal range: 0-34), and TSH-receptor antibody of 8.8 IU/L (normal range: 0.00-1.75). In Tc-99m thyroid scan, the uptake ratio was 4.8%. There was no elevation of serum antibodies for respiratory viruses including adenovirus, influenza, parainfluenza, and rhinovirus. He also tested negative for serum antibodies against tsutsugamushi, leptospira, and hantavirus.\n\nThe following day, MMI therapy was restarted after holding 42 hr because his fever had subsided and there was no evidence of agranulocytosis. However, 5 hr after he took the second dose of MMI (10 mg), abdominal pain and fever (39.2℃) developed again. At that time, laboratory studies showed a white blood cell count of 5,580/µL (72.7% neutrophils and 1.9% eosinophils), total bilirubin of 1.84 mg/dL, and CRP of 26.0 mg/L. His serum amylase and lipase levels increased to 265 IU/L and 682 IU/L, respectively. Electrophoresis revealed that his pancreatic amylase isoenzyme levels were elevated. An abdominal CT revealed a swollen pancreas with peripancreatic inflammatory fat stranding, suggestive of acute pancreatitis (Fig. 1A). An abdominal ultrasound was then performed, which showed no evidence of cholelithiasis or biliary duct dilatation (Fig. 1B).\n\nAfter the withdrawal of MMI, his fever and abdominal pain improved, and pancreatic enzyme levels began to decrease and finally normalized (Fig. 2). We measured IgG and IgG4 to exclude autoimmune pancreatitis. The serum levels of IgG and IgG subclass-4 were in the normal range (901.5 mg/dL, normal range: 700-1,600; and 349 mg/L, normal range: 30-2,010, respectively). The serologic typing of HLA alleles revealed DRB1*0803 and DQB1*0601. After discharge, PTU (50 mg t.i.d) was prescribed for treatment of Graves' disease and his hyperthyroidism was gradually controlled without any side-effects.\n\nDISCUSSION\nAcute pancreatitis is recently recognized as a rare major adverse event of MMI. There have been only four reports of MMI-induced acute pancreatitis since the first report in 1999 (2, 3, 4).\n\nBecause of the absence of cause-specific tests, the diagnosis of drug-induced pancreatitis (DIP) is usually based on the following criteria (5): 1) acute pancreatitis developed during the administration of a drug; 2) resolution of symptoms upon withdrawal of the drug; 3) recurrence after a rechallenge with the suspected agent; and 4) exclusion of all other common causes. In this case report, acute pancreatitis occurred 14 days after starting MMI in a 51-yr-old male. The episodic fever and abdominal pain subsided shortly after the withdrawal of the drugs. When MMI was re-administered, fever and abdominal pain rapidly reappeared. DIP by MMI was confirmed because there was no evidence of cholelithiasis, pancreatic and bile duct dilatation, or history of alcohol use to cause pancreatitis, normal triglyceride level, and the recurrence of pancreatitis occurred after the unintended rechallenge with MMI.\n\nThe diagnosis of MMI-induced DIP is commonly overlooked compared to drug-induced liver disease for several reasons (6). First, the index of suspicion for DIP is considerably lower than drug-induced hepatotoxicity. Unlike transaminases, serum amylase and lipase levels are not part of the metabolic profile obtained during a routine health checkup because of the differences in the latency period between the time of exposure and the development of acute pancreatitis; therefore, it takes an astute and motivated physician to diagnose DIP. In addition, even when DIP is diagnosed it is reported only rarely, and many cases might be often erroneously classified as being alcoholic or biliary in etiology by default. Finally, treatment invariably includes making the patient nil-per-os (NPO), which results in the inadvertent discontinuation of the possibly offending medication, which can remove the opportunity to diagnose DIP.\n\nAlthough cases of acute pancreatitis after MMI with positive rechallenge have been reported previously (3), detection of this adverse event has not been emphasized due to its low incidence. However, the accumulation of reports of such cases will encourage clinicians to suspect MMI-induced acute pancreatitis and to discontinue the use of MMI when patients taking MMI complain of abdominal pain and fever. Therefore, more active and systematic efforts will be necessary to detect cases and understand the mechanism by which MMI induces a hypersensitivity reaction or injures the pancreas.\n\nFour of the five cases of MMI-induced DIP were Asian and one was Caucasian, and all were females, and thus this is the first report in a male subject. We initially suspected that genetic susceptibility or an autoimmune mechanism could be involved in MMI-induced pancreatitis in our patient. Therefore, we analyzed the patient's HLA haplotype to identify the type frequently found in Korean Graves' disease and confirm that it was congruous with that of autoimmune pancreatitis (AIP). The HLA DRB1*0405-DQB1*0401 haplotype was associated with AIP in a Japanese study (7), but this did not correspond with the haplotype of our patient. However, the HLA DRB1*0803 and DQB1*0601 detected in this patient have been linked with autoimmune thyroid diseases such as Graves' disease, and have been reported to play a protective role in Type 1 diabetes (8). Type 1 AIP is more common in Asian subjects and in males, and is accompanied by elevated serum IgG, IgG4, and positive autoantibodies (9). IgG4 plays a major role in the pathogenesis of AIP (10), but IgG4 levels were not increased in our patient. We also excluded autoimmune type 1 diabetes because of negative anti-insulin and anti-GAD antibodies, which suggested that his hyperglycemia could have been caused by thyrotoxicosis.\n\nIn summary, we describe a 51-yr-old Korean male who developed acute pancreatitis after the administration of MMI for Graves' disease. He presented with acute pancreatitis after taking MMI for 14 days, and his fever and abdominal pain subsided after the withdrawal of MMI. When MMI was re-administered, acute pancreatitis rapidly recurred, which was confirmed by clinical, biochemical, and imaging studies. Acute pancreatitis is a rare but severe adverse reaction induced by MMI. If a patient taking MMI complains of abdominal symptoms and fever without neutropenia, clinicians should consider the rare possibility of MMI-induced pancreatitis and exclude all other potential causes of acute pancreatitis during diagnosis. Even after the pancreatitis has improved, MMI should not be administered again.\n\nThe authors declare that no competing financial interests exist.\n\nFig. 1 Abdominal computed tomography and ultrasound. (A) Abdominal CT scan showed a swollen pancreas with peripancreatic inflammatory fat stranding, suggestive of acute pancreatitis. (B) Abdominal ultrasound showed no evidence of cholelithiasis and biliary duct dilatation.\n\nFig. 2 Clinical course and pancreatic enzyme levels after taking MMI. The right axis shows the levels of pancreatic enzymes, and the left axis shows body temperature. MMI, methimazole; BT, body temperature.\n==== Refs\n1 Cooper DS Antithyroid drugs N Engl J Med 2005 352 905 917 15745981 \n2 Yang M Qu H Deng HC Acute pancreatitis induced by methimazole in a patient with Graves' disease Thyroid 2012 22 94 96 22136208 \n3 Taguchi M Yokota M Koyano H Endo Y Ozawa Y Acute pancreatitis and parotitis induced by methimazole in a patient with Graves' disease Clin Endocrinol (Oxf) 1999 51 667 670 10594530 \n4 Abraham A Raghavan P Patel R Rajan D Singh J Mustacchia P Acute pancreatitis induced by methimazole therapy Case Rep Gastroenterol 2012 6 223 231 22679409 \n5 Vinklerová I Procházka M Procházka V Urbánek K Incidence, severity, and etiology of drug-induced acute pancreatitis Dig Dis Sci 2010 55 2977 2981 20499176 \n6 Trivedi CD Pitchumoni CS Drug-induced pancreatitis: an update J Clin Gastroenterol 2005 39 709 716 16082282 \n7 Kawa S Ota M Yoshizawa K Horiuchi A Hamano H Ochi Y Nakayama K Tokutake Y Katsuyama Y Saito S HLA DRB10405-DQB10401 haplotype is associated with autoimmune pancreatitis in the Japanese population Gastroenterology 2002 122 1264 1269 11984513 \n8 Awata T Katsuren E Matsumoto C Nagayama I Uchigata Y Kuzuya N Kanazawa Y Absence of shared HLA class II (DR, DQ)-linked genetic basis between IDDM and autoimmune thyroid disease in Japanese Diabetes Care 1995 18 582 583 7497875 \n9 Okazaki K Uchida K Koyabu M Miyoshi H Takaoka M Recent advances in the concept and diagnosis of autoimmune pancreatitis and IgG4-related disease J Gastroenterol 2011 46 277 288 21452084 \n10 Hamano H Kawa S Horiuchi A Unno H Furuya N Akamatsu T Fukushima M Nikaido T Nakayama K Usuda N High serum IgG4 concentrations in patients with sclerosing pancreatitis N Engl J Med 2001 344 732 738 11236777\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "29(8)",
"journal": "Journal of Korean medical science",
"keywords": "Drug-Related Side Effects and Adverse Reactions; Graves Disease; Methimazole; Pancreatitis",
"medline_ta": "J Korean Med Sci",
"mesh_terms": "D015746:Abdominal Pain; D000208:Acute Disease; D003937:Diagnosis, Differential; D005335:Fever of Unknown Origin; D006111:Graves Disease; D006801:Humans; D008297:Male; D008713:Methimazole; D008875:Middle Aged; D010195:Pancreatitis; D016896:Treatment Outcome",
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"title": "Acute pancreatitis induced by methimazole treatment in a 51-year-old korean man: a case report.",
"title_normalized": "acute pancreatitis induced by methimazole treatment in a 51 year old korean man a case report"
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"abstract": "To report two cases of severe acute corneal hydrops that were resolved by intracameral gas injection alone.\nCase 1 is a 27-year-old woman with bilateral severe keratoconus who developed sequential acute corneal hydrops in the right eye followed by the left eye that were each successfully treated using intracameral 20% sulfur hexafluoride gas injection. Case 2 is a 62-year-old man that developed a large fluid cleft beneath a pre-existing LASIK flap, which resolved with intracameral 20% sulfur hexafluoride gas injection without the need for corneal transplantation.\nIn acute corneal hydrops, intracameral gas injection to tamponade Descemet's membrane tears with decompression of stromal fluid can be an effective intervention to delay or avoid keratoplasty in individuals whose corneal hydrops does not improve with conventional medical management.",
"affiliations": "Byers Eye Institute at Stanford, 2452 Watson Ct, Palo Alto, CA, 94303, USA.;Byers Eye Institute at Stanford, 2452 Watson Ct, Palo Alto, CA, 94303, USA.;Byers Eye Institute at Stanford, 2452 Watson Ct, Palo Alto, CA, 94303, USA.;Byers Eye Institute at Stanford, 2452 Watson Ct, Palo Alto, CA, 94303, USA.",
"authors": "Sayadi|Jamasb J|JJ|;Lam|Helene|H|;Lin|Charles C|CC|;Myung|David|D|",
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"doi": "10.1016/j.ajoc.2020.100994",
"fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936 Elsevier \n\nS2451-9936(20)30309-1\n10.1016/j.ajoc.2020.100994\n100994\nCase Report\nManagement of acute corneal hydrops with intracameral gas injection\nSayadi Jamasb J. ab Lam Helene ab Lin Charles C. a Myung David djmyung@stanford.eduabc∗ a Byers Eye Institute at Stanford, 2452 Watson Ct, Palo Alto, CA, 94303, USA\nb VA Palo Alto Health Care System, 3801 Miranda Ave, Palo Alto, CA, 94304, USA\nc Department of Chemical Engineering, Stanford, CA, 94305, USA\n∗ Corresponding author. Byers Eye Institute at Stanford, 2452 Watson Ct, Palo Alto, CA 94303, USA. djmyung@stanford.edu\n23 11 2020 \n12 2020 \n23 11 2020 \n20 10099422 11 2019 12 9 2020 15 11 2020 © 2020 Published by Elsevier Inc.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nTo report two cases of severe acute corneal hydrops that were resolved by intracameral gas injection alone.\n\nObservations\nCase 1 is a 27-year-old woman with bilateral severe keratoconus who developed sequential acute corneal hydrops in the right eye followed by the left eye that were each successfully treated using intracameral 20% sulfur hexafluoride gas injection. Case 2 is a 62-year-old man that developed a large fluid cleft beneath a pre-existing LASIK flap, which resolved with intracameral 20% sulfur hexafluoride gas injection without the need for corneal transplantation.\n\nConclusions and importance\nIn acute corneal hydrops, intracameral gas injection to tamponade Descemet's membrane tears with decompression of stromal fluid can be an effective intervention to delay or avoid keratoplasty in individuals whose corneal hydrops does not improve with conventional medical management.\n\nKeywords\nAcute corneal hydropsIntracameral gas injectionSulfur hexafluorideLASIKKeratoconusDescemet's membrane\n==== Body\n1 Introduction\nAcute corneal hydrops is characterized by sudden ingress of aqueous fluid into the corneal stroma secondary to a tear in Descemet's membrane. It is a known sequela of conditions that result in bowing and thinning of the cornea, ranging from keratoconus to laser in situ keratomileusis (LASIK)-associated ectasia.1,8 Typically, it is managed medically with hypertonic saline, topical steroids, and aqueous suppressants. For ensuing visually significant scars or persistent edema, deep anterior lamellar keratoplasty or penetrating keratoplasty may be performed.2 Other surgical treatments for unrelenting edema have been reported, such as endothelial keratoplasty and intracameral gas injection as ways to tamponade the posterior corneal fistula.2 In this series, we present three eyes of two patients with severe acute hydrops that resolved with intracameral gas injection. In Case 1, penetrating keratoplasty was ultimately needed in both eyes due to visually significant corneal scars. In Case 2, a large fluid cleft within the LASIK flap interface was completely resolved with sustained visual improvement, allowing the patient to avoid a corneal transplant.\n\n2 Findings\n2.1 Case 1\nA 27-year-old woman with bilateral severe keratoconus presented with a one-month history of worsening vision, pain, and photophobia in her right eye. Slit lamp exam of the right eye revealed severe acute corneal hydrops with a large stromal fluid cleft (Fig. 1a). Best uncorrected vision was light perception in the right eye and counting fingers at 3 feet in the left eye. Topical 5% sodium chloride solution, homatropine, prednisolone, timolol, and brimonidine were initiated, but two weeks later, clinical worsening was observed with progression of the hydrops and development of a giant stromal fluid cleft and a large tear in Descemet's membrane. The patient was taken to the operating room and, under monitored anesthesia care (MAC), underwent needle decompression of the stromal fluid cleft and intracameral injection of a 20% sulfur hexafluoride (SF6) gas bubble occupying 50% of the anterior chamber. The pupil was dilated to avoid pupillary block, and the patient reclined in a supine position overnight and alternated between 2 h on and 2 h off of supine positioning on post-operative day (POD) 1–2.Fig. 1 Case 1 – (a) Right Eye, Pre-operative Image. Anterior segment (AS)-OCT examination demonstrates severe acute corneal hydrops with a large stromal cleft in the right eye. (b) Right Eye, Post-Operative Month One. AS-OCT examination demonstrates significant reduction in the fluid cleft in the right eye. (c) Left Eye, Pre-operative Image. AS-OCT examination demonstrates severe acute corneal hydrops with a large stromal cleft in the left eye. (d) Left Eye, Post-Operative Week 2. AS-OCT examination reveals significant reduction in the fluid cleft in the left eye.\n\nFig. 1\n\nAt her post-operative month one visit, the fluid cleft in the right eye had significantly improved (Fig. 1b). Unfortunately, at the same visit, acute hydrops was observed in the contralateral eye (Fig. 1c). Topical homatropine, 5% sodium chloride, alcaftadine, timolol, and dorzolamide were initiated but no improvement was observed after one month, so the patient underwent the same procedure in that eye: needle decompression of the stromal fluid cleft and intracameral injection of a 20% SF6 gas bubble occupying 50% of the anterior chamber. Two weeks later, the corneal hydrops had substantially improved (Fig. 1d). Eventually, due to visually significant scarring, penetrating keratoplasty (PKP) was performed on both eyes. Her best uncorrected vision was 20/20 OU two years following PKP.\n\n2.2 Case 2\nA 62-year-old man presented to the emergency room with three days of worsening vision accompanied by a gritty sensation in the left eye. His prior history included bilateral LASIK followed by severe bilateral post-LASIK ectasia, which he managed with scleral contact lenses. Exam revealed acute left corneal hydrops secondary to a tear in Descemet's membrane with a large fluid cleft at the interface between the LASIK flap and the underlying stromal bed (Fig. 2). Uncorrected visual acuity (UCVA) was 20/100 pinhole (PH) 20/25 in the right eye and 20/100 PH 20/30 in the left eye. Intraocular pressure measured peripheral to the LASIK flap was 10 and 12 mm Hg in the right and left eye, respectively. He was started on 5% sodium chloride ophthalmic solution four times daily (QID), 5% sodium chloride ointment at bedtime, and prednisolone acetate 1% every four hours, which was tapered to QID after four days. His situation worsened, however, and five weeks after the onset of the acute corneal hydrops, best corrected vision decreased to count fingers (CF) at one foot in the left eye. The patient's exam revealed severe microcystic corneal edema affecting 75% of the cornea, including centrally. Prednisolone was changed to difluprednate QID without improvement.Fig. 2 Case 2. (a) Slit lamp examination demonstrated severe en face corneal clouding and (b) the presence of a fluid cleft at the LASIK flap interface. (c) AS-OCT revealed the presence of a large fluid cleft secondary to a tear in Descemet's membrane and resulting fistula in the posterior stromal bed in the left eye.\n\nFig. 2\n\nOne month later, the patient was taken to the operating room for surgery under topical/MAC anesthesia. A small surgical iridectomy was performed inferiorly using MST forceps (MicroSurgical Technology, Redmond, WA) and MST scissors. An intracameral injection of 20% SF6 gas was then placed to generate a bubble that occupied 90% of the anterior chamber, and a venting incision was then made through the LASIK flap inferonasally to decompress the fluid cleft. The patient was asked to remain in supine position overnight following the operation. On POD1, the fluid cleft was reduced by 85% on anterior segment OCT and clinical evaluation, with a small cleft persisting inferiorly. The patient was placed on prednisolone 1% QID and moxifloxacin QID and was asked to alternate 1h on and 1h off of supine positioning through POD2. By post-operative week one (POW1), his best corrected visual acuity (BCVA) in the left eye improved to 20/40 + 2 with a scleral lens, which was his pre-hydrops visual acuity.\n\nAt POW3, the patient reported significant improvement in his vision and no pain. Slit lamp exam revealed a clear cornea with a minimally discernable cleft of fluid in the LASIK flap interface inferiorly and no fluid centrally (Fig. 3). However, a Seidel test was positive at the venting incision, and he was placed on timolol 0.5% twice daily and a bandage contact lens (BCL). At post-operative month (POM) 1, the Seidel test remained slightly positive, and a 10-0 nylon suture was placed through the leaking incision in the minor procedure room. When the patient was seen one week later in the clinic, his cornea was Seidel negative, and his BCVA was 20/50 by pinhole. By POW6, his cornea was compact with no remaining interface fluid, and he had stopped all topical medications. By POM2.5, the patient's vision had stabilized to a BCVA by pinhole of 20/30. At his POM4.5 return visit, his BCVA in his left eye with scleral lens in place was 20/20. Given his improvement and excellent BCVA, the decision was made to continue observation without further surgical intervention. The ASC-OCT images of the patient's cornea at his postoperative visits are shown in Fig. 3(b-f). The appearance of the patient's cornea at POM6 is shown in Fig. 4. The patient has been stable and has not required corneal transplantation in either eye, which as of this publication is 19 months since the intracameral gas procedure.Fig. 3 Case 2 – Pre-operative (a) and successive post-operative AS-OCT images illustrating resolution of acute corneal hydrops. Images were taken 2 weeks (b), 4 weeks (c), 3 months (d), 5 months (e), and 7 months (f) post-operatively. The pre-operative image in (a) shows the presence of a stromal fistula within the stromal bed adjacent to the LASIK-flap interface.\n\nFig. 3Fig. 4 Case 2 – POM6 image of patient's cornea after intracameral 20% SF6 showing resolution of corneal edema and interfacial fluid. 10-0 nylon suture was placed to close the venting incision and was later removed. BCVA with scleral lens eventually improved to 20/20.\n\nFig. 4\n\n3 Discussion\nAcute corneal hydrops, a known sequela of keratoconus and post-LASIK ectasia, results in stromal edema accompanied by sudden onset of impaired vision, light sensitivity, and pain.1,3 In treating acute corneal hydrops, conservative management typically aims to provide symptomatic relief and promote spontaneous resolution of hydrops via aqueous suppressants, steroids, and hyperosmotic agents.2 Pain and photophobia can be managed with a BCL, cycloplegic agents, dark glasses, and topical steroids or non-steroidal anti-inflammatory drugs (NSAIDS).1,2 Administration of broad-spectrum antibiotics should be considered to prevent secondary infections, particularly when the epithelium is compromised and/or if a BCL is used.2\n\nWhen hydrops persists despite conservative measures, intracameral air or gas injection into the anterior chamber can be an effective first-line intervention.2,4 This procedure may effectively tamponade small to medium-sized Descemet's breaks and in turn promote more rapid wound healing of corneal endothelial cells.2,4 Options for intracameral injection include air or 20% SF6, with the latter offering a longer duration of action that generally reduces the need for repeat injections.5,6\n\nIn the setting of larger breaks, intracameral gas injection runs the risk of the bubble traversing into the fluid cleft and failing to form a secure tamponade.2 In these cases, a lamellar transplant procedure such as Descemet's stripping automated endothelial keratoplasty (DSAEK) may seal off the tear and in turn promote resolution of the hydrops.7 If hydrops persists despite these measures, PKP may be indicated, particularly when there is a large intrastromal cleft and/or corneal neovascularization.2\n\nIn this case series, Case 1 represents the first report of sequential bilateral acute hydrops that was successively and successfully treated using 20% SF6 gas injection in a single patient. While back-to-back acute hydrops in the same patient is rare, it was not surprising in this patient given her underlying history of keratoconus in both eyes. Although this patient ultimately required PKPs in both eyes due to visually significant scarring, this would not have been a good option initially due to acute inflammation and the large area of hydrops involvement that would have necessitated a large decentered graft extending to the limbus. By promoting apposition of the anterior and posterior stroma through resolution of the hydrops, initial interventions with intracameral gas injection and anterior needle decompression prepared the patient's corneas to ultimately undergo PKPs.\n\nIn contrast, Case 2 represents the first reported instance of using 20% SF6 gas injection to treat acute corneal hydrops in a patient with post-LASIK ectasia who had developed a large cleft of interface fluid. The LASIK flap provided an interface in which fluid could collect as it moved anteriorly from the tear in Descemet's membrane and through the fistula that had formed in the posterior stroma (Fig. 3a). What made this patient's case unique was the size and extent of the interface fluid cleft, which turned the LASIK flap into a very large, tense fluid bulla. This put the cornea at risk of rupture through either flap edge dehiscence or a direct tear through the flap.\n\nObservation alone was not considered a good option since the fistula did not spontaneously resolve. PKP would have definitively and simultaneously addressed the patient's underlying problems (the fluid cleft, the posterior fistula, and the ectatic cornea), but it was also the most invasive option and was complicated by the presence of the large cleft and extensive edema, which could have made suturing more challenging. DSAEK to cover the fistula posteriorly was also discussed as an option but would likely still have required a PKP in the future and thus would expend two donor grafts within relatively short succession. The most conservative surgical approach was intracameral gas tamponade alone without a graft. It was not clear pre-operatively whether a gas bubble alone would be sufficient to tamponade a fistula of this size and provide lasting resolution of the fluid cleft. While the venting incision successfully evacuated all the interface fluid at the time of surgery, a slow leak was noted at POW1, implying that the fistula was not completely closed and that fluid was still building up in the stroma. The leak was initially managed with aqueous suppression and a BCL. We posit that a secondary effect of conservatively managing the Seidel leak initially was that it gave the flap and posterior stroma time to gradually adhere together in parallel with complete closure of the fistula. If a suture had been placed earlier or even intraoperatively, the fluid cleft may have re-formed to its pre-operative size, since it was evident that fluid was still tracking into the cleft in the early post-operative period. After the incision was sutured at POM1, the cornea remained stable with no recurrence of the fluid cleft and only mild paracentral scarring overlying the site of the stromal fistula. His BCVA continued to improve and, by POM4.5, was 20/20 with scleral lens in place. The patient has since avoided the need for further intervention or surgery.\n\n4 Conclusions\nWhile medical management of acute hydrops may lead to full symptom resolution in some patients, surgical intervention may be required in refractory cases. 20% SF6 gas injection to tamponade Descemet's tears along with stromal fluid cleft decompression should be considered as an initial intervention before keratoplasty in individuals whose corneal hydrops does not improve despite treatment with aqueous suppression and steroids. Although visual improvement may ultimately require corneal transplantation, as was true for the first case presented herein, intracameral gas injection with fluid decompression alone may be sufficient to restore satisfactory visual acuity, as demonstrated in the second case.\n\nPatient consent\nWritten informed consent was obtained from patients for publication of these case reports and any accompanying images.\n\nAcknowledgements\nFunding: Departmental core grants from Research to Prevent Blindness (RPB) and the National Eye Institute (P30-EY026877) as well as career development awards for author D.M. from RPB and the National Eye Institute (K08EY028176). Author D.M. also acknowledges funding from the 10.13039/100010310E. Matilda Ziegler Foundation for the Blind.\n\nAuthorship\nAll authors attest that they meet the current ICMJE criteria for Authorship.\n\nDeclaration of competing interest\nThe following authors have no financial disclosures: JJS, HL, CL, DM.\n==== Refs\nReferences\n1 Tuft S.J. Gregory W.M. Buckley R.J. Acute corneal hydrops in keratoconus Ophthalmology 101 10 1994 1738 1744 7936572 \n2 Sharma N. Maharana P.K. Jhanji V. Vajpayee R.B. Management of acute corneal hydrops in ectatic corneal disorders Curr Opin Ophthalmol 23 4 2012 317 323 22569471 \n3 Maharana P.K. Sharma N. Vajpayee R.B. Acute corneal hydrops in keratoconus Indian J Ophthalmol 61 8 2013 461 464 23925338 \n4 Miyata K. Tsuji H. Tanabe T. Mimura Y. Amano S. Oshika T. Intracameral air injection for acute hydrops in keratoconus Am. J. Opthalmol. 133 2002 750 752 \n5 Basu S. Vaddavalli P.K. Ramappa M. Shah S. Murthy S.I. Sangwan V.S. Intracameral perfluoropropane gas in the treatment of acute corneal hydrops Ophthalmology 118 5 2011 934 939 21211841 \n6 Panda A. Aggarwal A. Madhavi P. Management of acute corneal hydrops secondary to keratoconus with intracameral injection of sulfur hexafluoride (SF6) Cornea 26 9 2007 1067 1069 17893535 \n7 Dapena I. Ham L. Melles G.R. Endothelial keratoplasty: DSEK/DSAEK or DMEK - the thinner the better? Curr Opin Ophthalmol 20 4 2009 299 307 19417653 \n8 Cooke M.D. Koenig S.B. Spontaneous resolution of acute corneal hydrops in a patient with post-LASIK ectasia Cornea 34 7 2015 Jul 835 837 25970433\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "20()",
"journal": "American journal of ophthalmology case reports",
"keywords": "Acute corneal hydrops; Descemet's membrane; Intracameral gas injection; Keratoconus; LASIK; Sulfur hexafluoride",
"medline_ta": "Am J Ophthalmol Case Rep",
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"title": "Management of acute corneal hydrops with intracameral gas injection.",
"title_normalized": "management of acute corneal hydrops with intracameral gas injection"
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{
"abstract": "OBJECTIVE\nLittle is known about pregnancy outcomes among women who have acquired human immunodeficiency virus (HIV) through perinatal infection and survived into adulthood. The objectives of this study were to describe pregnancy outcomes among women with perinatal HIV infection (PHIV) in Canada and to identify potential challenges in the prevention of perinatal HIV transmission in this population.\n\n\nMETHODS\nA retrospective review of all pregnancies among women with PHIV who were previously followed as children at two tertiary care centres in Montréal, Québec, was conducted. Data were extracted from pediatric and obstetrical records.\n\n\nRESULTS\nThere were 21 pregnancies among 11 women, and 18 of these pregnancies were unintentional. Mean age at first pregnancy was 19.5 years (range 15-29 years). At the first prenatal visit, 79% had a detectable viral load, 36% were immunosuppressed (CD4 T cell count <200 mm3), and only 36% were receiving antiretroviral therapy (ART). At the time of delivery, although all were prescribed ART, 50% of these women still had a detectable viral load, and 36% remained immunosuppressed. All of the women harboured mutations conferring drug resistance to zidovudine and lamivudine, and the majority (73%) were also resistant to nevirapine. None of the infants were HIV infected, although all received prophylaxis with agents to which their mother's virus was resistant.\n\n\nCONCLUSIONS\nUnplanned pregnancies, difficulties with adherence to ART, and drug resistance were identified challenges in the management of pregnancies among women with PHIV. This study highlights a gap in the reproductive counselling of adolescents with PHIV and the need for close follow-up and adherence support during pregnancy in this population.",
"affiliations": "Department of Obstetrics and Gynecology, McGill University Health Centre, Montréal, QC.;Department of Obstetrics and Gynecology, Centre Hospitalier Universitaire Sainte-Justine, Montréal, QC; Centre Maternel et Infantile sur le SIDA, Montréal, QC.;Centre Maternel et Infantile sur le SIDA, Montréal, QC; Department of Microbiology and Immunology, Centre Hospitalier Universitaire Sainte-Justine, Montréal, QC; Division of Pediatric Infectious Diseases, Centre Hospitalier Universitaire Sainte-Justine, Montréal, QC.;Centre Maternel et Infantile sur le SIDA, Montréal, QC; Division of Pediatrics Infectious Diseases, McGill University Health Centre, Montréal, QC.;Department of Pharmacy, Centre Hospitalier Universitaire Sainte-Justine, Montréal, QC.;Centre Maternel et Infantile sur le SIDA, Montréal, QC.;Centre Maternel et Infantile sur le SIDA, Montréal, QC.;Centre Maternel et Infantile sur le SIDA, Montréal, QC; Division of Pediatric Infectious Diseases, Centre Hospitalier Universitaire Sainte-Justine, Montréal, QC.;Centre Maternel et Infantile sur le SIDA, Montréal, QC; Division of Pediatric Infectious Diseases, Centre Hospitalier Universitaire Sainte-Justine, Montréal, QC. Electronic address: fatima.kakkar@umontreal.ca.",
"authors": "Trahan|Marie-Julie|MJ|;Boucher|Marc|M|;Renaud|Christian|C|;Karatzios|Christos|C|;Metras|Marie-Elaine|ME|;Valois|Silvie|S|;Ransy|Doris G|DG|;Lamarre|Valérie|V|;Kakkar|Fatima|F|",
"chemical_list": "D019380:Anti-HIV Agents; D015215:Zidovudine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jogc.2019.09.022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1701-2163",
"issue": "42(4)",
"journal": "Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC",
"keywords": "HIV; infectious disease transmission, vertical; long-term survivors; outcome; pregnancy; reproductive health",
"medline_ta": "J Obstet Gynaecol Can",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D002170:Canada; D005260:Female; D015658:HIV Infections; D020276:HIV Long-Term Survivors; D006801:Humans; D007223:Infant; D018445:Infectious Disease Transmission, Vertical; D055118:Medication Adherence; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D049168:Pregnancy, Unplanned; D011792:Quebec; D012189:Retrospective Studies; D019562:Viral Load; D055815:Young Adult; D015215:Zidovudine",
"nlm_unique_id": "101126664",
"other_id": null,
"pages": "446-452",
"pmc": null,
"pmid": "31882286",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pregnancies Among the First Generation of Survivors of Perinatal HIV Infection.",
"title_normalized": "pregnancies among the first generation of survivors of perinatal hiv infection"
} | [
{
"companynumb": "CA-GILEAD-2020-0463855",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RITONAVIR\\TIPRANAVIR"
},
"drugadditional": nul... |
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