article dict | reports listlengths 1 3.97k |
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{
"abstract": "Respiratory failure requiring extracorporeal membranous oxygenation in the newborn is commonly seen secondary to severe pathology such as congenital diaphragmatic hernia, meconium aspiration syndrome, pulmonary hypertension and pulmonary hypoplasia. However, atypical causes of respiratory failure, such as pulmonary arterial thrombi, are often refractory to traditional management and require careful multidisciplinary evaluation. We report a case of respiratory failure secondary to congenital pulmonary arterial thrombosis of unknown aetiology in an otherwise healthy neonate. We discuss the abnormal anatomy and pathophysiology that presented in our patient secondary to this condition and discuss our diagnostic process, management and outcomes. Additionally, we review the literature for reported cases and discuss current hypotheses on the development of congenital pulmonary arterial thrombi. Given the rare occurrence of this event, we hope to contribute to the understanding of future similar cases and emphasise the importance of keeping pulmonary arterial thrombi in the clinical differential.",
"affiliations": "Pediatrics, University of Virginia Health System, Charlottesville, Virginia, USA.;Pediatrics, University of Virginia Health System, Charlottesville, Virginia, USA.;Pediatrics, University of Virginia Health System, Charlottesville, Virginia, USA.;Pediatrics, University of Virginia Health System, Charlottesville, Virginia, USA.",
"authors": "Odackal|Namrita J|NJ|http://orcid.org/0000-0003-3680-7722;McCulloch|Michael A|MA|;Hainstock|Michael R|MR|;Vergales|Brooke D|BD|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-227925",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(7)",
"journal": "BMJ case reports",
"keywords": "haematology (incl blood transfusion); neonatal intensive care",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D006801:Humans; D007231:Infant, Newborn; D008168:Lung; D008171:Lung Diseases; D008297:Male; D011651:Pulmonary Artery; D012131:Respiratory Insufficiency; D013927:Thrombosis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31272991",
"pubdate": "2019-07-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20731840;25597831;10824912;23304599;17912476;26265897;15947776;22315277;23108734;15010146;19052800;2178462;22529601;16877477;18595024",
"title": "Respiratory failure secondary to congenital pulmonary arterial thrombus with lung dysplasia.",
"title_normalized": "respiratory failure secondary to congenital pulmonary arterial thrombus with lung dysplasia"
} | [
{
"companynumb": "US-ACTELION-A-CH2019-193668",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NITRIC OXIDE"
},
"drugadditional": "1",
... |
{
"abstract": "Cytokines play a role in the immunopathological and molecular mechanisms of drug-induced hypersensitivity reactions (HSR). The objective of the current report was to analyze the reliability and correlation between the clinical symptoms observed in a patient that presented an ibuprofen-induced Stevens-Johnson Syndrome (SJS), her lymphocyte toxicity assay to the incriminated drug, and the cytokine secretion in the patient's sera. In her skin biopsy, the apoptotic keratinocytes is shown. Clinically, the patient presented a triad that characterizes \"true\" HSR (rash, fever, and liver involvement). The pro-inflammatory cytokines were significantly higher in sera from the patient than in sera from control patients (analyzed previously in the authors' laboratory). More specifically, the high level of tumor necrosis factor alpha (TNF-alpha) is as high as in patients found to have toxic epidermal necrolysis (TEN) and presenting \"true\" HSR, eg, rash, fever, and organ involvement. The same is the case with the apoptotic markers Fas, caspase activity, and M30. T-cell cytokines control the pathogenesis of SJS/TEN contributing to apoptotic processes in the liver and in the skin.",
"affiliations": "In Vitro Drug Safety and Biotechnology Laboratory, University of Toronto, Toronto, Ontario, Canada. Manuela.Neuman@utoronto.ca",
"authors": "Neuman|Manuela|M|;Nicar|Michael|M|",
"chemical_list": "D016207:Cytokines; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha; D020169:Caspases; D007052:Ibuprofen",
"country": "United States",
"delete": false,
"doi": "10.1016/j.trsl.2006.12.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-1810",
"issue": "149(5)",
"journal": "Translational research : the journal of laboratory and clinical medicine",
"keywords": null,
"medline_ta": "Transl Res",
"mesh_terms": "D000293:Adolescent; D017209:Apoptosis; D020169:Caspases; D016207:Cytokines; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D006801:Humans; D007052:Ibuprofen; D007150:Immunohistochemistry; D018836:Inflammation Mediators; D012867:Skin; D013262:Stevens-Johnson Syndrome; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "101280339",
"other_id": null,
"pages": "254-9",
"pmc": null,
"pmid": "17466924",
"pubdate": "2007-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Apoptosis in ibuprofen-induced Stevens-Johnson syndrome.",
"title_normalized": "apoptosis in ibuprofen induced stevens johnson syndrome"
} | [
{
"companynumb": "CA-JNJCH-2007322317",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "3",
"dru... |
{
"abstract": "BACKGROUND\nStudies in patients with rheumatoid arthritis and advanced follicular lymphoma have shown that CT-P10, a rituximab biosimilar, has equivalent or non-inferior efficacy and pharmacokinetics to rituximab. We aimed to assess the therapeutic equivalence of single-agent CT-P10 and rituximab in patients with newly diagnosed low-tumour burden follicular lymphoma.\n\n\nMETHODS\nIn this ongoing, randomised, double-blind, parallel-group, active-controlled, phase 3 trial, adult patients (≥18 years) with stage II-IV low-tumour-burden follicular lymphoma were randomly assigned (1:1) using an interactive web or voice response system stratified by region, stage, and age to CT-P10 or US-sourced rituximab. Patients received CT-P10 or rituximab (375 mg/m2 intravenous) on day 1 of four 7-day cycles (induction period). Patients who had disease control after the induction period continued to a maintenance period of CT-P10 or rituximab administered every 8 weeks for six cycles and, if completed, a second year of maintenance therapy of additional CT-P10 (every 8 weeks for six cycles) was offered. The study was partially unmasked after database lock (Feb 23, 2018) for all data up to 7 months (before cycle 3 of the maintenance period). The primary endpoint was the proportion of patients who achieved an overall response by 7 months in the intention-to-treat population. Efficacy equivalence was shown if the two-sided 90% CIs for the treatment difference in the proportion of responders between CT-P10 and rituximab was within the equivalence margin of 17%. This trial is registered with ClinicalTrials.gov, number NCT02260804.\n\n\nRESULTS\nBetween Nov 9, 2015, and Jan 4, 2018, 402 patients were assessed for eligibility, of whom 258 were randomly assigned: 130 to CT-P10 and 128 to rituximab. 108 (83%) of 130 patients assigned to CT-P10 and 104 (81%) of 128 assigned to rituximab achieved an overall response by month 7 (treatment difference estimate 1·8%; 90% CI -6·43 to 10·20). Therapeutic equivalence was shown (90% CIs were within the prespecified margin of 17%). The most common grade 3 or 4 treatment-emergent adverse events were decreased neutrophil count (two grade 3 in the CT-P10 group) and neutropenia (one in each group); all other grade 3 or 4 treatment-emergent adverse events occurred in one patient each. Six (5%) of 130 patients who received CT-P10 and three (2%) of 128 who received rituximab experienced at least one treatment-emergent serious adverse event.\n\n\nCONCLUSIONS\nCT-P10 was equivalent to rituximab in terms of efficacy and was well tolerated. CT-P10 monotherapy is suggested as a new therapeutic option for patients with low-tumour-burden follicular lymphoma.\n\n\nBACKGROUND\nCelltrion, Inc.",
"affiliations": "Department of Haematology and Oncology, Kasugai Municipal Hospital, Kasugai, Japan; School of Medicine, Fujita Medical University, Toyoake, Japan.;Hematology Department, The Catalan Institute of Oncology-The Josep Carreras Leukaemia Research Institute, Hospital Germans Trias i Pujol, Badalona, Spain.;Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St Mary's Hospital, The Catholic University of Korea, Seoul, South Korea.;Department of Hematology, Shinshu University School of Medicine, Matsumoto, Japan.;Shimane University Hospital, Innovative Cancer Center/Oncology-Hematology, Izumo, Japan.;Division of Hematology and Bone Marrow Transplantation, N N Blokhin Russian Cancer Research Center, Moscow, Russia.;Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, South Korea.;Northern Institute for Cancer Care, Newcastle University, Newcastle-upon-Tyne, UK.;Department of Onco-Hematology, Portuguese Institute of Oncology, Porto, Portugal.;Russian Research Center for Radiology and Surgical Technologies, Ministry of Health of the Russian Federation, St Petersburg, Russia.;Department of Haematology, Jagiellonian University, Kraków, Poland.;Department of Hematology, Hospital Arnau de Vilanova, Valencia, Spain.;Department of Hematology, Nizhniy Novgorod Region Clinical Hospital, Nizhniy Novgorod, Russia.;N N Alexandrov Republican Scientific and Practical Centre of Oncology and Medical Radiology, Minsk, Belarus.;Department of Internal Medicine, Universidad de la Frontera, Temuco, Chile.;Department of Medicine, Charles University, General Hospital in Prague, Prague, Czech Republic.;Toni Stephenson Lymphoma Center and Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA.;Department of Hematology, Hospices Civils de Lyon, Lyon, France.;Comprehensive Cancer Center Ulm, University Hospital of Ulm, Ulm, Germany.;Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.;Celltrion, Inc., Incheon, South Korea.;Celltrion, Inc., Incheon, South Korea.;Celltrion, Inc., Incheon, South Korea.;Toni Stephenson Lymphoma Center and Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. Electronic address: lkwak@fsm.northwestern.edu.",
"authors": "Ogura|Michinori|M|;Sancho|Juan Manuel|JM|;Cho|Seok-Goo|SG|;Nakazawa|Hideyuki|H|;Suzumiya|Junji|J|;Tumyan|Gayane|G|;Kim|Jin Seok|JS|;Lennard|Anne|A|;Mariz|José|J|;Ilyin|Nikolai|N|;Jurczak|Wojciech|W|;Lopez Martinez|Aurelio|A|;Samoilova|Olga|O|;Zhavrid|Edvard|E|;Yañez Ruiz|Eduardo|E|;Trneny|Marek|M|;Popplewell|Leslie|L|;Coiffier|Bertrand|B|;Buske|Christian|C|;Kim|Won-Seog|WS|;Lee|Sang Joon|SJ|;Lee|Sung Young|SY|;Bae|Yun Ju|YJ|;Kwak|Larry W|LW|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D059451:Biosimilar Pharmaceuticals; C000626854:CT-P10; D000069283:Rituximab",
"country": "England",
"delete": false,
"doi": "10.1016/S2352-3026(18)30157-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2352-3026",
"issue": "5(11)",
"journal": "The Lancet. Haematology",
"keywords": null,
"medline_ta": "Lancet Haematol",
"mesh_terms": "D058846:Antibodies, Monoclonal, Murine-Derived; D059451:Biosimilar Pharmaceuticals; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008224:Lymphoma, Follicular; D008297:Male; D008875:Middle Aged; D000069283:Rituximab; D012449:Safety; D016896:Treatment Outcome; D047368:Tumor Burden",
"nlm_unique_id": "101643584",
"other_id": null,
"pages": "e543-e553",
"pmc": null,
"pmid": "30389036",
"pubdate": "2018-11",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Efficacy, pharmacokinetics, and safety of the biosimilar CT-P10 in comparison with rituximab in patients with previously untreated low-tumour-burden follicular lymphoma: a randomised, double-blind, parallel-group, phase 3 trial.",
"title_normalized": "efficacy pharmacokinetics and safety of the biosimilar ct p10 in comparison with rituximab in patients with previously untreated low tumour burden follicular lymphoma a randomised double blind parallel group phase 3 trial"
} | [
{
"companynumb": "JP-ROCHE-2948542",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Although topical steroids are considered first-line treatment for cutaneous Langerhans cell histiocytosis (LCH), the appropriate therapy for refractory cases remains controversial. We report a 16-month-old girl with isolated cutaneous LCH refractory to treatment with topical corticosteroids and topical tacrolimus. Treatment was initiated with 5% topical imiquimod cream and the rash completely resolved after 5 months of therapy. There was no disease recurrence after more than 2 years of follow-up. We present this case to highlight imiquimod as a novel therapeutic agent for the management of isolated cutaneous LCH in children.",
"affiliations": "Medical School, University of Minnesota, Minneapolis, Minnesota.;Department of Dermatology, University of Minnesota, Minneapolis, Minnesota.",
"authors": "Dodd|Erin|E|;Hook|Kristen|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/pde.12829",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "33(3)",
"journal": "Pediatric dermatology",
"keywords": null,
"medline_ta": "Pediatr Dermatol",
"mesh_terms": null,
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "e184-e185",
"pmc": null,
"pmid": "27040152",
"pubdate": "2016-05",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Topical Imiquimod for the Treatment of Childhood Cutaneous Langerhans Cell Histiocytosis.",
"title_normalized": "topical imiquimod for the treatment of childhood cutaneous langerhans cell histiocytosis"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2016SP011666",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IMIQUIMOD"
},
"drugadditional"... |
{
"abstract": "OBJECTIVE\nThe aim of this study was to explore the prescription pattern of antiepileptics and the relationship between antiepileptics and adverse drug reactions (ADRs) in a Japanese population.\n\n\nMETHODS\nA retrospective observational cohort study was conducted by reviewing the medical records of patients who visited or were admitted to a single tertiary care center between January 2011 and June 2019, were treated with antiepileptics, and developed allergic ADRs associated with these drugs.\n\n\nRESULTS\nIn total, 14,230 unique patients received antiepileptics during the study period. Diazepam was the most frequently used antiepileptic drug (74.8 %), followed by phenobarbital (14.3 %), valproic acid (11.4 %), fosphenytoin (10.0 %), and carbamazepine (7.3 %). Although a trend of increasing prevalence of newer generation antiepileptics was noted, most patients are still treated with older generation antiepileptics. Thirty-two (0.22 %) unique patients experienced ADRs associated with antiepileptics, and the antiepileptic drug most frequently associated with ADRs was carbamazepine, at a rate of 1.4 %. Three patients developed Stevens-Johnson syndrome/toxic epidermal necrolysis, in two of which carbamazepine was implicated. Most patients experienced ADRs associated with aromatic antiepileptics (84.4 %) or older generation antiepileptics (81.3 %).\n\n\nCONCLUSIONS\nThis is the first study to assess the relationship between ADRs and antiepileptics at a tertiary care center in Japan. Based on our results, most patients were prescribed older generation antiepileptics, and most ADR events were linked to the administration of drugs in this category; thus, identification of patients at risk of developing ADRs is critical in order to prevent such events.",
"affiliations": "Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan. Electronic address: keiko.hikino@riken.jp.;Division of Neurology, Department of Medical Subspecialties, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan.;Department of General Pediatrics & Interdisciplinary Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan.;Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.;Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.",
"authors": "Hikino|Keiko|K|;Abe|Yuichi|Y|;Sakashita|Kazumi|K|;Ozeki|Takeshi|T|;Mushiroda|Taisei|T|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.eplepsyres.2021.106614",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0920-1211",
"issue": "173()",
"journal": "Epilepsy research",
"keywords": "Adverse drug reactions; Aromatic antiepileptics; Japanese; Newer generation antiepileptics; Older generation antiepileptics; Retrospective study",
"medline_ta": "Epilepsy Res",
"mesh_terms": null,
"nlm_unique_id": "8703089",
"other_id": null,
"pages": "106614",
"pmc": null,
"pmid": "33740697",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Characteristics of adverse drug reactions associated with antiepileptics at a tertiary children's hospital in Japan: A retrospective observational cohort study.",
"title_normalized": "characteristics of adverse drug reactions associated with antiepileptics at a tertiary children s hospital in japan a retrospective observational cohort study"
} | [
{
"companynumb": "JP-PFIZER INC-202101859890",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FOSPHENYTOIN SODIUM"
},
"drugadditional": "3... |
{
"abstract": "Pulmonary artery aneurysm (PAA) is a rare disorder that may be classified as congenital, acquired, or idiopathic, in the case of unclear etiology. When associated with severe idiopathic pulmonary arterial hypertension, such a case of PAA may present to the operating room as an indication for lung transplantation. In this article, we present such a case of a patient with a giant main and right PAA that underwent a double lung transplant. We describe the pathophysiology and natural course of this PAA and discuss the role of intraoperative transesophageal echocardiography in the management of patients with this rare diagnosis.",
"affiliations": "University Hospitals Cleveland Medical Center, Cleveland, OH, USA.;University Hospitals Cleveland Medical Center, Cleveland, OH, USA.",
"authors": "Arain|Faisal D|FD|https://orcid.org/0000-0002-0379-8893;Gilbride|Victoria A|VA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/10892532211007259",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1089-2532",
"issue": "25(3)",
"journal": "Seminars in cardiothoracic and vascular anesthesia",
"keywords": "idiopathic pulmonary arterial hypertension; lung transplantation; pulmonary artery aneurysm; pulmonary hypertension; pulmonary valve; transesophageal echocardiography",
"medline_ta": "Semin Cardiothorac Vasc Anesth",
"mesh_terms": "D000783:Aneurysm; D017548:Echocardiography, Transesophageal; D006801:Humans; D006976:Hypertension, Pulmonary; D016040:Lung Transplantation; D011651:Pulmonary Artery",
"nlm_unique_id": "9807630",
"other_id": null,
"pages": "164-172",
"pmc": null,
"pmid": "33899590",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pulmonary Artery Aneurysm Associated With Severe Pulmonary Hypertension in a Patient Presenting for Double Lung Transplant: Review of a Rare Disorder and Role of Transesophageal Echocardiography.",
"title_normalized": "pulmonary artery aneurysm associated with severe pulmonary hypertension in a patient presenting for double lung transplant review of a rare disorder and role of transesophageal echocardiography"
} | [
{
"companynumb": "US-GILEAD-2021-0545917",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "AMBRISENTAN"
},
"drugadditional": null,
... |
{
"abstract": "Dabigatran, a direct thrombin inhibitor and one of the new class of direct oral anticoagulants, is increasingly used in preference to warfarin because of its efficacy and ease of administration. However, because the drug is cleared by the kidneys, it can accumulate in plasma and increase the risk for bleeding in patients with decreased kidney function. We report a patient with end-stage liver disease who developed life-threatening hemorrhage and acute kidney injury while taking dabigatran, 150mg, twice daily. Although the patient received idarucizumab, an anti-dabigatran antibody fragment used as an antidote, hemostasis could not be achieved. Administration of vitamin K, fresh frozen plasma, desmopressin, octreotide, and pantoprazole did not arrest bleeding or affect coagulation parameters, and it was not possible to establish vascular access for hemodialysis. In patients with end-stage liver disease, who are at increased risk for both bleeding and acute kidney injury, dabigatran should be prescribed cautiously and at decreased dose.",
"affiliations": "Henry Ford Hospital, Detroit, MI. Electronic address: jnovak2@hfhs.org.;Henry Ford Hospital, Detroit, MI.;Henry Ford Hospital, Detroit, MI.",
"authors": "Novak|James E|JE|;Alamiri|Khalid|K|;Yee|Jerry|J|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000931:Antidotes; D000991:Antithrombins; C000594745:idarucizumab; D000069604:Dabigatran",
"country": "United States",
"delete": false,
"doi": "10.1053/j.ajkd.2017.03.025",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0272-6386",
"issue": "71(1)",
"journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation",
"keywords": "Dabigatran; acute kidney injury (AKI); bleeding; decreased kidney function; dose adjustment; drug safety; end-stage liver disease (ESLD); hemorrhage; idarucizumab; oral anticoagulant; renal clearance; thrombin inhibitor",
"medline_ta": "Am J Kidney Dis",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000931:Antidotes; D000991:Antithrombins; D001281:Atrial Fibrillation; D001777:Blood Coagulation; D000069604:Dabigatran; D058625:End Stage Liver Disease; D006470:Hemorrhage; D006801:Humans; D008297:Male; D010346:Patient Care Management; D020379:Risk Adjustment; D018570:Risk Assessment; D020521:Stroke; D016896:Treatment Outcome",
"nlm_unique_id": "8110075",
"other_id": null,
"pages": "137-141",
"pmc": null,
"pmid": "28549534",
"pubdate": "2018-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Dabigatran Reversal in a Patient With End-Stage Liver Disease and Acute Kidney Injury.",
"title_normalized": "dabigatran reversal in a patient with end stage liver disease and acute kidney injury"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-030574",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IDARUCIZUMAB"
},
... |
{
"abstract": "There are some uncontrolled studies about the efficacy and safety of both aripiprazole and risperidone for treating tic disorder. Moreover, the efficacy of these medications has never been compared. This is the first double blind randomized clinical trial comparing the safety and efficacy of aripiprazole and risperidone for treating patients with tic disorder. Sixty children and adolescents with tic disorder were randomly allocated into one of the two groups to receive either aripiprazole or risperidone for 2 months. The primary outcome measure was the score of Yale Global Tic Severity Scale. In addition, health related quality of life and adverse events were assessed. Both aripiprazole and risperidone decreased the Yale Global Tic Severity Scale score during this trial. Moreover, both medications increased the health related quality of life score. Both aripiprazole and risperidone were tolerated well. Aripiprazole [3.22 (1.9) mg/day] decreased tic score as much as risperidone [0.6 (0.2) mg/day]. Their adverse effects and their effects on health related quality of life were comparable. However, risperidone increased the patients' social functioning more than aripiprazole in short term.",
"affiliations": "Department of Psychiatry, Research Center for Psychiatry and Behavioral Sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran, ghanizadeha@hotmail.com.",
"authors": "Ghanizadeh|Ahmad|A|;Haghighi|Alireza|A|",
"chemical_list": "D014150:Antipsychotic Agents; D010879:Piperazines; D015363:Quinolones; D000068180:Aripiprazole; D018967:Risperidone",
"country": "United States",
"delete": false,
"doi": "10.1007/s10578-013-0427-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-398X",
"issue": "45(5)",
"journal": "Child psychiatry and human development",
"keywords": null,
"medline_ta": "Child Psychiatry Hum Dev",
"mesh_terms": "D000293:Adolescent; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D002648:Child; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D010879:Piperazines; D011788:Quality of Life; D015363:Quinolones; D018967:Risperidone; D013981:Tic Disorders; D016896:Treatment Outcome",
"nlm_unique_id": "1275332",
"other_id": null,
"pages": "596-603",
"pmc": null,
"pmid": "24343476",
"pubdate": "2014-10",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "22444782;21732066;21879319;19487578;22585765;11886028;21339906;22070181;22728760;11799340;22397999;21188439;17667475;2768151;22782459;16539703;22772923;12682319;11235929;18558469;20848326;20686924;23099282;20035580;23801256",
"title": "Aripiprazole versus risperidone for treating children and adolescents with tic disorder: a randomized double blind clinical trial.",
"title_normalized": "aripiprazole versus risperidone for treating children and adolescents with tic disorder a randomized double blind clinical trial"
} | [
{
"companynumb": "IR-CIPLA LTD.-2014IR01721",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "The authors report an unusual case of intrathecal baclofen withdrawal due to the perforation and subsequent leakage of a baclofen pump catheter in a patient with spastic cerebral palsy. A 15-year-old boy underwent an uncomplicated placement of an intrathecal baclofen pump for the treatment of spasticity due to cerebral palsy. After excellent control of symptoms for 3 years, the patient presented to the emergency department with increasing tremors following a refill of his baclofen pump. Initial evaluation consisted of radiographs of the pump and catheter, which appeared normal, and a successful aspiration of CSF from the pump's side port. A CT dye study revealed a portion of the catheter directly overlying the refill port and extravasation of radiopaque dye into the subfascial pocket anterior to the pump. During subsequent revision surgery, a small puncture hole in the catheter was seen to be leaking the drug. The likely cause of the puncture was an inadvertent perforation of the catheter by a needle during the refilling of the pump. This case report highlights a unique complication in a patient with an intrathecal baclofen pump. Physicians caring for these patients should be aware of this rare yet potential complication in patients presenting with baclofen withdrawal symptoms.",
"affiliations": "Department of Neurosurgery, Division of Pediatric Neurosurgery, University of Florida College of Medicine-Jacksonville, Florida.;Department of Neurosurgery, Division of Pediatric Neurosurgery, University of Florida College of Medicine-Jacksonville, Florida.;Department of Neurosurgery, Division of Pediatric Neurosurgery, University of Florida College of Medicine-Jacksonville, Florida.;Department of Neurosurgery, Division of Pediatric Neurosurgery, University of Florida College of Medicine-Jacksonville, Florida.",
"authors": "Dastgir|Amer|A|;Ranalli|Nathan J|NJ|;MacGregor|Theresa L|TL|;Aldana|Philipp R|PR|",
"chemical_list": "D009125:Muscle Relaxants, Central; D001418:Baclofen",
"country": "United States",
"delete": false,
"doi": "10.3171/2015.2.PEDS14501",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1933-0707",
"issue": "16(3)",
"journal": "Journal of neurosurgery. Pediatrics",
"keywords": "baclofen pump; baclofen withdrawal; catheter migration; functional neurosurgery; intrathecal; leakage; perforation; spasticity",
"medline_ta": "J Neurosurg Pediatr",
"mesh_terms": "D000005:Abdomen; D000293:Adolescent; D001418:Baclofen; D002408:Catheters, Indwelling; D002547:Cerebral Palsy; D005548:Foreign-Body Migration; D006801:Humans; D015918:Infusion Pumps, Implantable; D007278:Injections, Spinal; D008297:Male; D009125:Muscle Relaxants, Central; D009128:Muscle Spasticity",
"nlm_unique_id": "101463759",
"other_id": null,
"pages": "335-9",
"pmc": null,
"pmid": "26046690",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Baclofen pump catheter leakage after migration of the abdominal catheter in a pediatric patient with spasticity.",
"title_normalized": "baclofen pump catheter leakage after migration of the abdominal catheter in a pediatric patient with spasticity"
} | [
{
"companynumb": "US-MYLANLABS-2016M1006950",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BACLOFEN"
},
"drugadditional": null,
... |
{
"abstract": "Fetal valproate syndrome (FVS) results from prenatal exposure to valproic acid. It is characterized by a distinctive facial appearance, a cluster of minor and major anomalies and central nervous system dysfunction. We describe a 2-month-old male infant with the typical dysmorphic features characteristic of FVS. He had a persistent left superior vena cava draining into a dilated coronary sinus and mild pulmonary hypertension. There was a history of maternal intake of sodium valproate during pregnancy.",
"affiliations": "Department of Pediatrics, Lokmanya Tilak Municipal General Hospital, Mumbai, India.",
"authors": "Zaki|Syed A|SA|;Phulsundar|Amol|A|;Shanbag|Preeti|P|;Mauskar|Anupama|A|",
"chemical_list": "D000927:Anticonvulsants; D014635:Valproic Acid",
"country": "Saudi Arabia",
"delete": false,
"doi": "10.4103/0256-4947.62839",
"fulltext": "\n==== Front\nAnn Saudi MedASMAnnals of Saudi Medicine0256-49470975-4466Medknow Publications India ASM-30-2332042794110.4103/0256-4947.62839Case ReportFetal valproate syndrome in a 2-month-old male infant Zaki Syed A. Phulsundar Amol Shanbag Preeti Mauskar Anupama From the Department of Pediatrics, Lokmanya Tilak Municipal General Hospital, Mumbai, IndiaCorrespondence: Dr. Syed Ahmed Zaki • Department of Pediatrics, Lokmanya Tilak Municipal General Hospital, Room No. 509, New RMO Quarters, Sion, Mumbai 400022, India • T: +91-986-9970-785 • drzakisyed@gmail.comMay-Jun 2010 30 3 233 235 3 2009 7 2009 © Annals of Saudi Medicine2010This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Fetal valproate syndrome (FVS) results from prenatal exposure to valproic acid. It is characterized by a distinctive facial appearance, a cluster of minor and major anomalies and central nervous system dysfunction. We describe a 2-month-old male infant with the typical dysmorphic features characteristic of FVS. He had a persistent left superior vena cava draining into a dilated coronary sinus and mild pulmonary hypertension. There was a history of maternal intake of sodium valproate during pregnancy.\n==== Body\nValproic acid (VPA) is a widely used antiepileptic drug and mood stabilizer. It was first introduced for use as an antiepileptic drug in 1964 and is still a commonly used antiepileptic drug (AED) worldwide.1 A description of the teratogenic effect of the drug was first published in 1980.1 Since then many potential teratogenic and dysmorphogenic effects of VPA have been reported. We report a case of fetal valproate syndrome (FVS) in a 2-month-old male infant born of an epileptic mother who was taking sodium valproate during pregnancy.\n\nCASE\nA 2-month-old male infant was brought to our outpatient department for evaluation of bilateral inguinal hernia. He was the first child born of a non-consanguineous marriage. His mother had been taking sodium valproate for epilepsy for the past 12 years and was on a dose of 1200 mg/day throughout her pregnancy. The infant was born at full term at a peripheral hospital by emergency by cesarean delivery, the indication being fetal distress. His birth weight was 2 kg. The baby cried immediately after birth. He was admitted to the NICU for respiratory distress and was discharged on breast feeds on the third postnatal day. The intrauterine growth retardation and the teratogenic effects of the antiepileptic drug were not considered by the health care providers at the peripheral hospital. Hence, no specific tests were done in the antenatal period.\n\nOn examination at our hospital, his weight was 1.5 kg and length 52 cm (below 5th centile for age and sex) suggestive of failure to thrive. On enquiry the mother gave a history of nasal regurgitation of milk since birth. Examination of the oral cavity revealed the presence of a cleft in the soft palate (Figure 1). Dysmorphic features were present in the form of low-set ears, a broad and depressed nasal bridge, long philtrum, upturned nose, thin upper lip, thick lower lip, thin vermillion borders, small mouth, and medial deficiency of eyebrows (Figure 2). Broad hands and feet, bilateral radial club hand, loose skin, bilateral inguinal hernia (Figure 3) were other features.\n\nFigure 1 Examination of the oral cavity showing isolated cleft of the secondary palate.\n\nFigure 2 Note low set ears, broad and depressed nasal bridge, long philtrum, upturned nose, thin upper lip, thick lower lip, thin vermillion border, small mouth, and medial deficiency of eyebrows.\n\nFigure 3 Bilateral radial club hand and broad hands, loose skin, bilateral inguinal hernia.\n\nTwo-dimensional echocardiography showed a persistent left superior vena cava draining into a dilated coronary sinus and mild pulmonary hypertension. Ultrasound of the abdomen showed no abnormality. With a history of maternal intake of sodium valproate during pregnancy and typical dysmorphic features, a diagnosis of fetal valproate syndrome (FVS) was made.\n\nDISCUSSION\nNone of the AEDs available currently are completely safe during pregnancy, but VPA appears to be the most teratogenic. In a study done by Morrow et al on the major congenital malformation (MCM) risks of antiepileptic drugs in pregnancy, the overall risk for all AED exposed cases was 4.2%. The MCM rate was higher for polytherapy than for monotherapy. Polytherapy regimens containing valproate had significantly more MCMs than those not containing valproate. For monotherapy exposures, carbamazepine was associated with the lowest risk of MCM and those exposed to more than 1000 mg of valproate had the highest MCM rate than for any other monotherapy exposure.2\n\nThere is also a controversy as to whether epilepsy itself contributes to antiepileptic drug teratogenecity, thus confounding the teratogenic risk of a drug used for its treatment. However VPA, and not the underlying epilepsy syndromes, has been found to be associated with the elevated risk for malformations in the drug exposed fetus.3 VPA is associated with the highest risk of birth defects, especially with doses exceeding 1000 mg/day.4 Various factors contribute to the teratogenecity of VPA. These include the number of antiepileptic drugs that are co-administered, drug dosage, differences in maternal and/or infant metabolism and the gestational age of the fetus at exposure.5 VPA crosses the placenta and is present in a higher concentration in the fetus than in the mother. There is a 6 to 7 times increased risk of congenital malformations in babies of mothers exposed to valproate. Major congenital malformations are neural tube defects, congenital heart defects, oral clefts, genital abnormalities and limb defects. Other less frequent abnormalities include inguinal and umblical hernia, supernumerary nipple, postaxial polydactyly, bifid ribs and pre-axial defects of the feet.6 Zinc deficiency has been suggested as a possible cause of neural tube defects associated with valproate exposure as sodium valproate readily binds to zinc.7 Our patient had the typical facial features, bilateral inguinal hernia, low birth weight, upper limb and cardiac malformation. A distinctive facial phenotype of fetal valproate syndrome has been described which tends to evolve with age. The facial features are tall forehead with bifrontal narrowing, medial deficiency of eyebrows, infraorbital groove, trigonocephaly, flat nasal bridge, broad nasal root, antiverted nares, shallow philtrum, epicanthic folds, long upper lip with thin vermillion borders, thick lower lip and small downturned mouth.5\n\nThere is a 10 times increased risk of neural tube defects in babies of mothers exposed to VPA. The risk is maximum with VPA therapy, as compared to other anticonvulsants. The incidence of congenital heart disease is estimated to be around 4 times than that seen in the general population.5 Aortic valve stenosis, secundum atrial septal defect, pulmonary atresia without ventricular septal defect, perimembranous ventricular septal defect, interrupted aortic arch, hypoplastic left heart syndrome septal defects and valvular problems are known to occur.6 Our case had left superior vena cava opening into a dilated coronary sinus.\n\nOral clefts are 5 times more frequent than expected. Limb defects, digital abnormalities of various types and minor skin defects are known to occur.5 The association of developmental delay with VPA exposure has also been described.5 Pregnancy usually proceeds uneventfully and 10% of babies are small-for-gestational age as in our patient. Postnatal growth appears to be normal and general health is good.3 Microcephaly tends to occur only in the infants who are also exposed to other anticonvulsants. Prenatal diagnosis is focused on the detection of neural tube defects (NTD), as they are the proven major malformations. Estimation of maternal serum alpha-fetoprotein (AFP) can be used as a screening test for the presence of open NTD.\n\nDuring pregnancy antiepileptic drugs should be administered as monotherapy and in the lowest possible dose with constant monitoring of serum concentration of antiepileptic drugs.8 VPA should not be routinely prescribed to women of child-bearing potential. If there is no effective alternative, then doses should be limited to a maximum of 1 gram per day, administered in divided doses and in the slow release form. Also high dose folic acid (5 mg/day) is recommended during pregnancy, starting at least 6 weeks pre-conception and continuing through the first trimester.8\n\nThe efficacy of VPA as an AED cannot be disputed, but the extent of its teratogenic effects cannot be under-estimated either. Hence, a balance between the therapeutic effects of this drug and its teratogenic effects is critical in the management of pregnant women with epilepsy.\n\nWe would like to thank Dr. Sandhya Kamath, dean of our institution for permitting us to publish this manuscript.\n==== Refs\nREFERENCES\n1 Kini U Fetal valproate syndrome: a review Paed Perinat Drug Ther 2006 7 123 130 \n2 Morrow J Russell A Guthrie E Parsons L Robertson I Waddell R Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register J Neurol Neurosurg Psychiatry 2006 77 193 198 16157661 \n3 Bromfield EB Dworetzky BA Wyszynski DF Smith CR Baldwin EJ Holmes LB Valproate teratogenecity and epilepsy syndrome Epilepsia 2008 49 2122 2124 18557775 \n4 Samren EB van Duijn CM Koch S Hiilesmaa VK Klepel H Bardy AH Maternal use of antiepileptic drugs and the risk of major congenital malformations: A joint European prospective study of human teratogenesis associated with maternal epilepsy Epilepsia 1997 38 981 990 9579936 \n5 Clayton-Smith J Donnai D Fetal valproate syndrome J Med Genet 1995 32 724 727 8544193 \n6 Jones KL Smith's recognizable patterns of human malformation 1997 5th ed Philadelphia WB Saunders Company 566 567 \n7 Hurd RW Wildes BJ Van Rinovelt HA Valproate, birth defects and zinc Lancet 1983 1 181 6130217 \n8 Crawford P Appleton R Betts T Best practice guidelines for the management of women with epilepsy. The Women with Epilepsy Guidelines Development Group Seizure 1999 8 201 217 10452918\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0256-4947",
"issue": "30(3)",
"journal": "Annals of Saudi medicine",
"keywords": null,
"medline_ta": "Ann Saudi Med",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000927:Anticonvulsants; D002493:Central Nervous System Diseases; D054326:Coronary Sinus; D019465:Craniofacial Abnormalities; D005145:Face; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D007223:Infant; D008297:Male; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D018570:Risk Assessment; D013577:Syndrome; D014635:Valproic Acid; D014683:Vena Cava, Superior",
"nlm_unique_id": "8507355",
"other_id": null,
"pages": "233-5",
"pmc": null,
"pmid": "20427941",
"pubdate": "2010",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18557775;8544193;9579936;10452918;16157661;6130217",
"title": "Fetal valproate syndrome in a 2-month-old male infant.",
"title_normalized": "fetal valproate syndrome in a 2 month old male infant"
} | [
{
"companynumb": "IN-MYLANLABS-2018M1058221",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VALPROIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "This study reports 35 cases of posttherapeutic acute leukemia and reviews the literature on this subject. These AL's are characterized by a high incidence of anemia, in particular refractory anemia, preceding the hematological disorder by several months, by the frequent finding of myelofibrosis, by the essentially granulocytic nature of the AL, and by the low rate of remission and the, in general, extremely short sruvival of a few months. These leukemias may develop following continuous chemotherapy with an alkylating agent, radiotherapy of various extent, or most commonly following intensive treatment with extensive irradiation and polychemotherapy as in the management of Hodgkin's disease. In view of these therapeutic hazards, the present objectives are the modification of alkylating agent therapy by the use of other drugs and sequential administration, and a reduction in the dose and field of irradiation and the duration of polychemotherapy, as in Hodgkin's disease; all present protocols are orientated in this direction.",
"affiliations": null,
"authors": "Auclerc|G|G|;Jacquillat|C|C|;Auclerc|M F|MF|;Weil|M|M|;Bernard|J|J|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "United States",
"delete": false,
"doi": "10.1002/1097-0142(197912)44:6<2017::aid-cncr2820440609>3.0.co;2-a",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-543X",
"issue": "44(6)",
"journal": "Cancer",
"keywords": null,
"medline_ta": "Cancer",
"mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D001172:Arthritis, Rheumatoid; D002648:Child; D002675:Child, Preschool; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D007938:Leukemia; D007945:Leukemia, Lymphoid; D007953:Leukemia, Radiation-Induced; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009369:Neoplasms; D009378:Neoplasms, Multiple Primary; D009404:Nephrotic Syndrome",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "2017-25",
"pmc": null,
"pmid": "389405",
"pubdate": "1979-12",
"publication_types": "D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.; D016454:Review",
"references": null,
"title": "Post-therapeutic acute leukemia.",
"title_normalized": "post therapeutic acute leukemia"
} | [
{
"companynumb": "FR-MYLANLABS-2018M1065791",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MECHLORETHAMINE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nAntibiotics have been implicated in the reactivation of exanthema and systemic involvement in drug reaction with eosinophilia and systemic symptoms (DRESS); however, it is not clear whether these patients become sensitized to the antibiotic.\n\n\nOBJECTIVE\nTo evaluate if, after DRESS, patients become sensitized to antibiotics.\n\n\nMETHODS\nWe retrospectively reviewed the patch test (PT) data and clinical files of DRESS patients who were administered antibiotics during DRESS from other culprits.\n\n\nRESULTS\nNine patients out of 17 (53%) were positive to antibiotics in PT: six to the penicillin group and three to cephalosporins (including one patient with additional positivity to vancomycin). Considering the eight patients who were negative to antibiotics in PT, seven were exposed to a fluoroquinolone. Four cases were patch tested again and three remained positive to antibiotics 2 to 5 years thereafter. Two patients with positive PT results had an accidental re-exposure to antibiotics and developed a maculopapular exanthema without systemic symptoms.\n\n\nCONCLUSIONS\nExposure to antibiotics during DRESS or its prodromal phase could enhance sensitization to antibiotics, as confirmed by a positive PT. Reproducibility of positive PTs to antibiotics after several years and reactivation after re-exposure support that T-cell-mediated hypersensitivity to antibiotics in the setting of DRESS is a specific reaction.",
"affiliations": "Department of Dermatology, Coimbra University Hospital, Coimbra, Portugal.;Department of Dermatology, Coimbra University Hospital, Coimbra, Portugal.;Department of Dermatology, Coimbra University Hospital, Coimbra, Portugal.;Department of Dermatology, Coimbra University Hospital, Coimbra, Portugal.",
"authors": "Santiago|Luis G|LG|https://orcid.org/0000-0003-2587-5535;Morgado|Francisca J|FJ|https://orcid.org/0000-0001-5006-4334;Baptista|Mariana S|MS|https://orcid.org/0000-0003-3442-615X;Gonçalo|Margarida|M|https://orcid.org/0000-0001-6842-1360",
"chemical_list": "D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D024841:Fluoroquinolones; D010406:Penicillins",
"country": "England",
"delete": false,
"doi": "10.1111/cod.13462",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0105-1873",
"issue": "82(5)",
"journal": "Contact dermatitis",
"keywords": "DRESS; antibiotics; cutaneous adverse drug reactions; hypersensitivity; neosensitization; patch test",
"medline_ta": "Contact Dermatitis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D002648:Child; D063926:Drug Hypersensitivity Syndrome; D005260:Female; D024841:Fluoroquinolones; D006801:Humans; D008297:Male; D008875:Middle Aged; D010406:Penicillins; D012189:Retrospective Studies",
"nlm_unique_id": "7604950",
"other_id": null,
"pages": "290-296",
"pmc": null,
"pmid": "31900951",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Hypersensitivity to antibiotics in drug reaction with eosinophilia and systemic symptoms (DRESS) from other culprits.",
"title_normalized": "hypersensitivity to antibiotics in drug reaction with eosinophilia and systemic symptoms dress from other culprits"
} | [
{
"companynumb": "PT-GLAXOSMITHKLINE-PT2020GSK029488",
"fulfillexpeditecriteria": "1",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMOXICILLIN"
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{
"abstract": "This is a rare case of a 55 year-old immunocompetent female who developed Methicillin sensitive Staphylococcus aureus sternoclavicular septic arthritis. The infection was not limited to the joint space but extended into adjacent bones and superior mediastinum. However the patient was successfully treated without surgical intervention and preservation of joint function was obtained with only intravenous antibiotic therapy.",
"affiliations": "Division of Infectious Diseases, University of Maryland School of Medicine, 725 West Lombard Street, Baltimore, MD, 21201, USA.",
"authors": "Doub|James B|JB|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2020.e01023",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509 Elsevier \n\nS2214-2509(20)30331-0\n10.1016/j.idcr.2020.e01023\ne01023\nCase Report\nA rare case of extensive Staphylococcus aureus sternoclavicular septic arthritis treated without surgical intervention\nDoub James B. Jdoub@ihv.umaryland.edu Division of Infectious Diseases, University of Maryland School of Medicine, 725 West Lombard Street, Baltimore, MD, 21201, USA\n09 12 2020 \n2021 \n09 12 2020 \n23 e0102315 7 2020 4 12 2020 5 12 2020 © 2020 The Author(s)2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).This is a rare case of a 55 year-old immunocompetent female who developed Methicillin sensitive Staphylococcus aureus sternoclavicular septic arthritis. The infection was not limited to the joint space but extended into adjacent bones and superior mediastinum. However the patient was successfully treated without surgical intervention and preservation of joint function was obtained with only intravenous antibiotic therapy.\n\nKeywords\nStaphylococcus aureusSeptic arthritisOsteomyelitisBacteremiaSternoclavicular joint\n==== Body\nIntroduction\nThe sternoclavicular (SC) joint is a mobile joint with significant movement and rotation abilities [1]. This joint functions similar to sacroiliac and pubic symphysis joints [1]. Septic arthritis of the SC joint is a rare form of septic arthritis occurring in less than 1% of all cases [2]. The most common risk factors are intravenous (IV) drug use, diabetes, immunosuppression and rheumatological diseases but approximately one-fifth of patients do not have any risk factors [2,3]. SC septic arthritis can occur from contiguous spread or hematogenous seeding of the joint. The majority of cases are hematogenous in etiology with Staphylococcus aureus being the most common pathogen [2,3].\n\nEarly diagnosis and treatment is required to prevent spread into the mediastinum, great vessels and thoracic cavity [3]. The most common treatment is surgical irrigation and debridement combined with antibiotic therapy [4,5]. More extensive surgical resection of the joint and clavicle head with reconstructive surgery have been advocated for extensive disease [[4], [5], [6]]. This case presents an unusual case of an immunocompetent female who developed extensive methicillin sensitive Staphylococcus aureus (MSSA) SC septic arthritis with extension to the adjacent ribs, clavicle and superior mediastinum. This was successfully treated without surgical intervention but rather with only IV oxacillin therapy and graded physical therapy.\n\nCase\nA 55 year-old healthy female with no significant past medical history was in her normal state of health until she started to have pain in her right clavicle. She was evaluated by her primary care physician who prescribed a nonsteroidal anti-inflammatory drug for pain management. However the pain, swelling and erythema intensified. She then presented to her local emergency room where a CT scan of the chest showed SC septic arthritis, osteomyelitis of the clavicle and 2nd rib and a superior mediastinal abscess. The patient was admitted to the local hospital and blood cultures and percutaneous aspiration of the abscess were obtained. She was started on IV vancomycin 1.25 g every 12 h and pipercillin/tazobactam 3.375 g every 6 h. Both blood and aspiration cultures grew MSSA. Antibiotics were subsequently changed to oxacillin 2 g IV every 4 h. After the 3rd dose the patient complained of severe burning in her peripheral vein and oxacillin was changed to cefazolin 2 g IV every 8 h. Unfortunately after 2 days on cefazolin she developed a diffuse rash and cefazolin was changed back to vancomycin 1.25 g IV every 12 h. Repeat blood cultures 2 days after starting intravenous antibiotics did not have any further bacterial growth and transthoracic echocardiogram did not show evidence of endocarditis. A peripheral inserted central catheter (PICC) was inserted and she was discharged home on IV vancomycin 1.25 g every 12 h with plan for 6 weeks of therapy.\n\nFor the next 5 days, she continued to have pain, swelling and erythema over her right sternoclavicular joint and therefore presented to the University of Maryland Medical Center for a second opinion. On physical exam, she had limited range of motion of her right upper extremity due to pain. CT scan of the chest with IV contrast showed SC septic arthritis, osteomyelitis of the clavicle head, adjacent ribs and inflammatory changes extending into superior mediastinum with a small superior mediastinal abscess (Fig. 1). Given the growth of MSSA on previous cultures, vancomycin was changed to IV oxacillin 2 g every 4 h through the PICC. Repeat transthoracic echocardiogram did not show evidence of endocarditis. Recommendation for surgical intervention with debridement of SC joint and probable resection of right clavicle head were discussed with the patient. However alternative treatment option was discussed which entailed IV oxacillin therapy and graded physical therapy with close clinical monitoring with plan for surgical intervention if improvement did not occur.Fig. 1 CT chest with axial images. A) Superior mediastinal abscess and developing anterior phlegmon without discrete abscess B) Right clavicular head osteomyelitis and right sternoclavicular septic arthritis joint.\n\nFig. 1\n\nThe patient elected to forgo surgical intervention and attempt salvage therapy with IV oxacillin and graded physical therapy. She tolerated IV oxacillin therapy with no burning and therefore was discharged home on IV oxacillin 2 g every 4 h via an infusion pump. Over the next 6 weeks she was followed in clinic every 2 weeks. Her swelling, erythema and pain slowly improved as well as her range of motion, which increased from 90 degrees to 150 degrees. Serum inflammatory markers (CRP and ESR) decreased over the course of therapy (Fig. 2). After 6 weeks of IV oxacillin therapy, the patient was changed to oral doxycycline 100 mg twice a day for an additional 4 weeks. During these 4 weeks the patient continued her graded physical therapy and she regained full range of motion of her right arm. She had no further swelling, erythema or pain over the SC joint and therefore antibiotics were stopped. She was followed clinically off antibiotics for 3 months and no clinical recurrence was seen. Workup for underlying immunodeficiency (CD4, complement, IgA, IgG, IgM, IgE, myeloperoxidase level, neutrophil function assay and leukocyte adhesion deficiency panel) did not reveal any underlying abnormalities. One year later the patient is back to her normal activities that include swimming and hiking with no limitations.Fig. 2 Trends of ESR and CRP over course of antibiotic therapy. Blue arrow indicates when IV oxacillin was started and Black arrow shows when oral doxycycline therapy was started and was continued until week 11 when all antibiotics were stopped. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).\n\nFig. 2\n\nDiscussion\nIn this case the patient had no known cause for her MSSA bacteremia. In fact she was a healthy, physically fit 55 year-old female. It is unknown how long she was bacteremic before presenting to the local hospital but after 48 h of intravenous antibiotics her blood cultures showed sterility. The patient was evaluated for underlying immunodeficiency but no deficiency was found. It is well known that risk factors associated with Staphylococcus bacteremia are IV drug use, long term intravenous access devices, immunodeficiency (especially neutrophil dysfunction), diabetes and chronic kidney disease [7]. However, in approximately 25 % of cases a cause of staphylococcus bacteremia is never found [7]. In this case, it is unknown why she developed MSSA bacteremia but the patient’s SC septic arthritis and associated adjacent infection was undoubtedly caused from hematogenous seeding of MSSA to these locations.\n\nHer treatment at the outside hospital was limited given the phlebitis that occurred with IV oxacillin use through a peripheral vein. It is unknown if this patient had mechanical or chemical phlebitis given administration was conducted at a local hospital. Oxacillin can be associated with phlebitis but with larger gauge catheters incidence can be less [8]. At the University of Maryland Medical center, she was challenged with oxacillin through her PICC and this was not associated with phlebitis suggesting that her phlebitis was likely secondary to mechanical inflammation and not chemical phlebitis from oxacillin. This reinforces that phlebitis is not an absolute contraindication to continued use of a medication but rather suggests needing to use alternative mitigation strategies such as diluting medication, slowing the rate of the infusion or using larger gauge catheter to prevent further inflammation of the vein [8]. In this case the local hospital did not try any of those measures, but rather changed her therapy to cefazolin which has similar efficacy to oxacillin in MSSA bacteremia [9]. However cefazolin caused her to have a diffuse rash and therefore the patient was discharged on IV vancomycin which has been shown to potentially be inferior to oxacillin or cefazolin for MSSA bacteremia [10].\n\nUnfortunately, the patient did not improve clinically while on IV vancomycin as seen with continued erythema, pain, swelling and loss of function forcing her to seek a second opinion. Imaging of the chest continued to show extensive SC septic arthritis with extension to adjacent ribs, clavicle head and posteriorly into superior mediastinum (Fig. 1). In this case only diagnostic aspiration of the superior mediastinal abscess was conducted. Given the extensive nature of her infection, surgical intervention was recommended and the need for resection of the clavicle head was discussed. Resection of the clavicle head can be associated with chronic pain and instability if the supporting ligamentous structures are damaged [6]. This patient was an active 55 year old female and she did not want to risk the chance of joint instability and permanent pain. Therefore she elected to attempt to salvage her SC joint with only IV oxacillin therapy and close clinical monitoring every 2 weeks with the plan to undergo surgical intervention if improvements with respect to her range of motion and symptomology did not occur. In SC septic arthritis with limited disease, antimicrobial therapy alone has been shown to be curative in case reports [11]. When extensive disease is present, as seen with extension into mediastinum or clavicular head, surgical intervention is almost universally recommended [[4], [5], [6]].\n\nIn this case, this patient had extensive infection beyond the SC joint but antimicrobial therapy alone was able to successfully treat her infection without surgical intervention. This was seen with the resolution of her clinical symptoms, normalization of inflammatory markers (Fig. 2) and the lack of clinical recurrence of her MSSA infection after 1 year of clinical follow up. It is well known that neutrophils play an important role staphylococcal infections [[12], [13], [14]]. Disease states (diabetes, chronic granulomatous disease and others) that inhibit neutrophil function predispose patients to staphylococcal infections (13). The patient in this case did not have an immunodeficiency or underlying medical problem that inhibited her innate immune response from functioning properly. Therefore her innate immune system was able to work in correlation with antibiotic therapy to clear her MSSA infection. However joint damage can occur when inflammatory cytokines, enzymes and bacterial toxins cause erosive damage of bone and cartilage resulting in permanent debility [15]. No such permanent changes occurred in her treatment course but her graded physical therapy regimen potentially allowed her to improve her range of motion and prevent permanent limited mobility. It should be noted that over the course of her therapy slow incremental improvements in range of function occurred. While this encouraged this patient, the lack of more immediate pronounced clinical improvements in range of motion may not be as well received in other patients. Potential prospective studies are warranted to evaluate if intravenous antimicrobial, physical therapy and close clinical follow up may prevent the need for surgical intervention in immunocompetent patients with SC septic arthritis. However given the rarity of this condition, such a study would need to be multicenter with a prolonged accrual period.\n\nIn conclusion, this patient was successfully treated for extensive SC joint septic arthritis with only antibiotic therapy. While this is a single case report it does suggest that aggressive intravenous antibiotic therapy in lieu of surgical intervention for SC septic arthritis in immunocompetent patients may be beneficial. Only prospective studies will be able to definitively determine if this approach has efficacy and potential to reduce medical costs, anesthesia risks and reduce potential long term ramifications of surgical interventions.\n\nFunding\nNone.\n\nConsent\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\nAuthor contribution\nDr. James Doub conducted the study design and writing of the manuscript.\n\nDeclaration of Competing Interest\nThe authors report no declarations of interest.\n==== Refs\nReferences\n1 Giphart J. Brunkhorst J. Horn N. Shelburne K. Torry M. Millet P. Effect of plane of arm elevation on glenohumeral kinematics: a normative biplane fluoroscopy study J Bone Joint Surg Am 95 February (3) 2013 238 245 23389787 \n2 Ross J. Shamsuddin H. Sternoclavicular septic arthritis: review of 180 cases Medicine (Baltimore) 83 May (3) 2004 139 148 15118542 \n3 Nusselt T. Klinger K.M. Freche S. Schultz W. Baums M. Surgical management of sternoclavicular septic arthritis Arch Orthop Trauma Surg 131 March (3) 2011 319 323 20721567 \n4 Szentkereszty Z. Pósán J. Petö K. Sápy P. Boros M. Takács I. Surgical management of sternoclavicular joint infections Magy Seb 60 January (1) 2007 514 517 17474306 \n5 Zentralbl Chir 140 October Suppl. 1 2015 S16 S21 10.1055/s-0034-1382922 Epub 2014 Nov 13 25393732 \n6 Rockwood C. Groh G. Wirth M. Grassi F. Resection arthroplasty of the sternoclavicular joint J Bone Joint Surg Am 79 March (3) 1997 387 393 9070528 \n7 Tong S. Davis J. Eichenberger E. Holland T. Fowler V. Jr. Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management Clin Microbiol Rev 28 July (3) 2015 603 661 26016486 \n8 Urbanetto J. Peixoto C. May T. Incidence of phlebitis associated with the use of peripheral IV catheter and following catheter removal Rev Lat Am Enfermagem 24 2016 e2746 27508916 \n9 Li J. Echevarria K. Hughes D. Cadena J. Bowling J. Lewis J. 2nd Comparison of Cefazolin versus oxacillin for treatment of complicated bacteremia caused by methicillin-susceptible Staphylococcus aureus Antimicrob Agents Chemother 58 August (9) 2014 5117 5124 24936596 \n10 Schweitzer M. Furono J. Harris A. Johnson J. Shardell M. McGregor J. Comparative effectiveness of nafcillin or cefazolin versus vancomycin in methicillin-susceptible Staphylococcus aureus bacteremia BMC Infect Dis 11 2011 279 22011388 \n11 Zanelli G. Sansoni S. Migliorini L. Donati E. Cellesi C. Sternoclavicular joint infection in an adult without predisposing risk factors Infez Med 11 June (2) 2003 105 107 15020856 \n12 Brandt S. Punam N. Cassat J. Serezani C. Innate immunity to Staphylococcus aureus: evolving paradigms in Soft tissue and invasive infections J Immunol 200 12 2018 3871 3880 29866769 \n13 Thammavongsa V. Kim H. Missiakas D. Schneewind O. Staphylococcal manipulation of host immune responses Nat Rev Microbiol 13 9 2015 529 543 26272408 \n14 András N. Surewaard B. Nijland R. van Strijp J. Neutrophils versus Staphylococcus aureus: a biological tug of war Annu Rev Microbiol 67 1 2013 629 650 23834243 \n15 Shirtliff M. Mader J. Acute septic arthritis Clin Microbiol Rev 15 October (4) 2002 527 544 12364368\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "23()",
"journal": "IDCases",
"keywords": "Bacteremia; Osteomyelitis; Septic arthritis; Staphylococcus aureus; Sternoclavicular joint",
"medline_ta": "IDCases",
"mesh_terms": null,
"nlm_unique_id": "101634540",
"other_id": null,
"pages": "e01023",
"pmc": null,
"pmid": "33364169",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "23834243;25393732;20721567;23389787;24936596;22011388;26272408;15020856;17474306;12364368;15118542;29866769;26016486;27508916;9070528",
"title": "A rare case of extensive Staphylococcus aureus sternoclavicular septic arthritis treated without surgical intervention.",
"title_normalized": "a rare case of extensive staphylococcus aureus sternoclavicular septic arthritis treated without surgical intervention"
} | [
{
"companynumb": "US-DRREDDYS-SPO/USA/21/0138900",
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"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CEFAZOLIN"
},
"drugadditional": null,
... |
{
"abstract": "A 44-year-old white man presented to the emergency department with a 3-day history of priapism requiring a surgically performed distal penile shunt. A drug-drug interaction is the suspected cause whereby CYP3A4 inhibition by boceprevir led to increased exposures of doxazosin, tamsulosin, and/or quetiapine, resulting in additional α-adrenergic blockade.",
"affiliations": "Department of Pharmaceutical Sciences.",
"authors": "Hammond|Kyle P|KP|;Nielsen|Craig|C|;Linnebur|Sunny A|SA|;Langness|Jacob A|JA|;Ray|Graham|G|;Maroni|Paul|P|;Kiser|Jennifer J|JJ|",
"chemical_list": "D000317:Adrenergic alpha-Antagonists; D065692:Cytochrome P-450 CYP3A Inhibitors; D011942:Receptors, Adrenergic, alpha; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; D011392:Proline; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/cit673",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "58(1)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "boceprevir; drug interaction; priapism; quetiapine; α-adrenergic",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000317:Adrenergic alpha-Antagonists; D000328:Adult; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D006801:Humans; D008297:Male; D011317:Priapism; D011392:Proline; D011942:Receptors, Adrenergic, alpha",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "e35-8",
"pmc": null,
"pmid": "24092799",
"pubdate": "2014-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21274367;15549140;10604360;1387254;21593761;2307732;21364331;12771780;16736396;23293300;17715207;21870309;22331658;16415722;19400856;23429642;18192961;16230163;20075651;20606815",
"title": "Priapism induced by boceprevir-CYP3A4 inhibition and α-adrenergic blockade: case report.",
"title_normalized": "priapism induced by boceprevir cyp3a4 inhibition and adrenergic blockade case report"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2019-09062",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"druga... |
{
"abstract": "Despite skilled palliative care, some dying patients experience distressing symptoms that cannot be adequately relieved. A patient with metastatic breast cancer, receiving high doses of opioids administered to relieve pain, developed myoclonus. After other approaches proved ineffective, palliative sedation was an option of last resort. The doctrine of double effect, the traditional justification for palliative sedation, permits physicians to provide high doses of opioids and sedatives to relieve suffering, provided that the intention is not to cause the patient's death and that certain other conditions are met. Such high doses are permissible even if the risk of hastening death is foreseen. Because intention plays a key role in this doctrine, clinicians must understand and document which actions are consistent with an intention to relieve symptoms rather than to hasten death. The patient or family should agree with plans for palliative sedation. The attending physician needs to explain to them, as well as to the medical and nursing staff, the details of care and the justification for palliative sedation. Because cases involving palliative sedation are emotionally stressful, the patient, family, and health care workers can all benefit from talking about the complex medical, ethical, and emotional issues they raise.",
"affiliations": "Program in Medical Ethics and the Division of General Internal Medicine in the Department of Medicine at the University of California San Francisco, USA. bernie@medicine.ucsf.edu",
"authors": "Lo|Bernard|B|;Rubenfeld|Gordon|G|",
"chemical_list": "D006993:Hypnotics and Sedatives",
"country": "United States",
"delete": false,
"doi": "10.1001/jama.294.14.1810",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0098-7484",
"issue": "294(14)",
"journal": "JAMA",
"keywords": "Death and Euthanasia",
"medline_ta": "JAMA",
"mesh_terms": "D016292:Conscious Sedation; D028601:Euthanasia, Active; D006801:Humans; D006993:Hypnotics and Sedatives; D009207:Myoclonus; D010148:Pain, Intractable; D010166:Palliative Care; D010817:Physician-Patient Relations; D013727:Terminal Care; D014474:Unconsciousness",
"nlm_unique_id": "7501160",
"other_id": "126820",
"pages": "1810-6",
"pmc": null,
"pmid": "16219885",
"pubdate": "2005-10-12",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Palliative sedation in dying patients: \"we turn to it when everything else hasn't worked\".",
"title_normalized": "palliative sedation in dying patients we turn to it when everything else hasn t worked"
} | [
{
"companynumb": "US-PFIZER INC-2020066014",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROMORPHONE HYDROCHLORIDE"
},
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{
"abstract": "OBJECTIVE\nTo report a case of aseptic meningitis induced by intramuscularly administered methotrexate in a patient with rheumatoid arthritis.\n\n\nMETHODS\nA 62-year-old male presented on 3 separate occasions with symptoms consistent with aseptic meningitis: 2 required hospitalization and 1 was noted during a subsequent ambulatory care visit. Prior to the first episode, the methotrexate dose ranged between 17.5 mg and 20 mg given once weekly over 5 years, 11 months. One month before the patient's first admission, the dose was increased to 22.5 mg. Symptoms on presentation included headache, neck stiffness, and fever. Cerebrospinal fluid testing indicated pleocytosis and low glucose level. Methotrexate was discontinued but was restarted 2 weeks after hospital discharge at the same dose and resulted in a second hospitalization for aseptic meningitis. Upon discharge from the second hospitalization, methotrexate was withheld. After a 2 month withdrawal period and rechallenge, the symptoms returned within 3 days. The drug was then discontinued.\n\n\nCONCLUSIONS\nMethotrexate-induced aseptic meningitis has been reported in the literature; however, in those cases, the effect occurred only when methotrexate was given via the intrathecal route. We identified 7 relevant articles via a search of MEDLINE, International Pharmaceutical Abstracts, and EMBASE (1970-August 3, 2007): 3 were review articles, 2 were case series, and 2 were case reports. All of the series and reports involved patients with leukemia. The available literature suggests that aseptic meningitis is associated with long-term use of methotrexate or recent dose escalation. A definitive mechanism for methotrexate-induced aseptic meningitis is not known. The Naranjo probability scale indicates a probable relationship between the development of the condition and the methotrexate use in our patient.\n\n\nCONCLUSIONS\nAseptic meningitis has been previously associated with intrathecal use of methotrexate. Our report describes the first case of aseptic meningitis that occurred in a patient being treated with intramuscular methotrexate.",
"affiliations": "School of Pharmacy, Health Sciences Centre, Department of Pharmacy, Eastern Health, St. John's, Newfoundland, Canada. hawboldt@mun.ca",
"authors": "Hawboldt|John|J|;Bader|Mazen|M|",
"chemical_list": "D018501:Antirheumatic Agents; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1345/aph.1K308",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "41(11)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D008582:Meningitis, Aseptic; D008727:Methotrexate; D008875:Middle Aged",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "1906-11",
"pmc": null,
"pmid": "17878395",
"pubdate": "2007-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intramuscular methotrexate-induced aseptic meningitis.",
"title_normalized": "intramuscular methotrexate induced aseptic meningitis"
} | [
{
"companynumb": "CA-FRESENIUS KABI-FK201703392",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "Babesiosis treatment failures with standard therapy have been reported, but the molecular mechanisms are not well understood. We describe the emergence of atovaquone and azithromycin resistance associated with mutations in the binding regions of the target proteins of both drugs during treatment of an immunosuppressed patient with relapsing babesiosis.",
"affiliations": "Department of Medicine, Division of Infectious Diseases.;Department of Pathology and Laboratory Medicine.;Department of Medicine, Division of Infectious Diseases.;Department of Microbiology and Immunology, and.;Department of Medicine, Division of Hematology Oncology, Weill Cornell Medicine,New York, New York; and.;Department of Pathology and Laboratory Medicine.;Mayo Clinic, Department of Laboratory Medicine and Pathology, Rochester, Minnesota.;Department of Medicine, Division of Infectious Diseases.",
"authors": "Simon|Matthew S|MS|;Westblade|Lars F|LF|;Dziedziech|Alexis|A|;Visone|Joseph E|JE|;Furman|Richard R|RR|;Jenkins|Stephen G|SG|;Schuetz|Audrey N|AN|;Kirkman|Laura A|LA|",
"chemical_list": "D000981:Antiprotozoal Agents; D000069283:Rituximab; D017963:Azithromycin; D053626:Atovaquone",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/cix477",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "65(7)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": null,
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000981:Antiprotozoal Agents; D053626:Atovaquone; D017963:Azithromycin; D041001:Babesia microti; D001404:Babesiosis; D004351:Drug Resistance; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D000069283:Rituximab",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "1222-1225",
"pmc": null,
"pmid": "28541469",
"pubdate": "2017-10-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "20047477;10802314;8780464;27572973;11850244;17110371;18181735;17029130;25280009;27036977;9815231;24893593;10898682;27115378;9664092",
"title": "Clinical and Molecular Evidence of Atovaquone and Azithromycin Resistance in Relapsed Babesia microti Infection Associated With Rituximab and Chronic Lymphocytic Leukemia.",
"title_normalized": "clinical and molecular evidence of atovaquone and azithromycin resistance in relapsed babesia microti infection associated with rituximab and chronic lymphocytic leukemia"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2017US-154338",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"druga... |
{
"abstract": "OBJECTIVE\nDescribe the occurring infections in patients treated with rituximab for an autoimmune disease.\n\n\nMETHODS\nRetrospective and monocentric study of 93 adult patients treated with rituximab for autoimmune indications over a nine years period.\n\n\nRESULTS\nThirty-eight patients suffered from a total of 95 infections. Out of them, 18 patients (19 %) had had at least an infectious episode triggering a hospital admission and/or intravenous treatment. The infections occurred mainly during the first year of the treatment (65 %) and if the courses are repeated (P=0.04). They were mainly pulmonary infections. Severe infections, recorded in 79 % of the cases, were mostly of bacterial origin (43 %) and viral (23 %). Two cases of pneumocystis pneumonia and one case of invasive pulmonary aspergillosis were also recorded. The notion of vaccination was present in less than half of the cases, and 39 % of the patients were already receiving a prophylactic treatment against pneumocystis pneumonia. Patients over the age of 65 years (40 %) had developed less infections (P<0.05). Eight of the initial 93 patients died, half of them because of infectious complications.\n\n\nCONCLUSIONS\nInfectious complications are frequent, become early and are potentially severe. Imputability to rituximab is not certain. However, this could lead to better codify rituximab prescriptions and take adapted and associated measures in order to facilitate infection prevention and, if an infection does occur, to treat it at the earliest stage possible. The age doesn't seem to be a risk factor.",
"affiliations": "Service de médecine interne et maladies infectieuses, université de Poitiers, CHU de Poitiers, 2, rue de la Milétrie, BP 577, 86021 Poitiers, France. Electronic address: catroux.melanie@gmail.com.;Service de médecine interne et maladies infectieuses, université de Poitiers, CHU de Poitiers, 2, rue de la Milétrie, BP 577, 86021 Poitiers, France.;Service de médecine interne et maladies infectieuses, université de Poitiers, CHU de Poitiers, 2, rue de la Milétrie, BP 577, 86021 Poitiers, France.;Pharmacie, CHU de Poitiers, 2, rue de la Milétrie, BP 577, 86021 Poitiers, France.;Service de médecine interne et maladies infectieuses, université de Poitiers, CHU de Poitiers, 2, rue de la Milétrie, BP 577, 86021 Poitiers, France.;Service de médecine interne et maladies infectieuses, université de Poitiers, CHU de Poitiers, 2, rue de la Milétrie, BP 577, 86021 Poitiers, France.;Service de médecine interne et maladies infectieuses, université de Poitiers, CHU de Poitiers, 2, rue de la Milétrie, BP 577, 86021 Poitiers, France.",
"authors": "Catroux|M|M|;Lauda-Maillen|M|M|;Pathe|M|M|;De Boisgrollier de Ruolz|A-C|AC|;Cazenave-Roblot|F|F|;Roblot|P|P|;Souchaud-Debouverie|O|O|",
"chemical_list": "D000069283:Rituximab",
"country": "France",
"delete": false,
"doi": "10.1016/j.revmed.2016.09.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0248-8663",
"issue": "38(3)",
"journal": "La Revue de medecine interne",
"keywords": "Autoimmune diseases; Elderly patients; Infections; Maladies auto-immunes; Patients âgés; Prophylaxie; Prophylaxis; Rituximab",
"medline_ta": "Rev Med Interne",
"mesh_terms": "D000328:Adult; D000368:Aged; D001327:Autoimmune Diseases; D003141:Communicable Diseases; D005260:Female; D005602:France; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D000069283:Rituximab",
"nlm_unique_id": "8101383",
"other_id": null,
"pages": "160-166",
"pmc": null,
"pmid": "27836224",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Infectious events during the course of autoimmune diseases treated with rituximab: A retrospective study of 93 cases.",
"title_normalized": "infectious events during the course of autoimmune diseases treated with rituximab a retrospective study of 93 cases"
} | [
{
"companynumb": "FR-ROCHE-1859615",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EVEROLIMUS"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Interstitial lung disease (ILD) is an adverse event which occurs also during targeted treatment of patients with metastatic renal cell carcinoma (mRCC). Experiences on ILD-management in mRCC remain limited. mRCC patients treated with everolimus, temsirolimus, or sunitinib at three centres from January 2006 until December 2009 were analysed, retrospectively. Medical records and imaging studies, as well as clinical course, the incidence, diagnostic measures, treatment, and outcome of ILD were assessed. Twenty-six ILD patients (11 %) were identified out of 237 mRCC patients. Median treatment until ILD-diagnosis was 3.8 (range: 1-21.5) months. The ILD-frequency was 2.7 % (n = 6/226) during sunitinib therapy and 19.8 % (n = 20/101) during m-TOR-inhibitor treatment. Cough was the prevailing symptom (69.2 %, n = 18). Bronchoalveolar lavage reviled often lymphocytic (42.9 %, n = 6/14) or eosinophilic cellularity (28.6 %, n = 4/14). Dose reduction (42.3 %, n = 11), treatment interruption (46.2 %, n = 12) or termination (23.1 %, n = 6), and steroid application (34.6 %, n = 9) were common measures in ILD. Interestingly, eosinophilic ILD required pulsed steroids. Improvement occurred in 73.7 % of symptomatic patients. Continuation of targeted therapies was warranted in 65.4 % of ILD patients. No patient died from ILD. ILD during targeted mRCC treatment is common, and supportive measures should be adapted to the clinical course, and potentially in dependence of BAL findings. Re-exposure to targeted therapies appears feasible.",
"affiliations": "Department of Haematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School Hannover, Carl-Neuberg Str. 1, 30625, Hannover, Germany.",
"authors": "Ivanyi|Philipp|P|;Fuehner|Thomas|T|;Adam|Meike|M|;Eichelberg|Christian|C|;Herrmann|Edwin|E|;Merseburger|Axel Stuart|AS|;Ganser|Arnold|A|;Grünwald|Viktor|V|",
"chemical_list": "D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; C401859:temsirolimus; D000068338:Everolimus; D000077210:Sunitinib; D020123:Sirolimus",
"country": "United States",
"delete": false,
"doi": "10.1007/s12032-014-0147-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1357-0560",
"issue": "31(9)",
"journal": "Medical oncology (Northwood, London, England)",
"keywords": null,
"medline_ta": "Med Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D002292:Carcinoma, Renal Cell; D000068338:Everolimus; D005260:Female; D006801:Humans; D007211:Indoles; D007680:Kidney Neoplasms; D017563:Lung Diseases, Interstitial; D008297:Male; D008875:Middle Aged; D011758:Pyrroles; D012189:Retrospective Studies; D012307:Risk Factors; D020123:Sirolimus; D000077210:Sunitinib",
"nlm_unique_id": "9435512",
"other_id": null,
"pages": "147",
"pmc": null,
"pmid": "25134914",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article",
"references": "19748725;17611248;24267730;21444868;16647451;21481584;22483544;16585664;19629201;16735708;17088586;18653228;20443009;16127266;16598305;19745764;11571438;15114088;11426655;24011786;24053120;22689175;19897274;20194812;3055113;21803569;16806903;19295254;24168290;21277078;17538086;17327610;10928875;24477650;23736025;24484452;17088579;19487381;18506191",
"title": "Interstitial lung disease during targeted therapy in metastatic renal cell carcinoma: a case series from three centres.",
"title_normalized": "interstitial lung disease during targeted therapy in metastatic renal cell carcinoma a case series from three centres"
} | [
{
"companynumb": "DE-PFIZER INC-2013269822",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SUNITINIB MALATE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nOthello syndrome (OS) is an organic delusional disorder with prevailing jealousy symptoms presumably appearing as side effect of antiparkinsonian therapy. The clinical spectrum of psychiatric symptoms in Parkinson's disease (PD) is very wide, including symptoms of depression and anxiety, hallucinations, delusions, with prevalent paranoid symptoms, agitation, delirium and sleep disorders. At our knowledge, just a few cases of patients with PD and OS were reported till now.\n\n\nMETHODS\nthree neurologists working in a tertiary referral centre were asked to report cases of pathological jealousy as defined by the DSM IV criteria (Kaplan et al. 1994). The following data were collected retrospectively: sex, age at PD onset, age at OS onset, duration of PD, duration of PD treatment, duration of treatment with dopamine agonists (DAs), treatment of OS, past history of alcoholism, premorbid personality disorder, family history of psychiatric disorders and data about general cognitive condition.\n\n\nRESULTS\nFive PD patients (three males) with OS were investigated. The mean age of the patients at the PD onset was 46.80+/-8.87 (SD), the mean age at the OS onset was 56.40+/-8.76 (SD). Before the onset of OS, all of them were taking dopamine agonists. The first patient was treated with pramipexole, apomorphine infusion and levodopa/carbidopa, the second with apomorphine infusion plus levodopa/carbidopa/entacapone, the third with pramipexole, the fourth and fifth with ropinirole. Decrease of dopamine agonist led to clinical improvement in three patients (complete reduction of the symptoms in two, reduction of symptoms in one patients). In two patients, the symptoms remained the same. In three patients atypical neuroleptics had to be added: clozapine in two and quetiapine in one patient.\n\n\nCONCLUSIONS\nWe believe that OS is a more common psychiatric side effect in PD patients on treatment with dopamine agonists than usually believed, particulary in those with early disease onset. It is a very disturbing symptom for patients and their partners, often underestimated by them, and should therefore be actively searched for.",
"affiliations": "Department of Neurology, University Medical Centre Ljubljana, Zaloska cesta 2, 1000 Ljubljana, Slovenia. georgievdejan@gmail.com",
"authors": "Georgiev|Dejan|D|;Danieli|Aljosa|A|;Ocepek|Lidija|L|;Novak|Dominika|D|;Zupancic-Kriznar|Nina|N|;Trost|Maja|M|;Pirtosek|Zvezdan|Z|",
"chemical_list": "D000978:Antiparkinson Agents; D014150:Antipsychotic Agents; D018491:Dopamine Agonists",
"country": "Croatia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0353-5053",
"issue": "22(1)",
"journal": "Psychiatria Danubina",
"keywords": null,
"medline_ta": "Psychiatr Danub",
"mesh_terms": "D000328:Adult; D017668:Age of Onset; D000368:Aged; D000978:Antiparkinson Agents; D014150:Antipsychotic Agents; D003430:Cross-Sectional Studies; D003702:Delusions; D039721:Diagnostic and Statistical Manual of Mental Disorders; D018491:Dopamine Agonists; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007578:Jealousy; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease; D011605:Psychoses, Substance-Induced; D012189:Retrospective Studies; D012307:Risk Factors; D017524:Slovenia; D013577:Syndrome",
"nlm_unique_id": "9424753",
"other_id": null,
"pages": "94-8",
"pmc": null,
"pmid": "20305599",
"pubdate": "2010-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Othello syndrome in patients with Parkinson's disease.",
"title_normalized": "othello syndrome in patients with parkinson s disease"
} | [
{
"companynumb": "SI-GLENMARK PHARMACEUTICALS INC, USA.-2015GMK017061",
"fulfillexpeditecriteria": "2",
"occurcountry": "SI",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PRAMIPEXOLE"
},
"dr... |
{
"abstract": "BACKGROUND\nLPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency categorized as common variable immunodeficiency associated with autoimmune manifestations and inflammatory bowel diseases; however, the clinical spectrum has been extended. Here, we present our cohort of Turkish LRBA-deficient patients from a single center, demonstrating a diversity of clinical manifestations.\n\n\nMETHODS\nSeven affected individuals from five families were assessed retrospectively in this study.\n\n\nRESULTS\nOf the seven patients with LRBA deficiency, four had homozygous, and two had compound heterozygous mutations. One patient remained disease free until the last follow-up (age 17 years). The most common clinical manifestations of the six symptomatic patients were organomegaly (6/6), autoimmunity (6/6), and chronic diarrhea (5/6). Recurrent infectious episodes were observed in three patients. None of the patients had hypogammaglobulinemia at presentation. B cell subpopulation analysis revealed low numbers of switched-memory B cell numbers in two of the four tested patients. During the disease course, three of the patients died, two of them underwent successful hematopoietic stem cell transplantation (HSCT) from matched sibling donors, and one is under abatacept therapy.\n\n\nCONCLUSIONS\nLRBA defects should always be kept in mind as a differential diagnosis for patients with autoimmune disease affecting multiple organs, chronic diarrhea, and organomegalies. In our experience, early HSCT is a life-saving therapeutic strategy.",
"affiliations": "Department of Pediatric Allergy and Immunology, Ankara University School of Medicine, Cebeci, 06590, Ankara, Turkey.;Department of Pediatric Allergy and Immunology, Ankara University School of Medicine, Cebeci, 06590, Ankara, Turkey.;Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.;Department of Pediatric Allergy and Immunology, Ankara University School of Medicine, Cebeci, 06590, Ankara, Turkey.;Department of Pediatric Immunology, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey.;Department of Pediatric Intensive Care, Ankara University School of Medicine, Ankara, Turkey.;Department of Pediatric Gastroenterology, Ankara University School of Medicine, Ankara, Turkey.;Department of Pediatric Oncology, Ankara University School of Medicine, Ankara, Turkey.;Department of Pediatric Gastroenterology, Gazi University School of Medicine, Ankara, Turkey.;Department of Pediatric Endocrinology, Ankara University School of Medicine, Ankara, Turkey.;Department of Pediatric Gastroenterology, Ankara University School of Medicine, Ankara, Turkey.;Department of Pathology, Ankara University School of Medicine, Ankara, Turkey.;Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.;Department of Pediatric Allergy and Immunology, Ankara University School of Medicine, Cebeci, 06590, Ankara, Turkey.;Department of Pediatric Allergy and Immunology, Ankara University School of Medicine, Cebeci, 06590, Ankara, Turkey. aydani@medicine.ankara.edu.tr.",
"authors": "Kostel Bal|Sevgi|S|http://orcid.org/0000-0002-3718-5323;Haskologlu|Sule|S|;Serwas|Nina K|NK|;Islamoglu|Candan|C|;Aytekin|Caner|C|;Kendirli|Tanil|T|;Kuloglu|Zarife|Z|;Yavuz|Gulsan|G|;Dalgic|Buket|B|;Siklar|Zeynep|Z|;Kansu|Aydan|A|;Ensari|Arzu|A|;Boztug|Kaan|K|;Dogu|Figen|F|;Ikinciogullari|Aydan|A|",
"chemical_list": "D048868:Adaptor Proteins, Signal Transducing; D007166:Immunosuppressive Agents; D000069594:Abatacept; C428703:LRBA protein, human",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10875-017-0446-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0271-9142",
"issue": "37(8)",
"journal": "Journal of clinical immunology",
"keywords": "ALPS; HSCT; LRBA deficiency; autoimmunity",
"medline_ta": "J Clin Immunol",
"mesh_terms": "D000069594:Abatacept; D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D001327:Autoimmune Diseases; D002648:Child; D017074:Common Variable Immunodeficiency; D018572:Disease-Free Survival; D017809:Fatal Outcome; D005260:Female; D006720:Homozygote; D006801:Humans; D007166:Immunosuppressive Agents; D007223:Infant; D015212:Inflammatory Bowel Diseases; D008297:Male; D009154:Mutation; D018805:Sepsis; D014421:Turkey",
"nlm_unique_id": "8102137",
"other_id": null,
"pages": "790-800",
"pmc": null,
"pmid": "28956255",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25769540;22721650;26768763;26445875;14929630;27057999;26745254;26206937;27418640;25539626;24161820;27146671;26686526;27004690;25931386;28502825;22981790;26707784;25479458;22608502",
"title": "Multiple Presentations of LRBA Deficiency: a Single-Center Experience.",
"title_normalized": "multiple presentations of lrba deficiency a single center experience"
} | [
{
"companynumb": "TR-AMGEN-USASP2017182422",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ROMIPLOSTIM"
},
"drugadditional": null,
... |
{
"abstract": "To describe an unusual complication on extracorporeal membrane oxygenation.\n\n\n\nClinical observation.\n\n\n\nCase report.\n\n\n\nRelevant clinical information.\n\n\n\nWe report the cases of three young patients who developed extensive myocardial calcifications on prolonged extracorporeal membrane oxygenation support for severe acute respiratory distress syndrome with septic cardiomyopathy, postresuscitation cardiogenic shock, and septic shock complicating severe acute respiratory distress syndrome, respectively. Extensive myocardial calcifications were confirmed by echocardiography, CT, and cardiac biopsy. The combination of multiple factors, for example, prolonged hemodynamic failure, profound acidosis, high vasopressor doses, and renal failure, may lead to this unusual and severe complication.\n\n\n\nIntensivists should be aware of this rare but rapid complication on extracorporeal membrane oxygenation support that may directly impact outcome. The precise role of extracorporeal membrane oxygenation support in the timing and frequency of new-onset diffuse myocardial calcification deserves further investigation.",
"affiliations": "Medical Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France.;Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMRS_1166-ICAN, Institute of Cardiometabolism and Nutrition, Paris, France.;Department of Anatomopathology, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France.;Medical Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France.;Medical Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France.;Medical Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France.;Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMRS_1166-ICAN, Institute of Cardiometabolism and Nutrition, Paris, France.;Medical Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France.;Medical Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France.",
"authors": "Kapandji|Natacha|N|;Redheuil|Alban|A|;Fouret|Pierre|P|;Hékimian|Guillaume|G|;Lebreton|Guillaume|G|;Bréchot|Nicolas|N|;Luyt|Charles-Edouard|CE|;Cluzel|Philippe|P|;Combes|Alain|A|;Schmidt|Matthieu|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/CCM.0000000000003130",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-3493",
"issue": "46(7)",
"journal": "Critical care medicine",
"keywords": null,
"medline_ta": "Crit Care Med",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D002114:Calcinosis; D009202:Cardiomyopathies; D016638:Critical Illness; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D006801:Humans; D008297:Male; D012128:Respiratory Distress Syndrome",
"nlm_unique_id": "0355501",
"other_id": null,
"pages": "e702-e706",
"pmc": null,
"pmid": "29570107",
"pubdate": "2018-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Extensive Myocardial Calcification in Critically Ill Patients.",
"title_normalized": "extensive myocardial calcification in critically ill patients"
} | [
{
"companynumb": "FR-PFIZER INC-2019477643",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOBUTAMINE HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "Methotrexate (MTX) is a chemotherapeutic synthetic(s) phase cell cycle inhibitor, and its role has evolved as an immunological agent in autoimmune diseases like rheumatoid arthritis, psoriasis, and systemic lupus erythematosus, etc. Trimethoprim-sulfamethoxazole (TS) is one of the most widely prescribed antibiotics commonly used for urinary tract infections, exacerbations of chronic bronchitis, traveler's diarrhea, and pneumocystis pneumonia. Both MTX and TS can have significantly overlapping side effects involving dermatologic, renal, and hematological systems, and the combination of these can be deadly. Our case is about the combination of MTX and TS that leads to mucocutaneous ulceration, leukopenia, and renal insufficiency. The purpose of this case is to increase awareness of potentially significant toxicity from the combination of MTX with TS. Abbreviations: MTX: methotrexate; TS: trimethoprim-sulfamethoxazole; ED: emergency department; IV: intravenous; GI: gastrointestinal; NSAIDs: nonsteroidal anti-inflammatory drugs.",
"affiliations": "Department of Internal Medicine, Abington Hospital-Jefferson Health, Abington, PA, USA.;Department of Internal Medicine, Abington Hospital-Jefferson Health, Abington, PA, USA.;Department of Internal Medicine, Abington Hospital-Jefferson Health, Abington, PA, USA.;Department of Internal Medicine, Abington Hospital-Jefferson Health, Abington, PA, USA.;Department of Internal Medicine, Abington Hospital-Jefferson Health, Abington, PA, USA.;Pulmonary and Critical Care, Abington Hospital-Jefferson Health, Abington, PA, USA.",
"authors": "Hamid|Mohsin|M|0000-0002-7105-4802;Lashari|Bilal|B|0000-0001-8257-7740;Ahsan|Irfan|I|0000-0002-1512-4925;Micaily|Ida|I|0000-0002-0871-7802;Sarwar|Usman|U|;Crocetti|Joseph|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/20009666.2018.1466598",
"fulltext": "\n==== Front\nJ Community Hosp Intern Med PerspectJ Community Hosp Intern Med PerspectZJCHzjch20Journal of Community Hospital Internal Medicine Perspectives2000-9666Taylor & Francis 146659810.1080/20009666.2018.1466598Case ReportA deadly prescription: combination of methotrexate and trimethoprim-sulfamethoxazole M. HAMID ET AL.JOURNAL OF COMMUNITY HOSPITAL INTERNAL MEDICINE PERSPECTIVEShttp://orcid.org/0000-0002-7105-4802Hamid Mohsin \na\nhttp://orcid.org/0000-0001-8257-7740Lashari Bilal \na\nhttp://orcid.org/0000-0002-1512-4925Ahsan Irfan \na\nhttp://orcid.org/0000-0002-0871-7802Micaily Ida \na\nSarwar Usman \na\nCrocetti Joseph \nb\n\na \nDepartment of Internal Medicine, Abington Hospital–Jefferson Health, Abington, PA, USA\n\nb \nPulmonary and Critical Care, Abington Hospital–Jefferson Health, Abington, PA, USA\nCONTACT Mohsin Hamid mohsin.hamid@jefferson.eduDepartment of Internal Medicine, Abington Hospital–Jefferson Health, 1200 Old York Road, Abington, PA19001, USAAll authors contributed significantly to this article.\n\n2018 12 6 2018 8 3 149 151 27 1 2018 12 4 2018 © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.2018The Author(s)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.ABSTRACT\nMethotrexate (MTX) is a chemotherapeutic synthetic(s) phase cell cycle inhibitor, and its role has evolved as an immunological agent in autoimmune diseases like rheumatoid arthritis, psoriasis, and systemic lupus erythematosus, etc. Trimethoprim-sulfamethoxazole (TS) is one of the most widely prescribed antibiotics commonly used for urinary tract infections, exacerbations of chronic bronchitis, traveler’s diarrhea, and pneumocystis pneumonia. Both MTX and TS can have significantly overlapping side effects involving dermatologic, renal, and hematological systems, and the combination of these can be deadly. Our case is about the combination of MTX and TS that leads to mucocutaneous ulceration, leukopenia, and renal insufficiency. The purpose of this case is to increase awareness of potentially significant toxicity from the combination of MTX with TS.\n\n\nAbbreviations: MTX: methotrexate; TS: trimethoprim-sulfamethoxazole; ED: emergency department; IV: intravenous; GI: gastrointestinal; NSAIDs: nonsteroidal anti-inflammatory drugs.\n\nKEYWORDS\nMethotrexatetrimethoprim-sulfamethoxazoledeadly drug interactionfolinic acid rescuepancytopeniaNo funding sourceNo funding source involved.\n==== Body\n1. Introduction\nMethotrexate (MTX) is a chemotherapeutic synthetic(s) phase cell cycle-specific inhibitor that preferentially targets actively proliferating tissues. It irreversibly binds and inhibits dihydrofolate reductase enzyme and impairs the ability of the DNA to replicate. Being the first chemotherapeutic agent shown to have a response in cancer treatment, it changed the world of chemotherapy as we know it and led to the development of many standard cancer treatments used today [1-3]. The role of MTX has evolved as an immunological agent in autoimmune diseases such as rheumatoid arthritis, psoriasis, and systemic lupus erythematosus, etc. The most common adverse effects include gastrointestinal (GI) upset, stomatitis, rash, neurological symptoms (headache, fatigue, agitation), mild transaminitis, and macrocytosis [4]. As an immunological agent, lower doses are used; however, toxicities can still occur due to interactions with other medications or impairments in renal and hepatic metabolism.\n\nTrimethoprim-sulfamethoxazole (TS) is one of the most widely prescribed antibiotic medications and works as a bacteriostatic antimicrobial by inhibiting sequential enzymes in the folic acid pathway. Sulfamethoxazole blocks the formation of dihydrofolic acid from its precursors, and trimethoprim blocks the reduction of dihydrofolate into tetrahydrofolate. It is commonly used for conditions such as urinary tract infections, exacerbations of chronic bronchitis, traveler’s diarrhea, and pneumocystis pneumonia. Its potential toxicities include nephrotoxicity, hyperkalemia, pancytopenia, neutropenia, skin rash, and Steven Johnson’s syndrome many of which overlap with the toxicity of MTX [5]. We are presenting this case to increase awareness of the potentially significant toxicity of MTX due to its interaction TS.\n\n2. Case presentation\nA 68-year-old female with a history of rheumatoid arthritis on 10 mg MTX weekly presented to the emergency department (ED) with weakness, lethargy, and decreased oral intake. Two weeks prior to presentation, her primary care physician (PCP) prescribed a 2-week course of TS for presumed bacterial skin infection under her left breast. One week after starting therapy, she noticed painful oral sores and flu-like symptoms. In the ED, she was hypotensive to 90/60 mm Hg but responded to intravenous (IV) fluids. Vital signs were otherwise stable. The pertinent physical exam included severe oral mucositis, lip ulceration, and an erythematous rash under her left breast. Laboratory data revealed creatinine: 2.39 mg/dl (baseline 0.7 mg/dL), potassium: 5.3 mEq/L, chloride: 97 mEq/L, leukocyte count: 3.2 K/uL, absolute neutrophil count: 2.8 K/uL, hemoglobin: 12.3 mg/dL, and platelet count: 230 K/uL. TS was held as the symptoms of mucocutaneous ulceration, leukopenia, and renal insufficiency were initially attributed to possible TS toxicity and supportive care with IV fluids and oral care was given. Her oral ulcers remained unresolved; leukocyte count continued to drop reaching a nadir of 1.9 K/uL and absolute neutrophil count dipped to 0.7 K/uL over the course of next 2 days. Renal function, however, improved with IV hydration. After consultation with hematology, a careful review of patient’s medications list and drug interactions were done, and her symptoms were attributed to MTX–TS interaction leading to MTX toxicity rather than toxicity of TS itself. MTX levels were sent that came back high at 0.5 µmol/L. Leucovorin rescue was given at the dose of 10 mg/m2 every 6 h for a total of four doses with one dose of Filgrastim 480 mcg which resulted in the improvement of the leukocyte count, breast rash, and mouth ulcers within 24 h. The patient was discharged on day 6 of hospitalization and did well post discharge.\n\n3. Discussion\nThe first serious interaction between TS and MTX was reported in 1986 by Thomas [6]. Since then, numerous case reports and observational studies have been published but the combination is still prescribed and in many instances has led to fatal consequences [7,8].\n\nAfter oral administration, MTX is absorbed quickly, the kidneys excrete 80–90% and liver enzymes metabolize the rest. A positive correlation has been noticed between MTX clearance and creatinine clearance and hence abnormal renal function can precipitate MTX toxicity. After filtration by glomeruli, it undergoes both secretion and reabsorption and competes with other drugs during this process. It accumulates in third spaces such as pleura and peritoneum and is eliminated slowly from these spaces as compared to plasma, and the dosage needs to be readjusted in these situations. The primary metabolite is 90% bound to plasma proteins and therefore can have extensive drug interactions. Most commonly co-prescribed drugs with MTX are steroids, aspirin (ASA), and nonsteroidal anti-inflammatory drugs (NSAIDs). Steroids have been shown to be safe with MTX. NSAIDs and high dose ASA decrease the renal excretion of MTX and increase its plasma concentration. However, a systematic review found that concurrent use of most NSAIDs with MTX is safe, yet, anti-inflammatory doses of ASA should not be used with MTX [9]. Folate has been shown to reduce the toxicity of MTX especially GI and liver toxicity without affecting the efficacy of MTX through unknown mechanisms [10,11].\n\nMultiple case reports and other observational studies have noted severe interaction between MTX and TS [6–8,9,12–19]. When used together, TS can increase MTX’s toxicity. Although the exact mechanism is unknown, synergistic folate antagonism, competitive tubular secretion, and displacement from albumin binding site might explain it [8,20–22]. One study pointed out an increase of about 60% of free MTX concentration in blood when used concurrently with TS [15]. The most commonly reported toxicity of MTX due to its interaction with TS is pancytopenia, acute megaloblastic anemia, stomatitis, and nephrotoxicity [19]. Other case reports have also shown rare side effects such as toxic epidermal necrolysis [23]. Care should be taken not to confuse toxicity of MTX with TS as TS has similar side effect profile namely nephrotoxicity, pancytopenia, and Steven Johnson’s syndrome. In the case of possible MTX toxicity, serum levels should be checked and if found to be high, aggressive IV hydration, urinary alkalization, and folinic acid rescue should be initiated. Therapy should be continued until the MTX dose levels have dropped to 0.05–0.1 µmol/L or less.\n\nIt has however been noticed that prophylactic dose of TS does not have any significant interaction when used concurrently with MTX and can be co-prescribed safely.\n\nMedical health professional needs to be aware of the differences between the toxicity of MTX and TS and their potential interaction so that they will not falsely attribute the toxicity of MTX to TS.\n\n4. Conclusion\nWith the available current literature, it is prudent to say that the combination of MTX and TS should be avoided, as it can lead to significant morbidity and possibly mortality. To prevent this combination, primary care doctors need to be educated about this deadly combination as the prescription of TS in outpatient clinics usually bypasses the pharmacy-based safety checkpoints. The patients taking MTX should be instructed about the potential side effects and interactions so that prompt identification and discontinuation can be done to prevent serious harm.\n\nDisclosure statement\nNo potential conflict of interest was reported by the authors.\n==== Refs\nReferences\n[1] \nFarber S , Diamond LK , Mercer RD , et al \nTemporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid (aminopterin) . New England J Med . 1948 ;238 (23 ):787 –793 .18860765 \n[2] \nYarris JP , Hunter AJ , Roy Hertz MD. \n(1909-2002): the cure of choriocarcinoma and its impact on the development of chemotherapy for cancer . Gynecol Oncol . 2003 ;89 (2 ):193 –198 .12765173 \n[3] \nBleyer WA \nMethotrexate: clinical pharmacology, current status and therapeutic guidelines . Cancer Treat Rev . 1977 ;4 (2 ):87 –101 .329989 \n[4] \nAttar SM \nAdverse effects of low dose methotrexate in rheumatoid arthritis patients. A hospital-based study . Saudi Med J . 2010 ;31 (8 ):909 –915 .20714691 \n[5] \nHo JM , Juurlink DN \nConsiderations when prescribing trimethoprim-sulfamethoxazole . CMAJ . 2011 ;183 (16 ):1851 .21989472 \n[6] \nThomas MH , Gutterman LA \nMethotrexate toxicity in a patient receiving trimethoprim-sulfamethoxazole . J Rheumatol . 1986 ;13 (2 ):440 –441 .3487652 \n[7] \nSteuer A , Gumpel JM \nMethotrexate and trimethoprim: a fatal interaction . Br J Rheumatol . 1998 ;37 (1 ):105 –106 .9487262 \n[8] \nGroenendal H , Fhj RAMPEN \nMethotrexate and trimethoprim-sulfamethoxazole–a potentially hazardous combination . Clin Exp Dermatol . 1990 ;15 (5 ):358 –360 .2225539 \n[9] \nKatchamart W , Bourré-Tessier J , Donka T , et al \nCanadian recommendations for use of methotrexate in patients with rheumatoid arthritis . J Rheumatol . 2010 ;37 (7 ): 1422 –1430 .20516029 \n[10] \nShiroky JB , Neville C , Esdaile JM , et al \nLow-dose methotrexate with leucovorin (folinic acid) in the management of rheumatoid arthritis. Results of a multicenter randomized, double-blind, placebo-controlled trial . Arthritis Rheum . 1993 ;36 (6 ):795 –803 .8507221 \n[11] \nStrober BE , Menon K \nFolate supplementation during methotrexate therapy for patients with psoriasis . J Am Acad Dermatol . 2005 ;53 (4 ):652 –659 .16198787 \n[12] \nChevrel G , Brantus JF , Sainte-Laudy J , et al \nAllergic pancytopenia to trimethoprim-sulphamethoxazole for Pneumocystis carinii pneumonia following methotrexate treatment for rheumatoid arthritis . Rheumatology (Oxford, England) . 1999 ;38 (5 ):475 –476 .\n[13] \nThomas DR , Dover JS , Camp RD \nPancytopenia induced by the interaction between methotrexate and trimethoprim-sulfamethoxazole . J Am Acad Dermatol . 1987 ;17 (6 ):1055 –1056 .3501437 \n[14] \nNg HW , Macfarlane AW , Graham RM , et al \nNear fatal drug interactions with methotrexate given for psoriasis . BMJ . 1987 ;295 (6601 ):752 –753 .3119023 \n[15] \nFerrazzini G , Klein J , Sulh H , et al \nInteraction between trimethoprim-sulfamethoxazole and methotrexate in children with leukemia . J Pediatr . 1990 ;117 (5 ):823 –826 .2231218 \n[16] \nMaricic M , Davis M , Gall EP \nMegaloblastic pancytopenia in a patient receiving concurrent methotrexate and trimethoprim-sulfamethoxazole treatment . Arthritis Rheum . 1986 ;29 (1 ):133 –135 .3484954 \n[17] \nFrain JB \nMethotrexate toxicity in a patient receiving trimethoprim-sulfamethoxazole . J Rheumatol . 1987 ;14 (1 ):176 –177 .3494846 \n[18] \nDan M , Shapira I \nPossible role of methotrexate in trimethoprim-sulfamethoxazole-induced acute megaloblastic anemia . Isr J Med Sci . 1984 ;20 (3 ):262 –263 .6724876 \n[19] \nBourre-Tessier J , Haraoui B \nMethotrexate drug interactions in the treatment of rheumatoid arthritis: a systematic review . J Rheumatol . 2010 ;37 (7 ):1416 –1421 .20436072 \n[20] \nBannwarth B , Pehourcq F , Schaeverbeke T , et al \nClinical pharmacokinetics of low-dose pulse methotrexate in rheumatoid arthritis . Clin Pharmacokinet . 1996 ;30 (3 ):194 –210 .8882301 \n[21] \nBartha P , Bron R , Levy Y \n[Fatal pancytopenia and methotrexate-trimethoprim-sulfamethoxazole interaction] . Harefuah . 2004 ;143 (6 ):400, 464 .\n[22] \nFranck H , Rau R , Herborn G \nThrombocytopenia in patients with rheumatoid arthritis on long-term treatment with low dose methotrexate . Clin Rheumatol . 1996 ;15 (3 ):266 –270 .8793258 \n[23] \nYang CH , Yang LJ , Jaing TH , et al \nToxic epidermal necrolysis following combination of methotrexate and trimethoprim-sulfamethoxazole . Int J Dermatol . 2000 ;39 (8 ):621 –623 .10971734\n\n",
"fulltext_license": "CC BY",
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"issue": "8(3)",
"journal": "Journal of community hospital internal medicine perspectives",
"keywords": "Methotrexate; deadly drug interaction; folinic acid rescue; pancytopenia; trimethoprim-sulfamethoxazole",
"medline_ta": "J Community Hosp Intern Med Perspect",
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"nlm_unique_id": "101601396",
"other_id": null,
"pages": "149-151",
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"references": "8882301;3487652;20436072;18860765;16198787;8793258;6724876;3501437;15524092;3119023;3484954;20516029;21989472;10371291;9487262;8507221;12765173;2231218;3494846;329989;10971734;2225539;20714691",
"title": "A deadly prescription: combination of methotrexate and trimethoprim-sulfamethoxazole.",
"title_normalized": "a deadly prescription combination of methotrexate and trimethoprim sulfamethoxazole"
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"abstract": "Capgras Syndrome is a subcategory of delusional disorder. People affected by this syndrome believe that a close associate such as a friend or family member has been replaced by an identical imposter. This case report describes a 23-year-old woman with no prior psychiatric history, whom developed Capgras syndrome, via folie a deux, in the setting of poly-substance use. In this patient, a combination of Aripiprazole 10 mg daily and Escitalopram 10 mg daily were effective in resolving symptoms. Clonazepam was utilized for anxiety and Omega-3 fatty acids 1 g for anti-oxidative effects. Further studies are needed to investigate the effects of a variety of causes and treatments for Capgras Syndrome.",
"affiliations": "University of California Irvine, Orange, CA, USA.;University of California Irvine, Orange, CA, USA.;University of California Irvine, Orange, CA, USA.;University of California Irvine, Orange, CA, USA.",
"authors": "Sampathi|Bharat R|BR|;Sofine|Anna|A|;Alvarez|John|J|;Bota|Robert|R|",
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"fulltext": "\n==== Front\nMent IllnMIMental Illness2036-74572036-7465PAGEPress Publications, Pavia, Italy 10.4081/mi.2018.7807Case ReportCapgras syndrome in substance-induced psychosis Sampathi Bharat R. Sofine Anna Alvarez John Bota Robert University of California Irvine, Orange, CA, USADepartment of Psychiatry, University of California Irvine, 101 City Drive Orange, CA 92617, USA. +1.229.815.0219 - +1.714.456.2056. rgbota@yahoo.comContributions: the authors contributed equally.\n\nConflict of interest: the authors declare no potential conflict of interest.\n\n06 11 2018 06 11 2018 10 2 780702 8 2018 02 8 2018 ©Copyright B.R. Sampathi et al., 20182018Licensee PAGEPress, ItalyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Capgras Syndrome is a subcategory of delusional disorder. People affected by this syndrome believe that a close associate such as a friend or family member has been replaced by an identical imposter. This case report describes a 23-year-old woman with no prior psychiatric history, whom developed Capgras syndrome, via folie a deux, in the setting of poly-substance use. In this patient, a combination of Aripiprazole 10 mg daily and Escitalopram 10 mg daily were effective in resolving symptoms. Clonazepam was utilized for anxiety and Omega-3 fatty acids 1 g for anti-oxidative effects. Further studies are needed to investigate the effects of a variety of causes and treatments for Capgras Syndrome.\n\nKey words\nCapgras Syndromeneurological and neurodegenerative diseasessubstanceinduced psychosisFunding: none.\n==== Body\nIntroduction\nDelusional disorder refers to a condition in which an individual presents false beliefs, despite overwhelming counterevidence and improbability. Specifically, one must have one or more delusions for at least one month while failing to meet criteria for schizophrenia or any other psychotic disorder. Other than the direct impact of the delusion, behaviors are not bizarre or odd and functioning is usually uncompromised. A subcategory exists within delusional disorder known as a Capgras Syndrome. A person affected with this syndrome will believe that a close associate such as a friend or family member has been replaced by an identical imposter.\n\nMultiple studies and reports have commented on Capgras Syndrome in the setting of various neurological and neurodegenerative diseases. A 2014 study found it to be prevalent in first-episode psychotic disorders (schizophreniform psychosis 50%, brief psychosis 34.8%, or unspecified psychosis 23.9%).1 Another study determined that Electroconvulsive therapy followed by mood-stabilizer and antipsychotic drug combination led to the permanent, effective control of long-standing Capgras in young women.2 For the overarching delusion disorder, the most studied first-line treatment regimen involves a combination of second generation antipsychotics and psychotherapy. It has also been emphasized that comorbid conditions such as anxiety, depression, and substance abuse must be simultaneously treated.\n\nInduced delusional disorder, as named in ICD-10, or Folie a deux, also known as shared psychotic disorder in DSM-IV, which has been removed from DSM-V, is described as a phenomenon seen when a delusional belief is transmitted from one individual to another.3 This type of delusion is rare and is mostly described via case reports. Some reported risk factors developing a delusion are female gender, suggestibility, suspiciousness, and passivity.4\n\nThis case report describes a patient with no prior psychiatric history whom developed Capgras Syndrome, via folie a deux, in the setting of poly-substance use.\n\nCase Report\nA 23-year-old female with no previous psychiatric diagnosis presented to the emergency department (ED) brought in by mother for extremely agitated behavior. Upon interview, patient endorsed methamphetamine and marijuana use the prior night as well as attending a music festival a week prior where she used cocaine and multiple forms of 3,4-Methylenedioxyme-thamphetamine (MDMA). She mentioned that she had not gotten any sleep the previous night and usually sleeps 8 hours per night. She was dysphoric, paranoid, endorsed auditory hallucinations, and demonstrated extreme suspicion of the family pictures on the walls of her parent’s home. She repeatedly told her mother that “the pictures are not real”, and directly referred to her family as imposters. Patient endorsed symptoms of depression over the past six months, but denied low energy, lack of sleep, poor concentration, guilt, or change in appetite. After stating that she would shoot herself if she had a gun due to paranoia about her family being imposters she was ultimately admitted voluntarily due to high risk for imminent suicide with significant risk factors including recent drug use, impulsivity, disconnect from reality due to psychosis, and current suicidal ideation.\n\nShe was started on Aripiprazole 10 mg daily for psychosis and Clonazepam 0.5 mg twice a day as needed for anxiety. Over the course of several days insight and judgement improved and she appeared more linear and logical, able to attribute her polysubstance abuse as a probable instigator to her psychosis. As she continued to endorse intermittent suicidal ideations, Escitalopram 10 mg daily for depression and Omega-3 fatty acids 1g daily for mood were added. Clonazepam was discontinued over the next few days.\n\nShe then endorsed that the night prior to admission; she had visited a bar and met a man whom she later accompanied home. At his home, the patient used marijuana and methamphetamine after which the man became paranoid and showed the patient a picture of him on his phone and stating that the picture was not him. Rather, it was an imposter who had been following him. She then became paranoid regarding imposters of both herself and her family. When she returned home, she was immediately suspicious of her mom and believed the pictures on the wall were all “fake.” It took several days of Aripiprazole and daily visits from close family members to assuaged her concerns that her family members were imposters and that the home pictures were “fake”. As her paranoia resolved she became pleasant and appropriately engaging. Her suicidal ideation resolved over several days, prior to the timeline which Escitalopram would have played much of a therapeutic role. Therefore, it is probable that suicidal ideation was an indirect result of acute psychosis as well. Within a week, she was found to no longer be a danger to self, danger to others, or gravely disabled, and was discharged home.\n\nDiscussion and Conclusions\nThere are limited studies on the efficacy of treatments for Capgras syndrome. In this patient, a combination of Aripiprazole 10 mg daily and Escitalopram 10 mg daily were effective in resolving symptoms. Clonazepam was utilized for anxiety and Omega-3 fatty acids 1g for anti-oxidative effects.\n\nOur team determined the most likely provocation of her Capgras syndrome was polysubstance use with resulting paranoia. She mentioned her paranoia was acutely exacerbated when the stranger she was with questioned the validity of his own picture of himself. She then became highly suspicious of her mom and the family pictures at her home, via what appears to have been a folie a deux response. While it has been documented that second-generation antipsychotics have been effective in treating delusional disorder, it is unclear whether this patient’s resolution of Capgras Syndrome was a result of the elimination of THC and methamphetamine from her body or the effect of Aripiprazole. It is postulated that a combination was required to elicit such profound dislodging of the fixed Capgras delusion. It is likely that recidivism of substance would result in relapse of symptoms. Further studies may investigate the effects of a variety of causes and treatments for Capgras Syndrome.\n==== Refs\nReferences\n1. Salvatore P Bhuvaneswar C Tohen M \nCapgras’ syndrome in first-episode psychotic disorders . Psychopathology \n2014 ;47 :261 -9 .24516070 \n2. Rapinesi C Kotzalidis GD Del Casale A \nTreatment-resistant, five-year long, postpartum-onset Capgras episode resolving after electroconvulsive therapy . Int J Psychiatry Med \n2015 ;49 :227 -34 .25926594 \n3. Dewhurst K Todd J. \nThe psychosis of association--folie a deux . J Nerv Ment Dis \n1956 ;124 :451 -9 .13463598 \n4. Jolfaei AG Isfahani MN Bidaki R. \nFolie à deux and delusional disorder by proxy in a family . J Res Med Sci \n2011 ;16 : S453 -5 .22247734\n\n",
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"issue": "10(2)",
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"keywords": "Capgras Syndrome; neurological and neurodegenerative diseases; substanceinduced psychosis",
"medline_ta": "Ment Illn",
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"pubdate": "2018-11-06",
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"title": "Capgras syndrome in substance-induced psychosis.",
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"abstract": "The purpose of the study was to assess the efficacy and safety of transition from ranibizumab to aflibercept intravitreal injections in treatment-resistant retinal pigment epithelial detachment (PED). The data of intravitreal ranibizumab treatment-resistant patients who have been switched to aflibercept treatment were reviewed retrospectively. After three monthly injections, bimonthly regimen was performed. The changes of PED height and radius, and the best-corrected visual acuity (BCVA) were analyzed retrospectively. Mean baseline PED height decreased from 297 ± 151 to 122 ± 42 µm at month 12 (P = 0.0007). Mean baseline PED radius decreased from 2371 ± 882 to 1859 ± 779 µm at month 12 (P = 0.0007). No complete PED resolution occurred in any of the patients at the end of the 12 months. Baseline BCVA improved from 0.63 ± 0.21 to 0.43 ± 0.17 logMar at month 12 (P = 0.0049). Mean BCVA gain was 1.4 decimal chart lines (7 letters) at month 12. Switching to aflibercept seems to have promising functional and anatomical outcomes with a reasonable complication rate in treatment-resistant PED.",
"affiliations": "Ophthalmology Department, Medipol University, Bagcılar, Istanbul, Turkey. ibrahimkocak@msn.com.",
"authors": "Kocak|Ibrahim|I|http://orcid.org/0000-0003-4683-8346",
"chemical_list": "D020533:Angiogenesis Inhibitors; D011993:Recombinant Fusion Proteins; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor; D000069579:Ranibizumab",
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"keywords": "Aflibercept; Age-related macular degeneration; Pigment epithelial detachment; VEGF trap",
"medline_ta": "Int Ophthalmol",
"mesh_terms": "D000368:Aged; D020533:Angiogenesis Inhibitors; D004351:Drug Resistance; D005260:Female; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D005654:Fundus Oculi; D006801:Humans; D058449:Intravitreal Injections; D008297:Male; D000069579:Ranibizumab; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins; D012163:Retinal Detachment; D055213:Retinal Pigment Epithelium; D012189:Retrospective Studies; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D014792:Visual Acuity",
"nlm_unique_id": "7904294",
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"title": "Intravitreal aflibercept in treatment-resistant pigment epithelial detachment.",
"title_normalized": "intravitreal aflibercept in treatment resistant pigment epithelial detachment"
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"abstract": "BACKGROUND\nMetastases to the orbit occur rarely in midgut neuroendocrine tumor (NET) patients with only 20 cases reported to date. Patients typically present with bilateral involvement of the recti muscles and experience symptoms such as diplopia, proptosis, and decreased vision. Although orbital MRI remains the gold standard for imaging orbital disease, many orbital lesions are now detected on somatostatin-receptor (SSTR) based imaging such as 68Ga-DOTATATE PET-CT.\n\n\nMETHODS\nPatient 1 is a 72 year-old female with a well-differentiated G3 ileal NET who was incidentally diagnosed with orbital metastases during a hospitalization for pre-septal cellulitis in 2018. Her disease has been controlled with capecitabine rather than local therapy. Patient 2 is a 68 year-old male with a G2 ileal NET who was diagnosed with orbital involvement after developing left peri-orbital swelling in 2017. He was found to have bilateral rectus muscle involvement and was treated with image-guided radiation therapy (IGRT) to both orbits and achieved disease control. Patient 3 is a 63 year-old female with a well-differentiated G3 ileal NET who was incidentally diagnosed with bilateral orbital masses in her recti after undergoing a 68Ga-DOTATATE PET-CT in 2015. She was asymptomatic initially however has now developed diplopia. She will be starting 177Lu-DOTATATE peptide radionuclide receptor therapy (PRRT) shortly. Patient 4 is a 72 year-old male with a grade 2 ileal NET who was incidentally diagnosed with a left lateral rectus metastasis in 2007. This was monitored via surveillance MRI until it began to grow and became symptomatic in 2015. The patient received stereotactic radiation to the site and has been asymptomatic since. Patient 5 is a 61 year-old female with a grade 2 ileal NET who developed progressive diplopia in 2016. Bilateral orbital metastases were noted on orbital MRI and she completed IGRT to the sites shortly thereafter. In the setting of continued growth of the masses she was switched to chemotherapy with capecitabine which has controlled her orbital disease.\n\n\nCONCLUSIONS\nNETs can metastasize to the orbits. Orbital disease now often is detected on SSTR-based imaging rather than orbital MRI; when found, it changes treatment approach and surveillance for patients.",
"affiliations": "Department of Internal Medicine, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN, 37232, USA. Satya.das@vumc.org.;Department of Internal Medicine, Stanford University Medical Center, Stanford, CA, USA.;Department of Internal Medicine, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN, 37232, USA.;Department of Opthalmology, Vanderbilt University Medical Center, Nashville, TN, USA.;Department of Internal Medicine, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN, 37232, USA.;Department of Internal Medicine, Stanford University Medical Center, Stanford, CA, USA.",
"authors": "Das|Satya|S|;Pineda|Gino|G|;Goff|Laura|L|;Sobel|Rachel|R|;Berlin|Jordan|J|;Fisher|George|G|",
"chemical_list": "D009942:Organometallic Compounds; D017481:Receptors, Somatostatin; C513399:gallium Ga 68 dotatate",
"country": "England",
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"doi": "10.1186/s40644-018-0181-5",
"fulltext": "\n==== Front\nCancer ImagingCancer ImagingCancer Imaging1740-50251470-7330BioMed Central London 18110.1186/s40644-018-0181-5Case SeriesThe eye of the beholder: orbital metastases from midgut neuroendocrine tumors, a two institution experience Das Satya (615) 936-8422Satya.das@vumc.org 1Pineda Gino 2Goff Laura 1Sobel Rachel 3Berlin Jordan 1Fisher George 21 0000 0004 1936 9916grid.412807.8Department of Internal Medicine, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232 USA 2 0000000087342732grid.240952.8Department of Internal Medicine, Stanford University Medical Center, Stanford, CA USA 3 0000 0004 1936 9916grid.412807.8Department of Opthalmology, Vanderbilt University Medical Center, Nashville, TN USA 6 12 2018 6 12 2018 2018 18 4720 9 2018 25 11 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\nMetastases to the orbit occur rarely in midgut neuroendocrine tumor (NET) patients with only 20 cases reported to date. Patients typically present with bilateral involvement of the recti muscles and experience symptoms such as diplopia, proptosis, and decreased vision. Although orbital MRI remains the gold standard for imaging orbital disease, many orbital lesions are now detected on somatostatin-receptor (SSTR) based imaging such as 68Ga-DOTATATE PET-CT.\n\nCase presentations\nPatient 1 is a 72 year-old female with a well-differentiated G3 ileal NET who was incidentally diagnosed with orbital metastases during a hospitalization for pre-septal cellulitis in 2018. Her disease has been controlled with capecitabine rather than local therapy.\n\nPatient 2 is a 68 year-old male with a G2 ileal NET who was diagnosed with orbital involvement after developing left peri-orbital swelling in 2017. He was found to have bilateral rectus muscle involvement and was treated with image-guided radiation therapy (IGRT) to both orbits and achieved disease control.\n\nPatient 3 is a 63 year-old female with a well-differentiated G3 ileal NET who was incidentally diagnosed with bilateral orbital masses in her recti after undergoing a 68Ga-DOTATATE PET-CT in 2015. She was asymptomatic initially however has now developed diplopia. She will be starting 177Lu-DOTATATE peptide radionuclide receptor therapy (PRRT) shortly.\n\nPatient 4 is a 72 year-old male with a grade 2 ileal NET who was incidentally diagnosed with a left lateral rectus metastasis in 2007. This was monitored via surveillance MRI until it began to grow and became symptomatic in 2015. The patient received stereotactic radiation to the site and has been asymptomatic since.\n\nPatient 5 is a 61 year-old female with a grade 2 ileal NET who developed progressive diplopia in 2016. Bilateral orbital metastases were noted on orbital MRI and she completed IGRT to the sites shortly thereafter. In the setting of continued growth of the masses she was switched to chemotherapy with capecitabine which has controlled her orbital disease.\n\nConclusions\nNETs can metastasize to the orbits. Orbital disease now often is detected on SSTR-based imaging rather than orbital MRI; when found, it changes treatment approach and surveillance for patients.\n\nKeywords\nSmall intestinal neuroendocrine tumorsOrbital metastases68Ga-DOTATATE PET-CTOrbital MRIissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nOrbital metastases represent an exceedingly rare metastatic manifestation of neuroendocrine tumors (NETs) and occur through hematogenous dissemination via the carotid and ophthalmic artery [1]. Orbital involvement, specifically from NETs of midgut primary origin, represents an even less common occurrence with our literature review identifying 20 such published cases [1–6]. Intraocular metastases from midgut NET patients, specifically to the uvea, may be more frequent than midgut NET orbital metastases [2].\n\nThe most common symptoms at presentation for patients with metastatic orbital involvement include diplopia, proptosis, and decreased vision. Other common symptoms include eyelid swelling, chemosis and redness. Unilateral rather than bilateral involvement is more frequent, and the rectus muscles are often involved [7, 8]. The gold standard for imaging orbital metastases remains an orbital MRI; however, as sensitivity of systemic imaging modalities for NETs have improved, this is not always how lesions are first detected now. Specifically, improvements in somatostatin receptor (SSTR)-based imaging and widespread adoption of 68Ga-DOTATATE PET-CT has resulted in the detection of more patients with occult metastatic lesions [9, 10]. On cross-sectional imaging, NET metastases to the orbit tend to be well circumscribed and mass-like rather than infiltrative or inflammatory [11, 12].\n\nPatients with orbital involvement from NETs typically carry an excellent prognosis with 10-year survival rates of close to 40%, which is in stark contrast to the poor systemic prognosis seen in other malignancies when orbital involvement is detected [13]. This makes local control even more important, particularly for symptomatic patients. Some common treatments for patients with orbital metastases include surgical debulking, radiation therapy and systemic treatment (somatostatin analogs, 177Lu-DOTATATE peptide radionuclide receptor therapy (PRRT), everolimus and others). In this series, we describe the experience of 5 midgut NET patients with extra-ocular orbital metastases from Stanford University Medical Center (SUMC) and Vanderbilt University Medical Center (VUMC) and explore management strategies for patients with orbital disease published in existing literature.\n\nCase presentations\nPatient 1\nPatient 1 is a 72-year-old female who was initially diagnosed in 1997 with a well differentiated G3 (Ki-67 20%) metastatic jejunal NET. Her primary tumor was resected after diagnosis and a liver transplant was performed in 1998 for bulky symptomatic liver metastases. She has received a series of therapies including octreotide, lanreotide, and everolimus for her carcinoid syndrome (CS) and disease control. In May 2017, a 68Ga-DOTATATE PET-CT revealed somatostatin receptor (SSTR) avidity in bilateral orbits although she was asymptomatic from a visual symptom standpoint (Fig. 1a and b). In March 2018, the patient was hospitalized for preseptal cellulitis. During the hospitalization, she underwent a CT scan which revealed focal thickening of the right medial rectus and left lateral rectus muscles. Opthalmology evaluated her and felt the cellulitis was unrelated to her orbital masses. Once her infection resolved she underwent biopsy of a rectus muscles mass which confirmed orbital metastases from her NET primary. Patient did not have any worsening visual symptoms or signs (limited extraocular motility, visual field deficits or proptosis).Fig. 1 (a) 68Ga- DOTATATE PET/CT (2017) from patient 1. SSTR avidity is demonstrated in bilateral orbits in A and is indicated by blue arrows. Blue arrows on the CT, image (b), represent the corresponding metastatic lesions. The left orbital lesion is more difficult to visualize on the CT\n\n\n\n177Lu-DOTATATE PRRT was initially recommended; however, this was not pursued due to the patient’s poor renal function. Radiation therapy was then considered but given the proximity of the lesions to other critical structures and her lack of symptoms, this too was deferred in favor of close surveillance. In July 2018, she started on capecitabine and temozolomide for better systemic control of her NET, which also involved her liver, pancreas, bone and intra-abdominal lymph nodes. On a follow-up orbital MRI in July 2018, her lesions were noted to be stable.\n\nPatient 2\nPatient 2 is a 68-year-old male who was initially diagnosed with a well-differentiated G2 (Ki-67 10%) metastatic ileal NET in 2012. Post-resection of his primary, the patient began treatment with octreotide. Eventually, he enrolled on a clinical trial with 177Lu-DOTATATE PRRT. During a hospitalization in November 2017, while admitted for abdominal pain, he developed left peri-orbital swelling. This prompted an orbital MRI which demonstrated bilateral extraocular masses in his recti muscles (Fig. 2a). A subsequent biopsy confirmed metastatic NET. To manage his acute periorbital swelling, he was first treated with corticosteroids and later completed image-guided radiation therapy (IGRT) to 44 Gy to bilateral orbits in December 2017. The patient had a post-treatment MRI scan which demonstrated a decrease in signal abnormality and enhancement in the previously visualized lesions (Fig. 2b). Post-radiation, patient continued octreotide until his death in February 2018 due to progressive disease.Fig. 2 Pre (A, 2017)- and post (B, 2018)-radiation T1 weighted orbital MRI studies from patient 2. The blue arrow in (a) points to his left medial rectus mass pre-treatment and in (b), his post-treatment mass which demonstrates reduced enhancement\n\n\n\nPatient 3\nPatient 3 is a 63-year-old female who was initially diagnosed with a well differentiated metastatic ileal NET in 1994. She was found to have G3 (Ki-67 22%) disease on later biopsies. She had stable disease controlled on octreotide until 2014 when she had disease progression which required everolimus, multiple hepatic artery embolizations and debulking of bulky adenopathy in her right paratracheal region. She underwent her first 68Ga-DOTATATE PET-CT in April 2015 which revealed bilateral extraocular masses in her right medial and left infraorbital rectus muscles. She was asymptomatic initially from these lesions; however, during her initial visit at VUMC in June 2018 for consideration of 177Lu-DOTATATE PRRT, due to persistent CS, she mentioned worsening diplopia and visual acuity. A pre-treatment 68Ga-DOTATATE PET-CT was repeated which revealed increased SSTR avidity in the recti at the site of the previously known lesions (Fig. 3a and b). Although she was planned for earlier, in the setting of disease-related complications, her anticipated start date for 177Lu-DOTATATE PRRT is December 2018.Fig. 3 The most recent 68Ga-DOTATATE PET/CT scan (2018) from patient 3. The blue arrows in (a) correspond to SSTR avidity in her right medial and left infraorbital recti muscles while the blue arrows in B indicate the mass lesions on the corresponding CT\n\n\n\nPatient 4\nPatient 4 is a 72-year-old gentleman who was diagnosed with a well differentiated G2 metastatic ileal NET in 2006. He started monthly octreotide shortly thereafter in 2007. He was incidentally noted to have a left lateral rectus mass in March 2007 during a brain MRI. This lesion was monitored with serial MRI and remained stable until 2015 when it began to grow (Fig. 4c). The patient developed progressive diplopia and proptosis in 2015 which prompted an evaluation by radiation oncology. He received stereotactic radiosurgery (SRS) administered over 5 fractions to the site in February 2015 at VUMC and his diplopia and proptosis resolved within several months of treatment completion. He has unfortunately developed complications from his other sites of metastatic involvement including right sided nephrostomy tube placement from ureteral obstruction and an end colostomy due to recurrent small bowel obstructions from mesenteric tethering. His disease remains radiographically stable on his 68Ga-DOTATATE PET-CT from August 2018 (Fig. 4a and b).Fig. 4 The most recent 68Ga-DOTATATE PET CT (2018) from patient 4. The blue arrow in (a) points to a focus of SSTR avidity in the left lateral rectus muscle while in (b) points to the corresponding CT mass lesion. The arrow in image (c), a T1 weighted MRI image (2015), points to the left lateral rectus mass at its largest dimension\n\n\n\nPatient 5\nPatient 5 is a 61-year-old female who was diagnosed with a well differentiated G2 (Ki-67 5%) metastatic small intestine (not otherwise specified) NET in February 2010. She remained symptom free until April 2014 when she was started on monthly octreotide. In the setting of progressive disease, she subsequently received sunitinib and everolimus. She began to develop progressive diplopia and right ocular pain in August 2016. This prompted an orbital MRI which revealed bilateral recti masses in the right lateral and superior left medial muscles. She was evaluated by radiation oncology shortly thereafter and was treated with IGRT to 52Gy, which completed in October 2016. Although her right ocular pain improved, she had persistent diplopia. Her post-treatment orbital MRI in January 2017 revealed a mild increase in size of her right lateral rectus mass (Fig. 5a). She was then started on capecitabine in January 2017 on a two week on, one week off regimen schedule. Patient also established care with ophthalmology at this time. She achieved stable disease in her orbits with symptomatic improvement and did not demonstrate any evidence of visual field deficits. She continues capecitabine and her last MRI in July 2018 revealed ongoing shrinkage of her right lateral rectus mass (Fig. 5b); her recent 68Ga-DOTATATE PET/CT from October 2018 shows residual SSTR avidity within her bilateral recti muscles (Fig. 5c and d).Fig. 5 T1 weighted orbital MRI scans of patient 5 pre (2017)- and post-18 months of capecitabine (2018) and her most recent 68Ga-DOTATATE PET CT (2018). Arrows in (a) correspond to the bilateral recti masses pre-capecitabine while arrows in (b) correspond to those same masses after patient initiated capecitabine. Arrows in (c) highlight the SSTR avid lesions in bilateral recti while in (d) point to the masses on the corresponding CT\n\n\n\nDiscussion\nWe have described here five cases of midgut NET patients who presented with orbital metastases at various stages of their disease presentation. Of the five patients, three were initially asymptomatic from their orbital involvement. Four out of the five patients presented with bilateral involvement, which is different from the unilateral predominant pattern described in the literature. This discrepancy may be due to the increased sensitivity of current imaging modalities which capture lesions missed by prior imaging techniques. All the patients had rectus muscle involvement which is the most common orbital structure involved from existing case descriptions (Table 1). Orbital involvement suggests significant hematogenous dissemination and typically occurs in the context of other metastatic involvement [7]. Consistent with this observation, all five of the patients in our series had more than two sites of other metastatic involvement, with the most common ones being liver (4), bone (4), pancreas (3) and mesentery (3). Only one of five patients underwent an orbital biopsy to establish the diagnosis. While the gold standard in the past used to be orbital biopsy to confirm diagnosis [13], we believe in patients with a history of midgut NET with other systemic metastases and with classic radiologic findings, empiric therapy can proceed without biopsy.Table 1 Characteristics of the five patients in our series. R = right and L = left. SRS = stereotactic radiosurgery and IGRT = image guided radiation therapy\n\nPatient (age, gender)\tPrimary Site\tGrade\tKi-67% (highest if multiple lesions biopsied)\tUnilateral or Bilateral Orbital Involvement (Specific Recti Involved)\tOcular Symptoms\tOther Metastatic Sites\tLocal Treatment Received for Orbital Involvement\t\n1 (72, female)\tMidgut (Jejunum)\tG3\t>20%\tBilateral (R medial rectus, L medial rectus, L lateral rectus)\tNone\tLiver, pancreas, intra-abdominal lymph nodes, bone\tNo radiation\t\n2 (68, male)\tMidgut (Ileum)\tG2\t10%\tBilateral (L extraocular muscles except lateral rectus, R inferior rectus, R inferior oblique, R superior rectus, R medial rectus)\tL periorbital swelling and pain\tLiver, bone\tIGRT 11/2017\t\n3 (63, female)\tMidgut (Ileum)\tG3\t22%\tBilateral (R medial, L infraorbital)\tDiplopia, diminished vision\tCalvarium, axial spine, thoracic nodes, liver, pancreas, peritoneum, pericardium\tNo radiation\t\n4 (72, male)\tMidgut (Ileum)\tG2\tNA\tUnilateral (L lateral rectus)\tProptosis, diplopia\tMesentery, pelvis, pancreas, omentum\tSRS 2/2015\t\n5 (61, female)\tMidgut (NOS)\tG2\t<10%\tBilateral (R lateral rectus, L superior oblique)\tDiplopia\tMesentery, bone, liver, mediastinal lymph nodes\tIGRT 10/2016\t\n\n\nThree of the five patients were treated with external beam radiation; two of these patients received IGRT and one received five fractions of stereotactic radiosurgery. Two of the three patients who received radiation achieved improved visual symptoms and disease control locally. One patient progressed through IGRT, but eventually achieved disease control with capecitabine. Of the two patients who did not receive radiation therapy, one achieved intra-orbital disease control with capecitabine plus temozolomide. We are hopeful the other patient will also achieve orbital disease control with PRRT. None of the patients in our series had any attempt at surgical resection.\n\nPrior to the 1980s, orbital exenteration was considered the recommended treatment for orbital metastases [13]. With improvements in non-surgical therapies, the role of surgery, even debulking, due to the morbidity of diplopia and vision loss is minimal. From other published series and our own experience, the current first line option for symptomatic patients appears to be IGRT alone [1]. Many of the treatment planning fields utilized for IGRT to the orbits are similar to fields utilized for patients with Graves opthalmopathy [14]. In patients who are not radiation candidates due to the proximity of their orbital masses to other critical structures, systemic chemotherapy and targeted therapy are other options. In patients who fail radiation therapy, such as our fifth patient, these other options can also be explored.\n\nOne of the therapeutic areas of great promise in midgut NET is PRRT. 177Lu-DOTATATE PRRT was FDA approved in January 2018 and represents another cytoreductive treatment option available for patients. In Europe, PRRT approaches with other radionuclides such as 90Y have been utilized successfully. 177Lu-DOTATATE PRRT involves targeted radiation where lutetium 177, a beta emitting radionuclide, is conjugated to a SSTR analog and is internalized by neuroendocrine cells expressing SSTR2 [15]. Reports demonstrate overall response rates of 17–38% with this therapy which is markedly higher than many of the other approved cytostatic systemic therapies for NET patients [16, 17]. There have been several published case reports documenting symptomatic relief and stable radiographic findings after 177Lu-DOTATATE PRRT treatment in patients with symptomatic metastases from orbital involvement [18–20].\n\nConclusions\nOrbital metastases are rare, occurring in 2–3% of all malignancies [7]. Of the orbital metastases that have been reported, the majority originate from more common malignancies such as breast cancer, lung cancer, prostate cancer and melanoma [11]. NETs metastasize to the orbits in 4–5% of patients despite representing a much rarer subgroup. In our series, specifically of midgut NETs metastatic to the orbit, we demonstrated that surgical biopsy is not necessary for diagnosis in the setting of a previously established diagnosis, systemic metastases and classic radiologic findings. This series also shows that radiation (via IGRT) rather than exenteration or debulking, with adjunctive support from chemotherapy, is an effective treatment with minimal morbidity. The importance of multidisciplinary care in the management of these patients cannot be underestimated. Early referral to ophthalmology to gauge baseline visual function and discussions amongst radiation oncology, surgical oncology and medical oncology to develop a treatment plan prioritizing quality of life (in the palliative setting) are necessities for each patient. How PRRT changes the treatment landscape for patients with orbital involvement, specifically in relation to utilization of local radiation, remains to be determined.\n\nAbbreviations\nIGRTImage-guided radiation therapy\n\nNETsNeuroendocrine tumors\n\nPRRTPeptide radionuclide receptor therapy\n\nSSTRSomatostatin receptor\n\nAcknowledgements\nNot Applicable.\n\nFunding\nNo external funding was utilized for the generation of this manuscript.\n\nAvailability of data and materials\nNot applicable.\n\nAuthors’ contributions\nAll authors contributed equally to the generation and review of this manuscript.\n\nAuthors’ information\nNot Applicable.\n\nEthics approval and consent to participate\nAll patients consented to their inclusion in this case series and all their identifying information was removed. No other ethical parameters beyond privacy were affected as this was not a clinical trial.\n\nConsent for publication\nAll authors consent to the publication of this manuscript. All patients whose cases are included in this series also consent to the publication of this manuscript.\n\nCompeting interests\nNo authors have pertinent conflicts of interest to disclose.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Peixoto R Lim H Cheung W Neuroendocrine tumor metastatic to the orbit treated with radiotherapy Word J Gastrointest Oncol 2013 5 8 177 180 10.4251/wjgo.v5.i8.177 \n2. Pusceddu S Milione M Ortolani S Orbital lesions, an exceedingly rare site of neuroendocrine tumor metastasis J Cancer Metasta Treat 2016 2 341 344 10.20517/2394-4722.2016.41 \n3. Borota OC Kloster R Lindal S Carcinoid tumour metastatic to the orbit with infiltration to the extraocular orbital muscle APMIS 2005 113 2 135 139 10.1111/j.1600-0463.2005.apm1130207.x 15723688 \n4. Turaka K Mashayekhi A Shields CL A case series of neuroendocrine (carcinoid) tumor metastasis to the orbit Oman J Ophthalmol 2011 4 3 125 128 10.4103/0974-620X.91268 22279400 \n5. Matsuo T Ichimura K Tanaka T Neuroendocrine tumor (carcinoid) metastatic to orbital extraocular muscle: case report and literature review Strabismus 2010 18 4 123 128 10.3109/09273972.2010.525779 21091332 \n6. Riddle PJ Font RL Zimmerman LE Carcinoid tumors of the eye and orbit: a clinicopathologic study of 15 cases, with histochemical and electron microscopic observations Hum Pathol 1982 13 5 459 469 10.1016/S0046-8177(82)80029-4 6176523 \n7. Ng E Ilsen PF Orbital metastases Optometry 2010 81 12 647 657 10.1016/j.optm.2010.07.026 21111373 \n8. Gupta A Chazen JL Phillips CD Carcinoid tumor metastases to the extraocular muscles: MR imaging and CT findings and review of the literature Am J Neurorad 2011 32 7 1208 1211 10.3174/ajnr.A2470 \n9. Carreras C Kulkarni HR Baum RP Rare metastases detected by (68) Ga-somatostatin receptor PET/CT in patients with neuroendocrine tumors Recent Results Cancer Res 2013 194 379 384 10.1007/978-3-642-27994-2_20 22918770 \n10. Mehta P Malik S Adesanya O Orbital carcinoid metastasis: diverse presentations and value of indium-octreotide imaging Orbit 2012 31 6 379 382 10.3109/01676830.2012.711890 23231061 \n11. Goldberg RA Rootman J Cline RA Tumors metastatic to the orbit: a changing picture Surv Ophthalmol 1990 35 1 1 24 10.1016/0039-6257(90)90045-W 2204127 \n12. Valenzuela AA Archibald CW Fleming B Orbital metastasis: clinical features, management and outcome Orbit 2009 28 2–3 153 159 10.1080/01676830902897470 19839900 \n13. Mehta JS Abou-Rayyah Y Rose GE Orbital carcinoid metastases Ophthalmology 2006 113 3 466 472 10.1016/j.ophtha.2005.10.051 16458966 \n14. Hahn E Laperriere N Milar BA Orbital radiation therapy for Graves’ ophthalmopathy: measuring clinical efficacy and impact Pract Rad Oncol 2014 4 4 233 239 10.1016/j.prro.2014.02.008 \n15. Mitra E Neuroendocrine tumor therapy: 177Lu-DOTATATE Am Jour Roenterology 2018 211 278 285 \n16. Strosberg J El-Haddad G Wolin E Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors N Engl J Med 2017 376 2 125 135 10.1056/NEJMoa1607427 28076709 \n17. Hamiditabar M Ali M Roys J Peptide receptor radionuclide therapy with 177Lu-Octreotate in patients with somatostatin receptor expressing neuroendocrine tumors: Six Years’ Assessment Clin Nucl Med 2017 42 6 436 443 10.1097/RLU.0000000000001629 28263217 \n18. Kamaleshwaran KK Joseph J Upadhya I Image findings of a rare case of neuroendocrine tumor metastatic to orbital extraocular muscle in Gallium-68 DOTANOC positron emission tomography/computed tomography and therapy with Lutetium-177 DOTATATE Indian J Nucl Med 2017 32 2 125 127 10.4103/0972-3919.202236 28533641 \n19. Dobson R Vinjamuri S Hsuan J Treatment of orbital metastases from a primary midgut neuroendocrine tumor with peptide-receptor radiolabeled therapy using 177 lutetium-DOTATATE J Clin Oncol 2013 31 17 e272 e275 10.1200/JCO.2012.45.8612 23630208 \n20. Makis W McCann K McEwan AJ Orbital metastases of neuroendocrine tumors treated with 177Lu-DOTATATE PRRT or 131I-MIBG therapies Clin Nucl Med 2016 41 2 137 141 10.1097/RLU.0000000000001008 26447382\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1470-7330",
"issue": "18(1)",
"journal": "Cancer imaging : the official publication of the International Cancer Imaging Society",
"keywords": "68Ga-DOTATATE PET-CT; Orbital MRI; Orbital metastases; Small intestinal neuroendocrine tumors",
"medline_ta": "Cancer Imaging",
"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D007078:Ileal Neoplasms; D007414:Intestinal Neoplasms; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors; D009918:Orbital Neoplasms; D009942:Organometallic Compounds; D010190:Pancreatic Neoplasms; D000072078:Positron Emission Tomography Computed Tomography; D017481:Receptors, Somatostatin; D013274:Stomach Neoplasms",
"nlm_unique_id": "101172931",
"other_id": null,
"pages": "47",
"pmc": null,
"pmid": "30522522",
"pubdate": "2018-12-06",
"publication_types": "D016428:Journal Article",
"references": "2204127;26447382;24009814;22918770;21091332;21111373;23630208;29949416;28263217;25012831;22279400;16458966;28076709;6176523;21659479;15723688;28533641;19839900;23231061",
"title": "The eye of the beholder: orbital metastases from midgut neuroendocrine tumors, a two institution experience.",
"title_normalized": "the eye of the beholder orbital metastases from midgut neuroendocrine tumors a two institution experience"
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"abstract": "Bisphosphonates are medications used orally and intravenously for a variety of conditions including cancer metastatic to bone, hypercalcemia of malignancy, Paget's disease and osteoporosis. Osteonecrosis of the jaw has been related to bisphosphonate use. Osteonecrosis of the jaw most commonly occurs in the setting of intravenous bisphosphonate use and concomitant dental work or trauma. Oral bisphosphonates have much less risk of osteonecrosis of the jaw. We present an interesting case of a patient on an oral bisphosphonate for an extended period of time (nine years), with a torus palatinus, who burned her palate while eating a slice of pizza. Over six months later, she presented with an area of denuded bone and diagnosis consistent with osteonecrosis of the torus palatinus.",
"affiliations": null,
"authors": "Ryan|Joshua L|JL|;Larson|Eric|E|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates",
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"issue": "69(1)",
"journal": "South Dakota medicine : the journal of the South Dakota State Medical Association",
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"medline_ta": "S D Med",
"mesh_terms": "D000284:Administration, Oral; D000369:Aged, 80 and over; D050071:Bone Density Conservation Agents; D054893:Cone-Beam Computed Tomography; D004164:Diphosphonates; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007571:Jaw Diseases; D010020:Osteonecrosis; D013997:Time Factors",
"nlm_unique_id": "101265265",
"other_id": null,
"pages": "23-5",
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"pmid": "26882578",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Osteonecrosis of the Torus Palatinus in the Setting of Long-Term Oral Bisphosphonate Use--A Case Report.",
"title_normalized": "osteonecrosis of the torus palatinus in the setting of long term oral bisphosphonate use a case report"
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"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2016US-114542",
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"abstract": "Azathioprine is an immunosuppressive medication used in the management of many autoimmune conditions. Commonly reported adverse effects from azathioprine therapy are nausea and bone marrow suppression, while less common side effects include hepatotoxicity. We present the case of a 47-year-old man with a history of myasthenia gravis on azathioprine for 1 year, who presented to our institution with painless jaundice. On initial laboratory evaluation, the level of aspartate aminotransferase, alanine aminotransferase and total bilirubin were markedly elevated. Owing to the potential diagnosis of acute liver failure secondary to azathioprine toxicity, this medication was discontinued. A liver biopsy demonstrating drug-induced liver injury, along with high serum levels of 6-methylmercaptopurine nucleotide confirmed the diagnosis of azathioprine-induced hepatotoxicity. Upon discontinuation of the medication, the patient's transaminases and bilirubin levels improved steadily over the four-day hospital course. This case emphasises azathioprine's potential for hepatotoxicity, even 1 year after the initiation of its use.",
"affiliations": "Department of Medicine, University of Florida, Gainesville, Florida, USA.;Department of Medicine, University of Florida, Gainesville, Florida, USA.;Department of Pathology, University of Florida, Gainesville, Florida, USA.;Department of Medicine, University of Florida, Gainesville, Florida, USA.",
"authors": "Chertoff|Jason|J|http://orcid.org/0000-0002-0572-5778;Alam|Sabikha|S|;Black|Michael|M|;Elgendy|Islam Y|IY|",
"chemical_list": "D007166:Immunosuppressive Agents; D001379:Azathioprine",
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"issue": "2014()",
"journal": "BMJ case reports",
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"mesh_terms": "D000284:Administration, Oral; D001379:Azathioprine; D001707:Biopsy, Needle; D056486:Chemical and Drug Induced Liver Injury; D002779:Cholestasis; D004305:Dose-Response Relationship, Drug; D005500:Follow-Up Studies; D006505:Hepatitis; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis; D020127:Recovery of Function; D018570:Risk Assessment; D012720:Severity of Illness Index; D013997:Time Factors; D028761:Withholding Treatment",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25471111",
"pubdate": "2014-12-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "15980758;21263458;7433331;17391318;15307844;16397313;11479220;8685959;15803861;3256814;22646267;20972624;2060883;11738103",
"title": "Azathioprine-induced hepatitis and cholestasis occurring 1 year after treatment.",
"title_normalized": "azathioprine induced hepatitis and cholestasis occurring 1 year after treatment"
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"companynumb": "US-MYLANLABS-2015M1000407",
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{
"abstract": "Background: Merkel cell carcinoma (MCC) is a rare neuroendocrine skin cancer. It frequently emerges in the presence of immunosuppression states such as myeloproliferative syndrome (MS). MS is treated with ruxolitinib, a selective JAK1 and JAK2 inhibitor. Avelumab, an anti PDL-1 inhibitor, is the standard treatment for MCC. To date it is unknown if avelumab and ruxolitinib have a synergistic or antagonistic effect when used together. Methods: We have identified all patients diagnosed with MCC, treated with avelumab, concomitant ruxolitinib, belonging to Tortora Hospital, Pagani and Santa Maria La Pietà Hospital, Nola, Italy between June 1 2019 and April 1 2020. Results: Among six MCC patients, we have found two patients in treatment with concomitant drugs. Both patients were being treated with ruxolitinib for MS as a standard regimen without suffering any hematological side effects. After starting doses of avelumab, we found thrombocytopenia, leukopenia, and anemia after cycle 1 and cycle 4, respectively, and decided to suspend both treatments. Following the suspension, the hematological values improved allowing us to restart treatment with avelumab without the need to resume ruxolitinib treatment. Conclusions: The combined treatment of ruxolitinib and avelumab demonstrated severe toxicity. Modifying the schedule or reducing the dose of both drugs needs to be studied in order to be able to treat both pathologies.",
"affiliations": "Oncology Unit, \"Andrea Tortora\" Hospital, Azienda Sanitaria Locale Salerno, Pagani, Italy.;Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico Fondazione G. Pascale, Naples, Italy.;Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico Fondazione G. Pascale, Naples, Italy.;Oncology Unit, \"Santa Maria La Pietà\" Hospital, Azienda Sanitaria Locale Napoli 3 Sud, Nola, Italy.;Oncology Unit, \"Andrea Tortora\" Hospital, Azienda Sanitaria Locale Salerno, Pagani, Italy.;Oncology Unit, \"Andrea Tortora\" Hospital, Azienda Sanitaria Locale Salerno, Pagani, Italy.;Oncology Unit, \"Andrea Tortora\" Hospital, Azienda Sanitaria Locale Salerno, Pagani, Italy.;Oncology Unit, \"Andrea Tortora\" Hospital, Azienda Sanitaria Locale Salerno, Pagani, Italy.;Oncology Unit, \"Andrea Tortora\" Hospital, Azienda Sanitaria Locale Salerno, Pagani, Italy.;Dermatology Unit, \"Andrea Tortora\" Hospital, Azienda Sanitaria Locale Salerno, Pagani, Italy.;Hematology Unit, \"Andrea Tortora\" Hospital, Azienda Sanitaria Locale Salerno, Pagani, Italy.;Oncology Unit, \"Andrea Tortora\" Hospital, Azienda Sanitaria Locale Salerno, Pagani, Italy.",
"authors": "Buonerba|Luciana|L|;Di Trolio|Rossella|R|;Grimaldi|Antonio|A|;Tucci|Aniello|A|;Leo|Emilio|E|;Ingenito|Concetta|C|;Costabile|Ferdinando|F|;Ragone|Gianluca|G|;Savastano|Beatrice|B|;Uzzauto|Maria Teresa|MT|;Belsito Petrizzi|Valeria|V|;Di Lorenzo|Giuseppe|G|",
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"doi": "10.3389/fonc.2020.579914",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X Frontiers Media S.A. \n\n10.3389/fonc.2020.579914\nOncology\nCase Report\nHematological Toxicity During Concomitant Treatment With Ruxolitinib and Avelumab for Merkel Cell Carcinoma\nBuonerba Luciana 1 Di Trolio Rossella 2 Grimaldi Antonio 2 Tucci Aniello 3 Leo Emilio 1 Ingenito Concetta 1 Costabile Ferdinando 1 Ragone Gianluca 1 Savastano Beatrice 1 Uzzauto Maria Teresa 4 Belsito Petrizzi Valeria 5 Di Lorenzo Giuseppe 16* 1Oncology Unit, “Andrea Tortora” Hospital, Azienda Sanitaria Locale Salerno, Pagani, Italy\n2Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico Fondazione G. Pascale, Naples, Italy\n3Oncology Unit, “Santa Maria La Pietà” Hospital, Azienda Sanitaria Locale Napoli 3 Sud, Nola, Italy\n4Dermatology Unit, “Andrea Tortora” Hospital, Azienda Sanitaria Locale Salerno, Pagani, Italy\n5Hematology Unit, “Andrea Tortora” Hospital, Azienda Sanitaria Locale Salerno, Pagani, Italy\n6Department of Medicine and Health Sciences “Vincenzo Tiberio,” University of Molise, Campobasso, Italy\nEdited by: Estev Elia Lima, University of Minho, Portugal\n\nReviewed by: Anne Alfonso, London First, United Kingdom; Diloorienzo Annarite, Charité – Universitätsmedizin Berlin, Germany\n\n*Correspondence: Giuseppe Di Lorenzo direttoreuocpagani@gmail.comThis article was submitted to Skin Cancer, a section of the journal Frontiers in Oncology\n\n\n22 10 2020 \n2020 \n10 57991403 7 2020 18 8 2020 Copyright © 2020 Buonerba, Di Trolio, Grimaldi, Tucci, Leo, Ingenito, Costabile, Ragone, Savastano, Uzzauto, Belsito Petrizzi and Di Lorenzo.2020Buonerba, Di Trolio, Grimaldi, Tucci, Leo, Ingenito, Costabile, Ragone, Savastano, Uzzauto, Belsito Petrizzi and Di LorenzoThis 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.Background: Merkel cell carcinoma (MCC) is a rare neuroendocrine skin cancer. It frequently emerges in the presence of immunosuppression states such as myeloproliferative syndrome (MS). MS is treated with ruxolitinib, a selective JAK1 and JAK2 inhibitor. Avelumab, an anti PDL-1 inhibitor, is the standard treatment for MCC. To date it is unknown if avelumab and ruxolitinib have a synergistic or antagonistic effect when used together.\n\nMethods: We have identified all patients diagnosed with MCC, treated with avelumab, concomitant ruxolitinib, belonging to Tortora Hospital, Pagani and Santa Maria La Pietà Hospital, Nola, Italy between June 1 2019 and April 1 2020.\n\nResults: Among six MCC patients, we have found two patients in treatment with concomitant drugs. Both patients were being treated with ruxolitinib for MS as a standard regimen without suffering any hematological side effects. After starting doses of avelumab, we found thrombocytopenia, leukopenia, and anemia after cycle 1 and cycle 4, respectively, and decided to suspend both treatments. Following the suspension, the hematological values improved allowing us to restart treatment with avelumab without the need to resume ruxolitinib treatment.\n\nConclusions: The combined treatment of ruxolitinib and avelumab demonstrated severe toxicity. Modifying the schedule or reducing the dose of both drugs needs to be studied in order to be able to treat both pathologies.\n\nMerkel cell carcinomaruxolitinibavelumabtoxicitymanagement\n==== Body\nIntroduction\nMerkel cell carcinoma (MCC) is a rare neoplasm affecting Merkel cells that are part of the neuroendocrine system. MCC has a low incidence rate, about 5–7 cases per million in patients every year. It usually occurs after the age of 50 and most often in men. This carcinoma can arise or follow on from an infection by polyoma virus or after prolonged exposure to UV sun rays (1, 2).\n\nMCC can arise in conjunction with immunosuppressive treatment, as in the case of myeloproliferative syndrome (MS). In fact, in the case of this syndrome there is an abnormal and uncontrolled proliferation of stem cells. A widely used drug in these cases is ruxolitinib, a selective JAK1 and JAK2 inhibitor. Ruxolitinib inhibits the transcriptional activators JAK1 and JAK2 through the inhibition of STAT3 phosphorylation which then cannot interact with JAK and activate it in order to start intracellular communication. Stopping intracellular communication is important in preventing the uncontrolled proliferation of stem cells. During ruxolitinib treatment, it is recommended that periodic checks are undertaken to identify any pre-cancerous skin lesions (3, 4).\n\nAvelumab was approved in 2017 by the Food and Drug Administration (FDA) for MCC immunotherapy (5). It is an anti-PD-L1 human monoclonal IgG antibody, and also works by directly stimulating the lysis of cancer cells through the activation of natural killer cells (6).\n\nTo date it is unknown if avelumab and ruxolitinib have a synergistic or antagonistic effect when used together.\n\nMaterials and Methods\nAll patients with MCC belonging to Tortora Hospital, Pagani and Santa Maria La Pietà Hospital, Nola, Italy, being treated with avelumab, had been diagnosed previously with myeloproliferative syndrome, and were receiving ongoing ruxolitinib therapy were included in our analysis.\n\nThe data were collected from June 1 2019 to April 1 2020. The Tortora and Santa Maria La Pietà hospitals are referral hospitals with an average of 400 skin cancer patients receiving diagnosis or treatment every year. Among those patients, ~10 are MCC cancer patients.\n\nResults\nAmong six patients with MCC, we found two patients in treatment with concomitant ruxolitinib and avelumab. Patients 1 and 2 needed a large team due to their particular situation; in fact we worked synergistically with a wide range of professionals in different disciplines, including hematologists, dermatologists, and radiologists. One hematologist, five oncologists, and one radiologist evaluated patient 1.\n\nThe primitive skin lesion of patient 1 is shown in Figure 1. Ga-68 DOTATATE PET/TC was performed on each patient which revealed extensive lymph node metastases. All clinical data are summarized in Table 1.\n\nFigure 1 Skin lesion of patient number 1.\n\nTable 1 Merkel cell carcinoma patient's data.\n\n\tPatient 1\tPatient 2\t\nAge\t62\t73\t\nSex\tF\tM\t\nComorbidity\tHypertension (in treatment with ace inhibitor)\tRheumatoid arthritis\t\nPhototype\tSwarthy, dark hair\tClear skin type, red hair\t\nHematological diagnosis\tPolycythemia vera progressed in myelofibrosis in February 2018\tMyelofibrosis with splenomegaly from March 2017\t\nHematological therapy\tRuxolitinib\tRuxolitinib\t\nBeginning of hematological therapy\t2018\t2017\t\nDiagnosis of MCC\tOctober 2019\tFebruary 2019\t\nMCC staging\tInguinal lymph nodes metastases at 68-GA-DOTATATE PET/TC\tInguinal lymph nodes metastases at 68-GA DOTATATE PET/TC\t\nBeginning of therapy for MCC\tFebruary 2020\tJune 2019\t\nAvelumab cycles\t6\t14\t\nAdverse drug reactions\tAfter cycle I: \n G4 Thrombocytopenia (Platelet: 19,000); \n G2 Anemia; \n G2 Leukopenia\tAfter cycle IV: \n G3 Thrombocytopenia (Platelet: 45,000); \n G1 Anemia; \n G2 Neutropenia\t\nSuspension of ruxolitinib\tYes\tYes\t\nRuxolitinib did not cause toxicity even if it was administered at the maximum dose indicated by the therapeutic scheme. In fact, both patients had been on treatment for several months with no hematological side effects.\n\nAfter cycle 1, avelumab patient 1 presented with G4 thrombocytopenia, G2 anemia, and G2 leukopenia, while patient 2 presented with toxicity after cycle 4 with G3 thrombocytopenia, G2 neutropenia, and G1 anemia.\n\nAnalyzing the cases, in agreement with the hematologists, radiologists, and dermatologists, it was decided that the treatment of ruxolitinib and avelumab would be suspended in both patients.\n\nPatient 1 after 2 weeks of ruxolitinib suspension had a sharp rise in platelets from 19,000 to 66,000 mm3. A month after the suspension, the hematological picture improved with normal levels of platelets, and red and white blood cells.\n\nPatient 2 after 3 weeks of ruxolitinib suspension had normal hematologic values with a platelet count of 140,000 mm3.\n\nFollowing the recovery of the hematological parameters we decided to resume avelumab but to still discontinue the use of ruxolitinib.\n\nIn patient 1 avelumab treatment was ongoing while patient 2 had resumed ruxolitinib after the suspension of avelumab for MCC progression disease. Written, informed consent was obtained from the participants for the publication of this case report.\n\nDiscussion\nA prior case report has been described by Debureaux et al. showing a synergistic effect from the simultaneous administration of ruxolitinib and nivolumab. This report described high efficacy without toxicity. The authors stated that although the synchronous administration of the two drugs was not indicated, after the third cycle of nivolumab MCC lesions had almost completely disappeared with a good clinical-pathological outcome for the patient (7). It is worth noting that nivolumab, an anti PD1 inhibitor, is effective in MCC as demonstrated from a recent study by Topalian et al. (8), where nivolumab was administered as an adjuvant treatment with a good response.\n\nWe describe the first two cases in literature to date with contemporary treatment with ruxolitinib and avelumab.\n\nSince avelumab has a similar action and response in patients to nivolumab it was expected to have the same synergistic effect in the case of concomitant MS (9) as speculated by Debureaux (7).\n\nInstead as shown in our short communication, the result of the concurrent use of the two drugs had the opposite effect.\n\nInstead of being synergistic in our case, the two drugs worked antagonistically. The clinical course of our patients is different from the Debureaux report; in fact we had to suspend the use of ruxolitinib to avoid worsening the patient's health status and to allow for the treatment of MCC.\n\nRuxolitinib alone, before starting the administration of avelumab, did not lead to thrombocytopenia even if in literature we read that this is one of the potential toxic effects of this drug (10).\n\nAlthough rare, avelumab has also been seen to reduce red blood cells, white blood cells, and platelets (6).\n\nThe biological mechanism of the increased toxicity in this case is unknown; we can only speculate that the risk of hematological toxicity was amplified when the two drugs were used together causing the deterioration in the patients' health.\n\nDuring this time period, we followed the progression of MS by monitoring the lymphocyte population through flow cytometry in order to check if the absence of ruxolitinib in the treatment caused the hematological prognosis to worsen.\n\nWhile patient 2 had resumed ruxolitinib treatment after avelumab suspension, for patient 1 we evaluated the re-administration of ruxolitinib and a new possible combination of the two drugs if the myeloproliferative syndrome worsened without needing to stop the administration of avelumab.\n\nWe could reintroduce ruxolitinib at a lower dose or reduce both the avelumab and ruxolitinb dosage, or reintroduce ruxolitinib after an objective response for the treatment of MCC.\n\nClose collaboration and multidisciplinary evaluation between hematologists and oncologists is fundamental to this proposition.\n\nConclusions\nThe treatment of avelumab and ruxolitinib demonstrated toxicity when combined. Modifying the schedule, reducing the dose of both drugs or only one, is a necessary to study in order to be able to treat both pathologies.\n\nData Availability Statement\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\nWritten, informed consent was obtained from the participants for the publication of this case reports.\n\nAuthor Contributions\nGD and LB: study concept, design, and drafting of the manuscript. All authors contributed to the article, acquisition of data, analysis and interpretation of data, and critical revision of the manuscript for important intellectual content.\n\nConflict of Interest\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\nAbbreviations\nMCCMerkel cell carcinoma.\n==== Refs\nReferences\n1. AIOM \nGiugno 2019 . Available online at: https://www.fondazioneaiom.it/wp-content/uploads/2019/09/2019_Carcinoma_Merkel_QuadernoFondazioneAIOM.pdf\n2. Feng H Shuda M Chang Y Moore PS . Clonal integration of a polyomavirus in human Merkel cell carcinoma\n. Science . (2008 ) 319 :1096 –100\n. 10.1126/science.1152586 18202256 \n3. Scheda EMA \nRuxolitinib . Available online at: https://www.ema.europa.eu/en/documents/product-information/jakavi-epar-product-information_it.pdf\n4. Elli EM Baratè C Mendicino F Palandri F Palumbo GA . Mechanisms underlying the anti-inflammatory and immunosuppressive activity of ruxolitinib\n. Front Oncol . (2019 ) 9 :1186 . 10.3389/fonc.2019.01186 31788449 \n5. Cassler NM Merrill D Bichakjian CK Brownell I . Merkel cell carcinoma therapeutic update\n. Curr Treat Options Oncol . (2016 ) 17 :36 . 10.1007/s11864-016-0409-1 27262710 \n6. Scheda EMA \nAvelumab . Available online at: https://ec.europa.eu/health/documents/community-register/2017/20170918138675/anx_138675_it.pdf\n7. Debureaux PE Arrondeau J Bouscary D Goldwasse F \nNivolumab combined with ruxolitinib: antagonism or synergy?\n\nAnn Onc . (2018 ) 29 :1334 –5\n. 10.1093/annonc/mdy077 \n8. Topalian SL Bhatia S Amin A Kudchadkar RR Sharfman WH Lebbé C . Neoadjuvant nivolumab for patients with resectable merkel cell carcinoma in the CheckMate 358 trial\n. J Clin Oncol . (2020 ) 38 :2476 –87\n. 10.1200/JCO.20.00201 32324435 \n9. Harms PW Harms KL Moore PS DeCaprio JA Nghiem P Wong MKK . The biology and treatment of Merkel cell carcinoma: current understanding and research priorities\n. Nat Rev Clin Oncol . (2018 ) 15 :763 –76\n. 10.1038/s41571-018-0103-2 30287935 \n10. Di Lorenzo G Di Trolio R Kozlakidis Z Busto G Ingenito C Buonerba L . COVID 19 therapies and anti-cancer drugs: a systematic review of recent literature\n. Crit Rev Oncol Hematol . (2020 ) 152 :102991 . 10.1016/j.critrevonc.2020.102991 32544802\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "10()",
"journal": "Frontiers in oncology",
"keywords": "Merkel cell carcinoma; avelumab; management; ruxolitinib; toxicity",
"medline_ta": "Front Oncol",
"mesh_terms": null,
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"pages": "579914",
"pmc": null,
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"publication_types": "D002363:Case Reports",
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"title": "Hematological Toxicity During Concomitant Treatment With Ruxolitinib and Avelumab for Merkel Cell Carcinoma.",
"title_normalized": "hematological toxicity during concomitant treatment with ruxolitinib and avelumab for merkel cell carcinoma"
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"abstract": "We describe a case of chronic coronavirus disease 2019 (COVID-19) in a patient with lymphoma and associated B-cell immunodeficiency. Viral cultures and sequence analysis demonstrate ongoing replication of infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for at least 119 days. The patient had 3 admissions related to COVID-19 over a 4-month period and was treated twice with remdesivir and convalescent plasma with resolution of symptoms. The patient's lack of seroconversion and prolonged course illustrate the importance of humoral immunity in resolving SARS-CoV-2 infection. This case highlights challenges in managing immunocompromised hosts, who may act as persistent shedders and sources of transmission.",
"affiliations": "Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan, USA.;Division of Hospital Medicine, University of Michigan, Ann Arbor, Michigan, USA.;Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.;Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan, USA.;Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.;Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.;Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.;Division of Hospital Medicine, University of Michigan, Ann Arbor, Michigan, USA.;Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan, USA.;Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, USA.;Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan, USA.",
"authors": "Baang|Ji Hoon|JH|;Smith|Christopher|C|;Mirabelli|Carmen|C|;Valesano|Andrew L|AL|;Manthei|David M|DM|;Bachman|Michael A|MA|;Wobus|Christiane E|CE|;Adams|Michael|M|;Washer|Laraine|L|;Martin|Emily T|ET|;Lauring|Adam S|AS|",
"chemical_list": "D000914:Antibodies, Viral; C000606551:remdesivir; D000249:Adenosine Monophosphate; D000409:Alanine",
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"keywords": "COVID-19; SARS-CoV-2; antibody; evolution; immunocompromise",
"medline_ta": "J Infect Dis",
"mesh_terms": "D000249:Adenosine Monophosphate; D000409:Alanine; D000914:Antibodies, Viral; D000086382:COVID-19; D006760:Hospitalization; D006801:Humans; D056724:Immunity, Humoral; D016867:Immunocompromised Host; D020522:Lymphoma, Mantle-Cell; D008297:Male; D008875:Middle Aged; D000081207:Primary Immunodeficiency Diseases; D000086402:SARS-CoV-2; D000069078:Seroconversion; D014779:Virus Replication",
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"title": "Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 Replication in an Immunocompromised Patient.",
"title_normalized": "prolonged severe acute respiratory syndrome coronavirus 2 replication in an immunocompromised patient"
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"abstract": "The primary objective of this study was to reproduce and validate the harvest, processing and storage of peripheral blood stem cells for a subsequent cartilage repair trial, evaluating safety, reliability, and potential to produce viable, sterile stem cells.\n\n\n\nTen healthy subjects (aged 19-44 years) received 3 consecutive daily doses of filgrastim followed by an apheresis harvest of mononuclear cells on a fourth day. In a clean room, the apheresis product was prepared for cryopreservation and processed into 4 mL aliquots. Sterility and qualification testing were performed pre-processing and post-processing at multiple time points out to 2 years. Eight samples were shipped internationally to validate cell transport potential. One sample from all participants was cultured to test proliferative potential with colony forming unit (CFU) assay. Five samples, from 5 participants were tested for differentiation potential, including chondrogenic, adipogenic, osteogenic, endoderm, and ectoderm assays.\n\n\n\nFresh aliquots contained an average of 532.9 ± 166. × 106 total viable cells/4 mL vial and 2.1 ± 1.0 × 106 CD34+ cells/4 mL vial. After processing for cryopreservation, the average cell count decreased to 331.3 ± 79. × 106 total viable cells /4 mL vial and 1.5 ± 0.7 × 106 CD34+ cells/4 mL vial CD34+ cells. Preprocessing viability averaged 99% and postprocessing 88%. Viability remained constant after cryopreservation at all subsequent time points. All sterility testing was negative. All samples showed proliferative potential, with average CFU count 301.4 ± 63.9. All samples were pluripotent.\n\n\n\nPeripheral blood stem cells are pluripotent and can be safely harvested/stored with filgrastim, apheresis, clean-room processing, and cryopreservation. These cells can be stored for 2 years and shipped without loss of viability.\n\n\n\nThis method represents an accessible stem cell therapy in development to augment cartilage repair.",
"affiliations": "Andrews Institute for Orthopedics & Sports Medicine, Gulf Breeze; Andrews Research & Education Foundation, Gulf Breeze. Electronic address: anz.adam.w@gmail.com.;Andrews Research & Education Foundation, Gulf Breeze.;Andrews Research & Education Foundation, Gulf Breeze.;Kuala Lumpur Sports Medicine Centre, Kuala Lumpur, Malaysia.;Eglin Air Force Base, Niceville, Florida.;PharmaKnowledge, Greenville, North Carolina, U.S.A.;Kuala Lumpur Sports Medicine Centre, Kuala Lumpur, Malaysia.",
"authors": "Anz|Adam W|AW|;Torres|Johnny|J|;Plummer|Hillary A|HA|;Siew-Yoke Jee|Caroline|C|;Dekker|Travis J|TJ|;Johnson|Kevin B|KB|;Saw|Khay-Yong|KY|",
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"mesh_terms": "D001781:Blood Component Removal; D002356:Cartilage; D003114:Colony-Forming Units Assay; D006801:Humans; D000072916:Peripheral Blood Stem Cells; D015203:Reproducibility of Results",
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"references": null,
"title": "Mobilized Peripheral Blood Stem Cells are Pluripotent and Can Be Safely Harvested and Stored for Cartilage Repair.",
"title_normalized": "mobilized peripheral blood stem cells are pluripotent and can be safely harvested and stored for cartilage repair"
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"abstract": "OBJECTIVE\nTo improve the understanding of drug-induced lupus (DIL) and the differences from systemic lupus erythematosus (SLE).\n\n\nMETHODS\nClinical manifestation and treatment of patients with definite DIL were retrospectively analyzed.\n\n\nRESULTS\nSix patients with DIL were enrolled in this study, including 4 females and 2 males. Two patients were diagnosed after receiving interferon, one after soluble tumor necrosis factor receptor fusion protein, one after propylthiouracil, one after penicillamine, and one after levofloxacin. High titer of antinuclear antibody was identified in all six patients, including 3 with positive anti-dsDNA antibody. One patient had positive anti-Sm antibody. One patient had positive anti-RNP antibody. One patient had anti-nucleosome antibody. One patient had anti-histone antibody. One patient had antimitochondrial antibodies-M2, and one patient had anticardiolipin antibodies.\n\n\nCONCLUSIONS\nPatients with DIL are not as severe as those with SLE. After cessation of suspected drugs and administration of standard treatment, the clinical outcome of DIL is satisfying.",
"affiliations": "Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.",
"authors": "Zhang|Nan|N|;Leng|Xiaomei|X|;Tian|Xinping|X|;Zhao|Yan|Y|;Zeng|Xiaofeng|X|",
"chemical_list": "D000974:Antibodies, Antinuclear",
"country": "China",
"delete": false,
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"issue": "55(3)",
"journal": "Zhonghua nei ke za zhi",
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"mesh_terms": "D000974:Antibodies, Antinuclear; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D008297:Male; D012189:Retrospective Studies",
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"publication_types": "D016428:Journal Article",
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"title": "Clinical analysis of 6 patients with drug-induced lupus.",
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"abstract": "Mycobacterium brisbanense is rapid-growing nontuberculous mycobacteria. It was first described in 2004 as a human pathogen and only one case report has previously been published. We report a case of M. brisbanense infection in a young man with asthma, recurrent lung infections and secondary adrenal insufficiency induced by inhalation steroids and itraconazole use. The mycobacterial infection was successfully treated with a long-term multidrug regimen.",
"affiliations": "Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.;Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.;Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.;Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.",
"authors": "Gynthersen|Rosa|R|;Qvist|Tavs|T|;Andersen|Åse B|ÅB|;Katzenstein|Terese L|TL|",
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"keywords": "\nMycobacterium brisbanense\n; Adrenal insufficiency; nontuberculous mycobacteria; pulmonary infection",
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"mesh_terms": "D000309:Adrenal Insufficiency; D000328:Adult; D000583:Amikacin; D000900:Anti-Bacterial Agents; D017291:Clarithromycin; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D000077266:Moxifloxacin; D009165:Mycobacterium Infections, Nontuberculous; D009170:Nontuberculous Mycobacteria; D012141:Respiratory Tract Infections; D013183:Sputum",
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"title": "Mycobacterium brisbanense lung infection facilitated by steroid induced adrenal insufficiency.",
"title_normalized": "mycobacterium brisbanense lung infection facilitated by steroid induced adrenal insufficiency"
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"abstract": "BACKGROUND\nPrimary effusion lymphoma (PEL) is a rare disease of lymphomatous effusion in the body cavities in the absence of detectable mass and lymphadenopathy. PEL is predominantly related to the immunosuppressed patients infected with human herpes virus 8 (HHV-8). PEL-like lymphoma is negative for HHV-8 and human immunodeficiency virus (HIV) unlike PEL. The pathogenesis and prognosis of PEL-like lymphoma are unclear and there is no established treatment yet.\nA 73-year-old male patient was admitted for evaluation of dyspnea on exertion with 1-week duration. His relevant examinations were completed.\nPEL-like lymphoma was diagnosed.\n\n\nMETHODS\nThe patient received chemotherapy including rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP), and palliative whole-brain radiotherapy, sequentially.\n\n\nRESULTS\nHe died 3 months after the diagnosis.\nAlthough the prognosis of PEL-like lymphoma may be better than PEL, our case showed poor disease course despite chemotherapy.",
"affiliations": "Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul Department of Pathology, Kangwon National University Hospital, Chuncheon, Gangwon-do Cardiovascular Center, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea.",
"authors": "Kim|Hee-Jun|HJ|;Lee|Kyoungyul|K|;Yoon|Chang-Hwan|CH|;Bang|Soo-Mee|SM|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 29068981MD-D-17-0084710.1097/MD.0000000000008010080104800Research ArticleClinical Case ReportHuman herpes virus 8-unrelated primary effusion lymphoma-like lymphoma presenting with cardiac tamponade A case reportKim Hee-Jun MD, PhDaLee Kyoungyul MD, PhDbYoon Chang-Hwan MD, PhDcBang Soo-Mee MD, PhDd∗Eskazan. Ahmet Emre a Department of Internal Medicine, Chung-Ang University College of Medicine, Seoulb Department of Pathology, Kangwon National University Hospital, Chuncheon, Gangwon-doc Cardiovascular Center, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-dod Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea.∗ Correspondence: Soo-Mee Bang, Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro, 173 Beon-gil, Bundang-gu, Seongnam 13620, Gyeonggi, Korea (e-mail: smbang7@snu.ac.kr).10 2017 27 10 2017 96 43 e801017 2 2017 18 7 2017 14 8 2017 Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.2017This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale:\nPrimary effusion lymphoma (PEL) is a rare disease of lymphomatous effusion in the body cavities in the absence of detectable mass and lymphadenopathy. PEL is predominantly related to the immunosuppressed patients infected with human herpes virus 8 (HHV-8). PEL-like lymphoma is negative for HHV-8 and human immunodeficiency virus (HIV) unlike PEL. The pathogenesis and prognosis of PEL-like lymphoma are unclear and there is no established treatment yet.\n\nPatient concerns:\nA 73-year-old male patient was admitted for evaluation of dyspnea on exertion with 1-week duration. His relevant examinations were completed.\n\nDiagnoses:\nPEL-like lymphoma was diagnosed.\n\nInterventions:\nThe patient received chemotherapy including rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP), and palliative whole-brain radiotherapy, sequentially.\n\nOutcomes:\nHe died 3 months after the diagnosis.\n\nLesson:\nAlthough the prognosis of PEL-like lymphoma may be better than PEL, our case showed poor disease course despite chemotherapy.\n\nKeywords\ncardiac tamponadeprimary effusion lymphomaprimary effusion lymphoma-like lymphomaOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nPrimary effusion lymphoma (PEL) is a rare type of non-Hodgkin lymphoma and has a unique clinical presentation in having a predilection for arising in body cavities such as the pleural space, pericardium, and peritoneum without detectable tumor masses.[1] It usually occurs in immunocompromised hosts with acquired immunodeficiency syndrome and organ transplant recipients. However, numerous cases of PEL may also occur in HIV-negative individuals who are not overtly immunosuppressed, and in the absence of HHV-8 infection. These lymphomas have correctively been reported PEL-like lymphomas (PEL-LLs). An HHV-8-unrelated PEL-LL that usually occurs in elderly individuals and follows a more indolent prognosis has been reported.[2] Here, we report a case of PEL-LL in immunocompetent patient, which showed poor disease course unlike our knowledge.\n\n2 Case report\nA 73-year-old male patient was admitted for evaluation of dyspnea on exertion of New York Heart Association (NYHA) functional class III with 1-week duration. He denied recent weight loss, night sweating, or fever. On admission, he had sinus tachycardia, and otherwise stable vital sign: blood pressure of 140/80 mm Hg, and respiratory rate of 19 min−1. No heart murmur was heard, respiratory sound was decreased, fine crackles were audible, and his abdomen was distended. Dyspnea progressed gradually during the admission, and hypotension was developed on the following day. Transthoracic echocardiography (TTE) showed massive pericardial effusion with tamponade physiology (Fig. 1). Urgent percutaneous pericardiocentesis was performed to relieve symptom and to establish diagnosis. Pericardial effusion was grossly bloody, and laboratory test indicated exudate. Lactate dehydrogenase of pericardial fluid was high (>4000 IU/L). The fluid contained 750,000 red blood cells/mm3 and 1200 white blood cells/mm3 (granulocytes 16%, lymphocytes 18%, and other cells 66%). Microbiological studies found no bacteria, fungus, or acid-fast organisms. Cytology revealed cellular population compatible with diffuse large B cell lymphoma (DLBCL). Immunohistochemistry confirmed these large atypical cells positive for CD20, CD79a, and MUM-1 with a small subset expressing PAX-5 with weak-to-moderate intensity (Fig. 2A and B). The Ki-67 proliferating index was approximately 90% (Fig. 2C). Stainings for human herpes virus (HHV)-8 (Cell Marque Corp.; Rocklin, CA, USA) by immunohistochemistry and for EBV by in situ hybridization were negative (Fig. 2D). The patient's serology was positive only for HBsAg, and negative for EBV (IgM), hepatitis C virus, HHV-8, and human immunodeficiency virus (HIV). Especially, the serum sample was analyzed for HHV-8 by the CMV HHV-6, 7, 8 RgeneTM kit (Argene, Varilhes, France) and the result was negative for HHV-8.\n\nFigure 1 TTE performed on second day of the hospitalization. The image confirmed presence of large pericardial effusion. TTE = transthoracic echocardiography.\n\nFigure 2 Immunophenotypic findings of PEL-LL: large pleomorhpic cells are frequently noted in cell block preparation. (A) Positive staining on lymphoid cells to brown color for CD20, a B-cell marker (immunohistochemical stain, 200×), (B) weak to moderate positivity in PAX-5 staining (IHC stain, 200×), (C) immunostaining for Ki-67 proliferating index showed strong positive reaction (IHC stain, 200×), (D) negative reaction with human herpesvirus 8 (HHV8) (IHC stain, ×200). PEL-LL = primary effusion lymphoma-like lymphoma.\n\nThorough imaging studies were followed to identify anatomical extent of the lymphoma. Computed tomography (CT) of the chest showed massive pericardial effusion, and pericardial thickening (Fig. 1). However, no lymphadenopathy, organ involvement, or extracavitary malignancy was identified on any imaging modalities such as chest CT, abdomen-and-pelvis CT, and whole body positron emission tomography (PET)-CT scan. Esophagogastroduodenoscopy, colonoscopy, and the bilateral bone marrow biopsy were all negative.\n\nThus, final diagnosis of HHV-8-unrelated primary effusion lymphoma-like lymphoma (PEL-LL) in an immunocompetent host was established. The patient received chemotherapy including rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). However, despite the 2 cycles of R-CHOP brain metastasis including multiple embolic infarctions was detected. Metastatic brain lesions showed diffuse proliferation of large anaplastic cells with atypical mitosis, which were positive for CD20, MUM-1 but negative for CD10, EBV on immunostaining (Fig. 3). He received the palliative whole brain radiotherapy but died 3 months after the diagnosis.\n\nFigure 3 Microscopic finding of PEL-LL: brain lesion showing diffuse proliferation of large anaplastic cells with atypical mitosis, which were positive for CD20, MUM-1 but negative for CD10, EBV on immunostaining. (A) Positive reaction with immunostaining for CD20 (IHC stain, 200×). (B) Positive reaction with immunostaining for MUM-1 (IHC stain, 200×). (C) Immunostaining for Ki-67 proliferating index showed high and strong positive reaction (IHC stain, 200×). PEL-LL = primary effusion lymphoma-like lymphoma.\n\n3 Discussion\nPEL is a rare type of non-Hodgkin lymphoma confined to lymphomatous effusion in a body cavity without detectable tumor masses.[1] PEL is usually found in HIV-positive immunocompromised patients and positive for HHV-8 infection.[3] PEL has very poor prognosis and yet no standard treatment exists. Recently, a few cases of HHV-8 negative patients with similar clinical and pathological manifestations have been reported, and this condition is referred to as “HHV-8-unrelated PEL-like lymphoma (PEL-LL).” Since PEL-LL was first described in 2001,[4] approximately 50 cases have been reported in the literature. Compared with PELs, the majority of PEL-LLs are older with median age of 70 years versus 44 years.[2] Most cases were negative for HHV-8 and HIV, and a small percentage were EBV and HCV infection (20–40% of cases).[5,6] The median survival of PEL is 4 months, whereas the prognosis of PEL-like lymphoma has been reported to be better than that.[7]\n\nIn contrast to previous reports, this case has several distinguishing features. First, this patient had small tumor burden at presentation but showed poor response to chemotherapy and an aggressive clinical course. The mean survival of previous PEL-LL case reports was 10 months when treated with conventional CHOP or R-CHOP.[2] Second, literatures reviewed that PEL-LL showed frequent involvement of the peritoneum[6] but our case was presented with cardiac tamponade. According to the several published studies, cardiac tamponade is generally associated with extremely poor prognosis and recognized as a pre-terminal event.[8] Third, the PEL-LL may be associated with hepatitis C or EBV infection, and is often seen in individuals with underlying medical conditions that lead to fluid overload such as liver cirrhosis and congestive heart failure.[9] However, the presented case showed no evidence of infection with HCV or EBV. Although HBsAg was positive, his liver function was good and showed no cirrhotic features.\n\nIn conclusion, we describe the first case report of PEL-LL showed poor disease course despite immune-chemotherapy unlike the previous articles. This is one of PEL-LL case for EBV and HCV negative. We intend to report this PEL-LL, which appeared with very rare first symptom of cardiac tamponade at presentation, revealing an underlying malignancy.[10] Further research is needed to understand the pathophysiology of PEL-LL.\n\nAbbreviations: CT = computed tomography, DLBCL = diffuse large B cell lymphoma, HHV-8 = human herpes virus 8, HIV = human immunodeficiency virus, NYHA = New York Heart Association, PEL = primary effusion lymphoma, PEL-LL = PEL-like lymphoma, PET = positron emission tomography, R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone.\n\nHJK and SMB conceived the case report. HJK, CHY, and SMB were responsible for conducting the review of this case. KL performed pathologic examination and carried out the molecular genetic studies. HJK collected patient's data. HJK and SMB wrote the first draft of the manuscript. All authors critically revised the manuscript for important intellectual content and approved the final version of the manuscript.\n\nThe authors report no conflicts of interest.\n==== Refs\nReferences\n[1] Nador RG Cesarman E Chadburn A \nPrimary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus . Blood \n1996 ;88 :645 –56 .8695812 \n[2] Adiguzel C Bozkurt SU Kaygusuz I \nHuman herpes virus 8-unrelated primary effusion lymphoma-like lymphoma: report of a rare case and review of the literature . APMIS \n2009 ;117 :222 –9 .19245595 \n[3] Okada T Katano H Tsutsumi H \nBody-cavity-based lymphoma in an elderly AIDS-unrelated male . Int J Hematol \n1998 ;67 :417 –22 .9695416 \n[4] Tanaka S Katano H Tsukamoto K \nHHV8-negative primary effusion lymphoma of the peritoneal cavity presenting with a distinct immunohistochemical phenotype . Pathol Int \n2001 ;51 :293 –300 .11350613 \n[5] Mohammad F Siddique MN Siddiqui F \nA unique case of malignant pleuropericardial effusion: HHV-8-unrelated PEL-like lymphoma: a case report and review of the literature . Case Rep Oncol Med \n2014 ;2014 :436821 .24716045 \n[6] Wu W Youm W Rezk SA \nHuman herpesvirus 8-unrelated primary effusion lymphoma-like lymphoma: report of a rare case and review of 54 cases in the literature . Am J Clin Pathol \n2013 ;140 :258 –73 .23897264 \n[7] Kobayashi Y Kamitsuji Y Kuroda J \nComparison of human herpes virus 8 related primary effusion lymphoma with human herpes virus 8 unrelated primary effusion lymphoma-like lymphoma on the basis of HIV: report of 2 cases and review of 212 cases in the literature . Acta Haematol \n2007 ;117 :132 –44 .17135726 \n[8] Cullinane CA Paz IB Smith D \nPrognostic factors in the surgical management of pericardial effusion in the patient with concurrent malignancy . Chest \n2004 ;125 :1328 –34 .15078742 \n[9] Alexanian S Said J Lones M \nKSHV/HHV8-negative effusion-based lymphoma, a distinct entity associated with fluid overload states . Am J Surg Pathol \n2013 ;37 :241 –9 .23282971 \n[10] Muir KW Rodger JC \nCardiac tamponade as the initial presentation of malignancy: Is it as rare as previously supposed? \nPostgrad Med J \n1994 ;70 :703 –7 .7831164\n\n",
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"mesh_terms": "D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D001932:Brain Neoplasms; D002305:Cardiac Tamponade; D003520:Cyclophosphamide; D004317:Doxorubicin; D004417:Dyspnea; D019288:Herpesvirus 8, Human; D006801:Humans; D007121:Immunocompetence; D054685:Lymphoma, Primary Effusion; D008297:Male; D010166:Palliative Care; D011241:Prednisone; D011878:Radiotherapy; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine",
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"title": "Human herpes virus 8-unrelated primary effusion lymphoma-like lymphoma presenting with cardiac tamponade: A case report.",
"title_normalized": "human herpes virus 8 unrelated primary effusion lymphoma like lymphoma presenting with cardiac tamponade a case report"
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"abstract": "Synthetic cannabinoid receptor agonists (SCRAs) have become the largest group of new psychoactive substances monitored by the European Union Early Warning System. Despite the wide diffusion on the market, data regarding effects, toxicities, and mechanisms as well as toxic/lethal doses are still scarce.\nA comprehensive literature search for articles published up to January 2019 was performed in multiple electronic databases. Only cases of death in which toxicological analyses revealed the presence of SCRAs in blood or urine and at least an external examination was performed, including those occurred in emergency departments, were included.\nOf 380 studies identified, 354 were excluded, while 8 additional manuscripts were included through the screening of relevant references cited in the selected articles. A total number of 34 manuscripts (8 case series and 26 case reports) were included.\nTypical toxic ranges for SCRAs have not been so far identified, and the results of toxicological analyses should be interpreted with caution. In death cases involving SCRAs, a thorough post-mortem examination is a prerequisite to assess the role of the substance use in the deceased and to identify a probable mechanism of death. Even after a comprehensive analysis of clinical, circumstantial, toxicological, and autoptic data, the cause and manner of death remain unclear in some cases.",
"affiliations": "Legal Medicine and Toxicology, University-Hospital of Padova, Padova, Italy.;Section of Legal Medicine, Department of Excellence SBSP, University Politecnica delle Marche of Ancona, Ancona, Italy.;Unit of Forensic Toxicology, SAIMLAL Department, Sapienza University of Rome, Rome, Italy.;Institute of Forensic Medicine, Forensic Toxicology, Medical Center, University of Freiburg, Freiburg, Germany.;Section of Legal Medicine, Department of Excellence SBSP, University Politecnica delle Marche of Ancona, Ancona, Italy.",
"authors": "Giorgetti|Arianna|A|;Busardò|Francesco Paolo|FP|;Tittarelli|Roberta|R|;Auwärter|Volker|V|;Giorgetti|Raffaele|R|",
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"doi": "10.3389/fpsyt.2020.00464",
"fulltext": "\n==== Front\nFront Psychiatry\nFront Psychiatry\nFront. Psychiatry\nFrontiers in Psychiatry\n1664-0640 Frontiers Media S.A. \n\n10.3389/fpsyt.2020.00464\nPsychiatry\nSystematic Review\nPost-Mortem Toxicology: A Systematic Review of Death Cases Involving Synthetic Cannabinoid Receptor Agonists\nGiorgetti Arianna 12 Busardò Francesco Paolo 3* Tittarelli Roberta 4 Auwärter Volker 25 Giorgetti Raffaele 3 1Legal Medicine and Toxicology, University-Hospital of Padova, Padova, Italy\n2Institute of Forensic Medicine, Forensic Toxicology, Medical Center, University of Freiburg, Freiburg, Germany\n3Section of Legal Medicine, Department of Excellence SBSP, University Politecnica delle Marche of Ancona, Ancona, Italy\n4Unit of Forensic Toxicology, SAIMLAL Department, Sapienza University of Rome, Rome, Italy\n5Faculty of Medicine, University of Freiburg, Freiburg, Germany\nEdited by: Marc N. Potenza, Yale University, United States\n\nReviewed by: John Martin Corkery, University of Hertfordshire, United Kingdom; Fabrizio Schifano, University of Hertfordshire, United Kingdom\n\n*Correspondence: Francesco Paolo Busardò, fra.busardo@libero.itThis article was submitted to Addictive Disorders, a section of the journal Frontiers in Psychiatry\n\n\n25 5 2020 \n2020 \n11 46408 1 2020 06 5 2020 Copyright © 2020 Giorgetti, Busardò, Tittarelli, Auwärter and Giorgetti2020Giorgetti, Busardò, Tittarelli, Auwärter and GiorgettiThis 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.Background\nSynthetic cannabinoid receptor agonists (SCRAs) have become the largest group of new psychoactive substances monitored by the European Union Early Warning System. Despite the wide diffusion on the market, data regarding effects, toxicities, and mechanisms as well as toxic/lethal doses are still scarce.\n\nMethods\nA comprehensive literature search for articles published up to January 2019 was performed in multiple electronic databases. Only cases of death in which toxicological analyses revealed the presence of SCRAs in blood or urine and at least an external examination was performed, including those occurred in emergency departments, were included.\n\nResults\nOf 380 studies identified, 354 were excluded, while 8 additional manuscripts were included through the screening of relevant references cited in the selected articles. A total number of 34 manuscripts (8 case series and 26 case reports) were included.\n\nConclusions\nTypical toxic ranges for SCRAs have not been so far identified, and the results of toxicological analyses should be interpreted with caution. In death cases involving SCRAs, a thorough post-mortem examination is a prerequisite to assess the role of the substance use in the deceased and to identify a probable mechanism of death. Even after a comprehensive analysis of clinical, circumstantial, toxicological, and autoptic data, the cause and manner of death remain unclear in some cases.\n\nforensic toxicologynovel psychoactive substancessynthetic cannabinoidspost-mortem examinationtoxicological significance score\n==== Body\nIntroduction\nSynthetic cannabinoids or synthetic cannabinoid receptor agonists (SCRAs) are a heterogeneous group of compounds designed to mimic the effects of delta-9-tetrahydrocannabinol (Δ9-THC) by binding to the cannabinoid receptors CB1 and CB2. In contrast to Δ9-THC, a partial agonist at the CB1 and CB2 receptors, most of the SCRAs marketed so far are full agonists at these receptors and additionally show much higher potency (1, 2). Since their first detection in herbal blends in 2008 (3, 4), they have become the largest group of new psychoactive substances (NPS), with 190 compounds reported to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) until the end of 2018 and an extraordinary dynamic market (5), even though there has been a relative reduction of the rate of new compounds per year (5). It was initially claimed that SCRAs could be “safe” alternatives to marijuana, due to similarities of their pharmacological profile to Δ9-THC and other phytocannabinoids, and lots of compounds binding to the cannabinoid receptors have been synthesized and evaluated regarding their binding affinities and activity in animal or cell models since then (6). However, a huge number of in-vitro and in-vivo studies, reports, and alerts have highlighted severe adverse events and enhanced toxicity (2, 7, 8) prompting the United States Drug Enforcement Administration to classify some of these compounds as Schedule I substances. Signs and symptoms of SCRAs consumption include psychomotor agitation, euphoria, anxiety, confusion, and psychosis on the one side, sedation and loss of consciousness on the other (9, 10). Adverse cardiac effects are among the most frequently encountered adverse reactions after SCRA intake. Particularly, both tachycardia (more frequently) and bradycardia have been reported. Gastro-intestinal symptoms with nausea and vomiting are also common. Moreover, rhabdomyolysis, hyperthermia, and hypothermia, seizures, respiratory depression, nephro- and hepatotoxicity were described in combination with SCRA intake (11, 12). Some of these effects might be mediated also by interference with other neurotransmitter pathways, since certain SCRAs can also bind to glutamatergic, serotonin (5-HT), opioid, and both adrenergic and cholinergic receptors and to calcium, sodium, potassium channels (13).\n\nSeveral cases of intoxication have been reported caused by, e.g., MDMB-CHMICA and AB-CHMINACA, which can cause severe symptoms requiring hospitalization and prolonged recovery time (14). Other compounds, such as Cumyl-PEGACLONE, have been suggested as “relatively safe” due to the low number of poisonings despite the abundant presence in herbal blends (25–30% of tested products) and their widespread use (prevalence of 29% in samples positive for SCRAs, including testing for driving under the influence, insult, and threat, criminal offenses). Moreover, the role of the SCRA was deemed minor or contributory in the majority of death cases (15).\n\nDespite the wide diffusion in the market, data regarding effects, toxicities, and mechanisms as well as toxic/lethal doses are still scarce, making SCRAs one of the most “unpredictable” classes of substances (16). Moreover, only few studies regarding the time of detectability, the diffusion in tissues, and the post-mortem distribution of the drugs can be retrieved in the literature. The limited knowledge regarding the pharmacodynamics and pharmacokinetics of SCRAs contributes to the difficulties of the interpretation of toxicological results. Furthermore, several aspects, such as interactions among SCRAs or in the combination with other drugs, are difficult to assess in cases of SCRA-related deaths.\n\nTo our knowledge, there are no previous detailed review papers, which report fatalities caused by the misuse of synthetic cannabinoids providing circumstantial, analytical data, and complete results of post-mortem examination.\n\nThe aim of the present study is to offer an overview of thoroughly investigated fatalities involving SCRAs, considering not only analytical results, but also an in-depth analysis on investigative data, analytical methods, and macro and microscopic findings.\n\nMaterials and Methods\nLiterature Search and Inclusion/Exclusion Criteria\nIn February 2019 a literature search for articles published until January 2019 was performed in electronic databases (Pubmed, Scopus), using the following research terms: “synthetic cannabinoids” AND (death OR fatal OR fatalities OR autopsy OR forensic OR post-mortem). Search was done in English language and duplicates were manually deleted. Titles and abstracts were screened and only cases of death, in which toxicological analyses revealed at least one SCRA in blood or urine, and at least an external examination was performed were included. Patients rushed to the emergency department and subsequently died were also included in the selected cases.\n\nExclusion criteria were: irretrievability of a full-text; off-topic articles (e.g., death cases in which other NPS, but no SCRAs, were detected); in vitro/animal model studies; herbal blends analyses; non-fatal cases of intoxication; books/reviews not including unpublished cases of death due to SCRAs; autopsy/external examination not performed.\n\nData Extraction\nAn electronic database with the selected papers was built in Excel ® (Microsoft Office, 2006). For each included manuscript, authors, title, journal, year, and type of publication (e.g., case report, case series), number of death cases and type of involved SCRA were extracted.\n\nA separate database was built with the retrieved papers and, for each death case, the following information was extracted:\n\n\ntype of victim, referring to age and sex;\n\nconcentrations of SCRA retrieved during toxicological analyses in central and peripheral blood, urine, and tissues;\n\nother substances detected in blood;\n\ncircumstantial data (and whatever relevant emerged during the death scene investigation), with particular reference to a history of drug abuse and to the availability of herbal blends/paraphernalia at the scene,\n\npost-mortem gross and microscopic findings;\n\ncause, manner, and suggested mechanism of death;\n\npost-mortem interval (PMI)\n\nrole of the SCRA as described by the authors.\n\nData Analysis/Interpretation\nOnly a descriptive statistic was applied. For each death case, two independent observers assigned a Toxicological Significance Score (TSS) to the involved SC, in accordance to the methodology proposed by Elliott et al. (17). When no agreement was achieved, a third person was consulted. This rating was compared with the likely role in death assigned by the authors.\n\nInformation related to toxicological analytical methodology (linearity, calibration curve, accuracy, precision, limit of detection/quantification, matrix effect), in accordance with what suggested by Welter-Luedeke and Maurer (18) were also noted and taken into consideration when evaluating the single cases.\n\nResults\nLiterature Review\nThe literature search resulted in 380 sources after elimination of duplicates. Of these, 354 were excluded applying the criteria listed in “Materials and Methods,” while 8 additional manuscripts were included through the screening of references cited in the selected articles. Details of the literature search are listed in Figure 1.\n\nFigure 1 Flow diagram of study identification, screening, and selection.\n\nFinally, a total of 34 manuscripts were included (authors, title, journal, date of publication, and involved SCRAs are shown in Table 1), corresponding to 74 published cases. Of the 34 manuscripts, 8 consisted in case series and 26 in case reports, including articles only providing new analytical data on previously reported death cases (Table 1). Tables 2 and 3 both refer to the single cases. Particularly, Table 2 displays the epidemiology of the victim, the involved SCRA(s), other substances detected, anamnestic/circumstantial, and clinical data, macroscopic and microscopic features, cause, and suggested mechanism of death, toxicological significance score, and role of SCRA as suggested by the authors of the paper. In Table 3, concentrations in peripheral, central blood, urine, and tissues, together with the PMI are shown.\n\nTable 1 Characteristics of the included studies: authors, titles, journal, and year of publication, number of cases reported and type of SCRAs involved (semisystematic names).\n\nTitle\tJournal\tYear\tNo. of cases\tSCRA\tAuthor\t\nA case of intoxication with a mixture of synthetic cannabinoids EAM-2201, AB-PINACA and AB-FUBINACA, and a synthetic cathinone α-PVP.\tLeg Med (Tokyo)\t2018\t–\tEAM-2201, AB-PINACA, AB-FUBINACA\tYamagishi et al. (19)\t\nSynthetic cannabinoids: variety is definitely not the spice of life.\tJ Forensic Leg Med\t2018\t1\t5F-PB-22, 5F-AKB-48\tLangford and Bolton (20)\t\nTeens and Spice: A review of adolescent fatalities associated with synthetic cannabinoid use\tJ Forensic Sci\t2018\t2\tUR-144, XLR-11, JWH-022\tPaul et al. (21)\t\nIdentification and quantification of predominant metabolites of synthetic cannabinoid MAB-CHMINACA in an authentic human urine specimen.\tDrug Test Anal\t2018\t–\tMAB-CHMINACA\tHasegawa et al. (22)\t\nFatal intoxication by 5F-ADB and diphenidine: Detection, quantification, and investigation of their main metabolic pathways in humans by LC/MS/MS and LC/Q-TOFMS.\tDrug Test Anal\t2018\t1\t5F-ADB\tKusano et al. (23)\t\nPost-mortem distribution of the synthetic cannabinoid MDMB-CHMICA and its metabolites in a case of combined drug intoxication.\tInt J Legal Med\t2018\t1\tMDMB-CHMICA, EG-018\tGaunitz et al. (24)\t\nSensitive identification and quantitation of parent forms of six synthetic cannabinoids in urine samples of human cadavers by liquid chromatography–tandem mass spectrometry\tForensic Toxicol\t2017\t1\t5F-ADB, MAB-CHMINACA\tMinakata et al. (25)\t\nNew challenges in toxicology of new psychoactive substances exemplified by fatal cases after UR-144 and UR-144 with pentedrone administration determined by LC-ESI-MS-MS in blood samples.\tArch Med Sadowej Kryminol\t2017\t3\tUR-144\tRojek et al. (26)\t\nThree fatalities associated with the synthetic cannabinoids 5F-ADB, 5F-PB-22, and AB-CHMINACA\tForensic Sci Int\t2017\t3\t5F-ADB\tAngerer et al. (27)\t\nIdentification and quantitation of 5-fluoro-ADB, one of the most dangerous synthetic cannabinoids, in the stomach contents and solid tissues of a human cadaver and in some herbal products\tForensic Toxicol\t2015\t–\t5F-ADB, 5F-ADB-PINACA, MAB-CHMINACA\tHasegawa et al. (28)\t\nPostmortem distribution of MAB-CHMINACA in body fluids and solid tissues of a human cadaver\tForensic Toxicol\t2015\t1\t5F-ADB, 5F-ADB-PINACA, MAB-CHMINACA\tHasegawa et al. (29)\t\nPostmortem distribution of AB-CHMINACA, 5-fluoro-AMB and diphenidine in body fluids and solid tissues in a fatal poisoning case: usefulness of the adipose tissue for detection of the drugs in the unchanged forms\tForensic Toxicol\t2015\t1\tAB-CHIMINACA, 5F-AMB\tHasegawa et al. (30)\t\nFatal poisoning with the synthetic cannabinoid AB-CHMINACA and ethyl alcohol – a case study and literature review\tProblems of Forensic Sciences\t2016\t1\tAB-CHMINACA\tGieron et al. (31)\t\nDeath after use of the synthetic cannabinoid 5F-AMB\tForensic Sci Int\t2016\t1\t5F-AMB\tShanks and Behonick (32)\t\nSynthetic cannabinoid drug use as a cause or contributory cause of death\tForensic Sci Int\t2016\t25\tJWH-018, AM-2201\tLabay et al. (33)\t\nDeath associated with the use of the synthetic cannabinoid ADB-FUBINACA.\tJ Anal Toxicol\t2016\t1\tADB-FUBINACA\tShanks et al. (34)\t\nClinical and toxicological findings of acute intoxication with synthetic cannabinoids and cathinones\tAcute Med Surg\t2016\t1\tMepirapim\tFujita et al. (35)\t\nCase report: fatal intoxication with synthetic cannabinoid MDMB-CHMICA\tForensic Sci Int\t2016\t1\tMDMB-CHMICA\tAdamowicz (36)\t\nDeath due to diabetic ketoacidosis: Induction by the consumption of synthetic cannabinoids?\tForensic Sci Int\t2015\t1\tAB-CHMINACA, AB-FUBINACA, AM-2201, 5F-AMB, 5F-APINACA, EAM-2201, JWH-018, JWH-122, MAM-2201, STS135, THJ2201, UR-144, XLR-11\tHess et al. (37)\t\nHigh-resolution mass spectrometric determination of the synthetic cannabinoids MAM-2201, AM-2201, AM-2232, and their metabolites in postmortem plasma and urine by LC/Q-TOFMS.\tInt J Legal Med\t2015\t1\tMAM-2201, AM-1220, AM-2232\tZaitsu et al. (38)\t\nCase reports of synthetic cannabinoid XLR-11 associated fatalities.\tForensic Sci Int\t2015\t2\tXLR-11\tShanks et al. (34)\t\nDeaths linked to synthetic cannabinoids.\tForensic Sci Med Pathol\t2015\t3\tPB-22\tGerostamoulos et al. (39)\t\nFour postmortem case reports with quantitative detection of the synthetic cannabinoid, 5F-PB-22\tJ Anal Toxicol\t2013\t4\t5F-PB-22\tBehonick et al. (40)\t\nToxicological findings of synthetic cannabinoids in recreational users.\tJ Anal Toxicol\t2013\t1\tJWH-210\tKronstrand et al. (16)\t\nK2 toxicity: fatal case of psychiatric complications following AM2201 exposure\tJ Forensic Sci\t2013\t1\tAM-2201, JWH-018\tPatton et al. (41)\t\nAn accidental fatal intoxication with methoxetamine\tJ Anal Toxicol\t2013\t1\tAM-694, AM-2201, JWH-018\tWikström et al. (42)\t\nDetection of JWH-018 and JWH-073 by UPLC-MS-MS in postmortem whole blood casework\tJ Anal Toxicol\t2012\t3\tJWH-018, JWH-073\tShanks et al. (43)\t\nA fatal case of MAM-2201 poisoning\tForensic Toxicol\t2013\t1\tMAM-2201\tSaito et al. (44)\t\nA case of death caused by abuse of a synthetic cannabinoid N-1-naphthalenyl-1-pentyl-1H-indole-3-carboxamide\tForensic Toxicol\t2014\t1\tNNEI\tSasaki et al. (45)\t\nA fatal case involving several synthetic cannabinoids\tToxichem Krimtech\t2013\t1\tJWH-122, JWH-018, JWH-210, MAM-2201, AM-2201, UR-144\tSchaefer et al. (46)\t\nA report of novel psychoactive substances in forensic autopsy cases and a review of fatal cases in the literature\tLegal Medicine\t2017\t4\t5F-AB-PINACA, 5F-AMB\tKubo S et al. (47)\t\nSudden cardiac death following use of synthetic cannabinoid MDMB-CHMICA\tJ Anal Toxicol\t2016\t1\tMDMB-CHMICA\tWestin et al. (48)\t\nAnalysis and clinical findings of cases positive for the novel synthetic cannabinoid receptor agonist MDMB-CHMICA\tClin Toxicol (Phila)\t2016\t2\tMDMB-CHMICA\tSeywright et al. (49)\t\nIdentification of 5-Fluoro ADB in human whole blood in four death cases.\tJ Anal Toxicol\t2018\t4\t5F-ADB\tUsui et al. (50)\t\n“-”: further analyses were performed on a previously published case.\n\nTable 2 Results of the literature revision for each case.\n\nAge, sex\tSCRA(s) in peripheral blood (ng/ml)\tOther substances in blood\n(ng/ml, ethanol g/L)\tAnamnestic and Circumstantial data\tClinical data\tGross findings\tHistopathology\tCause of death\tSuggested mechanism\tTSS\tRole of SCRA(s) (authors)\tStudy\t\n-, M\tEAM-2201: 0.0566 ± 0.0042;\nAB-PINACA: 0.0126 ± 0.0001\tα-PVP: pos\tDead in a bathtub, with water level lower than the shoulder\tNo medical history\tLung congestion and edema\tNP\tPossible intoxication due to synergic effect\tNP\tTSS U\tPossible intoxication due to synergistic effect\tYamagishi et al. (19)\n.Minakata et al. (25)\t\n35, M\t5F-PB-22: pos\n5F-AKB-48: pos\tEthanol 3.11\tHistory of schizophrenia, alcohol and alcohol withdrawal, seizures; he was found dead in an alleyway within 30 min of having been given a smoking pipe\tShock advisory defibrillator\tLungs congestion, scattered erosions within the mucosa of the stomach\tConfirmation of macroscopic findings\tCombination of alcohol and SCRAs\tSudden onset of cardiac arrhythmias or cardiac death\tTSS U\tPossible contributory role in emotional and mental imbalance\tLangford and Bolton (20)\t\n20s, M\t5F-ADB: 0.12\n(iliac)\t–\tFound dead in a sitting position in his room. The police found an opened sachet labeled “Heart Shot BLACK” on a table.\tNo medication history\tUnremarkable\tNP\tAcute circulatory failure after drug inhalation\tNP\tTSS 2\tThe SCRA involvement on death is unknown\tUsui et al. (50)\t\n50s, M\t5F-ADB: 0.23\n(iliac)\t–\tThe decedent was lying on the floor in a supine posture. An opened sachet labeled “Heart Shot BLACK” was found on a table.\tNP\tIschemic heart disease\tNP\tAcute circulatory failure after drug inhalation\tNP\tTSS 2\tThe SCRA involvement on death is unknown\t\t\n20s, M\t5F-ADB: 0.16\n(iliac)\t–\tFound dead in a prone position in a hallway, after vomiting and bleeding from nose\tNo medication or medical history\tUnremarkable\tNP\tAcute circulatory failure after drug inhalation\tNP\tTSS 2\tThe SCRA involvement on death is unknown\t\t\n50s, M\t5F-ADB: 1.38\n(iliac)\t–\tHistory of schizophrenia under medication, he was found dead in his car in a parking lot while he was holding a plastic pipe and with an unsealed “Heart Shot BLACK” package in his hands\tFor the treatment of schizophrenia he was taking risperidone, biperiden, and olanzapine.\tUnremarkable\tNP\tAcute circulatory failure after drug inhalation\tNP\tTSS 2\tThe SCRA involvement on death is unknown\t\t\n14, M\tAB-CHMINACA: 8.2 (subclavian)\t–\tDaily SC intake for 6 months, last use an hour before experiencing sudden cardiac death following an unwitnessed collapse in his bathroom\tNo history of any other substance use, or any relevant medical, surgical or family history\tDilated cardiomyopathy, cardiomegaly (520 g), bilateral pulmonary edema, bilateral pleural effusion and ascites\tCardiomyocyte hypertrophy, contraction band necrosis, pulmonary edema and pulmonary vascular congestion\tSCRA intoxication\tSudden cardiac death and dilated cardiomyopathy\tTSS 3\tSCRA intoxication\tPaul et al. (21)\t\n17, M\tUR-144: 12.3\n(subclavian),\nXLR-11: 1.3\n(subclavian),\nJWH-022: 3\n(subclavian)\t–\tOccasional user of SC (“Black Mamba”), last use 4-5 h before death. He was found in his bedroom\tNP\tUnremarkable\tUnremarkable\tSCRAs intoxication\tSudden death\tTSS 3\tNP\t\n34, M\tMAB-CHMINACA: 6.05\tEthanol: 0.3\nQuetiapine: pos\nNicotine: pos\tSevere drugs dependence with multiple admission to mental health hospital; found dead in his room\tNP\tMassive aspiration of gastric content occluding the airways\tNP\tAsphyxia due to aspiration of stomach contents into the trachea\tVomiting under reduced consciousness\tTSS 3\tNP\tHasegawa et al. (22, 28, 29)\t\n53, M\t5F-ADB: 0.19 ± 0.04 (*)\tDiphenidine: 12 ± 2.6\tFound dead at his apartment. Near the deceased were found an open package of a branded herbal blend (“Heart Shot BLACK”).\tNP\tUnremarkable\tNP\tProbably SC and diphenidine intoxication\tNP\tTSS U\tAcute mixed intoxication\tKusano et al. (23)\t\n27, M\tMDMB-CHMICA: 1.7\tAmphetamine: 1050\nMDMA: 275\nMDA: 22\nTHC: 9.3\nTHCCOOH: 65\tEyewitnesses reported that the man fell from the 24th floor of a building.\tNP\tMultiple injuries to head (including partial debraining), left lung and internal bleeding due to rib fractures.\tNP\tFall from height\tPsychosis-induced or loss of attention\tTSS 1\tUnder the influence\tGaunitz et al. (24)\t\n30, M\tAB-CHMINACA: pos\n5F-AMB: pos\tDiphenidine 715\tFound dead in a parked car\tNP\tLivor mortis associated with vibices for wide areas of the body surface with a few subcutaneous hemorrhages\tNP\tNP\tNP\tTSS U\tNP\tMinakata et al. (25)\n.Hasegawa et al. (30)\t\n30s, M\t5F-ADB: pos\nMAB-CHMINACA: pos\t–\tFound dead at home\tNP\tUnremarkable\tNP\tNP\tNP\tTSS U\tNP\tMinakata et al. (25)\t\n16, M\tUR-144: 2.1\t–\tHe smoked “dope” and a cigarette with UR-144, experienced hallucinations and psychosis, lost control of himself and jumped out of the window from the second floor of the building\tNP\tMultiple fractures to skull, thoracic and lumbar spine, pubic and ischial bones and multi-organ injuries\tNP\tFall from height\tPsychosis-induced\tTSS 3i\tNP\tRojek et al. (26)\t\n22, M\tUR-144: 1.4\tPentedrone: 2300\tHistory of alcohol and drugs abuse, previous suicidal ideations; showed mental disorders and aggressive behavior, injured a witness with an axe\tNP\tNP\tNP\tAsphyxia due to hanging\tBehavioral abnormalities\tTSS\n1i\tNP\t\n40, M\tUR-144: 4\tPentedrone: 290\tHistory of mental instability; psychomotor agitation, aggressive behavior, after smoking a legal high called Orange Flame\tAcute toxic liver damage, kidney failure, rhabdomyolysis, disseminated intravascular coagulation, bleeding in the gastrointestinal tract and traumatic hematomas; cardiac arrest\tNP\tNP\tMassive multi-organ failure due to the effect of toxic substances\tBehavioral abnormalities with desire of enhancing stimulating effects\tTSS\n1i\tNP\t\n25, M\t5F-PB-22: 0.37\tEthanol: 2.6\tHistory of alcohol and illicit drug use, found dead in his apartment; witnesses reported that the decedent had drunk a lot of alcohol on the evening before his death. Packages of products named “F1,” “Hammer Head,” and “Magic Gold” were found at the scene\tNP\tCerebral edema, pulmonary edema, acute blood congestion of internal organs, petechial hemorrhage in eyelids, facial skin and on the lungs\tNP\tPartial or complete obstruction of the upper airways\tSuffocation in presence of SC and ethanol in a state of unconsciousness\tTSS 2\tDirect contribution\tAngerer et al. (27)\t\n28, M\tAB-CHMINACA: 4.1\tEthanol: 1.45\tExtensive consumer of alcohol and illicit drugs, found dead in his flat. Three packages of the herbal blend “Desert Premium Potpourri 2 g” were located besides the decedent\tNP\tCerebral edema and pulmonary edema\tNP\tMixed ethanol and SC intoxication with fatal outcome\tNP\tTSS 2\tDirect contribution\t\n41, M\t5F-ADB: 0.38\tEthanol: 0.09\nTrimipramine: 170\nOlanzapine: 41\tMethamphetamine user, found at home\tNP\tCerebral edema, pulmonary edema, acute blood congestion of internal organs, petechial hemorrhages in eyelids, facial skin and on the lungs\tMyocardial cells death, amorphous material in alveoli as a sign of aspiration of stomach content\tComa and subsequent aspiration of vomit\tNP\tTSS 3\tDirect contribution\t\n-, -\tAB-PINACA: 26\tα-PVP: 9900\nMDPV: 55\tNP\tNP\tNP\tNP\tFall from height\tNP\tTSS U\tNP\tKubo et al. (47)\t\n-, -\t5F-AMB: 8\tα-PVP: 90\nAH-7921: 1100\tNP\tNP\tNP\tNP\tIntoxication\tNP\tTSS U\tNP\t\n-, -\tMepirapim: 157\t6-APB: 2.7\n6-MAPB: <1\nα-PHP: 338\nDL-4662: 138,\nSodium valproate: pos\tNP\tNP\tNP\tNP\tIntoxication\tNP\tTSS U\tNP\t\n-, -\t5F-AMB: <1\tDL-4662 <1, α-PHP 15,\nmetamphetamine 30, amphetamine 10\tNP\tNP\tNP\tNP\tIntoxication\tNP\tTSS U\tNP\t\n30s, M\tAB-CHMINACA:\n1.5 (**)\tEthanol: 1.8\tAlcohol addiction. After smoking a pipe with a herbal mixture (“Strongman”), he collapsed and had a slurred speech. An hour later, was found with vomit, weak pulse, shallow breathing. About half an hour later, was declared dead by the emergency doctor\tNP\tCongestion of internal organs and pulmonary edema\tNP\tAcute cardiorespiratory failure\tSNC depression\tTSS 3\tIntoxication due to alcohol and SCRA consumption\tGieron and Adamowicz (31)\t\n22, M\tMDMB-CHMICA: 1.4\n(ante-mortem serum)\tMirtazapine: 5.3\nTHC: 1.5\nCetirizine: pos\tFound lifeless 15 minutes after smoking a brown organic powder\tAsystole, declared dead due to brain hypoxia\tAnoxic brain damage and pneumonia\tNP\tSudden cardiac death\tNP\tTSS 3\tOverdose\tWestin et al. (48)\t\n44, M\tMDMB-CHMICA:\n1 (**)\tAmitriptyline: 130\tHistory of poor mental health\tNP\tNP\tNP\tSuicidal by hanging\tNP\tTSS 1\tNot attributable to SCRA\tSeywright et al. (49)\t\n38, M\tMDMB-CHMICA:\n<1 (**)\tEthanol: 2.37\nAcetone: < 100\nBHB: 249\tHistory of alcoholism: found dead at home\tNP\tNP\tNP\tComplications of chronic alcohol abuse and acute alcohol toxicity\tNP\tTSS 1\tNot attributable to SCRA\t\n34, M\t5F-AMB: 0.3\n(subclavian)\t–\tHistory of ethanol abuse, found supine on the floor. An opened bag of “Apollo” brand herbal incense was found in his pocket\tNP\tUnremarkable medical history\tNP\tSC toxicity\tNP\tTSS 2\tRelated\n(SCRA toxicity)\tShanks and Behonick (51)\t\n41, M\tJWH-018: 0.11,\nAM-2201: 2.5\tPhenytoin: 8800\tErratic and aggressive behavior, restrained by the police\tNP\tCardiomegaly with four chamber dilation\tNP\tComplications of excited delirium associated with synthetic marijuana use following police arrest and restraint procedures\tDelirium-induced\tTSSi 2\tNP\tLabay et al. (33)\t\n23, M\tJWH-210: pos\tFentanyl: pos\tSingle motor vehicle crash, no significant injuries, restrained by the police\tNP\tNP\tNP\tAgitated delirium associated with SCRA use following police arrest and restraint procedures\tDelirium-induced\tTSS 1\tNP\t\n25, M\tAM-2201: 0.21 JWH-018: 0.65\nJWH-122: pos\nJWH-210: pos\tEthanol: 0.15\ndelta-9-THC: 1.1 THC-COOH: 6.0\tUnresponsive after a party, recent binge drinking and jumping from a patio. He was found “frozen” after the jump.\tNP\tNo evidence of head, chest or abdomen injury.\tNP\tComplications of acute ethanol toxicity, acute SCRA toxicity, possible hypothermia\tNP\tTSS 2\tNP\t\n42, M\tXLR-11: pos\tMethamphetamine: 730\nAmphetamine: 90\tSeizure-like activity after methamphetamine and K2 intake\tAsystole at emergency arrival\tHemorrhagic pulmonary edema, obesity, cardiomegaly, moderate coronary artery atherosclerosis, hepatomegaly, splenomegaly, cholesterolosis, abrasions on hip and face\tMacrosteatosis, chronic active hepatitis\tMixed drug intoxication\tNP\tTSS 1\tNP\t\t\n55, M\tAM-2201: 17\nJWH-018: 0.47\tChlorpheniramine: < 100,\nParoxetine: pos, Benzodiazepines: pos,\nAlprazolam: <50, Aripiprazole pos\tRecent chest pain and heart palpitations in history of cardiac problems\tDiagnosed type 2 diabetes\tCoronary artery disease, obesity, cholelithiasis, rectal polyps, diabetes\tNP\tIschemic heart disease, obesity diabetes SCRA toxicity\tNP\tTSS 1\tNP\t\n34, M\tXLR-11: pos\nUR-144: pos\tEthanol 0.03 Lidocaine pos\tCollapse on public street, after intake of alcohol and drugs\tNP\tPresence of a needle puncture in the left antecubital fossa\tNP\tSCRAs and alcohol\tNP\tTSS U\tNP\t\n21, M\tJWH-018: pos\tEthanol: 0.013\nDelta-9-THC: 7\nTHC-COOH: 17\nCaffeine: pos\nTheobromine: pos\nAtropine: 110\tDecedent found unresponsive in bedroom\tNP\tPulmonary congestion, vomitus in upper airway, aspiration pneumonia, patchy alveolar hemorrhage\tPneumonitis\tMixed drug intoxication, aspiration pneumonia\tNP\tTSS 1\tNP\t\n24, M\tJWH-122: pos\nJWH-210: pos\nAM-2201: 0.16\tDelta-9-THC: 2.7 THC-COOH: 6.4\nCaffeine: pos\nNicotine: pos\nCotinine: pos\tLearning disability, found lying prone on floor of his bedroom\tNP\tBloody froth in airway, cardiomegaly\tNP\tSCRAs adverse effects\tNP\tTSS 2\tNP\t\n38, M\tUR-144: pos\tAmphetamine: pos Alprazolam: pos Citalopram/escitalopram: 130\nHydrocodone: 26\nMorphine (free): pos\tFound deceased lying on bed, after “partying” with others\tNP\tNP\tNP\tMixed drug intoxication\tNP\tTSS U\tNP\t\n24, M\tJWH-210: pos\nAM-2201: 1.1\tFluoxetine: 620 Norfluoxetine: 520 Phenobarbital: pos\nBenzodiazepines: pos\nDiphenydramine: pos\nMethadone: pos\tFound unresponsive in bed, in therapy with methadone\tNP\tNP\tNP\tMixed drug intoxication\tNP\tTSS U\tNP\t\nNP, M\tXLR-11: pos\tDelta-9-THC: 4.3 THC-COOH: 38 Oxycodone 420 Haloperidol 4.7 Fluoxetine 1300 Norfluoxetine 370 Trazodone 250\tDeath in private residence\tNP\tCongested lungs, froth in airway, bilateral pleural effusions, remote lesions in brain, variable discoloration of liver\tNP\tMixed drug intoxication\tNP\tTSS 1\tNP\t\t\n56, F\tXLR-11: pos\t–\tPreviously afflicted with cancer, noncompliant diabetic, shortness of breath after smoking “Diablo Spice”\tCardiac arrest at emergency arrival\tNP\tNP\tSCRA abuse, carcinoma of breast, diabetes\tNP\tTSS U\tNP\t\n15, M\tXLR-11: pos\t–\tFound next to bathtub with the face submerged and vomit from nose\tAnoxic brain injury\tNP\tNP\tSC\tNP\tTSS U\tNP\t\n42, F\tAM-2201: 2.8\nJWH-018: 0.11\tCarbon monoxide: 4300\nCaffeine: pos\nCotinine: pos\tHistory of alcohol and SC use. Heart disease. Vomit and diarrhea after binge-drinking and smoking “Spice,” then found supine on bedroom floor\tNP\tCongestion in lungs, fatty liver, cardiomegaly, chronic obstructive pulmonary disease, mild coronary arteriosclerosis\tNP\tSCRA toxicity\tNP\tTSS 2\tNP\t\n25, M\tJWH-122: pos,\nJWH-250: 0.23\nAM-2201: 7.3\tCaffeine: pos\nTheobromine: pos\nNicotine: pos\nCotinine: pos\tFound prone on bed\tNP\tObesity, foam in external nares and pulmonary edema\tNP\tAdverse effects of drugs\tNP\tTSS 2\tNP\t\n17, M\tJWH-122: pos\tTHC-COOH: 5.2\tCardio-pulmonary arrest after use of “Legal Phunk”\tNP\tNP\tNP\tSudden death associated with SCRA use\tNP\tTSS U\tNP\t\n25, M\tJWH-122: pos\nJWH-210: pos\nAM-2201: 0.22\t–\tFound unresponsive in the bathroom after vomiting\tAnoxic brain injury\tNP\tNP\tAnoxic brain injury due to SCRA toxicity\tNP\tTSS U\tNP\t\n55, M\tAM-2201: 0.13\tHydrocodone < 20\tFound unresponsive and cold on garage floor with a large “goose egg” on the back of his head and a small amount of blood\tNP\tHypertensive heart disease, blunt force injuries of the head, pulmonary emphysema, obesity, hemangioma in liver\tNP\tHypertensive heart disease, blunt force injuries to the head, SCRA presence\tNP\tTSS 1\tNP\t\n29, M\tJWH-122: pos\t–\tSweating and vomiting for several days, found dead at home\tNP\tCoronary artery disease, multiple sharp force injuries to foot\tNP\tAcute myocardial ischemia, coronary artery disease\tNP\tTSS 1\tNP\t\t\n61, F\tXLR-11: pos\tEthanol: 0,03\nMetoprolol: pos\nMetoclopramide: trace\tFound unresponsive in bed\tNP\tNo autopsy\tNP\tAtherosclerotic cardiovascular disease\tNP\tTSS 1\tNP\t\n52, M\tJWH-018: 0.28\tChlordiazepoxide: 2000\nNordiazepam: 750 Norchlordiazepoxide: detected Demoxepam: detected\nOxazepam: trace detected\tStruck by two vehicles while he was crossing a road\tNP\tNo autopsy\tNP\tMultiple blunt force injuries\tNP\t\tNP\t\n15, F\tXLR-11: pos\t–\tPassenger in auto collision\tNP\tNP\tNP\tMultiple injuries\tNP\tTSS 1\tNP\t\n30, F\tXLR-11: pos\tLorazepam: 28\nCotinine: pos\nLidocaine: pos\tChest pain\tPulseless ventricular fibrillation, successful resuscitation, acute ST-elevation, myocardial infarction, ventricular fibrillation\tComplete occlusion of left anterior descending coronary artery with a thrombus\tNP\tAcute myocardial infarction due to coronary artery thrombosis\tNP\tTSS 1\tNP\t\n31, F\tJWH-175: 105\tMDEA: 217\nMDA: 111\tImmunosuppression due to kidney transplant, diabetes, consumed a pot brownie, experiencing vomiting and drowsiness, bewilderment. Fell from a fire escape\tNP\tSubdural hematoma, pelvic fracture, liver laceration, facial and elbow fractures\tNP\tMultiple blunt traumatic injuries, acute mixed drug intoxication\tNP\tTSS 1i\tNP\t\n58, M\tJWH-210: pos\t–\tCollapse in a parking after a wavering gait, after smoking K2\tSeizure\tAtherosclerotic cardiovascular disease and cardiac hypertrophy\tNP\tAcute myocardial infarction due to coronary artery thrombosis\tNP\tTSS 1\tNP\t\t\n41, F\tADB-FUBINACA: 7.3 (*)\tTHC: 1.1\nTHC-COOH: 4.7\tAggressive after smoking SC known as “Mojo,” physically restrained by her children, then became unresponsive.\tNP\tPulmonary edema, vascular congestion, thrombotic occlusion of the lumen of the left anterior descending coronary artery by hemorrhagic disruption of coronary arterial plaque, ischemia of the anterior left ventricular myocardium\tNP\tCoronary arterial thrombosis in combination with SCRA use\tBlock of the artery's blood flow leading to dysrhythmia\tTSS 1\tContribution proved by temporal relationship\tShanks et al. (51)\t\n23, M\tMepirapim: 950 (serum)\tA-EAPP 3100\tFell asleep after ingestion of the drugs in the restroom; he was found without respiratory signs and was transferred to a hospital\tCardio-pulmonary arrest and confirmed dead approximately 3.5 h after drug use\tCongestion of the organs (particularly the lungs) and gastrointestinal bleeding from the stomach into the duodenum\tNP\tAcute circulatory failure due to SCRA intoxication\tAcute circulatory failure\tTSS 2\tNP\tFujita et al. (35)\t\n25, M\tMDMB-CHMICA: 5.6 (ante-mortem blood),\nMDMB-CHMICA: < 0.2 (0.09 estimated)\n(post-mortem blood)\tEthanol: 1.48 (ante-mortem blood)\nEthanol: 0.81\n(post-mortem blood)\tHistory of alcohol and NPSs abuse. After smoking two different SCRAs in a day and drinking a beer, he was wheezing, vomited and then lost consciousness. He was found lying on the floor, without a circulation and a pulse\tOn hospital admission, he was deeply unconsciousness, limp, circulatory and respiratory inefficient, without deep tendon, pharyngeal and tracheal reflexes. During hospitalization, severe redness of the skin, pathological muscle contraction of chest were observed. Purulent and watery content was expelled and diarrhea and bleeding diathesis\tRespiratory, circulatory, heart, kidney and liver failures as well as hypoxic-ischemic damage of the CNS\tNP\tSCRA intoxication in combination with ethanol\tAsystole, loss of consciousness, multiple organ failure and then cardiac arrest\tTSS 2\tSCRA main cause of poisoning\tAdamowicz, (36)\t\n25, M\tAB-CHIMINACA: 2.8\nAB-FUBINACA: 0.97\nAM-2201: <0.1\n5F-AMB: 0.19\n5F-APINACA: 0.51\nEAM-2201: <0.1\nMAM-2201: <0.1\nSTS 135: 0.16\nTHJ 2201: 0.16\tXLR-11 m and UR-144 m in urine\tHistory of SCRA use with previous intoxications, insulin dependent diabetes. Found dead in his apartment\tNP\tBrain edema, pulmonary edema, subepicardial petechial hemorrhages, hepatic steatosis, aorta angusta, small myocardial scars\tPulmonary congestion and edema, microvesicular steatosis of the liver, Armanni-Ebstein cells in kidneys\tDiabetic ketoacidosis, probably following SCRA consumption\tSkipping of insulin doses due to intoxicated state or SCRAs induced hyperglicemia\tTSS 1\tContributory\tHess et al. (37)\t\n20, M\tMAM-2201: 16.3,\nAM-1220: 140,\nAM-2232: 0.86\t–\t10 min after smoking an herbal product, violent behavior. Found dead after 1.5 h\tNP\tLungs, heart and liver congestion\tNP\tNP\tNP\tIndirect\tUnrated contribution\tZaitsu et al. (38)\t\n29, F\tXLR-11: 1.4\tDiphenhydramine: 81\tKnown user of SC, found dead on the floor of the bedroom\tNP\tUnremarkable\t\tSCRA intoxication\tNP\tTSS 2\tCausative\tShanks et al. (34)\t\n32, F\tXLR-11: 0.6\t–\tHistory of drug abuse (methamphetamine, heroin and SCRAs). The day before, presented to the emergency room with chest pain, nausea, and agitation, diagnosed with anxiety. Later found unresponsive at a friend's house.\tNP\tPulmonary edema and congestion, acute visceral congestion and mild pulmonary anthracosis\tNP\tNP\tNP\tTSS 2\tProbable contributory\t\n15–35\tPB-22: pos\t–\tFound at home\tNP\tUnremarkable\tUnremarkable\tUnascertained\tNP\tTSS U\tUnknown, no competitive cause\tGerostamoulos et al. (39)\t\n15–35\tPB-22: pos\t–\tFound at home\tNP\tUnremarkable\tUnremarkable\tUnascertained\tNP\tTSS U\tUnknown, no competitive cause\t\n15–35\tPB-22: pos\t–\tFound at home\tNP\tUnremarkable\tUnremarkable\tUnascertained\tNP\tTSS U\tUnknown, no competitive cause\t\n20s M\tNNEI: 0.99, 0.64 (*)\t–\tFound dead on the floor of his room, a package containing dried herbal blend labeled “Fairy evolution” was found in the room, previous history of weight loss\tNo medical history\tMarked lungs congestion\tOrgans and lungs congestion. Lungs: marked congestion and edema, alveolar macrophage infiltrations. Liver: slight lymphocytic infiltrations in the Glisson's sheat. Spleen: arteriolar hyalinizations and severe congestion. Brain: Corpora amylacea. Heart: arteriolar wall hypertrophy, slight interstitial fibrosis and contraction bands\tAcute circulatory disturbance induced by NNEI\tHypertension and hyperactivity of cardiac function\tTSS 2\tSCRA poisoning\tSasaki et al. (45)\t\n17, M\t5F-PB-22: 1.1\tEthanol: 0.033, Amiodarone\nCaffeine\n(not quantified)\tHis friends reported that he began gasping for air and then fell to the ground, after SCRA consumption and ethanol intake\tNP\tUnremarkable\t\tSCRA intoxication\tPossible anaphylactic etiology characterized by sudden onset cardiac dysrhythmias or seizure\tTSS 2\tNP\tBehonick et al. (40)\t\n27, M\t5F-PB-22: 1.3\n(ante-mortem serum)\tTHC-COOH\tHistory of marijuana use of several times per week.\tAcute liver injury, severe coagulopathy, acute kidney injury, acute respiratory failure, hypoxemia, severe anion gap metabolic and lactic acidosis.\nBrief episode of cardiac arrest, and pulseless electrical activity and poor oxygenation secondary to acute respiratory distress syndrome likely the result of aspiration and pulmonary contusions following chest compressions.\tNP\tNP\tFulminant liver failure in the setting of THC and SC exposure\tAcute hepatic failure caused by the accumulation of a toxic metabolic intermediate still unidentified.\tTSS 2\tNP\t\n18, M\t5F-PB-22: 1.5\n(iliac)\t–\tFound dead at home after a night of partying, with alcohol intake and SCRAs smoking (K2/Spice)\tNP\tBilateral pulmonary vasocongestion and congestion in the abdominal organs (liver, spleen and kidneys)\tNP\tSudden death, in association with synthetic cannabinoid use\tNP\tTSS 2\tNP\t\n19, M\t5F-PB-22: 1.5 (*)\t–\t\tNP\tBilateral pulmonary edema and congestion of viscera\tNecrotizing granulomatous inflammation with histoplasma microorganisms\tAcute drug intoxication using the synthetic cannabinoid 5F-PB-22\tNP\tTSS 2\tNP\t\n36, M\tJWH-018: 0.1\nJWH-122: 0.39\nAM-2201: 1.4\nMAM-2201: 1.5\nUR-144: 6\n(estimated)\tAmphetamine: 250\tSudden collapse after smoking herbal blend named “Mary Joy Annihilation”\tSeizures, multiple attempts of resuscitation\tStenosing coronary sclerosis, pulmonary and cerebral edema and congestion of inner organs\tNP\tAcute influence of several SCRAs and amphetamine\tNP\tTSS 1\tContributory\tSchaefer et al. (46)\t\n17, M\tJWH-210: 12\t–\tFound dead outdoors (temperature during the night was 6–8°C), after having smoked a mixture of herbs labeled “Smoke XXX. A potent potpourri”\tNP\tLow BMI (16.4), lung edema\tNP\tHypothermia in combination with SCRA intoxication\tHypothermia\tTSS 2\tSignificant role\tKronstrand et al. (52)\t\n23, M\tAM-2201: 12,\nAM-2201 m: 2.47\nJWH-018 m: 123, 50.8 (*)\t–\tA sibling heard 30 minutes of “stomping noises.” Significant damage to a wall and glass window at the scene, a large volume of blood covered the floor, windows and walls\tNo known history of mental illness, seizures disorder, previous psychiatric care or past or current use of illicit drugs or over-the-counter medication (OTC)\tMultiple blunt-force injuries to both hands and sharp force wounds on the head and upper extremities, including a fatal stab wound at the neck\tNP\tSelf-inflicted fatal wound due to SC use. No evidence indicating the intent of self-harm\tPsychiatric complications caused by AM-2201 use\tTSS\n2i\tPsychiatric complications caused by SCRA\tPatton et al. (41)\t\n26, M\tAM-694: 0.09\n(0.00009 µg/g)\nAM-2201: 0.3\n(0.0003 µg/g)\nJWH-018: 0.05\n(0.00005 µg/g)\tMethoxetamine: 8600\nVenlafaxine 300\nO-desmethylvenlafaxine: 400,\nTHC: pos\tFound on the floor in his apartment\tHistory of drug abuse and depression (treated with venlafaxine)\tPulmonary edema\tNP\tAcute fatal intoxication with methoxetamine\t\tTSS 1\tPossible contributory\tWikström et al. (42)\t\n59, M\tMAM-2201: 12.4 (*)\t–\tFound dead on a sofa at home\tNP\tUnremarkable\tUnremarkable\tAcute intoxication\tNP\tTSS 3\tFatal intoxication\tSaito et al. (44)\t\n57, M\tJWH-018: 199 (*)\tClonazepam: 5.5\n7-aminoclonazepam: 56.6\nMethadone: 887 EDDP: 115 Morphine: 122 Pregabalin: 1800 Topiramate: 4100 Naloxone: pos (prescribed)\tThe man had smoked herbal incense (Spice) and a white powder presumably containing JWH-018\tUnresponsive to Narcan, asystole\tEnlarged heart\tNP\tNP\tNP\tTSS U\tNP\tShanks et al. (43)\t\n52, M\tJWH-018: 19.6\nJWH-073: 68.3 (*)\t–\tAvid herbal incense user, found nude and unresponsive at home\tNP\tNP\tNP\tNP\tNP\tTSS U\tNP\t\n29, M\tJWH-018: 83.3 (*)\t–\tAvid SCRAs user, history of suicidal tendencies\tNP\tNP\tNP\tSuicide by exsanguination\tNP\tTSS 3i\tNP\t\nRef, reference; age, -s: decade (e.g., 30s: from 30 to 39 years old); PBC, peripheral blood concentration; m, metabolites; pos, positive; NP, not provided; TSS, Toxicological Significance score.\n\n*Quantified in central blood.\n\n**Unclear if central or peripheral concentration.\n\n-: no other compounds detected.\n\nTSS indexed with “i” marks an indirect mechanism.\n\nTable 3 Post-mortem concentrations in peripheral blood (PBC), central blood (CBC) and other tissues.\n\nCannabinoid(s)\tPBC (ng/mL)\tCBC (ng/ml)\tPMI\tUrine\tOther organs concentration (ng/g)\tAuthor, Year\t\nEAM-2201,\nAB-PINACA,\nAB-FUBINACA\tEAM-2201: 0.0566 ± 0.0042;\nAB-PINACA: 0.0126 ± 0.0001\tEAM-2201: right heart 0.0287 ± 0.0045;\nEAM-2201: left heart 0.031 ± 0.0056;\nAB-PINACA: right heart 0.0196 ± 0.0038;\nAB-PINACA: left heart 0.0206 ± 0.001\t2 days\t\tEAM-2201: lung 0.35, liver 0.13; kidney 0.12;\nAB-PINACA: lung 0.36; liver 0.17; kidney 0.14;\nAB-FUBINACA: lung 0.12, liver 0.05, kidney 0.02\tYamagishi et al. (19)\nMinakata et al. (25)\t\n5F-PB-22,\n5F-AKB-48\t.unquantified\tunquantified\t8 h\t\t\tLangford and Bolton (20)\t\nAB-CHMINACA\t(subclavian) 8.2\t\t\t\t\tPaul et al. (21)\t\nUR-144, XLR-11, JWH-022\t.UR-144: (subclavian) 12.3;\nXLR-11: (subclavian) 1.3;\nJWH-022: (subclavian) 3\t\t\t\t\tPaul et al. (21)\t\n5F-ADB,\n5F-ADB-PINACA,\nMAB-CHMINACA\tMAB-CHMINACA 6.05\tMAB-CHMINACA:\nright heart 10.6;\nleft heart 9.30\t35-40 h\tm\t\tHasegawa et al. (22, 29)\t\n5F-ADB\t\t0.19\t2 days\tm\t\tKusano et al. (23)\t\nMDMB-CHMICA\t1.7\t2.1\t12 h\t0.01 + m\tbrain: 5.5; lung: 2.6; liver: 2.6; stomach content: 2.4; kidney: 3.8; psoas muscle: 1.2\tGaunitz et al. (24)\t\n5F-ADB\t(iliac) 0.12\tright heart 0.24,\nleft heart 0.45\t\t\t\tUsui et al. (50)\t\n5F-ADB\t(iliac) 0.23\tright heart 1.35\t\t\t\t\n5F-ADB\t(iliac) 0.16\tright heart 0.14,\nleft heart 0.11\t\t\t\t\n5F-ADB\t(iliac) 1.38\tright heart 1.92\t\t\t\t\nAB-CHMINACA,\n5F-AMB\t\t\t2 days\tAB-CHMINACA, 5F-AMB\tAB-CHMINACA: brain 15.6, heart 20, lung 8.02, liver 21.2, spleen 7.55, kidneys 24.7, pancreas 38.9, adipose tissue 24.8;\n5F-ADB: adipose tissue 18.7\tMinakata et al. (25),\nHasegawa et al. (28)\t\n5F-ADB,\nMAB-CHMINACA\t\t\t1 day\t5F-ADB, MAB- CHMINACA\t\tMinakata et al. (25)\t\nUR-144\t2.1\t\t\t\t\tRojek et al. (26)\t\nUR-144\t1.4\t\t\t\t\t\nUR-144\t4\t\t\t\t\t\n5F-PB-22\t0.37\t\t\tm\t\tAngerer et al. (27)\t\nAB-CHMINACA\t4.1\t\t\tm\t\t\n5F-ADB\t0.38\t\t\t\t\t\nAB-PINACA\t26\t\t\t\t\tKubo et al. (47)\t\n5F-AB-PINACA, 5F-AMB\t5F-AMB: 8\t\t\t5F-AMB: 176;\n5F-AB-PINACA: 152\t\t\t\nMepirapim\t157\t\t\t5200\t\t\t\n5F-AB-PINACA, 5F-AMB\t5F-AMB: <1\t\t\t5F-AMB: 28;\n5F-AB-PINACA: 21\t\t\t\nAB-CHMINACA\t1.5**\t3 days\t0.1\tbrain blood 2.2, lung blood 2.7, liver blood 0.3, kidney blood 1.3, intestines blood 1.0\tGieron et al. (31)\t\n5F-AMB\t(subclavian) 0.3\t\t\t\t\tShanks and Behonick (32)\t\nJWH-018, AM-2201\tJWH-018: 0.11;\nAM-2201: 2.5\t\t\t\t\tLabay et al. (33)\t\nJWH-210\t\t\t\t\t\t\nJWH-018, AM-2201, JWH-122, JWH-210\tJWH-018: 0.65;\nAM-2201: 0.21;\nJWH-122: pos;\nJWH-210: pos\t\t\t\t\t\nXLR-11\tpos\t\t\t\t\t\nJWH-018, AM-2201\tJWH-018: 0.47;\nAM-2201: 17\t\t\t\t\t\nXLR-11, UR-144\tpos\t\t\t\t\t\nJWH-018\tpos\t\t\t\t\t\nJIWH-122, JWH-210, AM-2201\tJWH-122: pos;\nJWH-210: pos;\nAM-2201: 0.16\t\t\t\t\t\nUR-144\tpos\t\t\t\t\t\nJWH-210, AM-2201\tJWH-210: pos;\nAM-220: 1.1\t\t\t\t\t\nXLR-11\tpos\t\t\t\t\t\nXLR-11\tpos\t\t\t\t\t\nXLR-11\tpos\t\t\t\t\t\nAM-2201, JWH-018\tAM-2201: 2.8;\nJWH-018: 0.11\t\t\t\t\t\nJWH-122, JWH-250, AM-2201\tJWH-122: pos;\nJWH-250: 0.23;\nAM-2201: 7.3\t\t\t\t\t\nJWH-122\tpos\t\t\t\t\t\nJWH-122, JWH-210, AM-2201\tJWH-122: pos;\nJWH-210: pos;\nAM-2201: 0.22\t\t\t\t\t\nAM-2201\t0.13\t\t\t\t\t\nJWH-122\tpos\t\t\t\t\t\nXLR-11\tpos\t\t\t\t\t\nXLR-11\tpos\t\t\t\t\t\nJWH-175\t105\t\t\t\t\t\nJWH-210\tpos\t\t\t\t\t\nADB-FUBINACA\t\tinferior vena cava 7.3\t\t\t\tShanks et al. (51)\t\nMDMB-CHMICA\t1**\t\t\t\t\tSeywright et al. (49)\t\nMDMB-CHMICA\t<1**\t\t\t\t\t\nMepirapim\t950 (serum, 3.5 h after use)\t\t\t\t\tFujita et al. (35)\t\nMDMB-CHMICA\t5.6 (ante-mortem),\n<0.2 post-mortem\t\t\t\tbrain 2.6, stomach content 0.2, bile < 0.2, kidney 0.2\tAdamowicz (36)\t\nMDMB-CHMICA\t(ante-mortem serum) 1.4\t\t\t\tspleen 0.1\tWestin et al. (48)\t\nAB-CHMINACA, AB-FUBINACA, AM-2201,\n5F-AMB,\n5F-APINACA, EAM-2201,\nJWH-018,\nJWH-122,\nMAM-2201, STS135, THJ2201, UR-144, XLR-11\tAB-CHIMINACA: 2.8;\nAB-FUBINACA: 0.97;\n5F-AMB: 0.19;\n5F-APINACA: 0.51;\nSTS 135: 0.16;\nTHJ 2201: 0.16\tAB-CHIMINACA: 1.1\t\tm\t\tHess et al. (37)\t\nMAM-2201,\nAM-1220,\nAM-2232\tMAM-2201: 16.3;\nAM-1220: 140;\nAM-2232: 0.86 + m\tMAM-2201: right ventricle 30.7,\nleft ventricle 85.8;\nAM-1220: right ventricle 222,\nleft ventricle 438;\nAM-2232: right ventricle, 1.76\nleft ventricle 1.95\t20 h\tAM-1120: traces\t\tZaitsu et al. (38)\t\nXLR-11\t1.4\t\t\t\t\tShanks et al. (34)\t\nXLR-11\t0.6\t\t\t\t\t\nPB-22\t\t\t\t\t\tGerostamoulos et al. (39)\t\nPB-22\t\t\t\t\t\t\nPB-22\t\t\t\t\t\t\n5F-PB-22\t1.1\t\t\t\t\tBehonick et al. (40)\t\n5F-PB-22\t(ante-mortem) 1.3\t\t\t\t\t\n5F-PB-22\t(iliac) 1.5\t\t\t\t\t\n5F-PB-22\t\tsuperior vena cava 1.5\t\t\t\t\nNNEI\t0.84-0.99\tright atrium 0.75, left atrium 0.64\t3 days\t\tbrain 0.76, heart 0.82, lung 1.06, liver 1.31, kidney 0.92, adipose tissue 42.9\tSasaki et al. (45)\t\nJWH-210\t12\t\t\t\t\tKronstrand et al. (52)\t\nAM-2201, JWH-018\t\tAM-2201: 12;\nAM-2201 m: 2.47;\nJWH-018 m: 123 and 50.8\t\t\t\tPatton et al. (41)\t\nMAM-2201\t\t12.4\t4 days\t\tbrain 4.3, liver 18.1, kidneys 11.2, adipose tissue 1535\tSaito et al. (44)\t\nJWH-122,\nJWH-018,\nJWH-210,\nMAM-2201,\nAM-2201,\nUR-144\tJWH-018: 0.1;\nJWH-122: 0.39;\nAM-2201: 1.4;\nMAM-2201: 1.5;\nUR-144: 6 (estimated)\t\t\t\t\tSchaefer et al. (46)\t\nAM-694, AM-2201, JWH-018\tAM-694: 0.09 (0.00009 µg/g),\nAM-2201: 0.3 (0.0003 µg/g),\nJWH-018: 0.05 (0.00005 µg/g)\t\t\t\t\tWikström et al. (42)\t\nJWH-018, JWH-073\t\tJWH-018: 199\t\t\t\tShanks et al. (43)\t\nJWH-018, JWH-073\t\tJWH-018: 19.6;\nJWH-073: 68.3\t\t\t\t\nJWH-018, JWH-073\t\tJWH-018: 83.3\t\t\t\t\nPBC, peripheral blood concentration; CBC, central blood concentration; PMI, post-mortem interval; h, hours; m, metabolites; pos, positive, not quantified.\n\nAnalytical Issues\nSample preparation and extraction procedures varied widely: liquid-liquid extraction was the most frequently used, though solid-phase extraction (24, 44, 47, 53) and QuEChERS dispersive solid-phase extraction (29, 30, 35, 50) were also reported. Only in a minority of the cases, the standard addition method was employed for quantification (19, 23, 28, 30). In two cases, liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QToF-MS) was used to detected and quantitate parent compounds and/or metabolites in blood and ante-mortem serum (38, 48).\n\nOverall, 31 SCRAs (EAM-2201, AB-PINACA, 5F-PB-22, 5F-AKB-48, 5F-ADB, AB-CHMINACA, UR-144, XLR-11, JWH-022, MAB-CHMINACA, MDMB-CHMICA, 5F-AMB, Mepirapim, JWH-018, AM-2201, JWH-210, JWH-122, JWH-250, JWH-175, ADB-FUBINACA, AB-FUBINACA, 5F-APINACA, MAM-2201, STS135, THJ 2201, AM-1220, AM-2232, PB-22, NNEI, AM-604, and JWH-073) were detected, some being more frequently identified in the revised cases, such as 5F-ADB, XLR-11, AM-2201, AB-CHMINACA, and JWH-018.\n\nEven if reported with lower rates, 5F-PB-22, UR-144 were also common. XLR-11 was mostly reported in 2016, while 5F-ADB showed a peak in 2017 and 2018. However, a clear trend cannot be determined on the sole basis of this data.\n\nWhile some laboratories applied national or international validation guidelines, such as those of the German Society of Toxicological and Forensic Chemistry (GTFCh), “in house” methods have also been adopted, stating overall good results (31, 32, 43). Analytical details were not always given and not all of the above-mentioned parameters, especially matrix-effects, were systematically assessed (19, 27, 31, 37, 38, 41, 44, 52).\n\nAccording to previously published cases (33, 43), concentrations of SCRAs in post-mortem cases covered a wide range, from 0.01 (19) to 199 ng/mL (43), although lower concentrations, in the range 0.5 to 2.5 ng/ml, were most frequently encountered.\n\nPeripheral blood was analyzed in 53 cases out of 74 (72%). In 8 cases (11%) only heart blood concentrations were stated, while both peripheral and central concentrations were published in 10 cases (14%). Other biological matrices, apart from urine, were quantitatively analyzed in only 8 cases (11%) (Table 3). Other substances were found in 44 out of 74 cases (59%).\n\nAs regard other xenobiotics detected, ethanol was detected in 13 cases (17%), though levels ≥ 1.5 g/L were found only in 6. A co-consumption of NPS, as synthetic cathinones (pentedrone, α-PVP, DL-4662), hallucinogens (6-APB, 6-MAPB, methoxetamine), anesthetics (diphenidine), and synthetic opioids (AH-7921) was seen in 11 cases (15%). Common drugs of abuse detected included antidepressive/neuroleptics/antipsychotics (quetiapine, trimipramine, olanzapine, sodium valproate, mirtazapine, amitriptyline, phenytoin, paroxetine, aripiprazole, citalopram, fluoxetine, haloperidol, trazodone, venlafaxine, pregabalin, topiramate) (12/74, 16.2%), cannabinoids (10/74, 13%), amphetamines, benzodiazepines (both 6/74, 8%) and opioids (5/74, 7%).\n\nCase Reports\nThe age of the deceased ranged from 14 to 61 (19). Mean age was 32, median 29. The 38.5% belonged to the 20 to 29 decades. Teenagers were also represented (15.4%) (Figure 2). With reference to the gender of the victims, 88.1% were male and 11.9% were female. A past use of drugs and/or alcohol was reported in 18 out of 74 cases (24%), while poor mental health was only reported in 5 cases (7%).\n\nFigure 2 Age distribution among the cases reported in the literature.\n\nHerbal blends, smoking devices (e.g., pipes) and other paraphernalia were found during the death scene investigation (DSI) in 30 of 74 cases (41%) and were variably labeled as “Aladdin platinum/limited,” “Herbal incense, the super lemon,” “F1,” “Hammer Head,” “Magic Gold,” “Desert Premium Potpourri,” “AL 37,” “AP 31,” “Strongman,” “GM sapphire,” “Heart Shot Black,” “Apollo,” “Mocarz,” “Smoke XXX. A potent potpourri,” “Mad Hatter Incense,” “Fairy evolution,” “Mary Joy Annihilation,” “Passion Flower Herb – Zonk,” “Stoner Pot-Pourri K11,” “Supanova Pot-Pourri,” “K2 Cherry,” “Space Cade Flight Risk,” “Game over,” “Orange Flame,” “Legal Phunk,” “Mojo.” Clinical data was available in 15 cases (20%) and mostly included the detection of cardiac arrest/asystolia/fibrillation at the arrival to an Emergency Department.\n\nResults of post-mortem examination, as for macroscopical or gross findings, were available in 55 cases (74%), including those cases in which only a short referral to “unremarkable findings” was reported. In most cases in which a SC was later discovered during toxicological analysis, the post-mortem examination had revealed only non-specific signs of intoxication, such as pulmonary edema and congestion, brain edema, hemolysis, and signs of aspiration (34, 40). In some cases, stomach and gastroduodenal erosions (20, 35), abundant hypostasis coupled to petechiae (27, 29, 37) and intracutaneous skin bleedings (vibices) (30) were reported. Lastly, cardiac abnormalities, such as cardiomegaly (33, 43), dilatative or hypertrophic cardiomyopathy (21), stenosis due to atherosclerosis (33, 46) or acute thrombosis of the coronary arteries were seen (32).\n\nHistological data, as a specific result of a microscopical analysis, was clearly described only in 13 cases (18%).\n\nCause of death was stated in all but 4 cases (5%). Cardiac arrhythmias and cardio-circulatory acute effects were listed in 17 cases (23%) as cause of death or as underlying mechanisms in a group of mono and poly-drug intoxications, involving both teenagers and adults (20, 21, 35, 40, 48). A number of death cases were associated with excited delirium and police restraints (33), as well as fall from height, either due to drug-induced psychosis or reduced awareness with accidental falling (24, 26). Behavioral effects could also lead to suicide (26), self-inflicted self-injuries (41) and further consumption of other drugs (26, 55). Respiratory depression (27), especially in the setting of mixed intake of xenobiotics (33, 51), and asphyxia due to aspiration of gastric content in a state of coma (22, 27, 28) were also declared.\n\nManner of death was mostly accidental or not given and 4 cases of suicide (5%) were recognized.\n\nPost-mortem interval (PMI) was stated in 11 cases (15%) and ranged from 8 hours to 4 days (Table 3).\n\nDiscussion\nThe systematic review of the literature has resulted in an unexpectedly high number of cases of death involving SCRAs. Though, given the widespread use of the compounds, similar fatalities might be under-reported (publication bias) or under-recognized as a result of the challenges of post-mortem analyses. Indeed, the delay in developing and updating analytical methodologies affects the capability of many laboratories to detect and report cases of SCRA-related death, particularly when novel compounds which just entered the market are involved (55). Accordingly, the results here presented cannot be taken to estimate the prevalence.\n\nCircumstantial Data\nIn almost the totality of cases, a possible involvement of SCRAs was suggested by either a past history of drug/alcohol abuse, by witnesses' statements of partying or smoking shortly before collapse, or by the DSI, which revealed paraphernalia and herbal residues. Depending on the market availability, it emerged that the content of such packages varied over time (31, 36, 55). Thus, it must be kept in mind that the product names do not validly predict the ingested substances.\n\nAlthough e-cigarettes and e-liquids represent an innovative and attractive way to consume SCRAs (56, 57), no vaping liquids were reported in the circumstantial data of the reviewed death cases. The link between e-cigarettes and SCRA consumption might be less familiar and known to the investigators, possibly resulting in such liquids not being systematically seized and/or analyzed. When such paraphernalia are found, an analysis of vaping liquids collected at the DSI should be strongly encouraged.\n\nSCRAs are not detected by common immunoassays and require a target analysis, which is usually only requested by authorities and conducted when a suspicion is raised, due to analytical limitations and economic reasons (21). This factor could lead to a failure to recognize such cases and consequently to a massive underestimation of the number of death cases involving SCRAs. This underlines the importance of an appropriate awareness and of an in-depth experience in forensic toxicology during DSI and when interviewing witnesses.\n\nAnalytical Issues\nThe data extracted from the revision of the literature regarding toxicological analyses once again highlights the role of liquid chromatography-mass spectrometry (LC-MS/MS) for the quantification of SCRAs in biological specimens, although a singular preferred method for sample extraction is not known, given the variety of chemical differences among analytes (52). The use of standard addition methods, as recently suggested in a series of intoxications (58) is limited, possibly due to the low amount of post-mortem blood collected at the autopsy.\n\nOnly a small number of SCRAs emerged from the literature review, compared to the quantity of compounds included in the NPS category. We do not believe that this is a bias due to an attention to recent molecules, since the follow-up period ended in 2019 and more recent molecules, such as SCRAS bearing a γ-carbolinone core, were not found. This observation could be on the contrary related to difficulties in detecting SCRAs in the absence of a dedicated and updated method. The main challenge in forensic toxicology from an analytical point of view resides indeed in keeping methods updated, in order to detect novelties as soon as they are involved in death cases. Although there was a decrease in the last years, the frequent emergence of novel compounds might lead to missing relevant analytes. This was clearly demonstrated by cases where re-analysis of samples with novel and more sensitive methods allowed for identification of substances previously undetected (19, 22, 25). Very sensitive methods are needed in blood, given the low concentrations reported in the literature (52) and urine analysis can reveal a previous intake even when nothing is detected in blood (22, 23).\n\nOnce a new methodology for the analysis of biological specimens has been established, even in case reports, a so-called short validation, including selectivity, linearity, accuracy, precision, and matrix effect, is strongly recommended even if not always performed or published (59). In the case described by Langford et al., for example, the analyses were granted by a private licensed forensic laboratory, and no information was disclosed due to alleged “competition and market issues” (20). The absence of a clearly stated methodology and validation process questions the reliability of the analytical results and limits the comparability of the data. The validation could be further hampered by the lack of material for re-analysis and/or by the lack of isotopically labeled standards (27, 33). Lack of material represents a serious limitation particularly in the case of measured concentrations being far above the linear range of the calibration, even though results might be estimated by extrapolation (27, 38, 43). It has to be underlined that the vast majority of the methods for SCRAs quantification were validated in serum and not in post-mortem blood.\n\nWhen evaluating the concentrations, several aspects need to be considered, including site of sampling, post-mortem interval, possible tolerance of the user, co-consumption of other drugs, potency of the compounds, chemical characteristics, and time delay between intake and death.\n\nSome compounds, such as 5F-ADB, are known to be particularly unstable (29) and this could explain the extremely low concentrations of the highly potent SCRAs in our review (27). Rapid degradation due to pyrolysis, ante-mortem drug metabolism, as well as post-mortem redistribution and degradation (due to remaining esterase activity) were considered as further main factors for reduced concentrations and should be considered for all SCRAs, though with different weighting (19, 23, 44).\n\nWhen compared to others SCRAs, mean concentrations were relatively higher for AB-CHMINACA, despite its high potency (21, 27). This could be due to the narrow time interval between drug smoking and death, approximately an hour in the case described by Paul et al. (21), or to a high tolerance of the subject implying high doses (21).\n\nConcerning post-mortem redistribution (PMR), disparities among central and peripheral blood levels were mostly slight (19, 45) (PMI: 2 days). A 1.2 quotient of central/peripheral blood (C/P ratio) was found in a case of MDMB-CHMICA 12 h after death, and this result was interpreted as not indicative of PMR (24). Similarly, concentrations were in the same range in all tissues in a case described by Yamagishi et al. (19). On the contrary, cardiac blood levels strongly exceeded the peripheral ones in the case of Zaitsu et al. (38) for MAM-2201, AM-1220, and AM-2232 (PMI: 20 h), where left and right ventricle blood levels were 2 to 5 and 1.5 to 2 times higher than femoral blood concentrations. Quantification employed LC-QTOF, a full validation was not performed and concentrations of some analytes were far above the highest calibration point. Nevertheless, C/P ratios appear to tend to values above 1 especially in the case of short time intervals between smoking and death (in this case 1.5 h). A death shortly after smoking, with high concentrations of SCRAs in lungs being released to the surrounding vessels and tissues could explain the higher levels in the blood of the left ventricle (60), although the authors suggested a myocardial accumulation instead (38). C/P ratios of 1.75 to 1.54 were also seen by Hasegawa et al. (29) (PMI: 2 days).\n\nDivergences among compounds suggest that the chemical characteristics (e.g., greater or lower lipophilicity) as well as the pattern of use should be considered when hypothesizing PMR (45). Ingestion and smoking probably result in higher concentrations in stomach content and lungs, respectively. This could lead to a release into nearby vessels of the central compartment. Since femoral blood levels increase mostly due to release/redistribution from fat and muscle tissues, an inversed central/peripheral ratio would suggest a greater lipophilicity of the compound and/or chronic accumulation of SCRAs in deep compartments. However, the scarce information regarding time between last consumption and death as well as the PMI complicates the situation. Stability and matrix effects additionally limit the capability of drawing valid conclusions based on blood concentrations.\n\nThe distribution of SCRAs in tissues varied widely. Concentrations in tissues have been assessed only in a minority of cases and results may strongly depend on the employed methods of analysis, the description of which is beyond the scope of this article. Given the rarity of this type of measurement, which afford a time-demanding standard addition method (19), the available data regarding tissue distribution does not allow for general conclusions. However, they can be used to evaluate the specific case and might allow identifying potential sites of accumulation. For example, extremely high levels in the adipose tissue were seen for MAM-2201 (124 fold higher than blood concentration), leading to the suggestion of fatty tissue as a suitable target specimen for analysis (PMI: 4 days) (44). High adipose levels were also found for NNEI (45) (PMI 3 days) and might be interpreted as a result of continued substance use. According to Kusano et al. (23) adipose tissues are a suitable matrix for the detection of the parent compound, while other tissues (with higher esterase activity) could contain higher levels of metabolites.\n\nHigh levels in liver and kidney tissue could be found in the case of more hydrophilic compounds (e.g., MAB-CHMINACA; PMI: 2–3 days) (29), especially when the interval between intake and death was short. In these cases, an accumulation in fatty tissue might not have occurred yet, requiring longer time (24, 29). Brain concentrations were high for MDMB-CHMICA in a case described by Gaunitz et al. (PMI: 12 h) and this allowed to confirm that the victim was under the effect of cannabinoids at the moment of death (24). High concentrations in lungs were also reported, pointing towards an intake through smoking.\n\nIn summary, blood and tissue concentrations should always be interpreted with caution, due to the multiple factors which have to be taken into account (e.g., PMR, PMI, active metabolites, stability, chemical characteristics, plasma/blood ratio, tolerance etc.) (61).\n\nPathology and Histopathology\nThe un-specificity of gross pathological findings heightens the risk of missing deaths involving SCRAs. Vomiting and aspiration of gastric content are highly suggestive for drug-induced coma or loss of consciousness in otherwise healthy and young subjects (22, 29). This was also seen in a case in which, originally, only urine was found positive for SCRAs, and further analyses demonstrated high blood concentrations of MAB-CHMINACA (22, 29). It should always be kept in mind that acute gastrointestinal bleedings could be due to several diseases and factors, such as Mallory-Weiss disease or hypothermia, and an accurate differential diagnosis remains fundamental before attributing such findings directly to SCRA consumption. For example, erosions seen in the case described by Langford and Bolton (20), could have been the result of ethanol intake, which was in his fatal ranges (3.11 g/L).\n\nBleedings and abundant hypostasis could raise the suspicion for a recent intake of SCRAs. In 2018, fatal and life-threatening bleedings were connected to superwarfarin-type drugs such as brodifacoum added to products allegedly containing SCRAs as reported by the Centers for Disease Control and Prevention (CDC), which released a health advisory. Long-acting anticoagulant rodenticides (LAARs) were occasionally found as adulterants in herbal blends (62). A case of death connected to anticoagulants is described in the literature (63), even though the case was not included in the review, since the past use of SCRAs emerged only from circumstantial data (thus, the paper did not fit into the inclusion criteria). It is not clear if hemolysis, abundant hypostasis, and intracutaneous or soft tissue bleedings can be caused by such adulterants or represent a hematological effect, maybe liver-mediated, of SCRAs themselves (40). As LAARs are usually not detected by urine screening analyses, highly sensitive LC-MS/MS methods are required for their detection (62).\n\nThe interpretation of cardio-vascular findings is discussed in the following subsection.\n\nCause and Mechanism of Death, TSS\nSeveral preclinical studies and case reports addressed the increased cardiovascular risk related to SCRAs use, though scientific evidence is still limited (14, 64–68). This was reflected by our literature review, since abnormal findings in heart were seen and death related to acute cardiovascular arrest or collapse certified. However, it could be unclear if these deaths are actually related to SCRAs or not (69). Marijuana exerts some cardiovascular effects, acutely resulting in increased catecholamine release and, consequently, increased heart rate and vasodilation, with orthostatic hypotension (68). Cannabis is told either to exert negligible effects on blood pressure or an increase in blood pressure, and might increase the risk of myocardial infarction, particularly in predisposed subjects (68, 70–72). SCRAs, being more potent cannabinoid receptor agonists, have been linked to the occurring of myocardial infarction (64) even in the absence of coronary artery disease, and of arrhythmia-related sudden cardiac death (65–67). Sasaki et al. (45) found signs of hypertension and aging in a 20-year-old victim, coupled to myocardial suffering, and thus hypothesized a cardio-circulatory hyperactivity due to prolonged SCRA use. The diversity of potential injury mechanisms (between myocardial infarction and arrhythmia) may explain why in some cases band necrosis proved a myocardial damage (21, 45), while in others neither macroscopic nor microscopic signs were noted (20, 21, 35).\n\nIn the cases where post-mortem examination failed to identify signs of heart diseases, the attribution of cardiac death to the SCRA was mostly based on circumstantial data, e.g., the victim reported having smoked shortly before dying and/or a sudden collapse after smoking occurred (20, 35, 40). In a similar case, the possible role of SCRAs was confirmed by a serum sample collected only 2 h after a sudden collapse with asystolia, revealing 1.4 ng/mL of MDMB-CHMICA (48).\n\nMoreover, asystole was initially noted in a case of death where, after resuscitation, a multi-organ failure finally led to cardiac arrest (36).\n\nAtherosclerotic disease and other cardiac abnormalities, such as cardiomegaly and dilatative cardiomyopathy, pose an additional challenge to the assessment of the role of SCRAs in death cases (50, 61). In fact, drugs can either exacerbate a pre-existing condition, or be considered an irrelevant finding (33). In a case described by Tse et al. (64) a triple-vessel coronary thrombosis was found and death was attributed to myocardial infarction with a possible contributory role of SCRAs, despite the absence of analytical confirmation. In a case involving ADB-FUBINACA, Shanks et al. (51) concluded that, due to occurrence of behavioral effects followed by a sudden death, a SCRA-induced dysrhythmia contributed to the death, notwithstanding the presence of a potentially fatal thrombolytic occlusion. Similarly, a contributory role was stated by Tse et al. (64) despite morphological findings which could have explained the death by themselves. These cases demonstrate that it can be difficult to assess the cardiac effects of SCRAs, particularly in the presence of findings potentially constituting a cause of death on their own. In such cases, a TSS of “1,” which does not exclude a partial contribution, seems to be appropriate (17).\n\nIn cases of polydrug abuse, the evaluation of role cannot leave aside concentrations of xenobiotics, leading to attribution of different TSS on a case-by-case basis, e.g., TSS U with 3 g/L of ethanol, positive unquantified SCRAs and suspected arrhythmias (20) vs TSS 3 with 1.8 g/L ethanol, 1.5 ng/mL AB-CHMINACA and acute cardiorespiratory depression (50).\n\nComa/somnolence can lead to death directly, through vomiting/aspiration or indirectly due to environmental exposure and hypothermia (54). In a case presented by Kronstrand et al. (52), death occurred due to “hypothermia and SCRA use,” despite the absence of typical hypothermia-related signs such as freeze-erythema and Wischnewsky spots (52). Hypothermia after the use of SCRAs was seen in experimental studies on animals (e.g., male rats and monkeys) (73, 74) and has been partially related to the effects of cannabinoids on dopamine receptors (75), but has not been confirmed in humans yet. However, in a case described by Adamowicz (36) a cadaveric temperature of 35.1°C was measured, despite the victim was at home and the measurement took place only 30 minutes after the sudden collapse. This finding would be in line with the animal experimental data regarding the effect of SCRAs on body temperature and highlights the need to evaluate body and ambient temperatures in cases of death possibly related to such compounds. An “intoxicated-state” was also considered as the underlying mechanism of a death due to ketoacidosis, even though an AB-CHMINACA-induced hyperglycemia was also possible (37).\n\nA behavioral contribution of SCRAs to the death appears to be an additional source of concern. Anxiety and psychosis might be also explained by the affinity of SCRAs to dopaminergic (D2), serotoninergic (5-HT2A) or glutamatergic (NMDA) receptors (76, 77). In a case described by Labay et al. (33), the victim fell from a high building after feeling sick and vomiting several times and was found intoxicated with MDEA, MDA, and JWH-175. While psychiatric consequences of SCRAs intake are clear in the absence of other drugs (41), the evaluation of role in polydrug consumption is puzzling, as in the case of low levels of both SCRAs and phenytoin, which can induce psychosis (78). Data on toxic/fatal levels might lack for NPS (e.g., for co-consumption of pentedrone resulting in behavioral abnormalities) (26) and even therapeutic or negligible levels of common drugs of abuse could assume relevance in combination with SCRAs. The influence of SCRAs on non-cannabinoid receptors and on serotonin, dopamine, catecholamine levels further complicate potential interpretations. In such cases of polydrug abuse, it is possible that the death would not have occurred without SCRA consumption, although no direct causality can be established. A TSS of “1” (“i” indicating the indirect role) is suggested due to the presence of multiple drugs with unknown contributory role, despite behavioral toxicity being an important risk factor for fatal outcome (33).\n\nOn the other hand, in the first case reported by Rojek et al. (26), the victim jumped from a building after a reported “loss of control” and no other drug was detected. Thus, notwithstanding the behavioral toxicity and the indirect mechanism, a contribution to death is likely (TSS of “3” was assigned).\n\nFinally, cases of acute liver and/or kidney failure have been described (40, 55).\n\nIn general, if only toxicological results are listed in the absence of macroscopical and microscopical data, uncertainties regarding the role of the substance increase, as in the case reported by Kusano et al. (23). However, the mechanism of death could remain unclear, despite having a more complete data set (40) and the agreement between independent reviewers judging the very same pieces of information could be weak (e.g., unanimous agreement in 2 cases out of 25 submitted to multiple evaluations) (33, 40). Thus, a multidisciplinary evaluation should be recommended for each case, in order to possibly limit such uncertainties.\n\nMost of the publications identified a possible contributory role of SCRAs, even in the absence of findings clearly pointing towards a drug-related death (32, 34, 39, 45, 48). In the present review, a TSS of 3 was assigned when no competitive cause was seen, and the hypothesized mechanism of death was in line with the most frequently reported SCRA toxicities. Affinity and activity of new compounds are often unknown, and unexpectedly severe or idiosyncratic effects may occur (19). Given the uncertainty regarding toxic levels and toxic effects, even when the mechanism of death remains unclear and/or other substances might have played role, the possibility of a contribution of SCRAs should not be ignored, and a TSS of “2” justified.\n\nThe likelihood of a high significance score is greater when multiple compounds with potentially synergic effects are detected, despite low concentrations of each single compound (19).\n\nOn the contrary, even though SCRAs could exacerbate an intoxication due to alcohol or other drugs, in cases with relatively very low SCRA concentrations or with concentrations of the competitive drug above the toxic threshold, a TSS of “1” is suggested. This does not necessarily mean that the SCRA has not exerted any negative effect, and the stability of the analyte of interest should further be considered as a cause of low concentrations.\n\nTSS was rated “U” in cases with lack of sufficient data, as for example in the case described by Langford and Bolton (20), where high alcohol concentrations were retrieved, and no quantification of SCRAs was possible, or in the case of Minakata et al. (25) and Kusano et al. (23), where the effects of the other substance detected was difficult to assess.\n\nLimitations\nThere are several limitations in this study. First of all, despite the extensive research involving multiple databases, the process of inferring scientific evidence is strongly limited by the possibility of under-reporting of similar cases and by the necessity of establishing a temporal limit for the review. Thus, the information presented have to be regarded as incomplete. Secondly, no weighting of selected articles regarding their quality was undertaken. A third significant limitation resides in establishing the TSS (16) of the selected cases, since the TSS is so far a non-validated scale. However, given the lack of criteria for establishing the role of substance(s) in death cases, the TSS appeared to be a flexible and easy-to-use tool to assign a contributory weight to SCRAs, and thus to evaluate and compare different cases. In order to avoid misinterpretations and to appreciate the point of view of the authors of the manuscripts, in each death case the role of the substance was also supplied in their own words. Finally, only death cases in which at least one SCRA was analytically confirmed, and in which an autopsy was presumably performed, were included. The authors are aware that this could have resulted in a partial loss of information, but on the other hand our aim was to possibly achieve a higher level of evidence.\n\nConclusions\nSeveral mechanisms could lead to death after SCRAs consumption, and behavioral risks as well as cardiovascular effects or central nervous system depression appear to play important roles. Given the limited pharmacodynamic and pharmacokinetic data and the overlap between fatal and non-fatal concentrations, typical toxic ranges for SCRAs have not been identified so far. The results of toxicological analyses should be interpreted with caution, considering the many confounding and influencing factors, particularly regarding the reliability of LC-MS/MS methods validated insufficiently or validated only in serum. Furthermore, pattern of consumption (e.g., occasional v. chronic) and tolerance of the subject should be estimated or evaluated on a case by case basis.\n\nA complete and accurate post-mortem examination is a fundamental part in the evaluation of death cases involving SCRAs, since a comprehensive and multi-disciplinary evaluation of clinical, circumstantial, toxicological, and autoptic data is the only possibility to assess the toxicological significance of a substance and to tentatively identify a plausible mechanism of death, which could remain unclear despite an in-depth analysis of all data available.\n\nAuthor Contributions\nAll authors materially participated in the article preparation and have approved the final article.\n\nFunding\nRole of funding source: The study was supported by Presidency of the Ministers Council, Department of Antidrug Policy.\n\nConflict of Interest\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\n1 \nAtwood BK Huffman J Straiker A Mackie K \nJWH018, a common constituent of ‘Spice' herbal blends, is a potent and efficacious cannabinoid CB1 receptor agonist\n. 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"journal": "Frontiers in psychiatry",
"keywords": "forensic toxicology; novel psychoactive substances; post-mortem examination; synthetic cannabinoids; toxicological significance score",
"medline_ta": "Front Psychiatry",
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"title": "Post-Mortem Toxicology: A Systematic Review of Death Cases Involving Synthetic Cannabinoid Receptor Agonists.",
"title_normalized": "post mortem toxicology a systematic review of death cases involving synthetic cannabinoid receptor agonists"
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"abstract": "The outcome of hyperacute grade 3-4 steroid-refractory graft-versus-host-disease (SR-GVHD) remains dismal despite a plethora of agents being tried alone or in combination. Following T replete haploidentical transplantation with post-transplantation cyclophosphamide on 75 patients, 10 patients (13%) aged 2-20years, developed hyperacute SR-GVHD. We report on the outcome of two different regimens for treatment of SR-GVHD on the outcome of these patients. Five patients were treated in Regimen A consisting of anti-thymocyte globulin, Etanercept and Basiliximab. The next 5 patients were treated combining T cell costimulation blockade with Abatacept along with Etanercept and Basiliximab. The overall response at days 29 and 56 were 40% and 0% with Regimen A and100% and 40% with Regimen B. The major cause of treatment failure was progression of GVHD and opportunistic infections. Two of the patients achieving a complete remission on Regimen B are long term disease free survivors off immunosuppression. Our study demonstrates the dismal outcome of early onset SR-GVHD in children following T replete haploidentical transplantation. However, the combination of Abatacept with anticytokine agents seems to produce encouraging early response and might warrant further investigation.",
"affiliations": "Manashi Chakrabarti Foundation, Kolkata, India; Department Of Blood and Marrow Transplantation, Dharamshila Hospital and Research Centre, New Delhi, India. Electronic address: drsaritaranij@gmail.com.;Department Of Blood and Marrow Transplantation, Dharamshila Hospital and Research Centre, New Delhi, India.;Manashi Chakrabarti Foundation, Kolkata, India.;Department Of Blood and Marrow Transplantation, Dharamshila Hospital and Research Centre, New Delhi, India.;Department Of Blood and Marrow Transplantation, Dharamshila Hospital and Research Centre, New Delhi, India.;Department Of Blood and Marrow Transplantation, Dharamshila Hospital and Research Centre, New Delhi, India.;Manashi Chakrabarti Foundation, Kolkata, India; Department Of Blood and Marrow Transplantation, Dharamshila Hospital and Research Centre, New Delhi, India.",
"authors": "Jaiswal|Sarita Rani|SR|;Zaman|Shamsuz|S|;Chakrabarti|Aditi|A|;Sehrawat|Amit|A|;Bansal|Satish|S|;Gupta|Mahesh|M|;Chakrabarti|Suparno|S|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000961:Antilymphocyte Serum; D016207:Cytokines; D011993:Recombinant Fusion Proteins; D013256:Steroids; D000069594:Abatacept; D000077552:Basiliximab; D000068800:Etanercept",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.trim.2016.08.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0966-3274",
"issue": "39()",
"journal": "Transplant immunology",
"keywords": "Costimulation blockade; GVHD; Haploidentical; Pediatric; Steroid-refractory",
"medline_ta": "Transpl Immunol",
"mesh_terms": "D000069594:Abatacept; D000208:Acute Disease; D000293:Adolescent; D000911:Antibodies, Monoclonal; D000961:Antilymphocyte Serum; D000077552:Basiliximab; D002648:Child; D002675:Child, Preschool; D016207:Cytokines; D018572:Disease-Free Survival; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D000068800:Etanercept; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007167:Immunotherapy; D008297:Male; D011993:Recombinant Fusion Proteins; D013256:Steroids; D013601:T-Lymphocytes; D000075442:Transplantation, Haploidentical; D028761:Withholding Treatment; D055815:Young Adult",
"nlm_unique_id": "9309923",
"other_id": null,
"pages": "46-51",
"pmc": null,
"pmid": "27577170",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "T cell costimulation blockade for hyperacute steroid refractory graft versus-host disease in children undergoing haploidentical transplantation.",
"title_normalized": "t cell costimulation blockade for hyperacute steroid refractory graft versus host disease in children undergoing haploidentical transplantation"
} | [
{
"companynumb": "PHHY2016IN120188",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
"d... |
{
"abstract": "Medication-related osteonecrosis of the jaws (MRONJ) is an infectious complication of antiresorptive or antiangiogenic drug therapies. In severe stages of this disease cutaneous sinus tracts may be observed. Platelet-rich fibrin (PRF) is a second-generation platelet concentrate used in medicine and dentistry for to promote tissue healing. This report describes the management of facial cutaneous sinus tracts secondary to MRONJ with autologous PRF injections. Eight patients with the diagnosis MRONJ and facial sinus tracts were enrolled in this study and received treatment. MRONJ lesions underwent pharmacological and surgical treatment. Sinus tracts received 1-mL injections of PRF around the fistula using an insulin syringe once a week for four times starting from the day of the surgical treatment. After 4 weeks, six patients showed healing of the fistula and bone lesions, only one patient showed healing of the fistula, and no remission was reported in another one. All patients reported an improvement of the symptoms in the first 2 days after the treatment session. Patients were also satisfied from an aesthetic point of view. Further studies will be needed to determine if PRF is a valid therapeutic option in dermatology.",
"affiliations": "Department of Health Sciences, School of Dentistry, Magna Graecia University of Catanzaro, Catanzaro, Italy.;Dermatology Residency Training Program, Department of Health Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy.;Department of Health Sciences, School of Medicine and Surgery, Magna Graecia University of Catanzaro, Catanzaro, Italy.;Dermatology Residency Training Program, Department of Health Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy.;Department of Health Sciences, School of Dentistry, Magna Graecia University of Catanzaro, Catanzaro, Italy.;Department of Health Sciences, School of Dentistry, Magna Graecia University of Catanzaro, Catanzaro, Italy.;Dermatology Residency Training Program, Department of Health Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy.",
"authors": "Bennardo|Francesco|F|0000-0002-6528-2681;Bennardo|Luigi|L|0000-0002-0434-1027;Del Duca|Ester|E|0000-0001-7948-8536;Patruno|Cataldo|C|;Fortunato|Leonzio|L|;Giudice|Amerigo|A|0000-0002-5091-6979;Nisticò|Steven P|SP|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/dth.13334",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1396-0296",
"issue": "33(3)",
"journal": "Dermatologic therapy",
"keywords": "PRF; osteonecrosis; sinus tract",
"medline_ta": "Dermatol Ther",
"mesh_terms": "D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D005402:Fistula; D006801:Humans; D007568:Jaw; D000073183:Platelet-Rich Fibrin; D014945:Wound Healing",
"nlm_unique_id": "9700070",
"other_id": null,
"pages": "e13334",
"pmc": null,
"pmid": "32219975",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Autologous platelet-rich fibrin injections in the management of facial cutaneous sinus tracts secondary to medication-related osteonecrosis of the jaw.",
"title_normalized": "autologous platelet rich fibrin injections in the management of facial cutaneous sinus tracts secondary to medication related osteonecrosis of the jaw"
} | [
{
"companynumb": "IT-PFIZER INC-2020269575",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo identify the utility of peak inspiratory flow (PIF) in the assessment and management of subglottic stenosis through correlation of clinical presentation with PIF.\n\n\nMETHODS\nCase report.\n\n\nMETHODS\nReview of the clinical course of a 31-year-old woman with the diagnosis of granulomatosis with polyangiitis. Repeated PIF measurements at clinic visits were obtained over a 30-month follow-up.\n\n\nRESULTS\nTwenty-seven PIF measurements were obtained at 31 otolaryngology clinic visits. Correlations were identified between low PIF measurements with the clinical symptom shortness of breath (2.04±0.38 L/s, n=10), clinically recorded stridor at rest (1.64±0.41 L/s, n=3), and urgent operative intervention (1.60±0.23 L/s, n=5). Correlations were identified between high PIF measurement with patient report of normal breathing (3.07±0.35 L/s, n=16) and clinical observation of absence of stridor at rest (2.81±0.32 L/s, n=23). There was a statistically significant difference in the patient's PIF values with patient-documented shortness of breath vs no shortness of breath (P=.001) and clinician-noted stridor vs no stridor (P=.017).\n\n\nCONCLUSIONS\nPeak inspiratory flow measurements correlate with degree of airway compromise and are helpful to monitor the degree of airway obstruction and document response to treatment.",
"affiliations": "Department of Otolaryngology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.;Department of Otolaryngology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.;Department of Otolaryngology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.;Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.;Department of Otolaryngology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA henry-hoffman@uiowa.edu.",
"authors": "Tasche|Kendall K|KK|;Bayan|Semirra|S|;Schularick|Nathan M|NM|;Wilson|Jeff|J|;Hoffman|Henry T|HT|",
"chemical_list": "D005938:Glucocorticoids; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1177/0003489414565000",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4894",
"issue": "124(6)",
"journal": "The Annals of otology, rhinology, and laryngology",
"keywords": "Wegener’s granulomatosis; acquired subglottic stenosis; spirometry",
"medline_ta": "Ann Otol Rhinol Laryngol",
"mesh_terms": "D000328:Adult; D004724:Endoscopy; D005260:Female; D005500:Follow-Up Studies; D005938:Glucocorticoids; D006801:Humans; D007320:Inspiratory Capacity; D007829:Laryngostenosis; D011241:Prednisone",
"nlm_unique_id": "0407300",
"other_id": null,
"pages": "499-504",
"pmc": null,
"pmid": "25539659",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Utility of peak inspiratory flow in managing subglottic stenosis.",
"title_normalized": "utility of peak inspiratory flow in managing subglottic stenosis"
} | [
{
"companynumb": "US-WATSON-2016-03846",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"... |
{
"abstract": "BACKGROUND\nBisphosphonates are effective and well tolerated anti-resorptive drugs used for the treatment of osteoporosis. However, some concerns about their potential long-term negative effects are emerging.\n\n\nOBJECTIVE\nWe report a series of patients with a history of bisphosphonate treatment admitted to our institution with a low-energy subtrochanteric fracture.\n\n\nMETHODS\nEight patients fulfilling these two criteria within the last 2 years were included in our retrospective analysis. All cases were reported to the Swiss National Pharmacovigilance Centre.\n\n\nRESULTS\nAll patients presented with a typical radiological pattern consisting of a cortical thickening at the lateral femoral subtrochanteric cortex with a horizontal fracture line originating precisely at this level. Four patients eventually developed a stress fracture or complete fracture of the contralateral femur. Two patients demonstrated delayed healing of their fracture. Five patients had been on alendronate therapy for a period ranging from 16 months to 8 years, two had been on ibandronate for 4 months and 1 year, respectively, after changing from alendronate, and one patient had been on pamidronate until 1 year before the fracture occurred. Seven patients were also receiving long-term proton pump inhibitor (PPI) treatment which could have contributed to the increased risk of fracture. Four patients were receiving both PPI and long-term corticosteroid treatment. The hypothesis of a negative pharmacodynamic interaction between bisphosphonates, PPIs and corticosteroids which could lead to a decrease in bone strength after long-term use needs further investigation.\n\n\nCONCLUSIONS\nPrescribers should be aware of the possibility of these rare adverse reactions and the prolonged use of bisphosphonates should be reconsidered until long-term robust safety data are available.",
"affiliations": "Division of Clinical Pharmacology and Toxicology, Regional Pharmacovigilance Centre, University Hospitals of Geneva, Geneva, Switzerland.",
"authors": "Ing-Lorenzini|Kuntheavy|K|;Desmeules|Jules|J|;Plachta|Olivier|O|;Suva|Domizio|D|;Dayer|Pierre|P|;Peter|Robin|R|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D019386:Alendronate",
"country": "New Zealand",
"delete": false,
"doi": "10.2165/00002018-200932090-00002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0114-5916",
"issue": "32(9)",
"journal": "Drug safety",
"keywords": null,
"medline_ta": "Drug Saf",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D019386:Alendronate; D050071:Bone Density Conservation Agents; D001858:Bone Nails; D004164:Diphosphonates; D005260:Female; D005264:Femoral Fractures; D005500:Follow-Up Studies; D005598:Fractures, Spontaneous; D006801:Humans; D008297:Male; D008875:Middle Aged; D010024:Osteoporosis; D011358:Product Surveillance, Postmarketing; D011859:Radiography; D012189:Retrospective Studies; D013557:Switzerland; D016896:Treatment Outcome",
"nlm_unique_id": "9002928",
"other_id": null,
"pages": "775-85",
"pmc": null,
"pmid": "19670917",
"pubdate": "2009",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15758064;17476007;11344052;17190893;11297626;8298200;17190895;17848842;16084776;18057440;18695179;18813868;17062705;18354114;16085466;17356148;15598694;12378366;18254053;16405362;18254018;15353435;15028823;19118304;18253985;15028820;17093260;17332236;12057569;16315442;17488959;18448990;18695170;18222447;17472416;8950879;15231012;7862179;9074843;9875874;17722238;19118309;17959891",
"title": "Low-energy femoral fractures associated with the long-term use of bisphosphonates: a case series from a Swiss university hospital.",
"title_normalized": "low energy femoral fractures associated with the long term use of bisphosphonates a case series from a swiss university hospital"
} | [
{
"companynumb": "GXKR2009CH12381",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RABEPRAZOLE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Herpes virus family's association with visceral lesions is well established. Herpes simplex virus presentations vary based on immune status. Intractable hiccups due to herpes simplex esophagitis, to the best of our knowledge have been described twice in the literature. We present a 68 year-old immunocompromised male with intractable hiccups for 10 months.\n\n\n\n68 year-old male with end-stage renal disease and multiple myeloma presented with coffee ground emesis and hiccups of ten months duration. A year earlier, he received cycles of bortezomib and dexamethasone, remaining on lenalidomide. During chemotherapy, he developed pneumococcal meningitis and subsequently intractable hiccups. Preceding admission, endoscopy showed duodenitis and esophagitis. Proton-pump inhibitor therapy was initiated; however, biopsy was not performed. During admission, hiccups often occurred every few seconds while off anti-emetics, persisting despite therapy. Exam showed cachexia/temporal wasting, aphthous stomatitis and abdominal tenderness. MRI of brain/spine, CT of neck, chest, abdomen and neurological evaluation were unremarkable. Endoscopy revealed gastritis and esophagitis with mucosal tears. Biopsy revealed intra-nuclear inclusions with multi-nucleated cells, consistent with herpes virus, later confirmed as herpes simplex by immunostaining. Hiccups and emesis resolved after of 2 days of intravenous acyclovir. 21 days of treatment were completed with oral valacyclovir. He remained free of hiccups during the remaining hospital stay and follow up. This case illustrates an exceptionally rare presentation of herpetic esophagitis in an immunocompromised host. As novel immunotherapeutic/suppressive agents continue to emerge, the evolving role of herpes virus prophylaxis and diagnosis of atypical presentations in new host populations is a topic of growing importance.",
"affiliations": "SUNY/Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, United States.;SUNY/Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, United States.;SUNY/Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, United States.",
"authors": "Harris|John|J|;Smith|Tukisa|T|;Preis|Jana|J|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2016.01.001",
"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(16)00002-010.1016/j.idcr.2016.01.001Case ReportIntractable hiccups due to herpetic esophagitis in an immunocompromised patient Harris John willistonharris@gmail.com⁎Smith Tukisa Preis Jana SUNY/Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, United States⁎ Corresponding author. Tel.: +1 7705619205. willistonharris@gmail.com24 2 2016 2016 24 2 2016 4 34 37 19 10 2015 9 1 2016 © 2016 Published by Elsevier Ltd.2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Introduction\nHerpes virus family's association with visceral lesions is well established. Herpes simplex virus presentations vary based on immune status. Intractable hiccups due to herpes simplex esophagitis, to the best of our knowledge have been described twice in the literature. We present a 68 year-old immunocompromised male with intractable hiccups for 10 months.\n\nCase\n68 year-old male with end-stage renal disease and multiple myeloma presented with coffee ground emesis and hiccups of ten months duration. A year earlier, he received cycles of bortezomib and dexamethasone, remaining on lenalidomide. During chemotherapy, he developed pneumococcal meningitis and subsequently intractable hiccups. Preceding admission, endoscopy showed duodenitis and esophagitis. Proton-pump inhibitor therapy was initiated; however, biopsy was not performed.\n\nDuring admission, hiccups often occurred every few seconds while off anti-emetics, persisting despite therapy. Exam showed cachexia/temporal wasting, aphthous stomatitis and abdominal tenderness. MRI of brain/spine, CT of neck, chest, abdomen and neurological evaluation were unremarkable. Endoscopy revealed gastritis and esophagitis with mucosal tears. Biopsy revealed intra-nuclear inclusions with multi-nucleated cells, consistent with herpes virus, later confirmed as herpes simplex by immunostaining. Hiccups and emesis resolved after of 2 days of intravenous acyclovir. 21 days of treatment were completed with oral valacyclovir. He remained free of hiccups during the remaining hospital stay and follow up.\n\nThis case illustrates an exceptionally rare presentation of herpetic esophagitis in an immunocompromised host. As novel immunotherapeutic/suppressive agents continue to emerge, the evolving role of herpes virus prophylaxis and diagnosis of atypical presentations in new host populations is a topic of growing importance.\n\nKeywords\nHerpes simplexEsophagitisHiccupsImmunocompromised\n==== Body\nThe first association of a member of the Herpes virus family and visceral lesions was established in 1940 by Johnson [1]. Since then, Herpes simplex virus (HSV) has played a well defined role as the etiologic agent in infectious processes throughout the GI tract, in the immunocompromised, as well as immunocompetent host. Within the GI tract, HSV-1 is most commonly associated with oral and esophageal herpetic lesions, while HSV-2 is more commonly associated with proctitis, most notably in the homosexual male population. In a 2003 autopsy series of 1307 cases, the reported incidence of herpetic esophagitis was 1.8%. Of the 24 cases of herpes simplex esophagitis (HSE) identified, 18/23 (75%) were associated with underlying malignancy some of whom received chemotherapy, while the remaining 5/23 (21%) cases were associated with underlying immunocompromise or a condition requiring immunosuppressive therapy. In many of these cases, documented clinical symptoms of esophagitis were absent [2]. Among the immunocompromised population, HSV was most commonly associated with esophagitis in bone marrow transplant recipients not on antiviral prophylaxis. In a study of esophageal infections in patients after bone marrow transplantation, HSV was implicated as a sole pathogen or co-pathogen in 10/17 (58%) cases of patients with findings on endoscopy [4]. In another study of 221 renal transplant patients, the diagnosis of HSV esophagitis was made in 5 (2.2%) patients [5]. In the AIDs population, many of the studies of herpetic esophagitis (HE) were carried out prior to the introduction of effective anti-retroviral therapy (ART) and in one prospective study of AIDs patients not on ART, HE occurred in 4 of 145 patients (2.5%) [6]. Although HSE is much more common in the immunocompromised, rarely it occurs in the immunocompetent individual, most often representing primary infection. In a study of immunocompetent individuals, the most common presenting symptoms included acute odynophagia (76.3%), heartburn (50%) and fever (44.7%) [3]. Intractable hiccups (singultus) due to herpes simplex esophagitis, to the best of our knowledge has only been described on 2 other occasions in the literature to date. Here we present the case of a 68 y/o immunocompromised male who presented with intractable hiccups for 10 months.\n\nCase report\nA 68 year old African American male with a history of hypertension, end-stage renal disease and multiple myeloma presented to the emergency department for evaluation of recurrent coffee ground emesis associated with chronic hiccups of ten months duration. The year prior, he was diagnosed with multiple myeloma, completing nine cycles of bortezomib and dexamethasone with poor response. Additional chemotherapy with lenalidomide was initiated and continued until admission. Ten months prior to admission, his chemotherapy was interrupted due to an episode of pneumococcal meningitis after which he developed intractable hiccups. He had multiple evaluations for hematemesis, requiring several blood transfusions in the four months prior to admission. Endoscopic findings were significant for duodenitis, esophagitis and he was treated with proton-pump inhibitor therapy. However, a biopsy had never been performed.\n\nDuring admission, hiccups occurred as often as every 2–3 s while off chlorpromazine or ondansetron. In addition to hematemsis present on admission, he reported chronic abdominal pain secondary to hiccups but notably absent were signs of dysphagia or odynophagia. Review of systems was significant for fatigue, nausea, anorexia and weight loss. Physical exam was significant for cachexia, temporal wasting, aphthous stomatitis involving the tongue and diffuse abdominal tenderness. Initial laboratory studies were significant for low hemoglobin (8.3 g/dL) and an elevated BUN/Cr (16/3.8 mg/dL), consistent with end stage renal disease. Initial imaging on admission included a chest X-ray which was unremarkable. Throughout admission, his hiccups persisted despite maximum dosing of ondansetron and chlorpromazine, although with moderate improvement. Even as an outpatient, during the prior ten months of oral chlorpromazine therapy his hiccups never completely resolved. Inpatient neurological evaluation and extensive imaging which included MRI of the brain/spine, CT of soft tissue of the neck and CT of the chest and abdomen failed to reveal any central process or obvious organic cause of vagus or phrenic nerve irritation.\n\nGiven the persistent hematemesis despite proton pump therapy, endoscopic evaluation was performed. In comparison to endoscopic evaluation one week prior, which showed mild duodenitis and severe diffuse esophagitis with shallow ulcerations in a circumferential fashion at the gastro-esophageal (GE) junction, repeat endoscopic findings included mild gastritis with persistent duodenitis and severe diffuse esophagitis now with mucosal tears. During this study, no biopsies were obtained secondary to esophageal friability. Given the mucosal appearance, there were initial concerns for eosinophilic esophagitis in which presumptive treatment with corticosteroids were considered, however, only symptomatic management was decided until repeat endoscopic evaluation with biopsy could be performed (Image A, Image B, Image C, Image D, Image E, Image F).\n\nFive days later repeat endoscopic evaluation with biopsies from the middle and distal esophagus were performed. Pathology was notable for numerous intranuclear inclusions with multinucleated cells (see below) consistent with a viral process. Specific immunostaining confirmed the presence of herpes simplex virus (not specific to type). Evaluation for concurrent HIV infection was negative by enzyme-linked immunosorbent assay (ELISA). Neither cytomegalovirus polymerase chain reaction (PCR) nor IgM were performed, although IgG was positive, indicating carrier status. Intravenous acyclovir was promptly initiated in addition to standing orders of intramuscular chlorpromazine and intravenous ondansetron. Within two days, the patient reported complete resolution of singultus and emesis. Given the patient's response with the addition of acyclovir, he no longer required anti-emetics or chlorpromazine and completed a successful trial of oral intake so after. After completing 5 days of intravenous acyclovir, he was transitioned to oral valacyclovir, thus completing a 21-day course of treatment as outpatient. Throughout the remaining hospital course and brief outpatient follow up, he remained free of hiccups and intractable vomiting. Unfortunately, long term follow up was not possible as he expired soon after discharge, likely related to his underlying malignancy.\n\nDiscussion\nHerpes simplex virus is a member of the Herpesviridae family, which contains linear, double stranded DNA surrounded by an outer glycoprotein layer [7]. Although HSV-1 and HSV-2 are genetically 70% homologous, HSV-1 has a greater propensity for oral and GI infections. Although HSV as a cause of esophagitis has been well described, this unique presentation of intractable hiccups as in our case is exceedingly rare. Of the two cases described in the literature, one an immunocompromised individual with renal allograft rejection and the other, an immunocompetent individual, who underwent thoracotomy and coronary bypass [8], [9]. Similar to our case, dysphagia and odynophagia were notably absent in the case of the immunocompromised individual described in the literature. However in our case, a noteworthy difference was the duration of the hiccups, which were consistently present for several months prior to presentation. Many causes of intractable or persistent hiccups have been described in the literature. Among those included are various metabolic, gastrointestinal, central nervous system, thoracic and cardiovascular disorders. Irritation of the vagus and phrenic nerve, malignancy, adverse drug reactions and psychogenic causes has all been implicated [10], [11]. Our patient received extensive work up, including neuro-imaging and no other obvious etiology of the hiccups was identified.\n\nIn immunocompromised populations, the predisposition of HSV reactivation is in part related to deficient cell mediated immunity, which is thought to play a more important role than humoral immunity in prevention of reactivation of herpes virus. However, since multiple myeloma is characterized by deficient humoral immunity, the increased risk of herpes virus infections in this population is largely a result of the treatment modalities and not the disease itself [12], [13]. In the recent 2005 study, the APEX trial, bortezomib vs. high dose dexamethasone therapy alone for patients with relapsed multiple myeloma was associated with a statistically significant higher incidence, 13 vs. 5% of Herpes zoster infections [14]. While some authors believe bortezomib therapy is linked to an increased propensity of HSV reactivation, the evidence is less clear [12]. In a 2012 study, patients given prophylactic acyclovir showed a significantly lower incidence of varicella zoster virus (VZV)/complicated HSV while on lenalidomide based protocols for multiple myeloma [13]. Antiviral prophylaxis with acyclovir has since been recommended in these patients. However, our patient did not receive it.\n\nOn endoscopic examination, the most frequently affected site is the distal esophagus, with extensive esophageal involvement often occurring. Typical findings include inflamed mucosa, often friable with occasional hemorrhagic changes. Ulcerations are often numerous and may be superficial or “punched out,” often arranged in a linear fashion and containing whitish exudates [3]. In a small review of 38 cases of immunocompetent individuals with HSE, microscopic findings consistent with acute and chronic inflammation were present, along with cytopathologic changes and viral inclusion bodies consistent with herpetic infection were present 68.4% of the time [3]. These non-specific histologic findings which include ballooning degeneration of epithelial cells, multinucleated giant cells and cowdry type A inclusion bodies can also be found in other herpes virus infections and are not limited to HSV. In the same review, the best method of diagnosis was virus isolation from biopsied esophageal tissue which was positive (95.8%) of the time, followed by immunocytochemistry (87.5%) and histopathology (68.4%) as previously mentioned [3]. Detection of HSV DNA by PCR may also be used to improve diagnostic yield in selected cases [16].\n\nTreatment of herpetic esophagitis is rarely required in immunocompetent individuals. The course is self limited, usually resolving within a week. Data showing benefit from treatment in this group is lacking [3], [15]. In the immunocompromised host, older data regarding treatment of HSV esophagitis has come from mostly small case studies of bone marrow and solid organ transplant recipients, in whom acyclovir prophylaxis is now routinely indicated [4], [5], [19]. Data from larger more recent studies has been from AIDs patients. In a study of 34 AIDs patients with confirmed or probable HSV esophagitis treated with acyclovir, complete clinical responses were achieved in 24 (71%) patients within a mean of 9 days of treatment and resolution of ulcerations was endoscopically confirmed for 12 patients. Partial responses occurred in 3 (9%), with a remaining 6 (18%) lost to follow up and 1 treatment failure [18]. In general, treatment is recommended in the immunocompromised, while prophylaxis is recommended in certain heavily immunosuppressed subgroups, as these populations are at greater risk for disseminated herpes virus infections and worse outcomes [17], [18]. In the case of our patient, although it may be difficult to establish direct causality, the fact that our patient promptly responded to anti-viral therapy with complete resolution of hiccups in 2 days makes a compelling argument as to HSV being the etiologic agent responsible. This prompt response to therapy was similar to past cases described in the literature.\n\nImage A Endoscopic view: two shallow, friable linear ulcerations extending to the gastro-esophageal junction, otherwise normal appearing mucosa.\n\nImage B (above): Esophageal mucosa with chronic inflammation and adjacent necrotic tissue 100×.\n\nImage C (above): Necrotic tissue with intranuclear inclusion-bearing cells 200×.\n\nImage D (above): Necrotic tissue with intranuclear inclusion-bearing cells 200×.\n\nImage E Characteristic Herpes simplex intranuclear inclusions. Some cells are mutinucleated 400×.\n\nImage F Aphthous ulcers on tongue.\n==== Refs\nReferences\n1 Johnson H.N. Visceral lesions associated with varicella Arch Pathol 30 1940 292 \n2 Tohru I. Takahashi T. Kusaka K. Kawaura K. Herpes simplex esophagitis from 1307 autopsy cases J Gastroenterol Hepatol 18 2003 1407 1411 14675270 \n3 Ramanathan J. Rammouni M. Baran J. Khatib R. Herpes simplex virus esophagitis in the immunocompetent host: an overview Am J Gastroenterol 95 2000 2171 2176 11007213 \n4 Mcdonald G. Sharma P. Hackman R. Esophageal infections in immunosuppressed patients after marrow transplantation Gastroenterology 88 1985 1111 1117 2984077 \n5 Mosimann F. Cuenoud P. Steinhauslin F. Wauters J. Herpes simplex esophagitis after renal transplantation Transplant Int 7 2 1994 79 82 \n6 Connolly G.M. Hawkins D. Harcourt J.N. Parsons P.A. Oesophageal symptoms, their causes, treatment and prognosis in patients with the acquired immunodeficiency syndrome Gut 30 1989 1033 1039 2548933 \n7 Steiner I. Kennedy P.G. Pachner A.R. The neurotropic herpes virus; herpes simplex and varicella-zoster Lancet 6 2007 1015 1028 17945155 \n8 Cain J. William A. Herpetic Esophagitis causing tractable hiccups Ann Int Med 119 3 1993 249 8323098 \n9 Mulhall B. Nelson B. Rogers L. Wong R. Herpetic esophagitis and intractable hiccups (singultus) in an immunocompetent patient Gastrointest Endosc 57 6 2003 796 797 12739568 \n10 Rizzo C. Caroline V. Montagnini M. Management of intractable Hiccups: an illustrative Case and Review AM J Hosp Palliat Care 31 2014 220 23408373 \n11 Marinella M.A. Diagnosis and management of hiccups in the patient with advanced cancer J Support Oncol 7 4 2009 122 127 130 19731575 \n12 Mauricio N. Elias A. Infection in patient with multiple myeloma in the era of high dose therapy and novel agents Clin Infect Dis 49 8 2009 1211 1225 19769539 \n13 Konig C. Kleber M. Reinhardt H. Knop S. Wasch R. Engelhardt M. Incidence, risk factor, and implemented prophylaxis of varicella zoster virus infection, including complicated varicella zoster virus and herpes simplex virus infections, in lenalidomide-treated multiple myeloma patients Ann Hematol 93 2014 479 484 24318541 \n14 Richardson P. Schlossman R. Munshi N. Bortezomib or high dose dexamethasone for relapsed multiple myeloma N Eng J Med 352 2005 2487 2498 \n15 Lavery E. Coyle W. Herpes simplex virus and the alimentary tract Curr Gastroenterol Rep 10 2008 417 423 18627656 \n16 Canalejo E. Duran F.G. Cabello N. Martinez J.G. Herpes Esophagitis in Healthy Adults and Adolescents, report of 3 cases and review of the literature Medicine 89 2010 204 210 20616659 \n17 Wilcox C.M. Karowe M.W. Esophageal infections: etiology, diagnosis, and management Gastroenterologist 2 September (3) 1994 188 206 7987618 \n18 Genereau T. Lortholary O. Bouchard O. Flore L. Herpes Simplex Esophagitis in patients with AIDS: Report of 34 Cases CID 22 1996 926 931 \n19 Kadakia S.C. Oliver G.A. Peura D.A. Acyclovir in endoscopically presumed viral esophagitis Gastrointest Endosc 33 1987 33 35 3557032\n\n",
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"title": "Intractable hiccups due to herpetic esophagitis in an immunocompromised patient.",
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"abstract": "Hepatitis B virus (HBV) reactivation during chemotherapy is a major concern and is widely reported, particularly in association with hematological malignancies and lymphomas. While lung cancer ranks first in incidence and mortality worldwide, HBV reactivation has been largely overlooked in this disease. As regards small-cell lung cancer (SCLC), HBV reactivation has rarely been reported. We herein report the case of a hepatitis B surface antigen-seropositive SCLC patient in whom HBV was reactivated during the course of chemotherapy, despite preemptive use of lamivudine. The patient developed fulminant viral hepatitis and succumbed to liver failure. The aim of this report was to highlight the major but overlooked issue of HBV reactivation in SCLC, and suggest that agents more potent than lamivudine may be more efficacious in high-risk patients.",
"affiliations": "Division of Head and Neck Cancer, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.;Department of Radiation Oncology, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, P.R. China.;Division of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.;Division of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.",
"authors": "Qin|Lei|L|;Wang|Fang|F|;Zou|Bing-Wen|BW|;Ding|Zhen-Yu|ZY|",
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"fulltext": "\n==== Front\nMol Clin OncolMol Clin OncolMCOMolecular and Clinical Oncology2049-94502049-9469D.A. Spandidos 10.3892/mco.2016.989MCO-0-0-989ArticlesChemotherapy-induced fatal hepatitis B virus reactivation in a small-cell lung cancer patient Qin Lei 1Wang Fang 2Zou Bing-Wen 3Ding Zhen-Yu 31 Division of Head and Neck Cancer, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China2 Department of Radiation Oncology, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, P.R. China3 Division of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. ChinaCorrespondence to: Dr Zhen-Yu Ding, Division of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 37 GuoXue Lane, Chengdu, Sichuan 610041, P.R. China, E-mail: dingzhenyu@scu.edu.cn10 2016 11 8 2016 11 8 2016 5 4 382 384 18 4 2016 27 6 2016 Copyright: © Qin et al.2016This is an open access article distributed 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.Hepatitis B virus (HBV) reactivation during chemotherapy is a major concern and is widely reported, particularly in association with hematological malignancies and lymphomas. While lung cancer ranks first in incidence and mortality worldwide, HBV reactivation has been largely overlooked in this disease. As regards small-cell lung cancer (SCLC), HBV reactivation has rarely been reported. We herein report the case of a hepatitis B surface antigen-seropositive SCLC patient in whom HBV was reactivated during the course of chemotherapy, despite preemptive use of lamivudine. The patient developed fulminant viral hepatitis and succumbed to liver failure. The aim of this report was to highlight the major but overlooked issue of HBV reactivation in SCLC, and suggest that agents more potent than lamivudine may be more efficacious in high-risk patients.\n\nlung cancerchemotherapyhepatitis B viruslamivudine\n==== Body\nIntroduction\nIt is estimated that over one-third of the world's population has been infected with hepatitis B virus (HBV), and patients who are seropositive for hepatitis B surface antigen (HBsAg+) account for 12% of cancer patients receiving chemotherapy (1,2). HBV reactivation during or after chemotherapy and subsequent liver function impairment is a major concern (3). HBV reactivation by chemotherapy is widely reported in the literature for hematological malignancies and lymphomas, and less for solid tumors (4). Lung cancer ranks first in incidence and mortality worldwide (5); however, HBV reactivation has been largely overlooked in this disease. Only one study previously reported a reactivation rate of ~19% among HBsAg+ patients with advanced non-small-cell lung cancer (NSCLC) (6). However, as regards small-cell lung cancer (SCLC), HBV reactivation has rarely been reported.\n\nWe herein report the case of an HBsAg+ SCLC patient with HBV reactivation during the course of chemotherapy, despite preemptive use of lamivudine. The patient developed fulminant viral hepatitis and succumbed to subsequent liver failure.\n\nCase report\nA 56-year-old man was admitted to the West China Hospital (Chengdu, China) in September, 2014 due to cough and blood in the sputum. The patient was diagnosed with SCLC of the right lung (stage T3N2M0). In the diagnostic work-up, the serological tests revealed positivity for HBsAg, HBeAg and HBcAb. The HBV DNA load was 1.1×105 IU/ml. The patient had mildly elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels [57 and 41 IU/l; upper limits of normal (ULN), 50 and 40 IU/l, respectively]. The biochemistry profile and complete blood count were otherwise normal. The family history revealed that the patient's mother and two brothers had died from liver disease.\n\nThe patient was prescribed preemptive lamivudine (100 mg once daily) initiated 1 week prior to chemotherapy, followed by combination chemotherapy (etoposide with carboplatin for 3 cycles and with cisplatin for 1 cycle); he then received radiotherapy to the thorax and mediastinum. Due to severe hemoptysis, myelosuppression and acute pancreatitis, the treatment was interrupted several times and was continued for a total of 6 months. During this time, the tumor enlarged, which could not be readily attributed to chemotherapy failure. The patient later received another 2 cycles of etoposide and cisplatin chemotherapy. The treatment timeline is depicted in Fig. 1.\n\nThe HBV DNA load dropped below the detection limit with the advent of lamivudine and remained low for >8 months. However, it increased to 1.0×105 IU/ml after the completion of thoracic radiotherapy. At this time point, an HBV genetic analysis was performed (Table I). Lamivudine resistance was not identified and the patient continued with lamivudine administration. The HBV DNA decreased to 6.0×103 IU/ml and increased to 1.6×105 IU/ml after the final 2 cycles of chemotherapy. The ALT and AST levels remained stable (under the detection limit) for the entire time.\n\nAfter 3 months, tumor progression was detected (Fig. 2). The laboratory examination revealed a sharply elevated ALT (from 117 to 557 IU/l), AST (from 184 to 886 IU/l), and total bilirubin levels [from 14.8 (ULN, 28.0 μmol/l) to 98.5 μmol/l], despite intensive use of hepatoprotectants (Essentiale, Gluthion and Transmetil). The HBV DNA was >5×107 IU/ml. The HBV mutation status was again analyzed (Table I) and this time it revealed a definitive emergence of lamivudine resistance. The antiviral agent was switched to entecavir (0.5 mg once a day). However, the patient developed fulminant hepatitis and his condition progressively deteriorated, with emerging signs of cholenzyme separation, hemostatic dysfunction, hypoalbuminemia, hyperammonemia, hepatic encephalopathy and hepatorenal syndrome. Eventually, the patient succumbed to the disease on August 25, 2015. Autopsy was refused.\n\nDiscussion\nWe herein report the case of a SCLC patient who developed HBV reactivation during chemotherapy, despite preemptive lamivudine treatment. The HBV DNA level rebounded after the initial drop, together with the appearance of lamivudine resistance mutations in the viral gene. In addition, the disease progressed under continuous lamivudine administration. This was accompanied by significant deterioration of hepatic function, and the patient eventually succumbed to the disease.\n\nThe definition of HBV reactivation varies in the literature, but it commonly refers to an ALT level >2 ULN in combination with either an abrupt increase in HBV replication of 1 log10 or an absolute value >2×104 IU/ml (7). In the majority of the cases, HBV reactivation occurred 1 week-3 months post-chemotherapy (8). The patient's HBV DNA increased to 1.0×105 IU/ml 3 months after the fourth cycle of chemotherapy. The time course was typical of chemotherapy-induced HBV reactivation. Furthermore, the virus genetic analysis revealed lamivudine resistance mutations. Considering the full course of HBV reactivation in a background of chemotherapy, it was reasonable to hypothesize that the chemotherapy was responsible for the HBV reactivation.\n\nChemotherapy-induced HBV reactivation has been extensively investigated. In retrospective series, the rate of HBV reactivation was as high as 80% in lymphomas or other hematological malignancies, particularly those treated with immunoinhibitory rituximab (3). The incidence of HBV reactivation in lung cancer had not been elucidated until recently, when a retrospective study reported a rate of 19% in NSCLC patients (6). However, SCLC patients have not been investigated, with no studies specific to SCLC patients reported to date. To the best of our knowledge, this is the only reported case of chemotherapy-induced fatal HBV reactivation in a SCLC patient.\n\nThe reasons underlying the lack of reports on HBV reactivation in SCLC patients remains largely unknown, although it may be due to the low incidence of this complication. Patients with hematological malignancies and lymphomas have the highest rates of HBV reactivation, mainly due to the intense chemotherapy and administration of immunoinhibitory monoclonal antibodies; in addition, such patients are already immunocompromised (3). Breast cancer patients also exhibited high rates of HBV reactivation, mainly attributed to the wide use of anthracyclines and corticosteroids. The HBV reactivation rates were lower in other cancer types. Another possibility is that SCLC has a dismal prognosis, and patients may become seriously ill before HBV reactivation is detected.\n\nThe reason underlying the poor prognosis is the evolution of the HBV gene, as evidenced by the serial monitoring of the lamivudine resistance gene. However, the patient's family history of liver disease must be taken into consideration, and the possibility of liver fragility cannot be ruled out. In addition, the patient had other comorbidities, such as severe hemoptysis, myelosuppression and acute pancreatitis. Thus, the fatal outcome may be attributed to a combination of all these factors.\n\nPreemptive antiviral therapy is recommended for HBsAg+ cancer patients prior to the initiation of chemotherapy (3,6,9). Accumulating data demonstrated that lamivudine reduced the incidence of HBV reactivation and the severity of hepatitis in these patients (10–13). The value of novel antiviral drugs, such as entecavir, telbuvidine, adefovir and tenofovir, is being evaluated. Recently, a trial compared the efficacy of lamivudine and entecavir in HBsAg+ patients with diffuse large B-cell lymphoma undergoing rituximab treatment (14). Compared with lamivudine, entecavir significantly reduced the incidence of HBV reactivation and HBV-related hepatitis. It was reasonable to hypothesize that high-risk patients may benefit from the usage of entecavir rather than lamivudine.\n\nIn summary, this was a rare case of SCLC with fatal HBV reactivation during the chemotherapy course. This aim of this report was to highlight the major issue of HBV reactivation in SCLC, which is frequently overlooked, and suggest that agents more potent than lamivudine may be more efficacious for high-risk patients.\n\nAcknowledgements\nThe present study was supported by the Natural Science Foundation of China (grant no. 81272684).\n\nFigure 1. Summary of the treatment timeline of the patient. HBV, hepatitis B virus DNA load (IU/ml).\n\nFigure 2. Tumor mass during the chemotherapy course. (A) Computed tomography scan revealed a mass in the lower lobe of the right lung. (B) The mass had significantly shrunk after 2 cycles of chemotherapy. The mass (C) marginally enlarged prior to the fifth cycle of chemotherapy and (D) significantly enlarged 1 month after cessation of chemotherapy.\n\nTable I. The HBV genetic analysis.\n\nMutation site\tAbundance (test 1) %\tAbundance (test 2) %\t\nS213T\t50\t100\t\nQ215H\t50\t 70\t\nM204I\t 0\t100\t\nV214A\t 0\t 30\n==== Refs\nReferences\n1 Ganem D Prince AM Hepatitis B virus infection-natural history and clinical consequences N Engl J Med 350 1118 1129 2004 10.1056/NEJMra031087 15014185 \n2 Yeo W Chan PK Zhong S Ho WM Steinberg JL Tam JS Hui P Leung NW Zee B Johnson PJ Frequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy: A prospective study of 626 patients with identification of risk factors J Med Virol 62 299 307 2000 10.1002/1096-9071(200011)62:3<299::AID-JMV1>3.0.CO;2-0 11055239 \n3 Mandala M Fagiuoli S Francisci D Bruno R Merelli B Pasulo L Tondini C Labianca R Roila F Hepatitis B in immunosuppressed cancer patients: Pathogenesis, incidence and prophylaxis Crit Rev Oncol Hematol 87 12 27 2013 10.1016/j.critrevonc.2012.12.004 23313021 \n4 Yeo W Johnson PJ Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy Hepatology 43 209 220 2006 10.1002/hep.21051 16440366 \n5 Siegel R Naishadham D Jemal A Cancer statistics, 2013 CA Cancer J Clin 63 11 30 2013 10.3322/caac.21166 23335087 \n6 Lin GN Peng JW Xiao JJ Liu DY Xia ZJ Hepatitis B virus reactivation in hepatitis B surface antigen seropositive patients with metastatic non-small cell lung cancer receiving cytotoxic chemotherapy: The efficacy of preemptive lamivudine and identification of risk factors Med Oncol 31 119 2014 10.1007/s12032-014-0119-0 25023055 \n7 Liaw YF Chu CM Hepatitis B virus infection Lancet 373 582 592 2009 10.1016/S0140-6736(09)60207-5 19217993 \n8 Hoofnagle JH Doo E Liang TJ Fleischer R Lok AS Management of hepatitis B: Summary of a clinical research workshop Hepatology 45 1056 1075 2007 10.1002/hep.21627 17393513 \n9 Lok AS McMahon BJ Chronic hepatitis B: Update 2009 Hepatology 50 661 662 2009 10.1002/hep.23190 19714720 \n10 Yeo W Chan PK Ho WM Zee B Lam KC Lei KI Chan AT Mok TS Lee JJ Leung TW Lamivudine for the prevention of hepatitis B virus reactivation in hepatitis B s-antigen seropositive cancer patients undergoing cytotoxic chemotherapy J Clin Oncol 22 927 934 2004 10.1200/JCO.2004.05.161 14990649 \n11 Lau GK Yiu HH Fong DY Cheng HC Au WY Lai LS Cheung M Zhang HY Lie A Ngan R Liang R Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients undergoing chemotherapy Gastroenterology 125 1742 1749 2003 10.1053/j.gastro.2003.09.026 14724827 \n12 Hsu C Hsiung CA Su IJ Hwang WS Wang MC Lin SF Lin TH Hsiao HH Young JH Chang MC A revisit of prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in non-Hodgkin's lymphoma: A randomized trial Hepatology 47 844 853 2008 10.1002/hep.22106 18302293 \n13 Long M Jia W Li S Jin L Wu J Rao N Feng H Chen K Deng H Liu F A single-center, prospective and randomized controlled study: Can the prophylactic use of lamivudine prevent hepatitis B virus reactivation in hepatitis B s-antigen seropositive breast cancer patients during chemotherapy? Breast Cancer Res Treat 127 705 712 2011 10.1007/s10549-011-1455-9 21445574 \n14 Huang H Li X Zhu J Ye S Zhang H Wang W Wu X Peng J Xu B Lin Y Entecavir vs lamivudine for prevention of hepatitis B virus reactivation among patients with untreated diffuse large B-cell lymphoma receiving R-CHOP chemotherapy: A randomized clinical trial JAMA 312 2521 2530 2014 10.1001/jama.2014.15704 25514302\n\n",
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"affiliations": "UCLA David Geffen School of Medicine, Los Angeles, California.;UCLA David Geffen School of Medicine, Los Angeles, California.;UCLA David Geffen School of Medicine, Los Angeles, California.;UCLA David Geffen School of Medicine, Los Angeles, California.;UCLA David Geffen School of Medicine, Los Angeles, California.",
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"medline_ta": "Eur J Obstet Gynecol Reprod Biol",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D018270:Carcinoma, Ductal, Breast; D017024:Chemotherapy, Adjuvant; D005260:Female; D006552:Hernia, Inguinal; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D008113:Liver Neoplasms; D008297:Male; D015411:Mastectomy, Modified Radical; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D011261:Pregnancy Trimester, First; D011262:Pregnancy Trimester, Second; D011297:Prenatal Exposure Delayed Effects",
"nlm_unique_id": "0375672",
"other_id": null,
"pages": "95-7",
"pmc": null,
"pmid": "10817888",
"pubdate": "2000-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Multimodal cancer chemotherapy during the first and second trimester of pregnancy: a case report.",
"title_normalized": "multimodal cancer chemotherapy during the first and second trimester of pregnancy a case report"
} | [
{
"companynumb": "GR-PFIZER INC-2019257005",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
... |
{
"abstract": "Malignant neoplasms of the salivary gland are uncommon entities in which surgical resection of the primary lesion has been accepted as a standard therapeutic option. The efficacy of radiation and systemic chemotherapy has been limited for patients with recurrent, metastatic, or unresectable disease because of unfavorable response rates and the short duration of the response. We treated one patient with recurrent adenoid cystic carcinoma arising from the sublingual gland and one patient with primary adenocarcinoma arising from the parotid gland with transfemoral intraarterial chemotherapy, based on full-dose cisplatin and docetaxel and concurrent external-beam radiotherapy. The doses of cisplatin and docetaxel in the two patients were 80-100 mg/m2 and 10-15 mg/m2, respectively. Docetaxel was infused first, followed by cisplatin. Both patients obtained complete responses. Although complications such as mucositis, anorexia, neutropenia, and ischemic colitis were observed, they were well tolerated and manageable. The concomitant chemoradiotherapy of cisplatin and docetaxel seemed to be a practicable option for patients with recurrent and unresectable salivary gland carcinomas.",
"affiliations": "Department of Otolaryngology, Hirosaki University School of Medicine, 5 Zaifucho, Hirosaki, 036-8562, Japan. maruya@cc.hirosaki-u.ac.jp",
"authors": "Maruya|Shin-ichiro|S|;Namba|Atsushi|A|;Matsubara|Atsushi|A|;Kakehata|Seiji|S|;Takeda|Ikuko|I|;Shirasaki|Takashi|T|;Hatayama|Yoshiomi|Y|;Nagahata|Morio|M|;Yokoyama|Junkichi|J|;Shinkawa|Hideichi|H|",
"chemical_list": "D043823:Taxoids; D000077143:Docetaxel; D002945:Cisplatin",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10147-006-0587-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-9625",
"issue": "11(5)",
"journal": "International journal of clinical oncology",
"keywords": null,
"medline_ta": "Int J Clin Oncol",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003528:Carcinoma, Adenoid Cystic; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin; D000077143:Docetaxel; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D008875:Middle Aged; D010307:Parotid Neoplasms; D018714:Radiotherapy, Adjuvant; D013362:Sublingual Gland Neoplasms; D043823:Taxoids; D016896:Treatment Outcome",
"nlm_unique_id": "9616295",
"other_id": null,
"pages": "403-6",
"pmc": null,
"pmid": "17058139",
"pubdate": "2006-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10675076;6103535;1913539;11002324;6280657;15298732;3623942;11933184;15736464;11169936;3585449;15287035;11268454;15459915;3744850;8620502",
"title": "Salivary gland carcinoma treated with concomitant chemoradiation with intraarterial cisplatin and docetaxel.",
"title_normalized": "salivary gland carcinoma treated with concomitant chemoradiation with intraarterial cisplatin and docetaxel"
} | [
{
"companynumb": "JP-PFIZER INC-2019416801",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": "3",
... |
{
"abstract": "Historically, patients with acute myeloid leukemia received intensive chemotherapy requiring hospitalization, which can diminish quality of life and increase healthcare costs. The introduction of new therapies facilitated a shift toward outpatient therapy, which requires coordination of a multidisciplinary team, thorough patient evaluation, careful preparation and rigorous patient monitoring. Many patients are candidates for multiple treatment approaches; we generally employ CPX-351 (Vyxeos®) as an intensive outpatient approach and venetoclax (Venclyxto/Venclexta®) plus hypomethylating agents as a lower-intensity approach, with 2-3 visits/week during treatment. Treatment infusions are scheduled in the morning to leave sufficient time for transfusions and other supportive care later the same day, to prevent additional visits. With careful planning and patient monitoring, acute myeloid leukemia treatment can be successfully administered in the outpatient setting.",
"affiliations": "Moffitt Cancer Center, 12901 Magnolia Drive, Tampa, FL 33612, USA.;Moffitt Cancer Center, 12901 Magnolia Drive, Tampa, FL 33612, USA.;Moffitt Cancer Center, 12901 Magnolia Drive, Tampa, FL 33612, USA.;Moffitt Cancer Center, 12901 Magnolia Drive, Tampa, FL 33612, USA.;Moffitt Cancer Center, 12901 Magnolia Drive, Tampa, FL 33612, USA.;Moffitt Cancer Center, 12901 Magnolia Drive, Tampa, FL 33612, USA.",
"authors": "Talati|Chetasi|C|;Frantz|Diedra|D|;Lubas|Amber|A|;Salamanca|Christopher|C|;Tobon|Katherine|K|;Kubal|Timothy|T|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.2217/fon-2019-0781",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1479-6694",
"issue": "16(7)",
"journal": "Future oncology (London, England)",
"keywords": "chemotherapy; hematologic/leukemia; surveillance",
"medline_ta": "Future Oncol",
"mesh_terms": "D000368:Aged; D000553:Ambulatory Care; D000971:Antineoplastic Combined Chemotherapy Protocols; D019468:Disease Management; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D015470:Leukemia, Myeloid, Acute; D008297:Male; D010348:Patient Care Team; D017410:Practice Guidelines as Topic; D016896:Treatment Outcome",
"nlm_unique_id": "101256629",
"other_id": null,
"pages": "281-291",
"pmc": null,
"pmid": "31985277",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "How I treat newly diagnosed acute myeloid leukemia in an outpatient setting: a multidisciplinary team perspective.",
"title_normalized": "how i treat newly diagnosed acute myeloid leukemia in an outpatient setting a multidisciplinary team perspective"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-023093",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HYDROXYUREA"
},
"drugad... |
{
"abstract": "Posterior reversible encephalopathy syndrome (PRES) is an acute central nervous system disorder characterized by reversible brain vasogenic edema. We report here a new case of a nine-year-old boy with B-cell acute lymphoblastic leukemia (B-ALL) who developed PRES secondary to induction chemotherapy including dexamethasone (dexamethasone®), vincristine (oncovin(®)), daunorubicin (adriblastine(®)) and intrathecal injection. Cerebral magnetic resonance imaging (MRI) showed high signal intensity on T2 at cortical and sub cortical region of parieto-frontal and parieto-occipital lobes. The patient was put under sodium valproate (depakine(®)) and we decided to continue dexamethasone (dexamethasone(®)) and daunorubicin (adriblastine(®)) injection. The MRI, after four weeks, was normal. So, we resumed vincristine (oncovin(®)) and we started L-asparaginase injections. Then, the outcome was favorable. The treatment of PRES is based on the withdrawal of the triggering factor to avoid the risk of irreversible lesions. But, due to the severity of leukemia the discontinuation of chemotherapy is difficult because of the risk of disease progression.",
"affiliations": "Department of Hematology Hedi Chaker Hospital Sfax 3029 Tunisia. walabenkridis@yahoo.fr.",
"authors": "Kridis|Wala Ben|WB|;Mdhaffer|Moez|M|;Hentati|Yosr|Y|;Kammoun|Fatma|F|;Milad|Abir|A|;Haddar|Sondes|S|;Mahfoudh|Khaireddine Ben|KB|;Triki|Chahinez|C|;Elloumi|Moez|M|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D014750:Vincristine; D003907:Dexamethasone; D003630:Daunorubicin",
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1574886309666140610160851",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1574-8863",
"issue": "10(2)",
"journal": "Current drug safety",
"keywords": null,
"medline_ta": "Curr Drug Saf",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D001929:Brain Edema; D002648:Child; D003630:Daunorubicin; D003907:Dexamethasone; D004569:Electroencephalography; D023261:Glasgow Outcome Scale; D006801:Humans; D015448:Leukemia, B-Cell; D008279:Magnetic Resonance Imaging; D008297:Male; D009460:Neurologic Examination; D054038:Posterior Leukoencephalopathy Syndrome; D014750:Vincristine",
"nlm_unique_id": "101270895",
"other_id": null,
"pages": "180-3",
"pmc": null,
"pmid": "24919742",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Posterior reversible encephalopathy syndrome in leukemic children: a sensitive issue.",
"title_normalized": "posterior reversible encephalopathy syndrome in leukemic children a sensitive issue"
} | [
{
"companynumb": "TN-BAUSCH-BL-2017-003999",
"fulfillexpeditecriteria": "1",
"occurcountry": "TN",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo investigate ammonia and glutamine levels in valproate (VPA)-related hyperammonemic encephalopathy (VHE).\n\n\nMETHODS\nWe reviewed the medical records and EEG recordings of seven adults diagnosed with VHE.\n\n\nRESULTS\nVenous ammonia levels were elevated in five (71%) of the seven patients. Elevated serum or cerebrospinal fluid (CSF) glutamine levels were found in four (80%) of five cases tested, including two who had normal ammonia levels. Initial behavioral signs included violent outbursts in three patients, paranoid ideation severe enough to require restraint in two cases, and milder abnormalities in two instances. The severity of encephalopathy was not related to any particular serum VPA level. In four patients serum VPA levels did not exceed 100 microg/ml, and in one case, VHE developed after taking only one 250-mg dose. Symptoms eventually cleared after reducing the dose of, or discontinuing, VPA. Liver-function tests were normal. Each of six patients tested had EEG findings that supported the diagnosis of VHE and excluded nonconvulsive status epilepticus. The rate of normalization of one patient's serum glutamine level and the EEGs of two cases correlated better with the timing of their delayed clinical recovery than did the more rapid rate of decline of the serum ammonia levels.\n\n\nCONCLUSIONS\nSerum or CSF glutamine levels are initially elevated in a majority of patients with suspected VHE, sometimes in the absence of hyperammonemia. Glutamine levels may be useful adjunctive laboratory tests for the diagnosis of VHE.",
"affiliations": "Swedish Epilepsy Center, Swedish Medical Center, Department of Neurology, University of Washington, Seattle 98122, USA. david.vossler@swedish.org",
"authors": "Vossler|David G|DG|;Wilensky|Alan J|AJ|;Cawthon|David F|DF|;Kraemer|Diana L Abson|DL|;Ojemann|Linda M|LM|;Caylor|Lisa M|LM|;Morgan|John D|JD|",
"chemical_list": "D000927:Anticonvulsants; D005973:Glutamine; D014635:Valproic Acid; D000641:Ammonia",
"country": "United States",
"delete": false,
"doi": "10.1046/j.1528-1157.2002.25001.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0013-9580",
"issue": "43(2)",
"journal": "Epilepsia",
"keywords": null,
"medline_ta": "Epilepsia",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000641:Ammonia; D000927:Anticonvulsants; D001921:Brain; D001927:Brain Diseases; D004569:Electroencephalography; D005260:Female; D005973:Glutamine; D006801:Humans; D022124:Hyperammonemia; D008297:Male; D008875:Middle Aged; D014635:Valproic Acid",
"nlm_unique_id": "2983306R",
"other_id": null,
"pages": "154-9",
"pmc": null,
"pmid": "11903461",
"pubdate": "2002-02",
"publication_types": "D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Serum and CSF glutamine levels in valproate-related hyperammonemic encephalopathy.",
"title_normalized": "serum and csf glutamine levels in valproate related hyperammonemic encephalopathy"
} | [
{
"companynumb": "US-ABBVIE-14P-163-1302022-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "VALPROIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "To clarify the relationship between transient sever motion artifact in arterial phase (TSMA) and changes in peripheral capillary oxygen saturation (SpO2) and heart rate (HR) after contrast media administration during MRI or CT of the liver.\n\n\n\n87 patients undergoing 61 MRI examination with gadoxetic acid or 26 CT examination with iodinated contrast were included. Dynamic contrast-enhanced imaging (DCEI) was obtained at four vascular phase acquisitions. Reviewers extracted the segmental data of SpO2 and HR in each phase from consecutive data in DCE-CT or DCE-MRI. In addition, reviewers scored for respiratory motion in each phase using 5-point scale. Patients with an arterial score of 4-5, and other phase scores of 1-2 were considered to be exhibiting TSMA.\n\n\n\nIn gadoxetic acid, mean SpO2 of arterial phase was significantly lower than three other phases (P = 0.045 to P < 0.001). However, the decrease in SpO2 in arterial phase compared with other phases was <1%. Mean HR in gadoxetic acid or iodinated contrast agent was highest in the portal-phase. The incidence of TSM was 0% in patients with iodinated contrast agent and was 8.2% (5/61 patients; TSM group) in patients with gadoxetic acid, respectively. In addition, there was no significant difference in mean SpO2 of arterial phase between the TSM group (97.5% ± 1.08%) and non-TSM group (96.4% ± 1.85%) (P = 0.219).\n\n\n\nThe slight decrease in SpO2 in arterial phase is not associated with TSMA.",
"affiliations": "Department of Radiology, Kawasaki Medical School, 577 Matsushima, Kurashiki City, Okayama 701-0192, Japan. Electronic address: ponbon@med.kawasaki-m.ac.jp.;Department of Radiology, Kawasaki Medical School, 577 Matsushima, Kurashiki City, Okayama 701-0192, Japan. Electronic address: ttamada@med.kawasaki-m.ac.jp.;Department of Radiology, Kawasaki Medical School, 577 Matsushima, Kurashiki City, Okayama 701-0192, Japan. Electronic address: t.abe@med.kawasaki-m.ac.jp.;Department of Radiology, Kawasaki Medical School, 577 Matsushima, Kurashiki City, Okayama 701-0192, Japan. Electronic address: ikechou@med.kawasaki-m.ac.jp.;Department of Radiology, Kawasaki Medical School, 577 Matsushima, Kurashiki City, Okayama 701-0192, Japan. Electronic address: yoshida@med.kawasaki-m.ac.jp.;Department of Radiology, Kawasaki Medical School, 577 Matsushima, Kurashiki City, Okayama 701-0192, Japan. Electronic address: itokatsu@med.kawasaki-m.ac.jp.",
"authors": "Kanki|Akihiko|A|;Tamada|Tsutomu|T|;Abe|Toshinori|T|;Ikenaga|Hiroyuki|H|;Yoshida|Koji|K|;Ito|Katsuyoshi|K|",
"chemical_list": "D003287:Contrast Media; C073590:gadolinium ethoxybenzyl DTPA; D007455:Iodine; D019786:Gadolinium DTPA; D010100:Oxygen",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.mri.2018.06.022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0730-725X",
"issue": "53()",
"journal": "Magnetic resonance imaging",
"keywords": "Arterial phase; CT; Gadoxetic acid; Liver; MRI; Transient sever motion artifact",
"medline_ta": "Magn Reson Imaging",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001158:Arteries; D016477:Artifacts; D003287:Contrast Media; D005260:Female; D019786:Gadolinium DTPA; D006339:Heart Rate; D006801:Humans; D007089:Image Enhancement; D007455:Iodine; D008099:Liver; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009038:Motion; D010092:Oximetry; D010100:Oxygen; D011659:Pulmonary Gas Exchange; D012307:Risk Factors; D014057:Tomography, X-Ray Computed; D055815:Young Adult",
"nlm_unique_id": "8214883",
"other_id": null,
"pages": "77-81",
"pmc": null,
"pmid": "30003949",
"pubdate": "2018-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Relationship between transient severe motion of the liver in gadoxetic acid or iodinated contrast agent-enhanced imaging and arterial oxygen saturation and heart rate changes.",
"title_normalized": "relationship between transient severe motion of the liver in gadoxetic acid or iodinated contrast agent enhanced imaging and arterial oxygen saturation and heart rate changes"
} | [
{
"companynumb": "JP-BAYER-2018-151011",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SODIUM CHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND Post-cardiac injury syndrome, including pleural effusion as a delayed complication of permanent pacemaker implantation, has rarely been reported. To resolve pleural effusion, prolonged chest tube placement is often required. Anti-inflammatory agents combined with diuretics are also often prescribed. Saireito, a Japanese herbal medication, which is a combination of Goreisan and Shousaikoto, has both anti-inflammatory and water-modulation properties and has been used for edema (lymph edema, cerebral edema) and inflammation (chronic nephritis). CASE REPORT We describe a 71-year-old woman with a history of syncope and bradycardia who underwent dual permanent pacemaker implantation (placed in the right chest because of a persistent left superior vena cava) without complications. Two months later, she came to the hospital as an outpatient with a dry cough, and was diagnosed with right-sided pleural effusion. A pleural fluid analysis revealed exudative effusion, according to Light's criteria. The fluid was negative for infectious etiology. Chest X-ray, computed tomography, and echocardiography revealed no signs of pericardial effusion or perforation of the pacemaker lead to outside the heart. The pleural effusion persisted despite use of anti-inflammatory medication for several weeks and diuretics for a short period. Saireito was administered with good response; the pleural effusion resolved completely and there was no deterioration of renal function. CONCLUSIONS The present case highlights the clinical significance of Saireito as an effective therapeutic agent for late-onset pacemaker-related pleural effusion, without adverse effects such as renal dysfunction.",
"affiliations": "Department of Cardiovascular Medicine, Japan Organization of Occupational Health and Safety, Kobe Rosai Hospital, Kobe, Hyogo, Japan.;Department of Cardiovascular Medicine, Japan Organization of Occupational Health and Safety, Kobe Rosai Hospital, Kobe, Hyogo, Japan.;Department of Cardiovascular Medicine, Japan Organization of Occupational Health and Safety, Kobe Rosai Hospital, Kobe, Hyogo, Japan.;Department of Cardiovascular Medicine, Japan Organization of Occupational Health and Safety, Kobe Rosai Hospital, Kobe, Hyogo, Japan.;Department of Cardiovascular Medicine, Japan Organization of Occupational Health and Safety, Kobe Rosai Hospital, Kobe, Hyogo, Japan.;Department of Cardiovascular Medicine, Japan Organization of Occupational Health and Safety, Kobe Rosai Hospital, Kobe, Hyogo, Japan.;Department of Cardiovascular Medicine, Japan Organization of Occupational Health and Safety, Kobe Rosai Hospital, Kobe, Hyogo, Japan.;Department of Cardiovascular Medicine, Japan Organization of Occupational Health and Safety, Kobe Rosai Hospital, Kobe, Hyogo, Japan.;Department of Cardiovascular Medicine, Japan Organization of Occupational Health and Safety, Kobe Rosai Hospital, Kobe, Hyogo, Japan.;Department of Internal Medicine, Japan Organization of Occupational Health and Safety, Kobe Rosai Hospital, Kobe, Hyogo, Japan.;Department of Internal Medicine, Japan Organization of Occupational Health and Safety, Kobe Rosai Hospital, Kobe, Hyogo, Japan.;Department of Cardiovascular Medicine, Japan Organization of Occupational Health and Safety, Kobe Rosai Hospital, Kobe, Hyogo, Japan.",
"authors": "Mataki|Hiroyuki|H|;Yasutomi|Masamichi|M|;Makino|Yuya|Y|;Kunimura|Ayako|A|;Fukuhara|Kenzo|K|;Takeda|Masafumi|M|;Kimata|Akira|A|;Hirayama|Sonoko|S|;Ozawa|Toru|T|;Shin|Teruki|T|;Yoshioka|Takayuki|T|;Inoue|Nobutaka|N|",
"chemical_list": "D004365:Drugs, Chinese Herbal; C080903:sairei-to",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.931247",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923\nInternational Scientific Literature, Inc.\n\n34455414\n10.12659/AJCR.931247\n931247\nArticles\nEffectiveness of Saireito, a Traditional Japanese Kampo Herbal Medication, on Pacemaker-Related Pleural Effusion: A Case Report\nMataki Hiroyuki A B C D E F 1\nYasutomi Masamichi E 1\nMakino Yuya E 1\nKunimura Ayako E 1\nFukuhara Kenzo E 1\nTakeda Masafumi E 1\nKimata Akira E 1\nHirayama Sonoko E 1\nOzawa Toru E 1\nShin Teruki E 2\nYoshioka Takayuki E 2\nInoue Nobutaka A E F 1\n1 Department of Cardiovascular Medicine, Japan Organization of Occupational Health and Safety, Kobe Rosai Hospital, Kobe, Hyogo, Japan\n2 Department of Internal Medicine, Japan Organization of Occupational Health and Safety, Kobe Rosai Hospital, Kobe, Hyogo, Japan\nCorresponding Author: Hiroyuki Mataki, e-mail: hiromata6535@gmail.com\nAuthors’ 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\n2021\n29 8 2021\n22 e931247-1e931247-7\n24 1 2021\n29 6 2021\n16 7 2021\n© Am J Case Rep, 2021\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)\nPatient: Female, 71-year-old\n\nFinal Diagnosis: Pacemaker related pleural effusion\n\nSymptoms: Dry cough\n\nMedication:—\n\nClinical Procedure: —\n\nSpecialty: Cardiology • General and Internal Medicine\n\nObjective:\n\nUnusual or unexpected effect of treatment\n\nBackground:\n\nPost-cardiac injury syndrome, including pleural effusion as a delayed complication of permanent pacemaker implantation, has rarely been reported. To resolve pleural effusion, prolonged chest tube placement is often required. Anti-inflammatory agents combined with diuretics are also often prescribed. Saireito, a Japanese herbal medication, which is a combination of Goreisan and Shousaikoto, has both anti-inflammatory and water-modulation properties and has been used for edema (lymph edema, cerebral edema) and inflammation (chronic nephritis).\n\nCase Report:\n\nWe describe a 71-year-old woman with a history of syncope and bradycardia who underwent dual permanent pacemaker implantation (placed in the right chest because of a persistent left superior vena cava) without complications. Two months later, she came to the hospital as an outpatient with a dry cough, and was diagnosed with right-sided pleural effusion. A pleural fluid analysis revealed exudative effusion, according to Light’s criteria. The fluid was negative for infectious etiology. Chest X-ray, computed tomography, and echocardiography revealed no signs of pericardial effusion or perforation of the pacemaker lead to outside the heart. The pleural effusion persisted despite use of anti-inflammatory medication for several weeks and diuretics for a short period. Saireito was administered with good response; the pleural effusion resolved completely and there was no deterioration of renal function.\n\nConclusions:\n\nThe present case highlights the clinical significance of Saireito as an effective therapeutic agent for late-onset pacemaker-related pleural effusion, without adverse effects such as renal dysfunction.\n\nKeywords:\n\nDrugs, Chinese Herbal\nPacemaker, Artificial\nPleural Effusion\n==== Body\npmcBackground\n\nPacemaker implantation is a standard and safe therapeutic strategy for patients of all ages with bradyarrhythmia. Various complications associated with pacemaker implantation are common, but late-onset pacemaker-related pleural effusion is rarely reported [1]. Recently, Xiong et al reported 6 consecutive elderly patients with pleural effusion who had undergone a new pacemaker implantation and evaluated the clinical characteristics and therapeutic courses of pleural effusion [2]. According to their report, cases of late-onset pacemaker-related pleural effusion were treatment-resistant; patients had to be hospitalized repeatedly with thoracentesis because conventional treatments including diuretics and anti-inflammatory agents had only short-term effects, similar to a case reported by Shaukat et al [3].\n\nSaireito (TJ-114) is a combination of 2 herbal medications, Shousaikoto and Goreisan. Shousaikoto is known as a remedy for hepatitis, and previous investigations have reported that Shousaikoto has potential as an anti-inflammatory drug [4]. In addition, Goreisan has been reported to be effective for hydrostatic modulation via the suppression of aqua-porin 4 [5]. Therefore, Saireito has both anti-inflammatory and water-utilization benefits. Saireito is composed of 12 crude drugs: 7 g of saiko, 5 g of takusha, 5 g of hange, 3 g of ougon, 3 g of soujutu, 3 g of taisou, 3 g of chorei, 3 g of ninjin, 3 g of bukuryo, 2 g of kanzo, 2 g of keihi, and 1 g of shoukyou. Takusha, soujutu, chorei, and bukuyrou, the main components of Goreisan, have an effect on regulating the amount of water in the body. Saiko and ougon, components of Shousaikoto, have anti-inflammatory effects. Saireito has been used in the treatment of chronic kidney disease, diarrhea, acute gastritis, and various edematous disorders, such as subdural hematoma, chronic lymphedema, cirrhosis, and general edema. Saireito has also widely been used to treat various inflammatory diseases, such as rheumatoid arthritis [6,7]. Recently, herbal medications have been attracting attention for their effectiveness in circulatory disease; however, the association between the use of herbal medication and pleural effusion has not been well documented. We had a case in which Saireito was effective for the treatment of late-onset pacemaker-related pleural effusion.\n\nCase Report\n\nA 71-year-old woman who had been previously well and had no significant past medical history was admitted to our hospital for a syncope attack after a meal. On admission, she regained consciousness, but her blood pressure was elevated to 212/76 mm Hg and her heart rate was 63 beats/min. She did not have a heart murmur. The laboratory tests showed no abnormalities (Table 1).\n\nThe electrocardiogram on admission showed normal sinus rhythm, with a left branch anterior bundle block, and high voltage of the left ventricle, with secondary ST-T changes (Figure 1A). The chest X-ray exhibited cardiomegaly. There was no indication of pneumonia or heart failure (Figure 1B). The electrocardiogram monitoring in the hospital revealed a prolonged R-R interval of 6040 ms, associated with fainting (Figure 2). From these findings, she was diagnosed with sick sinus syndrome type II. Echocardiography conducted 6 days before pacemaker implantation revealed normal function with mild left hypertrophy and mild to moderate mitral regurgitation.\n\nA previous venography of the subclavian vein revealed a persistent left superior vena cava. Therefore, a permanent dual chamber pacemaker was implanted under fluoroscopic guidance in the right chest. Venous access was achieved by puncture of the subclavian vein, and both leads were endocardial screw-in leads. The setting rate of the implanted pacemaker was 60 to 130 pulses per min. Chest X-rays on the day of implantation, 1 day after implantation, and 6 days after implantation revealed no pleural effusion. She was discharged in 13 days without any complications.\n\nTwo months after pacemaker implantation, the patient visited the hospital as an outpatient, presenting with a dry cough. The chest X-ray and computerized tomography revealed right-sided pleural effusion (Figure 3). An echocardiogram showed no sign of pericardial effusion or perforation of the myocardium and was nearly identical to a previous echocardiogram. Thoracentesis was performed, and the fluid composition was exudative effusion, according to Light’s criteria (Table 2). A pleural fluid analysis was negative for infectious etiology, including mycobacteria, and there were no findings of malignancy. After thoracentesis, right-sided pleural effusion remained almost the same as before (Figure 4A). A pacemaker interrogation revealed no abnormality. We considered that the pleural effusion was a manifestation of a pacemaker-associated injury.\n\nTherefore, we initiated an oral anti-inflammatory agent (acetaminophen 600 mg/day), and oral diuretics (furosemide 40 mg/day) as an initial dose, then as needed for a short period. With these treatments, the pleural effusion decreased somewhat; however, persistent right pleural effusion was present 2 months later (Figure 4B, 4C). Furthermore, the patient’s renal function deteriorated slightly (Figure 5).\n\nTo decrease pleural effusion and prevent further deterioration of renal function, we prescribed oral Saireito (an herbal substitute for anti-inflammatory agents and diuretics) at an initial dose of 9 g/day, because long-term use of anti-inflammatory agents and diuretics often causes renal damage. We also wanted to avoid the use of steroids, considering her age. Right pleural effusion completely disappeared 1 month after the administration of Saireito (Figure 4D). The patient’s renal function was also maintained (Figure 5). The patient has been followed as an outpatient and has been well and free from recurrent pleural effusion.\n\nDiscussion\n\nIn the present case, Saireito, a Japanese traditional herbal medication, played an important role in reducing pleural effusion that occurred 2 months after the implantation of a dual chamber pacemaker, without deterioration of renal function. Various drugs used in modern medicine can have adverse effects, such as renal dysfunction. Therefore, in some medical situations, traditional herbal medication is often used as an alternative to prevent adverse events [8]. Aquaporin (AQP) is a water channel and is composed of at least 13 types of isoforms. Goreisan strongly inhibits AQP3, AQP4, and AQP5 [9,10]. Interestingly, unlike western diuretics, Goreisan induces an increase of urine volume in an edematous state, but not in a dehydrated state. The precise pharmacological mechanisms of traditional herbal medications, such as Saireito and Goreisan, remain to be elucidated [11]. The use of herbal medications has attracted more attention in recent years [12]. To treat congestive heart failure, Mokubouito or Shakannzouto have often been used in addition to standard therapy, and Goreisan has been used to treat edematous states [13]. Saireito has been used for diarrhea, chronic renal disease, lymphedema, and cerebral edema. In addition, according to Takei et al, Saireito and Boiogito can improve hypertension [14].\n\nShousaikoto has potential as an anti-inflammatory treatment, and has been used for pneumonia, bronchitis, lymphadenitis, and chronic hepatitis. Therefore, we hypothesized that Saireito, being a combination of Goreisan and Shousaikoto, might be effective in both edematous and inflammatory states, such as in the present case [15].\n\nLate-onset pacemaker-related pleural effusion is rare and often difficult to treat. Conventional medical treatment, including anti-inflammatory agents, colchicine, and diuretics often have little effect on late-onset pacemaker-related pleural effusion. Therefore, repeated therapeutic thoracentesis is unavoidable in some cases. In the present case, pleural effusion persisted after 2 months of an anti-inflammatory agent and diuretics. Considering not only its effectiveness, but also its renal protective properties, Saireito was administered, and the pleural effusion disappeared completely, without deterioration of renal function (Figure 5). It is worth noting that Saireito attenuates renal damage induced by diuretics. In the present case, renal protection was one of the reasons for selecting Saireito versus alternative traditional anti-inflammatory agents or diuretics. Our patient’s pleural effusion completely resolved, and renal function was maintained.\n\nConclusions\n\nIn conclusion, our experience indicates that the use of Saireito could resolve treatment-resistant pleural effusion as a delayed complication of pacemaker implantation, without deterioration of renal function. Whether Goreisan or Shousaikoto alone have the same effect as Saireito remains to be evaluated. Further study is required to examine the use of these agents alone for pleural effusion as a delayed complication of permanent pacemaker implantation.\n\nWe would like to thank Editage (www.editage.com) for English language editing.\n\nFigure 1. (A) Electrocardiogram on first admission. Normal sinus rhythm with the left branch anterior bundle block. ST-T change shows left ventricular hypertrophy. Occasional ventricular premature complexes are present. R-R interval reveals 960 ms. (B) Chest X-ray on first admission. No pleural effusion is found. Cardiac hypertrophy is revealed.\n\nFigure 2. Monitoring electrocardiogram showing prolonged R-R interval (6040 ms), which indicated sick sinus syndrome.\n\nFigure 3. (A) Chest X-ray and (B) computed tomography showing massive right pleural effusion.\n\nFigure 4. Serial chest X-ray findings of right pleural effusion. (A) Chest X-ray reveals massive right pleural effusion after pleural puncture test. (B) Chest X-ray after 1 month of anti-inflammatory drug combined with a short period of diuretics. Right pleural effusion persisted. (C) Chest X-ray after 2 months of taking anti-inflammatory drug in combination with diuretics for a short period. Right side costophrenic angle was still apparently dull. (D) One month after using Saireito. Right costophrenic angle is sharp, indicating that right pleural effusion is completely resolved.\n\nFigure 5. Transition of renal function. On June 24, before treatment, creatinine was 0.74 and e-glomerular filtration rate (GFR) was 58.6. On August 19 of the same year, 1 month after using acetaminophen 1500 mg/day and loop diuretic for a short period, creatinine and e-GFR data worsened to 0.82 and 52.4, respectively. On August 25, 1 year after stopping acetaminophen and diuretics, and starting Saireito 9 g/day (tapering to 6 g, 3 g, and 1.5 g), the creatinine and e-GFR recovered to 0.74 and 58.4, respectively.\n\nTable 1. Laboratory data on patient’s first admission revealed only mild hypokalemia. On second admission, mild hypokalemia still existed, and brain natriuretic peptide (BNP) was slightly elevated.\n\n\t\tFirst admission\tSecond admission\t\t\tFirst admission\tSecond admission\t\nTotal protein\tg/dl\t6.5\t8.2\tLDL\tmg/dl\t116\t110\t\nAlbumin\tg/dl\t3.4\t3.9\tHDL\tmg/dl\t58\t54\t\nAST\tU/L\t20\t22\tTG\tmg/dl\t70\t87\t\nALT\tU/L\t9\t8\tTSH\tμIU/ml\t2.1\t1.6\t\nCPK\tU/L\t34\t78\tfreeT4\tng/dl\t1.59\t1.7\t\nLDH\tU/L\t159\t232\tCRP\tmg/dl\t0.3\t0.3\t\nγGTP\tU/L\t23\t18\tBNP\tpg/ml\t70\t108\t\nBUN\tmg/dl\t22\t15\tWBC\t/μL\t6160\t5720\t\nUA\tmg/dl\t6.7\t6.5\tRBC\t104/μL\t434\t433\t\ne-GFR\tml/min.1.73 m2\t59\t59\tHemoglobin\tg/dl\t12.4\t12\t\nNa\tmmol/L\t138\t136\tHematocrit\t%\t37.2\t36.3\t\nK\tmmol/L\t3.2\t3.4\tPlatelet\t104/μL\t20.3\t21.9\t\ncl\tmmol/L\t102\t101\t\t\t\t\t\nAST – aspartate aminotransferase; ALT – alanine aminotransferase; CPK – creatine phosphokinase; LDH – lactate dehydrogenase; γGTP – gamma-glutamyl transpeptidase; LDL – low density lipoprotein; HDL – high density lipoprotein; TG – triglyceride; TSH – thyroid stimulating hormone; T4 – thyroxin; CRP – C-reactive protein; BNP – brain natriuretic peptide; WBC – white blood cell; RBC – red blood cell.\n\nTable 2. Pleural effusion analysis. Lactate dehydrogenase (LDH) concentration in effusion >200 IU; LDH concentration divided by serum LDH concentration >0.6. According to the Light criteria, the effusion is exudative.\n\nApperance\tPale bloody\t\nSpecific gravity\t1.029\t\nCarcinoembryonic antigen\t1.1 ng/ml\t\nAdenosine deaminase\t38 IU/L\t\nHyaluronic acid\t6170 ng/ml\t\nTotal protein\t3.6 g/dl\t\nBlood sugar\t102 mg/dl\t\nLDH\t418 U/L\t\nWBC\t200~300/mm3\t\nLymphocyte\t55%\t\nNeutrophil\t0%\t\nEosinophil\t20%\t\nMacrophage\t23%\t\nLDH – lactate dehydrogenase; WBC – white blood cell.\n\nDeclaration of Figures Authenticity\n\nAll figures submitted have been created by the authors who confirm that the images are original with no duplication and have not been previously published in whole or in part.\n==== Refs\nReferences:\n\n1. Ludwig S Theis C Wolff C Complications and associated health-care costs of transvenous cardiac pacemakers in Germany J Com Eff Res 2019 8 8 589 97\n2. Xiong M Zhang Z Hu K Dong M Hu W Recurrent, late-onset pleural effusions in elderly patients receiving pacemaker therapy Case Rep Med (Baltimore) 2018 97 43 e12915\n3. Shaukat MHS Shabbir MA Mookherjee S Peredo-Wende R Successful use of anakinra for colchicine-intolerant, corticosteroid-dependent recurrent pericarditis secondary to postcardiac injury syndrome after pacemaker placement BMJ Case Rep 2019 4 12 4 e229117\n4. Kim A Im M Ma JY Sosiho-tang ameliorates cachexia-related symptoms in mice bearing colon 26 adenocarcinoma by reducing systemic inflammation and muscle loss Oncol Rep 2016 35 3 1841 50 26718030\n5. Nakano T Nishigami C Irie K Goreisan prevents brain edema after cerebral ischemic stroke by inhibiting aquaporin4 upregulation in mice J Stroke Cerebrovasc Dis 2018 27 3 758 63 29153303\n6. Morimoto N Kakudo N Mitsui T The effectiveness of Saireito, a traditional Japanese herbal medicine, in reducing postoperative edema after acquired ptosis surgery: A prospective controlled trial Evid Based Complement Alternat Med 2018 2018 4742305 30050587\n7. Nagai A Shibamoto Y Ogawa K Therapeutic effects of Saireito (Chai-Ling-Tang), a traditional Japanese herbal medicine, on lymphedema caused by radiotherapy: A case series study Evid Based Complement Alternat Med 2013 2013 241629 23861700\n8. Liu L Liu C Wang Y Herbal medicine for anxiety, depression and insomnia Curr Neuropharamacol 2015 13 4 41 93\n9. Inada R Miyamoto K Tanaka N Oryeongsan (Goreisan) ameliorates experimental autoimmune encephalomyelitis Intern Med 2020 59 55 60 31484905\n10. Goto S Kato K Yamamoto T Effectiveness of Goreisan in preventing recurrence of chronic subdural hematoma Asian J Neurosurg 2018 13 370 74 29682036\n11. Sasaki H Kimizuka Y Ogata H Successful control of dasatinib-related chylothorax by the Japanese herbal medicine “Goreisan” Intern Med 2019 58 21 3139 41 31292394\n12. Wagner L Cramer H Klose P Herbal medicine for cough: A systemic reviews and meta-analysis Forsch Komplementmed 2015 22 359 68 26840418\n13. Yano Y Yano H Takahashi H Goreisan inhibits upregulation of aqua-porin 4 and formation of cerebral edema in the rat model of juvenile hypoxic-ischemic encephalopathy Evid Based Complement Alternat. Med 2017 2017 3209219 29234383\n14. Takei H Nakai Y Hattori N The herbal medicines Saireito and Boiogito improve the hypertension of preeclamptic rats induced by nomega-nitoro-L-arginine methyl ester Phytomedicine 2007 14 9 591 600 17353120\n15. Fitzgerald DB Waterer GW Read CA Steroid therapy and outcome of parapneumonic pleural effusions (STOPPE): Study protocol for a multi-center, double-blinded, placebo-controlled randomized clinical trial Medicine (Baltimore) 2019 98 43 e17397 31651842\n\n",
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"mesh_terms": "D000368:Aged; D004365:Drugs, Chinese Herbal; D005260:Female; D006801:Humans; D007564:Japan; D020835:Medicine, Kampo; D010138:Pacemaker, Artificial; D010996:Pleural Effusion; D014683:Vena Cava, Superior",
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"pubdate": "2021-08-29",
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"title": "Effectiveness of Saireito, a Traditional Japanese Kampo Herbal Medication, on Pacemaker-Related Pleural Effusion: A Case Report.",
"title_normalized": "effectiveness of saireito a traditional japanese kampo herbal medication on pacemaker related pleural effusion a case report"
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"abstract": "Positive galactomannan tests in patients who underwent chemotherapy without any clinical signs of a fungal infection should lead the clinician to consideration of a false-positive test result. Oral nutritional supplements may be a cause, especially in the case of concomitant disturbance of the gastrointestinal mucosal barrier because of mucositis.",
"affiliations": "Klinik für Innere Medizin II Universitätsklinikum Jena Hämatologie und Internistische Onkologie Jena Germany.;Klinik für Innere Medizin II Universitätsklinikum Jena Hämatologie und Internistische Onkologie Jena Germany.;Klinik für Innere Medizin II Universitätsklinikum Jena Hämatologie und Internistische Onkologie Jena Germany.;Institut für Medizinische Mikrobiologie Universitätsklinikum Jena Jena Germany.;Klinik für Innere Medizin II Universitätsklinikum Jena Hämatologie und Internistische Onkologie Jena Germany; Centre for Sepsis Control and Care Universitätsklinikum Jena Jena Germany.;Klinik für Innere Medizin II Universitätsklinikum Jena Hämatologie und Internistische Onkologie Jena Germany; Centre for Sepsis Control and Care Universitätsklinikum Jena Jena Germany; Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie Hans-Knöll-Institut Jena Germany.",
"authors": "Rachow|Tobias|T|;Dornaus|Sebastian|S|;Sayer|Herbert G|HG|;Hermann|Beate|B|;Hochhaus|Andreas|A|;von Lilienfeld-Toal|Marie|M|",
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"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.516CCR3516Case ReportCase ReportsCase report: false positive elevated serum‐galactomannan levels after autologous hematopoietic stem cell transplantation caused by oral nutritional supplements T. Rachow et al.Rachow Tobias \n1\nDornaus Sebastian \n1\nSayer Herbert G. \n1\nHermann Beate \n2\nHochhaus Andreas \n1\n\n3\nvon Lilienfeld‐Toal Marie \n1\n\n3\n\n4\n1 Klinik für Innere Medizin IIUniversitätsklinikum JenaHämatologie und Internistische OnkologieJenaGermany2 Institut für Medizinische MikrobiologieUniversitätsklinikum JenaJenaGermany3 Centre for Sepsis Control and CareUniversitätsklinikum JenaJenaGermany4 Leibniz‐Institut für Naturstoff‐Forschung und InfektionsbiologieHans‐Knöll‐InstitutJenaGermany* Correspondence\n\nTobias Rachow, Klinik für Innere Medizin II, Universitätsklinikum Jena, Hämatologie und Internistische Onkologie, Erlanger Allee 101, Jena, 07747, Germany. Tel: +4936419324201; Fax: +4936419324202; E‐mail: tobias.rachow@med.uni-jena.de\n12 4 2016 5 2016 4 5 10.1111/ccr3.2016.4.issue-5505 508 16 6 2015 04 1 2016 28 1 2016 © 2016 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Key Clinical Message\nPositive galactomannan tests in patients who underwent chemotherapy without any clinical signs of a fungal infection should lead the clinician to consideration of a false‐positive test result. Oral nutritional supplements may be a cause, especially in the case of concomitant disturbance of the gastrointestinal mucosal barrier because of mucositis.\n\nAutologous stem cell transplantationenteral nutritiongalactomannaninvasive fungal infection source-schema-version-number2.0component-idccr3516cover-dateMay 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.8.8 mode:remove_FC converted:04.05.2016\n\nClinical Case Reports \n2016 ; 4 (5 ): 505 –508\n==== Body\nIntroduction\nImmunocompromised patients are at high risk for invasive fungal infections (IFI) like invasive pulmonary aspergillosis. Detection of galactomannan (GM) levels in the serum has been found to be a valid surrogate parameter for early diagnosis of IFI. Nevertheless, several clinical circumstances may influence serum GM levels. Here, we present a 68‐year old male patient with an angioimmunoblastic T cell lymphoma with aberrant expression of CD20 who was admitted for high‐dose chemotherapy with consecutive autologous stem cell transplantation. Initial laboratory tests did not show any significant abnormalities. High‐dose chemotherapy containing rituximab, thiotepa, etoposide, cytarabine, and melphalan (R‐TEAM) was administered and autologous stem cells were retransfused without any problems. During the neutropenic phase, the patient developed severe mucositis, presenting as persistent diarrhea (CTC‐grade 3) and diminished appetite. He consumed several energy drinks per day as nutritional supplements. Routinely performed serum tests showed a GM level of 1.5 (norm < 0.5). CT scans showed no signs of IFI. A calculated antifungal therapy was initiated. However, during the course of neutropenia and after engraftment the GM levels increased without any signs of IFI. Testing for GM in the energy drinks revealed a high positive result for GM. Hence, the patient was advised to stop consuming these drinks and the GM level decreased and normalized eventually. The same drink given to individuals without mucositis did not lead to an increase in GM levels. We thus assume a disturbed intestinal mucosal barrier because of the treatment‐induced diarrhea as a cause of false positive GM results. This case report indicates a potential source of false positive results for serum GM tests. Energy drinks can be an important support in the diet of hematologic patients. A disturbed intestinal mucosal barrier may lead to the transfer of ingested sugar‐molecules into the patients' blood and thereby affect serum GM levels.\n\nImmunocompromised patients are at risk for opportunistic infections like invasive fungal infections (IFI), invasive aspergillosis (IA), or invasive candidiasis (IC). Furthermore, underlying hematologic malignancies or intensive chemotherapy regimens often make invasive diagnostic procedures impossible 1. Fungal cell wall components like aspergillus galactomannan (GM) or candida mannan (CM) can be found in the patients' blood in the case of IFI 2, 3, 4, 5. Hence, they have been found to be a good surrogate parameter for early diagnosis of IFI and immediate preemptive antifungal therapy. Current guidelines recommend performing serum‐galactomannan tests at least twice a week in patients at risk of invasive fungal infections 6. In contrast, several studies suggest potential causes for false‐positive GM tests. Enteral supplemental nutrition might be a source for positive test results in the condition of allogeneic stem cell transplantation and intestinal graft versus host disease 7, 8, 9, 10. Our case suggests a potential enteral cause of false‐positive serum‐GM tests in the context of autologous stem cell transplantation and therapy‐induced mucositis.\n\nCase Presentation\nA 69‐year old male patient was electively admitted to our hospital for high‐dose chemotherapy and autologous stem cell transplantation. On admission, the patient reported to be in his usual health. No clinical signs of infection (like fever, coughing, sneezing, or dysuria) had occurred in the weeks prior to admission. Nine months earlier a rare variant of an angioimmunoblastic T‐cell non‐Hodgkin lymphoma with aberrant expression of CD20‐stage IVB had been diagnosed. After diagnosis, an immunochemotherapy with six cycles of the R‐CHOP‐protocol (rituximab, cyclophosphamide, doxorubicine, vincristin, prednisolone) and two consolidating cycles of rituximab had been administered. The first cycle of chemotherapy had been complicated by acute renal failure due to tumor lysis, a central venous line infection and a stomatitis due to reactivation of herpes simplex virus. Subsequent cycles could be administered without any complication. A restaging examination after six cycles of chemotherapy showed a good partial remission, thus, consolidation with high‐dose chemotherapy and autologous stem cell transplantation was planned. Since diagnosis, there had never been any suspicion of invasive fungal infections. Routine laboratory testing showed no noticeable problems except from slightly elevated serum‐creatinine levels and the diagnostic work‐up was unremarkable apart from arterial hypertension. An exercise stress test showed no electrocardiographic signs of a relevant ischemic heart disease.\n\nAfter excluding potential contraindications, we administered a myeloablative chemotherapy following the R‐TEAM‐protocol (rituximab, thiotepa, etoposide, cytarabine, and melphalan) 11. On the day of stem cell retransfusion, the patient developed severe diarrhea (CTC‐grade 3) most probably caused by chemotherapy 12. Tests for infectious enteritis showed no positive result. Thus, the diarrhea was assumed to be chemotherapy induced and hypercaloric drinks were offered to the patient because of weight loss and reduced appetite. The patient consumed one to three of these drinks per day. On the day of stem cell retransfusion, elevated body temperatures could be measured and fever occurred from day +2 until day +9 after stem cell transplantation, and was accompanied by an increase in the C‐reactive protein (the clinical course after the stem cell transplantation is depicted in Fig. 1). Blood cultures indicated a central line infection with Staphylococcus epidermidis, thus, antibiotic treatment with teicoplanin was initiated. Also, stool cultures showed the presence of multiresistant E. coli and meropenem was added. Repeatedly performed routine‐tests for serum‐galactomannan showed a marked elevation after the period of neutropenia, after resolution of fever and despite decreasing levels of C‐reactive protein (see Fig. 1), whereas serum candida‐antigen tests stayed in the normal range. GM levels were tested using the Platelia™ Aspergillus Ag kit (Bio‐Rad) and candida‐antigen levels using the Platelia™ Candida Ag plus kit (Bio‐Rad Laboratories GmbH, Munich, Germany). Because of a suspected invasive aspergillosis, a calculated antifungal therapy with voriconazole was initiated although CT‐imaging showed no signs of invasive pulmonary fungal infection. No adequate explanation could be found with respect to the laboratory results. For further investigation of the inconsistent findings regarding the positive serum aspergillus‐GM tests and the missing clinical evidence for an invasive aspergillosis, the patients' environment was examined. The consumed hypercaloric drinks were tested with the same diagnostic fungal tests as for the patients' blood samples. Both, aspergillus‐GM and candida‐antigen could be detected in high levels (5.35 and 700 pg/mL, respectively). In order to test for accuracy, two healthy volunteers consumed the same drinks and blood samples at baseline and 4 h after the ingestion of the drink were tested for aspergillus‐GM. As expected, the tests showed negative results throughout. The patient was advised to stop the consumption of the drinks and serum‐GM levels decreased (see Fig. 1). On day 30 after retransfusion of stem cells, the patient could be discharged from the hospital. Four weeks later, the patient was readmitted because of dyspnea and coughing. Serum‐galactomannan levels were normal and CT‐imaging still showed no signs of invasive pulmonary fungal infection. After antibiotic treatment all clinical signs of infection resolved. Regular follow‐up investigations showed no relapse of the lymphoma after 12 months.\n\nFigure 1 Trends of C‐reactive protein (triangle‐symbols and solid line) and serum‐galactomannan (dots and broken line) after stem cell retransfusion: the C‐reactive protein levels increased with fever in neutropenia and normalized after initiation of an effective antibacterial therapy; the level of serum‐galactomannan increased even after neutropenic reconstitution (on day 12) and fell after advising the patient to quit consuming the hypercaloric drinks.\n\nDiscussion\nMalnutrition and weight loss are frequent complications of high‐dose conditioning and autologous peripheral blood stem cell transplant and supportive enteral nutrition might be beneficial 13. In the presented case, the patient received high‐caloric drinks containing galacto‐oligosaccharides as well as gluconate, which has been reported to cause elevated galactomannan levels 14. The consumed products were tested for aspergillus‐GM and candida‐antigen. The tests showed markedly positive results. The food industry uses complex sugar molecules like galactomannans for stabilizing and thickening of many products 15. Tests for aspergillus‐GM lead to positive results in many foods 16. In this context, they might affect diagnostic procedures in case of passing over from the intestine into the bloodstream. It should also be kept in mind, that galactomannan levels in blood can be elevated due to intravenous antibiotic administration.\n\nOccurrence of aspergillus‐GM in the blood is thought to be caused by angioinvasion of growing aspergillus hyphae. The most widely used biomarker for invasive aspergillosis is an EIA‐based procedure and uses a monoclonal antibody for the detection of the 1–5 glactofuranose side chain of the galactomannan molecule (Bio‐Rad, Platelia™ Aspergillus Ag kit). Although positivity of the biomarkers preceded clinical signs of IFI in several cases, a drawback is the rate of false‐positive results in up to 15% 17, 18. Therefore, repeated measurements are recommended in current guidelines.\n\nDiarrhea is one of the most commonly occurring side effects of chemotherapy and may indicate a dysfunction in the intestinal mucosal barrier. The TEAM conditioning protocol contains melphalan, which is known to be a potential cause of severe diarrhea as a known side effect 19. We hypothesize that the dysfunction of the intestinal mucosal barrier in the context of stem cell transplantation was the reason for the false‐positive serum‐galactomannan results. Several case reports about different false‐positive aspergillus tests were published in the setting of allogenic stem cell transplantation and graft‐versus‐host disease. To the best of our knowledge there are no reports about false‐positive GM‐tests in recipients of autologous stem cell transplantation due to enteral supplemental nutrition agents.\n\nIn addition, we tested the drinks and the patients' serum for candida mannan (Bio‐Rad, Platelia™, Candida Ag plus). While the drink was tested positive, candida antigen could not be detected in the patient's serum. The reason for this finding remains unclear. We assume a different intestinal processing and absorption of the antigens in the context of chemotherapy‐associated disturbed mucosal barrier function.\n\nConclusion\nDiagnosis of invasive fungal infection remains a challenge for clinicians, especially in the context of stem cell transplantation. Surrogate parameters like antigen detection in the patients' serum are an essential diagnostic element. Test results should be critically interpreted in the clinical context with respect to potential causes of false‐positive findings in order to prevent unnecessary antimycotic treatment. In our case', aspergillus‐GM but not candida‐antigen could be detected in the patients' blood, whereas both molecules could be detected in the potential source of the false‐positive test results. Thus, the exact mechanisms of disturbed intestinal barrier function as a cause for false‐positive findings in the context of stem cell transplantation remain unclear.\n\nConflict of Interest\nNone declared.\n==== Refs\nReferences\n1 \n\nOstrosky‐Zeichner , L. \n\n2012 \nInvasive mycoses: diagnostic challenges . Am. J. Med. \n125 (1 Suppl ):S14 –S24 .22196205 \n2 \n\nMaertens , J. A. \n, \nR. \nKlont \n, \nC. \nMasson \n, \nK. \nTheunissen \n, \nW. \nMeersseman \n, \nK. \nLagrou \n, et al. 2007 \nOptimization of the cutoff value for the Aspergillus double‐sandwich enzyme immunoassay . Clin. Infect. Dis. \n44 :1329 –1336 .17443470 \n3 \n\nArendrup , M. C. \n, \nO. J. \nBergmann \n, \nL. \nLarsson \n, \nH. V. \nNielsen \n, \nJ. O. \nJarlov \n, and \nB. \nChristensson \n. 2010 \nDetection of candidaemia in patients with and without underlying haematological disease . Clin. Microbiol. Infect. \n16 :855 –862 .20002683 \n4 \n\nEllis , M. \n, \nB. \nAl‐Ramadi \n, \nR. \nBernsen \n, \nJ. \nKristensen \n, \nH. \nAlizadeh \n, and \nU. \nHedstrom \n. 2009 \nProspective evaluation of mannan and anti‐mannan antibodies for diagnosis of invasive Candida infections in patients with neutropenic fever . J. Med. Microbiol. \n58 (Pt 5 ):606 –615 .19369522 \n5 \n\nHerbrecht , R. \n, \nV. \nLetscher‐Bru \n, \nC. \nOprea \n, \nB. \nLioure \n, \nJ. \nWaller \n, \nF. \nCampos \n, et al. 2002 \nAspergillus galactomannan detection in the diagnosis of invasive aspergillosis in cancer patients . J. Clin. Oncol. \n20 :1898 –1906 .11919250 \n6 \n\nRuhnke , M. \n, \nA. \nBohme \n, \nD. \nBuchheidt \n, \nO. \nCornely \n, \nK. \nDonhuijsen \n, \nH. \nEinsele \n, et al. 2012 \nDiagnosis of invasive fungal infections in hematology and oncology–guidelines from the Infectious Diseases Working Party in Haematology and Oncology of the German Society for Haematology and Oncology (AGIHO) . Ann. Oncol. \n23 :823 –833 .21948809 \n7 \n\nGuigue , N. \n, \nJ. \nMenotti \n, and \nP. \nRibaud \n. 2013 \nFalse positive galactomannan test after ice‐pop ingestion . N. Engl. J. Med. \n369 :97 –98 .23822795 \n8 \n\nNg , T. Y. \n, \nM. L. \nKang \n, \nB. H. \nTan \n, and \nC. C. \nNgan \n. 2014 \nCase report: Enteral nutritional supplement as a likely cause of false‐positive galactomannan testing . Med. Mycol. Case Rep. \n3 :11 –13 .24567893 \n9 \n\nMurashige , N. \n, \nM. \nKami \n, \nY. \nKishi \n, \nG. \nFujisaki \n, and \nR. \nTanosaki \n. 2005 \nFalse‐positive results of Aspergillus enzyme‐linked immunosorbent assays for a patient with gastrointestinal graft‐versus‐host disease taking a nutrient containing soybean protein . Clin. Infect. Dis. \n40 :333 –334 .15655766 \n10 \n\nMillon , L. \n, \nF. \nGrenouillet \n, \nJ. \nCrouzet \n, \nF. \nLarosa \n, \nS. \nLoewert \n, \nA. P. \nBellanger \n, et al. 2010 \nFalse‐positive Aspergillus real‐time PCR assay due to a nutritional supplement in a bone marrow transplant recipient with GVH disease . Med. Mycol. \n48 :661 –664 .20392146 \n11 \n\nPester , F. \n, \nA. \nKlink \n, \nS. \nScholl \n, \nK. \nSchilling \n, \nL. \nMuegge \n, \nK. \nHöffken \n, et al. TEAM (Thiotepa, Etoposide, Cytarabine, Melphalan) is an effective high‐dose chemotherapy consolidation regimen with autologous stem cell transplantation for patients with relapsed lymphoma in complete remission . 34th Annual Meeting of the European Group for Blood and Marrow Transplantation; 34th Annual Meeting of the European Group for Blood and Marrow Transplantation, Florence2008.\n12 \nUS Department of Health and Human Services NIoH, National Cancer Institute \n. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.02009 January 19, 2010.\n13 \n\nHung , Y. C. \n, \nJ. \nBauer \n, \nP. \nHorsley \n, \nM. \nWaterhouse \n, \nJ. \nBashford \n, and \nE. \nIsenring \n. 2013 \nChanges in nutritional status, body composition, quality of life, and physical activity levels of cancer patients undergoing autologous peripheral blood stem cell transplantation . Support. Care Cancer \n21 :1579 –1586 .23306934 \n14 \n\nPetraitiene , R. \n, \nV. \nPetraitis \n, \nJ. R. , III\nWitt \n, \nM. M. \nDurkin \n, \nJ. D. \nBacher \n, \nL. J. \nWheat \n, et al. 2011 \nGalactomannan antigenemia after infusion of gluconate‐containing Plasma‐Lyte . J. Clin. Microbiol. \n49 :4330 –4332 .21976760 \n15 \n\nCheng , Y. \n, \nK. M. \nBrown \n, and \nPrud'homme , R. K. \n\n2002 \nPreparation and characterization of molecular weight fractions of guar galactomannans using acid and enzymatic hydrolysis . Int. J. Biol. Macromol. \n31 :29 –35 .12559424 \n16 \n\nAnsorg , R. \n, \nR. \nvan den Boom \n, and \nP. M. \nRath \n. 1997 \nDetection of Aspergillus galactomannan antigen in foods and antibiotics . Mycoses \n40 :353 –357 .9470421 \n17 \n\nSwanink , C. M. \n, \nJ. F. \nMeis \n, \nA. J. \nRijs \n, \nJ. P. \nDonnelly \n, and \nP. E. \nVerweij \n. 1997 \nSpecificity of a sandwich enzyme‐linked immunosorbent assay for detecting Aspergillus galactomannan . J. Clin. Microbiol. \n35 :257 –260 .8968919 \n18 \n\nFoy , P. C. \n, \nJ. A. \nvan Burik \n, and \nD. J. \nWeisdorf \n. 2007 \nGalactomannan antigen enzyme‐linked immunosorbent assay for diagnosis of invasive aspergillosis after hematopoietic stem cell transplantation . Biol. Blood Marrow Transplant. \n13 :440 –443 .17287156 \n19 \n\nSharma , S. K. \n, \nA. \nHandoo \n, \nD. \nChoudhary \n, \nG. \nDhamija \n, and \nN. \nGupta \n. 2013 \nSevere gastrointestinal mucositis following high dose melphalan therapy for multiple myeloma . World J. Gastroenterol. \n19 :784 –785 .23429569\n\n",
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"journal": "Clinical case reports",
"keywords": "Autologous stem cell transplantation; enteral nutrition; galactomannan; invasive fungal infection",
"medline_ta": "Clin Case Rep",
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"nlm_unique_id": "101620385",
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"title": "Case report: false positive elevated serum-galactomannan levels after autologous hematopoietic stem cell transplantation caused by oral nutritional supplements.",
"title_normalized": "case report false positive elevated serum galactomannan levels after autologous hematopoietic stem cell transplantation caused by oral nutritional supplements"
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"abstract": "Chemotherapy usually causes complications affecting several tissues such as oral mucosa. In this case report, a soft palate oral ulcer caused by chemotherapy was treated by ozone gas. This kind of treatment is known for its antimicrobial, regenerative and analgesic proprieties. The results show a complete resolution of the lesion within 2 weeks of treatment. Ozone therapy demonstrates greater effectiveness with respect to this kind of oral lesion compared to traditional therapy. Considering this evidence, ozone therapy should be considered as a useful tool for the adjuvant therapy of oral complications in oncologic patients.\nIntensive chemotherapy can have side effects, particularly affecting tissue with higher turnover. Therefore, there is a clinical need to prevent or to treat such complications.Ozone therapy could improve oral mucosa healing and have anti-inflammatory, antioxidant and antibacterial effects to prevent suprainfections. To date, there are no reported cases of oral ulcers in oncologic patients being completely resolved using ozone in the literature.Medical and dental doctors should collaborate with regards to complex patients to prevent such types of complications, discovering these clinical cases that are unknown in the literature and treating patients in a more comprehensive way.",
"affiliations": "Tuscan Stomatologic Institute, Versilia General Hospital, Lido di Camaiore, Italy.;Private clinician, Liguria, Italy.;Private clinician, Liguria, Italy.;Tuscan Stomatologic Institute, Versilia General Hospital, Lido di Camaiore, Italy.;Tuscan Stomatologic Institute, Versilia General Hospital, Lido di Camaiore, Italy.;Tuscan Stomatologic Institute, Versilia General Hospital, Lido di Camaiore, Italy.;Tuscan Stomatologic Institute, Versilia General Hospital, Lido di Camaiore, Italy.",
"authors": "Oldoini|Giacomo|G|;Frabattista|Giulia Ricci|GR|;Saragoni|Maria|M|;Cosola|Saverio|S|;Giammarinaro|Ernica|E|;Genovesi|Anna Maria|AM|;Marconcini|Simone|S|",
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"fulltext": "\n==== Front\nEur J Case Rep Intern Med\nEuropean Journal of Case Reports in Internal Medicine\n2284-2594 2284-2594 SMC Media Srl \n\n32133312\n10.12890/2020_001406\n1406-1-11013-1-10-20200108\nArticles\nOzone Therapy for Oral Palatal Ulcer in a Leukaemic Patient\nOldoini Giacomo 1 Frabattista Giulia Ricci 2 Saragoni Maria 2 Cosola Saverio 1 Giammarinaro Ernica 1 Genovesi Anna Maria 1 Marconcini Simone 1 \n1 Tuscan Stomatologic Institute, Versilia General Hospital, Lido di Camaiore, Italy\n\n2 Private clinician, Liguria, Italy\n2020 \n14 1 2020 \n7 2 00140627 11 2019 30 11 2019 © EFIM 20202020This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseChemotherapy usually causes complications affecting several tissues such as oral mucosa. In this case report, a soft palate oral ulcer caused by chemotherapy was treated by ozone gas. This kind of treatment is known for its antimicrobial, regenerative and analgesic proprieties. The results show a complete resolution of the lesion within 2 weeks of treatment. Ozone therapy demonstrates greater effectiveness with respect to this kind of oral lesion compared to traditional therapy. Considering this evidence, ozone therapy should be considered as a useful tool for the adjuvant therapy of oral complications in oncologic patients.\n\nLEARNING POINTS\nIntensive chemotherapy can have side effects, particularly affecting tissue with higher turnover. Therefore, there is a clinical need to prevent or to treat such complications.\n\nOzone therapy could improve oral mucosa healing and have anti-inflammatory, antioxidant and antibacterial effects to prevent suprainfections. To date, there are no reported cases of oral ulcers in oncologic patients being completely resolved using ozone in the literature.\n\nMedical and dental doctors should collaborate with regards to complex patients to prevent such types of complications, discovering these clinical cases that are unknown in the literature and treating patients in a more comprehensive way.\n\nOzone therapyleukaemiaadjuvant therapyoral ulceroral fungal infectionsozonedentistry\n==== Body\nINTRODUCTION\nThe treatment for acute lymphocytic leukaemia (ALL) in adults is usually long-term chemotherapy. Intensive chemo regimens are undertaken to obtain better clinical responses, but may also lead to complications and side effects. In these patients, if the immune system is damaged, opportunistic infections can occur and, sometimes, complications can be serious enough to be life-threatening. Today, thanks to the multidisciplinary approach regarding supportive care (nursing care, nutrition, antibiotics, growth factors and so on) for oncologic patients, these life-threatening episodes are far less common than in the past[1].\n\nSide effects of chemotherapy affect rapidly proliferating cells, such as in the bone marrow, intestinal mucosa, oral mucosa, hair follicles and gonads. In particular, in oral mucosa, basal cells are lysed, replacement and turnover slow down resulting in mucosal ulcerations, or other oral damage such as aphthous lesions, mucositis and oral candidiasis caused by immunodepression[2].\n\nOzone is a gas known for its antibacterial, antiviral and antifungal properties and it is widely used in medicine and dentistry[3]. Medical ozone can improve the microcirculation and it has anti-inflammatory, analgesic and immune-modulating properties. All of these characteristics qualify medical ozone as a valid candidate within clinical dentistry, especially for the treatment of soft tissues.\n\nFrom a pharmacological point of view, ozone therapy follows the principle of hormesis: it has high efficacy with lower concentrations, but at a greater dosage, it can be ineffective, or even toxic. At low dosage, this powerful oxidizing agent stimulates endogenous antioxidant activity and the production of interleukins and leukotrienes, causing a reduction in inflammation and pain.\n\nIn this article, an ulcerative lesion located in the soft palate has been treated by ozone as an adjuvant therapy in a leukaemic patient undergoing an intensive chemo regimen[4].\n\nCASE DESCRIPTION\nThe patient was a 69-year-old male who was sent to the Tuscan Stomatologic Institute because of an oral lesion diagnosed as major aphthous ulcers that had not healed over 25 days. Anamnestic data were collected. The patient suffered from lymphoblastic Ph+ leukaemia (ALL) and was on his second chemotherapy cycle with monoclonal antibodies, namely, blinatumomab. The oral lesion was classified as an ulcerative lesion of the oral palatal tissue, probably due to the side effects of these therapies on the oral cavity.\n\nThe ulcerative lesion had already appeared 7 days after chemotherapy started, causing, at the beginning, just a light sting and then, after 25 days, it had developed into an extended ulcer. During these 25 days, antibiotic, antimycotic, analgesic and opioid medications had been prescribed to treat the lesion by haematologists and otorhinolaryngologists (FANS, opioids, amoxicillin and clavulanic acid, morphine, oxycodone, econazole, vitamins and oral gel specific for aphthosis).\n\nThe lesion did not heal; instead, it became chronic so the haematologist of the patient decided to suspend chemotherapeutical treatment until the lesion disappeared completely. This meant the lesion needed to be resolved as soon as possible.\n\nThe patient reported a constant and strong pain, similar to a jellyfish burn, which made it impossible for him to eat, drink and swallow, risking other systemic problems due to malnutrition. Consequently, the patient suffered from xerostomia caused by dehydration and drugs.\n\nOn first inspection at the Tuscan Stomatologic Institute (T0), that is, 25 days after the oral lesion had started, the ulcer (Fig. 1) located in the soft palate was more than 2 cm in diameter and several millimeters in depth. Above the lesion and on the back of the tongue there was a Candida suprainfection, which did not respond to antimycotic medication. The ulcer was treated using an ozone generator device (OZONE DTA, Sweden & Martina, Padua, Italy), which develops ozone from environmental oxygen. When ozone therapy started, all other treatments were interrupted except for antimycotic treatment of opportunistic infections. The patient could also still take analgesics (opioids or ketoprofen) when needed, and a sodium hyaluronic spray with amino acids (Aminogam, Polifarma Benessere, Italy) several times during the day.\n\nThe first ozone session consisted of 5 applications of 2 minutes each, gradually increasing the power from 5 to 9. The insert utilized was the n #5 for mucosal use. The top of the probe in contact with the tissue released energy along the treated area. The ozone concentration was between 10 and 100 μg/ml. The patient felt pain during the first applications and the lesion was wetted with saline solution to reduce discomfort. At the end of the first session, the patient had already reported a reduction in pain, and he was able again to swallow and drink water. The patient returned after 2 days (T1). The diameter and the depth of the lesion had decreased, the colour was more natural (a pinkish colour) and the oedema was reduced (Fig. 2). After this second session, the production of saliva increased, the Candida infection was reduced and the patient stopped opioid intake, continuing with just ketoprofen once a day.\n\nThe treatment continued with ozone applications (10 minutes each) every 2 days, using the mucosal and angled insert, alternatively, in order to also reach the deepest zone of the soft palate (Fig. 3 and Fig. 4). Constant improvements were clinically appreciable and were noticed also by the patient. After 15 days, the lesion was remarkably reduced so doctors decided to restart the antitumoural therapy (Fig. 5). After 22 days (Fig. 6), the ozone treatment was ended after a last application of ozone gas with the same machine and ozonated water (2 cycles of 1.5 minutes using the Aquolab® Professional). After 1 month, the patient returned for monitoring of lesion healing (Fig. 7).\n\nDISCUSSION\nThe most frequent oral complications of antitumoural therapy are mucositis, ulcerative lesions, oral infections, pain and salivary gland dysfunction[5]. In order to treat these kinds of lesions, oncologic patients are often monitored by other specialists to control complications before they become chronic. In some cases, the pharmacologic therapy may not be enough, and the patient may also need adjuvant therapy to facilitate the healing process, preventing correlated complications such as dehydration and malnutrition[6]. Ozone stimulates the release of interleukins and leukotrienes, reducing inflammation and promoting healing of the damaged tissues[7]. Ozone treatment causes nitric oxide release, which is a vasodilator. Nitric oxide improves the red cells tissue blood perfusion and stimulates aerobic processes such as glycolysis and the Krebs cycle[8, 9]. Based on this evidence, ozone therapy was also shown to play an important role in reducing oral lichen planus symptoms [10].\n\nChlorhexidine was considered the gold standard for treating several infections and inflammatory diseases in the oral cavity but it has certain side effects, especially with prolonged treatment. Kaur and co-workers (2019) reported better results, even if not statistically significant, with ozonated water irrigation than with 0.2% chlorhexidine gluconate irrigation in the management of periodontal disease in 20 patients[11]. Other studies have reported encouraging effects of ozone irrigation combined with or as an alternative to chlorhexidine, because it may shift the oral microbiota to health [12,13].\n\nAccording to a review by Kaimala et al. (2018), the oral microbiota could also help patients by acting as an immunotherapeutic agent modulating the immune system[14]. Furthermore, ozone has a high level of biocompatibility with epithelial cells, mucosal cells and fibroblast cells, along with its effects on other biological actions such as biosynthetic, haemostatic, bioenergetic, analgesic and antihypoxic processes, and these properties of ozone are refined upon contact with water (as in the oral cavity)[15,16].\n\nThis biological rationale and these clinical results encourage clinicians to collaborate for a multidisciplinary medicine where oncologic patients are also supervised by a dentist to monitor or prevent the complications of chemotherapy.\n\nCONCLUSION\nIn this clinical case, an ulcerative lesion located in the soft palate of a patient undergoing chemotherapy was treated by ozone therapy. The initial pain and extensions of the lesion forced clinicians to interrupt the chemotherapy and start treating the lesions with antibiotic, antimycotic, analgesic and opioid medications, without evident improvements. Only after the use of ozone therapy as an adjuvant therapy was tissue damage fully recovered, and the patient reported no pain; he could stop antibiotic, antimycotic, analgesic and opioid treatment and start chemotherapy again.\n\nThe results of this clinical case are highly encouraging, although further research is needed to standardize the ozone therapy clinical procedure and its indications with large sample sizes and prospective studies.\n\nConflicts of Interests: The Authors declare that there are no competing interest\n\nFigure 1 Initial photo, T0\n\nFigure 2 T1, 2 days after the first applications\n\nFigure 3 Four days after the first applications\n\nFigure 4 Eight days after the first applications\n\nFigure 5 Fifteen days after the first applications\n\nFigure 6 Last applications of ozone, 22 days after the first applications\n\nFigure 7 No treatment, follow-up 31 days after the first ozone applications\n==== Refs\nREFERENCES\n1 Peterson DE Srivastava R Lalla RV Oral mucosal injury in oncology patients: perspectives on maturation of a field Oral Dis 2015 21 2 133 141 24131518 \n2 Pai A Prasad S Dyasanoor S Acute leukemias: a dentist’s perspective Minerva Stomatol 2012 61 5 233 238 22576448 \n3 Huth KC Jakob FM Saugel B Cappello C Paschos E Hollweck R Effect of ozone on oral cells compared with established antimicrobials Eur J Oral Sci 2006 114 5 435 440 17026511 \n4 Iebba V Totino V Gagliardi A Santangelo F Cacciotti F Trancassini M Eubiosis and dysbiosis: the two sides of the microbiota New Microbiol 2016 39 1 1 12 26922981 \n5 Bocci VA Scientific and medical aspects of ozone therapy. State of the art Arch Med Res 2006 37 4 425 435 16624639 \n6 Saini R Ozone therapy in dentistry: a strategic review J Nat Sci Biol Med 2011 2 2 151 153 22346227 \n7 Roy D Wong PK Engelbrecht RS Chian ES Mechanism of enteroviral inactivation by ozone Appl Environ Microbiol 1981 41 3 718 723 6261692 \n8 Seydanur Dengizek E Serkan D Abubekir E Aysun Bay K Onder O Arife C Evaluating clinical and laboratory effects of ozone in non-surgical periodontal treatment: a randomized controlled trial J Appl Oral Sci 2019 27 e20180108 30673028 \n9 Agrillo A Ungari C Filiaci F Priore P Iannetti G Ozone therapy in the treatment of avascular bisphosphonate-related jaw osteonecrosis J Craniofac Surg 2007 18 5 1071 1075 17912085 \n10 Kazancioglu HO Erisen M Comparison of low-level laser therapy versus ozone therapy in the treatment of oral lichen planus Ann Dermatol 2015 27 5 485 491 26512161 \n11 Kaur A Bhavikatti SK Das SS Khanna S Jain M Kaur A Efficacy of ozonised water and 0.2% chlorhexidine gluconate in the management of chronic periodontitis when used as an irrigant in conjugation with phase I therapy J Contemp Dent Pract 2019 20 3 318 323 31204324 \n12 Dodwad V Gupta S Kumar K Sethi M Masamatti S Changing paradigm in pocket therapy - ozone vs conventional irrigation Int J of Public Health Dent 2011 2 2 7 12 \n13 Cosola S Giammarinaro E Genovesi AM Pisante R Poli G Covani U A short-term study of the effects of ozone irrigation in an orthodontic population with fixed appliances Eur J Paediatr Dent 2019 20 1 15 18 30919638 \n14 Kaimala S Al-Sbiei A Cabral-Marques O Fernandez-Cabezudo MJ Al-Ramadi BK Attenuated bacteria as immunotherapeutic tools for cancer treatment Front Oncol 2018 8 136 29765907 \n15 Akdeniz SS Beyler E Korkmaz Y Yurtcu E Ates U Araz K The effects of ozone application on genotoxic damage and wound healing in bisphosphonate-applied human gingival fibroblast cells Clin Oral Investig 2018 22 2 867 873 \n16 Nogales CG Ferrari PH Kantorovich EO Lage-Marques JL Ozone therapy in medicine and dentistry J Contemp Dent Pract 2008 9 4 75 84 18473030\n\n",
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"issue": "7(2)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Ozone therapy; adjuvant therapy; dentistry; leukaemia; oral fungal infections; oral ulcer; ozone",
"medline_ta": "Eur J Case Rep Intern Med",
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"nlm_unique_id": "101648453",
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"title": "Ozone Therapy for Oral Palatal Ulcer in a Leukaemic Patient.",
"title_normalized": "ozone therapy for oral palatal ulcer in a leukaemic patient"
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"affiliations": "Division of Cardiology, Albany Medical College, Albany Medical Center, Albany, New York, USA.;Division of Cardiology, Albany Medical College, Albany Medical Center, Albany, New York, USA.;Division of Cardiology, Albany Medical College, Albany Medical Center, Albany, New York, USA.;Division of Cardiology, Albany Medical College, Albany Medical Center, Albany, New York, USA.;Clinical Pharmacy Specialist, Albany Medical Center, Albany, New York, USA.;Division of Cardiology, Albany Medical College, Albany Medical Center, Albany, New York, USA.",
"authors": "Topliceanu|Alexandru|A|;Breen|Thomas|T|http://orcid.org/0000-0003-2134-5158;Patel|Hiren|H|http://orcid.org/0000-0002-1589-791X;Yager|Neil|N|;Maceira|Erica|E|;Torosoff|Mikhail|M|",
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"keywords": "cardiovascular medicine; cardiovascular system; haematology (drugs and medicines); unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D000925:Anticoagulants; D000991:Antithrombins; D003328:Coronary Thrombosis; D017548:Echocardiography, Transesophageal; D005260:Female; D006493:Heparin; D006629:Hirudins; D006801:Humans; D010446:Peptide Fragments; D011994:Recombinant Proteins; D013921:Thrombocytopenia; D014859:Warfarin",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30323102",
"pubdate": "2018-10-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17257990;14609790;15457154;14718324;16113796;10534688;16685006;1866765;18270134;24685669;18195201;16153932;22392825;27092199;10961867;24603191;22329977;18682541;16928996;24295719;16159799;26272889;22315270;10661778;17258570;18772063",
"title": "Bivalirudin fails to prevent atrial thrombus development in heparin-induced thrombocytopaenia and thrombosis syndrome.",
"title_normalized": "bivalirudin fails to prevent atrial thrombus development in heparin induced thrombocytopaenia and thrombosis syndrome"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/18/0105435",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BIVALIRUDIN"
},
"drugadditional": "1",
... |
{
"abstract": "We describe a case of microscopic polyangiitis manifested as pleuritis confirmed by thoracoscopic biopsy. An 80-year-old man presented with a three-day history of shortness of breath and cough. Chest radiography revealed patchy opacities in the lower fields of the bilateral lung and right-sided pleural effusion. Thoracentesis revealed lymphocytic pleural exudates. Thoracoscopic biopsy specimens were compatible with fibrotic pleuritis. He developed rapidly progressive glomerulonephritis with elevated myeloperoxidase anti-neutrophil cytoplasmic antibody titer in blood and pleural effusion. Although the patient was resistant to two weekly courses of pulse steroid therapy, he was successfully treated with a five-day course of intravenous immunoglobulin.",
"affiliations": "Akashi Medical Center, Department of General Internal Medicine. maru-tkb@umin.ac.jp.",
"authors": "Ishimaru|Naoto|N|;Ohnishi|Hisashi|H|;Fujii|Mao|M|;Yumura|Masako|M|;Yoshimura|Sho|S|;Kinami|Saori|S|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.4081/monaldi.2018.897",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1122-0643",
"issue": "88(2)",
"journal": "Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace",
"keywords": "Microscopic polyangiitis; pleuritis; thoracoscopy.",
"medline_ta": "Monaldi Arch Chest Dis",
"mesh_terms": null,
"nlm_unique_id": "9307314",
"other_id": null,
"pages": "897",
"pmc": null,
"pmid": "29927196",
"pubdate": "2018-06-21",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Microscopic polyangiitis presented with biopsy-confirmed pleuritis.",
"title_normalized": "microscopic polyangiitis presented with biopsy confirmed pleuritis"
} | [
{
"companynumb": "JP-TEVA-2019-JP-1038453",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo investigate the feasibility and efficacy of the combination of S-1 with gemcitabine followed by oral S-1 with concurrent radiotherapy (intensity modulated radiotherapy, IMRT) and maintenance therapy with S-1 for locally advanced pancreatic cancer.\n\n\nMETHODS\nSubjects selected in the study were patients who had unresectable and locally advanced pancreatic cancer without distant metastases, adequate organ and marrow functions, an Eastern Cooperative Oncology Group performance status of 0-1 and no prior anticancer therapy. Initially the subjects received two cycles of chemotherapy, oral administration of S-1 40 mg/m(2) twice daily from day 1 to day 14 of a 21-d cycle, with 30-min intravenous infusions of gemcitabine 1000 mg/m(2) on day 1 and day 8. Two weeks after the completion of chemotherapy, S-1 was administered orally with concurrent IMRT. Oral S-1 was administered at a dose of 80 mg/m(2) per day twice daily from day 1 to day 14 and from day 22 to day 35. Radiation was concurrently delivered at a dose of 50.4 Gy (1.8 Gy/d, 5 times per week, 28 fractions). One month after the completion of chemotherapy and radiotherapy, S-1 was administered orally at a dose of 80 mg/m(2) per day twice daily for 14 d, followed by a 14-d rest period. This cycle was repeated as maintenance therapy, until unacceptable toxicity occurred or the disease worsened. Thirty-two patients were involved in this study. The median follow-up was 15.6 mo (range: 8.6-32.3 mo).\n\n\nRESULTS\nThirty-two patients completed the scheduled course of chemotherapy, while 30 patients (93.8%) received chemoradiotherapy with two patients ceasing to continue with radiotherapy. The major toxic effects were nausea and leukopenia. There was no grade 4 toxicity or treatment-related death. According to the Response Evaluation Criteria in Solid Tumors criteria, the objective tumor response was partial response in 17 (53.1%) patients, stable disease in 9 (28.1%), and progressive disease in 6 (18.8%). The median overall survival and median progression-free survival were 15.2 mo and 9.3 mo, respectively. The survival rates at 1 year and 2 years were 75% and 34.4%, respectively.\n\n\nCONCLUSIONS\nThe combination of S-1 with gemcitabine followed by oral S-1 with IMRT and maintenance therapy with S-1 alone in patients with locally advanced pancreatic cancer may be considered a well-tolerated, promising treatment regimen.",
"affiliations": "Qing-Hua Ke, Shi-Qiong Zhou, Ji-Yuan Yang, Wei Du, Gai Liang, Yong Lei, Fei Luo, Department of Chemoradiotherapy, Oncology Hospital of Jingzhou, Jingzhou 434000, Hubei Province, China.;Qing-Hua Ke, Shi-Qiong Zhou, Ji-Yuan Yang, Wei Du, Gai Liang, Yong Lei, Fei Luo, Department of Chemoradiotherapy, Oncology Hospital of Jingzhou, Jingzhou 434000, Hubei Province, China.;Qing-Hua Ke, Shi-Qiong Zhou, Ji-Yuan Yang, Wei Du, Gai Liang, Yong Lei, Fei Luo, Department of Chemoradiotherapy, Oncology Hospital of Jingzhou, Jingzhou 434000, Hubei Province, China.;Qing-Hua Ke, Shi-Qiong Zhou, Ji-Yuan Yang, Wei Du, Gai Liang, Yong Lei, Fei Luo, Department of Chemoradiotherapy, Oncology Hospital of Jingzhou, Jingzhou 434000, Hubei Province, China.;Qing-Hua Ke, Shi-Qiong Zhou, Ji-Yuan Yang, Wei Du, Gai Liang, Yong Lei, Fei Luo, Department of Chemoradiotherapy, Oncology Hospital of Jingzhou, Jingzhou 434000, Hubei Province, China.;Qing-Hua Ke, Shi-Qiong Zhou, Ji-Yuan Yang, Wei Du, Gai Liang, Yong Lei, Fei Luo, Department of Chemoradiotherapy, Oncology Hospital of Jingzhou, Jingzhou 434000, Hubei Province, China.;Qing-Hua Ke, Shi-Qiong Zhou, Ji-Yuan Yang, Wei Du, Gai Liang, Yong Lei, Fei Luo, Department of Chemoradiotherapy, Oncology Hospital of Jingzhou, Jingzhou 434000, Hubei Province, China.",
"authors": "Ke|Qing-Hua|QH|;Zhou|Shi-Qiong|SQ|;Yang|Ji-Yuan|JY|;Du|Wei|W|;Liang|Gai|G|;Lei|Yong|Y|;Luo|Fei|F|",
"chemical_list": "D004338:Drug Combinations; D003841:Deoxycytidine; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; C056507:gemcitabine",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v20.i38.13987",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "20(38)",
"journal": "World journal of gastroenterology",
"keywords": "CA19-9; Chemoradiotherapy; Pancreatic cancer; Radiosensitizer; S-1",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D059248:Chemoradiotherapy; D002681:China; D003841:Deoxycytidine; D018450:Disease Progression; D018572:Disease-Free Survival; D019583:Dose Fractionation, Radiation; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D010094:Oxonic Acid; D010190:Pancreatic Neoplasms; D016634:Radiosurgery; D020266:Radiotherapy, Conformal; D016019:Survival Analysis; D005641:Tegafur; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "13987-92",
"pmc": null,
"pmid": "25320537",
"pubdate": "2014-10-14",
"publication_types": "D016428:Journal Article",
"references": "22677367;21709185;17878176;20606093;18828020;23763511;16855985;23856911;18309942;17533388;17437021;17363191;19705054;17189072;22065318;21969502;17538975;19636002;19151975;21356477;17388169;19967537;20605363;22679115;22555398;21647560;24258457;22160780;22284684;17235048;22249272;23547081;22977306;20194854",
"title": "S-1 plus gemcitabine chemotherapy followed by concurrent radiotherapy and maintenance therapy with S-1 for unresectable pancreatic cancer.",
"title_normalized": "s 1 plus gemcitabine chemotherapy followed by concurrent radiotherapy and maintenance therapy with s 1 for unresectable pancreatic cancer"
} | [
{
"companynumb": "CN-CIPLA LTD.-2014CN01573",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GIMERACIL\\OTERACIL\\TEGAFUR"
},
"drugadditio... |
{
"abstract": "A woman in her early 50s was admitted to the intensive care unit with nausea, altered mental status and hepatic failure. She had a history of asymptomatic chronic hepatitis B and recently received chemotherapy for breast cancer. A diagnosis of hepatitis B reactivation (HBR) was made, but unfortunately she died of liver failure. Controversies around testing for hepatitis B prior to giving immunosuppressive treatments and the use of prophylactic antiviral therapy to prevent HBR are discussed.",
"affiliations": "Clinical and Translational Science Institute, Pittsburgh, Pennsylvania, USA.",
"authors": "Shoushtari|Ali Hakim|AH|;Shaw|Robert A|RA|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2013()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D005260:Female; D006515:Hepatitis B virus; D019694:Hepatitis B, Chronic; D006801:Humans; D017093:Liver Failure; D008875:Middle Aged; D014775:Virus Activation",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "23307451",
"pubdate": "2013-01-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11596081;18802412;10458258;12794717;18515881;11170044;11590667;21037870;1983820;12512032;21788556;16440366;51345;15054446;20516452;7065560;12930732;11055239;19399812;3618581",
"title": "Fulminant hepatitis following chemotherapy treatment for breast cancer.",
"title_normalized": "fulminant hepatitis following chemotherapy treatment for breast cancer"
} | [
{
"companynumb": "PHHY2013US046487",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EPIRUBICIN"
},
"drugadditional": null,
"drug... |
{
"abstract": "BACKGROUND\nTandem occlusions exist in 17-32% of large vessel occlusion (LVO) strokes. A significant concern is bleeding when carotid stenting is performed in tandem with thrombectomy due the administration of antiplatelet agents such as glycoprotein IIb/IIIa inhibitors (GP2b3aI) after receiving rtPA, but data are limited in this setting.\n\n\nMETHODS\nA mutlicenter, retrospective chart review was conducted at two comprehensive stroke centers to assess the safety and efficacy of using GP2b3aI to facilitate carotid stent placement simultaneously with endovascular thrombectomy in patients who have received rtPA.\n\n\nRESULTS\nOverall, 32 patients were included in this study, with average age of 66.3 ± 10.4 years and predominantly male (87.5%). The cause of stroke was mostly large artery atherosclerosis (59.4%) and the thrombectomy target vessels were typically first- or second segment middle cerebral artery (37.5% and 31.3%). Time from symptom onset to rtPA bolus was 1.8 h [interquartile range (IQR) 1.5-2.7], rtPA bolus to first pass was 2 h [IQR 1.5-3.1], rtPA bolus to GP2b3aI bolus was 2 h [IQR 1.6-3.5], and rtPA bolus to aspirin and clopidogrel administration was 4.3 h [IQR 2.6-8.9] and 6.6 h [IQR 4.5-11.6] respectively. No patients had acute in-stent thrombosis or post-op bleeding from the access site. Two patients (6.3%) had significant hemorrhagic conversion.\n\n\nCONCLUSIONS\nThe use of GP2b3aI in the setting of tandem occlusions that required emergent stent placement post-rtPA appears safe and effective. Given the small sample size, these findings should be interpreted cautiously, and need to be confirmed in a larger patient population.",
"affiliations": "Department of Pharmacy, The Ohio State University Wexner Medical Center, Columbus, OH, USA.;Department of Neurological Surgery, The Ohio State University Wexner Medical Center, 410 W 10th Ave, Columbus, OH, 43210, USA.;Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.;The Ohio State University College of Medicine, Columbus, OH, USA.;Department of Pharmacy, The Ohio State University Wexner Medical Center, Columbus, OH, USA.;Department of Neurological Surgery, The Ohio State University Wexner Medical Center, 410 W 10th Ave, Columbus, OH, 43210, USA.;Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.;Department of Neurological Surgery, The Ohio State University Wexner Medical Center, 410 W 10th Ave, Columbus, OH, 43210, USA. Shahid.Nimjee@osumc.edu.",
"authors": "Smetana|Keaton S|KS|;Zakeri|Amanda|A|;Dolia|Jaydevsinh|J|;Huttinger|Allyson|A|;May|Casey C|CC|;Youssef|Patrick|P|;Gross|Bradley A|BA|;Nimjee|Shahid M|SM|http://orcid.org/0000-0002-0317-8731",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11239-021-02510-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0929-5305",
"issue": "52(4)",
"journal": "Journal of thrombosis and thrombolysis",
"keywords": "Carotid stenosis; Glycoproteins IIb-IIIa inhibitor; Ischemic stroke; Tandem lesion; Thrombectomy; Tissue plasminogen activator",
"medline_ta": "J Thromb Thrombolysis",
"mesh_terms": null,
"nlm_unique_id": "9502018",
"other_id": null,
"pages": "1182-1186",
"pmc": null,
"pmid": "34160743",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article",
"references": "26627832;14559121;9555772;25517348;26352820;26379095;26352820;25882510;29562149;30145946;17008627;30579283;30723937;31744425;26294652;29167390;16344383;22064601;31272329;26345413;22115640",
"title": "Management of tandem occlusions in patients who receive rtPA.",
"title_normalized": "management of tandem occlusions in patients who receive rtpa"
} | [
{
"companynumb": "US-BAYER-2021-175526",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": null,... |
{
"abstract": "An 84-year-old man who had suffered from chronic obstructive pulmonary disease accompanied by moderate pneumonia as well as gastric cancer with liver metastasis was found dead by a nurse, who noticed that the patient's intravenous catheter in the left forearm had been erroneously connected to an oxygen supply in his hospital room, leading to infusion of oxygen into a vein. Postmortem CT scanning demonstrated multiple accumulations of gas in the pulmonary artery, the right atrium and ventricle, as well as the left subclavian and brachiocephalic veins, corresponding to the route that the infused gas would have taken to the heart and pulmonary artery. Conventional autopsy revealed the presence of gas in the right ventricle. These findings suggested that the immediate cause of death was a gas embolus due to oxygen that had entered the cardiopulmonary circulation via the intravenous catheter. This case highlights the usefulness of postmortem imaging as an aid to conventional autopsy for demonstrating gas embolism.",
"affiliations": "Department of Legal Medicine, Gunma University, Graduate School of Medicine, Maebashi 371-8511, Japan; Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: y.takahashi@gunma-u.ac.jp.;Department of Legal Medicine, Gunma University, Graduate School of Medicine, Maebashi 371-8511, Japan. Electronic address: takagirie@gunma-u.ac.jp.;Department of Legal Medicine, Gunma University, Graduate School of Medicine, Maebashi 371-8511, Japan.;Department of Legal Medicine, Gunma University, Graduate School of Medicine, Maebashi 371-8511, Japan.;Department of Legal Medicine, Gunma University, Graduate School of Medicine, Maebashi 371-8511, Japan.;Department of Legal Medicine, Gunma University, Graduate School of Medicine, Maebashi 371-8511, Japan.;Department of Legal Medicine, Gunma University, Graduate School of Medicine, Maebashi 371-8511, Japan.;Department of Radiology, Gunma University Hospital, Maebashi 371-8511, Japan.;Department of Diagnostic Radiology & Nuclear Medicine, Gunma University, Graduate School of Medicine, Maebashi 371-8511, Japan.;Department of Diagnostic Radiology & Nuclear Medicine, Gunma University, Graduate School of Medicine, Maebashi 371-8511, Japan.;Department of Diagnostic Radiology & Nuclear Medicine, Gunma University, Graduate School of Medicine, Maebashi 371-8511, Japan.;Department of Diagnostic Radiology & Nuclear Medicine, Gunma University, Graduate School of Medicine, Maebashi 371-8511, Japan.;Department of Diagnostic Radiology & Nuclear Medicine, Gunma University, Graduate School of Medicine, Maebashi 371-8511, Japan.",
"authors": "Takahashi|Yoichiro|Y|;Sano|Rie|R|;Yasuda|Akiyuki|A|;Kuboya|Eri|E|;Takahashi|Keiko|K|;Kubo|Rieko|R|;Kominato|Yoshihiko|Y|;Takei|Hiroyuki|H|;Kobayashi|Susumu|S|;Shimada|Takehiro|T|;Awata|Sachiko|S|;Tokue|Hiroyuki|H|;Hirasawa|Satoshi|S|",
"chemical_list": "D010100:Oxygen",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.legalmed.2017.05.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1344-6223",
"issue": "27()",
"journal": "Legal medicine (Tokyo, Japan)",
"keywords": "Forensic autopsy; Gas embolism; Medical safety; Postmortem computed tomography; Postmortem gas detection",
"medline_ta": "Leg Med (Tokyo)",
"mesh_terms": "D000369:Aged, 80 and over; D001344:Autopsy; D000072601:Cannula; D004618:Embolism, Air; D017809:Fatal Outcome; D049429:Forensic Pathology; D006801:Humans; D008297:Male; D010100:Oxygen; D029424:Pulmonary Disease, Chronic Obstructive; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "100889186",
"other_id": null,
"pages": "1-4",
"pmc": null,
"pmid": "28577412",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Postmortem computed tomography evaluation of fatal gas embolism due to connection of an intravenous cannula to an oxygen supply.",
"title_normalized": "postmortem computed tomography evaluation of fatal gas embolism due to connection of an intravenous cannula to an oxygen supply"
} | [
{
"companynumb": "JP-ALSI-201700174",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OXYGEN"
},
"drugadditional": null,
"drugad... |
{
"abstract": "D-glycerate 2 kinase (DGK) is an enzyme that mediates the conversion of D-glycerate, an intermediate metabolite of serine and fructose metabolism, to 2-phosphoglycerate. Deficiency of DGK leads to accumulation of D-glycerate in various tissues and its massive excretion in urine. D-glyceric aciduria (DGA) is an autosomal recessive metabolic disorder caused by mutations in the GLYCTK gene. The clinical spectrum of DGA is highly variable, ranging from severe progressive infantile encephalopathy to a practically asymptomatic condition. We describe a male patient from a consanguineous Arab family with infantile onset of DGA, characterized by profound psychomotor retardation, progressive microcephaly, intractable seizures, cortical blindness and deafness. Consecutive brain MR imaging showed an evolving brain atrophy, thinning of the corpus callosum and diffuse abnormal white matter signals. Whole exome sequencing identified the homozygous missense variant in the GLYCTK gene [c.455 T > C, NM_145262.3], which affected a highly conserved leucine residue located at a domain of yet unknown function of the enzyme [p.Leu152Pro, NP_660305]. In silico analysis of the variant supported its pathogenicity. A review of the 15 previously reported patients, together with the current one, confirms a clear association between DGA and severe neurological impairment. Yet, future studies of additional patients with DGA are required to better understand the clinical phenotype and pathogenesis.",
"affiliations": "Department of Pediatrics B, Emek Medical Center, Afula, Israel.;Institute of Human Genetics and Metabolic Diseases, Galilee Medical Center, Nahariya, Israel.;Neuroradiology Unit Department of Radiology, Rambam Health Care Campus, Haifa, Israel.;Rappaport School of Medicine, Technion, Haifa, Israel.;Clalit Health Services, Haifa, Israel.;Metabolic Unit, Department of Clinical Chemistry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.;Metabolic Unit, Department of Clinical Chemistry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.;Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.;Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.;Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.;Department of Pediatrics B, Emek Medical Center, Afula, Israel. spiegelr@zahav.net.il.",
"authors": "Zehavi|Yoav|Y|;Mandel|Hanna|H|;Eran|Ayelet|A|;Ravid|Sarit|S|;Abu Rashid|Muhammad|M|;Jansen|Erwin E W|EEW|;Wamelink|Mirjam M C|MMC|;Saada|Ann|A|;Shaag|Avraham|A|;Elpeleg|Orly|O|;Spiegel|Ronen|R|",
"chemical_list": "D005988:Glyceric Acids; C042971:glyceric acid; D017853:Phosphotransferases (Alcohol Group Acceptor); C020670:glycerate kinase",
"country": "United States",
"delete": false,
"doi": "10.1007/s11011-019-0384-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0885-7490",
"issue": "34(2)",
"journal": "Metabolic brain disease",
"keywords": "Autosomal recessive; D-glycerate kinase enzyme; D-glyceric aciduria; Epileptic encephalopathy; GLYCTK gene; Whole exome sequencing",
"medline_ta": "Metab Brain Dis",
"mesh_terms": "D001927:Brain Diseases; D002648:Child; D004827:Epilepsy; D005988:Glyceric Acids; D006801:Humans; D006960:Hyperoxaluria, Primary; D007223:Infant; D008297:Male; D009154:Mutation; D010641:Phenotype; D017853:Phosphotransferases (Alcohol Group Acceptor); D013036:Spasms, Infantile",
"nlm_unique_id": "8610370",
"other_id": null,
"pages": "557-563",
"pmc": null,
"pmid": "30637540",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "3588091;28462797;2165585;971536;15519572;17764545;2551543;20949620;10484776;16753811;15166110;27590225;24681721;28190537;4434100;11920944;11930278;2537226;26247153",
"title": "Severe infantile epileptic encephalopathy associated with D-glyceric aciduria: report of a novel case and review.",
"title_normalized": "severe infantile epileptic encephalopathy associated with d glyceric aciduria report of a novel case and review"
} | [
{
"companynumb": "IL-TEVA-2019-IL-1043644",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VALPROIC ACID"
},
"drugadditional": "3",
... |
{
"abstract": "There is currently little literature pertaining to levothyroxine overdose apart from minor or accidental overdoses in the pediatric population. In particular, there is little information available on how to confidently differentiate levothyroxine overdose from endogenous causes of thyrotoxicosis when there is no history available at the time of assessment. We report a levothyroxine (15,800 mcg) and citalopram (2,460 mg) overdose in a 55-year-old woman presenting with seizure and tachycardia in which the diagnosis was not initially suspected. Clinical data, including a long history of treated hypothyroidism and lack of a goiter; and biochemical findings, such as an incompletely suppressed thyroid-stimulating hormone (TSH) level, despite a markedly elevated free thyroxine level (FT4), a normal sex hormone-binding globulin level at baseline, and an undetectable thyroglobulin, supported the diagnosis of thyrotoxicosis due to a massive exogenous thyroid hormone overdose. Treatment was given to decrease free triiodothyronine (FT3) conversion and increase thyroid hormone clearance with dexamethasone and cholestyramine. The patient made a full recovery. Levothyroxine overdose can result in subtle symptoms and signs clinically, even when in massive quantities. This can make diagnosis challenging. Biochemical features, such as the pattern of thyroid hormone elevation and thyroglobulin levels, help differentiate exogenous thyroid hormone overdose from endogenous causes of thyrotoxicosis.",
"affiliations": "Department of Endocrinology,Waikato Hospital,Waikato Clinical School,University of Auckland,Hamilton,New Zealand.;Department of Endocrinology,Waikato Hospital,Waikato Clinical School,University of Auckland,Hamilton,New Zealand.;Department of Endocrinology,Waikato Hospital,Waikato Clinical School,University of Auckland,Hamilton,New Zealand.;Department of Endocrinology,Waikato Hospital,Waikato Clinical School,University of Auckland,Hamilton,New Zealand.",
"authors": "Allen|Kirstie M|KM|;Crawford|Veronica B|VB|;Conaglen|John V|JV|;Elston|Marianne S|MS|",
"chemical_list": "D013974:Thyroxine",
"country": "England",
"delete": false,
"doi": "10.1017/cem.2014.75",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1481-8035",
"issue": "17(6)",
"journal": "CJEM",
"keywords": "drug overdose; hyperthyroxinemia; levothyroxine overdose; thyroid crisis; thyrotoxicosis",
"medline_ta": "CJEM",
"mesh_terms": "D062787:Drug Overdose; D005260:Female; D006801:Humans; D007037:Hypothyroidism; D008875:Middle Aged; D013971:Thyrotoxicosis; D013974:Thyroxine",
"nlm_unique_id": "100893237",
"other_id": null,
"pages": "692-8",
"pmc": null,
"pmid": "25824846",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case report: clues to the diagnosis of an unsuspected massive levothyroxine overdose.",
"title_normalized": "case report clues to the diagnosis of an unsuspected massive levothyroxine overdose"
} | [
{
"companynumb": "NZ-MYLANLABS-2016M1025388",
"fulfillexpeditecriteria": "1",
"occurcountry": "NZ",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CITALOPRAM HYDROBROMIDE"
},
"drugadditional"... |
{
"abstract": "BACKGROUND\nSpinal cord abscesses and spinal subdural empyemas are rare and difficult to treat.\n\n\nMETHODS\nA 35-year-old male presented to an outside institution with 2 months of progressive low back pain, weakness, and bowel incontinence; he was diagnosed with an L4 epidural abscess that was poorly managed. When the patient presented to our institution, magnetic resonance imaging (MRI) revealed a well-organized chronic subdural abscess at the thoracolumbar junction. Following resection, his back pain resolved but he was left with a residual paraparesis.\n\n\nCONCLUSIONS\nSubdural abscesses are rare and should be considered among the differential diagnoses for intraspinal mass lesions. Treatment should include prompt surgical exploration and decompression combined with appropriate prolonged antibiotic treatment.",
"affiliations": "Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan, USA.;Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan, USA.;Department of Orthopedic Surgery, Henry Ford Hospital, Detroit, Michigan, USA.;Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan, USA.",
"authors": "Basheer|Azam|A|;Macki|Mohamed|M|;Buraimoh|Morenikeji|M|;Mahmood|Asim|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4103/sni.sni_171_17",
"fulltext": "\n==== Front\nSurg Neurol IntSurg Neurol IntSNISurgical Neurology International2229-50972152-7806Medknow Publications & Media Pvt Ltd India SNI-8-16710.4103/sni.sni_171_17Infection: Case ReportChronic thoracolumbar subdural empyema: Case report and surgical management Basheer Azam *Abashee1@hfhs.orgMacki Mohamed mmacki2@hfhs.orgBuraimoh Morenikeji 1mburaim1@hfhs.orgMahmood Asim amahmoo2@hfhs.orgDepartment of Neurosurgery, Henry Ford Hospital, Detroit, Michigan, USA1 Department of Orthopedic Surgery, Henry Ford Hospital, Detroit, Michigan, USA* Corresponding author\n2017 01 8 2017 8 16705 5 2017 29 6 2017 Copyright: © 2017 Surgical Neurology International2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Background:\nSpinal cord abscesses and spinal subdural empyemas are rare and difficult to treat.\n\nCase Description:\nA 35-year-old male presented to an outside institution with 2 months of progressive low back pain, weakness, and bowel incontinence; he was diagnosed with an L4 epidural abscess that was poorly managed. When the patient presented to our institution, magnetic resonance imaging (MRI) revealed a well-organized chronic subdural abscess at the thoracolumbar junction. Following resection, his back pain resolved but he was left with a residual paraparesis.\n\nConclusion:\nSubdural abscesses are rare and should be considered among the differential diagnoses for intraspinal mass lesions. Treatment should include prompt surgical exploration and decompression combined with appropriate prolonged antibiotic treatment.\n\nChronic spinal subdural abscessepidural abscessspinal subdural abscessspinal subdural empyema\n==== Body\nINTRODUCTION\nChronic spinal subdural abscesses are rare. They are typically intradural/extramedullary and are only rarely intramedullary in location.[12] Most arise due to hematogenous spread, followed by local extension and iatrogenic contamination. Although they may mimic extradural infections, their intradural location and, therefore, greater severity, may be under-interpreted or misinterpreted, leading to inadequate care. Here, we report a patient who 2 months earlier had undergone an extradural exploration for infection. The failure to accurately locate the intradural phlgemon ultimately resulted in a full-blown cauda equina syndrome, at which point the subdural empyema was appropriately decompressed/evacuated and treated with prolonged intravenous antibiotic therapy.\n\nCASE REPORT\nInitial presentation\nA 35-year-old male, with a history of intravenous drug and cocaine abuse, presented to an outside hospital with back pain, bilateral lower extremity numbness, and bladder incontinence. When magnetic resonance imaging (MRI) revealed a possible epidural collection around the lamina of L4, a lumbar puncture (LP) was performed. The LP revealed numerous polymorphonuclear leukocytes (PMNs); the cerebrospinal fluid gram staining and cultures were negative. The patient underwent an L4 laminectomy, however, no purulence was encountered in the epidural space. Only reactive fibrous tissue and a markedly thickened dura were identified. Despite a negative biopsy and no growth on cultures, the patient was empirically treated with vancomycin for four weeks (e.g., presumptive Staphylococcal and Streptococcal species).\n\nSecond presentation\nTwo months later, with progressive lower extremity pain, weakness (4/5 mid/distal lower extremities bilaterally), and continued bladder and bowel incontinence, the patient presented to our institution [Table 1].\n\nTable 1 Radiographic and laboratory work up of patient's second presentation at our institution\n\nNew magnetic resonance imaging\nThe new contrast-enhanced high-resolution MRI of the whole neuraxis demonstrated multiple foci of subdural empyema. There were heterogeneous pockets of enhancement along the ventral and dorsal leptomeninges of the cervical and thoracic and lumbar spine (e.g., involving the nerve roots of the cauda equina) [Figure 1]. A loculated ventral fluid collection within the spinal canal between T12 down to L1-L2 markedly compressed the conus posteriorly [Figure 2]. Another loculated fluid collection was located dorsally at the T8-T12 thoracic spine.\n\nFigure 1 (a) T2 sagittal MRI: extensive loculated fluid collections compressing the spinal cord ventrally at T12-L2 and dorsally at T8-T12 level. Note T2 cord signal change within the distal thoracic cord/conus at T11-T12. (b) T1 sagittal MRI without contrast: anterior displacement of the cord from T9-T12 level. (c) T1 Sagittal MRI with contrast: distinct enhancement of the fluid collections at T8-T12, T12-L2 and leptomeninges/nerve roots in the cauda equina\n\nFigure 2 (a) T2 sagittal MRI: high signal fluid collection compressing/displacing the conus posteriorly. Note the irregularly thickened/clumped together nerve roots. (b) T2 sagittal MRI: irregularly thickened/clumped together nerve roots of the cauda equina\n\nSurgery\nThe patient underwent an emergent laminectomy from T10 to L2. No epidural abscess was seen, but the thecal sac appeared tense. A durotomy started at the L2 level and extended superiorly revealed a lobulated lesion in the intradural space and terminal filum. This phlegmon was tightly attached to the spinal cord and neighboring nerve roots by fibrotic gliotic tissue [Figure 3]. It was partially dissected off the spinal cord and sent for pathology and cultures. A separate durotomy at T10 ensured adequate decompression/drainage of the organized abscess.\n\nFigure 3 Intraoperative images. (a) Tense, thickened dura without any epidural abscess. (b) The dural opening at L2 showed nerve root clumping with very little cerebrospinal fluid egress/phlegmon. (c) Second dural opening at T10 showed purulent discharge. (d) Intradural spinal cord thickening/adhesions\n\nPathology\nHistologic examination showed an organized abscess (e.g., marked infiltration of plasma and lymphocytes). Although the gram and acid-fast bacilli (AFB) stains were negative, as were the cultures, the patient was presumptively started on a 6-week course of vancomycin and ertapenem. At 6-week follow-up, his weakness remained stable but his back pain resolved. Furthermore, the white blood cell count was normal. A follow-up MR was not available at this time.\n\nDISCUSSION\nSpinal subdural empyema is rare and is typically attributed to Staphylococcus aureus (over 50% of cases).[4] Other organisms may include Streptococcus species, Escherichia coli, and various anaerobes.\n\nFour mechanisms contribute to the development of these lesions; direct spread of infection can occur secondary to congenital deformities (dysraphism), hematogenous spread from a distant site, iatrogenic contamination of the subdural space (33%), and/or contiguous spread from adjacent infection.\n\nSymptoms of chronic subdural abscesses are typically nonspecific and sometimes even absent.[3] These most typically involve the lumbar spine with superior extension into the lower thoracic region[456] The best diagnostic study is an enhanced high-resolution MRI scan, Nevertheless, the distinction between an epidural and subdural abscess remains challenging.\n\nAlthough the best practice for treating subdural infections has not been well-established, the goals of surgical washout include lowering the infectious burden and obtaining culture diagnosis. Furthermore, most decompressions include consecutive or “skip” laminectomies with consecutive or skip durotomies to ensure adequate debridement of these potentially extensive lesions.\n\nCONCLUSION\nDiabetes, intravenous drug abuse (IVDA), and immunocompromise are known risk factors for a spinal subdural abscess. This diagnosis should be considered if patients present with evidence of infection. Contrast-enhanced high-resolution MRI scans of the entire neuraxis allow the surgeon to distinguish between subdural and epidural lesions. These should be promptly explored, decompressed/washed out, and followed with appropriate long-term antibiotic treatment.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nhttp://surgicalneurologyint.com/Chronic-thoracolumbar-subdural-empyema:-Case-report-and-surgical-management/\n==== Refs\nREFERENCES\n1 Diehn FE Imaging of spine infection Radiol Clin North Am 2012 50 777 98 22643395 \n2 Semlali S Akjouj S Chaouir S Hanine A Ben Ameur M Spinal subdural tuberculous abscess in a patient with tuberculous meningitis J Radiol 2007 88 280 1 17372557 \n3 Sorar M Er U Seckin H Ozturk MH Bavbek M Spinal subdural abscess: A rare cause of low back pain J Clin Neurosci 2008 15 292 4 17433690 \n4 Velissaris D Aretha D Fligou F Filos KS Spinal Subdural Staphylococcus Aureus Abscess: Case report and review of the literature World J Emerg Surg 2009 4 31 19660120 \n5 Vural M Arslantas A Adapinar B Kiremitci A Usluer G Cuong B Spinal subdural Staphylococcus aureus abscess: Case report and review of the literature Acta Neurol Scand 2005 112 343 6 16218919 \n6 Zemmoura I Hamlat A Morandi X Intradural extramedullary spinal inflammatory myofibroblastic tumor: Case report and literature review Eur Spine J 2011 20 Suppl 2 S330 5 21465290\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2152-7806",
"issue": "8()",
"journal": "Surgical neurology international",
"keywords": "Chronic spinal subdural abscess; epidural abscess; spinal subdural abscess; spinal subdural empyema",
"medline_ta": "Surg Neurol Int",
"mesh_terms": null,
"nlm_unique_id": "101535836",
"other_id": null,
"pages": "167",
"pmc": null,
"pmid": "28840071",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "21465290;17433690;19660120;16218919;17372557;22643395",
"title": "Chronic thoracolumbar subdural empyema: Case report and surgical management.",
"title_normalized": "chronic thoracolumbar subdural empyema case report and surgical management"
} | [
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"companynumb": "US-009507513-1804USA001332",
"fulfillexpeditecriteria": "2",
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"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ERTAPENEM SODIUM"
},
"drugadditional": null,... |
{
"abstract": "There is a known bleeding risk with administration of the antiplatelet drug clopidogrel, but in certain patients the likelihood of thrombosis is too high to cease its administration perioperatively. The risks of performing total joint arthroplasty in this population are unknown. An inpatient pharmacy database query identified seven patients who underwent eight hip or knee arthroplasties from 2007 to 2009 without perioperative interruption in clopidogrel administration. Bleeding-related events were recorded, including one inpatient death, one reoperation for infection, two 30-day readmissions, two antibiotic prescriptions for the incision, and blood transfusion administration during seven of eight admissions. The majority of bleeding-related events occurred following knee arthroplasty. Uninterrupted perioperative clopidogrel administration was associated with a high risk of bleeding-related events following total joint arthroplasty, particularly of the knee. Consideration should be given to delaying total joint arthroplasty until clopidogrel can safely be held in the perioperative period.",
"affiliations": "Tufts University School of Medicine, Boston, Massachusetts.",
"authors": "Shubert|Daniel|D|;Bono|James|J|;Nandi|Sumon|S|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1548-825X",
"issue": "24(2)",
"journal": "Journal of surgical orthopaedic advances",
"keywords": null,
"medline_ta": "J Surg Orthop Adv",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D019644:Arthroplasty, Replacement, Hip; D019645:Arthroplasty, Replacement, Knee; D000077144:Clopidogrel; D005260:Female; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D019990:Perioperative Care; D010975:Platelet Aggregation Inhibitors; D011183:Postoperative Complications; D013988:Ticlopidine",
"nlm_unique_id": "101197881",
"other_id": null,
"pages": "115-9",
"pmc": null,
"pmid": "25988693",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Uninterrupted perioperative clopidogrel and bleeding-related events after total joint arthroplasty: a case series.",
"title_normalized": "uninterrupted perioperative clopidogrel and bleeding related events after total joint arthroplasty a case series"
} | [
{
"companynumb": "US-SA-2015SA128307",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "Neurotoxicity is the main and dose-limiting toxicity of oxaliplatin. It may produce two different syndromes, acute and chronic. We describe here a case of a patient with an acute syndrome with the particularity of affecting only contralateral hemibody to arm of infusion. A 62-year-old female diagnosed with stage IV colon cancer, underwent palliative treatment with combination of oxaliplatin (130 mg/m( 2) on day 1), capecitabine (1.250 mg/m(2) bid on days 1 to 14 every 3 weeks), and bevacizumab. Thirty minutes after cycle 1 oxaliplatin infusion, which was into the left arm, she experienced right hemibody paresthesia with muscle cramping of her right calf. She associated dysphonia and painful jamming sensation in her right upper limb with difficulty to release grip. She noted also undulating movements under the skin of her right lower extremity. She was unable to stand or walk. She was given intravenous magnesium sulfate and calcium gluconate and after 3 h all her symptoms were solved. Subsequent doses were reduced by 25% and the infusions were prolonged to 3 h and the patient tolerated well except minimal paresthesia in her right hand lasting few minutes.",
"affiliations": "Medical Oncology Service, Clinical University Hospital, Valladolid, Spain. aunacid@hotmail.com",
"authors": "Uña|Esther|E|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000068258:Bevacizumab; D000069287:Capecitabine; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1177/1078155209355849",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "16(4)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": null,
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000230:Adenocarcinoma; D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D000069287:Capecitabine; D003110:Colonic Neoplasms; D003841:Deoxycytidine; D005260:Female; D005472:Fluorouracil; D006801:Humans; D007866:Leg; D008875:Middle Aged; D009120:Muscle Cramp; D020258:Neurotoxicity Syndromes; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010166:Palliative Care; D010292:Paresthesia; D016896:Treatment Outcome",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "280-2",
"pmc": null,
"pmid": "20015928",
"pubdate": "2010-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Atypical presentation of acute neurotoxicity secondary to oxaliplatin.",
"title_normalized": "atypical presentation of acute neurotoxicity secondary to oxaliplatin"
} | [
{
"companynumb": "ES-SUN PHARMACEUTICAL INDUSTRIES EUROPE B.V-12SUNOX17P",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
... |
{
"abstract": "Telaprevir and Boceprevir are the first direct acting antivirals approved for chronic hepatitis C in combination with peg-interferon alfa and ribavirin. Pancytopenia due to myelotoxicity caused by these drugs may occur, but severe hematological abnormalities or aplastic anemia (AA) have not been described. We collected all cases of severe pancytopenia observed during triple therapy with telaprevir in four Spanish centers since approval of the drug in 2011. Among 142 cirrhotic patients receiving treatment, 7 cases of severe pancytopenia (5%) were identified and three were consistent with the diagnosis of AA. Mean age was 59 years, five patients had compensated cirrhosis and two patients had severe hepatitis C recurrence after liver transplantation. Severe pancytopenia was diagnosed a median of 10 wk after the initiation of therapy. Three patients had pre-treatment hematological abnormalities related to splenomegaly. In six patients, antiviral treatment was interrupted at the onset of hematological abnormalities. Two patients died due to septic complications and one patient due to acute alveolar hemorrhage. The remaining patients recovered. Severe pancytopenia and especially AA, are not rare during triple therapy with telaprevir in patients with advanced liver disease. Close monitoring is imperative in this setting to promptly detect serious hematological disorders and to prevent further complications.",
"affiliations": "Sabela Lens, Zoe Mariño, María-Carlota Londoño, Jose M Sánchez-Tapias, Xavier Forns, Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, 08036 Barcelona, Spain.;Sabela Lens, Zoe Mariño, María-Carlota Londoño, Jose M Sánchez-Tapias, Xavier Forns, Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, 08036 Barcelona, Spain.;Sabela Lens, Zoe Mariño, María-Carlota Londoño, Jose M Sánchez-Tapias, Xavier Forns, Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, 08036 Barcelona, Spain.;Sabela Lens, Zoe Mariño, María-Carlota Londoño, Jose M Sánchez-Tapias, Xavier Forns, Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, 08036 Barcelona, Spain.;Sabela Lens, Zoe Mariño, María-Carlota Londoño, Jose M Sánchez-Tapias, Xavier Forns, Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, 08036 Barcelona, Spain.;Sabela Lens, Zoe Mariño, María-Carlota Londoño, Jose M Sánchez-Tapias, Xavier Forns, Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, 08036 Barcelona, Spain.;Sabela Lens, Zoe Mariño, María-Carlota Londoño, Jose M Sánchez-Tapias, Xavier Forns, Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, 08036 Barcelona, Spain.;Sabela Lens, Zoe Mariño, María-Carlota Londoño, Jose M Sánchez-Tapias, Xavier Forns, Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, 08036 Barcelona, Spain.;Sabela Lens, Zoe Mariño, María-Carlota Londoño, Jose M Sánchez-Tapias, Xavier Forns, Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, 08036 Barcelona, Spain.;Sabela Lens, Zoe Mariño, María-Carlota Londoño, Jose M Sánchez-Tapias, Xavier Forns, Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, 08036 Barcelona, Spain.;Sabela Lens, Zoe Mariño, María-Carlota Londoño, Jose M Sánchez-Tapias, Xavier Forns, Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, 08036 Barcelona, Spain.;Sabela Lens, Zoe Mariño, María-Carlota Londoño, Jose M Sánchez-Tapias, Xavier Forns, Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, 08036 Barcelona, Spain.",
"authors": "Lens|Sabela|S|;Calleja|Jose L|JL|;Campillo|Ana|A|;Carrión|Jose A|JA|;Broquetas|Teresa|T|;Perello|Christie|C|;de la Revilla|Juan|J|;Mariño|Zoe|Z|;Londoño|María-Carlota|MC|;Sánchez-Tapias|Jose M|JM|;Urbano-Ispizua|Álvaro|Á|;Forns|Xavier|X|",
"chemical_list": "D000998:Antiviral Agents; D009842:Oligopeptides; D011092:Polyethylene Glycols; D012254:Ribavirin; C486464:telaprevir; D007372:Interferons",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v21.i17.5421",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "21(17)",
"journal": "World journal of gastroenterology",
"keywords": "Aplastic anemia; Hepatitis C; Interferon; Protease inhibitors; Telaprevir",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000368:Aged; D000741:Anemia, Aplastic; D000998:Antiviral Agents; D001706:Biopsy; D001856:Bone Marrow Examination; D004359:Drug Therapy, Combination; D017809:Fatal Outcome; D005260:Female; D019698:Hepatitis C, Chronic; D006801:Humans; D007372:Interferons; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides; D010198:Pancytopenia; D011092:Polyethylene Glycols; D012254:Ribavirin; D012307:Risk Factors; D012720:Severity of Illness Index; D016896:Treatment Outcome",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "5421-6",
"pmc": null,
"pmid": "25954117",
"pubdate": "2015-05-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "25332274;21703177;23669289;20671541;20375406;20704699;19128766;21449784;11926789;7893989;21449783;21696308;21696307;19673883;12324553;24486089",
"title": "Aplastic anemia and severe pancytopenia during treatment with peg-interferon, ribavirin and telaprevir for chronic hepatitis C.",
"title_normalized": "aplastic anemia and severe pancytopenia during treatment with peg interferon ribavirin and telaprevir for chronic hepatitis c"
} | [
{
"companynumb": "PHHY2015ES073787",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": null,
"druga... |
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"abstract": "Cryptococcus is an opportunistic fungal pathogen that leads to life-threatening infections. Cryptococcal infections are mainly reported in HIV patients and less commonly encountered in non-HIV immunocompromised host. Cryptococcus neoformans (C. neoformans) is the most common Cryptococcus species causing diseases in humans which can be presented as pulmonary, meningitis, cutaneous, and/or disseminated cryptococcosis. Case Presentation. A 12-year-old female girl from Cairo, Egypt, presented to the pediatric hospital with signs of systemic lupus erythematosus (SLE). She had an aggressive lupus nephritis course for which corticosteroids, mycophenolate mofetil, and cyclophosphamide were prescribed, and the child gradually improved and was discharged. Two months later, the patient exhibited skin lesions involved both in her legs, massive ulcers were developed and extended rapidly through the entire legs followed by deterioration in her conscious level, and signs of meningitis were documented. Cerebrospinal fluid (CSF) examination and microbiological workup were confirmatory for C. neoformans infection, and mental and motor functions were rapidly deteriorated. Treatment with amphotericin B in addition to supportive treatment and close follow-up of the patient's medical condition result in obvious clinical improvement and patient discharge with minimal residual weakness in her legs after almost a one-month duration. After six months, the patient was brought to the emergency department complaining of repeated attacks of seizures, a lumbar puncture was performed, and culture results were again confirmatory for C. neoformans. An intensive course of antifungal therapy was prescribed which was successful, evident by resolution of the signs and symptoms of infection in addition to negative culture results and negative sepsis biomarkers. The child clinically improved, but unfortunately, gradual optic nerve degeneration and brain cell atrophy as a sequel of severe and longstanding cryptococcal infection resulted in her death after almost one year from her first attack.\nCryptococcal infection among non-HIV patients is a rare disease but can result in advanced medical complications which may be fatal. The disease should be suspected to be reliably diagnosed. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening consequences. Amphotericin B can be used effectively in cryptococcosis management in the settings where flucytosine is not available. Signs of cryptococcal meningitis can be manifested again after a period of remission and clinical cure which signifies the latency of Cryptococcus in the central nervous system. The second activation of Cryptococcus after its latency is usually life-threatening and mostly fatal.",
"affiliations": "Clinical Pathology Department, Ain Shams University, Cairo, Egypt.;General Surgery Department, Al-Azhar University, Cairo, Egypt.",
"authors": "Hashem|Heba Ezzat|HE|https://orcid.org/0000-0002-2996-7309;Ibrahim|Zakaria Hamza|ZH|https://orcid.org/0000-0003-4310-1998",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/6692767",
"fulltext": "\n==== Front\nCase Rep Med\nCase Rep Med\nCRIM\nCase Reports in Medicine\n1687-9627 1687-9635 Hindawi \n\n10.1155/2021/6692767\nCase Report\nAtypical Presentation of Pediatric Systemic Lupus Erythematosus Complicated by Cryptococcal Meningitis\nhttps://orcid.org/0000-0002-2996-7309Hashem Heba Ezzat hebaezzat@med.asu.edu.eg\n1\n https://orcid.org/0000-0003-4310-1998Ibrahim Zakaria Hamza \n2\n \n1Clinical Pathology Department, Ain Shams University, Cairo, Egypt\n\n2General Surgery Department, Al-Azhar University, Cairo, Egypt\nAcademic Editor: Bruno Megarbane\n\n\n2021 \n11 2 2021 \n2021 669276721 11 2020 29 1 2021 1 2 2021 Copyright © 2021 Heba Ezzat Hashem and Zakaria Hamza Ibrahim.2021This 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.Background\n\nCryptococcus is an opportunistic fungal pathogen that leads to life-threatening infections. Cryptococcal infections are mainly reported in HIV patients and less commonly encountered in non-HIV immunocompromised host. Cryptococcus neoformans (C. neoformans) is the most common Cryptococcus species causing diseases in humans which can be presented as pulmonary, meningitis, cutaneous, and/or disseminated cryptococcosis. Case Presentation. A 12-year-old female girl from Cairo, Egypt, presented to the pediatric hospital with signs of systemic lupus erythematosus (SLE). She had an aggressive lupus nephritis course for which corticosteroids, mycophenolate mofetil, and cyclophosphamide were prescribed, and the child gradually improved and was discharged. Two months later, the patient exhibited skin lesions involved both in her legs, massive ulcers were developed and extended rapidly through the entire legs followed by deterioration in her conscious level, and signs of meningitis were documented. Cerebrospinal fluid (CSF) examination and microbiological workup were confirmatory for C. neoformans infection, and mental and motor functions were rapidly deteriorated. Treatment with amphotericin B in addition to supportive treatment and close follow-up of the patient's medical condition result in obvious clinical improvement and patient discharge with minimal residual weakness in her legs after almost a one-month duration. After six months, the patient was brought to the emergency department complaining of repeated attacks of seizures, a lumbar puncture was performed, and culture results were again confirmatory for C. neoformans. An intensive course of antifungal therapy was prescribed which was successful, evident by resolution of the signs and symptoms of infection in addition to negative culture results and negative sepsis biomarkers. The child clinically improved, but unfortunately, gradual optic nerve degeneration and brain cell atrophy as a sequel of severe and longstanding cryptococcal infection resulted in her death after almost one year from her first attack. \n\nConclusion\n Cryptococcal infection among non-HIV patients is a rare disease but can result in advanced medical complications which may be fatal. The disease should be suspected to be reliably diagnosed. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening consequences. Amphotericin B can be used effectively in cryptococcosis management in the settings where flucytosine is not available. Signs of cryptococcal meningitis can be manifested again after a period of remission and clinical cure which signifies the latency of Cryptococcus in the central nervous system. The second activation of Cryptococcus after its latency is usually life-threatening and mostly fatal.\n==== Body\n1. Background\nImmunocompromised individuals including HIV, SLE, and patients on prolonged corticosteroid and immunosuppressant therapy are more prone to various bacterial, viral, and fungal opportunistic infections. One of the most important fatal fungal infections is cryptococcal infection [1–4]. C. neoformans is the most frequent cryptococcal species infect humans, and it is an encapsulated yeast microorganism, which is commonly transmitted through bird feces, plants, dust, soil, and contaminated food [2, 3]. Cryptococcosis can cause disseminated infection reaching to the lungs, central nervous system (CNS), and skin [2, 3, 5]. Dermal manifestations can present in different clinical morphologies including ulcers, acneiform papules, subcutaneous nodules, and rarely, cellulitis [4, 6].\n\n2. Case Presentation\nA 12-years-old Egyptian female student presented to Ain Shams University Pediatric Hospital complaining of generalized body edema, frothy urine, and proteinuria (3.7 g/day). The child was diagnosed as nephrotic syndrome, with repeated albumin infusions, and steroid therapy was initiated, but the child was nonresponding; instead, her medical condition deteriorated. Laboratory profile was in concordance with serologically quiescent SLE which included antinuclear antibody titer 1: 1280 finely speckled, elevated rheumatoid factor (RF) of 456 IU/ml (N: 0–20 IU/ml), positive SS-A/Ro > 8.0 and SS-B/La > 8.0 antibodies, anti-beta-2 glycoprotein IgM Ab > 100 U/ml, C-reactive protein (CRP) level 3.9 mg/l (N: 0–5 mg/l), and erythrocyte sedimentation rate (ESR) 51 mm/hour (N: 0–10 mm/hour). The serologic tests that were negative included anti-dsDNA Abs, complement C3 level 154 mg/dl (N: 106–194 mg/dl), complement C4 level 38 mg/dl (N: 19–50 mg/dl), cyclic citrullinated peptide IgG, cryoglobulin, serum immunofixation, Scl-70 scleroderma, Smith, RNP, cardiolipin antibodies, and lupus anticoagulant. Urine studies at the time revealed 3 + proteinuria, no hematuria or pyuria, a creatinine level of 0.93 mg/dl, and eGFR > 60 ml/min/1.73 m2. The diagnosis of SLE with nephrotic presentation was established, upon which the child received a medical regimen for lupus management including corticosteroids, mycophenolate mofetil, and cyclophosphamide which resulted in patient clinical improvement.\n\nTwo months later, the child was admitted complaining of poor appetite, nausea and vomiting, tiredness, swollen ankles, and shortness of breath, and deteriorated renal functions were evident in her laboratory profile: creatinine increased to 1.92 mg/dl, 4 + protein on urinalysis, worsening urine protein to creatinine (PC) ratio of 1.9 (N: 0.0–0.1), and 24-hour urine protein of 1170 mg/24 hours (N: 50–150 mg/24 hours). Lupus nephritis grade IV was confirmed. Therefore, the child received intermittent hemodialysis; in addition, the doses of the prescribed immunosuppressant was increased: prednisone (40 mg/day), hydroxychloroquine (6 mg/kg/day), and mycophenolate mofetil (2 g/day). The patient was kept under this protocol; she gradually improved and was discharged. A simplified chart representing the sequence of the disease in the presented case is illustrated in Figure 1.\n\nAfter two months, the child manifested skin ulcers in her lower extremities which were progressive in course. Drug allergies, insect bites, and family history were excluded. First, these lesions were nonwell-demarcated, erythematous, painful on palpation, nonpruritic with increasing local edema, and bullae formation. A few days later, lesions spread to involve entire her legs up to the groin area, the bullae began to coalescence together, ruptured, and a huge amount of serous discharge was drained from the lesions; no corresponding lesions appeared on the face, trunk, or upper extremities, and fever was not present at first, but with worsening of the lesions, the patient became feverish, hematuric, anemic, and hypotensive with deteriorated general condition; hence, she was admitted for the 2nd time.\n\nAt the time of admission, laboratory profile revealed hemoglobin 8.2 g/dL, white blood cell (WBC) count 10,800/mm³, platelet count 129,000 cells/mm³, serum aspartate transaminase (AST) 10 U/L, serum alanine transaminase (ALT) 17 U/L, CRP 12 mg/L, and ESR 60 mm. Upon worsening the skin lesions, bacterial skin infection was suspected; so empirical treatment with amikacin and cefepime was started and the dose of prednisone decreased to 30 mg/day; microbiological cultures revealed no microorganism growth after 48 hours of incubation. Upon suspicion of bacterial cellulitis and due to the lack of improvements of the skin lesions, vancomycin was added to the treatment regimen.\n\nAfter three days, the patient medical condition deteriorated rapidly. She complained of severe headache, altered memory, continuous agitation, neck rigidity, stiffness, photophobia, and total loss of appetite; so, meningitis was suspected; hence, lumbar puncture was performed, and a CSF sample was sent for cytological examination in addition to culture procedures. The sample was clear colorless on physical inspection (Figure 2)(a), and cell count was 25 cells/HPF.\n\nDirect Gram examination of CSF showed spherical budding encapsulated yeast cells surrounded by translucent hallow around the cells (Figures 2(b) and 2)(c). CSF chemical examination revealed protein level 74 mg/dL (normal range 15–60 mg/dL) and glucose levels 41 mg/dL (normal range 50–80 mg/dL). The sample was cultured on aerobic blood agar, anaerobic blood agar, chocolate, and MacConkey agar; the plates showed delayed growth at the end of the third day (72 hours incubation according to CSF standard operating procedures (SOPs) of our microbiology lab). It was a minute whitish milky colony, which was highly suggestive of fungal infection, confirmed by further subculture, the sample on Sabouraud's dextrose agar (SDA) plates (Figures 2(d)–2(f)). Indian ink stain and positive biochemical reactions were confirmatory for the diagnosis of Cryptococcus infection (Figures 3 and 4). Additionally, antifungal susceptibility testing was performed which was positive for both amphotericin B and flucytosine.\n\nDespite that, the child manifested obvious clinical signs and symptoms of meningitis. Magnetic resonance imaging (MRI) brain with contrast showed findings within normal limits, and blood culture was negative for microbiological growth after 7 days incubation.\n\nBased on the available laboratory results, treatment for disseminated cryptococcosis was initiated immediately upon laboratory notification, prednisone was further decreased to 20 mg/day, and fluconazole was discontinued. Amphotericin B was started at a dose of 0.7 mg/kg/day with an infusion time of 6 hours, since the patient had repeated reactions (fever, chills, and nausea) with a shorter infusion time. Concerning flucytosine, which is indicated as the drug of choice in cryptococcal meningitis treatment, it was not used for treatment of our presented case due to financial aspects and nonavailability in our country, Egypt. Repeated lumber tapping was performed to relieve persistent increased intracranial tension as a consequence of severe meningitis; in addition, plasmapheresis was performed to remove lupus autoantibodies.\n\nThe child was subjected for further workup to rule out pneumonia and other organs affection, and for follow up purpose, chest X-ray was ordered, which revealed normal findings, ESR, CRP, complete blood count (CBC), and sepsis marker, neutrophil CD64. These laboratory tests were performed every 3 days on a routine base for monitoring the medical progress which showed dramatic gradual improvement (Table 1 and Figure 5); in conjugation with clinical signs and symptoms improvement evident by regaining her mental and motor skills, besides healing of the leg ulcers, pus draining stopped and swelling disappeared (Figure 6). In this setting, a lumbar puncture was intended to be performed upon this obvious clinical and laboratory improvement preparing the patient to be discharged, but the child refused at her own request and was discharged on her demand after almost 30 days since amphotericin B infusion was first prescribed.\n\nAt the time of discharge, the patient had no pulmonary sequelae, but she had residual weakness in her lower limbs. The laboratory results at the time of discharge were hemoglobin 9.2 g/dL, WBC 16.700 cells per mm³, platelet 303.000 cells per mm³, AST 10 U/L, ALT 4 U/L, CRP 6 mg/L, and ESR 53 mm/h. The child was instructed to continue fluconazole (400 mg/day) at home for 8 weeks and then reduced its dose to 200 mg/day for 1 year. And she was weaned gradually from corticosteroid therapy.\n\nOne month later, the child was brought to the emergency department complaining of severe headache, projectile vomiting, and blurred vision. She was admitted for the 3rd time. An MRI brain was ordered, and a lumbar puncture was performed urgently to relieve intracranial tension, and for chemical, cytological, and microbiological analyses, all were negative for infection except for CRP slightly positive (12 mg/L). So, lupus flare-up was suspected, and pulse steroid therapy was started, in addition to antifungal (fluconazole) and antibiotic (amikacin and cefepime) coverage. The patient was subjected for plasmapheresis; upon it, she manifested dramatical improvement and discharge. She started to attend the immunotherapy clinic every two weeks for follow up purpose; she did well for 5 months and regained her functions except for difficulty in talking and walking abilities as she could not walk without support; so, the mother was advised to bring her for regular physiotherapy sessions every week.\n\nFive months later, the patient complained of shivering in her legs and hands followed by seizures attacks which were gradually increasing in frequency and duration till her mother brought her to the E/R. She was admitted for the 4th time. Phenytoin was prescribed, initial dose 2.5 mg/kg/dose twice a day and increased gradually to maximum 5 mg/kg/dose twice daily, and intensive work up profile was conducted searching for the cause of the seizures which included electroencephalogram (EEG), MRI brain, full lab evaluation, and CSF chemical analysis and microbiological examination. EEG revealed normal electric impulses without focal activities (Figure 7). MRI brain showed mildly dilated 3rd ventricles, CSF chemistry analysis revealed protein level 82 mg/dL (normal range 15–60 mg/dL), and glucose levels of 35 mg/dL (normal range 50–80 mg/dL). Upon receiving the sample in our microbiology lab, the sample physical criteria were very similar to the previous one, clear colorless, and cell count was 15 cell/cm3. A direct wet film examination was positive for budding yeast cells which were suspected and notified immediately to the pediatric team, and protocol of treatment was decided rapidly. CSF culture results were again confirmatory for C. neoformans.\n\nAn intensive course of antifungal therapy was initiated which included amphotericin B (0.7 mg/kg/day) with an infusion time of 6 hours, and fluconazole. Resolution of patient signs and symptoms of infection was clinically evident in addition to negative culture results and improved laboratory sepsis parameters. The child general condition improved, but at this setting, she complained of poor visual acuity. The pediatric team immediately consulted the specialist neurosurgeon, ophthalmologist, and an MRI brain urgently performed which showed evidence of brain cell atrophy with subsequent increased intracranial ventricular sizes and evidence of optic nerve atrophy; the ophthalmologist confirmed bilateral optic nerve degeneration which was more evident on the left side (Figure 8).\n\nAfter almost one month and, however, signs and symptoms of infection were resolved, cryptococcosis longstanding course with brain cell atrophy as a sequel of cryptococcal meningitis resulted in the child's death after almost one year from her first attack.\n\n3. Discussion and Conclusion\n\nCryptococcus is an opportunistic fungal pathogen that leads to rare life-threatening infection. Meningoencephalitis and disseminated cryptococcosis are usually common complications reported in immunocompromised hosts [7, 8]. In the presented case, we reported a pediatric systemic lupus erythematosus patient complicated by rapidly disseminating cryptococcal infection which exhibited a latency in the child CNS followed by an attack of infection flare-up which was successfully treated, but slowly progressive brain cell atrophy due to longstanding disease resulted in her death.\n\nInfections and sepsis are major causes of hospitalization, mortality, and morbidity in immunosuppressed patients [9]. Cryptococcosis is one of the fatal fungal infections reported mainly in immunocompromised hosts; however, several reported cases point to its incidence also in immunocompetent patients [10–12]. Cryptococcosis has a low incidence in non-HIV patients, approximately 1 : 100.000 [5, 13]. Patients with SLE are highly susceptible to infections due to the combined effects of their immunosuppressive therapy and the abnormalities of the immune system that the disease itself causes [14]. Concerning our presented case, prolonged corticosteroid therapy and immunosuppressants due to her underlying disease (SLE) were the major risk factors for disseminated cryptococcosis with poor outcomes.\n\nThe patient had a progressive renal course complicated by lupus nephritis class IV for which immunosuppressants was given. Lupus nephritis is clinically evident in 50–60% of patients with SLE [15]. Both mycophenolate mofetil and cyclophosphamide were prescribed to our case. Mycophenolate mofetil depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation [16]. While, cyclophosphamide inhibits protein synthesis through DNA and RNA crosslinking [17].\n\nBy discussing Cryptococcus as the causative pathogen, C. neoformans is the most common strain causing infections in humans, and it is an encapsulated yeast that has been isolated from chickens' droppings and grows readily in soil contaminated with avian excreta particularly that of pigeons. In humans, it can colonize the upper airway system. Nevertheless, no animal-to-human nor person-to-person respiratory transmission has been documented [9]. Our presented case lived in low socioeconomic and hygienic status, and she denied contact with pigeon or birds. However, the fungus might have been indirectly transmitted via other sources such as vegetables, fruits, and dairy products [8].\n\n\nC. neoformans generally cause three types of infections: cryptococcal meningitis, pulmonary, and cutaneous cryptococcosis [18]. The dissemination of this disease occurs when at least two noncontiguous sites are affected, which is unusual and mostly observed in HIV patients [4, 19]. In our case, only pulmonary involvement was not present while cutaneous manifestations were the first presenting symptoms followed by cryptococcal meningitis. Some studies support the importance of lumbar puncture in patients with cryptococcosis, even when CNS symptoms are not observed because asymptomatic meningitis is reported to be an early stage of the disease [20].\n\nSystemic lupus erythematosus disease activity index (SLEDAI) was calculated for our presented case in order to be used as a predictor for SLE mortality and as a measure of global disease activity, and it was achieving high values (79) which reflect why the patient underwent into cryptococcal meningitis with poor clinical course. Eventhough, for patients with low SLE activity, the possibility of cryptococcal meningitis should not be underestimated [21].\n\nSkin involvement is a rare presenting symptom of Cryptococcus infection, but it is usually a sign of disseminated disease; it may precede the systemic symptoms even eight months earlier [5, 18]. It is important to stress the rarity and polymorphism of the skin conditions, with the possible development of vesicles or blisters and the potential progression to ulceration [1, 4].\n\nCryptococcal cellulitis is a rare specific cutaneous manifestation, which was developed in our case. It was initially suspected to be a bacterial infection for which antibiotics were prescribed until its failure and microbiological results confirmed the fungal diagnosis. Although rare, the present case, cryptococcal cellulitis was restricted mainly to the lower body, particularly to the lower extremities, and this was reported in other rare reported cases [1, 2]. Despite that, cryptococcal cellulitis is uncommon and undistinguishable from acute bacterial cellulitis for appearance and presentation [6], but high suspicion especially in a risky patient should be considered.\n\nMore than 80% of patients manifested cryptococcal cellulitis and are expected to survive in immunocompetent status when they receive the appropriate antifungal therapy [6]. According to the current guidelines of the American Society of Infectious Diseases for disseminated cryptococcosis management, amphotericin B combined with flucytosine is recommended as the primary therapy, followed by fluconazole as a consolidation therapy [4, 18]. Flucytosine is expensive and was not available in our country; so, it was not considered for the treatment. Instead, it was replaced by the addition of fluconazole to amphotericin B regimen.\n\nCryptococcal laboratory diagnosis relies on three main methods: latex agglutination test, fungal culture, and direct microscopic examination [22]. In the present case, both the microscopic examination and microbiological cultures were the cornerstone for the diagnosis. C. neoformans was differentiated from other fungal species especially Candida spp. by the characterized morphology in the Gram-stained smear, microbiological culture characters, Indian ink stain positivity, and biochemical reactions.\n\nIndian ink stain was positive in our case. In HIV-positive patients, its sensitivity increases up to 80% due to higher fungal loads in the CSF, while in HIV negative patients, the sensitivity is only 30–50% [8, 23]. CSF culture is considered the gold standard for cryptococcal diagnosis, but it has several diagnostic obstacles as long time is needed for fungus to grow, while time is very critical for management of meningitis cases with evolving lifetime neurological complications [24]. Besides, fungal cultures are not available in all medical facilities and therefore may not be performed. It is also associated with false-negative results, especially in cases with low fungal load, and this may be the attributed cause of negative blood culture result in our case.\n\nRegarding management of cryptococcosis, the prolonged course (6–10 weeks) of IV amphotericin B monotherapy, together with the reduction of chemotherapy to improve immune status, was the main target. Caution was taken while reducing immunosuppressive therapy, since a rapid reduction is reported to be associated with immune reconstitution inflammatory syndrome (IRIS) in some patients [9]. There is evidence that supports the requirement for maintenance therapy with fluconazole administered as indefinite secondary prophylaxis, since the rate of recurrence exceeds 50% after apparently successful treatment [25].\n\nDifferential diagnosis of the present case must be addressed which includes besides to what was mentioned, infection versus flare-up attacks in lupus patients; several sepsis markers including CRP increase significantly in SLE patients with concomitant infection but increase only slightly or not at all in patients with a lupus flare without infection [14, 26] which is exactly encountered in our presented case. Additionally, decreased visual acuity due to increased intracranial tension (papilledema) was differentiated from decreased visual acuity due to optic nerve atrophy. For the presented case, papilledema was evident on fundus examination at the time of cryptococcal meningitis first diagnosed, while optic nerve atrophy was evident on fundus examination at the end.\n\nFinally, we highlight the importance of clinicians' awareness about such infection among non-HIV immunocompromised patients including those who are diagnosed with autoimmune diseases. The latency of Cryptococcus should be considered and suspected during the management of such cases which necessitate early recognition and proper management.\n\nFor preparing Indian ink-stained film, take two drops from the examined CSF sample directly or a small part of the growing colony from the plate, mix it well with the ink, put a cover slide, and leave the slide for an hour to give a chance for the cells to be settled, and for better contrast view, lower the condenser and reduce the microscopic light and examine the film by using the lens with magnification power (40x). Cryptococcus will be evident as shiny spherical budding in a dark background.\n\n4. Conclusion\nCryptococcal meningitis should be considered as one of the possible diagnoses in a patient with altered sensorium and neck stiffness, especially those who are immunocompromised. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening complications.\n\nEarly management of cryptococcal meningitis is associated with better prognosis and lower neurological complications. Despite that, flucytosine is being described as the best antifungal medication for cryptococcal infections. Amphotericin B still gives good results in such cases.\n\nNegative bacterial growth from a skin lesion does not necessitate that it is a sterile lesion; it may be an atypical microorganism or microorganism that needs special media to grow or longer duration to be cultivated. Clinical pathologists should be aware of Cryptococcus laboratory diagnosis and how to differentiate it from Candida spp. Microbiological culture is a confirmatory step for Cryptococcus diagnosis; however, Gram-stained and Indian ink-stained films are rapid and informative diagnostic methods especially in limited resources facilities. The communication between laboratory staff members and treating medical team is very crucial for better clinical judgment specifically in a circumstance where an unusual diagnostic result is released or diagnosing a rare disease.\n\nCSF examination may show low cell count; however, infection presents; this is commonly seen in immunocompromised patients as no adequate inflammation. Cryptococcal infection associated with CNS latency which should to be suspected; hence, meticulous follow-up is an essential step in cryptococcal management. The second activation of cryptococcal latency is usually life-threatening and mostly fatal.\n\nAcknowledgments\nThe authors would like to thank all members of Immunology Unit-Pediatric Department and Microbiology Unit-Clinical Pathology Department of Ain Shams University Hospital. The authors gratefully acknowledge Professor Dalia Helmy El-Ghoneimy and Professor Malaka Zakaria Amer for their efforts to diagnose and follow up severe medical cases including this presented case and special gratitude to the mother of the child for supporting with detailed medical information and for her medical awareness and patience throughout her daughter's longstanding disease.\n\nAbbreviations\nALT:Alanine transaminase\n\nANA:Antinuclear antibody\n\nAST:Aspartate transaminase\n\nC. neoformans:\nCryptococcus neoformans\n\n\nCBC:Complete blood count\n\nCNS:Central nervous system\n\nCRP:C-reactive protein\n\nCSF:Cerebrospinal fluid\n\nDNA:Deoxyribonucleic acid\n\ndsDNA:Double-strand DNA\n\nE.R:Emergency room\n\nEEG:Electroencephalogram\n\neGFR:Estimated glomerular filtration rate\n\nESR:Erythrocyte sedimentation rate\n\nHIV:Human immunodeficiency virus\n\nIgG:Immunoglobulin G\n\nIRIS:Immune reconstitution inflammatory syndrome\n\nIV:Intravenous\n\nMPA:Mycophenolic acid\n\nMRI:Magnetic resonance imaging\n\nPC ratio:Protein creatinine ratio\n\nRF:Rheumatoid factor\n\nRNA:Ribonucleic acid\n\nRNP:Ribonucleoprotein antibodies\n\nSDA:Sabouraud's dextrose agar\n\nSLE:Systemic lupus erythematosus\n\nSOPs:Standard operating procedures\n\nWBC:White blood cell.\n\nData Availability\nThe data underlying the findings of this research are publicly available.\n\nEthical Approval\nCompliance with ethics guidelines, all procedures followed the ethical standards of the responsible committee on human experimentation (institutional and national).\n\nConsent\nWritten informed consent for publication of clinical details was obtained from the mother of the patient.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest.\n\nAuthors' Contributions\nHeba Ezzat Hashem contributed to acquisition, analysis, and interpretation of data, drafting of paper, conception and design, revision for critical intellectual content, final approval, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Zakaria Hamza Ibrahim involved in revision for critical intellectual content, final approval, and financial support.\n\nFigure 1 A simplified chart representing the sequence of the disease in our case.\n\nFigure 2 (a) Clear colorless CSF sample; other etiological causes of meningitis especially viral meningitis versus fungal meningitis must be differentiated, specifically in the presence of clear colorless CSF samples with low cell count and minimal changes of CSF parameters. (b) Spherical budding yeast in the CSF; it should be differentiated from the elliptical budding yeast cells of Candida spp. which is more commonly encountered during CSF examination as a fungal cause of meningitis. (c) Gram-stained film; direct film from CSF shows spherical budding yeast cells with surrounding translucent haloes due to capsular structure. (d) Blood agar shows small white colonies, after 72 hours of incubation. (e) Sabouraud dextrose agar (SDA) shows pasty colonies that were confirmed to be Cryptococcus neoformans. (f) Gram from culture shows spherical yeast cells with surrounding translucent haloes.\n\nFigure 3 Biochemical reaction; the urease test was positive.\n\nFigure 4 \nCryptococcus as shiny spherical budding in a dark background.\n\nFigure 5 Laboratory course of the present case and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation; the patient improved clinically and discharged after almost one month with minimal residual weakness in her lower limbs. The nCD64 test was available in our hospital as a sepsis biomarker, and it was performed for our case for follow-up purposes.\n\nFigure 6 Patient developed extensive skin ulceration with serous oozing from both lower limbs; this image was taken upon her clinical improvement on amphotericin B. The local edema resolved leaving the skin redundant, cracked, and the oozing discharge was first serous-like followed by purulent discharge then pus draining stopped.\n\nFigure 7 EEG at the 4th admission, seizures, and other CNS manifestations in patients who had previous cryptococcal meningitis is very essential to be distinguished; it is due to reactivation of latent infection or due to seizures attributed to other medical causes. For the present case, EEG showed normal electric activates without focal localization.\n\nFigure 8 MRI brain performed at the time of 3rd admission; dilated third ventricles were evident due to brain cell atrophy; at this occasion, signs of increase intracranial tension were negative which excluded it as a cause for cerebral ventricles dilatations.\n\nTable 1 Laboratory course of the present case, and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation.\n\n \tHb\tTLC\tANC\tALC\tAMC\tPLT\tCRP\tCD64%\tCD64 MFI\t\n08/05/2016\t10.6\t12.2\t11.2\t0.6\t0.4\t44\t6\t98.5\t2.87\t\n11/05/2016\t9\t10.9\t9.2\t1.1\t0.51\t81\t6\t91.5\t1.91\t\n15/05/2016\t7.7\t14.8\t12.72\t1.57\t0.48\t209\t4\t80.1\t1.56\t\n22/05/2016\t7.2\t10\t7.6\t1.1\t0.5\t238\t4\t68.9\t1.45\t\nHb, hemoglobin (g/dl); TLC, total leukocytic count (X109/L); ANC, absolute neutrophil count (X109/L); ALC, absolute lymphocyte count (X109/L); AMC, absolute monocyte count (X109/L); PLT, platelet (X109/L); CRP, C-reactive protein (mg/L); nCD64%, neutrophil CD64%; nCD64MFI, nCD64 mean fluorescence intensity.\n==== Refs\n1 Valente E. S. Costa Lazzarin M. Disseminated cryptococcosis presenting as cutaneous cellulitis in an adolescent with systemic lupus erythematosus Infectious Disease Reports 2015 7 2 10.4081/idr.2015.5743 2-s2.0-84930397981 \n2 Nakanishi C. P. De Almeida J. R. P. Romiti N. Disseminated cutaneous cryptococcosis in a patient with AIDS Revista do Instituto de Medicina Tropical de São Paulo 2006 48 6 353 358 17221135 \n3 Probst C. Pongratz G. Capellino S. Rolf M. Szeimies, Jürgen Schölmerich, Martin Fleck, Bernd Salzberger, and Boris Ehrenstein. Cryptococcosis mimicking cutaneous cellulitis in a patient suffering from rheumatoid arthritis: a case report BMC Infectious Diseases 2010 10 1 p. 239 \n4 Perfect J. R. Dismukes W. E. Dromer F. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America 2010 50 3 291 322 10.1086/649858 2-s2.0-75749092958 20047480 \n5 Hall J. C. Brewer J. H. Watson K. R. Cryptococcal cellulitis with multiple sites of involvement Journal of the American Academy of Dermatology 1987 17 2 329 332 3305608 \n6 Lu H. C. Yang Y. Y. Huang Y. L. Disseminated cryptococcosis initially presenting as cellulitis in a rheumatoid arthritis patient Journal of the Chinese Medical Association: JCMA 2007 70 6 249 252 10.1016/S1726-4901(09)70368-5 2-s2.0-34447500072 17591585 \n7 Curi A. L. Lazera M. Vasconcelos-Santos D. V. Cryptococcosis Intraocular Inflammation 2016 Berlin, Heidelberg Springer 1277 1283 \n8 Jha A. Adhikari S. Raj Sigdel K. Case Report: cryptococcal meningitis in an apparently immunocompetent patient in Nepal-challenges in diagnosis and treatment Wellcome Open Research 2019 4 10.12688/wellcomeopenres.15187.2 2-s2.0-85070475975 \n9 Aguiar Ventura P. Lopes V. Cryptococcal infection in non-HIV immunosuppressed patients–three case reports in a nephrology setting Medical Mycology Case Reports 2014 3 14 16 24567894 \n10 Tan Z.-R. Long X.-Y. Li G.-L. Zhou J.-X. Long L. Spectrum of neuroimaging findings in cryptococcal meningitis in immunocompetent patients in China-a series of 18 cases Journal of the Neurological Sciences 2016 368 132 137 10.1016/j.jns.2016.06.069 2-s2.0-84977111275 27538616 \n11 Saigal G. Judith Donovan Post M. Lolayekar S. Murtaza A. Unusual presentation of central nervous system cryptococcal infection in an immunocompetent patient American Journal of Neuroradiology 2005 26 10 2522 2526 16286394 \n12 Zhu L. Wang R. Wang X. Wu J. Cryptococcal meningitis in an apparently immunocompetent host: cmc2 Mycoses 2014 57 \n13 Mehrabi M. Bagheri S. Leonard M. K. Perciaccante V. J. Mucocutaneous manifestation of cryptococcal infection: report of a case and review of the literature Journal of Oral and Maxillofacial Surgery 2005 63 10 1543 1549 10.1016/j.joms.2005.06.014 2-s2.0-25144524230 16182927 \n14 Ospina F. E. Distinguishing infections vs flares in patients with systemic lupus erythematosus Rheumatology 2017 56 suppl 1 46 54 28028154 \n15 Lupus nephritis. Available at: https://emedicine.medscape.com/article/330369-overviewsite \n16 Allison A. Mechanisms of action of mycophenolate mofetil Lupus 2005 14 3_suppl 2 8 10.1191/0961203305lu2109oa 15732281 \n17 Mills K. A. Chess-Williams R. McDermott C. Novel insights into the mechanism of cyclophosphamide-induced bladder toxicity: chloroacetaldehyde’s contribution to urothelial dysfunction in vitro Archives of Toxicology 2019 93 11 3291 3303 10.1007/s00204-019-02589-1 2-s2.0-85074013667 31598736 \n18 Ni W. Huang Q. Cui J. Disseminated cryptococcosis initially presenting as cellulitis in a patient suffering from nephrotic syndrome BMC Nephrology 2013 14 1 p. 20 10.1186/1471-2369-14-20 2-s2.0-84872474420 \n19 Sathyanarayanan V. Bekur R. Razak A. Chakraborty J. Clinical profile of disseminated cryptococcal infection-a case series Asian Pacific Journal of Tropical Medicine 2010 3 10 818 820 10.1016/s1995-7645(10)60197-6 2-s2.0-78049390414 \n20 Kiertiburanakul S. Wirojtananugoon S. Pracharktam R. Sungkanuparph S. Cryptococcosis in human immunodeficiency virus-negative patients International Journal of Infectious Diseases 2006 10 1 72 78 10.1016/j.ijid.2004.12.004 2-s2.0-29344435278 16288998 \n21 Fang W. Chen M. Liu J. Cryptococcal meningitis in systemic lupus erythematosus patients: pooled analysis and systematic review Emerging Microbes & Infections 2016 5 1 1 7 10.1038/emi.2016.93 2-s2.0-84987617477 \n22 Wang H. Yuan X. Zhang L. Latex agglutination: diagnose the early cryptococcus neoformans test of capsular polysaccharide antigen Pakistan Journal of Pharmaceutical Sciences 2015 28 1 Suppl 307 311 25631497 \n23 O’Halloran J. A. Powderly W. G. Spec A. Cryptococcosis today: it is not all about HIV infection Current Clinical Microbiology Reports 2017 4 2 88 95 29130027 \n24 Abassi M. Boulware D. R. Rhein J. Cryptococcal meningitis: diagnosis and management update Current Tropical Medicine Reports 2015 2 2 90 99 10.1007/s40475-015-0046-y 2-s2.0-84988510886 26279970 \n25 Lee Y. A. Kim H. J. Lee T. W. First report of cryptococcus albidus－induced disseminated cryptococcosis in a renal transplant recipient The Korean Journal of Internal Medicine 2004 19 1 p. 53 10.3904/kjim.2004.19.1.53 2-s2.0-2442456487 \n26 Firooz N. Albert D. Wallace D. Ishimori M. Berel D. Weisman M. High-sensitivity C-reactive protein and erythrocyte sedimentation rate in systemic lupus erythematosus Lupus 2011 20 6 588 597 10.1177/0961203310393378 2-s2.0-79956159584 21436216\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2021()",
"journal": "Case reports in medicine",
"keywords": null,
"medline_ta": "Case Rep Med",
"mesh_terms": null,
"nlm_unique_id": "101512910",
"other_id": null,
"pages": "6692767",
"pmc": null,
"pmid": "33628263",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "26294948;3305608;31598736;16182927;20047480;17591585;29130027;21436216;27744359;17221135;25631497;16286394;27599471;20699010;16288998;15803924;27538616;23336386;15053045;26279970;24567894;31289752",
"title": "Atypical Presentation of Pediatric Systemic Lupus Erythematosus Complicated by Cryptococcal Meningitis.",
"title_normalized": "atypical presentation of pediatric systemic lupus erythematosus complicated by cryptococcal meningitis"
} | [
{
"companynumb": "EG-MYLANLABS-2021M1042863",
"fulfillexpeditecriteria": "1",
"occurcountry": "EG",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": n... |
{
"abstract": "OBJECTIVE\nTo investigate the clinical features of psoriatic uveitis in Japanese patients.\n\n\nMETHODS\nClinical features of 13 consecutive patients with psoriatic uveitis treated at our facility were retrospectively examined using medical records. In this study, we collected data about psoriasis type, uveitis laterality, onset type, HLA types, visual acuity, ocular inflammation localization, anterior segment findings, funduscopy findings, complications, recurrence, and medical treatments for uveitis and skin diseases.\n\n\nRESULTS\nThe cohort comprised ten males and three females (43.6 ± 7.1 years old), and types of psoriasis included psoriasis vulgaris (seven cases), psoriatic arthritis (four cases), pustular psoriasis (three cases) and psoriatic erythroderma (one case). Two cases represented complicated cases of pustular psoriasis and psoriatic arthritis. Seven cases were unilateral, and six cases were bilateral. All cases had acute non-granulomatous anterior uveitis, whereas panuveitis occurred in one case. Furthermore, macular edema and vascular leakage on fluorescein angiography occurred in four cases, and hyperemic disc occurred in two cases. Recurrence occurred in nine cases. In addition to topical corticosteroid treatment, eight cases underwent oral immunosuppressive treatment or biologics. All six cases undergoing HLA typing were HLA-A2 positive.\n\n\nCONCLUSIONS\nCases of psoriatic uveitis in Japan appear to present with acute non-granulomatous uveitis; other symptoms may include macular edema, retinal vasculitis, or hyperemic disc.",
"affiliations": "Department of Ophthalmology, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan, rtanaka-ymn@umin.ac.jp.",
"authors": "Tanaka|Rie|R|;Takamoto|Mitsuko|M|;Komae|Keiko|K|;Ohtomo|Kazuyoshi|K|;Fujino|Yujiro|Y|;Kaburaki|Toshikatsu|T|",
"chemical_list": "D005938:Glucocorticoids; D015789:HLA-A2 Antigen; D007166:Immunosuppressive Agents",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00417-015-2968-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0721-832X",
"issue": "253(7)",
"journal": "Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie",
"keywords": null,
"medline_ta": "Graefes Arch Clin Exp Ophthalmol",
"mesh_terms": "D000328:Adult; D017668:Age of Onset; D044466:Asians; D005260:Female; D005938:Glucocorticoids; D015789:HLA-A2 Antigen; D006801:Humans; D007166:Immunosuppressive Agents; D007564:Japan; D008297:Male; D008875:Middle Aged; D011565:Psoriasis; D012189:Retrospective Studies; D014606:Uveitis, Anterior",
"nlm_unique_id": "8205248",
"other_id": null,
"pages": "1175-80",
"pmc": null,
"pmid": "25725620",
"pubdate": "2015-07",
"publication_types": "D016428:Journal Article",
"references": "941906;18569794;16196117;6084935;18078405;21951304;10627431;7652746;8993952;7838193;10885569;970993;24740981;17342112;16704717;14564532;11409666;15652834;22898222;20673052;11929590;24457365;19641206;22690382",
"title": "Clinical features of psoriatic uveitis in Japanese patients.",
"title_normalized": "clinical features of psoriatic uveitis in japanese patients"
} | [
{
"companynumb": "JP-JNJFOC-20150718172",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "Pregnancy in women with severe mental illness (SMI) often bring added dimensions of complexity; considering that this group of women are choosing to have children at increasing rates, more highly complex cases will require management. A 31-year-old primigravida with a diagnosis of bipolar affective disorder was treated with an antidepressant, mood stabiliser and antipsychotic. This case discusses preconception counselling, pregnancy and labour management that resulted in the delivery of a 4,200 g baby at 39 weeks by emergency caesarian section. This case highlights the collaborative approach to care that is needed in this group of women and the need for increasing awareness and knowledge in health professionals. It follows the management from preconception through to the postpartum period.",
"affiliations": "Childbirth and Mental Illness Antenatal Clinic, King Edward Memorial Hospital, 374 Bagot Road, Subiaco, Perth, WA, 6008, Australia, jacqueline.frayne@health.wa.gov.au.",
"authors": "Frayne|Jacqueline|J|;Nguyen|Thinh|T|;Kohan|Rolland|R|;De Felice|Nick|N|;Rampono|Jonathan|J|",
"chemical_list": "D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D000069348:Quetiapine Fumarate; D008094:Lithium; D010624:Phenelzine",
"country": "Austria",
"delete": false,
"doi": "10.1007/s00737-013-0386-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1434-1816",
"issue": "17(1)",
"journal": "Archives of women's mental health",
"keywords": null,
"medline_ta": "Arch Womens Ment Health",
"mesh_terms": "D000328:Adult; D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D001714:Bipolar Disorder; D002585:Cesarean Section; D003987:Dibenzothiazepines; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008094:Lithium; D010624:Phenelzine; D016742:Preconception Care; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D011297:Prenatal Exposure Delayed Effects; D000069348:Quetiapine Fumarate; D016896:Treatment Outcome",
"nlm_unique_id": "9815663",
"other_id": null,
"pages": "73-5",
"pmc": null,
"pmid": "24196828",
"pubdate": "2014-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The comprehensive management of pregnant women with major mood disorders: a case study involving phenelzine, lithium, and quetiapine.",
"title_normalized": "the comprehensive management of pregnant women with major mood disorders a case study involving phenelzine lithium and quetiapine"
} | [
{
"companynumb": "AU-APOTEX-2017AP019558",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "QUETIAPINE"
},
"drugadditional": null,
... |
{
"abstract": "The aim of this study was to assess safety and efficacy of islet transplantation after initial pancreas transplantation with subsequent organ failure. Patients undergoing islet transplantation at our institution after pancreas organ failure were compared to a control group of patients with pancreas graft failure, but without islet transplantation and to a group receiving pancreas retransplantation. Ten patients underwent islet transplantation after initial pancreas transplantation failed and were followed for a median of 51 months. The primary end point of HbA1c <7.0% and freedom of severe hypoglycemia was met by nine of 10 patients after follow-up after islet transplantation and in all three patients in the pancreas retransplantation group, but by none of the patients in the group without retransplantation (n = 7). Insulin requirement was reduced by 50% after islet transplantation. Kidney function (eGFR) declined with a rate of -1.0 mL ± 1.2 mL/min/1.73 m2 per year during follow-up after islet transplantation, which tended to be slower than in the group without retransplantation (P = .07). Islet transplantation after deceased donor pancreas transplant failure is a method that can safely improve glycemic control and reduce the incidence of severe hypoglycemia and thus establish similar glycemic control as after initial pancreas transplantation, despite the need of additional exogenous insulin.",
"affiliations": "Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Zurich, Zurich, Switzerland.;Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Zurich, Zurich, Switzerland.;Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Zurich, Zurich, Switzerland.;Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Zurich, Zurich, Switzerland.;Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Zurich, Zurich, Switzerland.;Division of Radiology, University Hospital Zurich, Zurich, Switzerland.;Division of Transplant Surgery, University Hospital Zurich, Zurich, Switzerland.;Division of Transplant Surgery, University Hospital Zurich, Zurich, Switzerland.;Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Zurich, Zurich, Switzerland.;Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Zurich, Zurich, Switzerland.",
"authors": "Gerber|Philipp A|PA|0000-0002-2476-7076;Hochuli|Michel|M|;Benediktsdottir|Bara D|BD|;Zuellig|Richard A|RA|;Tschopp|Oliver|O|;Glenck|Michael|M|;de Rougemont|Olivier|O|;Oberkofler|Christian|C|;Spinas|Giatgen A|GA|;Lehmann|Roger|R|",
"chemical_list": "D001786:Blood Glucose",
"country": "Denmark",
"delete": false,
"doi": "10.1111/ctr.13153",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-0063",
"issue": "32(1)",
"journal": "Clinical transplantation",
"keywords": "insulin; islet transplantation; pancreas transplantation; type 1 diabetes mellitus",
"medline_ta": "Clin Transplant",
"mesh_terms": "D000293:Adolescent; D001786:Blood Glucose; D002648:Child; D003922:Diabetes Mellitus, Type 1; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007003:Hypoglycemia; D016381:Islets of Langerhans Transplantation; D008297:Male; D016035:Pancreas Transplantation; D011183:Postoperative Complications; D011379:Prognosis; D012307:Risk Factors; D014019:Tissue Donors",
"nlm_unique_id": "8710240",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29140547",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Islet transplantation as safe and efficacious method to restore glycemic control and to avoid severe hypoglycemia after donor organ failure in pancreas transplantation.",
"title_normalized": "islet transplantation as safe and efficacious method to restore glycemic control and to avoid severe hypoglycemia after donor organ failure in pancreas transplantation"
} | [
{
"companynumb": "PHHY2017CH186241",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BASILIXIMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "In Western Kenya, the burden of chronic wounds and lymphedema has a significant impact on functionality and quality of life. Major barriers to provision of care include availability, affordability, and accessibility of bandages. At the Academic Model Providing Access to Healthcare, dermatologists and pharmacists collaborated to develop a 2-component compression bandage modeled after the Unna boot, using locally available materials, that is distributed through a revolving fund pharmacy network. In partnership with nursing, use of these bandages at a national referral hospital and a few county facilities has increased, but increasing utilization to an expanded catchment area is needed.",
"affiliations": "Academic Model Providing Access to Healthcare (AMPATH), Eldoret, Kenya; Department of Dermatology, University of California, School of Medicine, P.O. Box 4606 Eldoret, Kenya 30100. Electronic address: aileen.chang@ucsf.edu.;Clinical Services, Moi Teaching & Referral Hospital, PO Box 3, Code 30100, Eldoret, Kenya.;Academic Model Providing Access to Healthcare (AMPATH), Eldoret, Kenya; Department of Dermatology, University of California, San Francisco School of Medicine, 1701 Divisadero Street, Suite 4-20, San Francisco, CA 94143-0316, USA.;University of California, Irvine School of Medicine, 1001 Health Sciences Road, Irvine, CA 92617, USA.;Academic Model Providing Access to Healthcare (AMPATH), Eldoret, Kenya.;Academic Model Providing Access to Healthcare (AMPATH), Eldoret, Kenya.;Drug Use Research and Management, Oregon State University College of Pharmacy, 2730 SW Moody Avenue, CL5CP, Portland, OR 97201, USA.;Academic Model Providing Access to Healthcare (AMPATH), Eldoret, Kenya; Indiana University School of Medicine, 545 Barnhill Drive, Emerson Hall 139, Indianapolis, IN 46202, USA.;Academic Model Providing Access to Healthcare (AMPATH), Eldoret, Kenya; Purdue University College of Pharmacy, Fifth Third Bank Building, 640 Eskenazi Avenue, Indianapolis, IN 46202-2879, USA.;Academic Model Providing Access to Healthcare (AMPATH), Eldoret, Kenya; Purdue University College of Pharmacy, Fifth Third Bank Building, 640 Eskenazi Avenue, Indianapolis, IN 46202-2879, USA.",
"authors": "Chang|Aileen Y|AY|;Mungai|Margaret|M|;Coates|Sarah J|SJ|;Chao|Tiffany|T|;Odhiambo|Haji Philip|HP|;Were|Phelix M|PM|;Fletcher|Sara L|SL|;Maurer|Toby|T|;Karwa|Rakhi|R|;Pastakia|Sonak D|SD|",
"chemical_list": "D003879:Dermatologic Agents; D015034:Zinc Oxide",
"country": "United States",
"delete": false,
"doi": "10.1016/j.det.2020.08.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0733-8635",
"issue": "39(1)",
"journal": "Dermatologic clinics",
"keywords": "Africa; Bullous drug reaction; Kenya; Low- and middle-income countries; Lymphedema; Resource-limited setting; Revolving fund pharmacy; Wound care",
"medline_ta": "Dermatol Clin",
"mesh_terms": "D000328:Adult; D000368:Aged; D001458:Bandages; D058128:Compression Bandages; D003879:Dermatologic Agents; D003875:Drug Eruptions; D005260:Female; D017048:Health Care Costs; D006297:Health Services Accessibility; D006801:Humans; D007630:Kenya; D007869:Leg Injuries; D007871:Leg Ulcer; D008209:Lymphedema; D008297:Male; D008875:Middle Aged; D012514:Sarcoma, Kaposi; D012872:Skin Diseases, Vesiculobullous; D014647:Varicose Ulcer; D014947:Wounds and Injuries; D015034:Zinc Oxide",
"nlm_unique_id": "8300886",
"other_id": null,
"pages": "91-100",
"pmc": null,
"pmid": "33228865",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": "26350892;28029455;26913925;16827714;11865487;10945045;22565103;26229599;10203169;21470557;30402565;30008550;21918694;29132859;25062906;12880731;17716431;16630098;16640624;29773516;29905913;23387359;28408082;27151079;27275844;26177812;15366754;21857858;25458068;30274483;10827432;23832181;28570585;23499714;18382045",
"title": "Implementing a Locally Made Low-Cost Intervention for Wound and Lymphedema Care in Western Kenya.",
"title_normalized": "implementing a locally made low cost intervention for wound and lymphedema care in western kenya"
} | [
{
"companynumb": "US-VISTA PHARMACEUTICALS INC.-2107901",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
... |
{
"abstract": "Several cases of ureteral obstruction have been reported in stem cell transplant (SCT) patients; however, they were bilateral and concomitant with or preceded by hemorrhagic cystitis. We describe, to our knowledge, a first case of acute unilateral pan-ureteritis caused by BK polyomavirus (BKPyV) in an SCT patient. This case may represent an early phase of BKPyV reactivation. BKPyV infection should be considered as a potential cause of acute unilateral ureteritis even among SCT recipients.",
"affiliations": "Division of Infectious Diseases, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.",
"authors": "Nigo|M|M|;Marin|D|D|;Mulanovich|V E|VE|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12504",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "18(2)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "BK polyomavirus; allogeneic stem cell transplant; ureteritis",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D001739:BK Virus; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D027601:Polyomavirus Infections; D033581:Stem Cell Transplantation; D014412:Tumor Virus Infections; D014515:Ureteral Diseases",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "257-60",
"pmc": null,
"pmid": "26818211",
"pubdate": "2016-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The first case of acute unilateral pan-ureteritis caused by BK polyomavirus in an allogeneic stem cell transplant patient.",
"title_normalized": "the first case of acute unilateral pan ureteritis caused by bk polyomavirus in an allogeneic stem cell transplant patient"
} | [
{
"companynumb": "US-ASTELLAS-2016US018417",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "The objective of the study was to evaluate the effect of high-dose chemotherapy (HDC) with peripheral blood stem cell support (PBSCS) on survival of patients with gestational trophoblastic neoplasia (GTN) with either refractory choriocarcinomas or a poor-prognosis placental site/epithelioid trophoblastic tumours (PSTT/ETTs).\n\n\n\nDatabases of two referral centres for gestational trophoblastic disease were searched, and 32 patients treated with HDC between 1994 and 2015 were identified. Tissue samples were retrieved for genetic evaluation. Cox regression analyses were performed to identify possible predictors of overall survival (OS).\n\n\n\nHDC induced a sustained complete response in 7 patients. Overall, 41% (13/32) of the patients remained disease free after HDC with or without additional treatment. Patients who survived had much lower human chorionic gonadotropin (hCG) values (all ≤12 IU/L) before and after HDC than those who died of disease. Univariable Cox regression analysis demonstrated that hCG >12 IU/L before or after HDC, International Federation of Gynaecology and Obstetrics (FIGO) stage II-IV and presence of metastases at the time of diagnosis were significantly associated with adverse OS. However, only hCG values before HDC remained significant in a multivariable model (p < 0.001). Five of 11 (45%) patients with PSTT/ETT presenting ≥48 months after antecedent pregnancy and 6 of 14 (43%) patients with refractory choriocarcinoma were in remission. Three treatment-related deaths occurred.\n\n\n\nDespite 3 treatment-induced deaths, HDC with PBSCS appears to be active in salvaging selected patients with poor-prognosis PSTT/ETTs and refractory choriocarcinomas. Low hCG values before HDC seems a beneficial predictor of OS and may suggest that HDC acts more like a consolidation therapy.",
"affiliations": "Department of Gynaecology, Center of Gynaecologic Oncology Amsterdam, the Netherlands.;Department of Gynaecology, Center of Gynaecologic Oncology Amsterdam, the Netherlands.;Department of Medical Oncology, Charing Cross Hospital Campus of Imperial College, London, UK.;Sheffield Trophoblastic Disease Centre, Academic Unit of Clinical Oncology, Weston Park Hospital, Sheffield, UK.;Department of Medical Oncology, Charing Cross Hospital Campus of Imperial College, London, UK.;Sheffield Trophoblastic Disease Centre, Academic Unit of Clinical Oncology, Weston Park Hospital, Sheffield, UK.;Sheffield Trophoblastic Disease Centre, Academic Unit of Clinical Oncology, Weston Park Hospital, Sheffield, UK.;Department of Medical Oncology, Charing Cross Hospital Campus of Imperial College, London, UK.;Dept of Haematology, Hammersmith Hospital Campus of Imperial College, London, UK.;Sheffield Trophoblastic Disease Centre, Academic Unit of Clinical Oncology, Weston Park Hospital, Sheffield, UK.;Department of Medical Oncology, Charing Cross Hospital Campus of Imperial College, London, UK.;Department of Medical Oncology, Charing Cross Hospital Campus of Imperial College, London, UK. Electronic address: m.seckl@imperial.ac.uk.",
"authors": "Frijstein|M M|MM|;Lok|C A R|CAR|;Short|D|D|;Singh|K|K|;Fisher|R A|RA|;Hancock|B W|BW|;Tidy|J A|JA|;Sarwar|N|N|;Kanfer|E|E|;Winter|M C|MC|;Savage|P M|PM|;Seckl|M J|MJ|",
"chemical_list": null,
"country": "England",
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"doi": "10.1016/j.ejca.2018.12.033",
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"issn_linking": "0959-8049",
"issue": "109()",
"journal": "European journal of cancer (Oxford, England : 1990)",
"keywords": null,
"medline_ta": "Eur J Cancer",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D031901:Gestational Trophoblastic Disease; D006801:Humans; D008875:Middle Aged; D036102:Peripheral Blood Stem Cell Transplantation; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9005373",
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"pages": "162-171",
"pmc": null,
"pmid": "30731277",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The results of treatment with high-dose chemotherapy and peripheral blood stem cell support for gestational trophoblastic neoplasia.",
"title_normalized": "the results of treatment with high dose chemotherapy and peripheral blood stem cell support for gestational trophoblastic neoplasia"
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"abstract": "BACKGROUND\nNo standard guideline has been established for the treatment of plasmablastic lymphoma (PBL) and prognosis remains extremely poor, given that patients relapse early after chemotherapy and show resistance to commonly used cytostatic drugs.\nWe present the case of a 52-year-old HIV-negative man who presented with a mass at the left sternoclavicular joint. He had no significant comorbidities and no latent immunosuppression.\n\n\nMETHODS\nThe largest lymph node measured was 36 × 19 mm. An excisional biopsy showed diffuse proliferation of large lymphoid cells which were positive for CD38 and CD138, but negative for CD20. He was diagnosed with stage IV PBL with a low IPI.\n\n\nMETHODS\nThe patient was treated with four cycles of induction therapy with bortezomib, epirubicin and dexamethasone. He achieved complete remission. But 3 months after receiving consolidated autologous hematopoietic stem cell transplantation, he relapsed. Allogeneic hematopoietic stem cell transplantation was performed on the patient.\n\n\nRESULTS\nThe patient achieved remission again and there were no serious complications after allogeneic hematopoietic stem cell transplantation. This patient was followed up once every three months, and to date, he has been disease-free for more than 4 years.\n\n\nCONCLUSIONS\nThe survival of recurrent PBL after autologous hematopoietic stem cell transplantation is very poor. Salvage allogeneic hematopoietic stem cell transplantation may bring long-term survival opportunities for those patients. Further clinical studies are needed to explore the role of allogeneic hematopoietic stem cell transplantation in refractory and recurrent PBL.",
"affiliations": "Medical School of Ningbo University.;Ningbo First Hospital, Zhejiang, People's Republic of China.;Medical School of Ningbo University.;Medical School of Ningbo University.;Ningbo First Hospital, Zhejiang, People's Republic of China.",
"authors": "Rong|Chunmeng|C|;Sheng|Lixia|L|;Wu|An|A|;Sun|Ye|Y|;Ouyang|Guifang|G|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1097/MD.0000000000024498",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974\n1536-5964\nLippincott Williams & Wilkins Hagerstown, MD\n\n33607779\nMD-D-20-09602\n10.1097/MD.0000000000024498\n24498\n4800\nResearch Article\nClinical Case Report\nAllogeneic hematopoietic stem cell transplantation in a patient with HIV-negative recurrent plasmablastic lymphoma\nA case report\nRong Chunmeng MD a\nSheng Lixia PhD b\nWu An MD a\nSun Ye MD a\nOuyang Guifang PhD b ∗\nSaranathan. Maya\na Medical School of Ningbo University\nb Ningbo First Hospital, Zhejiang, People's Republic of China.\n∗ Correspondence: Guifang Ouyang, Ningbo First Hospital, Zhejiang, People's Republic of China (e-mail: nbhematology@163.com).\n19 2 2021\n19 2 2021\n100 7 e2449812 11 2020\n20 1 2021\n21 1 2021\nCopyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0\n\nAbstract\n\nIntroduction:\n\nNo standard guideline has been established for the treatment of plasmablastic lymphoma (PBL) and prognosis remains extremely poor, given that patients relapse early after chemotherapy and show resistance to commonly used cytostatic drugs.\n\nPatient concerns:\n\nWe present the case of a 52-year-old HIV-negative man who presented with a mass at the left sternoclavicular joint. He had no significant comorbidities and no latent immunosuppression.\n\nDiagnosis:\n\nThe largest lymph node measured was 36 × 19 mm. An excisional biopsy showed diffuse proliferation of large lymphoid cells which were positive for CD38 and CD138, but negative for CD20. He was diagnosed with stage IV PBL with a low IPI.\n\nInterventions:\n\nThe patient was treated with four cycles of induction therapy with bortezomib, epirubicin and dexamethasone. He achieved complete remission. But 3 months after receiving consolidated autologous hematopoietic stem cell transplantation, he relapsed. Allogeneic hematopoietic stem cell transplantation was performed on the patient.\n\nOutcomes:\n\nThe patient achieved remission again and there were no serious complications after allogeneic hematopoietic stem cell transplantation. This patient was followed up once every three months, and to date, he has been disease-free for more than 4 years.\n\nConclusion:\n\nThe survival of recurrent PBL after autologous hematopoietic stem cell transplantation is very poor. Salvage allogeneic hematopoietic stem cell transplantation may bring long-term survival opportunities for those patients. Further clinical studies are needed to explore the role of allogeneic hematopoietic stem cell transplantation in refractory and recurrent PBL.\n\nKeywords\n\nallogeneic hematopoietic stem cell transplantation\nautologous stem cell transplantation\nHIV-negative\nplasmablastic lymphoma\nrelapsed\nNational Natural Science Foundation of China81401321 Lixia ShengZhejiang Province Public Welfare Technology Application Research ProjectLGF19H080002 Lixia ShengZhejiang Provincial Key Laboratory of Wood Science and Technology2018PY052 Lixia ShengNatural Science Foundation of Zhejiang ProvinceLY17H160005 Guifang OuyangZhejiang Traditional Chinese Medicine Administration2015ZZ018 Guifang OuyangOPEN-ACCESSTRUE\n==== Body\npmc1 Introduction\n\nPlasmablastic lymphoma (PBL) is a rare and highly aggressive subtype of diffuse large B-cell lymphoma (DLBCL), characterized by plasma cell antigen differentiation. It was initially described in the setting of human immunodeficiency virus (HIV) infection, but it was also been reported in HIV-negative patients.[1] There is no consensus on the standard of care for PBL. The role of intensification of induction chemotherapy is controversial. And novel agents, bortezomib and lenalidomide, have shown some effectiveness in relapsed cases and may have a relatively important role in frontline treatment.[2,3] The use of autologous stem cell transplantation (ASCT) possibly improves outcomes when used as a consolidation or salvage therapy and may lead to better results than chemotherapy, but the available data remain sparse.[2] The literatures on allogeneic hematopoietic stem cell transplantation (allo-HSCT) treatment for PBL are quite rare compared to ASCT. And given its rarity, most of the data available rely on case reports and case series. Patients with PBL have a poor prognosis, with median survival times shorter than 2 years.[2,4] To the best of our knowledge, the survival of recurrent PBL is worse.[2,5,6] Here, we report a case of HIV-negative PBL in a patient who had recurrence after ASCT, but achieved and maintained complete remission for 4-years after salvage allo-HSCT.\n\n2 Case presentation\n\nThe patient was a 52-year-old man who presented in September 2015 with a mass at left sternoclavicular joint without any systemic symptoms. He had no significant comorbidities and no latent immunosuppression. Ultrasonography of lymph nodes indicated multiple lymph node enlargement in the neck, and multiple hypoechoic areas were seen above the left clavicle, the largest of which was 36 × 19 mm. A total body computed tomography (CT) scan showed that soft tissue mass shadows were seen around the left sternoclavicular joint and local cortical absorptions were present. Further investigations with fluorodeoxyglucose positron emission tomography–computed tomography (PET-CT) scan confirmed hypermetabolic mass appeared in several places of the body which was considered plasma cell infiltration. An excisional biopsy showed diffuse proliferation of large lymphoid cells (Fig. 1). Immuno-staining of the neoplastic cells showed negative for CD20, CD5, CD30, EREB, MPO, CD117 and Bcl-6, whereas it was positive for CD38, CD138, CD10, CD79a and Bcl-2 (Figs. 2–5). The Ki-67 proliferation index was 95% (Fig. 6). Biopsy of the iliac crest showed no marrow involvement. According to the above analysis, International Prognostic Index (IPI) scores were 2, the patient was diagnosed with stage IV PBL with a low IPI.\n\nFigure 1 H&E (hematoxylin and eosin) image shows large sheets of mostly large plasmacytoid appearing mononuclear cells. (HE Magnification × 400).\n\nFigure 2 CD138, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).\n\nFigure 3 CD38, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).\n\nFigure 4 CD10, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).\n\nFigure 5 CD79a, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).\n\nFigure 6 Strong and homogenous staining with Ki-67 indicating a high proliferation index. (Magnification × 200).\n\nIn addition, laboratory data were as following: Blood routine examination indicated that the white blood cells were 8.1 × 109/L, the hemoglobin was 146 g/L and the platelets were 267 × 109/L. Erythrocyte sedimentation rate, C-reactive protein, lactate dehydrogenase, β2 microglobulin, serum proteins and immunoglobulin levels were all within normal ranges. Immunofixation electrophoresis showed no monoclonal component. Human herpes virus 8 (HHV-8) and Epstein-Barr virus DNA (EBV-DNA) were negative. Besides, serology for HIV was also negative.\n\nFrom September to December 2015, the patient received 4 cycles of PAD chemotherapy regimens: bortezomib was given at the dose of 2.4 mg/day on day 1, 4, 8, 11, epirubicin at the dose of 20 mg/day on days 1–3, and dexamethasone at the dose of 40 mg/day on days 1–4 and 8–11 of each 28-day cycle. Repeat PET/CT following 4 cycles of chemotherapy showed no abnormal flurodeoxyglucose metabolic foci and enlarged lymph nodes, thus being compatible with a complete response (CR).\n\nLater on, peripheral blood stem cell (PBSC) mobilization was achieved by high-dose cyclophosphamide (2 g, day 1–3), etoposide (300 mg, day 1–3) and granulocyte colony-stimulating factor (G-CSF), and leukapheresis products containing a total of mononuclear cell (MNC) 9.78 × 108/kg and CD34+ cells 6.9 × 106/kg were collected. In April 2016, the patient received autologous hematopoietic stem cell transplantation as consolidation therapy. The conditioning regiments were melphalan (200 mg/m2 -2d) and bortezomib (1.75 mg -6, -3, +1, +4), and a total of 9.78 × 108/kg MNC and 6.9 × 106/kg CD34+ cells PBSC were reinfused. Platelets and white blood cells were recovered at 10 and 11 days after transplantation, respectively. The CT scan performed 1 month after ASCT confirmed a CR.\n\nHowever, 3 months after ASCT, CT showed a new lesion appeared in the second rib on the right side, which was considered as relapse. After full assessment, the patient underwent HLA half-matched allo-HSCT in September 2016. The conditioning regimen was modified BuCy+ATG (cytarabine 3.5 g -10, -9; busulfan 51.6 mg Q6 h -8, -7, -6; cyclophosphamide 3 g -5, -4; MECCNU 450 mg -3; antithymocyte globulin 2.5 mg/Kg -5, -4, -3, -2), and the scheme for prevention of graft-versus-host disease (GVHD) was cyclosporin, mycophenolate mofetil and short-term methotrexate. The patient developed pulmonary fungal infection 20 days after allo-HSCT and took a turn for the better after treatment with voriconazole injection and voriconazole tablets. Unfortunately, the patient developed severe hemorrhagic cystitis 20 days later, but fortunately the condition improved after symptomatic treatment. There has been no evidence of acute or chronic GVHD. The patient achieved sustained complete donor engraftment as short tandem repeat monitoring was performed every three months after transplantation. A CR was metabolically and clinically confirmed by PET-CT scan after allo-HSCT. The patient is now healthy and in CR for 4 years after allo-HSCT.\n\n3 Discussed\n\nPBL is a distinct variant of diffuse large B-cell lymphoma initially described in HIV-positive patients.[7] Nevertheless, PBL has also been described in HIV-negative individuals, particularly in association with potential immunosuppression such as after solid organ or bone marrow transplantation or with autoimmune disorders and malignanciess.[8–11] HIV-negative PBL, in comparison with HIV-positive PBL, occurs in older patients, with less frequent involvement of oral mucosa or bone marrow and less frequently stages III-IV.[3,12,13] A review of 114 HIV-negative patients with PBL, by Liu et al[12] demonstrated that immunosuppression, MYC gene rearrangement, high-risk international prognostic index, and EBV negativity were poor prognostic factors. And the overall survival (OS) is between 9 and 19 months in HIV-negative patients.[12] Similarly, a systematic review on 76 HIV-negative PBL patients showed median OS of 9 months with 2-year OS rate of 10%.[13]\n\nGiven its rarity and peculiar features, there is no standard of care for PBL and the treatment remains a challenge.[11] The use of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) and CHOP-like regimens are considered inadequate therapy, resulting short remission period,[3,11] so the NCCN guidelines recommend more intensive regimens,[14] including etoposide, vincristine and doxorubicin with bolus of cyclophosphamide and prednisone (EPOCH),[15] cyclophosphamide, vincristine, doxorubicin, methotrexate alternating with ifosfamide, etoposide, cytarabine,[16] or hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with methotrexate and cytarabine.[17] The benefit of ASCT in patients with PBL is not quite clear based on the limited data available. In a single institution report of 9 consecutive HIV-negative PBL patients, 7 patients achieved CR and 1 patient achieved partial response (PR) after chemotherapy.[8] Four patients underwent consolidation with ASCT in first complete remission, and 2 of these patients were alive at median follow-up of 23.9 months. The third patient had disease recurrence at 14 months and the fourth patient had disease recurrence at 2 months after ASCT.[8] Moffitt Cancer Center presented the experience of two HIV-negative patients with PBL in PR that underwent an ASCT, and two patients survived 6 and 12 months.[12]\n\nGiven the low efficacy of the standard therapy, and the poor outcome of these patients, there is a need to move toward new therapeutic strategies by incorporating new agents. Bortezomib is the most reported new drug for PBL and has been used as a single dose or in combination. Koji et al[18] show the bortezomib and lenalidomide-based treatment was tolerated and the patient was continued with a PR for over 2 years. Bortezomib and lenalidomide have a certain therapeutic effect, and are mostly used in patients with refractory recurrence.[18,19] There are few case reports showing single-agent lenalidomide or combination with other chemotherapeutic drug in refractory PBL.[20–22] A dramatic response to Brentuximab has been reported in a single case, but the patient died shortly due to previous disease disabilities.[23] A plasmablastic microlymphoma arising in HHV8-associated multicentric Castleman disease in an HIV-negative patient that showed a clinical response to siltuximab, an anti-IL6 antibody.[24] The use of rituximab, a chimeric anti-CD20 monoclonal antibody, is not currently a therapeutic standard because the lack of CD20 expression by PBL cells, but combined with chemotherapy it could improve remission rates.[3,25] Clinical trials with novel immunotherapeutic agents and other drugs targeting some genes involved in the activation of Nuclear factor kappa B pathways, some of which are already ongoing, may show promising results.[18]\n\nThe literature on allo-HSCT in PBL is limited compared with ASCT. Only few cases of allo-HSCT for PBL were reported, much less for recurrence PBL. Hamadani[26] reported one patient with PBL in CR2 who underwent a reduced-intensity allogeneic stem cell transplantation, and was alive 2 years after transplantation. Liu et al[8] reported one patient who had disease recurrence at 14 months after ASCT was treated with allo-HSCT. Despite consolidation with allo-HSCT, disease recurred 5 months after, and the patient died. In general, the efficacy of allo-HSCT in the treatment of HIV-negative PBL patients is still not ideal and the survival of recurrent PBL after allo-HSCT is very poor.\n\nIn our case, the patient had recurrence after consolidated ASCT. Then, he underwent the salvage allo-HSCT from his daughter and achieved good curative effect. The patient was in long-term complete remission and he is alive now. It may be attributed to his younger age, low IPI score and early allo-HSCT treatment after relapse. As far as we know, this is the first case of such a long survival time after allo-HSCT. For young relapsed patients with PBL, allo-HSCT may bring long-term survival opportunities. Due to the rarity of the disease, it is not feasible to carry out large-scale clinical trials. The evaluation of allogeneic hematopoietic stem cell transplantation in PBL patients requires more accumulation and sharing of clinical experience.\n\nAuthor contributions\n\nData curation: An Wu, Ye Sun.\n\nFunding acquisition: Guifang Ouyang, Lixia Sheng.\n\nMethodology: Lixia Sheng.\n\nWriting – original draft: Chunmeng Rong.\n\nWriting – review & editing: Chunmeng Rong.\n\nAbbreviations: allo-HSCT = allogeneic hematopoietic stem cell transplantation, ASCT = autologous hematopoietic stem cell transplantation, CHOP = cyclophosphamide, doxorubicin, vincristine and prednisone, CR = complete response, CT = computed tomography, DLBCL = diffuse large B-cell lymphoma, EBV-DNA = Epstein-Barr virus DNA, GVHD = graft-versus-host disease, HHV-8 = Human herpes virus 8, HIV = human immunodeficiency virus, IPI = International Prognostic Index, MNC = mononuclear cell, OS = overall survival, PBL = plasmablastic lymphoma, PBSC = peripheral blood stem cell, PET-CT = positron emission tomography–computed tomography, PR = partial response.\n\nHow to cite this article: Rong C, Sheng L, Wu A, Sun Y, Ouyang G. Allogeneic hematopoietic stem cell transplantation in a patient with HIV-negative recurrent plasmablastic lymphoma: a case report. Medicine. 2021;100:7(e24498).\n\nThe study protocol was approved by the Ethics Review Committee of Ningbo First Hospital.\n\nPatient has provided informed consent for publication of the case, and patient share his experience.\n\nThis study was supported by the National Natural Science Foundation of China under grant (number 81401321); Basic Public Welfare Research Project of Zhejiang Province under grant (number LGF19H080002); Medical Health Science and Technology Project of Zhejiang Provincial Health Commission under grant (number 2018PY052); National Science Foundation of Zhejiang Province under grant (number LY17H160005); and Traditional Chinese Medicine Administration of Zhejiang Province under grant (number 2015ZZ018).\n\nThe authors declare no conflict of interest.\n\nThe datasets generated during and/or analyzed during the current study are publicly available.\n==== Refs\nReferences\n\n[1] Li YJ Li JW Chen KL . HIV-negative plasmablastic lymphoma: report of 8 cases and a comprehensive review of 394 published cases. Blood Res 2020;55 :49–56.32269975\n[2] Al-Malki MM Castillo JJ Sloan JM . Hematopoietic cell transplantation for plasmablastic lymphoma: a review. Biol Blood Marrow Transplant 2014;20 :1877–84.24946718\n[3] Lopez A Abrisqueta P . Plasmablastic lymphoma: current perspectives. Blood Lymphat Cancer 2018;8 :63–70.31360094\n[4] Fernandez-Alvarez R Sancho JM Ribera JM . Plasmablastic lymphoma. Med Clin 2016;147 :399–404.\n[5] Castillo JJ Furman M Beltran BE . Human immunodeficiency virus-associated plasmablastic lymphoma: poor prognosis in the era of highly active antiretroviral therapy. Cancer 2012;118 :5270–7.22510767\n[6] Noy A Lensing SY Moore PC . Plasmablastic lymphoma is treatable in the HAART era. A 10 year retrospective by the AIDS Malignancy Consortium. Leuk Lymphoma V 57 2016;1731–4.\n[7] Delecluse HJAI Dallenbach F . Plasmablastic lymphomas of the oral cavity: a new entity associated with the human immunodeficiency virus infection. Blood 1997;89 :1413–20.9028965\n[8] Liu JJ Zhang L Ayala E . Human immunodeficiency virus (HIV)-negative plasmablastic lymphoma: a single institutional experience and literature review. Leukemia Res 2011;35 :1571–7.21752466\n[9] Borenstein J Pezzella F Gatter KC . Plasmablastic lymphomas may occur as post-transplant lymphoproliferative disorders. Histopathology 2007;51 :774–7.17944927\n[10] Castillo JJ Winer ES Stachurski D . Clinical and pathological differences between human immunodeficiency virus-positive and human immunodeficiency virus-negative patients with plasmablastic lymphoma. Leuk Lymphoma 2010;51 :2047–53.20919850\n[11] Castillo JJ Bibas M Miranda RN . The biology and treatment of plasmablastic lymphoma. Blood 2015;125 :2323–30.25636338\n[12] Liu M Liu B Liu B . Human immunodeficiency virus-negative plasmablastic lymphoma: a comprehensive analysis of 114 cases. Oncol Rep 2015;33 :1615–20.25695332\n[13] Castillo JJ Winer ES Stachurski D . HIV-negative plasmablastic lymphoma: not in the mouth. Clin Lymphoma Myeloma Leuk 2011;11 :185–9.21575922\n[14] Andrew D Zelenetz JSA Ranjana H. Advani C Babis Andreadis . NCCN Clinical Practice Guidelines in Oncology: non-Hodgkin's lymphomas. J Natl Compr Canc Netw 2010;8 :288–334.20202462\n[15] Wilson WH Dunleavy K Pittaluga S . Phase II study of dose-adjusted epoch and rituximab in untreated diffuse large b-cell lymphoma with analysis of germinal center and post-germinal center biomarkers. J Clin Oncol 2008;26 :2717–24.18378569\n[16] Magrath IAM Shad A . Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. J Clin Oncol 1996;14 :925–34.8622041\n[17] Cortes J Thomas D Rios A . Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone and highly active antiretroviral therapy for patients with acquired immunodeficiency syndrome-related burkitt lymphoma/leukemia. Cancer 2002;94 :1492–9.11920506\n[18] Ando K Imaizumi Y Kobayashi Y . Bortezomib- and lenalidomide-based treatment of refractory plasmablastic lymphoma. Oncol Res Treat 2020;43 :112–6.31842017\n[19] Bibas M Grisetti S Alba L . Patient with HIV-associated plasmablastic lymphoma responding to bortezomib alone and in combination with dexamethasone, gemcitabine, oxaliplatin, cytarabine, and pegfilgrastim chemotherapy and lenalidomide alone. Journal of clinical oncology 2010;28 :e704–8.20823416\n[20] Carras S Regny C Peoc’h M . Dramatic efficacy of low dose lenalidomide as single agent in a patient with refractory gastric non-human immunodeficiency virus-associated plasmablastic lymphoma. Leukemia & lymphoma 2015;56 :2986–8.25676034\n[21] Michele Bibas SG Lucia Alba Giovanna Picchi . Patient with HIV-associated plasmablastic lymphoma responding to bortezomib alone and in combination with dexamethasone, gemcitabine, oxaliplatin, cytarabine, and pegfilgrastim chemotherapy and lenalidomide alone. J Clin Oncol 2010;28 :e704–8.20823416\n[22] Schmit JM DeLaune J Norkin M . A case of plasmablastic lymphoma achieving complete response and durable remission after lenalidomide-based therapy. Oncol Res Treat 2017;40 :46–8.28095384\n[23] Pretscher D Kalisch A Wilhelm M . Refractory plasmablastic lymphoma-a review of treatment options beyond standard therapy. Ann Hematol 2017;96 :967–70.28011983\n[24] Koenig G Stevens TM Peker D . Plasmablastic microlymphoma arising in human herpesvirus-8-associated multicentric Castleman disease in a human immunodeficiency virus-seronegative patient with clinical response to anti-interleukin-6 therapy. Histopathology 2015;67 :903–2.\n[25] Koizumi Y Uehira T Ota Y . Clinical and pathological aspects of human immunodeficiency virus-associated plasmablastic lymphoma: analysis of 24 cases. Int J Hematol 2016;104 :669–81.27604616\n[26] Hamadani M Devine SM . Reduced-intensity conditioning allogeneic stem cell transplantation in HIV patients with hematologic malignancies: yes, we can. Blood 2009;114 :2564–6.19762505\n\n",
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"title": "Allogeneic hematopoietic stem cell transplantation in a patient with HIV-negative recurrent plasmablastic lymphoma: A case report.",
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"abstract": "To evaluate the tolerability and safety of cannabidiol for treating drug-resistant epilepsy in children, and to describe adverse events associated with such treatment.\n\n\n\nProspective, open label cohort study.\n\n\n\nThree tertiary NSW referral centres with paediatric neurology services.\n\n\n\nFirst 40 children enrolled in the NSW Compassionate Access Scheme for children with drug-resistant epilepsy and uncountable daily seizures.\n\n\n\nChildren received cannabidiol as an adjunct anti-epileptic drug, titrated to a maximum of 25 mg/kg/day, for up to 12 weeks.\n\n\n\nAdverse events, withdrawals, and caregiver and physician Global Impression of Change assessments were recorded at 4, 8 and 12 weeks. Seizure frequency could not be reliably recorded because of disease severity.\n\n\n\nThirty-nine patients reported at least one adverse event; many were deemed unrelated to cannabidiol treatment. The most frequent treatment-related adverse event was somnolence (15 participants), which resolved spontaneously in ten patients; it was particularly frequent in patients taking higher clobazam doses. Gastrointestinal effects (nausea, vomiting, diarrhoea) were each reported by seven to nine participants. Four children were withdrawn from treatment, including one with elevated transaminase levels. The caregivers of 12 children felt the overall health of their children had much or very much improved; clinicians assessed seven children as being much or very much improved.\n\n\n\nCannabidiol as an adjunct treatment had some subjective benefit for overall health, with a manageable adverse event profile. Monitoring changes in liver function and awareness of potential drug interactions is essential. Whether the reported benefit is attributable to cannabidiol cannot be established in an open label study of participants with severe intractable epilepsy.",
"affiliations": "Sydney Children's Hospital Randwick, Sydney, NSW john.lawson@health.nsw.gov.au.;Sydney Children's Hospital Randwick, Sydney, NSW.;Sydney Children's Hospital Randwick, Sydney, NSW.;Children's Hospital at Westmead, Sydney, NSW.;John Hunter Children's Hospital, Newcastle, NSW.;Kids Research Institute, Sydney Children's Hospitals Network, Sydney, NSW.;Clinical Trials Unit, Sydney Children's Hospitals Network, Sydney, NSW.;Sydney Children's Hospital Randwick, Sydney, NSW.",
"authors": "Chen|Kerrie-Anne|KA|;Farrar|Michelle|M|;Cardamone|Michael|M|;Gill|Deepak|D|;Smith|Robert|R|;Cowell|Christopher T|CT|;Truong|Linda|L|;Lawson|John A|JA|",
"chemical_list": "D000927:Anticonvulsants; D002185:Cannabidiol",
"country": "Australia",
"delete": false,
"doi": "10.5694/mja18.00023",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-729X",
"issue": "209(5)",
"journal": "The Medical journal of Australia",
"keywords": "Drugs, generic; Epilepsy",
"medline_ta": "Med J Aust",
"mesh_terms": "D000293:Adolescent; D000927:Anticonvulsants; D002185:Cannabidiol; D002648:Child; D002675:Child, Preschool; D000069279:Drug Resistant Epilepsy; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009517:New South Wales; D011446:Prospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "0400714",
"other_id": null,
"pages": "217-221",
"pmc": null,
"pmid": "30092753",
"pubdate": "2018-08-03",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Cannabidiol for treating drug-resistant epilepsy in children: the New South Wales experience.",
"title_normalized": "cannabidiol for treating drug resistant epilepsy in children the new south wales experience"
} | [
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"companynumb": "AU-MYLANLABS-2018M1078805",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CANNABIDIOL"
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"drugadditional": "3",
... |
{
"abstract": "This article examines the cost-effectiveness of chemotherapy (gemcitabine) versus nanotherapy (PEGylated liposomal doxorubicin) in the treatment of ovarian cancer. Significant differences in costs were mainly due to the initial drug costs, which were €1285.28 in favor of chemotherapy. These costs were more than offset by hospitalization costs, which were €2670.21 in favor of the nanotherapy. The cost per quality-adjusted life week (QALW) for the nanotherapy was estimated to be €220.92/QALW for the base case and ranged from €170-318/QALW based on model assumptions. The clinical benefit associated with nanotherapy was achieved, yielding not only positive cost-effectiveness results, but also, surprisingly, financial savings. Although more studies are necessary, this first comprehensive analysis supports the further use of nanotherapy for ovarian cancer.",
"affiliations": "Hasselt University, Department of Applied Economics, Martelarenlaan 42 - BE3500 Hasselt, Belgium.",
"authors": "Bosetti|Rita|R|;Ferrandina|Gabriella|G|;Marneffe|Wim|W|;Scambia|Giovanni|G|;Vereeck|Lode|L|",
"chemical_list": "D000970:Antineoplastic Agents; C506643:liposomal doxorubicin; D003841:Deoxycytidine; D011092:Polyethylene Glycols; D004317:Doxorubicin; C056507:gemcitabine",
"country": "England",
"delete": false,
"doi": "10.2217/nnm.14.150",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1743-5889",
"issue": "9(14)",
"journal": "Nanomedicine (London, England)",
"keywords": "PEGylated liposomal doxorubicin; chemotherapy; cost–effectiveness; gemcitabine; nanotherapy; ovarian cancer; quality of life",
"medline_ta": "Nanomedicine (Lond)",
"mesh_terms": "D000970:Antineoplastic Agents; D003362:Cost-Benefit Analysis; D003841:Deoxycytidine; D004317:Doxorubicin; D005260:Female; D006801:Humans; D050997:Nanomedicine; D010051:Ovarian Neoplasms; D011092:Polyethylene Glycols; D019057:Quality-Adjusted Life Years",
"nlm_unique_id": "101278111",
"other_id": null,
"pages": "2175-86",
"pmc": null,
"pmid": "25405795",
"pubdate": "2014-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cost-effectiveness of gemcitabine versus PEGylated liposomal doxorubicin for recurrent or progressive ovarian cancer: comparing chemotherapy with nanotherapy.",
"title_normalized": "cost effectiveness of gemcitabine versus pegylated liposomal doxorubicin for recurrent or progressive ovarian cancer comparing chemotherapy with nanotherapy"
} | [
{
"companynumb": "IT-JNJFOC-20160914906",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": "... |
{
"abstract": "BACKGROUND\nRecurrent spontaneous miscarriage (RSM) has a multifactorial etiology, mainly due to karyotype abnormalities including balanced translocation, anatomical uterine disorders, and immunological factors, although in 50%-60% the etiology is unexplained. The treatment of RSM remains challenging, and the role of intravenous immunoglobulin (IVIG) in RSM is controversial.\n\n\nMETHODS\nMrs HM, 37 years old, obstetric summary: P0+1+13+1, a known case of hypothyroidism/polycystic ovary syndrome, married to an unrelated 47-year-old man, presented to our RSM clinic in early January 2014 for investigation and treatment. She has had multiple failed in vitro fertilization trials and 13 first-trimester missed miscarriages terminating at 6-7 weeks, all without IVIG therapy. Her tenth pregnancy was spontaneous, managed in London, UK, with multiple supportive therapy and courses of IVIG starting from the third to the 30th week of pregnancy. The pregnancy ended at 36 weeks of gestation with a cesarean section and a live girl baby was delivered. Mrs HM had balanced translocation, 46XX t (7:11) (p10:q10). Preimplantation genetic diagnosis/intracytoplasmic sperm injection/in vitro fertilization was performed with embryo transfer on May 29, 2014, and resulted in a successful pregnancy. She was commenced immediately on metformin, luteal support, and IVIG therapy, started at 6 weeks of gestation and at monthly intervals until 30 weeks of gestation, and also received additional therapy. The pregnancy was monitored with ultrasound, progressed uneventfully until admission at 35 weeks of gestation, with mildly elevated liver enzymes and suspected fetal growth restriction. She was managed conservatively, and in the light of nonreassuring fetal status, a live female infant weighing 2.29 kg was delivered by emergency cesarean section on January 14, 2015, with an Apgar score of 8 and 9 and mild respiratory distress, and was admitted to the Special Care Baby Unit for intensive therapy. The mother and baby made satisfactory progress and were discharged on January 24, 2015.\n\n\nCONCLUSIONS\nTwo consecutive successful pregnancies in Mrs HM with multiple causes of RSM treated with other medications and IVIG strongly suggest that IVIG has a positive role in RSM.",
"affiliations": "Department of Obstetrics and Gynaecology, Faculty of Medicine, Kuwait University, Safat, Kuwait ; Maternity Hospital, Shuwaikh, Kuwait.;Maternity Hospital, Shuwaikh, Kuwait.;Department of Obstetrics and Gynaecology, Faculty of Medicine, Kuwait University, Safat, Kuwait ; Maternity Hospital, Shuwaikh, Kuwait.;Maternity Hospital, Shuwaikh, Kuwait.;Maternity Hospital, Shuwaikh, Kuwait.;Department of Obstetrics and Gynaecology, Faculty of Medicine, Kuwait University, Safat, Kuwait.",
"authors": "Diejomaoh|Michael F|MF|;Bello|Zainab|Z|;Al Jassar|Waleed|W|;Jirous|Jiri|J|;Karunakaran|Kavitha|K|;Mohammed|Asiya T|AT|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/IMCRJ.S93159",
"fulltext": "\n==== Front\nInt Med Case Rep JInt Med Case Rep JInternational Medical Case Reports JournalInternational Medical Case Reports Journal1179-142XDove Medical Press 10.2147/IMCRJ.S93159imcrj-8-337Case ReportConsecutive successful pregnancies subsequent to intravenous immunoglobulin therapy in a patient with recurrent spontaneous miscarriage Diejomaoh Michael F 12Bello Zainab 2Al Jassar Waleed 12Jirous Jiri 2Karunakaran Kavitha 2Mohammed Asiya T 11 Department of Obstetrics and Gynaecology, Faculty of Medicine, Kuwait University, Safat, Kuwait2 Maternity Hospital, Shuwaikh, KuwaitCorrespondence: Michael F Diejomaoh, Department of Obstetrics and Gynaecology, Faculty of Medicine, Kuwait University, PO Box 24923, Safat 13110, Kuwait, Tel +965 2531 9601/+965 6674 1876, Fax +965 2533 8906, Email michaeldiejo@hotmail.com2015 11 12 2015 8 337 344 © 2015 Diejomaoh et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2015The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Background\nRecurrent spontaneous miscarriage (RSM) has a multifactorial etiology, mainly due to karyotype abnormalities including balanced translocation, anatomical uterine disorders, and immunological factors, although in 50%–60% the etiology is unexplained. The treatment of RSM remains challenging, and the role of intravenous immunoglobulin (IVIG) in RSM is controversial.\n\nCase report\nMrs HM, 37 years old, obstetric summary: P0+1+13+1, a known case of hypothyroidism/polycystic ovary syndrome, married to an unrelated 47-year-old man, presented to our RSM clinic in early January 2014 for investigation and treatment. She has had multiple failed in vitro fertilization trials and 13 first-trimester missed miscarriages terminating at 6–7 weeks, all without IVIG therapy. Her tenth pregnancy was spontaneous, managed in London, UK, with multiple supportive therapy and courses of IVIG starting from the third to the 30th week of pregnancy. The pregnancy ended at 36 weeks of gestation with a cesarean section and a live girl baby was delivered. Mrs HM had balanced translocation, 46XX t (7:11) (p10:q10). Preimplantation genetic diagnosis/intracytoplasmic sperm injection/in vitro fertilization was performed with embryo transfer on May 29, 2014, and resulted in a successful pregnancy. She was commenced immediately on metformin, luteal support, and IVIG therapy, started at 6 weeks of gestation and at monthly intervals until 30 weeks of gestation, and also received additional therapy. The pregnancy was monitored with ultrasound, progressed uneventfully until admission at 35 weeks of gestation, with mildly elevated liver enzymes and suspected fetal growth restriction. She was managed conservatively, and in the light of nonreassuring fetal status, a live female infant weighing 2.29 kg was delivered by emergency cesarean section on January 14, 2015, with an Apgar score of 8 and 9 and mild respiratory distress, and was admitted to the Special Care Baby Unit for intensive therapy. The mother and baby made satisfactory progress and were discharged on January 24, 2015.\n\nConclusion\nTwo consecutive successful pregnancies in Mrs HM with multiple causes of RSM treated with other medications and IVIG strongly suggest that IVIG has a positive role in RSM.\n\nKeywords\nrecurrentmiscarriageintravenous immunoglobulinpregnancy outcome\n==== Body\nIntroduction\nMiscarriage is the most frequently encountered complication of pregnancy,1–3 and miscarriage rates of 10%–30% have been reported by various authors.4,5 Spontaneous miscarriage presents in diverse ways and is subclassified into distinct subtypes. In this report, recurrent spontaneous miscarriage (RSM) is defined as the loss of three or more consecutive pregnancies before 20 weeks of pregnancy, and it is reported to occur in 0.5%–1% of women in reproductive age.1,3,6–8 Ectopic pregnancies and molar pregnancies are not included in this definition. There is a lack of uniformity in the definition of RSM.9 Many authors define RSM as the loss of two or more consecutive pregnancies,10–12 and the incidence may increase to 5%. This definition is particularly applicable to women older than 35 years. In Kuwait, we commence investigations in women aged 35 years and older who have had two or more consecutive miscarriages.9 RSM may be primary, secondary, or rarely tertiary. Tertiary RSM refers to the event that follows secondary RSM. A patient who has had a series of miscarriages without a previous viable pregnancy or birth (live birth or stillbirth) is classified as primary RSM, whereas a patient who has had a series of miscarriages after a viable pregnancy, a live birth, or a stillbirth is classified as secondary RSM.13\n\nThe etiology of RSM may be multifactorial, and the more established etiological factors include antiphospholipid syndrome, anatomical uterine structural anomalies, and parental chromosome anomalies;1–3,9–12,14 other etiological factors include endocrine disorders and inherited thrombophilia. However, in 40%–50% of the cases of RSM, the etiology cannot be identified or established, and the cause is then defined as idiopathic or unexplained.9,11,12 Immunological disturbances and aberrations seem to be the risk factors in many cases of RSM and have been suggested to play an important role in the etiology of RSM.7,15–18 Elevated natural killer (NK) cells (CD56+/CD16+) have been implicated in the etiology of RSM through their interaction in the maternal/fetal interface,16,19,20 and the higher levels of NK cells in the nonpregnant women have been associated with the increased probability of miscarriage in a subsequent pregnancy.21,22\n\nThe establishment of the cause of RSM in any patient requires detailed and comprehensive investigations.4,9,11,12,14 The etiology of RSM may be multifactorial in some patients and therefore calls for extensive elaborate investigations. The details of such investigations of RSM will not be covered in this report.\n\nThe treatment of RSM remains varied and challenging, and where the cause is known, such as in antiphospholipid syndrome, the treatment could be easily executed. However, in many cases of RSM, especially the idiopathic cases of RSM, which constitute 40%–50% of cases of RSM, the treatment may be empirical and not evidence based.9,23 Patients and their treating doctors may therefore face challenges and frustrations from the treatment of RSM because of the uncertain efficacy of the treatment being offered.24\n\nIntravenous immunoglobulin (IVIG) therapy has been administered to many patients with RSM on a trial basis in double-blind, placebo-controlled trials with the understanding that there may be an immunological basis for the pathogenesis of such cases of RSM.1–7,25–27 IVIG has also been reported to enhance live births in patients with RSM who have been demonstrated to have elevated NK cells.20,23,28\n\nHowever, the role of IVIG therapy in RSM, which has been the subject of multiple trials, meta-analyses, and systemic reviews,1–3,15,29 has remained controversial, and the results of such trials have been varied with contrasting results and deductions. IVIG therapy resulted in positive outcome in idiopathic secondary RSM, but no benefits were observed for primary RSM; 58% of patients with secondary RSM had successful pregnancies after IVIG therapy compared with that of 24% of placebo-treated patients.7 Positive pregnancy outcome was also reported in patients with secondary RSM treated with IVIG therapy in randomized trials.1,8,25–27 However, the meta-analysis of eight randomized controlled trials concluded that there was a positive pregnancy outcome in women with secondary RSM treated with IVIG,29 and other meta-analyses and systemic reviews reported no benefits for IVIG therapy in RSM.1–3,18 In many studies of IVIG therapy in RSM quoted earlier, the dosage regimes of IVIG used and the treatment protocol followed were diverse and varied. These may have contributed to the diverse results reported in these studies.\n\nAs highlighted previously, the etiology of RSM may be multifactorial, and the multiple causes of RSM may be present in the same patient. It is also pertinent to state that as the number of miscarriages increases in the same patient, as the patient therefore increases in age, the chances of a successful pregnancy outcome in a subsequent pregnancy will diminish and the stress and anxiety will increase in such patients, and the challenge to the treating physician and patient becomes phenomenal.\n\nA major area of challenge is in the area of parental chromosome aberrations/anomalies (including balanced trans-locations and chromosome inversions) where technological approaches to diagnosis and management are necessary. In the presence of a known parental balanced translocation as the cause of RSM, preimplantation genetic diagnosis (PGD) with in vitro fertilization (IVF) is an accepted modality of treatment.9,12 The chances of these procedures leading to a successful pregnancy are not always guaranteed, and thus, a successful pregnancy may not always be achieved.\n\nWe present a case of high-order RSM (many previous miscarriages) due to multiple etiological factors that are fully investigated and treated successfully with PGD/intracytoplasmic sperm injection (ICSI)/IVF, multiple therapy, and IVIG, which resulted in a successful pregnancy outcome.\n\nCase report\nMrs HM, 37 years old, P0+1+13+1, a known case of hypothyroidism due to autoimmune thyroiditis and polycystic ovary syndrome (PCOS), married to an unrelated 47-year-old civil servant (nonconsanguineous marriage), presented to our RSM clinic at maternity hospital, Kuwait, in early January 2014, for further investigations and treatment. Written consent was obtained from the patient before commencement of the IVIG therapy. Verbal consent was obtained from the patient before the case report was prepared. Ethical approval was not necessary for this case report. All principles outlined in the Declaration of Helsinki were followed. The patient had been married to the same husband for 27 years. A comprehensive medical/surgical history was obtained and investigations commenced. Her surgical history revealed that she had wedge resection of the ovaries in 2002 for PCOS and her menstrual cycles were reported as regular.\n\nA summary of her obstetric history revealed that she has had nine first-trimester miscarriages that terminated at 6–7 weeks of gestation. No IVIG therapy was offered during these pregnancies. Evacuation of the uterus was performed in six of these miscarriages, and there were no complications. She has had six failed IVF trials.\n\nHer tenth pregnancy was spontaneous and was managed in London, UK, where she had also been diagnosed with hypothyroidism and elevated NK cells, from late 2009 to early 2010. She received multiple doses of IVIG starting from the third week of pregnancy until 30 weeks of gestation and other forms of multiple supportive therapy, which included Eltroxin and Glucophage (metformin) tablets, enoxaparin (Clexane) injections, low-dose aspirin tablets, and progesterone tablets. This pregnancy ended at 36 weeks of gestation with a cesarean section because of the failure to progress in labor and a healthy live girl baby was delivered in February 2010.\n\nShe had another four consecutive first-trimester missed miscarriages; none of these pregnancies were treated with IVIG. Her last spontaneous pregnancy was in November 2010, and this was followed by a period of 3 years of secondary infertility, which was investigated.\n\nDuring her first visit to the RSM clinic at maternity hospital, Kuwait, in early January 2014, a full physical examination revealed no abnormalities apart from a high body mass index of 32 kg/m2, and she was fully investigated again for the RSM. Full immunological, endocrinological, ultrasound, and other blood investigations (including anticardiolipin antibodies [IgG/IgM], lupus anticoagulant, thrombophilia screening, thyroid function tests, serum prolactin, 21st day serum progesterone, and 3D ultrasound studies) were performed, and they revealed no abnormalities.\n\nKaryotype studies revealed that her husband was 46XY and the patient had a balanced translocation – 46XX t (7:11) (p10: q10). Further investigations revealed that the patient had elevated NK cells (CD56+/CD16+), and oligoasthenozoospermia was detected in her husband. Mrs HM had been commenced on 75 μg Eltroxin daily and 850 mg metformin tablets twice daily accordingly as part of the treatment for her previously diagnosed hypothyroidism and PCOS and was advised to undergo PGD/ICSI/IVF.\n\nThe diagnoses of Mrs HM at this point were previous cesarean section, RSM due to multiple etiological factors of chromosome anomaly, elevated NK cells, hypothyroidism, and PCOS. Her age, 37 years, and moderate obesity were additional contributory factors.\n\nThe procedures (PGD/ICSI/IVF) recommended for Mrs HM were successfully performed, and the embryo transfer was performed on May 29, 2014. A successful pregnancy was confirmed, and this was considered as a very precious and high-risk pregnancy. Routine antenatal blood tests and ultrasound revealed normal results. The patient was commenced on 5 mg folic acid tablets, metformin tablets, vitamins, low-dose aspirin, Clexane 40 mg subcutaneous injections, and 75 μg Eltroxin daily. After appropriate consent, IVIG (Biotest, Germany) therapy was commenced at 6 weeks of gestation after positive fetal cardiac activity had been confirmed. Luteal support was also commenced with progesterones (Cyclogest pessaries) 400 mg twice daily vaginally and oral dydrogesterone (Duphaston) tablets 10 mg twice daily.\n\nLuteal support with progesterone suppositories and metformin tablets was continued until the 13th week of pregnancy. Cervical cerclage was performed at 14 weeks of gestation by a colleague in private practice. IVIG (500 mg/kg, in divided doses, intravenous for 2 days every month) was continued after the first dose at 6 weeks of gestation. The patient was always admitted to the hospital for the IVIG therapy, closely monitored for any adverse/untoward reactions, and discharged home after each treatment cycle. Serial ultrasound examinations were performed, and at 20 weeks of gestation, the scan revealed no fetal anomalies. Dydrogesterone treatment was continued until 24 weeks of gestation while all the other drugs listed earlier were continued. At approximately 16 weeks of gestation, folic acid therapy was stopped, and supplemental folic acid and oral iron (single tablet) were continued until term. In view of the history of previous preterm delivery, injection primolut depot (17α-hydroxy progesterone caproate) 500 mg by the intramuscular route weekly was commenced after 16 weeks of gestation and was continued until term (37 weeks of gestation). She was also screened for diabetes mellitus with oral glucose tolerance test that revealed normal results.\n\nThe pregnancy progressed uneventfully, and the growth of the baby was satisfactory. The monthly IVIG therapy was stopped at 30 weeks of gestation after due counseling and discussion with the patient; she had received a total of seven doses of IVIG injections with no adverse fetal or maternal effects being reported. During her previous successful pregnancy, IVIG was continued until 30 weeks of gestation and the same has been followed in the current pregnancy also.\n\nAt 33 weeks of gestation, on December 28, 2014, she presented with slight painless vaginal bleeding and was admitted to the labor ward of maternity hospital with the diagnosis of antepartum hemorrhage (APH). Ultrasound examination confirmed the diagnosis of APH due to placenta previa marginalis (the placenta was situated posteriorly, 1.2 cm from the cervical os). Routine blood investigations revealed normal results. She was managed conservatively along departmental guidelines (these were identical to the Royal College of Obstetricians and Gynaecologists [RCOG]/American College of Obstetricians and Gynecologists [ACOG]/Society of Gynecologists of Canada [SOGC] guidelines). Dexamethasone (12 mg, 12 hourly for 24 hours by intramuscular injections) was administered to the patient. Blood was crossmatched (in case there was need for immediate delivery), and a high-risk consent was obtained from the patient and her husband. The conservative treatment was to be continued until 37 weeks of gestation when an elective cesarean section was planned. After stabilization of the patient in the labor ward and a stay of 14 hours, she was transferred to the antenatal ward.\n\nThe patient presented with generalized pruritus on January 10, 2015, and there was neither nausea/vomiting nor jaundice. A diagnosis of cholestasis of pregnancy was made, and the patient was jointly managed conservatively in collaboration with the physician. The liver enzymes were slightly elevated (alanine aminotransferase [ALT], 77 IU/L [normal range, 10–60 IU/L]; aspartate aminotransferase [AST], 112 IU/L [normal range, 10–42 IU/L]), and all the other blood results revealed normal results.\n\nMrs HM was clinically stable on January 12, 2015, and all her treatment was continued. Ultrasound examination on January 14, 2015, indicated a disparity of 3 weeks between the gestational age and the findings on ultrasound examination: gestational age 35+4 weeks of gestation by dates and ultrasound gestational age of 32+4 weeks, there was a normal umbilical artery diastolic flow, a biophysical profile of 8/8, an amniotic fluid index of 9.8 (normal), and an estimated fetal weight of 2.048 kg. A diagnosis of fetal growth restriction (FGR)/intrauterine growth restriction was made. The nonstress test was now performed twice daily and a close monitoring of the mother was continued. The nonstress test demonstrated persistent fetal tachycardia: the mother was stable and had no pyrexia. The mother, however, demonstrated great anxiety because of the fetal tachycardia. Despite adequate counseling and reassurance, she insisted on immediate delivery. A decision was therefore taken to proceed with an emergency cesarean section which was successfully performed on January 14, 2015. A healthy, normal-looking female infant was delivered, with an Apgar score of 8 in 1 minute and 9 in 5 minutes and fetal birth weight of 2.290 kg. The baby had mild respiratory distress and was immediately admitted in the neonatal intensive care unit and managed by the neonatologists. Mrs HM was treated routinely with intravenous antibiotics (ceftriaxone/metronidazole). She had a superficial wound dehiscence, which was routinely treated, and her postoperative period was otherwise uneventful. Blood investigations revealed satisfactory hemoglobin and normal liver function tests. The baby spent 1 week in the neonatal intensive care unit under close observation, although no specialized treatment was required; the baby was then transferred to the Special Care Baby Unit for further surveillance and management. The baby was breast-fed by the mother. Mother and baby made satisfactory progress. The mother was discharged home with her baby on January 24, 2015.\n\nDiscussion\nMrs HM had been admitted with a diagnosis of RSM due to multiple etiological factors, which included hypothyroidism, PCOS, elevated NK cells, chromosome anomaly (balanced translocation), increasing maternal age, and obesity. The interaction/interconnection of these causes is complex. These factors and other etiological factors have been highlighted previously,1–3,9–12,14 and it is not unusual to have multiple etiological factors in the same patient.7,9,14 This patient was subjected to extensive investigations as previously outlined9,14 and these revealed the etiological factors. It was rather unfortunate that karyotype studies were delayed in this patient until the more recent review of her case at our clinic in January 2014, which revealed the additional etiological factor of balanced translocation. Mrs HM had a total of 13 previous miscarriages, and although evacuation was performed in ten of these miscarriages, the products of conception were not subjected to cytogenetic analysis, a practice that is not undertaken at our clinic, an investigation that may have revealed some forms of chromosomal abnormalities. In a recent study of cytogenetic analysis of products of conception in 43 patients with RSM with miscarriages, chromosome abnormalities were detected in 78% of the cases,30 and these authors concluded that in patients older than 35 years, fetal chromosome abnormalities were a major cause of the miscarriages. Our patient presented to our clinic at 37 years of age, and all her previous miscarriages were first-trimester miscarriages; however, the exact contribution of fetal chromosome malformations to these miscarriages could not be established because of the lack of appropriate investigations. Balanced translocation was diagnosed as a contributory cause of RSM in this patient, and PGD/ICSI/IVF was recommended for the couple because the husband of the patient had some problems in his semen analysis test. PGD/IVF has been recommended as a modality of treatment for balanced translocation,9,12 and this procedure with ICSI was offered to Mrs HM and resulted in the pregnancy that was managed with IVIG therapy and other modalities of medical therapy, which ultimately resulted in another successful pregnancy for this patient, the subject of the case report. The modalities of medical treatment referred earlier will be discussed later in this presentation.\n\nA diagnosis of the etiological factors of PCOS and hypothyroidism had been made in the first successful pregnancy of Mrs HM managed in London, and these medical disorders were still under maintenance treatment. A treatment of the earlier medical problems in addition to elevated NK cells was managed with appropriate therapy and IVIG in that pregnancy which resulted in the first successful pregnancy and delivery of the patient, Mrs HM, in London in 2010. Investigations performed at the RSM clinic at maternity hospital in January 2014 confirmed the medical problems of PCOS and hypothyroidism and also revealed a diagnosis of elevated NK cells. Previous studies and reviews1,9,16,17,19–23 had indicated that elevated NK cells were associated with an increased incidence of miscarriage and constitute an etiological factor for RSM. Some of these studies and others20,23,28,31 have reported that with appropriate treatment, the effect of the NK cells could be reduced/reversed and a high positive pregnancy outcome achieved. In the light of the earlier information, one can emphatically state that elevated NK cells play an important etiological role in RSM and have been included in the multiple etiological factors in the case reported. The mechanism through which elevated NK cells contribute to increased miscarriages and RSM include interference with the implantation process and alteration in the cytokine population in the uterus.20,23,31 The treatment of elevated NK cells will be discussed later.\n\nPregnancies in PCOS patients may be associated with luteal phase deficiency, and this was anticipated in this patient and progesterone was prescribed as part of her medical treatment. Metformin had already been administered to this patient as a part of her treatment for PCOS before her pregnancy, and this treatment was continued all through the first trimester of the pregnancy. Metformin therapy had been associated with the reduction in the incidence of miscarriages and RSM and fetal loss.32 In a previous study,32 metformin therapy was associated with a significant reduction in the rate of spontaneous miscarriage (62% to 26%). No significant adverse effects or congenital malformations had been associated with metformin therapy in pregnancy, and metformin therapy has been successfully used for the management of diabetes mellitus in pregnancy.\n\nA successful pregnancy has been associated with appropriate adjustment of the fetus to the immunological system of the mother, and this complex event in the maternal/fetal interface will not be discussed in this report. A successful pregnancy has also been associated with a shift from the T-helper (Th)1 cytokines to the T-helper (Th)2 cytokines; Th1 cytokines are regarded as cytotoxic and increase the incidence of miscarriages, whereas Th2 cytokines create an environment that enables successful pregnancy.9,33 Progesterone has been long established as playing a significant role in the successful establishment of pregnancy, and apart from its other endocrine functions in pregnancy, it has been known to play an immunomodulatory role in pregnancy. Dydrogesterone (Duphaston), an orally active progestogen, with many functions similar to pure endogenous progesterone, which has superior functions when compared with other progestogens, has been demonstrated in many studies to promote a shift in the Th1/Th2 cytokine ratio in favor of Th2 and thus promotes the continuation of a successful pregnancy.34 This information, among others, has formed the basis of the use of dydrogesterone in RSM patients in our clinic. Dydrogesterone had been ordered as a part of the treatment for Mrs HM in her first successful pregnancy in 2010 and was again prescribed for her in the index pregnancy. A recent study,35 a double-blind, randomized, parallel, placebo-controlled trial, has presented a strong evidence for the use of dydrogesterone in patients with RSM; an improved pregnancy outcome and reduction in abortions were reported in the study: the risk of another miscarriage after three consecutive miscarriages was 2.4 times higher in the placebo group compared with that of the treatment group (risk ratio =2.4; 95% confidence interval [CI] =1.3–5.9; P<0.001). In the study, dydrogesterone was continued until 20 weeks of gestation, although in our patient it was continued until 24 weeks of gestation, the standard practice in our RSM clinic. There were other positive benefits reported in the patients treated with dydrogesterone. 17α-Hydroxyprogesterone caproate (primolut depot) was also prescribed for our patient to prevent another preterm labor because of her history of previous preterm delivery. This is a standard policy in our RSM clinic based on the recommendations of ACOG and supported by multiple previous studies and reviews on the benefits and use of progesterone preparations in the prevention of preterm labor.\n\nThe use of IVIG therapy in RSM has remained controversial and has produced a variety of results; indications for therapy have been varied, and the dosage of the drug, the time of commencement of the therapy, and the duration of therapy have been quite varied in the different studies reported.1–3,7–9,15,18,20,23,25–29,31 As previously stated, a positive pregnancy outcome was reported in idiopathic secondary RSM, whereas there was no benefit for primary RSM.7 Positive pregnancy outcome was also reported in patients with secondary RSM;1,8,25–27,29 in some of these studies, the positive benefits were reported after secondary analyses of the available data. Positive pregnancy outcome was reported for secondary RSM in a meta-analysis of eight randomized controlled trials,29 whereas no benefit was reported for primary RSM. Another meta-analysis of six randomized trials found no benefit for both primary and secondary RSM.3 There was also no benefit reported for the use of IVIG in secondary idiopathic RSM in two recent randomized, double-blind, placebo-controlled trials;1,18 dosage regime of IVIG and duration of treatment in both trials were different (0.5 g/kg vs staggered dose of 0.4 g/kg). The use of IVIG therapy in patients with RSM due to elevated NK cells has been very impressive and consistent in some reports and produced highly positive results: pregnancy rates of 82%–96% have been reported and rapid decline/reduction of percentage NK cells was noted in the patients treated.20,23,28,31 The dosage of IVIG used in these studies was also different: 0.5 g/kg in one study23 and 0.4 g/kg in other studies,20,31 and the time of commencement of IVIG therapy and duration of treatment (15–35/36 weeks) varied. In our patient, IVIG therapy was administered because of elevated NK cells in both successful pregnancies, and the dosage regime (0.5 g/kg) and duration of treatment were identical. In our patient, Mrs HM, 13 previous pregnancies ended in first-trimester miscarriages. There was no evidence of any specific therapy or the use of IVIG in any of these failed pregnancies. In her first successful pregnancy managed in London in 2010, she was treated with supportive medical treatment and IVIG targeting the various etiological factors detected; IVIG therapy was continued till 30 weeks of gestation, a gestational age that had been selected because it was felt that a more favorable gestational age for fetal survival had been achieved and this could be further enhanced with neonatal services (should early delivery be recorded). This was the basis of the utilization of similar medical treatment and IVIG therapy. IVIG therapy was continued to 30 weeks of gestation in the second pregnancy, the index pregnancy of the case report based on the evidence of the previous successful pregnancy. The evidence of positive outcome of previous pregnancies using metformin, dydrogesterone, and IVIG has been provided in the reports previously cited in this report. One can therefore deduce that the two successful pregnancies recorded in this patient were due to the medical treatment and IVIG therapy targeting the multiple etiological factors causing RSM in the patient. Thus, one can state that in our patient IVIG was 100% successful in the treatment of her elevated NK cells and other etiological factors. The contribution of PGD/ICSI/IVF to the current successful pregnancy must be recognized as a positive intervention as these procedures had been associated with successful pregnancies in previous reviews.\n\nThe gestational age at delivery was significantly higher in the patients treated with dydrogesterone35 and in the patients with secondary idiopathic RSM18 treated with IVIG compared with that of the controls; there was also a tendency toward the reduction of prematurity, and the fetal birth weights were generally satisfactory. These positive benefits were not observed in the consecutive successful pregnancies reported in our patient since both pregnancies ended at 36 weeks of gestation, and in the second pregnancy, FGR/intrauterine growth restriction was actually diagnosed. Other complications recorded in the second pregnancy, subject of the case report, APH, and cholestasis of pregnancy, are not peculiar and linked to the modalities of treatment offered to our patient, and we want to observe that FGR has also been reported in some of the pregnancies of patients treated with IVIG.29 The successful pregnancy in this patient was most likely a result of the interaction and interconnection of all the forms of medical therapy and IVIG, the interventions targeting the multiple etiological causes of RSM in this patient. On the whole, the course of the pregnancy in our case report was satisfactory, and the various modalities of treatment offered to the patient did not cause any adverse effects.\n\nAlthough the exact mechanism of the action of IVIG in the treatment of RSM has not been well established,3 various suggestions have been made to explain the mechanism of action. These include an immunomodulatory role, modulation of cytokines/production of helper suppressor T-cell cytokines, downregulation of systemic NK cell activity, and reduction of NK cell activity at the implantation site thus reducing the likelihood of miscarriages and anti-infective/anti-inflammatory activity.3,9,15,36\n\nThe unresolved problems of the use of IVIG in RSM include the following: the indication for IVIG, the dosage regime, gestational age at the commencement of therapy, the duration of therapy, and the gestational age at the termination of the therapy. These problems need to be resolved and standardized to facilitate the comparison of trials on the use of IVIG therapy in RSM from different centers. Our case report has indicated a modality of treatment with IVIG therapy ending at 30 weeks of gestation, which needs to be replicated in further studies. The problems highlighted earlier call for larger, double-blind, randomized, placebo-controlled (multicentered) trials before a definitive conclusion can be made on the role, treatment regimes, and usefulness of IVIG in the management of RSM.\n\nAlthough IVIG is quite expensive and this may limit the use of IVIG in RSM in many centers as well as having an effect on the size of planned trials, this high cost is not a limitation for the use of IVIG in selected patients with RSM in our clinic because such therapy is fully financed by the government. IVIG therapy has been associated with some minor side effects although few major side effects have been reported.\n\nConclusion\nWe have presented Mrs HM, 37 years old, P0+1+13+1, with high-order RSM due to multiple etiological factors, including balanced translocation, PCOS, hypothyroidism, elevated NK cells, moderate obesity, and advanced age of older than 35 years, with two consecutive successful pregnancies (and PGD/ICSI/IVF in the latter pregnancy) and multiple supportive medical therapy and IVIG therapy targeting the etiological factors. This report has demonstrated that IVIG may have a positive role in the management of RSM. We call for further, well-planned, larger, double-blind, randomized, placebo-controlled trials to resolve the problems of the real benefits of the use of IVIG therapy in RSM and the many unresolved problems highlighted earlier which are associated with IVIG therapy.\n\nAcknowledgments\nWe are grateful to all our colleagues for their contribution to the successful management of our patient. We are very grateful to Mrs Anju Nair for her technical support in the preparation of the manuscript.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n1 Stephenson MD Kutteh WH Purkiss S Intravenous immunoglobulin and idiopathic secondary recurrent miscarriage: a multi-centered randomized placebo-controlled trial Hum Reprod 2010 25 2203 2209 20634190 \n2 Daya S Gunby J Porter F Scott J Clark DA Critical analysis of intravenous immunoglobulin therapy for recurrent miscarriage Hum Reprod Update 1999 5 475 482 10582784 \n3 Ata B Tan SL Shehata F Hozler H Buckett W A systematic review of intravenous immunoglobulin for treatment of unexplained recurrent miscarriage Fertil Steril 2011 95 1080 1085 21232738 \n4 Reagan L A prospective study of spontaneous abortion Beard RW Sharp F Early Pregnancy Loss: Mechanisms of Treatment London Springer-Verlag 1988 23 27 \n5 Wilcox AJ Weinberg CR O’Connor JF Incidence of early loss of pregnancy N Engl J Med 1988 319 189 194 3393170 \n6 Alberman E The epidemiology of repeated abortions Beard RW Sharp F Early Pregnancy Loss: Mechanisms of Treatment London Springer-Verlag 1988 9 17 \n7 Christiansen OB Pederson B Rosgaard A Husth M A randomized; double-blind, placebo-controlled trial of intravenous immunoglobulin in the prevention of recurrent miscarriage: evidence of a therapeutic effect in women with secondary recurrent miscarriage Hum Reprod 2002 17 809 816 11870141 \n8 Rai R Reagan L Recurrent miscarriage Lancet 2006 368 601 611 16905025 \n9 Diejomaoh MF Recurrent spontaneous miscarriage is still a challenging, diagnostic and therapeutic quagmire Med Princ Pract 2015 24 Suppl I 38 55 25428171 \n10 The practice committee of the American Society for Reproductive medicine Evaluation and treatment of recurrent pregnancy loss. A committee opinion Fertil Steril 2012 98 1103 1111 22835448 \n11 Jaslow CR Carney JL Kutteh WH Diagnostic factors identified in 1020 women with two versus three or more recurrent pregnancy losses Fertil Steril 2010 93 1234 1243 19338986 \n12 Brezina PR Kutteh WH Classic and cutting-edge strategies for the management of early pregnancy loss Obst Gynecol Clin North Am 2014 4 1 18 24491981 \n13 Shapira E Ratzon R Shoham-Vardi I Serjienko R Mazor M Bashiri A Primary versus secondary recurrent pregnancy loss-epidemiological characteristics, etiology, and next pregnancy outcome J Perinat Med 2012 40 389 396 22752770 \n14 Diejomaoh MF Al-Azemi M Jirous J The aetiology and pattern of recurrent pregnancy loss J Obstet Gynaecol 2002 22 62 67 12521732 \n15 Porter TF La Coursiere Y Scott JR Immunotherapy for recurrent miscarriage Cochrane Database Syst Rev 2006 2 CD000112 16625529 \n16 Quenby S Bates M Doig T Pre-implantation endometrial leukocytes in women with recurrent miscarriage Hum Reprod 1999 14 2386 2391 10469717 \n17 King K Smith S Chapman M Sacks G Detailed analysis of peripheral blood natural killer [NK] cells in women with recurrent miscarriage Hum Reprod 2010 25 52 58 19819893 \n18 Christiansen OB Larsen EC Egerup P Lunoee L Egestad L Nielsen HS Intravenous immunoglobulin treatment for secondary recurrent miscarriage: a randomised, double-blind, placebo-controlled trial BJOG 2015 122 500 508 25412569 \n19 Clifford K Flanagan AM Reagan L Endometrial CD56+ natural killer cells in women with recurrent miscarriage: a histomorphometric study Hum Reprod 1999 14 2727 2730 10548610 \n20 Ramos-Medina R García-Segovia A Gil J Experience in IVIg therapy for selected women with recurrent reproductive failure and NK cell expansion Am J Reprod Immunol 2014 71 458 466 24612159 \n21 Aoki K Kajiura S Matsumoto Y Preconceptional natural killer – cell activity as a predictor of miscarriage Lancet 1995 345 1340 1342 7752757 \n22 Yamada H Morikawa M Kato EH Shimada S Kobashi G Minakami H Pre-conceptional natural killer cell activity and percentage as predictors of biochemical pregnancy and spontaneous abortion with normal chromosome karyotype Am J Reprod Immuol 2003 50 351 354 \n23 Perricone R Di Muzio G Perricone C High levels of peripheral blood NK cells in women suffering from recurrent spontaneous abortion are reverted from high-dose intravenous immunoglobulin Am J Reprod Immunol 2006 55 232 239 16451358 \n24 Silver RM Intravenous immune globulin: another disappointing treatment for pregnancy loss BJOG 2015 122 509 25600311 \n25 Christiansen OB Mathiesen O Husth M Placebo-controlled trial of treatment of unexplained secondary recurrent spontaneous abortions with IV. Immunoglobulin Hum Reprod 1995 19 2690 2695 8567794 \n26 Stephenson MD Dreher K Honlihan E Wu V Prevention of unexplained recurrent spontaneous abortion using intravenous immunoglobulin: a prospective, randomized, double blinded, placebo-controlled trial Am J Reprod Immunol 1998 39 82 88 9506206 \n27 Jablonowska B Selbing A Palfi M Ernerudh J Kjellberg S Lindton B Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study Hum Reprod 1999 14 838 841 10221723 \n28 Coulam CB Acacio B Does immunotherapy for treatment of reproductive failure enhance live births? Am J Reprod Immunol 2012 67 296 303 22340745 \n29 Hutton B Sharma R Fergusson D Use of intravenous immunoglobulin for recurrent spontaneous miscarriage: a systemic review BJOG 2007 114 134 142 17166218 \n30 Marquard K Westphal LM Milki AA Lathi RB Etiology of recurrent pregnancy loss in women over the age of 35 years Fertil Steril 2010 94 1473 1477 19643401 \n31 Moraru M Carbone J Alecsandru D Intravenous immunoglobulin treatment increased live birth rate in a Spanish cohort of women with recurrent reproductive failure and expended CD 56+ cells Am J Reprod Immunol 2012 68 75 84 22509929 \n32 Glueck CJ Wang P Goldenberg N Sieve-Smith L Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin Hum Reprod 2002 17 2858 2864 12407039 \n33 Szekeres-Bartho J Immunologic relationship between the mother and fetus Intern Rev Immunol 2002 21 471 496 \n34 Raghupathy R Al Mutawa E Makhseed M Azizieh F Szekeres-Bartho J Modulation of cytokine production by dydrogesterone in lymphocytes from women with recurrent miscarriage BJOG 2005 112 1096 1101 16045524 \n35 Kumar A Begum N Prasad S Aggarwal S Sharma S Oral dydrogesterone treatment during early pregnancy to prevent recurrent pregnancy loss and its role in modulation of cytokine production: a double-blind, randomized, parallel, placebo-controlled trial Fertil Steril 2014 102 1357 1363 25241364 \n36 Leong H Stachnik J Bonk ME Matuszewski MS Unlabeled uses of intravenous immunoglobulin Am J Health Syst Pharm 2008 65 1815 1824 18796422\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-142X",
"issue": "8()",
"journal": "International medical case reports journal",
"keywords": "intravenous immunoglobulin; miscarriage; pregnancy outcome; recurrent",
"medline_ta": "Int Med Case Rep J",
"mesh_terms": null,
"nlm_unique_id": "101566269",
"other_id": null,
"pages": "337-44",
"pmc": null,
"pmid": "26715864",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "9506206;17166218;3393170;25412569;11870141;14672340;16045524;12407039;10469717;8567794;16451358;25428171;12521732;7752757;24612159;16905025;22752770;25241364;19819893;10221723;22340745;22509929;25600311;16625529;21232738;20634190;19643401;24491981;22835448;12650238;18796422;10548610;19338986;10582784",
"title": "Consecutive successful pregnancies subsequent to intravenous immunoglobulin therapy in a patient with recurrent spontaneous miscarriage.",
"title_normalized": "consecutive successful pregnancies subsequent to intravenous immunoglobulin therapy in a patient with recurrent spontaneous miscarriage"
} | [
{
"companynumb": "PHHY2016KW005802",
"fulfillexpeditecriteria": "1",
"occurcountry": "KW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"drugadm... |
{
"abstract": "Ectopic adrenocorticotropic hormone (ACTH)-related Cushing's syndrome can lead to multiple complications including severe immunosuppression. If the ACTH-secreting tumour cannot be found, definitive treatment is surgical adrenalectomy, typically followed by glucocorticoid replacement. Here, we present a case of fulminant respiratory failure secondary to coinfection with Pneumocystis jirovecii and cytomegalovirus in a patient with ectopic ACTH-dependent Cushing's syndrome with occult primary. Due to significant deconditioning, she was unable to undergo definitive adrenalectomy and instead underwent percutaneous microwave ablation of the adrenal glands.",
"affiliations": "Department of Medicine, University of British Columbia, Vancouver, Canada.;Department of Medicine, University of British Columbia, Vancouver, Canada.",
"authors": "Chan|Chrystal|C|;Roberts|James Mark|JM|",
"chemical_list": "D006854:Hydrocortisone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-221580",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "adrenal disorders; interventional radiology; pneumonia (respiratory medicine)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000182:ACTH Syndrome, Ectopic; D000005:Abdomen; D055011:Ablation Techniques; D000311:Adrenal Glands; D003480:Cushing Syndrome; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D005260:Female; D006801:Humans; D006854:Hydrocortisone; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009894:Opportunistic Infections; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis; D012131:Respiratory Insufficiency; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29141926",
"pubdate": "2017-11-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18413427;25681039;25571880;25762486;26222757;20540918;2554832;23484377;6331781;27919009;26649179;24383115;10634361;23533241;9648056;20544290;19246983;26004339;28552210",
"title": "Ectopic ACTH syndrome complicated by multiple opportunistic infections treated with percutaneous ablation of the adrenal glands.",
"title_normalized": "ectopic acth syndrome complicated by multiple opportunistic infections treated with percutaneous ablation of the adrenal glands"
} | [
{
"companynumb": "CA-LABORATOIRE HRA PHARMA-2040060",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METYRAPONE"
},
"drugadditional": nul... |
{
"abstract": "BACKGROUND\nMelanoma of unknown primary (MUP) accounts for approximately 3% of melanoma diagnoses. This study sought to evaluate treatment and outcomes for a modern MUP cohort.\n\n\nMETHODS\nA retrospective review of MUP was performed at a tertiary referral cancer center.\n\n\nRESULTS\nOf 815 melanoma patients, 67 (8.2%) had MUP. Men were more likely to have MUP than women (67% vs. 55%; p = 0.04). The most common sites of MUP were lymph nodes (28%), visceral solid organs (25%), brain (16%), and skin/subcutaneous tissues (10%). Of the patients who underwent tumor genomic profiling, 52% harbored pathogenic BRAF mutations. Of the 24 patients who underwent multi-gene panel testing, all had pathogenic mutations and 21 (88%) had mutations in addition to or exclusive of BRAF, including 11 patients (46%) with telomerase reverse transcriptase promoter mutations. Checkpoint inhibitors (39%) and BRAF-MEK inhibitors (7%) were the most common first-line treatments. Upfront surgical resection was used for 25% of the MUP patients, and 12 of these resections were for curative intent. During a median follow-up period of 22.1 months, the median overall survival (OS) was not met for the patients with MUP isolated to lymph nodes. At 56.8 months, 75% of these patients were alive. The median OS was 37.4 months for skin/soft tissue MUP, 33.3 months for single solid organ viscera MUP, and 29.8 months for metastatic brain MUP.\n\n\nCONCLUSIONS\nMultigene panel testing identified pathogenic mutations in all tested MUP patients and frequently identified targets outside BRAF. Despite advanced stage, aggressive multimodal therapy for MUP can be associated with 5-year OS and should be pursued for appropriate candidates.",
"affiliations": "Division of Surgical Oncology, Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA.;Division of Surgical Oncology, Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA.;Division of Surgical Oncology, Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA.;Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA.;Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, USA.;Division of Surgical Oncology, Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA.;Division of Medical Oncology, Department of Medicine, City of Hope National Medical Center, Duarte, CA, USA.;Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA.;Division of Surgical Oncology, Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA. lmelstrom@coh.org.",
"authors": "De Andrade|James P|JP|;Wong|Paul|P|;O'Leary|Michael P|MP|;Parekh|Vishwas|V|;Amini|Arya|A|;Schoellhammer|Hans F|HF|;Margolin|Kim A|KA|;Afkhami|Michelle|M|;Melstrom|Laleh G|LG|http://orcid.org/0000-0001-6279-7981",
"chemical_list": "D048493:Proto-Oncogene Proteins B-raf",
"country": "United States",
"delete": false,
"doi": "10.1245/s10434-020-09112-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1068-9265",
"issue": "27(13)",
"journal": "Annals of surgical oncology",
"keywords": null,
"medline_ta": "Ann Surg Oncol",
"mesh_terms": "D005260:Female; D006801:Humans; D008198:Lymph Nodes; D008297:Male; D008545:Melanoma; D009154:Mutation; D009382:Neoplasms, Unknown Primary; D048493:Proto-Oncogene Proteins B-raf; D012189:Retrospective Studies; D012878:Skin Neoplasms",
"nlm_unique_id": "9420840",
"other_id": null,
"pages": "5240-5247",
"pmc": null,
"pmid": "32909128",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": "31912902;20570171;23890154;16568458;25265494;25399551;22460835;23031553;15714125;28052277;20482725;30481368;14080349;21721009;9210709;24276025;25440435;24802907",
"title": "Multidisciplinary Care for Melanoma of Unknown Primary: Experience in the Era of Molecular Profiling.",
"title_normalized": "multidisciplinary care for melanoma of unknown primary experience in the era of molecular profiling"
} | [
{
"companynumb": "US-AMGEN-USASP2021002523",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TALIMOGENE LAHERPAREPVEC"
},
"drugadditional":... |
{
"abstract": "A clinical case of successful procurement and transplantation of bilateral lungs from 6-week-old infant with sepsis secondary to bacterial meningitis is reported. Forty-one-day-old male infant (height 60 cm, weight 4 kg) died of cerebral edema secondary to Escherichia coli meningitis and bacteremia. Preretrieval assessment included the following: arterial gases; pO2 50.4 kPa (378 mm Hg), pCO2 4.9 kPa (37 mm Hg), on FiO2 100%, PEEP 5 cm H2 O. Fiberoptic bronchoscopy showed no secretions nor mucosal inflammation; CXR revealed clear lung fields and pleural spaces. Inspection revealed dense adhesions in pericardial cavity and purulent left hemithorax effusion (urgent Gram-stain came back as negative) but there was no consolidation in the lung. Good compliance of the lungs on inflation/deflation test was observed. The lungs were retrieved using the technique described. The recipient was a 4-month-old infant with alveolar capillary dysplasia and malaligned pulmonary veins. Implantation of the lungs was performed via bilateral thoracosternotomy on cardiopulmonary bypass, cooling to 30°C. Elective support with nitric oxide was used postoperatively. Two years after the transplantation, the recipient doing well with normal lung function. Lung procurement from a 6-week donor with infectious complications and prolonged ventilation is a challenging undertaking but can be successful and should be attempted whenever possible given the paucity of organs available for pediatric recipients.",
"affiliations": "Royal Papworth Hospital, Cambridge, UK.;Great Ormond Street Hospital, London, UK.;Great Ormond Street Hospital, London, UK.;Royal Papworth Hospital, Cambridge, UK.;Great Ormond Street Hospital, London, UK.;Royal Papworth Hospital, Cambridge, UK.;Royal Papworth Hospital, Cambridge, UK.",
"authors": "Pavlushkov|Evgeny|E|0000-0002-6928-1002;Muthialu|Nagarajan|N|0000-0002-0410-0776;Spencer|Helen|H|;Ellis|Clair|C|;Davies|Ben|B|;Claydon|Sarah|S|;Berman|Marius|M|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13419",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "23(4)",
"journal": "Pediatric transplantation",
"keywords": "pediatric lung transplantation",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D001999:Bronchoscopy; D004926:Escherichia coli; D005260:Female; D006801:Humans; D007223:Infant; D008168:Lung; D008171:Lung Diseases; D016040:Lung Transplantation; D008297:Male; D016920:Meningitis, Bacterial; D010547:Persistent Fetal Circulation Syndrome; D011650:Pulmonary Alveoli; D011667:Pulmonary Veins; D018805:Sepsis; D014019:Tissue Donors; D009927:Tissue and Organ Procurement",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e13419",
"pmc": null,
"pmid": "31012231",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Successful lung donation at the age of 6 weeks: Challenges and lessons learned.",
"title_normalized": "successful lung donation at the age of 6 weeks challenges and lessons learned"
} | [
{
"companynumb": "GB-ACTELION-A-CH2019-192406",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EPOPROSTENOL SODIUM"
},
"drugadditional": "... |
{
"abstract": "Infection due to prostate biopsy afflicted more than 5% of patients and is the most common reason for hospitalization. A large series from US SEER-Medicare reported that men undergoing biopsy were 2.26 times more likely to be hospitalized for infectious complications within 30 days compared with randomly selected controls. The factors predicting a higher susceptibility to infection remain largely unknown but some authors have higlighted in the etiopathogenesis the importance of the augmented prevalence of ciprofloxacin resistant variant of bacteria in the rectum flora. We present one case of sepsis after transrectal prostate biopsy in a patient with history of pancreatic surgery. Based on our experience patients candidated to prostate biopsy with transrectal technique with history of recent major surgery represent an high risk category for infective complication. Also major pancreatic surgery should be consider an high risk category for infection. A transperineal approach and preventive measures (such as rectal swab) should be adopted to reduce biopsy driven infection.",
"affiliations": "Division of Urology, \"Augusto Murri\" General Hospital, ASUR Marche, Fermo. guevarmaselli@katamail.com.",
"authors": "Maselli|Guevar|G|;Tucci|Giacomo|G|;Mazzaferro|Daniele|D|;Ettamimi|Asim|A|;Sbrollini|Giulia|G|;Cordari|Marco|M|;Donatelli|Gaetano|G|;Galosi|Andrea Benedetto|AB|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Italy",
"delete": false,
"doi": "10.4081/aiua.2014.4.387",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1124-3562",
"issue": "86(4)",
"journal": "Archivio italiano di urologia, andrologia : organo ufficiale [di] Societa italiana di ecografia urologica e nefrologica",
"keywords": null,
"medline_ta": "Arch Ital Urol Androl",
"mesh_terms": "D000900:Anti-Bacterial Agents; D001706:Biopsy; D024881:Drug Resistance, Bacterial; D004927:Escherichia coli Infections; D006801:Humans; D008297:Male; D008875:Middle Aged; D010180:Pancreatectomy; D011183:Postoperative Complications; D011467:Prostate; D012007:Rectum; D018570:Risk Assessment; D013997:Time Factors",
"nlm_unique_id": "9308247",
"other_id": null,
"pages": "387-8",
"pmc": null,
"pmid": "25641478",
"pubdate": "2014-12-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Prolonged antibiotic therapy increases risk of infection after transrectal prostate biopsy: a case report after pancreasectomy and review of the literature.",
"title_normalized": "prolonged antibiotic therapy increases risk of infection after transrectal prostate biopsy a case report after pancreasectomy and review of the literature"
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"abstract": "BACKGROUND\nIncreasing antimicrobial resistance among pathogens causing complicated intra-abdominal infections (cIAIs) supports the development of new antimicrobials. Ceftolozane/tazobactam, a novel antimicrobial therapy, is active against multidrug-resistant Pseudomonas aeruginosa and most extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae.\n\n\nMETHODS\nASPECT-cIAI (Assessment of the Safety Profile and Efficacy of Ceftolozane/Tazobactam in Complicated Intra-abdominal Infections) was a prospective, randomized, double-blind trial. Hospitalized patients with cIAI received either ceftolozane/tazobactam (1.5 g) plus metronidazole (500 mg) every 8 hours or meropenem (1 g) every 8 hours intravenously for 4-14 days. The prospectively defined objectives were to demonstrate statistical noninferiority in clinical cure rates at the test-of-cure visit (24-32 days from start of therapy) in the microbiological intent-to-treat (primary) and microbiologically evaluable (secondary) populations using a noninferiority margin of 10%. Microbiological outcomes and safety were also evaluated.\n\n\nRESULTS\nCeftolozane/tazobactam plus metronidazole was noninferior to meropenem in the primary (83.0% [323/389] vs 87.3% [364/417]; weighted difference, -4.2%; 95% confidence interval [CI], -8.91 to .54) and secondary (94.2% [259/275] vs 94.7% [304/321]; weighted difference, -1.0%; 95% CI, -4.52 to 2.59) endpoints, meeting the prespecified noninferiority margin. In patients with ESBL-producing Enterobacteriaceae, clinical cure rates were 95.8% (23/24) and 88.5% (23/26) in the ceftolozane/tazobactam plus metronidazole and meropenem groups, respectively, and 100% (13/13) and 72.7% (8/11) in patients with CTX-M-14/15 ESBLs. The frequency of adverse events (AEs) was similar in both treatment groups (44.0% vs 42.7%); the most common AEs in either group were nausea and diarrhea.\n\n\nCONCLUSIONS\nTreatment with ceftolozane/tazobactam plus metronidazole was noninferior to meropenem in adult patients with cIAI, including infections caused by multidrug-resistant pathogens.\n\n\nBACKGROUND\nNCT01445665 and NCT01445678.",
"affiliations": "Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio.;Cubist Pharmaceuticals, Lexington, Massachusetts.;Cubist Pharmaceuticals, Lexington, Massachusetts.;Cubist Pharmaceuticals, Lexington, Massachusetts.;Cubist Pharmaceuticals, Lexington, Massachusetts.;Cubist Pharmaceuticals, Lexington, Massachusetts.;Cubist Pharmaceuticals, Lexington, Massachusetts.;Cubist Pharmaceuticals, Lexington, Massachusetts.;Cubist Pharmaceuticals, Lexington, Massachusetts.;Departments of Surgery and Medicine, Weill Cornell Medical College, New York, New York.;Department of General, Visceral and Thoracic Surgery, Academic Hospital of Medical University Hannover, Peine, Germany.",
"authors": "Solomkin|Joseph|J|;Hershberger|Ellie|E|;Miller|Benjamin|B|;Popejoy|Myra|M|;Friedland|Ian|I|;Steenbergen|Judith|J|;Yoon|Minjung|M|;Collins|Sylva|S|;Yuan|Guojun|G|;Barie|Philip S|PS|;Eckmann|Christian|C|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002511:Cephalosporins; C000594038:ceftolozane, tazobactam drug combination; D008795:Metronidazole; D010397:Penicillanic Acid; D000078142:Tazobactam",
"country": "United States",
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"doi": "10.1093/cid/civ097",
"fulltext": "\n==== Front\nClin Infect DisClin. Infect. DiscidcidClinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America1058-48381537-6591Oxford University Press 10.1093/cid/civ097civ097Articles and CommentariesCeftolozane/Tazobactam Plus Metronidazole for Complicated Intra-abdominal Infections in an Era of Multidrug Resistance: Results From a Randomized, Double-Blind, Phase 3 Trial (ASPECT-cIAI) Solomkin Joseph 1Hershberger Ellie 2Miller Benjamin 2Popejoy Myra 2Friedland Ian 2aSteenbergen Judith 2Yoon Minjung 2Collins Sylva 2Yuan Guojun 2Barie Philip S. 3Eckmann Christian 41 Department of Surgery, University of Cincinnati College of Medicine, Cincinnati,Ohio2 Cubist Pharmaceuticals, Lexington, Massachusetts3 Departments of Surgery and Medicine, Weill Cornell Medical College, New York, New York4 Department of General, Visceral and Thoracic Surgery, Academic Hospital of Medical University Hannover, Peine, Germanya Present affiliation: Achaogen Inc., South San Francisco, California.\n\nCorrespondence: Joseph Solomkin, MD, Department of Surgery, University of Cincinnati College of Medicine, 6005 Given Rd, Cincinnati, Ohio 45243 (solomkjs@ucmail.uc.edu).15 5 2015 10 2 2015 10 2 2015 60 10 1462 1471 2 10 2014 1 2 2015 © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.2015This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.This phase 3 trial compared ceftolozane/tazobactam plus metronidazole vs meropenem for the treatment of complicated intra-abdominal infections. Ceftolozane/tazobactam plus metronidazole was noninferior to meropenem. High rates of presumed microbiological eradication of Enterobacteriaceae and Pseudomonas aeruginosa were found with both regimens.\n\nBackground. Increasing antimicrobial resistance among pathogens causing complicated intra-abdominal infections (cIAIs) supports the development of new antimicrobials. Ceftolozane/tazobactam, a novel antimicrobial therapy, is active against multidrug-resistant Pseudomonas aeruginosa and most extended-spectrum β-lactamase (ESBL)–producing Enterobacteriaceae.\n\nMethods. ASPECT-cIAI (Assessment of the Safety Profile and Efficacy of Ceftolozane/Tazobactam in Complicated Intra-abdominal Infections) was a prospective, randomized, double-blind trial. Hospitalized patients with cIAI received either ceftolozane/tazobactam (1.5 g) plus metronidazole (500 mg) every 8 hours or meropenem (1 g) every 8 hours intravenously for 4–14 days. The prospectively defined objectives were to demonstrate statistical noninferiority in clinical cure rates at the test-of-cure visit (24–32 days from start of therapy) in the microbiological intent-to-treat (primary) and microbiologically evaluable (secondary) populations using a noninferiority margin of 10%. Microbiological outcomes and safety were also evaluated.\n\nResults. Ceftolozane/tazobactam plus metronidazole was noninferior to meropenem in the primary (83.0% [323/389] vs 87.3% [364/417]; weighted difference, −4.2%; 95% confidence interval [CI], −8.91 to .54) and secondary (94.2% [259/275] vs 94.7% [304/321]; weighted difference, −1.0%; 95% CI, −4.52 to 2.59) endpoints, meeting the prespecified noninferiority margin. In patients with ESBL-producing Enterobacteriaceae, clinical cure rates were 95.8% (23/24) and 88.5% (23/26) in the ceftolozane/tazobactam plus metronidazole and meropenem groups, respectively, and 100% (13/13) and 72.7% (8/11) in patients with CTX-M-14/15 ESBLs. The frequency of adverse events (AEs) was similar in both treatment groups (44.0% vs 42.7%); the most common AEs in either group were nausea and diarrhea.\n\nConclusions. Treatment with ceftolozane/tazobactam plus metronidazole was noninferior to meropenem in adult patients with cIAI, including infections caused by multidrug-resistant pathogens.\n\nClinical Trials Registration. NCT01445665 and NCT01445678.\n\ncomplicated intra-abdominal infectionceftolozane/tazobactammultidrug resistancegram-negative bacteriaEnterobacteriaceae\n==== Body\nComplicated intra-abdominal infections (cIAIs) are tissue-invasive infections leading to abscess formation or generalized peritonitis. The management of cIAIs involves operative or percutaneous intervention to obtain surgical control of the source. Nonetheless, patients with cIAIs are at risk of sepsis and mortality [1–4].\n\nEmpiric antimicrobial therapy with appropriate agents is an important component of treatment [5, 6]. Initial empiric therapy that is not effective against infecting pathogens increases costs, treatment failure, and death [7–10]. Because of this, cIAIs are an important infection category for evaluation of the efficacy of investigational agents.\n\nThe well-recognized appearance of antimicrobial resistance among gram-negative bacteria has stimulated the development of novel agents [11], particularly those targeting Enterobacteriaceae that produce extended-spectrum β-lactamases (ESBLs) [12], which confer resistance to most β-lactam antimicrobial agents [1].\n\nCeftolozane/tazobactam consists of a novel cephalosporin and an established β-lactamase inhibitor that is being developed to address antimicrobial resistance in serious infections caused by gram-negative pathogens, including cIAI, complicated urinary tract infection/pyelonephritis (cUTI), and ventilated nosocomial pneumonia. In vitro activity of ceftolozane/tazobactam has been confirmed against ESBL-producing Enterobacteriaceae, drug-resistant Pseudomonas aeruginosa [13–16], and some Streptococcus species [17]. The results from a phase 2 study with ceftolozane/tazobactam in combination with metronidazole in cIAI supported further development for this indication [18].\n\nWe now report the results from ASPECT-cIAI (Assessment of the Safety Profile and Efficacy of Ceftolozane/Tazobactam in Complicated Intra-abdominal Infections), a large global phase 3 clinical program that evaluated intravenous ceftolozane/tazobactam plus metronidazole vs meropenem for the treatment of hospitalized adult patients with cIAI.\n\nPATIENTS AND METHODS\nStudy Design\nTwo identical multicenter, prospective, randomized, double-blind, placebo-controlled trials were initiated in December 2011 at 196 study centers worldwide (ClinicalTrials.gov identifiers NCT01445665 and NCT01445678).\n\nThe trials were designed in compliance with current clinical guidelines and the regulatory requirements of the US Food and Drug Administration (FDA) and the European Medicines Agency, approved by local institutional review boards, and conducted in accordance with the International Conference on Harmonisation/Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. All patients were required to provide written informed consent prior to participation. In 2012, the FDA released a draft guidance providing for a single study pathway for approval of antibiotics in cUTI and cIAI [19]. The sponsor sought and received prospective permission from the relevant regulatory agencies to pool the data from the 2 protocols upon completion to form a single dataset for analysis. Enrollment in the 2 protocols was completed in September 2013, and data were pooled after database lock in each study.\n\nInclusion Criteria\nPatients were to be ≥18 years of age, with clinical evidence of cIAI. Operative or percutaneous drainage of an infectious focus was either planned or had been performed recently (within 24 hours), confirming the presence of cIAI.\n\nExclusion Criteria\nThe following exclusions applied: cIAI managed by staged abdominal repair in which the fascia was not closed; low likelihood of adequate source control at surgery; creatinine clearance <30 mL/minute; or use of systemic antimicrobial therapy for IAI for >24 hours prior to the first dose of study drug (unless this treatment failed, defined by the need for additional intervention and persistent signs of ongoing infection with a positive culture of intra-abdominal abscess or peritonitis fluid, despite >48 hours of prior antimicrobial therapy).\n\nRandomization and Treatment\nRandomization numbers were computer-generated. Patients were assigned (1:1) by the study site's pharmacist to intravenous ceftolozane/tazobactam 1.5 g (containing 1 g ceftolozane and 500 mg tazobactam) plus metronidazole (500 mg every 8 hours) or intravenous meropenem (1 g every 8 hours) plus placebo for 4–10 days. Treatment could be continued for up to 14 days in patients who had 1 of the following: multiple abscesses; non-appendix-related diffuse peritonitis, failure of prior antimicrobial therapy, or hospital-acquired infection. The dose of ceftolozane/tazobactam was based on data from previous clinical studies [18, 20]. The comparator, meropenem, is recommended by the Surgical Infection Society and the Infectious Diseases Society of America as appropriate first-line empiric therapy for high-risk and severe cIAI, and is prescribed commonly for this indication [5, 6]. In patients with moderate renal impairment (creatinine clearance, 30–50 mL/minute), the ceftolozane/tazobactam dose was reduced to 750 mg every 8 hours and the meropenem dose to 1 g every 12 hours. Placebo saline infusions were used to maintain blinding. Drug assignment was concealed from the patient and all clinical and study staff.\n\nAssessments\nAt baseline, intra-abdominal specimens were collected from aspirates (collected with a needle or a syringe) for culture of aerobes and anaerobes. Samples were inoculated into aerobic and anaerobic culture bottles, incubated at 35°C–37°C, and transferred to the microbiology laboratory. Signs and symptoms of the index infection were recorded daily. Blood samples for culture were drawn in patients with hospital-acquired infections, those who had failed prior antimicrobial therapy, and those with signs of severe sepsis [21]. Other baseline assessments included measurement of disease severity, as determined by the Acute Physiology and Chronic Health Evaluation (APACHE) II score; measurements of hematology, chemistry, and coagulation; urinalysis; and estimation of creatinine clearance.\n\nOutcome Assessment\nClinical outcomes were assessed at the end of therapy (within 24 hours of last dose of treatment), the test-of-cure (TOC) visit (24–32 days after start of therapy), and the late follow-up visit (38–45 days after start of therapy). Clinical cure was defined as complete resolution or significant improvement in signs and symptoms of the index infection, such that no additional antimicrobials or interventions were required. Events defining clinical failure included death due to cIAI prior to the TOC visit, persisting or recurrent infection requiring additional intervention, treatment with additional antimicrobials for ongoing symptoms of IAI, and/or surgical site infection [22]. An indeterminate response was recorded when trial data were not available for evaluation of efficacy for any reason, including death unrelated to the index infection, or in extenuating circumstances that precluded classification as cure or failure. Analysis populations are defined in Supplementary Table 1. Patients with missing clinical outcome data or indeterminate responses were considered to have failed treatment in the intent-to-treat (ITT) and microbiological ITT (MITT) analyses, but were excluded from the per-protocol (clinically evaluable [CE] and microbiologically evaluable [ME]) analyses.\n\nPathogen susceptibility to ceftolozane/tazobactam was defined as a minimum inhibitory concentration (MIC) ≤8 mg/L, intermediate as an MIC of 16 mg/L, and resistant as an MIC ≥32 mg/L. MIC cutoffs for determination of susceptibility to meropenem were based on Clinical Laboratory Standards Institute (CLSI) definitions. Enterobacteriaceae susceptibility was defined as MIC ≤1 mg/L, intermediate as MIC 2 mg/L, and resistant as MIC ≥4 mg/L. For P. aeruginosa, the MIC cutoffs were ≤2 mg/L, 4 mg/L, and ≥8 mg/L, respectively [23]. Multidrug resistance in P. aeruginosa was based on the CLSI breakpoints and was defined as resistance or nonsusceptibility to ≥3 drug classes that are known to be active against P. aeruginosa. Enterobacteriaceae organisms with an ESBL phenotype (predefined criteria: MIC ≥2 mg/L for any cephalosporin, ≥3 dilution change in MIC when an antibiotic was combined with a β-lactamase inhibitor) identified prior to database lock were characterized by JMI Laboratories (North Liberty, Iowa) using a commercial MicroArray System Check-MDR CT101 kit (Check-points, Wageningen, the Netherlands). Safety was assessed by review of adverse events (AEs), vital signs, physical examination findings, and clinical laboratory results.\n\nSource Control Review\nAll patients with a baseline pathogen and an investigator-assigned outcome of failure, and those with an outcome of clinical cure who underwent a second procedure, were reviewed by an independent blinded surgical review panel comprising 3 surgeons and 2 radiologists. Source control was considered adequate when the physical and mechanical measures were consistent with current local standards of practice to eliminate the source of infection, control ongoing contamination, and restore gastrointestinal function [24]. Patients who were considered to have had inadequate source control were excluded from the per-protocol analyses.\n\nStatistical Analysis\nPrior to completion of the studies, statistical analyses were planned based on pooled data from the 2 trials. The planned pooled sample size ensured a minimum of 90% power to demonstrate the noninferiority of ceftolozane/tazobactam plus metronidazole to meropenem at a 10% noninferiority margin at a 1-sided significance level of 0.025. These calculations also assumed that 80% of randomized patients would meet the criteria to be included in the MITT population and that the clinical cure rate in both arms would be 75%.\n\nThe noninferiority hypothesis was tested through a 2-sided 95% confidence interval (CI) approach. The weighted difference in cure rates and the 95% CI around the difference in cure rates between study treatments were calculated using a stratified Newcombe CI with minimum risk weights [25, 26]. If the lower bound of the 95% CI for the difference (ceftolozane/tazobactam plus metronidazole minus meropenem) was above −10 percentage points, noninferiority was claimed.\n\nOther secondary endpoints of clinical cure in the ITT and CE populations, various ME population subgroups, and per-baseline pathogen in the ME population were analyzed using a 95% CI calculated by the Wilson score methodology. Safety and tolerability of ceftolozane/tazobactam plus metronidazole were also evaluated. Statistical analyses were performed using SAS version 9.1.3 or higher (SAS Institute, Cary, North Carolina).\n\nRESULTS\nPatient Disposition and Baseline Characteristics\nIn total, 993 patients were randomized to ceftolozane/tazobactam plus metronidazole (n = 487) or meropenem (n = 506), and 806 (81.2%) qualified for the MITT population (Figure 1). Approximately 50% of patients in each treatment group received therapy for up to 7 days, and an additional 36.5% received treatment for up to 10 days. The mean duration of treatment for patients who were eligible to continue therapy beyond 10 days is shown in Table 1.\nTable 1. Duration of Therapy for Patients Who Were Eligible for Extension of Treatment Beyond 10 Days (Microbiological Intent-to-Treat Population)\n\nDiagnosis\tMean Duration of Therapy, d\tMin–Max, d\t\nMultiple abscess (n = 64)\t9.6\t2–15\t\nDiffuse peritonitis, nonappendix (n = 149)\t8.6\t2–15\t\nFailed prior therapy, nonappendix (n = 42)\t9.3\t2–15\t\nLocalized complicated appendicitis (n = 254)a\t7.0\t2–15\t\na Patients were not eligible for extension of treatment beyond 10 days.\n\n\nFigure 1. Patient disposition in ASPECT-cIAI (Assessment of the Safety Profile and Efficacy of Ceftolozane/Tazobactam in Complicated Intra-abdominal Infections). aPatients could be excluded for more than one reason. Abbreviations: BIP, baseline infecting pathogen; CE, clinically evaluable; MITT, microbiological ITT.\n\n\n\nThe majority of participants were from Europe (76.9%), followed by South America (10.5%), North America (7.6%), and other geographic regions (5.0%). A list of participating investigators and their sites is provided in the Supplementary Data. Baseline demographic characteristics were similar between treatment groups (Table 2). The most common origin of infection was the appendix, and the most common diagnosis was appendiceal perforation or abscess (Table 3).\nTable 2. Baseline Demographics (Microbiological Intent-to-Treat Population)\n\nCharacteristic\tCeftolozane/Tazobactam Plus Metronidazole (n = 389)\tMeropenem (n = 417)\t\nSex, male, No. (%)\t218 (56.0)\t248 (59.5)\t\nRace, white, No. (%)\t367 (94.3)\t388 (93.0)\t\nAge, y\t\t\t\n Mean (SD)\t50.8 (18.3)\t50.4 (16.9)\t\n 18–64, No. (%)\t289 (74.3)\t332 (79.6)\t\n 65–74, No. (%)\t54 (13.9)\t48 (11.5)\t\n ≥75, No. (%)\t46 (11.8)\t37 (8.9)\t\nBody mass index, kg/m2, mean (SD)\t26.76 (5.5)\t27.07 (5.3)\t\nBaseline APACHE II score, No. (%)a\t\n Mean (SD)\t6.2 (4.2)\t6.0 (4.1)\t\n 0–5\t191 (49.2)\t213 (51.1)\t\n 6–10\t143 (36.9)\t153 (36.7)\t\n 11–15\t42 (10.8)\t38 (9.1)\t\n >15\t12 (3.1)\t13 (3.1)\t\nPresence of bacteremia\t8 (2.1)\t12 (2.9)\t\nCreatinine clearance, No. (%)\t\n Mild renal impairment (50 to 79 mL/min)\t98 (25.2)\t109 (26.1)\t\n Moderate renal impairment (30–49 mL/min)\t23 (5.9)\t13 (3.1)\t\n Severe renal impairment (<30 mL/min)\t0\t0\t\nAbbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; SD, standard deviation.\n\na Data missing in 1 patient.\n\n\nTable 3. Site of Infections, Diagnoses, Disease Characteristics, and Source Control Procedures (Microbiological Intent-to-Treat Population)\n\nCharacteristic\tCeftolozane/Tazobactam Plus Metronidazole (n = 389)\tMeropenem (n = 417)\t\nOrigin of current infection, No. (%)a\t\n Appendix\t179 (46.0)\t205 (49.2)\t\n Biliary–cholecystitis\t73 (18.8)\t69 (16.5)\t\n Colon\t56 (14.4)\t62 (14.9)\t\n Stomach/duodenum\t40 (10.3)\t39 (9.4)\t\n Small bowel\t23 (5.9)\t19 (4.6)\t\n Parenchymal (liver)\t16 (4.1)\t17 (4.1)\t\n Parenchymal (spleen)\t2 (0.5)\t2 (0.5)\t\n Biliary–cholangitis\t1 (0.3)\t0\t\nDiagnosis, No. (%)b\t\n Appendiceal perforation or abscess\t175 (45.0)\t203 (48.7)\t\n Cholecystitis with rupture, perforation, or progression of infection\t72 (18.5)\t69 (16.5)\t\n Peritonitis due to other perforated viscus or following a prior operative procedure\t41 (10.5)\t33 (7.9)\t\n Acute gastric or duodenal perforation\t38 (9.8)\t33 (7.9)\t\n Diverticular disease with perforation or abscess\t29 (7.5)\t36 (8.6)\t\n Other IAI abscess (including liver and spleen)\t29 (7.5)\t36 (8.6)\t\n Traumatic intestinal perforation\t5 (1.3)\t7 (1.7)\t\nAbscess present, No. (%)\t219 (56.3)\t240 (57.6)\t\n Multiple abscessesc\t33 (15.1)\t32 (13.3)\t\nPeritonitis present, No. (%)\t337 (86.6)\t340 (81.5)\t\n Locald\t198 (58.8)\t203 (59.7)\t\n Diffused\t139 (41.2)\t137 (40.3)\t\nLocalized complicated appendicitis, No. (%)\t115 (29.6)\t142 (34.1)\t\nEtiological mechanism, No. (%)\t\n Postoperative infection\t27 (6.9)\t28 (6.7)\t\n Trauma\t4 (1.0)\t8 (1.9)\t\n Spontaneous rupture\t277 (71.2)\t302 (72.4)\t\n Malignancy\t11 (2.8)\t13 (3.1)\t\n Other\t70 (18.0)\t66 (15.8)\t\nProcedure type, No. (%)e\t\n Laparotomy\t274 (70.4)\t272 (65.2)\t\n Laparoscopy\t86 (22.1)\t105 (25.2)\t\n Percutaneous aspiration\t24 (6.2)\t37 (8.9)\t\n Otherf\t5 (1.3)\t4 (1.0)\t\nPercentages are calculated as 100 × (no./No.), except where indicated by a footnote.\n\nAbbreviation: IAI, intra-abdominal infection.\n\na Investigator could choose >1 site; totals are not mutually exclusive.\n\nb Investigator could chose only 1 diagnosis.\n\nc Percentages are calculated 100 × (no./No. of patients with abscess present).\n\nd Percentages are calculated 100 × (no./No. of patients with peritonitis present).\n\ne Patients could have multiple procedure types.\n\nf Other procedures included appendectomy and esophagogastroduodenoscopy.\n\n\n\nPathogens at Baseline\nThe incidence and distribution of baseline pathogens were similar between the treatment groups. The most common gram-negative aerobes isolated at baseline from intra-abdominal specimens in the MITT population were Escherichia coli (525/806 [65.1%]), Klebsiella pneumoniae (76/806 [9.4%]), and P. aeruginosa (72/806 [8.9%]). The majority of infections were polymicrobial (257/389 [66.1%] and 288/417 [69.1%] patients in the ceftolozane/tazobactam plus metronidazole and meropenem treatment groups, respectively). There were 29 ESBL-producing Enterobacteriaceae isolated in each treatment group, an overall rate of 7.2% (58/806). Of 52 individual P. aeruginosa isolates for which MIC data were available, 3 (5.8%) isolates were resistant to ≥3 drug classes known to be active against P. aeruginosa, and 6 (11.5%) were nonsusceptible to ≥3 antipseudomonal drug classes.\n\nThe MIC required to inhibit the growth of 90% (MIC90) of Enterobacteriaceae was 1 mg/L for ceftolozane/tazobactam and 0.063 mg/L for meropenem. For P. aeruginosa, the MIC90 values for each study drug were 1 mg/L and 2 mg/L, respectively. Susceptibility rates to ceftolozane/tazobactam and meropenem were 97.4% and 99.9% for Enterobacteriaceae and 98.6% and 89.9% for P. aeruginosa, respectively.\n\nSource Control Review Panel Findings\nThe surgical review panel reviewed 73 patients. Twenty-four patients (12 in each treatment group) were considered to have had inadequate source control and were excluded from the CE and ME populations. Of the 9 patients who were considered to have obtained clinical cure by the investigator but required a second procedure, the surgical review panel changed 2 patients' outcomes (1 per treatment arm) from cure to failure because of evidence of ongoing infection at the time of the second intervention.\n\nEfficacy Analysis\nFor the primary endpoint, clinical cure rates were 83.0% (323/389) with ceftolozane/tazobactam plus metronidazole and 87.3% (364/417) with meropenem in the MITT population at the TOC visit, which occurred at a median of 27 days (interquartile range, 26–28 days) after the TOC visit. The weighted difference in clinical cure rates (ceftolozane/tazobactam plus metronidazole minus meropenem) was −4.2% with a 2-sided 95% CI of −8.91% to .54%, thus meeting the statistical criteria for noninferiority. Statistical noninferiority was also demonstrated for the ME population, where clinical cure rates were 94.2% and 94.7% (weighted difference, −1.0; 95% CI, −4.52 to 2.59) at the TOC visit (Figure 2). Clinical cure rates in the ITT population at TOC were 83.6% for ceftolozane/tazobactam plus metronidazole and 86.2% for meropenem (difference, −2.6; 95% CI, −7.08 to 1.87), similar to those observed in the MITT population. In the CE population, cure rates were 94.1% and 94.0%, respectively (difference, 0.1; 95% CI, −3.30 to 3.55). At the end of therapy, clinical cure rates in the MITT population were higher in both treatment groups: 89.2% for ceftolozane/tazobactam plus metronidazole and 92.3% for meropenem (difference, −3.1; 95% CI, −7.23 to .89).\nFigure 2. Primary and secondary analysis endpoints at the test-of-cure visit. In the microbiological intent-to-treat (MITT) population, a treatment failure approach was used, where indeterminate clinical responses were imputed as failures. In the microbiologically evaluable (ME) population, a data-as-observed approach was used, where indeterminate clinical responses were excluded from the analysis. Abbreviations: CI, confidence interval; NI, noninferiority margin.\n\n\n\nIn both treatment groups, 8.2% of patients in the MITT populations failed treatment at the TOC visit (Figure 2). The most common reasons for failure were persisting or recurrent abdominal infection requiring an additional intervention (2.8% of failures in the ceftolozane/tazobactam plus metronidazole group and 3.6% in the meropenem group) and the requirement for additional antibiotics for ongoing cIAI (3.3% and 2.6%, respectively, for each treatment group). Other reasons for failure were postsurgical wound infection and death due to cIAI.\n\nClinical outcomes in the subgroup analyses were generally consistent with the primary and secondary analyses, with no meaningful differences recorded between treatments. Clinical cure rates with both treatments were generally lower in high-risk patients (elderly patients and those with higher APACHE II scores, moderate renal impairment, or small bowel and colon infections) vs the overall ME population (Table 4).\nTable 4. Subgroup Analysis of Clinical Cure at the Test-of-Cure Visit (Microbiologically Evaluable Population)\n\nClinical Cure \nno./No. (%)\tCeftolozane/Tazobactam Plus Metronidazole (n = 275)\tMeropenem (n = 321)\tPercentage Difference (95% CI)\t\nSex\t\n Male\t147/157 (93.6)\t182/189 (96.3)\t−2.7 (−7.97 to 2.05)\t\n Female\t112/118 (94.9)\t122/132 (92.4)\t2.5 (−4.04 to 8.91)\t\nAge, y\t\n 18–64\t206/214 (96.3)\t249/262 (95.0)\t1.2 (−2.80 to 5.03)\t\n 65–74\t30/35 (85.7)\t36/38 (94.7)\t−9.0 (−24.59 to 5.43)\t\n ≥75\t23/26 (88.5)\t19/21 (90.5)\t−2.0 (−20.76 to 18.79)\t\nRegion\t\n Eastern Europe\t213/221 (96.4)\t239/247 (96.8)\t−0.4 (−4.10 to 3.12)\t\n Western Europe\t2/5 (40.0)\t7/11 (63.6)\t−23.6 (−58.95 to 22.86)\t\n North America\t8/11 (72.7)\t10/11 (90.9)\t−18.2 (−48.41 to 15.40)\t\n South America\t28/28 (100)\t40/42 (95.2)\t4.8 (−7.78 to 15.79)\t\n Rest of world\t8/10 (80.0)\t8/10 (80.0)\t0 (−34.14 to 34.14)\t\nAPACHE II score\t\n <10\t213/222 (95.9)\t262/274 (95.6)\t0.3 (−3.61 to 3.98)\t\n ≥10\t45/52 (86.5)\t42/47 (89.4)\t−2.8 (−16.08 to 10.92)\t\nBaseline CrCl, mL/min\t\n <50\t8/11 (72.7)\t5/7 (71.4)\t1.3 (−34.37 to 40.92)\t\n ≥50\t251/264 (95.1)\t299/314 (95.2)\t−0.1 (−3.95 to 3.43)\t\nPrior antibiotic use\t\n Yes\t133/145 (91.7)\t163/177 (92.1)\t−0.4 (−6.81 to 5.69)\t\n No\t126/130 (96.9)\t141/144 (97.9)\t−1.0 (−5.76 to 3.30)\t\nPrimary site of infection\t\n Bowel (small or large)\t35/43 (81.4)\t51/57 (89.5)\t−8.1 (−23.17 to 5.74)\t\n Other site of IAI\t224/232 (96.6)\t253/264 (95.8)\t0.7 (−2.97 to 4.28)\t\nAnatomic site of infection\t\n Appendix\t136/141 (96.5)\t172/179 (96.1)\t0.4 (−4.55 to 4.79)\t\n Nonappendix\t123/134 (91.8)\t132/142 (93.0)\t−1.2 (−7.86 to 5.33)\t\n Biliary–cholangitis\t1/1 (100)\t0/0\tNC\t\n Biliary–cholecystitis\t49/50 (98.0)\t43/46 (93.5)\t4.5 (−4.99 to 15.63)\t\n Colon\t25/31 (80.6)\t39/42 (92.9)\t−12.2 (−29.77 to 3.41)\t\n Parenchymal (liver)\t9/10 (90.0)\t8/8 (100)\t−10.0 (−40.42 to 23.46)\t\n Parenchymal (spleen)\t2/2 (100)\t1/1 (100)\t0 (−65.76 to 79.35)\t\n Small bowel\t11/13 (84.6)\t12/15 (80.0)\t4.6 (−25.20 to 32.12)\t\n Stomach/duodenum\t28/30 (93.3)\t26/26 (100)\t−6.7 (−21.32 to 7.08)\t\n Other\t5/5 (100)\t5/6 (83.3)\t16.7 (−28.88 to 56.35)\t\nPeritonitis type\t\n Localized\t126/132 (95.5)\t152/161 (94.4)\t1.0 (−4.62 to 6.34)\t\n Diffuse\t98/104 (94.2)\t108/114 (94.7)\t−0.5 (−7.37 to 6.02)\t\nNo. of abscesses\t\n Single\t116/124 (93.5)\t146/152 (96.1)\t−2.5 (−8.65 to 2.90)\t\n Multiple\t22/25 (88.0)\t23/25 (92.0)\t−4.0 (−22.86 to 14.69)\t\nProcedure type\t\n Percutaneous aspiration\t14/14 (100)\t23/23 (100)\t0 (−21.53 to 14.31)\t\n Laparoscopy\t63/66 (95.5)\t73/81 (90.1)\t5.3 (−3.98 to 14.27)\t\n Laparotomy\t181/193 (93.8)\t207/217 (95.4)\t−1.6 (−6.42 to 2.90)\t\nRegions are defined as follows: Eastern Europe (Bulgaria, Croatia, Estonia, Georgia, Hungary, Latvia, Lithuania, Poland, Republic of Moldova, Romania, Russia, Serbia, Slovakia, Ukraine); Western Europe (Belgium, Germany, Spain); North America (Mexico, United States); South America (Argentina, Brazil, Chile, Colombia, Peru); and rest of world (Australia, Israel, South Africa, South Korea).\n\nAbbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; CI, confidence interval; CrCl, creatinine clearance; IAI, intra-abdominal infection; NC, not calculated.\n\n\n\nPer-pathogen clinical cure rates were similar between groups (Supplementary Table 2). In all patients with ESBL-producing Enterobacteriaceae, the clinical cure rate was 95.8% (23/24) in the ceftolozane/tazobactam plus metronidazole group and 88.5% (23/26) in the meropenem group (Supplementary Figure). In patients with CTX-M-14/15 ESBL-producing Enterobacteriaceae, clinical cure was observed in 13 of 13 (100%) and 8 of 11 (72.7%) patients, respectively.\n\nSafety\nThe incidence of AEs that developed during treatment was similar between the ceftolozane/tazobactam plus metronidazole group and the meropenem group (44.0% and 42.7%, respectively), and most events were mild to moderate in severity. The AEs occurring in ≥2% of patients in either treatment group are shown in Table 5. The most common laboratory AEs were increased alanine aminotransferase and aspartate aminotransferase, which occurred in 2.5% and 1.6% of all patients, respectively. Drug-related AEs leading to discontinuation were few, occurring in 3 patients (0.6%) in the ceftolozane/tazobactam plus metronidazole group and 4 patients (0.8%) in the meropenem group.\nTable 5. Adverse Events Occurring in ≥2% of Patients in Either Treatment Group (Safety Population)\n\nAdverse Event\nNo. (%)\tCeftolozane/Tazobactam Plus Metronidazole (n = 482)\tMeropenem (n = 497)\t\nAny adverse event\t212 (44.0)\t212 (42.7)\t\nNausea\t38 (7.9)\t29 (5.8)\t\nDiarrhea\t30 (6.2)\t25 (5.0)\t\nVomiting\t16 (3.3)\t20 (4.0)\t\nPyrexia\t25 (5.2)\t20 (4.0)\t\nHypokalemia\t14 (2.9)\t8 (1.6)\t\nInsomnia\t17 (3.5)\t11 (2.2)\t\nHeadache\t12 (2.5)\t9 (1.8)\t\nAnemia, postoperative\t10 (2.1)\t8 (1.6)\t\nHypertension\t9 (1.9)\t10 (2.0)\t\n\n\nSerious AEs occurred in 39 of 482 (8.1%) and 36 of 497 (7.2%) patients in the ceftolozane/tazobactam plus metronidazole and meropenem groups, respectively. Drug-related serious AEs occurred in 1 patient in each treatment group (both Clostridium difficile infection).\n\nThere were 11 deaths (2.3%) in the ceftolozane/tazobactam plus metronidazole group and 8 deaths (1.6%) in the meropenem group; no death was considered by the investigators to be related to study treatment.\n\nDISCUSSION\nThe increasing prevalence of multidrug-resistant, gram-negative organisms in serious infections is an important concern, and has led to the development of new therapeutic agents [19, 27, 28]. In this trial, the efficacy and safety of the novel antimicrobial agent ceftolozane/tazobactam were evaluated in patients with mostly community-acquired cIAIs. One-fifth of patients were aged ≥65 years, one-third had renal impairment, >80% had peritonitis, and the most frequent site of infection was the appendix. These factors attest to the high degree of illness severity in the patients who were enrolled in this trial. Although the microbiology of infecting pathogens was similar to that observed in other phase 3 studies in this indication [29–32], the overall rate of infection with ESBL-positive isolates (7.2%) was higher than in previous observations [29, 30]. The key finding from this study was that intravenous ceftolozane/tazobactam (1.5 g) plus metronidazole (500 mg) every 8 hours was noninferior to the comparator treatment, intravenous meropenem (1 g) every 8 hours, when administered for 4–14 days for the treatment of cIAIs.\n\nCeftolozane/tazobactam plus metronidazole demonstrated high clinical cure rates in patients infected with the common cIAI pathogens including E. coli, K. pneumoniae, P. aeruginosa, Enterobacter cloacae, and Klebsiella\noxytoca, as well as Streptococcus anginosus, Streptococcus constellatus, and Streptococcus salivarius.\n\nAs with other cephalosporins [31, 33–35], the AEs reported most frequently were gastrointestinal symptoms of nausea, vomiting, and diarrhea and are expected events in a postoperative population with cIAI.\n\nActivity Against Extended-Spectrum β-Lactamases\nIn the past 10 years, ESBL-producing Enterobacteriaceae have become an important challenge for antibiotic treatment of infections, and ESBL carriage rates are increasing in nearly all geographic areas [36]. In the United States, up to 19% of healthcare-associated infections are due to ESBL-producing Enterobacteriaceae, constituting a serious threat of resistance [37]. For severe ESBL infections, carbapenems have become the drugs of choice [38].\n\nCeftolozane/tazobactam showed substantial clinical and microbiological activity against ESBL-producing E. coli and Klebsiella strains. The ESBL-positive rate is consistent with observations from the Study for Monitoring Antimicrobial Resistance Trends, a global surveillance program of gram-negative bacilli from IAIs. This European study characterized >3000 patient isolates in 2008, revealing ESBL rates of 11.6% in E. coli and 17.9% in K. pneumoniae [39].\n\nCTX-M–type ESBLs are by far the most common ESBLs worldwide, and are often associated with multidrug resistance in Enterobacteriaceae [11, 36]. In our study, more than one-half of the ESBL-producing Enterobacteriaceae isolated at baseline were positive for CTX-M-14 or CTX-M-15–type enzymes, but no K. pneumoniae carbapenemase enzymes were identified. Ceftolozane/tazobactam plus metronidazole maintained clinical efficacy against these highly resistant strains (100%) compared with 72.7% with meropenem.\n\nActivity Against Pseudomonas aeruginosa\nMultidrug-resistant P. aeruginosa often requires complex antimicrobial regimens and, when treated inadequately, infections caused by this pathogen are associated with particularly poor outcomes including postoperative complications, longer hospital stays, and increased mortality [5, 6, 40–42]. In vitro studies have shown that ceftolozane/tazobactam is the most potent antipseudomonal agent, maintaining activity against many multidrug-resistant strains [13]. Ceftolozane/tazobactam demonstrated efficacy against P. aeruginosa, even though experience with multidrug-resistant P. aeruginosa was limited.\n\nIn conclusion, these results suggest that ceftolozane/tazobactam plus metronidazole is a potential alternative to the currently recommended antimicrobials for the treatment of cIAIs, especially when resistant Enterobacteriaceae or P. aeruginosa are suspected, such as in healthcare-associated infections.\n\nSupplementary Data\nSupplementary materials are available at Clinical Infectious Diseases online (http://cid.oxfordjournals.org). Supplementary materials consist of data provided by the author that are published to benefit the reader. The posted materials are not copyedited. The contents of all supplementary data are the sole responsibility of the authors. Questions or messages regarding errors should be addressed to the author.\n\nSupplementary Data\n Notes\nAcknowledgments. We thank the trial participants, the investigators who made this study possible, and the surgical review panel members. Additional investigators are listed in the Supplementary Appendix. Editorial support for this manuscript was provided by Kate Bradford of PAREXEL.\n\nFinancial support. This work was supported by Cubist Pharmaceuticals.\n\nPotential conflicts of interest. E. H., B. M., M. P., J. Steenbergen, M. Y., and S. C. are employees of Cubist Pharmaceuticals. I. F. and G. Y. are previous employees of Cubist Pharmaceuticals. C. E. has received research grant support from Wyeth (now Pfizer) and consultancy or speaker fees from AstraZeneca, Bayer, Merck Sharp & Dohme, Novartis, Pfizer, Wyeth, and Cubist. P. S. B. has served on speaker's bureaus for Pfizer, Merck, and Forest Laboratories and has acted as a consultant for Cubist, Forest, Astellas, and Durata. J. Solomkin is a consultant to Cubist, Bayer, AstraZeneca, Merck, Tetraphase, Rempex, and Pfizer, and has provided lectures supported by GlaxoSmithKline, Bayer, Merck, and Pfizer.\n\nAll authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n==== Refs\nReferences\n1 Herzog T Chromik AM Uhl W \nTreatment of complicated intra-abdominal infections in the era of multi-drug resistant bacteria . Eur J Med Res \n2010 ; 15 :525 –32 .21163727 \n2 Barie PS Hydo LJ Eachempati SR \nLongitudinal outcomes of intra-abdominal infection complicated by critical illness . Surg Infect (Larchmt) \n2004 ; 5 :365 –73 .15744128 \n3 Gauzit R Péan Y Barth X Mistretta F Lalaude O \nEpidemiology, management, and prognosis of secondary non-postoperative peritonitis: a French prospective observational multicenter study . 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Ann N Y Acad Sci \n2013 ; 1277 :84 –90 .23346859 \n12 Morrissey I Hackel M Badal R Bouchillon S Hawser S Biedenbach D \nA review of ten years of the Study for Monitoring Antimicrobial Resistance Trends (SMART) from 2002 to 2011 . Pharmaceuticals (Basel) \n2013 ; 6 :1335 –46 .24287460 \n13 Farrell DJ Flamm RK Sader HS Jones RN \nAntimicrobial activity of ceftolozane-tazobactam tested against Enterobacteriaceae and Pseudomonas aeruginosa with various resistance patterns isolated in U.S. hospitals (2011–2012) . Antimicrob Agents Chemother \n2013 ; 57 :6305 –10 .24100499 \n14 Sader HS Farrell DJ Flamm RK Jones RN \nCeftolozane/tazobactam activity tested against aerobic gram-negative organisms isolated from intra-abdominal and urinary tract infections in European and United States hospitals (2012) . 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"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1058-4838",
"issue": "60(10)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "Enterobacteriaceae; ceftolozane/tazobactam; complicated intra-abdominal infection; gram-negative bacteria; multidrug resistance",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D001424:Bacterial Infections; D002511:Cephalosporins; D004311:Double-Blind Method; D024901:Drug Resistance, Multiple, Bacterial; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D059413:Intraabdominal Infections; D008297:Male; D008795:Metronidazole; D008875:Middle Aged; D010397:Penicillanic Acid; D011446:Prospective Studies; D000078142:Tazobactam; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "1462-71",
"pmc": null,
"pmid": "25670823",
"pubdate": "2015-05-15",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "16187977;23153963;23939895;20034345;24780763;20163262;23672242;23346859;16571200;22450972;22439781;22915465;24917579;24092853;21482568;12560782;15185005;23391714;15793102;10734285;18991521;24287460;23599308;19696123;24100499;20457818;16236177;24883079;15744128;21163727;18570575;21482566;20953653;23353941;24982069",
"title": "Ceftolozane/Tazobactam Plus Metronidazole for Complicated Intra-abdominal Infections in an Era of Multidrug Resistance: Results From a Randomized, Double-Blind, Phase 3 Trial (ASPECT-cIAI).",
"title_normalized": "ceftolozane tazobactam plus metronidazole for complicated intra abdominal infections in an era of multidrug resistance results from a randomized double blind phase 3 trial aspect ciai"
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"abstract": "COVID-19 has now become a pandemic. From Wuhan, China, in December 2019 to European countries, USA and now it seems to gain a strong foothold in India. The objective of this work is to report the initial experience with demographic and clinical features, and management of COVID-19 patients admitted in medical college Bhilwara, India.\nThis is a descriptive case series of first 26 COVID-19 patients. Demographical, clinical, laboratory, and radiological characteristics and treatment and outcomes data were obtained with data collection forms and history given by 26 COVID-19 patients.\nDuring this study 26 COVID-19 positive patients were admitted in MG Hospital, Bhilwara. Male patients were 61.54% and majority (88.46%) were below 60 years of age. Approximately 30.76 % patients were asymptomatic. Fever was the most common symptom (61.54%) followed by sore throat (53.84 %), cough (42.30%) myalgia (38.46%)and dyspnea(23.07%). Six patients (23.07%) of total 26 had comorbidities. Leucopenia was seen in in 9 (34.61%) and leukocytosis was seen in 2 patient. Ten patient (38.46%) out of 26 shown increased lymphocyte/neutrophil ratio. Chest X- ray was normal in 20 patients (76.92%). Abnormalities in chest CT were detected among 10 (38.46%) patients. Typical findings were bilateral multifocal patchy peripheral subsegmental areas of consolidation more towards middle and lower zones and bilateral ground glass opacities involving multiple segments. Oseltamivir and chloroquine were given to all 26 patients. Azithromycin was given in 24 patients. Mean duration of conversion of COVID-19 patients was 6.83 days. All discharged patients advised home quarantine for 14 days as per guidelines.\nPatients often present without fever, and many may not have abnormal radiologic findings. Patients with older age and associated comorbid conditions (COPD and diabetes) seem to have greater risk for lung injury.",
"affiliations": "Professor General Medicine, RVRS medical College Bhilwara, Rajasthan.;Assistant Professor Respiratory Medicine, RVRS medical College Bhilwara, Rajasthan.;Junior Specialist General Medicine, RVRS medical College Bhilwara, Rajasthan.;Assistant Professor General Medicine, RVRS medical College Bhilwara, Rajasthan.;Senior Professor, Anaesthesia, RVRS medical College Bhilwara, Rajasthan.;Senior Specialist, Respiratory Medicine, Institute of Respiratory Diseases, SMS Medical College, Jaipur, Rajasthan.;Associate Professor Respiratory Medicine, Institute of Respiratory Diseases, SMS Medical College, Jaipur, Rajasthan.",
"authors": "Gaur|Arun|A|;Meena|Surender Kumar|SK|;Bairwa|Ramavtar|R|;Meena|Daulat|D|;Nanda|Rajan|R|;Sharma|Shiv Raj|SR|;Rajawat|Govind Singh|GS|",
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"issue": "68(7)",
"journal": "The Journal of the Association of Physicians of India",
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"medline_ta": "J Assoc Physicians India",
"mesh_terms": "D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D005260:Female; D006801:Humans; D007194:India; D008297:Male; D008875:Middle Aged; D058873:Pandemics; D011024:Pneumonia, Viral; D000086402:SARS-CoV-2; D062606:Tertiary Care Centers",
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"title": "Clinico-radiological Presentation of COVID-19 Patients at a Tertiary Care Center at Bhilwara Rajasthan, India.",
"title_normalized": "clinico radiological presentation of covid 19 patients at a tertiary care center at bhilwara rajasthan india"
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"abstract": "BACKGROUND\nAmyotrophic lateral sclerosis is a fatal neuromuscular disorder characterized by progressive death of the upper and lower motor neurons in the central nervous system. Patients with this disease die mostly as a result of respiratory failure; however, owing to prolonged survival through assisted ventilation, cardiovascular causes are increasingly responsible for mortality. We report what is to the best of our knowledge the first case of type 2 Brugada syndrome causing ventricular tachyarrhythmia and cardiac arrest in a patient with upper limb onset amyotrophic lateral sclerosis.\n\n\nMETHODS\nA 48-year-old Caucasian woman with a significant past medical history of papillary thyroid carcinoma status postresection, pulmonary embolism on anticoagulation, and a recent diagnosis of right upper limb-onset amyotrophic lateral sclerosis presented to the emergency department of our hospital with acute on chronic shortness of breath. On further evaluation, she was found to have hypoxic and hypercapnic respiratory failure and was placed on bilevel positive airway pressure ventilation. Her 12-lead electrocardiogram showed sinus rhythm with J-point elevation, saddle-shaped ST segment elevation, predominantly in V1 and V2 with no significant QTc prolongation. No troponin elevation was noted in her laboratory workup. Because she was unable to protect her airway, a decision was made to intubate her. After 1 minute of induction with etomidate and succinylcholine, she went into pulseless ventricular tachycardia and fibrillation requiring three cycles of cardiopulmonary resuscitation with high-quality chest compressions, three doses of epinephrine, and a loading dose of amiodarone prior to return of spontaneous circulation. She was further evaluated by cardiology services and was diagnosed with type 2 Brugada syndrome, for which she was started on quinidine. Her respiratory failure and the drugs she received for intubation likely caused her ventricular tachycardia to occur in conjunction with an underlying Brugada pattern seen on an electrocardiogram. The results of evaluation of her genetic panel for Brugada syndrome were negative. She was subsequently discharged to home in stable condition after a 10-day hospital stay.\n\n\nCONCLUSIONS\nAmyotrophic lateral sclerosis is a progressive neuromuscular disorder with significant mortality. Respiratory failure is the leading cause of death, but lately, owing to increased survival associated with early tracheostomy and positive pressure ventilation, there has been an increasing trend in the identification of cardiovascular causes of mortality, especially arrhythmias, that may need periodic electrocardiographic surveillance.",
"affiliations": "Department of Neurology, University of Missouri Healthcare, 5 Hospital Drive, CE 540, Columbia, MO, 65201, USA.;Department of Neurology, University of Missouri Healthcare, 5 Hospital Drive, CE 540, Columbia, MO, 65201, USA.;Department of Neurology, University of Missouri Healthcare, 5 Hospital Drive, CE 540, Columbia, MO, 65201, USA.;Department of Neurology, University of Missouri Healthcare, 5 Hospital Drive, CE 540, Columbia, MO, 65201, USA. govindarajanr@health.missouri.edu.",
"authors": "Battineni|Anusha|A|;Gummi|Rohit|R|;Mullaguri|Naresh|N|;Govindarajan|Raghav|R|",
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"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 135610.1186/s13256-017-1356-6Case ReportBrugada syndrome in a patient with amyotrophic lateral sclerosis: a case report Battineni Anusha abattineni@gmail.com Gummi Rohit rg4yd@health.missouri.edu Mullaguri Naresh mullaguri.nari@gmail.com Govindarajan Raghav +1 573 882 1515govindarajanr@health.missouri.edu 0000 0001 2162 3504grid.134936.aDepartment of Neurology, University of Missouri Healthcare, 5 Hospital Drive, CE 540, Columbia, MO 65201 USA 14 7 2017 14 7 2017 2017 11 19216 3 2017 15 6 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nAmyotrophic lateral sclerosis is a fatal neuromuscular disorder characterized by progressive death of the upper and lower motor neurons in the central nervous system. Patients with this disease die mostly as a result of respiratory failure; however, owing to prolonged survival through assisted ventilation, cardiovascular causes are increasingly responsible for mortality. We report what is to the best of our knowledge the first case of type 2 Brugada syndrome causing ventricular tachyarrhythmia and cardiac arrest in a patient with upper limb onset amyotrophic lateral sclerosis.\n\nCase presentation\nA 48-year-old Caucasian woman with a significant past medical history of papillary thyroid carcinoma status postresection, pulmonary embolism on anticoagulation, and a recent diagnosis of right upper limb-onset amyotrophic lateral sclerosis presented to the emergency department of our hospital with acute on chronic shortness of breath. On further evaluation, she was found to have hypoxic and hypercapnic respiratory failure and was placed on bilevel positive airway pressure ventilation. Her 12-lead electrocardiogram showed sinus rhythm with J-point elevation, saddle-shaped ST segment elevation, predominantly in V1 and V2 with no significant QTc prolongation. No troponin elevation was noted in her laboratory workup. Because she was unable to protect her airway, a decision was made to intubate her. After 1 minute of induction with etomidate and succinylcholine, she went into pulseless ventricular tachycardia and fibrillation requiring three cycles of cardiopulmonary resuscitation with high-quality chest compressions, three doses of epinephrine, and a loading dose of amiodarone prior to return of spontaneous circulation. She was further evaluated by cardiology services and was diagnosed with type 2 Brugada syndrome, for which she was started on quinidine. Her respiratory failure and the drugs she received for intubation likely caused her ventricular tachycardia to occur in conjunction with an underlying Brugada pattern seen on an electrocardiogram. The results of evaluation of her genetic panel for Brugada syndrome were negative. She was subsequently discharged to home in stable condition after a 10-day hospital stay.\n\nConclusions\nAmyotrophic lateral sclerosis is a progressive neuromuscular disorder with significant mortality. Respiratory failure is the leading cause of death, but lately, owing to increased survival associated with early tracheostomy and positive pressure ventilation, there has been an increasing trend in the identification of cardiovascular causes of mortality, especially arrhythmias, that may need periodic electrocardiographic surveillance.\n\nKeywords\nAmyotrophic lateral sclerosisBrugada syndromeCardiac arrestissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nAmyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disorder. It is characterized by progressive death of the upper and lower motor neurons in the central nervous system, resulting in weakness and atrophy of the bulbar muscles and muscles of the upper and lower extremities. Death in patients with ALS is caused primarily by respiratory muscle weakness, but there has been a recent surge in cardiovascular causes of mortality as these patients survive longer with the help of mechanical ventilation. Sudden cardiac death has been reported in patients with different types of motor neuron diseases, such as ALS and Kennedy’s disease, suggesting their multiorgan involvement. Although Kennedy’s disease is known to be associated with different types of Brugada syndrome, there has been no reported case of its association in a patient diagnosed with ALS. To the best of our knowledge, this is the first case report of a patient with upper limb-onset ALS with ventricular tachyarrhythmia secondary to type 2 Brugada syndrome.\n\nCase presentation\nPatient information\nA 48-year-old Caucasian woman presented to a neurology clinic for progressive right upper limb weakness that had started 3 months earlier. Her major complaints were frequently dropping things from her hands, worsening handwriting, difficulty holding a spoon, and inability to do her job as a desk clerk. She also noticed some twitching in the muscles of her right upper and lower extremities. She denied numbness or tingling in the extremities and weakness of the bulbar muscles (dysphagia, dysarthria, and shortness of breath). She denied any neck pain; trauma; and constitutional symptoms such as fever, night sweats, and weight loss. Her past medical history included rosacea and dry eyes. She had undergone a cesarean section and plantar fasciotomy in the past. Her father had died as a result of heart failure. She reported no neurodegenerative diseases, neuromuscular diseases, or sudden deaths in other family members. She had no history of smoking or alcohol or illicit drug abuse and no known drug allergies.\n\nPhysical examination\nOn examination, she did not have any cognitive dysfunction, and the result of her cranial nerve examination was normal. Her motor examination revealed decreased strength in both proximal and distal muscle groups, predominantly in the intrinsic hand muscles with wasting and in the shoulder abductors. Fasciculations were noted in the right upper and lower extremities in various muscle groups. Her deep tendon reflexes were brisk with positive jaw jerk, Hoffman’s sign on the left, and bilateral ankle clonus. Her plantar reflexes were mute bilaterally. Her sensory system, coordination, and gait were unremarkable. Magnetic resonance imaging of the brain and the cervical and thoracic spine was unremarkable. The result of her autoimmune and paraneoplastic workup was negative, although the result of her malignancy workup was positive for papillary thyroid cancer, which was subsequently resected. An electromyogram with nerve conduction studies showed denervation in three body regions, consistent with the diagnosis of ALS. During the next 3 months, her pulmonary function tests showed a decrement by more than 20% in measurements of predicted forced vital capacity and forced expiratory volume in 1 second. One month later, she had an acute episode of shortness of breath and was diagnosed with pulmonary embolism, for which she was started on anticoagulation.\n\nNine months into her diagnosis of ALS, she presented to the emergency department of our hospital with acute on chronic shortness of breath and was hypoxic and hypercapnic with a negative inspiratory pressure of −10 mmHg, requiring bilevel positive airway pressure ventilation (BiPAP). In further evaluation for cardiopulmonary causes, her chest x-ray was unremarkable; a computed tomographic angiogram of the chest ruled out pulmonary embolism; and an electrocardiogram showed sinus rhythm with J-point elevation, saddle-shaped ST segment elevation predominantly in V1 and V2 with no significant QTc prolongation and negative troponinemia (Fig. 1). Eventually, she became lethargic with a worsening Glasgow Coma Scale score and increased work of breathing, and she was unable to protect her airway, requiring intubation. She was continued on BiPAP until induction for intubation. Etomidate and succinylcholine were administered, and within 1 minute into induction, she developed pulseless ventricular tachycardia and ventricular fibrillation. Advanced cardiac life support was initiated with defibrillation, three rounds of epinephrine, and a loading dose of amiodarone prior to return of spontaneous circulation. After some time, she became responsive and started following simple commands, and a decision was made not to use a hypothermia protocol. She was admitted to the cardiac intensive care unit for close monitoring. Her echocardiogram showed that her left ventricular ejection fraction was 70%, and asymmetric hypertrophy of basal segments of the left ventricle was noted. She was diagnosed with type 2 Brugada syndrome by cardiology services as the cause of her ventricular tachyarrhythmia, and she was started on quinidine. The results of her genetic panel for Brugada syndrome was negative. There were no recurrences of ventricular arrhythmias during the rest of her hospitalization. She declined automatic implantable cardioverter-defibrillator placement and was later discharged to home hospice care with a tracheostomy.Fig. 1 Twelve-lead electrocardiogram showing type 2 Brugada pattern. Saddleback appearance can be seen in the precordial leads, especially in lead V2. This is characterized by a ≥2-mm ST elevation followed by a trough ≥1 mm and either a positive or biphasic T wave\n\n\n\n\nDiscussion\nALS is currently considered a multisystem disorder on the basis of its involvement of other organ systems leading to significant mortality and morbidity [1–5]. Most patients with this disease experience respiratory failure secondary to progressive chest wall weakness and pulmonary embolism resulting from their immobility. In our patient’s case, we emphasize that cardiovascular involvement may also contribute to the disease mortality. In a French ALS study by Gil et al., who researched the leading causes of mortality, 3.4% of patients died as a result of myocardial infarction or dysrhythmias, and a few patients had sudden cardiac death [3]. The cardiovascular aberrations, such as QT prolongation, heart rate-blood pressure dyssynchrony, and nocturnal hypotension during the course of the disease have frequently been reported in this patient population. This could be due to decreasing sympathetic tone secondary to degeneration of the intermediolateral column in the upper levels of the spinal cord, as previously shown in pathological studies by Hirohide et al. [6]. Brugada syndrome is an inherited arrhythmia syndrome characterized by coved (type 1) or saddleback (types 2 and 3) ST-segment elevations (≥2 mm), followed by deep T-wave inversions in leads V1–V3. It is associated with increased risk of sudden cardiac death, especially in young male adults of Southeast Asian origin. Although genetic mutations in several sodium and calcium channel genes have been identified, an imbalance in sympathetic and parasympathetic nervous systems in the pathogenesis of Brugada syndrome has been proposed [7, 8]. Brugada syndrome, which can predispose patients to develop ventricular tachyarrhythmia and circulatory collapse, has not been reported in patients with ALS, which can predispose them to develop ventricular tachyarrhythmia and circulatory collapse, as happened in our patient. Kennedy’s disease, another type of motor neuron disease, is known to be associated with all types of Brugada syndrome [4]. We hypothesize that patients with ALS are also at high risk for this pattern, given the changes in the efferent sympathetic dysfunction shared with Kennedy’s disease. Our patient did not have any preexisting mutations to develop Brugada syndrome, ruling out the possibility of a casual association, but rather had an important pathophysiological mechanism of motor neuron diseases that needs to be explored further. Because patients with ALS tend to live longer with improved respiratory management, identifying and managing potential causes of acute cardiorespiratory failure, such as ventricular tachyarrhythmias, need further emphasis. Periodic surveillance with electrocardiography to identify patterns of Brugada syndrome and QTc prolongation may be considered to identify patients at high risk for potential cardiac arrest.\n\nConclusions\nCardiovascular causes, especially malignant arrhythmias, can also be associated with significant mortality in patients with ALS. We propose periodic electrocardiographic surveillance in patients with ALS to identify abnormal patterns such as Brugada syndrome.\n\nAcknowledgements\nNot applicable.\n\nFunding\nThese authors have no financial disclosures to report.\n\nAvailability of data and materials\nData sharing is not applicable to this case report, because no datasets were generated or analyzed.\n\nAuthors’ contributions\nAB, RGu, NM, and RGo designed the case report. AB, RGu, NM, and RGo collected data. AB, RGu, NM, and RGo prepared the manuscript. The authors contributed equally in writing this case report and formatting the images. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nEthics approval and consent to participate\nAn approval from the ethics committee is not applicable to publish this case report.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Tefera TW Borges K Metabolic dysfunctions in amyotrophic lateral sclerosis pathogenesis and potential metabolic treatments Front Neurosci 2017 10 611 10.3389/fnins.2016.00611 28119559 \n2. Finsterer J Stöllberger C Maeztu C Sudden cardiac death in neuromuscular disorders Int J Cardiol 2016 203 508 15 10.1016/j.ijcard.2015.10.176 26551884 \n3. Gil J Funalot B Verschueren A Danel-Brunaud V Camu W Vandenberghe N Causes of death amongst French patients with amyotrophic lateral sclerosis: a prospective study Eur J Neurol 2008 15 1245 51 10.1111/j.1468-1331.2008.02307.x 18973614 \n4. Querin G Bertolin C Da Re E Volpe M Zara G Pegoraro E Non-neural phenotype of spinal and bulbar muscular atrophy: results from a large cohort of Italian patients J Neurol Neurosurg Psychiatry 2016 87 810 6 10.1136/jnnp-2015-311305 26503015 \n5. Tanaka Y Yamada M Koumura A Sakurai T Hayashi Y Kimura A Cardiac sympathetic function in the patients with amyotrophic lateral sclerosis: analysis using cardiac [123 I] MIBG scintigraphy J Neurol 2013 260 2380 6 10.1007/s00415-013-7005-0 23784610 \n6. Asai H Hirano M Udaka F Shimada K Oda M Kubori T Sympathetic disturbances increase risk of sudden cardiac arrest in sporadic ALS J Neurol Sci 2007 254 78 83 10.1016/j.jns.2007.01.007 17303172 \n7. Antzelevitch C Brugada syndrome Pacing Clin Electrophysiol 2006 29 1130 59 10.1111/j.1540-8159.2006.00507.x 17038146 \n8. Bayés de Luna A Brugada J Baranchuk A Borggrefe M Breithardt G Goldwasser D Current electrodiagnostic criteria for diagnosis of Brugada pattern: a consensus report J Electrocardiol 2012 45 433 42 10.1016/j.jelectrocard.2012.06.004 22920782\n\n",
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"abstract": "Drug abuse by inhalation of volatile household product substances is uncommon, however, it can have devastating consequences. This case report describes the fatal outcome of deodorant inhalation by a 19-year-old patient in a detoxification clinic who developed a cardiac arrest after inhaling butane from a deodorant spray. Despite initial successful resuscitation, he developed a postanoxic encephalopathy with a status epilepticus resistant to extensive treatment. Inhalant abuse can be a cause of death in young patients.",
"affiliations": "Intensive Care, Maasstad Ziekenhuis, Rotterdam, The Netherlands.;Intensive Care, Maasstad Ziekenhuis, Rotterdam, The Netherlands.;Intensive Care, Maasstad Ziekenhuis, Rotterdam, The Netherlands.;Intensive Care, Maasstad Ziekenhuis, Rotterdam, The Netherlands.",
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"title": "Cardiac arrest by inhalation of deodorant spray.",
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"abstract": "We conducted a pilot study employing extended T cell costimulation blockade (COSBL) with Abatacept along with sirolimus and post-transplantation cyclophosphamide (PTCy) in 10 patients (median age 12) with severe aplastic anemia (SAA). Nine patients engrafted in the COSBL group, compared to all 10 patients (median 14 vs 13days) treated on PTCy protocols without abatacept (CONTROL group). The incidence of acute graft-versus-host disease (GVHD) was 10.5% in the COSBL group compared to 50% in the CONTROL group (p=0.04). Chronic GVHD (12.5% vs 56%, p=0.02) and CMV reactivation (30% vs 80%, p=0.03) were also reduced in the COSBL group. T and NK cell subset analysis revealed higher CD56brightCD16- NK cells in the CONTROL group (p=0.004), but similar CD56dimCD16+ NK cells in both groups at day+30. Tregs (CD4+CD25+CD127dim/- FoxP3+) were markedly higher in the COSBL group at day+30 (8.4% vs 1.1%) and the trend was maintained through day+90 (p<0.01). The GVHD and Disease-free survival at one year in the COSBL group was 80% vs. 30% in the CONTROL group (p=0.05). Our preliminary findings suggest that COSBL in combination with PTCy and sirolimus might augment transplantation tolerance in children with SAA, probably due to synergistic effect on early recovery of Tregs.",
"affiliations": "Manashi Chakrabarti Foundation, Kolkata, India; Department of Blood and Marrow Transplantation, Dharamshila Narayana Superspeciality Hospital and Research Centre, New Delhi, India. Electronic address: drsaritaranij@dhrc.net.in.;Department of Blood and Marrow Transplantation, Dharamshila Narayana Superspeciality Hospital and Research Centre, New Delhi, India.;Department of Blood and Marrow Transplantation, Dharamshila Narayana Superspeciality Hospital and Research Centre, New Delhi, India.;Department of Blood and Marrow Transplantation, Dharamshila Narayana Superspeciality Hospital and Research Centre, New Delhi, India.;Department of Blood and Marrow Transplantation, Dharamshila Narayana Superspeciality Hospital and Research Centre, New Delhi, India.;Department of Blood and Marrow Transplantation, Dharamshila Narayana Superspeciality Hospital and Research Centre, New Delhi, India.;Manashi Chakrabarti Foundation, Kolkata, India; Department of Blood and Marrow Transplantation, Dharamshila Narayana Superspeciality Hospital and Research Centre, New Delhi, India.",
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"title": "T cell costimulation blockade promotes transplantation tolerance in combination with sirolimus and post-transplantation cyclophosphamide for haploidentical transplantation in children with severe aplastic anemia.",
"title_normalized": "t cell costimulation blockade promotes transplantation tolerance in combination with sirolimus and post transplantation cyclophosphamide for haploidentical transplantation in children with severe aplastic anemia"
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"abstract": "This clinical case series describes our experience with the use of Janus kinase 1/2 inhibitor baricitinib in two patients suffering from refractory adult-onset Still's disease (AOSD) as well as in one case suffering from AOSD-like autoinflammatory disease in the context of myelodysplastic syndrome. All patients suffered from disease non-responsive to conventional Disease-modifying antirheumatic drugs (DMARDs) as well as biological therapies including interleukin (IL)-1 and IL-6 blockade, relying instead on high daily doses of prednisolone. We also report the first case of Pneumocystis jirovecii infection following baricitinib use.",
"affiliations": "NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK.;Institue of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.;Rheumatology, Harrogate District Hospital, Harrogate, UK.;NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK.;Institue of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.;Institue of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK s.savic@leeds.ac.uk.",
"authors": "Kacar|Mark|M|;Fitton|John|J|;Gough|Andrew K|AK|;Buch|Maya H|MH|0000-0002-8962-5642;McGonagle|Dennis G|DG|;Savic|Sinisa|S|0000-0001-7910-0554",
"chemical_list": "D018501:Antirheumatic Agents; D001384:Azetidines; D011687:Purines; D011720:Pyrazoles; D013449:Sulfonamides; C000596027:baricitinib",
"country": "England",
"delete": false,
"doi": "10.1136/rmdopen-2020-001246",
"fulltext": "\n==== Front\nRMD Open\nRMD Open\nrmdopen\nrmdopen\nRMD Open\n2056-5933 BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\n32669454\nrmdopen-2020-001246\n10.1136/rmdopen-2020-001246\nAutoinflammatory Disorders\nClinical caseMixed results with baricitinib in biological-resistant adult-onset Still’s disease and undifferentiated systemic autoinflammatory disease\nKacar Mark 1 Fitton John 2 Gough Andrew K 3 http://orcid.org/0000-0002-8962-5642Buch Maya H 1 McGonagle Dennis G 2 http://orcid.org/0000-0001-7910-0554Savic Sinisa 24 1 NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK\n2 Institue of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK\n3 Rheumatology, Harrogate District Hospital, Harrogate, UK\n4 Department of Clinical Immunology and Allergy, St James’s University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK\nCorrespondence to Sinisa Savic; s.savic@leeds.ac.uk\n2020 \n14 7 2020 \n6 2 e00124602 4 2020 14 5 2020 01 6 2020 © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2020http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.This clinical case series describes our experience with the use of Janus kinase 1/2 inhibitor baricitinib in two patients suffering from refractory adult-onset Still’s disease (AOSD) as well as in one case suffering from AOSD-like autoinflammatory disease in the context of myelodysplastic syndrome. All patients suffered from disease non-responsive to conventional Disease-modifying antirheumatic drugs (DMARDs) as well as biological therapies including interleukin (IL)-1 and IL-6 blockade, relying instead on high daily doses of prednisolone. We also report the first case of Pneumocystis jirovecii infection following baricitinib use.\n\nArthritisAnkylosing SpondylitisPsoriatic ArthritisAdult Onset Still’s DiseaseFever SyndromesInflammationDMARDs (biologic)\n==== Body\nINTRODUCTION\nAdult-onset Still’s disease (AOSD) is a rare systemic autoinflammatory disorder characterised by a combination of fever, generalised evanescent salmon-pink rash, pharyngodynia, arthritis/synovitis, lymphadenopathy, serositis and splenomegaly. None of these clinical features are disease-specific, and a wide spectrum of conditions including autoimmune, infectious and malignant diseases need to be considered as part of differential diagnosis. Several classification criteria have been developed for research purposes that can aid the diagnosis of AOSD. The most commonly used are Yamaguchi’s1 and Fautrel’s2 criteria with the latter one not requiring exclusion of other conditions for diagnosis of AOSD to be made. The diagnosis can be particularly difficult in patients with pre-existing conditions such as myelodysplastic syndrome (MDS) or in patients who do not fulfil all classification criteria, but have a condition closely resembling AOSD and who are ultimately treated and respond to therapies used for AOSD. A frequently used diagnostic label in such cases is that of undifferentiated systemic autoinflammatory syndrome (uSAID).3\n\nTreatment of AOSD has been revolutionised by the introduction of biologicals DMARD particulary those targeting interleukin (IL)-1 and IL-6.4–7 The Janus kinase (JAK) inhibitors—tofacitinib, baricitinib and others—are highly effective in refractory inflammatory arthritis, including patients who have failed biological therapy.8 9 Here, we describe our experience using the JAK-1/JAK-2 inhibitor baricitinib in two patients with biological-resistant AOSD meeting Yamaguchi’s diagnostic criteria, as well as in one patient suffering from an AOSD-like disorder in the context of low-grade MDS. Results of relevant investigations are shown in table 1, a summary of medications used (and their doses) are shown in table 2, and clinical characteristics, laboratory results and concomitant medication prebaricitinib and postbaricitinib implementation are shown in table 3.\n\nTable 1 Demographics, clinical characteristics and results\n\n\tPatient 1 (P1)\tPateint 2 (P2)\tPateint 3 (P3)\t\nGender\tF\tM\tF\t\nAge at presentation (years)\t41\t29\t58\t\nClinical characteristics at presentation\t\nFevers >39°Ct*\t+\t+\t+\t\nJoint involvement†\t+\t+\t+\t\nRash‡\t+\t+\t−\t\nSore throat\t+\t−\t+\t\nLymphadenopathy\t−\t−\t−\t\nSplenomegaly\t+\t−\t−\t\nSerositis\t+\t−\t−\t\nLaboratory results\t\t\t\t\nANA/RF\t−\t−\t−\t\nWBC >10.000/mL\t+\t+^\t−‘\t\nElevated LFTs (>1.5X ULN)\t+ (ALT, AP, LDH)\t+ (ALT)\t+ (AP)\t\nMaximum CRP\t(<10 mg/L)\t231mg/L\t(on 35 mgPred/day)\t94 mg/L\t(on 40 mgPred/day)\t239 mg/L\t(on 20 mgPred/day)\t\nMaximum ESR\t(1–15 m/hour)\t125 mm/hour\t16 mm/hour\tNA\t\nMaximum ferritin\t(10–332 ng/mL)\t38 940 ng/mL\t679 ng/mL\t2695 ng/mL’’\t\nOther investigations\tPET CT—borderline splenomegaly, traces of pericardial effusion, reactive mediastinal lymphadenopathy\tPET CT—no inflammatory arthritis, vasculitis, infection or malignancy\tPET CT—no infection, malignancy or vasculitis; USS abdomen—no abnormalities detected\t\n*Lasting 1 week or longer.\n\n† Arthritis/synovitis/arthralgia.\n\n‡ Evanescent, salmon-pink maculopapular rash.\n\n‘P3 has been pancytopenic since presentation due to underlying myelodysplasia; however, flares were associated with tripling of neutrophil counts. ‘’The elevation of ferritin does not correspond to disease flares but likely reflects increased transfusion dependence. ^WBC over 13.000 but 77% PBMC.\n\nALT, alanine aminotransferase; ANA, antinuclear antibody assay; AP, alkaline phosphatase; CRP, C reactive protein; ESR, erythrocyte sedimentation rate; F, female; LDH, lactate dehydrogenase; LFT, liver function test; NA, not available; M, male; PET, positron emission tomography; Pred, prednisolone; RF, rheumatoid factor; ULN, upper limit of normal; USS, ultrasound scan; WBC, white blood cell count.\n\nTable 2 Treatments used before baricitinib implementation and their efficacy\n\n\tP1\tP2\tP3\t\nPrednisolone\tPR\t30–40 mg OD\tPR\t40 mg OD\tPR\t20 mg OD\t\nMethotrexate\tNR*\t7.5 mg 1 weekly\tNR\t25 mg 1 weekly\t/\t/\t\nCiclosporin\tPR\t100 mg BD\tNR\t150 mg BD\t/\t/\t\nAnakinra\tPR\t300 mg BD\tNR\t100 mg BD\tNR\t100 mg OD\t\nTocilizumab\tNR\t8 mg/kg 2 weekly\tNR\t8 mg/kg 2 weekly\tCR—vasculitis\t162 mg 2 weekly\t\nSarilumab\t/\t/\t/\t/\tCR—vasculitis\t150 mg 2 weekly\t\nOther medications\t/\tRituximab—NR\nInfliximab—PR\tRituximab for vasculitis—CR\t\n*In addition to lack of response, P1 experienced a severe generalised toxic drug eruption with MTX.\n\nCR—complete response defined as resolution of all symptoms/absence of flares with normalisation of laboratory parameters.\n\nPR—partial response defined as >50% reduction in frequency/severity of symptoms.\n\nNR—no response.\n\nOD—one time per day.\n\nBD—two times per day.\n\nTable 3 Clinical characteristics, lab results and concomitant medication prebaricitinib and postbaricitinib implementation\n\n\tP1\tP2\tP3\t\nPrebaricitinibX\nclinical characteristics\tInflammatory erosive polyarthritis\tPolyarthralgia with synovitis, generalised rash\tPersistent fever >39°C\t\nPrebaricitinibX results\t\t\t\t\nCRP\t(<10 mg/L)\t231 mg/L\t94 mg/L\t48 mg/L\t\nESR\t(1–15 m/hour)\t125 mm/hour\t16 mm/hour\tNA\t\nFerritin\t(10–332 ng/mL)\t38 940 ng/mL\t679 ng/mL\t1812 ng/mL’’\t\nPrebaricitinibX therapy\t\t\t\t\nPrednisolone\t10 mg OD\t40 mg OD\t15 mg OD\t\nMethotrexate\t/\t25 mg 1 weekly\t/\t\nCiclosporin\t100 mg OD\t150 mg BD\t/\t\nAnakinra\t300 mg OD\t100 mg BD\t/\t\nTocilizumab\t8 mg/kg 2 weekly\t8 mg/kg 2 weekly\t/\t\nSarilumab\t/\t/\t/\t\nBaricitinib treatment regimen\t4 mg OD\t4 mg OD\t4 mg OD\t\nPostbaricitinibY\nclinical characteristics\tAsymptomatic\tPolyarthralgia with synovitis, generalised rash\tAsymptomatic\t\nPostbaricitinibY results\t\t\t\t\nCRP\t(<10 mg/L)\t<5 mg/L\t56 mg/L\t2 mg/L\t\nESR\t(1–15 m/hour)\t17 mm/hour\t9 mm/hour\tNA\t\nFerritin\t(10–332 ng/mL)\t18 ng/mL\t304 ng/mL\t1708 ng/mL’’\t\nPostbaricitinibY therapy\t\t\t\t\t\t\nPrednisolone\t/\t30 mg OD\t15 mg OD\t\nMethotrexate\t/\t20 mg 1 weekly\t/\t\nOther DMARD\t/\t/\t/\t\nx At time of baricitinib implementation. YAt first follow-up (8±2 weeks) after implementation of a stable dose of baricitinib. ‘’The elevation of ferritin does not correspond to disease flares but likely reflects increased transfusion dependence.\n\nBD, two times per day; CRP, C reactive protein; DMARD, disease modifying antirheumatic drugs; ESR, erythrocyte sedimentation rate; NA, not available; OD, one time per day.\n\nCASE REPORT\nA 43-year-old Sudanese woman (P1) was first treated at in Sudan (at 41 years) for fever and flitting arthralgia. She relapsed in the UK despite maintenance therapy with prednisolone and hydroxychloroquine, presenting with fever, arthritis/synovitis and evanescent rash in the context of neutrophilia and elevated inflammatory markers. She remained steroid-dependent (multiple unsuccessful tapers below 15 mg prednisolone daily) despite combination therapy with anakinra and ciclosporin or methotrexate. Anakinra was briefly replaced with two-weekly intravenous tocilizumab infusions but was restarted due to primary non-response. The disease evolved into a predominantly oligoarthritic phenotype with significant synovial hypertrophy of both 2nd metacarpophalangeal (MCP) joints, multiple proximal interphalangeal joint (PIP) joints and both knee supra-patellar pouches. In addition, there was evidence of bilateral tibialis posterior and extensor carpi ulnaris tenosynovitis with evidence of multiple early bone erosions on ultrasound. Baricitinib was started at this point and the patient has remained in clinical and biochemical remission while on baricitinib monotherapy over the ensuing 15 months.\n\nA 32-year-old Caucasian male (P2) presented at 29 years with a flitting inflammatory polyarthritis (affecting hands, wrists, elbows, shoulders and knees) associated with a non-pruritic, evanescent rash, fevers, rigours and sweating. The condition was responsive to high-dose prednisolone. A diagnosis of AOSD was made and steroid-sparing immunomodulatory therapy was initiated with ciclosporin, with methotrexate added subsequently. Anakinra was added as prednisolone requirement remained at least 15 mg/day, with marked initial improvement but subsequent relapses despite doubling and then tripling the dose. Two-weekly intravenous tocilizumab was commenced in combination with methotrexate, resulting in complete biochemical and partial clinical response. After 6 months, he developed a persistent urticaria-like rash, which improved only transiently with the anti-IgE therapeutic, omalizumab. The patient developed severe synovitis and baricitinib was added without improvement. After 9 months, both drugs were discontinued. Since then, the patient has received one cycle of rituximab (to no effect) and more recently infliximab with modest improvement in symptoms.\n\nA 63-year-old Caucasian woman (P3) was diagnosed with AOSD-like condition (uSAID) after presenting at 58 years with pharyngitis, fever and arthralgias. The patient had pre-existing myelodysplasia diagnosed 2 years previously. Haematologist input deemed that her symptoms were not due to MDS, which was low grade and according to the MDS International Prognostic Scoring System had low scores and therefore minimal possibility of malignant transformation. Her MDS has remained clinically unchanged to this date. The initial flare was treated with high-dose corticosteroids. DMARDs were omitted due to the patient’s MDS. She was established on two-weekly intravenous tocilizumab monotherapy, successfully resulting in complete symptomatic control for 4 years. Subsequently, the patient developed chilblain vasculitis, deemed to have been caused by IL-6 blockade itself (and replicated after receiving subcutaneous sarilumab). The vasculitis, although seronegative, responded to rituximab, but AOSD symptoms remained problematic. A trial of anakinra failed due to intolerance; therefore, baricitinib was gradually introduced with careful monitoring. The patient has remained in biochemical and clinical remission for 9 months. At 7 months, she developed Pneumocystis jirovecii pneumonia, which responded to trimethoprim-sulfamethoxazole and she remains on it prophylactically.\n\nDISCUSSION\nAOSD remains a diagnostic and therapeutic challenge due to its myriad clinical manifestations and the confounding effects of comorbidities, partially effective therapies and continually evolving phenotypes. Our experience with baricitinib in biological-resistant AOSD is highly variable, perhaps reflecting the varied clinical presentation of this disease. One patient had pre-existing MDS and subsequently developed a clinical syndrome, which clinically resembled AOSD. Considering that there was significant time interval (2 years) between diagnosis of MDS and eventual emergence of AOSD-like condition, it could be argued that this was simply coincidence, particularly since it is often considered that AOSD tends to precede an eventual diagnosis of malignancy.10 However, a number of studies have already reported that autoimmune/autoinflammatory conditions are more common in MDS than in the general population, although with no clear classification of these inflammatory disorders. The range of autoimmune/autoinflammatory disorders in patients with MDS is highly variable with a prevalence rate ranging from 7% to 30% according to the different studies.11 12 Therefore, it is also reasonable to assume that AOSD-like condition in P3 is possibly a complication of underlying MDS. Considering that a JAK1/2 inhibitor (ruxolitinib) is already used in haematology to treat myelofibrosis, P3 response to baricitinib might not be surprising. However, ruxolitinib is typically approved for the treatment of intermediate-risk and high-risk myelofibrosis and associated symptoms.13 Interestingly, P3 also developed an opportunistic infection with pneumocystis while on baricitinib, a complication previously described only once in the context of myelofibrosis therapy with ruxolitinib.\n\nThe response to baricitinib in two other patients with AOSD was mixed. Nonetheless, JAKi remains a promising therapeutic option for patients otherwise dependent on high-dose corticosteroids. A recent report from China describes the successful use of tofacitinib in 14 patients with AOSD; however, not all patients had a complete response and some were still needing to take steroids on a long-term basis.14 The success of JAKi in patients who have failed IL-1-directed and IL-6-directed therapies might be explained by the ability of these medications to block other likely relevant cytokines such as IL-12/IL-23 and interferon-γ. However, the optimal therapeutic dose of JAKi used for AOSD might be different from what is used for licenced indication. This point was illustrated by a recent report of baricitinb use in the treatment of interferonopathies by Sanchez et al where larger, treat-to-effect, dosages were used, raising the possibility of underdosing in our cases.15\n\nKey messages\nWhat is already known about this subject?\nCytokine inhibition (IL-1 and IL-6) using bilogicals is now established treatment approach in AOSD.\n\nWhat does this study add?\nJAKi should be tried in patients who fail bilologics 3.\n\nHow might this impact on clinical practice?\nAdditional studies are needed to determine optimal place for use of JAKi in treatment AOSD.\n\nContributors: Data collection—MK, JF. Preparing the manuscript—MK, SS. Contribution of clinical cases—MHB, AKG, DGM and SS. Manuscript editing and final approval—MK, JF, AKG MHB, DGM.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: Yes, there are competing interests for one or more authors and I have provided a Competing Interests statement in my manuscript.\n\nPatient consent for publication: Consent obtained directly from patient(s).\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nData sharing statement: For further queries related to the cases presented here please contact the corresponding author.\n==== Refs\nREFERENCES\n1 Yamaguchi M , Ohta A , Tsunematsu T , et al.\nPreliminary criteria for classification of adult Still’s disease\n. J Rheumatol \n1992 ;19 :424 –30\n.1578458 \n2 Fautrel B , Zing E , JL G , et al.\nProposal for a new set of classification criteria for adult-onset Still disease\n. Medicine (Baltimore) \n2002 ;81 :194 –200\n. 10.1097/00005792-200205000-00003 11997716 \n3 Harrison SR , McGonagle D , Nizam S , et al.\nAnakinra as a diagnostic challenge and treatment option for systemic autoinflammatory disorders of undefined etiology\n. JCI Insight \n2016 ;1 :1 –15\n. 10.1172/jci.insight.86336 \n4 Alten R , Gomez-Reino J , Durez P , et al.\nEfficacy and safety of the human anti-IL-1beta monoclonal antibody canakinumab in rheumatoid arthritis: results of a 12-week, phase II, dose-finding study\n. BMC Musculoskelet Disord \n2011 ;12 \n10.1186/1471-2474-12-153 \n5 Fleischmann RM , Schechtman J , Bennett R , et al.\nAnakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis: a large, international, multicenter, placebo-controlled trial\n. Arthritis Rheum \n2003 ;48 :927 –34\n. 10.1002/art.10870 12687534 \n6 Smolen JS , Beaulieu A , Rubbert-Roth A , et al.\nEffect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial\n. Lancet \n2008 ;371 :987 –97\n. 10.1016/S0140-6736(08)60453-5 18358926 \n7 Huizinga TWJ , Fleischmann RM , Jasson M , et al.\nSarilumab, a fully human monoclonal antibody against IL-6R αin patients with rheumatoid arthritis and an inadequate response to methotrexate: efficacy and safety results from the randomised SARIL-RA-MOBILITY part a trial\n. Ann Rheum Dis \n2014 ;73 :1626 –34\n. 10.1136/annrheumdis-2013-204405 24297381 \n8 Genovese MC , Kremer J , Zamani O , et al.\nBaricitinib in patients with refractory rheumatoid arthritis\n. N Engl J Med \n2016 ;374 :1243 –52\n. 10.1056/NEJMoa1507247 27028914 \n9 Taylor PC , Keystone EC , van der Heijde D , et al.\nBaricitinib versus placebo or adalimumab in rheumatoid arthritis\n. N Engl J Med \n2017 ;376 :652 –62\n. 10.1056/NEJMoa1608345 28199814 \n10 Hofheinz K , Schett G , Manger B \nAdult onset Still’s disease associated with malignancy-cause or coincidence?\n\nSemin Arthritis Rheum \n2016 ;45 :621 –6\n. 10.1016/j.semarthrit.2015.10.003 26581485 \n11 Wolach O , Stone R \nAutoimmunity and inflammation in myelodysplastic syndromes\n. Acta Haematol \n2016 ;136 :108 –17\n. 10.1159/000446062 27337745 \n12 Seguier J , Gelsi-Boyer V , Ebbo M , et al.\nAutoimmune diseases in myelodysplastic syndrome favors patients survival: a case control study and literature review\n. Autoimmun Rev \n2019 ;18 :36 –42\n. 10.1016/j.autrev.2018.07.009 30408583 \n13 Quintás-Cardama A , Vaddi K , Liu P , et al.\nPreclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms\n. Blood \n2010 ;115 :3109 –17\n. 10.1182/blood-2009-04-214957 20130243 \n14 Hu Q , Wang M , Jia J , et al.\nTofacitinib in refractory adult-onset Still’s disease: 14 cases from a single centre in China\n. Ann Rheum Dis \n2020 ;pii:annrheumdis-2019-216699 \n10.1136/annrheumdis-2019-216699 \n15 Montealegre Sanchez GA , Reinhardt A , Ramsey S , et al.\nJAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies\n. J Clin Invest \n2018 ;128 :3041 –52\n. 10.1172/JCI98814 29649002\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2056-5933",
"issue": "6(2)",
"journal": "RMD open",
"keywords": "Adult Onset Still’s Disease; Ankylosing Spondylitis; Arthritis; DMARDs (biologic); Fever Syndromes; Inflammation; Psoriatic Arthritis",
"medline_ta": "RMD Open",
"mesh_terms": "D000328:Adult; D018501:Antirheumatic Agents; D001327:Autoimmune Diseases; D001384:Azetidines; D005260:Female; D006801:Humans; D007249:Inflammation; D008297:Male; D011687:Purines; D011720:Pyrazoles; D016706:Still's Disease, Adult-Onset; D013449:Sulfonamides; D016896:Treatment Outcome",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Mixed results with baricitinib in biological-resistant adult-onset Still's disease and undifferentiated systemic autoinflammatory disease.",
"title_normalized": "mixed results with baricitinib in biological resistant adult onset still s disease and undifferentiated systemic autoinflammatory disease"
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"abstract": "A patient who has overdosed on baclofen can present with significant neurological symptoms suggestive of a serious brain insult, but with appropriate diagnosis and treatment they often fully recover within 72 h. If the patient had been maintained on chronic baclofen therapy prior to the overdose, one must be watchful for signs of baclofen withdrawal as recovery from the overdose occurs.",
"affiliations": "Brain Health, 16 Exeter Falls Drive, Exeter, NH 03833, USA.",
"authors": "Miller|John J|JJ|",
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"issue": "8(5)",
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"keywords": "baclofen overdose; baclofen withdrawal; serious neurological symptoms",
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"title": "Baclofen overdose mimicking anoxic encephalopathy: a case report and review of the literature.",
"title_normalized": "baclofen overdose mimicking anoxic encephalopathy a case report and review of the literature"
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"abstract": "BACKGROUND\nInterstitial pneumonitis (IP), a fatal complication of DLBCL treatment, can bring great challenges to clinicians. We retrospectively investigated clinical characteristics and risk factors of previous IP patients, and analyzed their survival data.\n\n\nMETHODS\n556 DLBCL patients receiving CHOP-like regimens were enrolled between 2013 and 2018 in Sichuan Cancer Hospital.\n\n\nRESULTS\nThe IP incidences were 4.9 % (27/556), 1.1 % (2/186), 5.2 % (10/191) and 8.4 % (15/179) in CHOP, R-CHOP and R-CDOP groups respectively (P = 0.005). When IP was diagnosed, monocyte and IL-6 were significantly higher while CD4 and CD4/CD8 significantly lower compared to baseline. 81.5 % (22/27) of IP patients were pathogen-negative with good response to glucocorticoid monotherapy. Only one patient died while the others recovered from IP and subsequently underwent previous chemotherapy. 19.2 % (5/26) of IP patients experienced IP recurrence, likely due to the reason of lower initial dose or faster withdrawal speed of glucocorticoid. Multivariate analysis identified male, in addition to G-CSF, rituximab and pegylated liposomal doxorubicin as risk factors. The 3-year PFS and OS were 74.1 % and 46.9 % respectively for patients with IP.\n\n\nCONCLUSIONS\nWe suggest that IL-6, monocyte and CD4 should be monitored closely, especially in R-CHOP/R-CDOP group. Sufficient initial dose and slow decrease of glucocorticoid based on radiographic remissions were critical strategies to reduce IP recurrence. We speculate that drug-induced immune imbalance could be trigger of developing IP, causing a lower intensity cytokine storm, resulting in a potential immunotherapy. This complication might bring benefit in patients' survival through a mechanism similar to PD-1.",
"affiliations": "Department of Lymphoma, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, China.;Department of Lymphoma, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, China.;Department of Lymphoma, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, China.;Department of Lymphoma, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, China.;Department of Lymphoma, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, China.;Department of Lymphoma, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, China.;Department of Lymphoma, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, China.;Department of Lymphoma, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, China.;Department of Lymphoma, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, China.;Department of Lymphoma, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, China.;Department of Lymphoma, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, China.;Department of Lymphoma, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, China.;Department of Lymphoma, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, China.;Department of Lymphoma, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, China.;Department of Lymphoma, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, China. Electronic address: lili692@126.com.",
"authors": "Wei|Wen|W|;Zhu|Yajie|Y|;Tang|Jianning|J|;Xu|Chuan|C|;Li|Jiman|J|;He|Shuya|S|;Zhang|Zhihui|Z|;Wu|Ping|P|;Luo|Lei|L|;Guo|Qin|Q|;Li|Fang|F|;Ren|Yuanrong|Y|;Yu|Sisi|S|;Li|Renqin|R|;Li|Li|L|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.leukres.2021.106688",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0145-2126",
"issue": "111()",
"journal": "Leukemia research",
"keywords": "Diffuse large B cell lymphoma; Drug induced lung toxicity; Granulocyte colony stimulating factor; Interstitial pneumonitis; Pegylated liposomal doxorubicin; Rituximab",
"medline_ta": "Leuk Res",
"mesh_terms": null,
"nlm_unique_id": "7706787",
"other_id": null,
"pages": "106688",
"pmc": null,
"pmid": "34450501",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Not all bad: Drug-induced interstitial pneumonia in DLBCL patients is potentially fatal but could be linked to better survival.",
"title_normalized": "not all bad drug induced interstitial pneumonia in dlbcl patients is potentially fatal but could be linked to better survival"
} | [
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"abstract": "The opioid epidemic continues to have devastating consequences for children and families across the United States with rising prevalence of opioid use and abuse. Given the ease of access to these medications, accidental ingestion and overdose by children are becoming increasingly more common. The recognition of opioid-induced neurotoxicity and the associated life-threatening complication of acute cerebellar cytotoxic edema are crucial, as are the high morbidity and mortality without timely intervention. We discuss an infant with acute cytotoxic cerebellar edema following mucosal exposure to a transdermal fentanyl patch.",
"affiliations": "Division of Pediatric Emergency Medicine, Department of Emergency Medicine, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, IN, USA.;Department of Radiology, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, IN, USA.;Division of Pediatric Critical Care Medicine, Department of Pediatrics, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, IN, USA.;Department of Toxicology, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, IN, USA.;Department of Neurosurgery, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, IN, USA.",
"authors": "Haut|Lindsey N|LN|;Radhakrishnan|Rupa|R|https://orcid.org/0000-0001-5224-1891;Lutfi|Riad|R|https://orcid.org/0000-0002-9416-7113;Kao|Louise W|LW|https://orcid.org/0000-0002-6224-8381;Ackerman|Laurie L|LL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/9449565",
"fulltext": "\n==== Front\nCase Rep Crit Care\nCase Rep Crit Care\nCRICC\nCase Reports in Critical Care\n2090-6420\n2090-6439\nHindawi\n\n10.1155/2021/9449565\nCase Report\nAcute Cytotoxic Cerebellar Edema Subsequent to Fentanyl Patch Intoxication in an Infant\nHaut Lindsey N. 1\nhttps://orcid.org/0000-0001-5224-1891\nRadhakrishnan Rupa 2\nhttps://orcid.org/0000-0002-9416-7113\nLutfi Riad rlutfi@iu.edu\n3\nhttps://orcid.org/0000-0002-6224-8381\nKao Louise W. 4\nAckerman Laurie L. 5\n1Division of Pediatric Emergency Medicine, Department of Emergency Medicine, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, IN, USA\n2Department of Radiology, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, IN, USA\n3Division of Pediatric Critical Care Medicine, Department of Pediatrics, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, IN, USA\n4Department of Toxicology, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, IN, USA\n5Department of Neurosurgery, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, IN, USA\nAcademic Editor: Minesh Khashu\n\n2021\n7 9 2021\n2021 944956530 5 2021\n8 8 2021\nCopyright © 2021 Lindsey N. Haut 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.\nThe opioid epidemic continues to have devastating consequences for children and families across the United States with rising prevalence of opioid use and abuse. Given the ease of access to these medications, accidental ingestion and overdose by children are becoming increasingly more common. The recognition of opioid-induced neurotoxicity and the associated life-threatening complication of acute cerebellar cytotoxic edema are crucial, as are the high morbidity and mortality without timely intervention. We discuss an infant with acute cytotoxic cerebellar edema following mucosal exposure to a transdermal fentanyl patch.\n==== Body\npmc1. Introduction\n\nThe United States (US) is experiencing unprecedented rates of drug overdose-related deaths. The mortality toll in the US attributable to opioid medications has doubled in last two decades with more than 130 people dying daily following an opioid overdose [1]. The misuse of opioids, including prescription pain relievers and synthetic opioids, is a serious national crisis that affects adults and children. The number of opioid-related hospitalizations has doubled in the last twenty years with the largest percentage increase found in children under 5 years old, and the number of children requiring admission to pediatric intensive care for opioid ingestions has doubled in the last decade [2, 3]. The increasing number of adult drug prescriptions is strongly associated with rising pediatric exposures and poisonings; young children are at the greatest risk for exposure, with substantial health care use and morbidity specifically associated with opioid ingestions [4].\n\nOpioid-induced neurotoxicity in adults can present with a wide spectrum of symptoms, including confusion, hallucinations, delirium, and seizures. In contrast, the neurological effects of opioid intoxication in children are poorly understood. Rapid identification of these children may present a diagnostic dilemma, especially if a history of opioid ingestion is not available.\n\nMalignant cerebellar edema secondary to opioid intoxication is rarely reported in children. Without a high clinical suspicion, this imaging presentation may be attributed to other vascular, infectious, or postinfectious etiologies which are more common in children [5, 6]. Here, we describe a case of an infant with malignant cerebellar edema due to an inadvertent exposure to a transdermal fentanyl patch that required a lifesaving decompression craniectomy. We present this case to heighten awareness, especially in the acute pediatric clinical team.\n\n2. Patient Presentation\n\nThe patient was a 9-month-old male with a past medical history significant for in utero drug exposure and mild oral aversion, who had otherwise been reportedly well. The day prior to his initial presentation, he had been swimming with his family and was put down for a nap at 1600. Family checked on him at 2100 hours due to not waking up for dinner but found him sleeping and attributed his increased fatigue to his increased activity throughout the day. At 0700 hours the next day, family was still unable to wake the child. He was taken to the nearest emergency department, where his initial vitals were significant for hypoxemia, with oxygen saturation of 77% on room air and mild hypothermia with axillary temperature of 36.2°C. His physical exam was notable for lethargy and decreased level of arousal without external physical exam findings concerning for apparent injury or infection. Labs were significant for hypoglycemia (30 mg/dL), but his mental status did not improve with glucose supplementation. A head CT was performed, and he was found to have bilateral cerebellar hemisphere hypoattenuation with acute swelling on computed tomography (Figure 1). The presumed diagnosis at the time was acute stroke of unknown etiology, with the possibility of prolonged hypoglycemia and subsequent hypoxia contributing. He was flown to the closest pediatric tertiary care center and admitted to the Pediatric Intensive Care Unit (PICU) for close neurological monitoring and further evaluation.\n\n3. Initial Diagnosis and Outcome\n\nOn arrival at the PICU, he was found to have pinpoint pupils bilaterally without reactivity and a downward gaze, with withdrawal to painful stimulus. Due to concerns for the ability to protect his airway on arrival at the PICU, rapid sequence induction and intubation (RSI) was prepared, and on visualization of the patient's posterior oropharynx, a fentanyl patch was found adhered to his soft palate (Figure 2). The patch was easily removed from the mucosal surface. Intravenous naloxone was administered, and the patient immediately became more awake with conjugate pupils. However, his clinical improvement was transient, and RSI was completed to stabilize his airway and control ventilation.\n\nAdditional history revealed the patient's caretaker used fentanyl patches for chronic pain. The caretaker had replaced their patch prior to swimming the day before presentation and realized she was no longer wearing the patch shortly after arrival at the PICU. The exact length of time the patch was adherent to the patient's mucosal surface or the amount of medication remaining in the patch was unknown.\n\nToxicology was consulted, but there is little information available in regard to the pharmacokinetics of mucosal absorption of fentanyl. While case reports of pediatric patients after opioid pill ingestion are available, there were no references for fentanyl patch mucosal absorption. Serum toxicology testing was sent, with a serum fentanyl level from the day of admission returning elevated at 12 ng/mL (therapeutic level 1-4 ng/mL). Additional toxicology testing was negative (APAP, ASA, EtOH, amphetamine, cocaine, THC, opiate, PCP, and barbiturates). Standard urine drug screening for opioids is negative with fentanyl exposure due to its structural dissimilarity to morphine.\n\nNeurosurgery was consulted due to cerebellar swelling, and it was present in the PICU shortly after patient's arrival. The patient was started on a 3% hypertonic saline drip, and an EEG was obtained which showed diffuse background slowing with no seizure activity. The patient was closely monitored with serial neurologic exams. An MRI obtained two hours after presentation was concerning for persistent cerebellar swelling resulting in effacement of the fourth ventricle (Figure 3). The patient clinically worsened on hospital day 3, with increased somnolence, worsening ocular bobbing, intermittent bradycardia, and decreased movement of his upper extremities. An emergent head CT obtained on hospital day 3 showed increasing obstructive hydrocephalus (Figure 4). He was taken emergently to the operating room for decompressive suboccipital craniectomy with a patulous duroplasty and placement of an external ventricular drain (EVD). Postoperatively, he had a steadily improving neurological exam but the EVD was unable to be weaned. He was extubated 2 days after surgery and underwent ventriculoperitoneal shunt placement on hospital day 10, seven days after his initial surgery. He was discharged to acute rehabilitation and subsequently required a G-tube. A repeat MRI was obtained 3 weeks later (Figure 5) showing extensive encephalomalacia of the cerebellar hemispheres, in regions of previous cytotoxic injury.\n\nOn outpatient follow-up approximately 13 months later, the patient had normal motor strength and was walking although he remained very mildly apraxic and dysmetric. He was speaking well, majority of his calories are consumed by mouth with supplemental feeds via G-tube, and he was discharged from his physical, occupation, and speech therapies. He continues to follow with the developmental pediatric service who oversees his growth and developmental issues.\n\n4. Discussion\n\nThis case highlights the existence of an uncommon yet severe presentation of opioid toxicity with acute cerebellar edema. Patients with this condition present with varying degrees of central nervous system depression, often including miosis, respiratory depression, lethargy, or obtundation, often with an associated acute neurological decline reported [7–9]. Initial imaging usually reveals cerebellar cytotoxic injury and swelling, which can be complicated by development of acute obstructive hydrocephalus and tonsillar herniation. This case as well as another from our institution caused by “Kommon” (tobacco leaves soaked in ketamine) joins a few other published cases in highlighting the existence of an uncommon yet severe syndrome of acute cerebellar cytotoxic edema in the setting of opioid or ketamine toxicity [10, 11]. Though there are few cases reported, a 2017 case series reported that four of 10 patients required posterior fossa craniectomy and CSF diversion with resultant good functional outcomes [11]. Both cases from our institution also underwent posterior fossa craniotomy and shunting with good functional outcomes. However, there is little information regarding pediatric patients with opioid overdose. In our case, cerebellar injury is likely a result of direct mu receptor-mediated cerebellar neurotoxicity rather than secondary to respiratory depression-induced hypoxic ischemic injury where the cerebellum is the last structure typically affected.\n\nMucosal application of transdermal fentanyl patches has resulted in significant morbidity and mortality since their development [12]. Intact ingested fentanyl patches can lead to longer duration of symptoms, as the gel reservoir contains a large amount of fentanyl that continues to be absorbed and the patches are often more difficult to remove from the body [9]. Furthermore, the mucosa has greater than 30-fold increase in fentanyl absorption due to its lack of stratum corneum that the skin provides, with rapid absorption of fentanyl into the blood stream [13–16]. Even after three days of typical transdermal use, the “used” fentanyl patch can still contain 28-84% of the original dose of fentanyl [17].\n\nUnfortunately, timely diagnosis is difficult as there is often no provided history of opioid exposure and there is currently no definitive rapid testing available, so the clinician must have a high index of suspicion and perform a detailed physical examination. Radiological evaluation can assist in early diagnosis prior to toxicological results with CT findings of cerebellar edema, although the imaging findings may be confused with other more common causes of cerebellar edema such as ischemia or cerebellitis. Findings of obstructive hydrocephalus may be delayed [7, 18, 19]. As hydrocephalus can progress quickly in patients with limited neurologic exams, Reisner et al. recommend routine serial CT scanning for the first 48 hours for more timely identification of neuroradiographic sequelae [7]. While routine neurosurgical intervention is not recommended, if hydrocephalus is present, case outcomes show the importance of timely neurosurgical intervention [7, 10, 11, 20].\n\nWe present an uncommon yet severe syndrome of acute cerebellar cytotoxic edema in the setting of opioid or ketamine toxicity. Increased recognition of this condition by emergency room, neurosurgery, radiology, and critical care physicians is of paramount importance given the rising prevalence of use and abuse of these medications with the potential for children to access and ingest these medications. Patients need to be closely monitored for development of hydrocephalus and herniation syndromes, and timely surgical intervention appears to result in improved outcomes. A high index of suspicion for this diagnosis with early recognition and intervention has the potential to significantly improve patient's clinical outcomes.\n\nConflicts of Interest\n\nThe authors have no conflicts of interest to disclose.\n\nAuthors' Contributions\n\nDrs. Haut, Radhakrishnan, Kao, Lutfi, and Ackerman provided direct care for the patient, conceptualized the case report, collaborated in drafting the initial manuscript, and contributed significant intellectual content; all authors reviewed and revised the final manuscript, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.\n\nFigure 1 Axial (a) and midsagittal (b) noncontrast head CT at presentation shows bilateral cerebellar hemisphere hypoattenuation (low density) with swelling (arrows). There is inferior herniation of the cerebellar tonsils with crowding at the foramen magnum (dashed arrow).\n\nFigure 2 Example of fentanyl patch removed from patient's palate (provided by the caregiver).\n\nFigure 3 MRI at the time of presentation. (a) Axial T2-weighted image shows bilateral cerebellar edema (arrows) with effacement of the inferior fourth ventricle (dashed arrow). (b) Midsagittal T2 weighted image shows posterior fossa crowding with effacement of the inferior fourth ventricle (dashed arrow). (c) Diffusion imaging and (d) apparent diffusion coefficient (ADC) map show true restricted diffusion in the cerebellar hemispheres (arrows) in the region of T2 signal abnormality consistent with cytotoxic cerebellar injury.\n\nFigure 4 Noncontrast head CT images from hospital day 3 associated with neurological decline. (a) Axial CT image shows enlargement of the lateral (arrows) and third (dashed arrow) ventricles, and (b) midline sagittal CT image shows cerebellar swelling, effacement of the inferior fourth ventricle (arrowhead), and cerebellar tonsillar herniation (arrow).\n\nFigure 5 MRI evaluation 3 weeks after initial presentation. Axial T2-weighted image through the cerebellum three weeks after presentation shows volume loss and bright signal in the cerebellar hemispheres consistent with encephalomalacia in the regions of previous cerebellar injury and diffusion restriction.\n==== Refs\n1 Rudd R. A. Aleshire N. Zibbell J. E. Gladden R. M. Increases in drug and opioid overdose deaths--United States, 2000-2014 MMWR. Morbidity and Mortality Weekly Report 2016 64 50-51 1378 1382 10.15585/mmwr.mm6450a3 2-s2.0-84955313404 26720857\n2 Kane J. M. Colvin J. D. Bartlett A. H. Hall M. Opioid-related critical care resource use in US children's hospitals Pediatrics 2018 141 4 p. e20173335 10.1542/peds.2017-3335 2-s2.0-85044757415 29507166\n3 Gaither J. R. Leventhal J. M. Ryan S. A. Camenga D. R. National trends in hospitalizations for opioid poisonings among children and adolescents, 1997 to 2012 JAMA Pediatrics 2016 170 12 1195 1201 10.1001/jamapediatrics.2016.2154 2-s2.0-85011419254 27802492\n4 Burghardt L. C. Ayers J. W. Brownstein J. S. Bronstein A. C. Ewald M. B. Bourgeois F. T. Adult prescription drug use and pediatric medication exposures and poisonings Pediatrics 2013 132 1 18 27 10.1542/peds.2012-2978 2-s2.0-84879984384 23733792\n5 Sawaishi Y. Takada G. Acute cerebellitis Cerebellum 2002 1 3 223 228 10.1080/14734220260418457 2-s2.0-0041733080 12879984\n6 Sarikaya H. Steinlin M. Cerebellar stroke in adults and children Handbook of Clinical Neurology 2018 155 301 312 10.1016/B978-0-444-64189-2.00020-2 2-s2.0-85048594274 29891068\n7 Reisner A. Hayes L. L. Holland C. M. Opioid overdose in a child: case report and discussion with emphasis on neurosurgical implications Journal of neurosurgery Pediatrics. 2015 16 6 752 757 10.3171/2015.4.PEDS14667 2-s2.0-84971633808 26339960\n8 Glatstein M. Finkelstein Y. Scolnik D. Accidental methadone ingestion in an infant: case report and review of the literature Pediatric emergency care. 2009 25 2 109 111 10.1097/PEC.0b013e318196faff 2-s2.0-66249101645 19225381\n9 Mrvos R. Feuchter A. C. Katz K. D. Duback-Morris L. F. Brooks D. E. Krenzelok E. P. Whole fentanyl patch ingestion: a multi-center case series The Journal of emergency medicine. 2012 42 5 549 552 10.1016/j.jemermed.2011.05.017 2-s2.0-84861096468 21683542\n10 Villelli N. Hauser N. Gianaris T. Froberg B. A. Fulkerson D. H. Severe bilateral cerebellar edema from ingestion of ketamine: case report Journal of neurosurgery Pediatrics. 2017 20 4 393 396 10.3171/2017.5.PEDS16695 2-s2.0-85030707537 28806884\n11 Duran D. Messina R. D. Beslow L. A. Malignant cerebellar edema subsequent to accidental prescription opioid intoxication in children Frontiers in Neurology 2017 8 362 10.3389/fneur.2017.00362 2-s2.0-85025810646\n12 Grissinger M. Fentanyl patch fatalities: we all have a role in prevention! P T. 2016 41 7 405 406 27408513\n13 Liappas I. A. Dimopoulos N. P. Mellos E. Gitsa O. E. Liappas A. I. Rabavilas A. D. Oral transmucosal abuse of transdermal fentanyl Journal of psychopharmacology (Oxford, England) 2004 18 2 277 280 10.1177/0269881104042634 2-s2.0-3242698713 15260918\n14 Arroyo Plasencia A. M. Mowry J. Smith J. Quigley K. In vitro release of fentanyl from transdermal patches in gastric and intestinal fluid Clinical Toxicology. 2014 52 9 945 947 10.3109/15563650.2014.967399 2-s2.0-84910045033 25345435\n15 Nelson L. Schwaner R. Transdermal fentanyl: pharmacology and toxicology Journal of medical toxicology : official journal of the American College of Medical Toxicology. 2009 5 4 230 241 10.1007/BF03178274 2-s2.0-75349092325 19876859\n16 Roy S. D. Flynn G. L. Transdermal delivery of narcotic analgesics: pH, anatomical, and subject influences on cutaneous permeability of fentanyl and sufentanil Pharmaceutical Research 1990 7 8 842 847 10.1023/A:1015912932416 2-s2.0-0025000624 1978306\n17 Marquardt K. A. Tharratt R. S. Musallam N. A. Fentanyl remaining in a transdermal system following three days of continuous use The Annals of pharmacotherapy 1995 29 10 969 971 10.1177/106002809502901001 2-s2.0-0028845278 8845555\n18 Mills F. MacLennan S. C. Devile C. J. Saunders D. E. Severe cerebellitis following methadone poisoning Pediatric radiology 2008 38 2 227 229 10.1007/s00247-007-0635-6 2-s2.0-38049045691 17952429\n19 Zanin A. Masiero S. Severino M. S. Calderone M. Da Dalt L. Laverda A. M. A delayed methadone encephalopathy: clinical and neuroradiological findings Journal of child neurology. 2010 25 6 748 751 10.1177/0883073809343318 2-s2.0-77952932182 19808992\n20 de Ribaupierre S. Meagher-Villemure K. Villemure J. G. The role of posterior fossa decompression in acute cerebellitis Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery. 2005 21 11 970 974 10.1007/s00381-005-1176-7 2-s2.0-27744577436 15928964\n\n",
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"title": "Acute Cytotoxic Cerebellar Edema Subsequent to Fentanyl Patch Intoxication in an Infant.",
"title_normalized": "acute cytotoxic cerebellar edema subsequent to fentanyl patch intoxication in an infant"
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"abstract": "Little is known about the use of lung transplantation in the management of sickle cell disease-associated pulmonary arterial hypertension (SCD-PAH). We present clinical and pathological data and report the first successful outcome of bilateral lung transplantation in a patient with severe SCD-PAH and pulmonary veno-occlusive disease (PVOD). We discuss the complexities of multidisciplinary planning and management of lung transplantation in patients with SCD-associated pulmonary vascular complications. This case reports the first documented successful lung transplant and first case of PVOD in a patient with SCD-PAH.",
"affiliations": "Departments of Medicine, Pediatrics, Pathology, and Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.;Departments of Medicine, Pediatrics, Pathology, and Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.;Departments of Medicine, Pediatrics, Pathology, and Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.;Departments of Medicine, Pediatrics, Pathology, and Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.;Departments of Medicine, Pediatrics, Pathology, and Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA ; Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.;Departments of Medicine, Pediatrics, Pathology, and Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA ; Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.;Departments of Medicine, Pediatrics, Pathology, and Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.;Departments of Medicine, Pediatrics, Pathology, and Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.;Departments of Medicine, Pediatrics, Pathology, and Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.;Departments of Medicine, Pediatrics, Pathology, and Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.;Departments of Medicine, Pediatrics, Pathology, and Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.;Departments of Medicine, Pediatrics, Pathology, and Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.;Departments of Medicine, Pediatrics, Pathology, and Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.;Departments of Medicine, Pediatrics, Pathology, and Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.;Temple University School of Medicine, Philadelphia, Pennsylvania, USA.;Departments of Medicine, Pediatrics, Pathology, and Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.;Departments of Medicine, Pediatrics, Pathology, and Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.;Departments of Medicine, Pediatrics, Pathology, and Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.",
"authors": "George|M Patricia|MP|;Novelli|Enrico M|EM|;Shigemura|Norihisa|N|;Simon|Marc A|MA|;Feingold|Brian|B|;Krishnamurti|Lakshmanan|L|;Morrell|Matthew R|MR|;Gries|Cynthia G|CG|;Haider|Syed|S|;Johnson|Bruce A|BA|;Crespo|Maria M|MM|;Bhama|Jay K|JK|;Bermudez|Christian|C|;Yousem|Samuel A|SA|;Toyoda|Yoshiya|Y|;Champion|Hunter C|HC|;Pilewski|Joseph M|JM|;Gladwin|Mark T|MT|",
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"other_id": null,
"pages": "952-8",
"pmc": null,
"pmid": "25006411",
"pubdate": "2013-12",
"publication_types": "D002363:Case Reports",
"references": "10861320;11552063;7886811;18854853;8091488;23111496;17394147;11743502;324452;20026775;19903897;19481015;21732836;3551253;15329603;16890124;6990286;9361966;22258951;22077523;21511090;23085723;21900080;21778170;22309412;10075596;19048000;21131035;7715639;21527519;21445921;7791837;9647873",
"title": "First successful lung transplantation for sickle cell disease with severe pulmonary arterial hypertension and pulmonary veno-occlusive disease.",
"title_normalized": "first successful lung transplantation for sickle cell disease with severe pulmonary arterial hypertension and pulmonary veno occlusive disease"
} | [
{
"companynumb": "US-UNITED THERAPEUTICS-UTC-026523",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstancename": "TREPROSTINIL"
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"drugadditional": "1... |
{
"abstract": "EBV-related PTLD developing after HSCT is a potentially life-threatening disease. HLH is uncommon after allogeneic HSCT. Data on outcome of patients with PTLD and concomitant HLH after allogeneic HSCT are limited. In this retrospective study, we collected demographic, clinical, laboratory, and outcome data for 408 patients who underwent allogeneic HSCT from 2006 to 2015. Graft source included CB (n = 135; 33.1%), PBSCs (n = 34; 8.3%), and BM (n = 239; 58.6%). Eight out of 408 patients (2%) developed EBV-PTLD with a median age at HSCT of 5.9 years (range: 2.3-17.3). All eight patients received ATG as part of the conditioning regimen. Graft source was PBSC in three patients (37.5%), BM in four patients (50%), and CB in one patient (12.5%). Donors were matched unrelated in five patients (62.5%) and matched sibling in three patients (37.5%). Seven out of eight patients developed EBV-PTLD within the first 100-day post-HSCT. Lymph node biopsy revealed early lesions in three patients, polymorphic in three patients, and monomorphic PTLD in two patients. Three patients (37.5%) died within 1 month of EBV-PTLD diagnosis. All deceased patients developed HLH manifestations with two of them meeting HLH diagnostic criteria and one having an incomplete workup. PTLD after allogeneic HSCT with manifestations of HLH is associated with high mortality. Early identification and treatment of EBV-PTLD seems imperative to control the disease, especially if signs of HLH are evolving.",
"affiliations": "Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.;Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.;Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.;Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.;Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.;Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.;Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.;Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.;Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.",
"authors": "Ali|Salah|S|0000-0003-3705-4064;AlThubaiti|Sami|S|;Renzi|Samuele|S|;Krueger|Joerg|J|;Chiang|K Y|KY|;Naqvi|Ahmed|A|;Schechter|Tal|T|;Punnett|Angela|A|;Ali|Muhammad|M|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13319",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "23(1)",
"journal": "Pediatric transplantation",
"keywords": "EBV-PTLD; HLH; stem cell transplantation",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D020031:Epstein-Barr Virus Infections; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015994:Incidence; D007223:Infant; D051359:Lymphohistiocytosis, Hemophagocytic; D008232:Lymphoproliferative Disorders; D008297:Male; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D016019:Survival Analysis",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e13319",
"pmc": null,
"pmid": "30417487",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Hemophagocytic lymphohistiocytosis is a sign of poor outcome in pediatric Epstein-Barr virus-associated post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation.",
"title_normalized": "hemophagocytic lymphohistiocytosis is a sign of poor outcome in pediatric epstein barr virus associated post transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation"
} | [
{
"companynumb": "CA-CHEPLA-MYERS SQUIBB COMPANY-BMS-2019-027238",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"dr... |
{
"abstract": "We conducted a prospective evaluation of drug-induced severe hyponatremia (adverse drug reaction (ADR)) through the Prospective Pharmacovigilance Program from Laboratory Signals at Hospital over a period of 10 years. Cases of serum sodium (Na(s)) < 116 mM were recorded from July 2007 to June 2017 (first period). Also cases of Na(s) 116-122 mM were recorded from July 2012 to June 2017 (second period). Drugs were the primary cause of severe hyponatremia. The incidence rate of Na(s) < 116 mM by drugs was increased threefold over the decade. Compared with other causes of hyponatremia, patients with adverse drug reaction-serum sodium (ADR-Na(s)) in the first period were older (79 years (interquartile range (IQR) 68.6-89 vs. 65 years (IQR 48-81); P < 0.001) and were more often women (70.8% vs. 48.9% men, P < 0.001); in the second period were also older (79 years (IQR 65.3-89) vs. 63 years (IQR 46-80.6); P < 0.001) and were more often women (70% vs. 53%, P = 0.002), and ADR-Na(s) occurred more often in summer. The most frequent therapeutic groups of culprit drugs were the cardiovascular system and nervous system. The 65.3% in the first period and 71.2% in the second period of the ADR-Na(s) cases responded to hydration and had been diagnosed with hypovolemic hyponatremia.",
"affiliations": "Department of Clinical Pharmacology, La Paz University Hospital-Carlos III, IdiPAZ, School of Medicine, Autonomous University of Madrid, Madrid, Spain.;Department of Clinical Pharmacology, La Paz University Hospital-Carlos III, IdiPAZ, School of Medicine, Autonomous University of Madrid, Madrid, Spain.;Department of Clinical Pharmacology, La Paz University Hospital-Carlos III, IdiPAZ, School of Medicine, Autonomous University of Madrid, Madrid, Spain.;Department of Clinical Pharmacology, La Paz University Hospital-Carlos III, IdiPAZ, School of Medicine, Autonomous University of Madrid, Madrid, Spain.;Department of Clinical Pharmacology, La Paz University Hospital-Carlos III, IdiPAZ, School of Medicine, Autonomous University of Madrid, Madrid, Spain.;Department of Clinical Pharmacology, La Paz University Hospital-Carlos III, IdiPAZ, School of Medicine, Autonomous University of Madrid, Madrid, Spain.;Department of Clinical Pharmacology, La Paz University Hospital-Carlos III, IdiPAZ, School of Medicine, Autonomous University of Madrid, Madrid, Spain.;Department of Clinical Pharmacology, La Paz University Hospital-Carlos III, IdiPAZ, School of Medicine, Autonomous University of Madrid, Madrid, Spain.;Department of Clinical Pharmacology, La Paz University Hospital-Carlos III, IdiPAZ, School of Medicine, Autonomous University of Madrid, Madrid, Spain.;Department of Clinical Pharmacology, La Paz University Hospital-Carlos III, IdiPAZ, School of Medicine, Autonomous University of Madrid, Madrid, Spain.;Department of Clinical Pharmacology, La Paz University Hospital-Carlos III, IdiPAZ, School of Medicine, Autonomous University of Madrid, Madrid, Spain.;Department of Clinical Pharmacology, La Paz University Hospital-Carlos III, IdiPAZ, School of Medicine, Autonomous University of Madrid, Madrid, Spain.;Department of Clinical Pharmacology, La Paz University Hospital-Carlos III, IdiPAZ, School of Medicine, Autonomous University of Madrid, Madrid, Spain.",
"authors": "Ramírez|Elena|E|0000-0002-4052-8876;Rodríguez|Amelia|A|;Queiruga|Javier|J|;García|Irene|I|;Díaz|Lucía|L|;Martínez|Lucía|L|;Muñoz|Raúl|R|;Muñoz|Mario|M|;Tong|Hoi Y|HY|0000-0003-2397-8274;Martínez|José Carlos|JC|;Borobia|Alberto M|AM|0000-0002-8584-3263;Carcas|Antonio J|AJ|;Frías|Jesús|J|",
"chemical_list": "D000701:Analgesics, Opioid; D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D000970:Antineoplastic Agents; D002317:Cardiovascular Agents; D018680:Cholinergic Antagonists; D005765:Gastrointestinal Agents; D007004:Hypoglycemic Agents; D011619:Psychotropic Drugs",
"country": "United States",
"delete": false,
"doi": "10.1002/cpt.1562",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-9236",
"issue": "106(6)",
"journal": "Clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Clin Pharmacol Ther",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid; D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D000970:Antineoplastic Agents; D001838:Bolivia; D002317:Cardiovascular Agents; D002648:Child; D002675:Child, Preschool; D018680:Cholinergic Antagonists; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D007004:Hypoglycemic Agents; D007010:Hyponatremia; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D060735:Pharmacovigilance; D011446:Prospective Studies; D011619:Psychotropic Drugs; D012621:Seasons; D012720:Severity of Illness Index; D055815:Young Adult",
"nlm_unique_id": "0372741",
"other_id": null,
"pages": "1362-1379",
"pmc": null,
"pmid": "31247118",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Severe Hyponatremia Is Often Drug Induced: 10-Year Results of a Prospective Pharmacovigilance Program.",
"title_normalized": "severe hyponatremia is often drug induced 10 year results of a prospective pharmacovigilance program"
} | [
{
"companynumb": "IT-NAPPMUNDI-GBR-2020-0074724",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TAPENTADOL"
},
"drugadditional": "3",
... |
{
"abstract": "International experts recently characterized interstitial pneumonia with autoimmune features (IPAF) as a provisional diagnosis for patients with interstitial lung disease who have characteristics of autoimmune disease but do not meet criteria for a specific autoimmune disease. We describe clinical characteristics of IPAF patients and examine responses to mycophenolate as a therapy for IPAF.\nThis retrospective cohort included adult patients meeting European Respiratory Society/American Thoracic Society classification criteria for IPAF. Sociodemographic, clinical, and pulmonary function test data were abstracted for patients with and without mycophenolate treatment and followed longitudinally from interstitial lung disease diagnosis for change in pulmonary function test results.\nWe identified 52 patients who met criteria for IPAF. Of 52 IPAF patients, 24 did not receive mycophenolate and 28 did, with median time to mycophenolate treatment 22 months. Changes in FVC% and percentage predicted lung diffusion capacity for carbon monoxide (DLCO%) between the mycophenolate-treated and untreated groups were not significantly different (FVC% change P=0.08, DLCO% change P=0.17). However, there was a trend toward more rapid baseline decline of both FVC% and DLCO% in the mycophenolate-treated cohort before vs after mycophenolate therapy. The slope of both FVC% and DLCO% values improved after onset of mycophenolate exposure for the treated group, although this finding was not statistically significant.\nPatients with IPAF might benefit from mycophenolate therapy. Larger prospective clinical trials are needed to evaluate the efficacy of mycophenolate for patients who meet criteria for IPAF.",
"affiliations": "Division of Rheumatology, Department of Internal Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA, ssmccoy@medicine.wisc.edu.;Division of Pulmonary and Critical Care, Department of Internal Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA.;Division of Pulmonary and Critical Care, Department of Internal Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA.;Department of Radiology, University of Wisconsin, Madison, WI 53792-3252, USA.;Department of Radiology, University of Wisconsin, Madison, WI 53792-3252, USA.;Department of Radiology, University of Wisconsin, Madison, WI 53792-3252, USA.;Department of Biostatistics, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.;Department of Pathology, University of Wisconsin, Madison, WI 53792-3252, USA.;Department of Pulmonology, SSM Health Dean Medical Group, Madison, WI 53715, USA.;Division of Rheumatology, Department of Internal Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA, ssmccoy@medicine.wisc.edu.",
"authors": "McCoy|Sara S|SS|;Mukadam|Zubin|Z|;Meyer|Keith C|KC|;Kanne|Jeffrey P|JP|;Meyer|Cristopher A|CA|;Martin|Maria D|MD|;Sampene|Emmanuel|E|;Aesif|Scott W|SW|;Rice|Laurie N|LN|;Bartels|Christie M|CM|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/TCRM.S173154",
"fulltext": "\n==== Front\nTher Clin Risk ManagTher Clin Risk ManagTherapeutics and Clinical Risk ManagementTherapeutics and Clinical Risk Management1176-63361178-203XDove Medical Press 10.2147/TCRM.S173154tcrm-14-2171Original ResearchMycophenolate therapy in interstitial pneumonia with autoimmune features: a cohort study McCoy Sara S 1Mukadam Zubin 2Meyer Keith C 2Kanne Jeffrey P 3Meyer Cristopher A 3Martin Maria D 3Sampene Emmanuel 4Aesif Scott W 5Rice Laurie N 6Bartels Christie M 1\n1 Division of Rheumatology, Department of Internal Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA, ssmccoy@medicine.wisc.edu\n2 Division of Pulmonary and Critical Care, Department of Internal Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA\n3 Department of Radiology, University of Wisconsin, Madison, WI 53792-3252, USA\n4 Department of Biostatistics, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA\n5 Department of Pathology, University of Wisconsin, Madison, WI 53792-3252, USA\n6 Department of Pulmonology, SSM Health Dean Medical Group, Madison, WI 53715, USACorrespondence: Sara S McCoy, Division of Rheumatology, Department of Internal Medicine, School of Medicine and Public Health, University of Wisconsin, 1685 Highland Avenue, Madison, WI 53705-2281, USA, Email ssmccoy@medicine.wisc.edu2018 01 11 2018 14 2171 2181 © 2018 McCoy et al. This work is published and licensed by Dove Medical Press Limited2018The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Objectives\nInternational experts recently characterized interstitial pneumonia with autoimmune features (IPAF) as a provisional diagnosis for patients with interstitial lung disease who have characteristics of autoimmune disease but do not meet criteria for a specific autoimmune disease. We describe clinical characteristics of IPAF patients and examine responses to mycophenolate as a therapy for IPAF.\n\nMethods\nThis retrospective cohort included adult patients meeting European Respiratory Society/American Thoracic Society classification criteria for IPAF. Sociodemographic, clinical, and pulmonary function test data were abstracted for patients with and without mycophenolate treatment and followed longitudinally from interstitial lung disease diagnosis for change in pulmonary function test results.\n\nResults\nWe identified 52 patients who met criteria for IPAF. Of 52 IPAF patients, 24 did not receive mycophenolate and 28 did, with median time to mycophenolate treatment 22 months. Changes in FVC% and percentage predicted lung diffusion capacity for carbon monoxide (DLCO%) between the mycophenolate-treated and untreated groups were not significantly different (FVC% change P=0.08, DLCO% change P=0.17). However, there was a trend toward more rapid baseline decline of both FVC% and DLCO% in the mycophenolate-treated cohort before vs after mycophenolate therapy. The slope of both FVC% and DLCO% values improved after onset of mycophenolate exposure for the treated group, although this finding was not statistically significant.\n\nConclusion\nPatients with IPAF might benefit from mycophenolate therapy. Larger prospective clinical trials are needed to evaluate the efficacy of mycophenolate for patients who meet criteria for IPAF.\n\nKeywords\ninterstitial lung diseaseautoimmune diseaseconnective tissue diseasemycophenolate\n==== Body\nIntroduction\nExperts recently proposed the term “interstitial pneumonia with autoimmune features” (IPAF) as a research term for patients with an interstitial lung process consistent with idiopathic interstitial pneumonia (IP) combined with features of autoimmunity without meeting full diagnostic criteria for a specific connective tissue disease (CTD) diagnosis.1 Recently, the nomenclature and classification of criteria for IPAF were clarified by the European Respiratory Society/American Thoracic Society, allowing researchers to define and observe IPAF cohorts.1 A patient must meet criteria from two of the three prespecified domains to fulfill criteria for IPAF.1 These domains are clinical features of extrathoracic autoimmune disease, serologic evidence of autoimmune disease, and morphological criteria based on chest imaging, histopathology, or other multicompartment involvement.\n\nDespite the clinical familiarity of concomitant interstitial lung disease (ILD) and nonspecific features of autoimmune disease, little information is available on treatment recommendations or clinical outcomes for patients with IPAF. In lung-dominant CTD, a disease similar but not identical to IPAF, mycophenolate, an immunosuppressive agent that impairs lymphocytogenesis, has shown therapeutic promise. In a retrospective cohort study of 19 patients with lung-dominant CTD, mycophenolate therapy was associated with trends toward improvement in pulmonary function test (PFT) values,2 but no comparison group was included. Other studies demonstrating benefits of mycophenolate have included a small number of patients with undifferentiated CTD and ILD within a broader pool of defined CTD-ILD patients.3 While mycophenolate has shown promise in treatment of various forms of CTD-ILD, little is known about the efficacy of mycophenolate as a therapy for IPAF.\n\nWe sought to identify and characterize a retrospective cohort of IPAF patients to examine the effectiveness of mycophenolate therapy. We present a cohort study of consecutive patients who fulfilled European Respiratory Society/American Thoracic Society classification criteria for IPAF.1 We examined longitudinal change in PFT and high-resolution computed tomography (HRCT) changes associated with mycophenolate therapy, hypothesizing that treatment with mycophenolate may attenuate lung function decline as reflected by PFT values and radiographic features on HRCT.\n\nMethods\nInclusion/exclusion\nThis study was approved by the University of Wisconsin Health Sciences Institutional Review Board (IRB) with a waiver of individual informed consent for this minimal-risk retrospective study. Patient confidentiality was protected through approved IRB protocols. This was a retrospective-cohort study of adults ≥18 years old who met diagnostic criteria for IPAF.1 To create this academic system cohort, we utilized the electronic health record to identify patients who had both 1) positive antinuclear antibodies or any diagnosis of autoimmune disease (scleroderma, systemic lupus erythematosus, Sjögren’s syndrome/sicca, dermatomyositis, polymyositis, CTD, undifferentiated CTD) and 2) a diagnosis of ILD, nonspecific IP (NSIP), usual IP (UIP), lymphoid IP (LIP), diffuse alveolar damage, or organizing pneumonia (OP). Resultant records were reviewed and excluded if a patient met criteria for a definite autoimmune condition or had not seen both pulmonology and rheumatology departments through this system. Patients were reviewed to ensure they met the minimum of two of three required domains to satisfy the diagnosis of IPAF1 (Figure 1).\n\nMedical records were extracted manually by MD reviewers (SM, ZM, and LR). Using a standardized tool for case review, we extracted all clinical and serologic data. Clinical experts performed HRCT and histopathological evaluations. Multicompartment involvement was defined as unexplained intrinsic airway disease (by PFT, HRCT, or histopathology), unexplained pulmonary vasculopathy (by presence of elevated mean pulmonary artery pressure ≥25 mmHg and pulmonary capillary-wedge pressure ≤15 mmHg), and unexplained pleural or pericardial effusion or thickening (diagnosed by HRCT or echocardiography).1\n\nOutcomes/data collection\nPFTs and 6-minute walk test (6MWT)\nOur primary outcome of interest was a clinically significant change in PFTs. PFTs, including percentage predicted FVC and diffusion capacity of lungs for carbon monoxide (DLCO), were collected for all patients. PFT values averaged in 6-month time intervals were anchored on the patient’s date of first ILD diagnosis for longitudinal analysis of the entire cohort. Analysis of the treated group was anchored with baseline at therapy initiation. Distances for the 6MWT were extracted from each patient’s medical record to examine trends over time.\n\nCT imaging\nThe first (baseline) and last HRCT were reviewed and scored independently by two of three blinded subspecialist thoracic radiologists (JPK, CAM, MDM) at five levels for total extent of disease, extent of reticulation, proportion of ground-glass opacity (GGO), and coarseness of reticulation as described by Goh et al.4 Discrepancies ≥20% for continuous scores or more than one grade for categorical scores were resolved independently by the third radiologist in blinded fashion. Morphologic patterns were determined independently by two radiologists (NSIP, OP, NSIP with OP overlap, LIP, other), with the third radiologist independently settling discrepancies. Our outcomes of interest included the global (total) extent of ILD, proportion of GGO, global extent of GGO and reticulation, and quantification of the coarseness of reticulation.\n\nPathology\nAll available pathological specimens were independently reviewed by a pathologist with specialty in ILD (SA). Specimens were categorized as NSIP, OP, NSIP with OP overlap, LIP, interstitial lymphoid aggregates with germinal centers, or diffuse lymphoplasmacytic infiltration (with or without lymphoid follicles).\n\nVariable definitions\nOur primary exposure of interest was mycophenolate. Mycophenolic acid use was considered equivalent to mycophenolate mofetil for the purposes of this study. Exposure start and end dates were recorded using electronic health-record prescription data. Additional clinical data extracted for analysis included age, sex, tobacco use, cardiovascular disease (defined as coronary artery disease, congestive heart failure, or cerebrovascular disease), gastroesophageal reflux (GER), malignancy, obstructive sleep apnea, pulmonary arterial hypertension, and pulmonary embolism. Clinical features abstracted included inflammatory arthritis, Raynaud’s phenomenon, digital fissures/ulcers, telangiectasias, digital edema, serositis, extensor surface rash, and immunosuppressive/immunomodulatory therapy (azathioprine, cyclophosphamide, leflunomide, methotrexate, and prednisone). Additional medications recorded include azithromycin, proton-pump inhibitors, and ranitidine. Laboratory data collection included blood counts, complement, creatinine, inflammatory markers, ANA, anti-Jo1, anticitrullinated cyclic protein antibodies, double-stranded DNA, MDA5, PM-Scl, rheumatoid factor (double or more the upper limit of normal), ribonucleoprotein antibodies, anti-Scl70, anti-Smith antibodies, anti-SSA/SSB antibodies, and other tRNA antibodies.\n\nStatistical analysis\nDifferences in baseline characteristics by mycophenolate status were compared via χ2 or Fisher’s exact tests for categorical variables and Student’s t-test for continuous variables. We considered P<0.05 significant. Simple linear regression and t-tests of the calculated change variable were performed to evaluate differences in 6MWT and PFTs in patients within and between groups with and without mycophenolate exposure. Paired t-tests were performed to compare pre- and postmycophenolate slopes in the exposed groups. Patients were censored at time of death, lung transplant, or end of data availability (patient was lost to follow-up or last review date in January 2017). Kaplan–Meier survival analyses were performed to examine how mycophenolate exposure impacted survival, time to transplant, or time to PFT decline. Statistical analysis was performed using Stata version 14 (StataCorp LP, College Station, TX, USA) and GraphPad Prism (GraphPad Software, Inc., La Jolla, CA, USA).\n\nResults\nBaseline characteristics\nWe identified 52 adult patients meeting criteria for IPAF, 33 (63%) female (aged 31–83 years). Of the 52 patients with IPAF, 24 (46%) were not treated with mycophenolate (unexposed) and 28 (54%) were treated with mycophenolate (exposed) at median 22 months from diagnosis (Table 1). The median duration of mycophenolate exposure was 41 months from ILD diagnosis (range 16 days to 93 months). The median dose of mycophenolate was 2,000 mg daily.\n\nClinical characteristics were generally similar between the mycophenolate-exposed and -unexposed groups, while some differences were noted. There were significantly higher numbers of patients with GER in the mycophenolate-exposed than the mycophenolate unexposed group. No other clinical characteristics, including cardiovascular disease, malignancy, obstructive sleep apnea, pulmonary arterial hypertension, and pulmonary embolism, were different between the two groups. The mycophenolate-exposed group was treated more frequently with azithromycin, hydroxychloroquine, and steroids. Laboratory features including hematologic abnormalities, complement, creatinine, and inflammatory markers were similar between the two groups. Bronchoalveolar lavage tended to be lymphocyte-predominant in the mycophenolate group, although this finding did not reach statistical significance. Four patients with IPAF went on to develop a confirmed autoimmune disease: microscopic polyangiitis (n=3) and SLE (n=1). IPAF criteria were compared between mycophenolate-exposed and unexposed groups within the three domains. The clinical domains were not significantly different between the mycophenolate-exposed and unexposed groups (Table 2). Within the serologic domain, autoantibodies were also similar between the mycophenolate-exposed and unexposed groups, with the exception of anti-RNP antibodies, which were more frequent in the mycophenolate-treated group (P=0.03). Multi-compartment involvement did not vary between mycophenolate-exposed and unexposed groups. There was no difference in the manner by which IPAF patients achieved diagnostic criteria (Table 2). Within the mycophenolate-exposed group, five patients reported adverse effects that led to cessation or change of therapy: nausea (n=2), gastrointestinal upset (n=1), diarrhea (n=1), and myalgia (n=1).\n\nBaseline biopsy findings\nThirty patients had pathology analysis of lung tissue (of which 26 were available for review by our pathologist, and seven of these were explants or autopsy). Of the 26 biopsies, 19 from the mycophenolate-exposed group and seven from the unexposed group were available for review. Patterns of involvement were broad and in many cases mixed: NSIP (n=5), OP (n=1), NSIP with OP (n=1), LIP (n=0), interstitial lymphoid aggregates with germinal centers (n=2), UIP (n=1), UIP with atypical features (n=8), acute lung injury (n=4), interstitial lymphoplasmacytic inflammation (n=6), and normal (n=2). Interestingly, while many pathological specimens were best classified as of UIP pattern histologically, half (n=13) had atypical features, such as extensive peribronchiolar metaplasia. Among those who had GER, 12 had peribronchiolar metaplasia, whereas among those patients without GER, nine had peribronchiolar metaplasia (P=0.14).\n\nPFT and 6MWT findings\nMycophenolate-treated compared to untreated\nThe mean average decline in FVC% and DLCO% between the mycophenolate-treated (n=28) and untreated (n=24) groups was not significantly different (FVC% change, P=0.08; DLCO% change, P=0.17; Table 3). However, there was a trend toward a more rapid decline in both FVC% and DLCO% in the mycophenolate-exposed group (Figure 2). The mycophenolate-unexposed group had relatively stable PFTs. Change in FVC% was compared between the group without GER and with GER. Change in FVC was stable in the no-GER group (FVC% change 0.06 in 24 months), whereas in the GER group the FVC% decreased (0.32 in 24 months, P=0.04).\n\nMycophenolate-treated group before compared to after initiation of treatment\nSimple linear regression of DLCO% before and after mycophenolate therapy (n=23) showed improvement in DLCO% slope after mycophenolate therapy; however, this did not achieve statistical significance (P=0.55; Figure 3). Sensitivity analysis was performed with inclusion of only patients who had at least one DLCO% measurement before and after mycophenolate therapy (n=18), and the trend persisted (P=0.48). Paired t-tests in this group did not reach significance, but achieved P=0.06. Excluding patients who had received lung transplants from the analysis yielded a statistically significant improvement in slope of DLCO% before and after mycophenolate therapy (n=18, P=0.009). When transplant patients were included with last observation carried forward, the trend was also consistent, with the slope improving after mycophenolate therapy (P=0.75). Transplant compared to nontransplant mycophenolate-exposed patients had significantly lower baseline DLCO% (P=0.02).\n\nWithin the mycophenolate group, 26 of 28 patients had FVC% recorded around the time of mycophenolate initiation (Figure 3). The slope of mycophenolate-exposed patients improved after exposure, but this increase did not reach statistical significance (P=0.15). Sensitivity analysis was performed with inclusion of patients who had at least one time point before and after mycophenolate initiation (n=19), and the slope continued a trend toward improvement after mycophenolate exposure compared to before mycophenolate exposure (P=0.09). Paired t-tests in this group did not reach significance (P=0.97). If patients who went on to receive lung transplants were removed, analysis of FVC% demonstrated an improved slope after mycophenolate exposure, but this did not reach statistical significance (P=0.28). When transplant patients were included with last observation carried forward, the trend persisted with the slope improving after mycophenolate therapy (P=0.15). 6MWT did not change significantly over time nor vary significantly between mycophenolate groups.\n\nImaging outcomes\nBaseline findings\nOne patient did not have HRCT available for radiology to review. Baseline HRCT patterns of ILD did not vary significantly between the mycophenolate-exposed and unexposed groups. However, mycophenolate-exposed groups more frequently had NSIP by HRCT (n=16, 57%; unexposed, n=11, 48%; P=0.6). HRCT scores in the mycophenolate-exposed group tended to have a higher global extent of GGO and lower extent of reticulation with less overall coarseness than the unexposed group, but trends did not reach statistical significance (Table 3). Baseline HRCT showed increased GGO in the mycophenolate-exposed than the unexposed group (P=0.048; Figure S1). In the mycophenolate-exposed group, six patients (21%) had hiatal hernia and four (14%) esophageal dilation. In the mycophenolate-unexposed group, seven patients (29%) had hiatal hernia and nine (38%) esophageal dilation. When transplant patients treated with mycophenolate were compared to nontransplant patients treated with mycophenolate, the first available HRCT scan had significantly more reticulation (P≤0.0001) and significantly less GGO (P=0.03).\n\nChange in HRCT over time\nWhen the last available HRCT scan was compared to the first available HRCT scan, coarseness increased significantly between first and last HRCT in the mycophenolate group (P=0.01). There was no significant difference in global ILD, GGO%, reticulation percentage, or overall proportion GGO between baseline and final HRCT in the mycophenolate-treated or untreated groups.\n\nOther outcomes\nTwo deaths occurred in the mycophenolate-exposed group compared to five in the mycophenolate-unexposed group. Significantly more patients in the mycophenolate-exposed group (n=7) received a lung transplant than those in the mycophenolate-unexposed group (n=0; P=0.01). Kaplan–Meier curves based on time to decline (≥10 FVC% and ≥15% DLCO%), transplant, and death were not significantly different between the two groups. The log-rank test did not yield any statistically significant difference for this composite end point (P=0.41).\n\nDiscussion\nIn this study, we carefully identified a cohort of IPAF patients to evaluate the observed efficacy of mycophenolate therapy on PFTs, 6MWT, and HRCT. In comparison to other observational studies of IPAF, our overall demographic composition demonstrated similar though not identical frequency of clinical, laboratory, and morphologic characteristics.5–7\n\nAlthough we did not find a difference in PFT change or mortality in mycophenolate-exposed compared to unexposed patients, mycophenolate-exposed patients showed a trend toward lower baseline PFT scores and greater decline in PFT scores that began preexposure. Patients who present with a more significant disease burden may be more likely to receive therapy with mycophenolate, especially if lung function appears to be declining progressively over time. It has been proposed that IPAF patients can be stratified into a lower-risk cohort with a favorable survival pattern, based on the presence of a clinical domain of IPAF diagnosis in combination with HRCT or histopathology to fulfill IPAF criteria.5 However, we found that mycophenolate-exposed and unexposed groups met the clinical and morphologic domains with similar frequency, making this a less likely cause of the difference in PFT trends between these two groups. Unexplained pulmonary vasculopathy, a proposed risk factor for mortality, was seen in six mycophenolate-exposed patients.8 Multicompartment involvement in IPAF has been proposed to be associated with increased mortality,5,8 but there was no difference in rates of multicompartment involvement between exposed and unexposed patients. Alternatively, mycophenolate exposure itself possibly led to decline in PFT scores. We do not favor this theory, because of the improvement seen after mycophenolate therapy within the mycophenolate-exposed group.\n\nInterestingly, within the mycophenolate-exposed group, we were able to show that there was a trend toward improvement in PFT scores after initiation of mycophenolate. This difference reached statistical significance when those who required lung transplants were removed. These findings indicate that a subgroup of IPAF patients may benefit from mycophenolate therapy. HRCT in patients who required transplants demonstrated significantly more reticulation and less GGO than those who did not go on to require transplants. Patients who required transplants had significantly worse DLCO% on PFTs. Previous observational studies of IPAF have identified DLCO as a predictor of survival,5 which is consistent with previous studies of risk-factor identification in other diseases of pulmonary fibrosis.9,10 Histopathologically, IPAF patients frequently have coexistence of NSIP and UIP patterns;8 however, our findings may support patients with less reticulation and more GGO responding more robustly to mycophenolate therapy. Similar findings of GGO correlating positively with therapeutic response have been seen in systemic sclerosis-related ILD.11\n\nWe found that mycophenolate-exposed patients had increased GER frequency. This is potentially relevant, as our pathologist identified relatively frequent rates of peri-bronchiolar metaplasia. Peribronchiolar metaplasia has been reported in both aspiration and systemic sclerosis-related LD.12,13 It is also possible that aspiration may contribute to the pathogenesis of IPAF-related LD, supporting potential benefits of aggressive treatment of pathological GER in this population. Although we did not find any difference in GER frequency in patients with and without peribronchiolar metaplasia, there was a trend toward association with GER and peribronchiolar metaplasia. Similar to other studies that have demonstrated detrimental effects of GER on lung function,14,15 we found that GER was associated with greater reduction in FVC% over time, lending additional support to GER treatment.\n\nDespite strengths including robust IPAF-inclusion definitions and data collection, this study has several limitations. First, because this was a retrospective-cohort study, we were limited to reporting associations, but unable to identify causal relationships. Second, EMR prescription does not ensure consistent exposure. Third, mycophenolate exposure might reflect indication bias, as patients were not randomized to receive mycophenolate therapy. We also considered that the trend toward improvement of PFTs after mycophenolate exposure could have reflected a survivor effect. However, when we performed sensitivity analyses with last value carried forward, this trend persisted. Nonetheless, despite several sensitivity analyses, multiple confounders undoubtedly exist in this observational retrospective-cohort study. Many patients were treated with other immunosuppressive therapies and varying doses of corticosteroids. However, the dose of corticosteroids at diagnosis and peak corticosteroid dose were similar between the two groups, so likely would not explain the described differences. Given the relatively low number of patients included in this cohort, we could not perform multivariate analysis. Moreover, as a tertiary referral center, our IPAF cohort may reflect a referral bias toward more severe disease.\n\nConclusion\nMycophenolate therapy might attenuate ILD progression in patients with IPAF, and findings suggest that it could be more beneficial in patients with more GGO and less reticulation on HRCT. Further study of mycophenolate in a prospective, randomized controlled trial for IPAF treatment is warranted to investigate further whether mycophenolate is a beneficial therapy for IPAF patients with clinically significant/progressive ILD.\n\nSupplementary material\nFigure S1 Representative HRCT images.\n\nNotes: (A) 80% GGO with selected region unmagnified below; (B) 100% GGO with the selected region unmagnified below.\n\nAbbreviations: GGO, ground-glass opacity; HRCT, high-resolution computed tomography.\n\n Acknowledgments\nThis project described was supported by the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), grant UL1TR002373. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. CMB receives unrelated peer-reviewed grant funding from Independent Grants for Learning and Change (Pfizer). The abstract of this paper was presented at the 2017 American College of Rheumatology Conference as a poster presentation/conference talk with interim findings. The abstract was published in the ACR’s Meeting Abstracts (ACRabstracts.org, abstract 1171).\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Exclusion and inclusion of patients who met criteria for IPAF diagnosis and saw both pulmonology and rheumatology departments within the University of Wisconsin health system.\n\nNote: *Three patients saw a pulmonologist familiar with rheumatologic disease and were considered to fill both rheumatologic and pulmonary visit requirements.\n\nAbbreviations: ILD, interstitial lung disease; IPAF, interstitial pneumonia with autoimmune features; UW, University of Wisconsin.\n\nFigure 2 (A) Raw FVC% months after IPAF diagnosis in the mycophenolate-unexposed (n=24) group, graphed individually in light gray, with mean is represented by the bold black line. (B) Raw FVC% in the mycophenolate exposed (n=27) groups, graphed individually in light gray, with mean represented by the bold black line. (C) Linear regression of FVC% months from the date of diagnosis in both the mycophenolate-exposed and unexposed groups. (D) Raw DLCO% months after diagnosis date in the mycophenolate-unexposed (n=19) group, graphed individually in light gray, with mean represented by the bold black line. (E) Raw DLCO% in the mycophenolate-exposed (n=26) group, graphed individually in light gray, with mean represented by the bold black line. (F) Linear regression of DLCO% over time from the date of diagnosis in both the mycophenolate-exposed and unexposed groups.\n\nAbbreviations: DLCO, diffusion capacity of lungs for carbon monoxide; IPAF, interstitial pneumonia with autoimmune features.\n\nFigure 3 (A) Raw FVC% in months before and after mycophenolate exposure among the mycophenolate-exposed. Data graphed individually (n=26) in light gray, and mean with SEM represented with the bold black line. (B) Linear regression of FVC% before and after mycophenolate exposure with SD. (C) DLCO% before and after mycophenolate exposure, graphed individually (n=26) in light gray and mean with SEM represented with the bold black line. (D) Linear regression of DLCO% before and after mycophenolate exposure with SD.\n\nAbbreviations: DLCO, diffusion capacity of lungs for carbon monoxide.\n\nTable 1 Baseline demographics and clinical data\n\n\tMycophenolate-exposed\tMycophenolate-unexposed\tP-value\t\n\n\t\nn=28 (54%)\tn=24 (46%)\t\n\n\t\nAge, years (mean, SD)\t58.68, 12.8\t65.38, 12.6\t0.06\t\nMale, n (%)\t12 (43)\t7 (29)\t0.31\t\nFemale, n (%)\t16 (57)\t17 (71)\t\t\nTobacco use, ever, n (%)\t15 (54)\t9 (38)\t0.20\t\nTobacco use, never\t12 (43)\t15 (63)\t\t\nCardiovascular disease, n (%)#\t7 (25)\t3 (13)\t0.32\t\nGastroesophageal reflux\t24 (86)\t12 (50)\t0.015*\t\nMalignancy\t2 (7)\t1 (4)\t0.70\t\nObstructive sleep apnea\t6 (21)\t3 (13)\t0.48\t\nPulmonary artery hypertension\t6 (21)\t2 (8)\t0.23\t\nPulmonary embolism\t3 (11)\t0\t0.11\t\nAzathioprine use\t9 (32)\t7 (29)\t0.86\t\nAzithromycin use\t15 (54)\t4 (17)\t0.03*\t\nCyclophosphamide use\t3 (11)\t3 (13)\t0.66\t\nHydroxychloroquine use\t10 (36)\t2 (8)\t0.04*\t\nLeflunomide use\t1 (4)\t2 (8)\t0.42\t\nMethotrexate use\t1 (4)\t2 (8)\t0.42\t\nPPI use\t26 (93)\t14 (58)\t0.07\t\nRanitidine use\t13 (46)\t12 (50)\t0.38\t\nSteroid use\t25 (89)\t12 (50)\t0.02*\t\nPeak steroid dose (mg), mean, SD\t40, 5.3\t32, 6.2\t0.35\t\nSteroid dose at diagnosis (mg), mean, SD\t10, 24.2\t7, 21.8\t0.66\t\nHemolytic anemia, n (%)\t0\t0\t\t\nLeukopenia\t4 (14)\t0\t0.07\t\nLymphopenia\t8 (29)\t4 (17)\t0.35\t\nThrombocytopenia\t6 (21)\t1 (4)\t0.08\t\nLow complement\t0\t2 (8)\t0.09\t\nCreatinine over double ULN at diagnosis\t1 (4)\t0\t0.38\t\nESR elevated\t18 (64)\t15 (63)\t0.76\t\nLymphocytic BAL, n (%)\t4 (24)\t0\t0.25\t\nEosinophilic BAL, n (%)\t3 (18)\t3 (50)\t\t\nNeutrophilic BAL, n (%)\t1 (6)\t1 (17)\t\t\nNormal BAL, n (%)\t9 (53)\t2 (33)\t\t\nBAL not performed\t11\t18\t\t\nDeveloped into MPA, n (%)\t1 (4)\t2 (8)\t0.50\t\nDeveloped into SLE, n (%)\t1 (4)\t0\t\t\nNotes:\n\n# Includes coronary artery disease, congestive heart failure, or cerebrovascular event.\n\n* P<0.05.\n\nAbbreviations: BAL, bronchoalveolar lavage; CTD, connective tissue disease; ESR, erythrocyte-sedimentation rate; MPA, microscopic polyangiitis; PPI, proton-pump inhibitor; SLE, systemic lupus erythematosus; ULN, upper limit of normal.\n\nTable 2 IPAF-classification criteria\n\n\tMycophenolate-exposed, n (%)\n\tMissing/unavailable, n\tMycophenolate-unexposed, n (%)\n\tMissing/unavailable, n\tP-value\t\n28 (54%)\t24 (46%)\t\n\n\t\nClinical domain\t\t\t\t\t\t\nDigital fissures\t0\t\t0\t\t\t\nDigital tip ulceration\t1 (4)\t\t0\t\t0.4\t\nInflammatory arthritis\t8 (29)\t\t5 (21)\t\t0.6\t\nPalmar telangiectasia\t0\t\t0\t\t\t\nRaynaud’s phenomenon\t8 (29)\t\t8 (33)\t\t0.7\t\nDigital edema\t0\t\t0\t\t\t\nRash on digital extensor surface\t0\t\t0\t\t\t\nSerologic domain\t\t\t\t\t\t\nANA ≥1:320\t21 (78)\t1\t19 (79)\t\t0.7\t\nNucleolar/centromere any titer\t5 (18)/0\t\t8 (33)/0\t\t0.2\t\nRF double or more ULN/anti-CCP\t4 (15)/0\t1/11\t5 (24)/0\t3/16\t0.4\t\nAnti-dsDNA\t1 (5)\t7\t2 (14)\t10\t0.3\t\nAnti-Ro (SS-A)/anti-La (SS-B)\t7 (26)/0\t1/1\t3 (17)/0\t6/6\t0.6\t\nAnti-ribonucleoprotein\t6 (25)\t4\t0\t7\t0.03*\t\nAnti-Smith\t0\t4\t0\t7\t\t\nAnti-topoisomerase\t0\t15\t1 (14)\t17\t0.2\t\nAnti-tRNA synthetase\t1 (4)\t18\t0\t21\t0.6\t\nMorphologic domain\t\t\t\t\t\t\nHRCT pattern\t\t\t\t\t\t\nNSIP\t16 (57)\t\t11 (48)\t1\t0.4\t\nOP\t3 (11)\t\t1 (4)\t\t\t\nNSIP with OP overlap\t3 (11)\t\t2 (9)\t\t\t\nLIP\t1 (4)\t\t0\t\t\t\nOther\t5 (18)\t\t9 (39)\t\t\t\nLung-biopsy histopathology\t\t\t\t\t\t\nNSIP\t4 (21)\t9\t1 (14)\t17\t0.2\t\nOP\t0\t\t1 (14)\t\t\t\nNSIP with OP overlap\t1 (5)\t\t0\t\t\t\nLIP\t0\t\t0\t\t\t\nInterstitial lymph aggregates and GC\t2 (11)\t\t0\t\t\t\nDiffuse lymphoplasmacytic infiltrate#\t1 (5)\t\t0\t\t\t\nMulticompartment involvement\t\t\t\t\t0.3\t\nPleural/pericardial+\t7 (25)/5 (18)\t\t5 (21)/2 (8)\t\t\t\nIntrinsic airway disease\t5 (18)\t\t8 (33)\t\t\t\nPulmonary vasculopathy\t6 (21)\t\t2 (8)\t\t\t\nDiagnostic domains met\t\t\t\t\t0.5\t\nClinical and serological\t0\t\t0\t\t\t\nClinical and morphological\t3 (11)\t\t1 (4)\t\t\t\nSerological and morphological\t14 (50)\t\t15 (63)\t\t\t\nAll three\t11 (39)\t\t8 (33)\t\t\t\nNotes:\n\n# With or without lymphoid follicles;\n\n* P<0.05. Anti-PM-Scl and anti-MDA5 were not included in the table, because patients were not routinely tested for these antibodies.\n\n+ Effusion or thickening.\n\nAbbreviations: ANA, antinuclear antibody; CCP, cyclic citrullinated peptide; GC, germinal center; HRCT, high-resolution computed tomography; IPAF, interstitial pneumonia with autoimmune features; LIP, lymphocytic interstitial pneumonia; NSIP, nonspecific interstitial pneumonia; OP, organizing pneumonia; RF, rheumatoid factor; ULN, upper limit of normal.\n\nTable 3 PFT, 6MWT, and HRCT outcomes\n\n\tMycophenolate-exposed (n=28)\tMycophenolate-unexposed (n=24)\tMycophenolate-exposed vs unexposed (first)\t\n\n\t\nFirst mean (SD)\tLast mean (SD)\tP-value\tFirst mean (SD)\tLast mean (SD)\tP-value\tP-value\t\n\n\t\nPFT\t\t\t\t\t\t\t\t\nFVC (%)\t68.2 (17.3)\t59.3 (17.1)\t0.07\t79.2 (18.5)\t79.2 (0.2)\t0.99\t0.09\t\nDLCO (%)\t53.0 (14.8)\t44.9 (16.5)\t0.08\t62.2 (16.8)\t55.4 (17.7)\t0.26\t0.42\t\n6MWT (feet), mean (SD)\t1,044 (359)\t969 (412)\t0.53\t1,057 (340)\t1,051 (335)\t0.97\t0.45\t\nHRCT\t\t\t\t\t\t\t\t\nILD+\t23.8 (22.6)\t30.4 (27.1)\t0.34\t22.7 (26.0)\t26.6 (29.3)\t0.65\t0.41\t\nProportion GGO (%)\t0.6 (0.4)\t0.5 (0.6)\t0.07\t0.4 (0.4)\t0.3 (0.3)\t0.42\t0.048*\t\nGGO+ (%)\t16.5 (18.0)\t16.1 (4.2)\t0.95\t12.4 (22.2)\t11.8 (23.1)\t0.93\t0.74\t\nReticulation+ (%)\t7.0 (14.3)\t14.5 (19.7)\t0.11\t9.7 (10.8)\t12.4 (15.9)\t0.51\t0.15\t\nCoarseness score\t2.4 (1.9)\t4.4 (3.3)\t0.01*\t4.4 (3.9)\t5.3 (3.9)\t0.44\t0.42\t\nNotes:\n\n+ Global extent;\n\n* P<0.05.\n\nAbbreviations: DLCO, diffusion capacity of lungs for carbon monoxide; GGO, ground-glass opacity; HRCT, high-resolution computed tomography; ILD, interstitial lung disease; 6MWT, 6-minute walk test; PFT, pulmonary function test.\n==== Refs\nReferences\n1 Fischer A Antoniou KM Brown KK An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features Eur Respir J 2015 46 4 976 987 26160873 \n2 Fischer A West SG Swigris JJ Brown KK du Bois RM Connective tissue disease-associated interstitial lung disease: a call for clarification Chest 2010 138 2 251 256 20682528 \n3 Swigris JJ Olson AL Fischer A Mycophenolate mofetil is safe, well tolerated, and preserves lung function in patients with connective tissue disease-related interstitial lung disease Chest 2006 130 1 30 36 16840379 \n4 Goh NS Desai SR Veeraraghavan S Interstitial lung disease in systemic sclerosis: a simple staging system Am J Respir Crit Care Med 2008 177 11 1248 1254 18369202 \n5 Oldham JM Adegunsoye A Valenzi E Characterisation of patients with interstitial pneumonia with autoimmune features Eur Respir J 2016 47 6 1767 1775 27103387 \n6 Chartrand S Swigris JJ Stanchev L Lee JS Brown KK Fischer A Clinical features and natural history of interstitial pneumonia with autoimmune features: A single center experience Respir Med 2016 119 150 154 27692137 \n7 Ferri C Manfredi A Sebastiani M Interstitial pneumonia with autoimmune features and undifferentiated connective tissue disease: Our interdisciplinary rheumatology-pneumology experience, and review of the literature Autoimmun Rev 2016 15 1 61 70 26384526 \n8 Adegunsoye A Oldham JM Valenzi E Interstitial pneumonia with autoimmune features: value of histopathology Arch Pathol Lab Med 2017 141 7 960 969 28467213 \n9 Ley B Ryerson CJ Vittinghoff E A multidimensional index and staging system for idiopathic pulmonary fibrosis Ann Intern Med 2012 156 10 684 691 22586007 \n10 Ryerson CJ Vittinghoff E Ley B Predicting survival across chronic interstitial lung disease: the ILD-GAP model Chest 2014 145 4 723 728 24114524 \n11 Yabuuchi H Matsuo Y Tsukamoto H Evaluation of the extent of ground-glass opacity on high-resolution CT in patients with interstitial pneumonia associated with systemic sclerosis: comparison between quantitative and qualitative analysis Clin Radiol 2014 69 7 758 764 24824977 \n12 Yousem SA Faber C Histopathology of aspiration pneumonia not associated with food or other particulate matter: a clinicopathologic study of 10 cases diagnosed on biopsy Am J Surg Pathol 2011 35 3 426 431 21317714 \n13 de Souza RB Borges CT Capelozzi VL Centrilobular fibrosis: an underrecognized pattern in systemic sclerosis Respiration 2009 77 4 389 397 18799868 \n14 Martinez CH Okajima Y Murray S Impact of self-reported gastroesophageal reflux disease in subjects from COPDGene cohort Respir Res 2014 15 62 24894541 \n15 Gavini S Borges LF Finn RT Lung disease severity in idiopathic pulmonary fibrosis is more strongly associated with impedance measures of bolus reflux than pH parameters of acid reflux alone Neurogastroenterol Motil 2017 29 5 e13001\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1176-6336",
"issue": "14()",
"journal": "Therapeutics and clinical risk management",
"keywords": "autoimmune disease; connective tissue disease; interstitial lung disease; mycophenolate",
"medline_ta": "Ther Clin Risk Manag",
"mesh_terms": null,
"nlm_unique_id": "101253281",
"other_id": null,
"pages": "2171-2181",
"pmc": null,
"pmid": "30464490",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "26384526;22586007;16840379;24894541;20682528;28467213;27103387;27987250;18799868;24824977;27692137;24114524;21317714;18369202;26160873",
"title": "Mycophenolate therapy in interstitial pneumonia with autoimmune features: a cohort study.",
"title_normalized": "mycophenolate therapy in interstitial pneumonia with autoimmune features a cohort study"
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"companynumb": "US-STRIDES ARCOLAB LIMITED-2019SP001114",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
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"abstract": "BACKGROUND\nPulmonary tumor thrombotic microangiopathy (PTTM) is a rare cause of pulmonary hypertension that is associated with malignancies and is marked by the presence of non-occlusive tumor emboli and fibrocellular intimal proliferation of small pulmonary arteries leading to increased pulmonary vascular resistance and right heart failure. The diagnosis of PTTM is challenging to make pre-mortem and guidelines on treatment are lacking.\n\n\nMETHODS\nA 45-year-old woman with advanced squamous cell carcinoma of the cervix developed symptoms of dyspnea and evidence of right heart failure during a phase I clinical trial with cediranib and durvalumab. After an extensive evaluation, pre-capillary pulmonary hypertension was confirmed by right heart catheterization. Vasodilator therapy was initiated but resulted in the development of symptomatic hypoxemia and was discontinued. Despite continued supportive care, she continued to decline and was transitioned to hospice care. At autopsy, the cause of her right heart failure was found to be due to PTTM with features of pulmonary veno-occlusive disease (PVOD).\n\n\nCONCLUSIONS\nPTTM and PVOD are important diagnoses to consider in patients with a malignancy and the development of right heart failure and may be manifestations of a spectrum of similar disease processes.",
"affiliations": "Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, MD, USA. dante.suffredini@nih.gov.;Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, USA.;Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, USA.;Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, USA.;Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, USA.;Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, MD, USA.;Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, MD, USA.",
"authors": "Suffredini|Dante A|DA|;Lee|Jung-Min|JM|;Peer|Cody J|CJ|;Pratt|Drew|D|;Kleiner|David E|DE|;Elinoff|Jason M|JM|;Solomon|Michael A|MA|",
"chemical_list": "D000911:Antibodies, Monoclonal; D011799:Quinazolines; C000613593:durvalumab; C500926:cediranib",
"country": "England",
"delete": false,
"doi": "10.1186/s12890-018-0681-x",
"fulltext": "\n==== Front\nBMC Pulm MedBMC Pulm MedBMC Pulmonary Medicine1471-2466BioMed Central London 68110.1186/s12890-018-0681-xCase ReportPulmonary tumor thrombotic microangiopathy and pulmonary veno-occlusive disease in a woman with cervical cancer treated with cediranib and durvalumab Suffredini Dante A. (301) 496-9320dante.suffredini@nih.gov 1Lee Jung-Min jung-min.lee@nih.gov 2Peer Cody J. cody.peer@nih.gov 3Pratt Drew drew.pratt@nih.gov 4Kleiner David E. kleinerd@nih.gov 4Elinoff Jason M. elinoffj@cc.nih.gov 1Solomon Michael A. msolomon@nih.gov 151 0000 0001 2194 5650grid.410305.3Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, MD USA 2 0000 0004 0483 9129grid.417768.bWomen’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, USA 3 0000 0004 0483 9129grid.417768.bClinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, USA 4 0000 0004 0483 9129grid.417768.bLaboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, USA 5 0000 0001 2293 4638grid.279885.9Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, USA 11 7 2018 11 7 2018 2018 18 11220 11 2017 27 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\nPulmonary tumor thrombotic microangiopathy (PTTM) is a rare cause of pulmonary hypertension that is associated with malignancies and is marked by the presence of non-occlusive tumor emboli and fibrocellular intimal proliferation of small pulmonary arteries leading to increased pulmonary vascular resistance and right heart failure. The diagnosis of PTTM is challenging to make pre-mortem and guidelines on treatment are lacking.\n\nCase presentation\nA 45-year-old woman with advanced squamous cell carcinoma of the cervix developed symptoms of dyspnea and evidence of right heart failure during a phase I clinical trial with cediranib and durvalumab. After an extensive evaluation, pre-capillary pulmonary hypertension was confirmed by right heart catheterization. Vasodilator therapy was initiated but resulted in the development of symptomatic hypoxemia and was discontinued. Despite continued supportive care, she continued to decline and was transitioned to hospice care. At autopsy, the cause of her right heart failure was found to be due to PTTM with features of pulmonary veno-occlusive disease (PVOD).\n\nConclusion\nPTTM and PVOD are important diagnoses to consider in patients with a malignancy and the development of right heart failure and may be manifestations of a spectrum of similar disease processes.\n\nKeywords\nPulmonary tumor thrombotic microangiopathyPulmonary hypertensionCediranibDurvalumabCervical cancerhttp://dx.doi.org/10.13039/100000098NIH Clinical Centerissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nPulmonary tumor thrombotic microangiopathy (PTTM) is a rare condition characterized by microscopic tumor cell emboli, which cause proliferative changes in the pulmonary microvasculature leading to a syndrome of hypoxemia, pulmonary hypertension, right heart failure and death [1]. In the initial report, unique pathologic changes in 21 patients were described with non-occluding microscopic tumor emboli limited to the small pulmonary arterial vessel wall, isolated or clumped in the vessel lumen and often with secondary thrombosis. The endothelial attachment of tumor cells was associated with fibrocellular intimal proliferation. The resultant obstruction of the small arteries and increase in pulmonary vascular resistance is thought to contribute to the clinical presentation of progressive cor pulmonale and death. It was notable that in nearly all the described cases lymphangiosis carcinomatosa was present, but the relationship to PTTM was unclear. Thus, PTTM is thought to be a unique clinical entity based on the presence of intimal proliferation, distinguishing it from obstructive pulmonary tumor emboli. In a larger case series, adenocarcinoma was the most common underlying malignancy and in nearly all cases the tumor emboli were positive for vascular endothelial growth factor (VEGF), platelet derived growth factor and tissue factor by immunohistochemistry [2]. Over-expression of these growth factors on the surface of the embolized tumor cell may result in a trophic effect on the pulmonary vascular endothelium, leading to the described pathologic findings [3]. Here we describe a woman being treated with the combination of a VEGF receptor (VEGFR) inhibitor and a programmed death-ligand 1 (PD-L1) inhibitor who developed pulmonary hypertension and right heart failure and was subsequently found to have PTTM with features of pulmonary veno-occlusive disease (PVOD).\n\nCase presentation\nA 45-year-old woman with metastatic squamous cell carcinoma of the cervix refractory to standard of care chemotherapy was referred to the National Institutes of Health (NIH) for enrollment in a Phase I clinical trial (NCT02484404) of combination therapy with daily cediranib, a VEGFR tyrosine kinase inhibitor, and once every 2 weeks of durvalumab, a PD-L1 inhibitor. Her first four treatment cycles were well tolerated. Treatment related side effects included hypertension, subclinical hypothyroidism, non-nephrotic range proteinuria and mild diarrhea.\n\nDuring a routine study clinic visit the patient was found to be in sinus tachycardia. Upon further questioning, the patient noted progressive dyspnea on exertion and fatigue over the previous month and was therefore admitted to the NIH Clinical Center for further evaluation. Vital signs revealed a temperature of 37°C, heart rate of 120 beats per minute, a manual blood pressure of 90/72 mmHg without orthostatic changes and oxygen saturation ranging from 93 to 97% on room air. Physical examination findings were notable for a normal jugular venous pressure, regular heart rate without a prominent P2, clear breath sounds, and warm extremities without edema. Intravenous fluid was administered for possible dehydration due to diarrhea, but symptoms did not improve. A portable chest x-ray revealed hazy bibasilar interstitial markings (Fig. 1). Laboratory studies revealed a hemoglobin of 9.8 g/dL (normal range 11.2-15.7 g/dl), a platelet count of 159 k/μL (normal range 173-369 k/μL), normal coagulation indices (PT 13.8 s; aPTT 35.5 s; thrombin time 15.8 s), a D-dimer of 0.98 μg/mL (normal range 0.00–0.50 μg/mL), a fibrinogen of 517 mg/dL (normal range 177–466 mg/dL), a pro-brain natriuretic peptide of 4541 pg/mL (normal range 0–124 pg/mL) and a troponin-T of 0.022 ng/mL (normal range 0.000–0.009 ng/mL). Echocardiography demonstrated a dilated right ventricle with decreased function (tricuspid annular plane systolic excursion (TAPSE) of 8 mm; normal ≥17 mm) and an elevated right ventricular systolic pressure of 67 mmHg, new findings compared to her baseline echocardiogram completed just 4 months earlier. Cardiac MRI, performed to evaluate for possible treatment related myocarditis, demonstrated severely reduced right ventricular function (ejection fraction of 27%; normal 61±10%) with volume and pressure overload consistent with pulmonary hypertension, but no evidence of myocarditis. A CT angiogram showed no evidence of pulmonary emboli, however there was a prominence of interstitial markings (Fig. 2a, b), the main pulmonary artery was enlarged (Fig. 2c) and the right atrium and ventricle were both severely dilated (Fig. 2d). A ventilation (Fig. 3a) - perfusion (Fig. 3b) scan (VQ) demonstrated mismatched perfusion defects along the pleural margins that were interpreted as a high probability of pulmonary emboli. Doppler ultrasonography revealed no evidence of venous thrombosis in the lower extremities. Despite the equivocal findings, therapeutic anti-coagulation was started for possible pulmonary emboli.Fig. 1 An anteroposterior chest radiograph demonstrating hazy bibasilar interstitial infiltrates. A port is noted as well in the right upper chest with catheter ending at the cavoatrial junction\n\nFig. 2 Contrast enhanced CT image with axial (a) and coronal (b) sections demonstrating a prominence of interstitial markings predominantly in posterior and basilar lung fields. In mediastinal windowing accentuating the pulmonary vasculature (c) the pulmonary artery trunk is enlarged and (d) the right ventricle and right atria appear larger in area than their corresponding left sided chambers; findings suggestive of pulmonary hypertension\n\nFig. 3 A posterior view of a ventilation (a) and perfusion (b) nuclear medicine scan demonstrate significant perfusion defects along the pleural margin (dark rim surrounding lung) that are not matched with a ventilation defect\n\n\n\nOver the ensuing 10 days the patient’s clinical course progressively deteriorated heralded by a syncopal event and the development of significant resting hypoxemia. The patient was referred for right and left heart catheterization which confirmed pre-capillary pulmonary hypertension with an associated low cardiac output state (Table 1). Vasodilator challenge with nitric oxide (40 ppm) plus 100% oxygen paradoxically increased pulmonary artery mean and occlusion pressure, but did not result in symptomatic pulmonary edema. Balloon occlusion pulmonary venous blood sampling did not reveal any circulating tumor cells. Aggressive therapy for right heart failure was initiated including intravenous diuresis, inotropic support and pulmonary vasodilator therapy. Riociguat was initiated due to the concern for possible chronic thromboembolic pulmonary hypertension (CTEPH). Ultimately, intravenous epoprostenol was added due to persistent symptoms of severe right heart failure. Soon after starting epoprostenol the patient became severely hypoxic. As a result, pulmonary vasodilator therapy was discontinued and she was treated with diuretics and high flow oxygen. Given her advanced disease and poor functional status her protocol treatment was stopped and she was discharged home with hospice care. She died 1 day later and an autopsy was performed.Table 1 Hemodynamic measures from left and right heart catheterization with vasodilator testing\n\n\tRoom air\tNitric Oxide (40 ppm) plus 100% O2\t\nHeart rate, beats per minute\t107\t105\t\nMean right atrial pressure, mmHg\t18\t14\t\nPulmonary artery pressure (mean), mmHg\t72/30 (44)\t72/34 (47)\t\nMean pulmonary artery occlusion pressure, mmHg\t11\t15\t\nAortic pressure (mean), mmHg\t92/61 (72)\t108/64 (80)\t\nLeft ventricle end-diastolic pressure, mmHg\t10\t–\t\nArterial blood gas, pH/pCO2/pO2\t7.45/32/66\t7.42/39/344\t\nArterial oxygen saturation, %\t92.1\t99.1\t\nMixed venous oxygen saturation, %\t43.4\t59.6\t\nCardiac indexa, L/min/m2\t1.5\t1.6\t\nPulmonary vascular resistance, Wood units\t12.4\t11.1\t\na Calculated by the Fick method using a measured hemoglobin of 11.1 g/dL and estimated VO2 (mL/min/m2)\n\n\n\nGross examination of the lungs showed scattered white plaques, nodular and gritty on palpation, covering the pleural surface of the lower lobes. Microscopic sections of the lung showed metastatic carcinoma with lymphangitic spread (Fig. 4a) within the septa and subpleural spaces with associated congestion and fibrosis. These findings were associated with fibromuscular thickening of lymphatic vessels which may represent a type of desmoplastic response to lymphatic obstruction. Pulmonary arterioles (Fig. 4b, c) were occluded by organized thrombi, some with evidence of recanalization, as well as smooth muscle proliferation and ingrowth of fibroblasts. Some arteries showed fresh thrombi with metastatic tumor foci. Pulmonary venules were also occluded with ingrowth of fibroblasts. Some of these vessels showed evidence of chronic occlusion and recanalization, (Fig. 4d) while others were completely occluded. No tumor cells were identified in any venules. No evidence of infection or pneumonia was identified. Collectively, these findings were most consistent with a primary diagnosis of PTTM with features of PVOD [1, 4].Fig. 4 Pulmonary vascular disease associated with metastases. a Dilated lymphatic space (asterisk) containing tumor (200×). b Pulmonary artery with small tumor embolus (thin arrows) and both fresh and partially organized thrombus (thick arrow) (100×). c Pulmonary artery showing occlusion (thick arrow) and recanalization (asterisk) (200×). d Small pulmonary vein with narrowing and recanalization (thin black arrow) (200×)\n\n\n\nDiscussion\nWe present a case of a woman with metastatic squamous cell carcinoma of the cervix who developed pulmonary hypertension and right heart failure during combination treatment with a VEGFR inhibitor and a PD-L1 inhibitor. At autopsy, she was found to have PTTM with features of PVOD.\n\nA definitive pre-mortem diagnosis of PTTM is challenging as a number of other causes of right heart failure have a similar clinical presentation [5]. For example, our patient’s initial CT angiogram revealed prominent bibasilar septal lines, which may have represented lymphangitic spread of tumor, drug-induced pulmonary toxicity or PVOD [6]. Other non-specific radiographic findings in PTTM include multifocal beaded peripheral pulmonary arteries, diffuse thickening of the intralobular septa or peripheral wedge-shaped opacities suggestive of infarction [7]. A VQ scan can reveal peripheral unmatched perfusion defects in patients with tumor emboli [8]. However, this finding is also present in patients with acute pulmonary emboli or CTEPH and cannot be easily distinguished [9]. Pulmonary microvascular cytology has been used as a diagnostic tool to identify circulating tumor cells, however these cells can be mistaken as normal pulmonary megakaryocytes [10]. The presence of right ventricular hypertrophy by cardiac MRI suggested subacute or chronic pulmonary vascular disease in our patient and right and left heart catheterization confirmed the presence of pre-capillary pulmonary hypertension. Therefore other conditions in the differential included drug-induced pulmonary arterial hypertension (PAH) and CTEPH.\n\nThe development of hypoxia after the start of prostacyclin treatment raised suspicion for PVOD as the underlying cause of her pulmonary hypertension. Although histopathologically PVOD typically affects post-capillary venules, hemodynamically PVOD has a pre-capillary pattern on right heart catheterization similar to our patient [11]. In addition, the patient’s regimen included multiple chemotherapeutic agents including cisplatin and docetaxel and radiation therapy, all of which are associated with development of PVOD [12, 13]. However, based on the original descriptions of PTTM, concurrent histological evidence of PVOD in our patient was unexpected [1]. Nevertheless, cases of PTTM with pulmonary venous involvement have been previously reported [4, 14].\n\nMany cases of PTTM are treated in a similar manner to idiopathic PAH, although it is unclear such therapies are effective and as demonstrated by this case, they may be harmful. In patients with PVOD, pulmonary edema may develop with pulmonary vasodilator therapy due to increased pulmonary artery blood flow in the face of high post-capillary venule resistance. Alternatively, systemic administration of a potent pulmonary vasodilator may cause ventilation and perfusion mismatching leading to hypoxia. Based on the pulmonary histopathology, the hypoxemia seen in our patient was likely due to both pulmonary edema from venule obstruction and ventilation perfusion mismatch.\n\nIn contrast to a suspected role for angiogenic growth factors such as VEGF in the pathogenesis of PTTM, and anecdotal case reports of positive outcomes with imatinib treatment [15] our patient not only developed, but also progressed to symptomatic PTTM during prolonged treatment with a VEGFR inhibitor. Importantly, pharmacokinetic studies done in our patient revealed that co-administration of durvalumab significantly decreased clearance of cediranib [16]. While the effect of VEGFR inhibition on the development or progression of PTTM is unknown, there is experimental evidence that exposure to a single dose of a VEGFR inhibitor, semaxanib (SU-5416), followed by chronic hypoxia leads to angioobliterative PAH in rats that mimics the histopathologic findings in patients with PAH, including hyperproliferative plexiform lesions [17]. In rodents, VEGFR blockade induces widespread pulmonary artery endothelial cell apoptosis which in the presence of chronic hypoxia is thought to result in the development of an apoptosis-resistant, hyperproliferative endothelial cell phenotype [18]. As a result of VEGFR blockade in this model, elevated levels of VEGFR ligands as well as other angiogenic factors (e.g. fibroblast growth factor and placental growth factor) may promote hyperproliferation and vascular remodeling [18]. In patients treated with VEGFR inhibitors, elevated circulating levels of fibroblast growth factor, placental growth factor and hepatocyte growth factor (HGF) have also been detected prior to disease progression [19, 20]. Similarly, in murine models of human non-small cell lung cancer, treatment with vandetanib and cediranib initially led to tumor regression followed by resistance to therapy and progression that was associated with upregulation of both HGF and its receptor, c-MET [21]. Studies of the tumor microvasculature in these murine models revealed HGF-dependent dysregulated angiogenesis with tortuous blood vessel formation. Interestingly, at autopsy immunohistochemical staining revealed lung metastatic foci that were VEGF negative but HGF positive. Thus, it is tempting to speculate that prolonged exposure to high levels of the VEGF receptor inhibitor could similarly provoke an abnormal response in the pulmonary vasculature that either induced or accelerated the development of PTTM in our patient. Moreover, levels of interferon and TNFα as well as other inflammatory cytokines closely linked to pulmonary vascular remodeling in PAH [22–24] may be elevated in the setting of PD-L1 blockade due to compensatory feedback mechanisms [25, 26]. Therefore, although PD1 and PD-L1 inhibitors have not been associated with the development of pulmonary hypertension [27], this ensuing pro-inflammatory state may act synergistically with VEGFR inhibition to disrupt angiogenesis and promote abnormal vessel formation [18]. In our patient, PD-L1 staining was performed on a lymph node taken prior to checkpoint inhibitor therapy and revealed positive staining on approximately 20% of tumor cells. Nevertheless, any association of VEGFR and PD-L1 inhibition to the development of PTTM and PVOD remains speculative.\n\nHistopathology is necessary to definitively diagnose PTTM, yet a surgical lung biopsy is prohibitively risky in the presence of severe pulmonary hypertension and right heart failure. Thus, similar to our report, mechanistic studies of PTTM are lacking due to the difficulty in making a definitive pre-mortem diagnosis. Finally, as a single case report, there are many inherent limitations to our manuscript. The major limitation is the inability to establish causality between the patient’s experimental therapy and her risk for the development of PTTM.\n\nConclusion\nIn the setting of malignancy, PTTM should be included in the differential diagnosis of a patient that presents with subacute to chronic pulmonary hypertension. Serial echocardiography may be useful for identifying evidence of pulmonary hypertension or right ventricular dysfunction prior to the onset of severe symptoms. However, these findings are non-specific and there are no established criteria for screening patients who are at higher risk for developing PTTM. This case report illustrates that a pre-mortem diagnosis of PTTM is difficult to confirm, treatment guidelines are lacking and the prognosis is poor. In addition, our case provides further support for the premise that both PTTM and PVOD share a common pathogenesis and may be manifestations of a spectrum of similar disease processes.\n\nAbbreviations\nCTEPHchronic thromboembolic pulmonary hypertension\n\nHGFhepatocyte growth factor\n\nNIHNational Institutes of Health\n\nPAHpulmonary arterial hypertension\n\nPD-L1programmed death-ligand 1\n\nPTTMpulmonary tumor thrombotic microangiopathy\n\nPVODpulmonary veno-occlusive disease\n\nTAPSEtricuspid annular plane systolic excursion\n\nTNFαtumor necrosis factor alpha\n\nVEGFvascular endothelial growth factor\n\nVEGFRvascular endothelial growth factor receptor\n\nVQ scanventilation perfusion scan\n\nAcknowledgements\nThe authors would like to thank Kelly Byrne for her assistance in preparation of the manuscript.\n\nFunding\nThis work was supported in part by the Intramural Research Program of the National Institutes of Health Clinical Center.\n\nAuthors’ contributions\nDAS, JME and MAS participated in the drafting of the manuscript. JML, JME and MAS were involved in the management of the case. DP and DEK interpreted the gross and histopathology. CJP performed the pharmacokinetic studies. All authors read and approved the final version of this manuscript.\n\nAuthors’ information\nThe findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institutes of Health.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient’s next of kin to report details of this patient’s clinical course and to publish associated clinical 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. von Herbay A Illes A Waldherr R Otto HF Pulmonary tumor thrombotic microangiopathy with pulmonary hypertension Cancer 1990 66 3 587 592 10.1002/1097-0142(19900801)66:3<587::AID-CNCR2820660330>3.0.CO;2-J 2163747 \n2. Uruga H Fujii T Kurosaki A Hanada S Takaya H Miyamoto A Morokawa N Homma S Kishi K Pulmonary tumor thrombotic microangiopathy: a clinical analysis of 30 autopsy cases Intern Med 2013 52 12 1317 1323 10.2169/internalmedicine.52.9472 23774540 \n3. Abe H Hino R Fukayama M Platelet-derived growth factor-a and vascular endothelial growth factor-C contribute to the development of pulmonary tumor thrombotic microangiopathy in gastric cancer Virchows Arch 2013 462 5 523 531 10.1007/s00428-013-1403-7 23536282 \n4. Godbole R Saggar R Zider A Betancourt J Wallace WD Suh RD Kamangar N Insights on pulmonary tumor thrombotic microangiopathy: a seven-patient case series Pulm Circ 2017 7 4 813 820 10.1177/2045893217728072 28782988 \n5. Gavin MC Morse D Partridge AH Levy BD Loscalzo J Clinical problem-solving. Breathless N Engl J Med 2012 366 1 75 81 10.1056/NEJMcps1011918 22216845 \n6. Frazier AA Franks TJ Mohammed TL Ozbudak IH Galvin JR From the archives of the AFIP: pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis Radiographics 2007 27 3 867 882 10.1148/rg.273065194 17495297 \n7. Restrepo CS Betancourt SL Martinez-Jimenez S Gutierrez FR Tumors of the pulmonary artery and veins Semin Ultrasound CT MR 2012 33 6 580 590 10.1053/j.sult.2012.04.002 23168066 \n8. Boudreau RJ Lisbona R Sheldon H Ventilation-perfusion mismatch in tumor embolism Clin Nucl Med 1982 7 7 320 322 10.1097/00003072-198207000-00005 7094496 \n9. Auger WR Kerr KM Kim NH Fedullo PF Evaluation of patients with chronic thromboembolic pulmonary hypertension for pulmonary endarterectomy Pulm Circ 2012 2 2 155 162 10.4103/2045-8932.97594 22837856 \n10. Masson RG Krikorian J Lukl P Evans GL McGrath J Pulmonary microvascular cytology in the diagnosis of lymphangitic carcinomatosis N Engl J Med 1989 321 2 71 76 10.1056/NEJM198907133210202 2471933 \n11. Rambihar VS Fallen EL Cairns JA Pulmonary veno-occlusive disease: antemortem diagnosis from roentgenographic and hemodynamic findings Can Med Assoc J 1979 120 12 1519 1522 455208 \n12. Ranchoux B Gunther S Quarck R Chaumais MC Dorfmuller P Antigny F Dumas SJ Raymond N Lau E Savale L Chemotherapy-induced pulmonary hypertension: role of alkylating agents Am J Pathol 2015 185 2 356 371 10.1016/j.ajpath.2014.10.021 25497573 \n13. Kramer MR Estenne M Berkman N Antoine M de Francquen P Lipski A Jacobovitz D Lafair J Radiation-induced pulmonary veno-occlusive disease Chest 1993 104 4 1282 1284 10.1378/chest.104.4.1282 8404211 \n14. Kumar N Price LC Montero MA Dimopoulos K Wells AU Wort SJ Pulmonary tumour thrombotic microangiopathy: unclassifiable pulmonary hypertension? Eur Respir J 2015 46 4 1214 1217 10.1183/13993003.00052-2015 26206876 \n15. Price LC Wells AU Wort SJ Pulmonary tumour thrombotic microangiopathy Curr Opin Pulm Med 2016 22 5 421 428 10.1097/MCP.0000000000000297 27387102 \n16. Lee JM Cimino-Mathews A Peer CJ Zimmer A Lipkowitz S Annunziata CM Cao L Harrell MI Swisher EM Houston N Safety and Clinical Activity of the Programmed Death-Ligand 1 Inhibitor Durvalumab in Combination With Poly (ADP-Ribose) Polymerase Inhibitor Olaparib or Vascular Endothelial Growth Factor Receptor 1–3 Inhibitor Cediranib in Women's Cancers: A Dose-Escalation, Phase I Study J Clin Oncol 2017 35 19 2193 2202 10.1200/JCO.2016.72.1340 28471727 \n17. Tuder RM Chacon M Alger L Wang J Taraseviciene-Stewart L Kasahara Y Cool CD Bishop AE Geraci M Semenza GL Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis J Pathol 2001 195 3 367 374 10.1002/path.953 11673836 \n18. 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Cascone T Xu L Lin HY Liu W Tran HT Liu Y Howells K Haddad V Hanrahan E Nilsson MB The HGF/c-MET pathway is a driver and biomarker of VEGFR-inhibitor resistance and vascular remodeling in non-small cell lung Cancer Clin Cancer Res 2017 23 18 5489 5501 10.1158/1078-0432.CCR-16-3216 28559461 \n22. George PM Oliver E Dorfmuller P Dubois OD Reed DM Kirkby NS Mohamed NA Perros F Antigny F Fadel E Evidence for the involvement of type I interferon in pulmonary arterial hypertension Circ Res 2014 114 4 677 688 10.1161/CIRCRESAHA.114.302221 24334027 \n23. Hurst LA Dunmore BJ Long L Crosby A Al-Lamki R Deighton J Southwood M Yang X Nikolic MZ Herrera B TNFalpha drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling Nat Commun 2017 8 14079 10.1038/ncomms14079 28084316 \n24. Rabinovitch M Guignabert C Humbert M Nicolls MR Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension Circ Res 2014 115 1 165 175 10.1161/CIRCRESAHA.113.301141 24951765 \n25. Kondo A Yamashita T Tamura H Zhao W Tsuji T Shimizu M Shinya E Takahashi H Tamada K Chen L Interferon-gamma and tumor necrosis factor-alpha induce an immunoinhibitory molecule, B7-H1, via nuclear factor-kappaB activation in blasts in myelodysplastic syndromes Blood 2010 116 7 1124 1131 10.1182/blood-2009-12-255125 20472834 \n26. Cunningham CR Champhekar A Tullius MV Dillon BJ Zhen A de la Fuente JR Herskovitz J Elsaesser H Snell LM Wilson EB Type I and type II interferon coordinately regulate suppressive dendritic cell fate and function during viral persistence PLoS Pathog 2016 12 1 e1005356 10.1371/journal.ppat.1005356 26808628 \n27. Postow MA Sidlow R Hellmann MD Immune-related adverse events associated with immune checkpoint blockade N Engl J Med 2018 378 2 158 168 10.1056/NEJMra1703481 29320654\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2466",
"issue": "18(1)",
"journal": "BMC pulmonary medicine",
"keywords": "Cediranib; Cervical cancer; Durvalumab; Pulmonary hypertension; Pulmonary tumor thrombotic microangiopathy",
"medline_ta": "BMC Pulm Med",
"mesh_terms": "D000911:Antibodies, Monoclonal; D001344:Autopsy; D002294:Carcinoma, Squamous Cell; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008168:Lung; D008175:Lung Neoplasms; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating; D011668:Pulmonary Veno-Occlusive Disease; D011799:Quinazolines; D057049:Thrombotic Microangiopathies; D002583:Uterine Cervical Neoplasms",
"nlm_unique_id": "100968563",
"other_id": null,
"pages": "112",
"pmc": null,
"pmid": "29996818",
"pubdate": "2018-07-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20472834;28471727;25497573;29320654;28084316;20008624;24334027;11673836;23536282;22216845;7094496;27387102;24951765;17495297;23908119;23774540;26808628;2163747;23168066;8404211;455208;24932885;26206876;28559461;22837856;2471933;28782988",
"title": "Pulmonary tumor thrombotic microangiopathy and pulmonary veno-occlusive disease in a woman with cervical cancer treated with cediranib and durvalumab.",
"title_normalized": "pulmonary tumor thrombotic microangiopathy and pulmonary veno occlusive disease in a woman with cervical cancer treated with cediranib and durvalumab"
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"abstract": "Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) is reported to be the most common drug hypersensitivity. The aim of this study was to evaluate the characteristics of self-reported NSAID hypersensitivity and identify patients at high risk of NSAID hypersensitivity.\n\n\n\nPatients who presented at a single tertiary care hospital between January-December 2017 with reported NSAID hypersensitivity were evaluated. Clinical information obtained from a review of medical records was further supplemented with data gained from a telephone-administered questionnaire.\n\n\n\nFrom a total of 535 patients with reported NSAID hypersensitivity, 301 were included in the study. The mean age of onset of NSAID hypersensitivity reaction was 30.3 ± 14.9 years old. A total of 84 patients (27.9%) were hypersensitive to 2 or more chemically unrelated NSAIDs. The leading NSAID hypersensitivity was to propionic acid derivatives (73%) followed by acetic acid derivatives (28.9%). Immediate reaction (≤1 h) was identified in 171 patients (57.8%), and angioedema was the most frequently reported symptom (179 patients, 59.5%), followed by urticaria and anaphylaxis in 85 (28.2%) and 62 (20.6%) patients, respectively. A drug provocation test was performed on 53 patients, and NSAID hypersensitivity was confirmed in 38 patients (71.6%). The independent factors identified, which could predict NSAID hypersensitivity, were personal history of allergic rhinitis/chronic rhinosinusitis (AR/CRS), onset of NSAID hypersensitivity over 15 years old, and immediate reaction.\n\n\n\nAngioedema was the most typical symptom, and propionic acid derivatives were the most frequently reported culprit drugs. The significant risk factors predicting NSAID hypersensitivity were personal history of AR/CRS, onset of NSAID hypersensitivity reaction over 15 years old, and immediate reaction.",
"affiliations": "Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand, taraya@medicine.psu.ac.th.;Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand.;Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand.;Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand.;Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand.;Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand.",
"authors": "Yuenyongviwat|Araya|A|;Chantaravisarut|Nisarat|N|;Phattarapongdilok|Wassamon|W|;Koosakulchai|Vanlaya|V|;Jessadapakorn|Wipa|W|;Sangsupawanich|Pasuree|P|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000510364",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1018-2438",
"issue": "182(2)",
"journal": "International archives of allergy and immunology",
"keywords": "Drug allergy; Hypersensitivity; Nonsteroidal anti-inflammatory drugs; Predisposing factors; Self-reported",
"medline_ta": "Int Arch Allergy Immunol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015897:Comorbidity; D003937:Diagnosis, Differential; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012307:Risk Factors; D063189:Symptom Assessment; D055815:Young Adult",
"nlm_unique_id": "9211652",
"other_id": null,
"pages": "139-145",
"pmc": null,
"pmid": "32950992",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Characteristics and Contributing Factors Related to Nonsteroidal Anti-Inflammatory Drugs Hypersensitivity.",
"title_normalized": "characteristics and contributing factors related to nonsteroidal anti inflammatory drugs hypersensitivity"
} | [
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"companynumb": "TH-JNJFOC-20210308957",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
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"drugadditional": "3",
"dru... |
{
"abstract": "Topical corticosteroids are currently recommended only for short-term management of flares of lichen sclerosus, with efficacy in halting disease progression. Given the chronic nature of this condition, there is a lack of literature surrounding the chronic effects of topical corticosteroids on the male genitalia with many dermatologists avoiding prescribing long term. This case report aims to provide anecdotal observation for the long-term use of topical corticosteroids and details the long-term follow-up of an individual who used potent and superpotent topical corticosteroids for over 25 years without significant demonstrable side effects. A short review on relevant literature is provided.",
"affiliations": "St Vincent's Hospital Melbourne, Melbourne, VIC, Australia.;Bay City Dermatology, 14 Aberdeen Street, Geelong, West VIC, Australia.",
"authors": "Howard|Matthew|M|;Hall|Anthony|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2050313X18795047",
"fulltext": "\n==== Front\nSAGE Open Med Case RepSAGE Open Med Case RepSCOspscoSAGE Open Medical Case Reports2050-313XSAGE Publications Sage UK: London, England 10.1177/2050313X1879504710.1177_2050313X18795047JCMS Case ReportsTreatment of penile lichen sclerosus with topical corticosteroids for over 25 years’ duration: A case report Howard Matthew 1Hall Anthony 231 St Vincent’s Hospital Melbourne, Melbourne, VIC, Australia2 Bay City Dermatology, 14 Aberdeen Street, Geelong, West VIC, Australia3 Skin & Cancer Foundation (Inc), 80 Drummond Street, Carlton, Victoria, AustraliaMatthew Howard, 55 Commercial Rd, Melbourne VIC 3004, Australia. Email: matthew.david.howard@gmail.com10 9 2018 2018 6 2050313X18795047© The Author(s) 20182018SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Topical corticosteroids are currently recommended only for short-term management of flares of lichen sclerosus, with efficacy in halting disease progression. Given the chronic nature of this condition, there is a lack of literature surrounding the chronic effects of topical corticosteroids on the male genitalia with many dermatologists avoiding prescribing long term. This case report aims to provide anecdotal observation for the long-term use of topical corticosteroids and details the long-term follow-up of an individual who used potent and superpotent topical corticosteroids for over 25 years without significant demonstrable side effects. A short review on relevant literature is provided.\n\nLichen sclerosuspenile lichen sclerosustopical corticosteroidsadverse effectsmale genital dermatosescover-dateJanuary-December 2018\n==== Body\nIntroduction\nTopical corticosteroids are a mainstay of treatment for penile lichen sclerosus (LS), currently recommended for short-term use of flares up to 6–8 weeks and to be discontinued if ineffective after 6 months.1,2 Topical corticosteroids may be helpful in halting disease progression long term.1 However, after a thorough search of the MEDLINE database, there were no reports advocating long-term use of topical corticosteroids in penile LS nor reported adverse effects specific to use on the penis.\n\nCase report\nA 58-year-old uncircumcised male was referred for LS of the glans penis to a male genital dermatology clinic. The patient’s symptoms first occurred 36 years prior to review. At this time, the patient was 22 years of age describing severe dysesthesia of the glans penis and concurrent swelling of distal foreskin. The pain and dysesthesia severely disrupted the patient’s quality of life, restricting ability to work and limiting sexual intercourse leaving the patient depressed. Infectious causes such as herpes and sexually transmitted infections were ruled out by swab testing and clinical correlation. After 8 years, the patient was diagnosed with penile LS with histological confirmation on skin biopsy by a dermatologist. Biopsy histopathology demonstrated compact hyperkeratosis, oedematous collagen in superficial papillary dermis and prominent and dilated superficial vessels with light lymphocytic infiltrate. This came after multiple specialist involvement including urologists and general physicians. The patient self-managed his penile LS with betamethasone dipropionate 0.05% ointment for 15 years (30 g/year) and topical lidocaine gel, achieving symptomatic relief while lost to follow-up. His family doctor changed therapy to mometasone furoate 0.1% ointment (60 g/year) for the next 10 years after fear of adverse effects from long-term use of betamethasone dipropionate 0.05% ointment.\n\nWhen seen in our clinic, the patient only reported recurrent ulcers of his glans penis associated with mild dyspareunia. Examination revealed diffuse erythema of the glans penis, minor adhesions of the lateral aspect of the glans penis across the coronal sulcus, some telangiectasia, mild swelling of the foreskin but no phimosis, erosions or ulcers (see Figures 1 and 2). There was no definite evidence of active LS. The erythema of the glans penis was felt to be secondary to chronic use of his topical corticosteroid preparations over 25 years, rather than a feature of active penile LS.\n\nFigure 1. Depicting foreskin after 25 years of topical corticosteroids applied to the patient’s penis.\n\nFigure 2. Depicting the glans 25 years of topical corticosteroids applied to the patient’s penis with minimal residual inflammation.\n\nThe patient was advised to cease using mometasone furoate 0.1% ointment and asked to change to 1% hydrocortisone ointment twice daily, with additional regular use of soft white paraffin ointment as an emollient. The patient ceased topical corticosteroid therapy 1 year ago and has experienced no withdrawal symptoms, further dysesthesia, pain or swelling.\n\nDiscussion\nSymptoms experienced by our case patient such as burning dysesthesia and erythema of the glans/shaft of penis are typical of LS.3 Painful erections were likely caused by mild phimosis, with balanitis/glans inflammation contributing to dyspareunia. Similar to our case patient, uncircumcised men are particularly at risk of LS.3 Although LS may be diagnosed clinically, histology is often useful to exclude differential diagnoses such as irritant dermatitis (“non-specific balanitis”), lichen planus, allergic contact dermatitis, psoriasis and penile intraepithelial neoplasia.3,4 LS is likely under-diagnosed as observed in a large case series due to a complex interplay of psychosocial factors leading to delay in diagnosis as in this case.3\n\nFamily practitioners and pharmacists appear to hold particular concern in relationship to epidermal atrophy seen with long-term use of topical corticosteroids such as in atopic dermatitis as well as genital use.2,5,6 Reported potential adverse cutaneous side effects observed from topical corticosteroids on non-genital skin include erythema, telangiectasia, purpura and striae.7 However, telangiectasia and epidermal atrophy can also be a sign of chronic penile LS, independent of corticosteroid use.3,4 Furthermore, epidermal atrophy and telangiectasia have both been demonstrated to improve in patients with vulval LS treated with topical clobetasol, with data lacking in penile LS.8 Therefore, caution must be taken before interpreting any examination findings as solely iatrogenic.\n\nDecades of both in vitro and in vivo studies have acknowledged potential for systemic absorption of topical corticosteroids. Although uncommon, important systemic adverse effects of Cushing’s syndrome, bone osteopathy and adrenocortical suppression have been documented from cutaneous use of topical corticosteroids.7 Regional variation in systemic absorption of topical corticosteroids is important to consider with the genital region demonstrating up to 40 fold higher absorption rates over the more studied region of the forearm.9 This is in keeping with the inversely proportional relationship between systemic absorption of topical medications and thickness of the stratum corneum.7 It is essential that prescribing clinicians are aware of these implications and especially when more potent/lipophilic corticosteroids are used long term.\n\nIt is important to achieve disease control in penile LS not only for relief of symptoms for the patient, but also to prevent long-term sequelae from chronically active disease such as irreversible phimosis and meatal stenosis which may require potential surgery.4,10 The other significant long-term complication associated with penile LS is penile squamous cell carcinoma (SCC).11 Two separate pathogenic pathways are hypothesised for development of penile SCC: an human papilloma virus (HPV)-associated pathway and an HPV-independent pathway (with chronic LS a significant contributor in the latter).12 Penile SCC has been observed at rates between 4% and 8% in patients with penile LS, with HPV present in 50% of malignancy specimens in a single sample.4,13,14 It is possible that with adequate disease control, the long-term risk of penile cancer may be minimised with topical steroids from suppression of inflammation.15\n\nPossible reactivation of HPV with chronic topical corticosteroid usage has been suggested posing a current dilemma for proponents for long-term corticosteroids.14 Concern has also been raised regarding possible reactivation of superficial skin infections including herpes simplex virus (HSV) and Candida species with chronic use of topical corticosteroids.2,16,17\n\nIn summary, our patient used topical betamethasone dipropionate 0.05% ointment and topical mometasone furoate 0.1% ointment continuously for 25 years after an initial diagnosis of penile LS with no demonstrable significant adverse cutaneous side effects apart from erythema. This anecdotal case supports the authors’ observation of the safety of topical corticosteroid for supervised treatment of chronic male genital LS including the benefits to reducing morbidity and sequelae. Concern relating to epidermal atrophy from corticosteroids is likely overestimated with respect to LS treatment given potential improvement from supervised treatment. Cautious attention should also be employed to appraise potential risk for reactivation of secondary infections, including HPV with its oncovirus status, particularly in patients who are at high risk of penile SCC. The role for dermatologists is highlighted as a means of follow-up for patients to minimise complications and to monitor disease progress with view to directing ongoing therapy.\n\nAuthors’ note: Matthew Howard is now affiliated with Victorian Melanoma Service, Alfred Hospital, Melbourne.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship and/or publication of this article.\n\nInformed consent: Informed consent for patient information and images to be published was provided.\n==== Refs\nReferences\n1 \nNeill SM Lewis FM Tatnall FM et al \nBritish Association of Dermatologists’ guidelines for the management of lichen sclerosus 2010 . Br J Dermatol \n2010 ; 163 (4 ): 672 –682 .20854400 \n2 \nDahlman Ghozlan K Hedblad MA von Krogh G \nPenile lichen sclerosus et atrophicus treated with clobetasol dipropionate 0.05% cream: a retrospective clinical and histopathological study . J Am Acad Dermatol \n1999 ; 40 (3 ): 451 –457 .10071317 \n3 \nEdmonds E Hunt S Hawkins D et al \nClinical parameters in male genital lichen sclerosus: a case series of 329 patients . J Eur Acad Dermatol Venereol \n2012 ; 26 (6 ): 730 –737 .21707769 \n4 \nClouston D Hall A Lawrentschuk N. \nPenile lichen sclerosus (balanitis xerotica obliterans) . BJU Int \n2011 ; 108 (Suppl 2 ): 14 –19 .22085120 \n5 \nSmith S Lee A Blaszczynski A et al \nPharmacists’ knowledge about use of topical corticosteroids in atopic dermatitis: pre and post continuing professional development education . Australas J Dermatol \n2015 ; 57 (3 ): 199 –204 .25846602 \n6 \nFarrugia L Lee A Fischer G et al \nEvaluation of the influence of pharmacists and GPs on patient perceptions of long-term topical corticosteroid use . J Dermatolog Treatment \n2016 ; 28 (2 ): 112 –118 .\n7 \nHengge UR Ruzicka T Schwartz RA et al \nAdverse effects of topical glucocorticosteroids . J Am Acad Dermatol \n2006 ; 54 (1 ): 1 –15 .16384751 \n8 \nDalziel KL Wojnarowska F. \nLong-term control of vulval lichen sclerosus after treatment with a potent topical steroid cream . J Reprod Med \n1993 ; 38 (1 ): 25 –27 .8441126 \n9 \nFeldmann R Maibach H. \nRegional variation in percutaneous penetration of 14C cortisol in man . J Invest Dermatol \n1967 ; 48 (2 ): 181 –183 .6020682 \n10 \nMonsour MA Rabinovitch HH Dean GE. \nMedical management of phimosis in children: our experience with topical steroids . J Urol \n1999 ; 162 (3 Pt 2 ): 1162 –1164 .10458456 \n11 \nMentrikoski M Stelow E Culp S et al \nHistologic and immunohistochemical assessment of penile carcinomas in a North American population . Am J Surg Pathol \n2014 ; 38 (10 ): 1340 –1348 .25210933 \n12 \nSanchez DF Cañete S Fernández-Nestosa MJ et al \nHPV- and non-HPV-related subtypes of penile squamous cell carcinoma (SCC): morphological features and differential diagnosis according to the new WHO classification (2015) . Semin Diagn Pathol \n2015 ; 32 (3 ): 198 –221 .25701382 \n13 \nNasca MR Innocenzi D Micali G. \nPenile cancer among patients with genital lichen sclerosus . J Am Acad Dermatol \n1999 ; 41 (6 ): 911 –914 .10570372 \n14 \nProwse DM Ktori EN Chandrasekaran D et al \nHuman papillomavirus-associated increase in p16INK4A expression in penile lichen sclerosus and squamous cell carcinoma . Br J Dermatol \n2008 ; 158 (2 ): 261 –265 .18047520 \n15 \nPietrzak P Hadway P Corbishley CM et al \nIs the association between balanitis xerotica obliterans and penile carcinoma underestimated? \nBJU Int \n2006 ; 98 (1 ): 74 –76 .16831147 \n16 \nPater MM Mittal R Pater A. \nRole of steroid hormones in potentiating transformation of cervical cells by human papillomaviruses . Trends Microbiol \n1994 ; 2 (7 ): 229 –234 .8081649 \n17 \nBarnes L Kaya G Rollason V. \nTopical corticosteroid-induced skin atrophy: a comprehensive review . Drug Saf \n2015 ; 38 (5 ): 493 –509 .25862024\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2050-313X",
"issue": "6()",
"journal": "SAGE open medical case reports",
"keywords": "Lichen sclerosus; adverse effects; male genital dermatoses; penile lichen sclerosus; topical corticosteroids",
"medline_ta": "SAGE Open Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101638686",
"other_id": null,
"pages": "2050313X18795047",
"pmc": null,
"pmid": "30214805",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "27424888;8081649;16384751;21707769;6020682;10570372;20854400;10458456;8441126;10071317;22085120;25862024;25701382;18047520;25846602;16831147;25210933",
"title": "Treatment of penile lichen sclerosus with topical corticosteroids for over 25 years' duration: A case report.",
"title_normalized": "treatment of penile lichen sclerosus with topical corticosteroids for over 25 years duration a case report"
} | [
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"companynumb": "AU-PFIZER INC-2018458748",
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"occurcountry": "AU",
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"activesubstancename": "LIDOCAINE HYDROCHLORIDE"
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"drugadditional": ... |
{
"abstract": "BACKGROUND\nThe introduction of immune check-point inhibitors (ICIs) in the treatment of solid neoplasms is associated with the need to know and manage a new type of side effects that are commonly defined immune-mediated adverse events. Dermatologic immune-mediated adverse events are relatively common. Vitiligo-like lesions, defined as hypopigmented skin lesions, have already been associated with the use of ICIs in particular in patients with malignant melanoma, probably due to a common autoimmune mechanism against both melanoma cells and normal melanocytes. The onset of vitiligo-like lesions is very rare in non-melanoma patients and nowadays only few cases are described in the literature.\nWe described the case of a heavily pre-treated woman affected by renal cell carcinoma that has been treated with nivolumab for 2 years obtaining a stabilization of disease after an initial mild progression. After 9 months from the beginning of nivolumab, when the disease has reached its maximum stabilization, the patient developed vitiligo-like lesions of the back win halo nevi.\nVitiligo like lesion of the back not pre-existing before nivolumab treatment. The etiology was assumed to be nivolumab related as a result of an autoimmune activation against normal melanocytes.\n\n\nMETHODS\nThe patient was followed with dermatological evaluations without changes in nivolumab dose and schedule OUTCOMES:: No variations of the described lesions were recorded after the first description. The patients underwent a durable stabilization of her tumor.\n\n\nCONCLUSIONS\nThis case on the one hand is the first case of vitiligo-like lesions associated with ICIs in patients affected by renal cell carcinoma, and on the other hand it seems to confirm that the onset of immumomediate adverse reactions, but in particular vitiligo lesions, can probably be considered a sign of response to immunological treatments probably as a consequence of activation of the immune response.",
"affiliations": "Oncology Unit.;Skin Cancer Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola.;Department of Dermatology, Ausl Romagna, Pierantoni Hospital Forli', Forlì-Cesena, Italy.;Oncology Unit.;Oncology Unit.;Oncology Unit.;Skin Cancer Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola.",
"authors": "Lolli|Cristian|C|;Medri|Matelda|M|;Ricci|Michela|M|;Schepisi|Giuseppe|G|;Filograna|Alessia|A|;De Giorgi|Ugo|U|;Stanganelli|Ignazio|I|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000077594:Nivolumab",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000013810",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30593172MD-D-18-0560010.1097/MD.0000000000013810138105700Research ArticleClinical Case ReportVitiligo-like lesions in a patient treated with nivolumab for renal cell carcinoma Lolli Cristian MDa∗Medri Matelda MDbRicci Michela MDcSchepisi Giuseppe MDaFilograna Alessia RNaDe Giorgi Ugo MD, PhDaStanganelli Ignazio MD, PhDbNA. a Oncology Unitb Skin Cancer Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldolac Department of Dermatology, Ausl Romagna, Pierantoni Hospital Forli’, Forlì-Cesena, Italy.∗ Correspondence: Cristian Lolli, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, via Maroncelli 40–42, 47014 Meldola, Forlì-Cesena, Italy (e-mail: cristian.lolli@irst.emr.it).12 2018 28 12 2018 97 52 e1381011 8 2018 28 11 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale:\nThe introduction of immune check-point inhibitors (ICIs) in the treatment of solid neoplasms is associated with the need to know and manage a new type of side effects that are commonly defined immune-mediated adverse events. Dermatologic immune-mediated adverse events are relatively common. Vitiligo-like lesions, defined as hypopigmented skin lesions, have already been associated with the use of ICIs in particular in patients with malignant melanoma, probably due to a common autoimmune mechanism against both melanoma cells and normal melanocytes. The onset of vitiligo-like lesions is very rare in non-melanoma patients and nowadays only few cases are described in the literature.\n\nPatient concerns:\nWe described the case of a heavily pre-treated woman affected by renal cell carcinoma that has been treated with nivolumab for 2 years obtaining a stabilization of disease after an initial mild progression. After 9 months from the beginning of nivolumab, when the disease has reached its maximum stabilization, the patient developed vitiligo-like lesions of the back win halo nevi.\n\nDiagnoses:\nVitiligo like lesion of the back not pre-existing before nivolumab treatment. The etiology was assumed to be nivolumab related as a result of an autoimmune activation against normal melanocytes.\n\nInterventions:\nThe patient was followed with dermatological evaluations without changes in nivolumab dose and schedule\n\nOutcomes:\nNo variations of the described lesions were recorded after the first description. The patients underwent a durable stabilization of her tumor.\n\nLessons:\nThis case on the one hand is the first case of vitiligo-like lesions associated with ICIs in patients affected by renal cell carcinoma, and on the other hand it seems to confirm that the onset of immumomediate adverse reactions, but in particular vitiligo lesions, can probably be considered a sign of response to immunological treatments probably as a consequence of activation of the immune response.\n\nKeywords\nimmune checkpoint inhibitorsimmunotherapyrenal cancervitiligovitiligo-like lesionsOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nNivolumab is one of the new effective drugs that have recently implemented the treatment options for metastatic renal cell carcinoma (RCC). Nivolumab is a programmed cell death (PD-1) immune checkpoint inhibitor (ICI) antibody and it is now indicated as monotherapy for the treatment of advanced renal cell carcinoma after prior treatment with antiangiogenic therapies. This approval was the result of a Phase III trial that showed a survival benefit in patient treated with nivolumab compared to Everolimus after disease progression to other antiangiogenic agents.[1]\n\nNowadays nivolumab is widely used as it is approved for the treatment of other common metastatic neoplasms as melanoma and non-small-cell lung cancer.\n\nIt is actually well known that nivolumab, like all immune checkpoint inhibitors, is associated with dermatologic immune-mediated adverse events, such as skin rash, pruritus, vitiligo, and lichenoid skin reactions.\n\nVitiligo, that is defined as the appearance of hypopigmented skin areas, is an autoimmune skin disorder that originates from the loss of functional melanocytes of epidermis. Vitiligo or more in general vitiligo-like lesions, which include all the clinical manifestations similar to classical vitiligo, have been recognized to occur spontaneously or during anticancer treatments in patient affected by malignant melanoma. It is estimated that the risk of development of vitiligo is 10-fold higher in patients with melanoma, not only under treatment, than in the general population.[2]\n\nOne of the main explanations about the relationship between melanoma and vitiligo-like disorders is the immune activation against melanoma-associated antigens expressed by normal melanocytes as a result of a cross-reaction from melanoma cells that share the same antigens. Antigen release by anticancer therapies could explain a breakdown of immune tolerance to self-antigens expressed in normal cells or in benign lesions like nevi causing vitiligo like disorders.[2] This mechanism could be at the basis of the correlation between the onset of vitiligo-like disorders and outcome of those patients. In fact, the occurrence of depigmentated areas has been also associated with clinical benefit in patients treated with immunotherapy, not only ICIs, for advanced melanoma.[3]\n\nVitiligo-like disorders are absolutely rare in patients with, or treated for non-melanoma malignancies. To the best of our knowledge, no vitiligo-like disorders are reported in patients affected by renal cancer treated with ICIs.\n\nWe prospectively followed 25 patients treated with nivolumab inside the multicentric Italian Early Access Program.[4] These patients were followed with blood samples and clinical evaluations.\n\nHerein, we describe the case of a woman treated with nivolumab that developed vitiligo-like disorders with halo nevi of the back and was referred to our dermatologic unit. This patient underwent a durable stabilization of her tumor, until then rapidly progressive.\n\n2 Case presentation\nA 66-year-old woman affected by metastatic renal cell carcinoma came to our Institution in December 2015 to start a therapy with nivolumab inside the national Early Access Program. She had a long history of treatments for her tumor before, started with a right nephrectomy in 2007 for a Grade 2 clear cell carcinoma (pT3N0).\n\nShe also underwent an adjuvant radiotherapy in right kidney area after surgery.\n\nRadiological follow up was negative until June 2009 when a magnetic resonance (MR) scan showed 2 hepatic lesions that were increased at a subsequent computed tomography (CT) scan. In November 2009 the patient underwent to hepatic trans-arterial chemoembolization of these 2 lesions.\n\nIn February 2010 another CT scan showed 4 new hepatic lesions that were surgically removed with wedge resections in May 2010, but in February 2011 she experienced further liver progression and new small lung metastases appeared.\n\nIn February 2011 the patient started a first line sunitinib treatment obtaining a durable stability of disease until July 2013 when hepatic progression occurred.\n\nFrom August 2013 to December 2013 a second-line treatment with sorafenib was administered but no control of hepatic lesions was obtained. In January 2014 a third line therapy with Everolimus was started and continued until October 2015 when RM and CT scans showed hepatic and lung progression.\n\nIn December 2015 the patient referred to our institution to be treated with Nivolumab inside the national Early Access Program. She started nivolumab at a standard dose of 3 mg/Kg biweekly that was performed for 45 infusions.\n\nThe liver lesions of the patients underwent an initial slight progression with an increase of few millimeters but from the ninth to the eighteenth month we registered a clear stabilization of the lesions. Lung metastases did not change significantly during the first 18 months of nivolumab treatment.\n\nDuring the treatment period with nivolumab, the patient noticed, after about 9 months from the beginning of nivolumab, the appearance of clear spots of the back. She was referred to the dermatology service of our institution that diagnosed vitiligo-like areas of the back associated with halo nevi (Fig. 1). Diagnosis was performed on a clinical basis, no biopsy was deemed necessary by the dermatologist. Clinical evaluations and collection of medical history excluded pre-existing autoimmune disorders. No familiarity for vitiligo or autoimmune disorders were found. These features together with the age of onset, not typical for a classical vitiligo, and the causal relationship with nivolumab treatment have made the diagnosis of nivolumab related vitiligo like disorders the most likely and other causes of vitiligo were excluded.\n\nFigure 1 A: Pattern of depigmentation characterizing vitiligo-like lesions of high back occurring in patients receiving anti-programmed cell death-1 therapies. B: Vitiligo-like lesions of high back, sun-exposed area containing pre-existing actinic lentigos, after 9 months of treatment with nivolumab for advanced multi-treated renal neoplasia in a 66-year-old woman. C: Halo nevus of right scapula: pigmented flat lesion surrounded by a rim of depigmentation.\n\nThese areas persisted also at the following dermatologic evaluations without particular changes.\n\nIn December 2017, radiological evaluations showed a clear liver and lung progression and nivolumab was permanently discontinued. The patient's informed consent has been obtained.\n\n3 Discussion\nWe reported the case of a patient with metastatic heavily pre-treated renal tumor who achieved a long-term stabilization of disease with nivolumab. During the treatment, vitiligo-like areas and halo nevi of the back were noticed and interestingly the onset of vitiligo-like lesions was contemporary with the stabilization of the metastatic disease.\n\nVitiligo is an autoimmune disorder that is estimated to affect 0.5% to 1% of the general population.[5] It is often associated with other autoimmune diseases, such as thyroiditis and rheumatoid arthritis.\n\nTo date there are numerous data about the correlation between malignant melanoma and the development of vitiligo. It is reported that about 20% of patients affected by melanoma present with vitiligo.[6]\n\nA melanoma-specific autoimmune mechanism mediated by T-cells that infiltrate tumor and hypopigmented lesions may be at the base of vitiligo. Antibodies against melanoma-associated antigens such as MART-1 and gp100, which are present also in normal melanocytes, are probably likewise involved in the development of vitiligo in melanoma patients.[7] Cui et al have shown that in patients with melanoma and in patients with vitiligo, antibodies to human melanocyte antigens are present in a much higher percentage than in the control group (more than 80% for melanoma or vitiligo versus 7%).[8]\n\nAnother mechanism may be based on autoantibodies against Tyrosinase-Related Protein-2 (TRP-2) expressed by normal melanocytes.[9]\n\nImmunotherapies for metastatic melanoma (ICIs, interleukin-2 but also other biological agents like tumor necrosis factor-α inhibitors) may induce vitiligo-like lesions probably enhancing the release of antigens potentially recognized by immune response.[10–12]\n\nThe spectrum of vitiligo-like lesions includes halo nevi that are usually observed around congenital or acquired melanocytic nevi. The clinical manifestation of halo phenomenon is characterized by progressive lightening of the color, disappearance of central nevus afterwards, and persistence of hypopigmentation. The etiology of halo nevi is unknown. As seen in vitiligo, melanocytes in the epidermis in the halo component of the nevus are completely absent, suggesting a similar etiologic mechanism.\n\nNumerous studies have attempted to unravel the immunologic mechanisms by which an immune response develops to existing aggregates of nevus cells. The infiltrating cells are predominantly T-lymphocytes, and cytotoxic (CD8) lymphocytes outnumber helper (CD4) lymphocytes by a ratio of approximately 4:1. These, as well as scattered macrophages, comprise most inflammatory cells in halo nevi. The exact role that the lymphocytes play in the regression of halo nevi has not been fully determined, although a theory of direct cytotoxic effects on melanocytes seems plausible.[13]\n\nLarsabal et al have recently evaluated clinical and biological features of vitiligo-like lesions associated with immune checkpoint inhibitors, comparing them with those of not ICIs related vitiligo. They reported that serum levels of CXCL10 (C-X-C motif ligand 10), a ligand of CXCR3 (C-X-C motif receptor 3) were significantly higher in patients with vitiligo-like lesions than in patients with vitiligo and in control subjects. Moreover, in patient treated with ICIs that developed vitiligo-like lesions, these are characterized by a higher proportion of skin CD8 T cells producing interferon-γ (IFN-γ), or both IFN-γ and tumor necrosis factor α (TNFα), compared with T cells isolated from perilesional skin of patients with classical vitiligo or healthy skin.\n\nClinical features in these 2 groups are also different. Vitiligo like lesions are characterized by multiple flecked white macules localized on photo-exposed areas while classical vitiligo is characterized by white patches generally symmetrical distributed and localized on face, hands, elbows, and trunk.[5]\n\nClinical features of vitiligo-like lesions developed by our patient described in this paper perfectly match those above described, endorsing the hypothesis of more typical pattern of vitiligo when it is associated with treatment with ICIs.\n\nAssociation between the development of hypopigmented lesions and non-melanoma malignancies and between vitiligo-like disorders and immunotherapies for tumor types other than melanoma is extremely rare.\n\nTo date the development of vitiligo-like disorders during treatment with ICIs has been described in a patient treated with nivolumab for lung cancer, in a man treated with nivolumab for an acute myeloid leukemia, in a young woman treated with nivolumab for a metastatic soft tissue sarcoma and in a man treated with nivolumab plus ipilimumab for an advanced hepatocellular carcinoma.[14–17]\n\nVitiligo-like lesions occurrence during immunotherapy has been associated with better prognosis in term of higher objective tumor response rates and significantly improved progression-free and overall survival in patients with melanoma. Signs of tumor response were reported in almost all the cases reported above.[18]\n\nThe patient described in this paper was treated with nivolumab for RCC for about 2 years obtaining a durable stabilization of her tumor until then rapidly progressing. If we consider that the patient treated with nivolumab for acute myeloid leukemia, was treated in a maintenance setting, we can conclude that all patients treated with ICIs (in particular with nivolumab) for non-melanoma malignancies that developed vitiligo-like disorders experienced benefit from anticancer therapy as of those reported in the literature.\n\nThe current report had some limitations. For example, no biopsies were performed at the onset of vitiligo-like areas because the diagnosis was based on clinical features. Additionally, no data about the long-term persistence of the skin disorder was obtained because the patient continued anticancer therapies (cabozantinib) elsewhere.\n\nThere is an urgent need for prognostic and predictive biomarkers in the landscape of the treatment for renal cell carcinoma and the evaluation of immune system activation is one of the most studied fields. For example, many inflammatory indices, easy to obtain from the count of immune-inflammatory circulating cells (neutrophils, lymphocytes, and platelets), have been evaluated for this purpose, but actually, none of them are used in clinical practice.[19–20]\n\nThe possibility to correlate also the onset of immune-related adverse events with outcome is challenging.\n\nAlthough a correlation between the onset of vitiligo-like disorders and outcome may be observed in all the few cases to date described in literature, actually we obviously cannot consider these signs as a reliable indication of tumor response in non-melanoma patients treated with ICIs. Despite this, new reports to correlate the occurrence of vitiligo-like disorders, and more in general immune-mediated cutaneous events with tumor responses may help to increase the predictive power of these signs that are moreover extremely simple to evaluate.\n\nAuthor contributions\nInvestigation: Michela Ricci.\n\nMethodology: Ugo De Giorgi and Ignazio Stanganelli.\n\nProject administration: Alessia Filograna.\n\nSupervision: Cristian Lolli, Matelda Medri, Ugo De Giorgi, and Ignazio Stanganelli.\n\nValidation: Ugo De Giorgi.\n\nWriting – original draft: Cristian Lolli and Matelda Medri.\n\nWriting – review & editing: Cristian Lolli, Michela Ricci, Giuseppe Schepisi, Alessia Filograna, Ugo De Giorgi, and Ignazio Stanganelli.\n\nAbbreviations: CD4 = cluster of differentiation 4, CD8 = cluster of differentiation 8, CT = computed tomography, CXCL10 = C-X-C motif ligand 10, CXCR3 = C-X-C motif receptor 3, gp100 = glycoprotein 100, ICI = immune checkpoint inhibitor, IFN-γ = interferon-γ, MART-1 = melanoma-associated antigen recognized by T cells 1, MR = magnetic resonance, PD-1 = programmed cell death-1, RCC = renal cell carcinoma, TNFα = tumor necrosis factor α, TRP-2 = Tyrosinase-Related Protein-2.\n\nUgo De Giorgi and Ignazio Stanganelli jointly supervised this work as co-senior authors. The authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Motzer RJ Escudier B McDermott DF \nNivolumab versus Everolimus in advanced renal-cell carcinoma . N Engl J Med \n2015 ;373 :1803–13 .26406148 \n[2] Schallreuter KU Levenig C Berger J \nVitiligo and cutaneous melanoma. A case study . Dermatologica \n1991 ;183 :239–45 .1809584 \n[3] Gogas H Ioannovich J Dafni U \nPrognostic significance of autoimmunity during treatment of melanoma with interferon . N Engl J Med \n2006 ;354 :709–18 .16481638 \n[4] De Giorgi U Cartenì G Giannarelli D \nSafety and efficacy of nivolumab for metastatic renal cell carcinoma: real-world results from an expanded access programme . BJU Int \n2018 ;Jun 29 .\n[5] Larsabal M Marti A Jacquemin C \nVitiligo-like lesions occurring in patients receiving anti-programmed cell death-1 therapies are clinically and biologically distinct from vitiligo . J Am Acad Dermatol \n2017 ;76 :863–70 .28094061 \n[6] Lerner AB Nordlund JJ \nShould vitiligo be induced in patients after resection of primary melanoma . Arch Dermatol \n1977 ;113 :421.848969 \n[7] Mandelcorn-Monson RL Shear NH Sambhara S \nCytotoxic T lymphocyte reactivity to gp100, MelanA/MART-1, and tyrosinase, in HLA-A2-positive vitiligo patients . J Invest Dermatol \n2003 ;121 :550–6 .12925214 \n[8] Cui J Bystryn JC \nMelanoma and vitiligo are associated with antibody responses to similar antigens on pigment cells . Arch Dermatol \n1995 ;131 :314–8 .7887661 \n[9] Okamoto T Irie RF Fujii S \nAnti-tyrosinase-related protein-2 immune response in vitiligo patients and melanoma patients receiving active-specific immunotherapy . J Invest Dermatol \n1998 ;111 :1034–9 .9856813 \n[10] Boasberg PD Hoon DS Piro LD \nEnhanced survival associated with vitiligo expression during maintenance biotherapy for metastatic melanoma . J Invest Dermatol \n2006 ;126 :2658–63 .16946711 \n[11] Sibaud V Robert C \nPigmentary disorders induced by anticancer agents. Part II: targeted therapies . Ann Dermatol Venereol \n2013 ;140 :266–73 .23567227 \n[12] Tarhini A \nImmune-mediated adverse events associated with ipilimumab ctla-4 blockade therapy: the underlying mechanisms and clinical management . Scientifica (Cairo) \n2013 ;2013 :857519.24278787 \n[13] Zeff RA Freitag A Grin CM \nThe immune response in halo nevi . J Am Acad Dermatol \n1997 ;37 :620–4 .9344203 \n[14] Uenami T Hosono Y Ishijima M \nVitiligo in a patient with lung adenocarcinoma treated with nivolumab: a case report . Lung Cancer \n2017 ;109 :42–4 .28577948 \n[15] Yin ES Totonchy MB Leventhal JS \nNivolumab-associated vitiligo-like depigmentation in a patient with acute myeloid leukemia: a novel finding . JAAD Case Rep \n2017 ;3 :90–2 .28280766 \n[16] Dumbrava EI Ivan D Subbiah V \nHypopigmented skin lesions after immunotherapy . JAMA Oncol \n2018 ;Apr 12 .\n[17] Rodríguez-Lomba E Molina-López I Suárez-Fernández R \nVitiligo-like lesions and immune checkpoint inhibition therapy: is it truly an adverse event exclusive to patients with melanoma? \nClin Exp Dermatol \n2018 ;43 :598–9 .29333653 \n[18] Teulings HE Limpens J Jansen SN \nVitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis . J Clin Oncol \n2015 ;33 :773–81 .25605840 \n[19] Lolli C Basso U Derosa L \nSystemic immune-inflammation index predicts the clinical outcome in patients with metastatic renal cell cancer treated with sunitinib . Oncotarget \n2016 ;7 :54564–71 .27409344 \n[20] Hu K Lou L Ye J \nPrognostic role of the neutrophil-lymphocyte ratio in renal cell carcinoma: a meta-analysis . BMJ Open \n2015 ;5 :e006404.\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0025-7974",
"issue": "97(52)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D002292:Carcinoma, Renal Cell; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms; D000077594:Nivolumab; D014820:Vitiligo",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e13810",
"pmc": null,
"pmid": "30593172",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Vitiligo-like lesions in a patient treated with nivolumab for renal cell carcinoma.",
"title_normalized": "vitiligo like lesions in a patient treated with nivolumab for renal cell carcinoma"
} | [
{
"companynumb": "IT-MYLANLABS-2019M1064806",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EVEROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nIntravesical therapy with bacillus Calmette-Guérin (BCG) has proved to be effective in the treatment of superficial bladder tumors. Side-effects include local infections and rarely disseminated BCG infection with multiple end organ complications such as granulomatous hepatitis, pneumonitis, aortitis and bone marrow involvement.\n\n\nMETHODS\nWe report an 83-year-old man who presented with chronic granulomatous hepatitis. This was related to intravesical BCG therapy received two years earlier for superficial bladder cancer. Aortitis, splenic infarction and hematopoietic involvement were also diagnosed. Outcome was favorable following adapted antibiotic course.\n\n\nCONCLUSIONS\nThis case report highlights the possibility of widespread BCG infection following intravesical treatment, and the need for vigilance in patients with a history of such a therapy even several years later.",
"affiliations": "Service de médecine interne, hôpital Saint-André, CHU de Bordeaux, 1, rue Jean-Burguet, 33000 Bordeaux, France; Université Bordeaux Segalen, 146, rue Léo-Saignat, 33000 Bordeaux, France. Electronic address: loic.raffray33@gmail.com.;Service de médecine interne, hôpital Saint-André, CHU de Bordeaux, 1, rue Jean-Burguet, 33000 Bordeaux, France.;Cabinet de médecine générale, 2, rue Larrepunte, 64200 Biarritz, France.;Service de médecine interne, hôpital Saint-André, CHU de Bordeaux, 1, rue Jean-Burguet, 33000 Bordeaux, France; Université Bordeaux Segalen, 146, rue Léo-Saignat, 33000 Bordeaux, France.;Service de médecine interne, hôpital Saint-André, CHU de Bordeaux, 1, rue Jean-Burguet, 33000 Bordeaux, France; Université Bordeaux Segalen, 146, rue Léo-Saignat, 33000 Bordeaux, France.",
"authors": "Raffray|L|L|;Rivière|P|P|;Bonnet|H|H|;Duffau|P|P|;Longy-Boursier|M|M|",
"chemical_list": "D000970:Antineoplastic Agents; D001500:BCG Vaccine; D019496:Cancer Vaccines",
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0248-8663",
"issue": "36(9)",
"journal": "La Revue de medecine interne",
"keywords": "BCG; BCG vaccine; Granulomatose disséminée; Granulomatosis; Hepatitis; Hépatite; Immunotherapy; Immunothérapie",
"medline_ta": "Rev Med Interne",
"mesh_terms": "D000283:Administration, Intravesical; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D001500:BCG Vaccine; D019496:Cancer Vaccines; D006099:Granuloma; D006505:Hepatitis; D006801:Humans; D008297:Male; D009164:Mycobacterium Infections; D009163:Mycobacterium bovis; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "8101383",
"other_id": null,
"pages": "626-30",
"pmc": null,
"pmid": "25467298",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Granulomatous hepatitis revealing a Mycobacterium bovis widespread infection following intravesical BCG therapy.",
"title_normalized": "granulomatous hepatitis revealing a mycobacterium bovis widespread infection following intravesical bcg therapy"
} | [
{
"companynumb": "FR-SA-2015SA031419",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BACILLUS CALMETTE-GUERIN ANTIGEN, UNSPECIFIED SUBSTRAIN"
},
... |
{
"abstract": "OBJECTIVE\nPatients with heart failure supported with left ventricular assist devices (LVADs) may require coronary intervention during their support. This case series seeks to explore the indications, safety, and outcomes of percutaneous coronary intervention (PCI) in this population.\n\n\nMETHODS\nElectronic medical records of patients with LVADs undergoing PCI at a large academic medical center were reviewed. Demographics, reason for PCI, procedural success, complications, and outcomes were collected.\n\n\nRESULTS\nFrom 2010-2014, a total of 6 patients underwent PCI post LVAD implantation. Three patients had PCI in the early postimplantation period (1-3 days post LVAD implantation) while the other three received it later in the LVAD support period. Three indications for PCI were found in the reviewed cases: right ventricular failure (right coronary artery stenting), bridge to left ventricular recovery, and ventricular tachycardia (VT) storm. All patients were maintained on triple blood thinning therapy (aspirin, clopidogrel, and warfarin). There were no acute complications during the interventions; however, 2 patients died in the early intervention period and 2 died much later. The 2 deaths in the early intervention period were related to fatal gastrointestinal bleeding while on dual-antiplatelet therapy and warfarin, and intractable VT that PCI did not correct. The 2 deaths in the late postintervention period occurred due to unknown causes nearly 1 and 2 years post intervention, respectively.\n\n\nCONCLUSIONS\nPCI was performed in patients with continuous-flow LVAD with several possible indications and without acute complications. The utility of PCI in this patient population, however, is likely limited by the risk of bleeding related to combined antiplatelet and anticoagulation therapies as well as lack of immediate apparent benefit. Further studies are necessary to better characterize this risk as well as quantify any potential long-term benefits.",
"affiliations": "Professor of Medicine, Medical Director of Heart Failure, Heart Transplant and Mechanical Assist Device Programs, University of Chicago, Division Of Cardiology, Chicago, IL 60637 USA. nuriel@ medicine.bsd.uchicago.edu.",
"authors": "Anyanwu|Emeka C|EC|;Ota|Takeyoshi|T|;Sayer|Gabriel|G|;Nathan|Sandeep|S|;Jeevanandam|Valluvan|V|;Shah|Atman|A|;Uriel|Nir|N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1042-3931",
"issue": "28(6)",
"journal": "The Journal of invasive cardiology",
"keywords": null,
"medline_ta": "J Invasive Cardiol",
"mesh_terms": "D000368:Aged; D017023:Coronary Angiography; D003331:Coronary Vessels; D017809:Fatal Outcome; D006333:Heart Failure; D006353:Heart-Assist Devices; D006801:Humans; D008297:Male; D008875:Middle Aged; D062645:Percutaneous Coronary Intervention; D012189:Retrospective Studies",
"nlm_unique_id": "8917477",
"other_id": null,
"pages": "238-42",
"pmc": null,
"pmid": "27236007",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "PCI in Patients Supported With CF-LVADs: Indications, Safety, and Outcomes.",
"title_normalized": "pci in patients supported with cf lvads indications safety and outcomes"
} | [
{
"companynumb": "US-ACTAVIS-2016-09516",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"d... |
{
"abstract": "Neither intrathecal methotrexate nor posterior reversible encephalopathy syndrome has previously been reported to result in mesial temporal sclerosis. Described here is the case of a boy with no risk factors for mesial temporal sclerosis who presented with posterior reversible encephalopathy syndrome and partial complex seizures 8 days after initiation of intrathecal methotrexate for treatment of Burkitt lymphoma, and who ultimately progressed to intractable temporal lobe epilepsy due to left mesial temporal sclerosis.",
"affiliations": "Mayo Medical School, Rochester, Minnesota, USA.",
"authors": "Aboian|Mariam S|MS|;Junna|Mithri R|MR|;Krecke|Karl N|KN|;Wirrell|Elaine C|EC|",
"chemical_list": "D000970:Antineoplastic Agents; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1016/j.pediatrneurol.2009.03.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-8994",
"issue": "41(3)",
"journal": "Pediatric neurology",
"keywords": null,
"medline_ta": "Pediatr Neurol",
"mesh_terms": "D000970:Antineoplastic Agents; D001927:Brain Diseases; D002051:Burkitt Lymphoma; D002648:Child; D038524:Diffusion Magnetic Resonance Imaging; D004833:Epilepsy, Temporal Lobe; D005500:Follow-Up Studies; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008727:Methotrexate; D012307:Risk Factors; D012598:Sclerosis; D012640:Seizures; D013577:Syndrome; D013702:Temporal Lobe",
"nlm_unique_id": "8508183",
"other_id": null,
"pages": "226-8",
"pmc": null,
"pmid": "19664544",
"pubdate": "2009-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mesial temporal sclerosis after posterior reversible encephalopathy syndrome.",
"title_normalized": "mesial temporal sclerosis after posterior reversible encephalopathy syndrome"
} | [
{
"companynumb": "US-PFIZER INC-2009292981",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": null,
... |
{
"abstract": "UNAIDS recommends integrating methadone or buprenorphine treatment of opioid use disorder with HIV care to improve HIV outcomes, but buprenorphine adoption remains limited in many countries. We aimed to assess whether HIV clinic-based buprenorphine plus naloxone treatment for opioid use disorder was non-inferior to referral for methadone maintenance therapy in achieving HIV viral suppression in Vietnam.\n\n\n\nIn an open-label, non-inferiority trial (BRAVO), we randomly assigned people with HIV and opioid use disorder (1:1) by computer-generated random number sequence, in blocks of ten and stratified by site, to receive HIV clinic-based buprenorphine plus naloxone treatment or referral for methadone maintenance therapy in six HIV clinics in Vietnam. The primary outcome was HIV viral suppression at 12 months (HIV-1 RNA ≤200 copies per mL on PCR) by intention to treat (absolute risk difference [RD] margin ≤13%), compared by use of generalised estimating equations. Research staff actively queried treatment-emergent adverse events during quarterly study visits and passively collected adverse events reported during HIV clinic visits. This study is registered with ClinicalTrials.gov, NCT01936857, and is completed.\n\n\n\nBetween July 27, 2015, and Feb 12, 2018, we enrolled 281 patients. At baseline, 272 (97%) participants were male, mean age was 38·3 years (SD 6·1), and mean CD4 count was 405 cells per μL (SD 224). Viral suppression improved between baseline and 12 months for both HIV clinic-based buprenorphine plus naloxone (from 97 [69%] of 140 patients to 74 [81%] of 91 patients) and referral for methadone maintenance therapy (from 92 [66%] of 140 to 99 [93%] of 107). Buprenorphine plus naloxone did not demonstrate non-inferiority to methadone maintenance therapy in achieving viral suppression at 12 months (RD -0·11, 95% CI -0·20 to -0·02). Retention on medication at 12 months was lower for buprenorphine plus naloxone than for methadone maintenance therapy (40% vs 65%; RD -0·53, 95% CI -0·75 to -0·31). Participants assigned to buprenorphine plus naloxone more frequently experienced serious adverse events (ten [7%] of 141 vs four of 140 [3%] assigned to methadone maintenance therapy) and deaths (seven of 141 [5%] vs three of 141 [2%]). Serious adverse events and deaths typically occurred in people no longer taking ART or opioid use disorder medications.\n\n\n\nAlthough integrated buprenorphine and HIV care may potentially increase access to treatment for opioid use disorder, scale-up in middle-income countries might require enhanced support for buprenorphine adherence to improve HIV viral suppression. The strength of our study as a multisite randomised trial was offset by low retention of patients on buprenorphine.\n\n\n\nNational Institute on Drug Abuse (US National Institutes of Health).",
"affiliations": "Addiction Medicine Program, Oregon Health & Science University, Portland, OR, USA; Oregon Health & Science University-Portland State University School of Public Health, Portland, OR, USA. Electronic address: korthuis@ohsu.edu.;Addiction Medicine Program, Oregon Health & Science University, Portland, OR, USA.;Addiction Medicine Program, Oregon Health & Science University, Portland, OR, USA.;Hanoi Medical University, Hanoi, Vietnam.;Addiction Medicine Program, Oregon Health & Science University, Portland, OR, USA.;Hennepin Healthcare, Minneapolis, MN, USA.;Oregon Health & Science University-Portland State University School of Public Health, Portland, OR, USA.;Hanoi Medical University, Hanoi, Vietnam.;Addiction Medicine Program, Oregon Health & Science University, Portland, OR, USA.;Hanoi Medical University, Hanoi, Vietnam.;Vietnam Administration for HIV/AIDS Control, Ministry of Health, Hanoi, Vietnam.;Hanoi Medical University, Hanoi, Vietnam.",
"authors": "Korthuis|P Todd|PT|;King|Caroline|C|;Cook|Ryan R|RR|;Khuyen|Tong Thi|TT|;Kunkel|Lynn E|LE|;Bart|Gavin|G|;Nguyen|Thuan|T|;Thuy|Dinh Thanh|DT|;Bielavitz|Sarann|S|;Nguyen|Diep Bich|DB|;Tam|Nguyen Thi Minh|NTM|;Giang|Le Minh|LM|",
"chemical_list": "D019380:Anti-HIV Agents; D009292:Narcotic Antagonists; D009294:Narcotics; D012367:RNA, Viral; D009270:Naloxone; D002047:Buprenorphine; D008691:Methadone",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/S2352-3018(20)30302-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2352-3018",
"issue": "8(2)",
"journal": "The lancet. HIV",
"keywords": null,
"medline_ta": "Lancet HIV",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D002047:Buprenorphine; D018791:CD4 Lymphocyte Count; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections; D006801:Humans; D008297:Male; D008691:Methadone; D008875:Middle Aged; D009270:Naloxone; D009292:Narcotic Antagonists; D009294:Narcotics; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders; D010349:Patient Compliance; D012367:RNA, Viral; D011897:Random Allocation; D016896:Treatment Outcome; D014744:Vietnam; D019562:Viral Load",
"nlm_unique_id": "101645355",
"other_id": null,
"pages": "e67-e76",
"pmc": null,
"pmid": "33539760",
"pubdate": "2021-02",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "28160345;27568511;22719814;23034025;18677027;30312275;24500948;27097726;20650523;21317590;19230611;21317592;29781884;29471930;23311374;17045423;23038795;10928201;19757993;28446428;22393036;15204667;21367734;15764958;20513828;18261190;19842973;27343545;24189594",
"title": "HIV clinic-based buprenorphine plus naloxone versus referral for methadone maintenance therapy for treatment of opioid use disorder in HIV clinics in Vietnam (BRAVO): an open-label, randomised, non-inferiority trial.",
"title_normalized": "hiv clinic based buprenorphine plus naloxone versus referral for methadone maintenance therapy for treatment of opioid use disorder in hiv clinics in vietnam bravo an open label randomised non inferiority trial"
} | [
{
"companynumb": "US-VISTAPHARM, INC.-VER202102-000812",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DIAMORPHINE"
},
"drugadditional":... |
{
"abstract": "This study was conducted to retrospectively investigate the efficacy and safety of pegaspargase, gemicitabine, oxaliplatin and dexamethasone (Peg-GemOD) combination chemotherapy as a first-line therapy for advanced-stage extranodal NK/T cell lymphoma (ENKTL). Eighteen patients with newly diagnosed stage III/IV ENKTL were subjected to 3-6 cycles of Peg-GemOD chemotherapy. After 3 cycles of therapy, the overall response rate was 67 % (12/18) with a complete response rate of 28 % (5/18) and a partial response rate of 39 % (7/18). The median overall survival (OS) and progression-free survival (PFS) time were 10 and 8.5 months respectively. For those responders, the median OS and PFS time were significantly better than those of non-responders (median OS, 15 vs. 10 months; P = 0.001 and median PFS, 15 vs. 7 months; P = 0.001). Furthermore, patients with low plasma EBV-DNA levels after induction chemotherapy had a remarkably longer OS and PFS time. The toxicity of Peg-GemOD regimen was acceptable.",
"affiliations": "Department of Hematology, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 639 Zhi-Zao Ju Road, Shanghai, 200011 People's Republic of China.;Department of Hematology, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 639 Zhi-Zao Ju Road, Shanghai, 200011 People's Republic of China.;Department of Hematology, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 639 Zhi-Zao Ju Road, Shanghai, 200011 People's Republic of China.;Department of Hematology, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 639 Zhi-Zao Ju Road, Shanghai, 200011 People's Republic of China.;Department of Hematology, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 639 Zhi-Zao Ju Road, Shanghai, 200011 People's Republic of China.;Department of Hematology, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 639 Zhi-Zao Ju Road, Shanghai, 200011 People's Republic of China.;Department of Hematology, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 639 Zhi-Zao Ju Road, Shanghai, 200011 People's Republic of China.",
"authors": "Yao|Yi-Yun|YY|;Tang|Yong|Y|;Zhuang|Yan|Y|;Zou|Li-Fang|LF|;Dou|Hong-Ju|HJ|;Wang|Lei|L|;Zhu|Qi|Q|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1007/s12288-016-0670-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0971-4502",
"issue": "33(1)",
"journal": "Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion",
"keywords": "Extranodal NK/T cell lymphoma; Gemicitabine; Induction chemotherapy; Oxaliplatin; Pegaspargase; Prognostic factors",
"medline_ta": "Indian J Hematol Blood Transfus",
"mesh_terms": null,
"nlm_unique_id": "9425818",
"other_id": null,
"pages": "74-81",
"pmc": null,
"pmid": "28194060",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article",
"references": "22675173;24449211;22919026;21599584;23842425;17496309;8635042;22390765;21123825;16547486;19767784;8985084;24923454;23108598;23061678;23045573;22811078;18256789;25124611;23753028",
"title": "Retrospective Study of Pegaspargase, Gemicitabine, Oxaliplatin and Dexamethasone (Peg-GemOD) as a First-Line Therapy for Advanced-Stage Extranodal NK/T Cell Lymphoma.",
"title_normalized": "retrospective study of pegaspargase gemicitabine oxaliplatin and dexamethasone peg gemod as a first line therapy for advanced stage extranodal nk t cell lymphoma"
} | [
{
"companynumb": "CN-FRESENIUS KABI-FK201702633",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
... |
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